National
Institute on
Drug
Abuse
MONOGRAPH SERIES
Problems Of
Drug Dependence
1979
Proceedings of the
41st Annual Scientific Meeting
The Committee on Problems
of Drug Dependence, Inc.
U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE
Public Health Service • Alcohol, Drug Abuse, and Mental Health Administration
Problems of Drug
Dependence, 1979
Proceedings of the 41st Annual Scientific Meeting, The
Committee on Problems of Drug Dependence, Inc.
Editor: Louis S. Harris, Ph.D.
NIDA Research Monograph 27
1979
DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE
Public Health Service
Alcohol, Drug Abuse, and Mental Health Administration
National Institute on Drug Abuse
Division of Research
5600 Fishers Lane
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For sale by the Superintendent of Documents. U.S. Government Printing Office
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Stock No. 017-024-00981-4
The NIDA Research Monograph series is prepared by the Division of Research of
the National Institute on Drug Abuse. Its primary objective is to provide critical reviews of research problem areas and techniques, the content of state-of-the-art
conferences, integrative research reviews and significant original research. Its
dual publication emphasis is rapid and targeted dissemination to the scientific
and professional community.
Editorial Advisory Board
Avram Goldstein, M.D.
Addiction Research Foundation
Palo Alto, California
Jerome Jaffe, M.D.
College of Physicians and Surgeons
Columbia University, New York
Reese T. Jones, M.D.
Langley Porter Neuropsychiatric institute
University of California
San Francisco, California
William McGlothlin, Ph.D.
Department of Psychology. UCLA
Los Angeles, California
Jack Mendelson, M.D.
Alcohol and Drug Abuse Research Center
Harvard Medical School
McLean Hospital
Belmont, Massachusetts
Helen Nowlis, Ph.D.
Office of Drug Education, DHEW
Washington, D.C.
Lee Robins, Ph.D.
Washington University School of Medicine
St. Louis, Missouri
NIDA Research Monograph series
William Pollin, M.D.
DIRECTOR, NIDA
Marvin Snyder, Ph.D.
DIRECTOR, DIVISION OF RESEARCH, NIDA
Robert C. Petersen, Ph.D.
EDITOR-IN-CHIEF
Eleanor W. Waldrop
MANAGING EDITOR
Parklawn Building, 5600 Fishers Lane, Rockville, Maryland 20857
Problems of Drug Dependence, 1979
Proceedings of the 41st Annual Scientific Meeting, The
Committee on Problems of Drug Dependence, Inc.
MEMBERS, COMMITTEE ON PROBLEMS OF DRUG DEPENDENCE, INC.
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Joseph Cochin, Chairman
Joseph Brady
Troy Duster
Charles Gorodetzky
Louis Harris
Theresa Harwood
Arthur Jacobson
Jerome Jaffe
Arthur Keats
Harold Kalant
Everette May
Jack Mendelson
John O'Donnell
C. R. Schuster
Henry Swain
EXECUTIVE SECRETARY
Dr. Leo Hollister
MEMBERS, BOARD OF DIRECTORS
Dr. E. L. Way, Chairman
Am. Soc. Pharmacol. Exptl. Ther.
Dr. D. X. Freedman
Am. Psychiatric Assn.
Dr. K. F. Killam
Am. Coll. Neuropsychopharmacol.
Dr. Everette May
Am. Chemical Society
Dr. Edward C. Senay
Am. Medical Assn.
Dr. Beny J. Primm
Natl. Medical Assn.
Dr. James Woods
Am. Psychological Assn.
Dr. Raymond W. Houde
Am. Soc. Clin. Pharmacol. Ther.
MEMBERS, PROGRAM COMMITTEE
Dr. Louis S. Harris, Chairman
Dr. Everette L. May
Mrs. Linda C. Thornton
MEMBERS, COMMITTEE ON ARRANGEMENTS
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
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Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Martin W. Adler
Alexander L. Beckman
Alan Cowan
Loretta Finnegan
Ellen B. Geller
Alexander Gero
Concetta Harakal
Jeffrey B. Malick
Charles O'Brien
Thaddeus P. Pruss
Charles Puglia
Peter T. Ridley
Frank Robinson
Ronald J. Tallarida
Vernon G. Vernier
ACKNOWLEDGMENT
The papers in this monograph were presented or read
by title at the 41st Annual Scientific Meeting of
the Committee on Problems of Drug Dependence, Inc.,
in Philadelphia, on June 4-6, 1979.
The National Institute on Drug Abuse has obtained
permission from the copyright holders to print
material, as noted, on pages 48-53, 177-183, and
402-408. Further reproduction of this material.
without specific permission of the copyright holders is prohibited. All other material except short
quoted passages from copyrighted sources is in the
public domain and may be reproduced without permission. Citation as to source is appreciated.
The United States Government does not endorse or
favor any specific commercial product or commodity.
Trade or proprietary names appearing in this
publication are used only because they are considered essential in the context of the studies reported herein.
Library of Congress catalog card number 80-600008
DHEW publication number (ADM) 80-901
Printed 1980
NIDA Research Monographs are indexed in the Index
Medicus. They are selectively included in the
coverage of Biosciences Information Service, Chemical
Abstracts, Psychological Abstracts, and Psychopharmacology Abstracts.
v
CONTRIBUTING FIRMS 1978 - 1979
The following firms have supported the work of the Committee on
Problems of Drug Dependence, Inc. through contributions during the
previous fiscal year.
Abbott Laboratories
Bristol Laboratories
C. H. Boehringer Sohn
Burroughs Wellcome and Company
Chemie Linz AG
Clin-Midy of America, Inc.
Eli Lilly and Company
Endo Laboratories, Inc.
Hoffman - La Roche, Inc.
ICI Americas, Inc.
Knoll Pharmaceutical Company
Lederle Laboratories
McNeil Laboratories
Mead Johnson
Merck, Sharpe & Dohme
Merrell - National Laboratories, Inc.
Miles Laboratories, Inc.
Pennwalt Corporation
Pfizer Central Research
Reckitt & Colman Products, Ltd.
A. H. Robins Company
SISA, Inc.
Smith, Kline & French
Sterling Drug, Inc.
The Upjohn Company
USV Pharmaceutical Corporation
vi
Foreword
The National Institute on Drug Abuse is pleased to publish Problems
of Drug Dependence, 1979, in its Research Monograph series. These
are the proceedings of the 41st annual scientific meeting of the
Committee on Problems of Drug Dependence, Inc., which was held in
Philadelphia on June 4-6, 1979.
The Committee, now incorporated as an independent entity, was for
47 years affiliated with the National Academy of Sciences--National
Research Council. Its membership is drawn from all fields of clinical medicine, psychiatry, public health, pharmacology, chemistry,
and the social sciences. This year, as in previous years, its
annual meeting represents a high point in the science activities
relevant to drug abuse and neurosciences.
The Committee's annual scientific meetings typically present a
truly comprehensive assemblage of reports of ongoing research relating to all aspects of drug abuse and drug dependence. The papers present contributions to new knowledge of agents involved in
drug abuse or significantly affecting the central nervous system:
their pharmacological action, biological disposition, abuse potential, safety, tolerance liability, or clinical usefulness, and related experimental and clinical methodology.
In addition to papers presented or read by title at the meeting,
the proceedings include summaries from a special satellite session
on khat and the annual progress reports of NIDA-supported dependence
studies of new compounds.
To meet space limitations for this volume, many of the papers have
been condensed by the authors. The broad range of subjects treated
may be easily seen by looking through the detailed index, which
gives full accessibility to the contents.
vii
We believe that this up-to-date review of the field of drug dependence will be of value to readers who will bring to it as wide a
variety of backgrounds, interests, and concerns as that represented
by the Committee on Problems of Drug Dependence itself.
William Pollin, M.D.
Director
National Institute on Drug Abuse
viii
Contents
Foreword
William Pollin
vii
PAPERS PRESENTED AT THE 41ST ANNUAL CPDD MEETING
Hooked for Thirty Years: Tales of an Investigator
E. L. Way
1
The Prescription of Controlled Substances: What's Right and
What's Wrong?
S. Cohen
11
Effects of Scheduling on the Economics of Drug Development
C. J .
Cavallito
17
The Impact of Regulations on the Development of Psychoactive
Drugs
L. Lasagna
29
The Influence of the Mode of Morphine Administration on
Tolerance and Dependence
J. Cochin; J. M. Miller; C. E. Rosow; R. Grell;
J. L . Poulsen
36
Biosynthesis of the Enkephalins in the Myenteric Plexus of
the Guinea-Pig Ileum.
Further Analysis of the Interaction
of the Enkephalins and Their Analogues With the Opiate Receptors
H. W. Kosterlitz; A. T. McKnight; A. D. Corbett;
M. G. C. Gillan; S. W. Paterson; L. E. Robson; R. P. Sosa. 48
The Binding of LAAM and its Metabolites to Blood Constituents
E. Toro-Goyco; B. R. Martin; L. S. Harris
54
Progress Report From the NIDA Addiction Research Center
D. R. Jasinski; E. J. Cone; C. W. Gorodetzky; M. E. Risner;
H. E. Shannon; T. P. Su; D. B. Vaupel
61
Drug Dependence Programme of the World Health Organization
70
I . Khan
ix
Fifty Years of International Control of DependenceProducing Drugs
S. Kaymakcalan
74
A New Synthetic Codeine Substitute: (-)-3-Phenoxy-NMethylmorphinan
E. Mohacsi; W. Leimgruber; H. Baruth
77
Stereospecific and Potent Analgetic Activity for Nantradol-A Structurally Novel, Cannabinoid-Related Analgetic
G. M. Milne; B. K. Koe; M. R. Johnson
84
8ß-Alkyl-N-Cycloalkyl-Dihydro-Codeinones and -Morphinones as
Analgesic Narcotic Antagonists
M. P. Kotick; D. L. Leland; J. O. Polazzi; R. N. Schut
93
The Pharmacology of TR5109, a New Narcotic Agonist/Antagonist
Analgesic
J. F. Howes; P. F. Osgood; R. K. Razdan; F. Moreno;
A. Castro; J. Villareal
99
Dependence Potential of Loperamide Studied in Rhesus Monkeys
T. Yanagita; K. Miyasato; J. Sato
106
Opioid Self-Administration and REM Sleep EEG Power Spectra
G. F. Steinfels; G. A. Young; N. Khazan
114
Motor Activity and Learning Ability in Rats Perinatally
Exposed to Methadone
I. S. Zagon; P. J. McLuughlin
121
Narcotic Drug Discriminations by Rhesus Monkeys and Pigeons
J. H. Woods; S. Herling; R. J. Valentino; D. W. Hein;
E. H. Coale, Jr.
128
Effects of Closing the Bakersfield Methadone Clinic
W. H. McGlothlin; M. D. Anglin
135
An Improved Evaluation Instrument for Substance Abuse
Patients: The Addiction Severity Index
A. T. McLellan; L. Luborsky; C. P. O'Brien; G. E. Woody
142
Development of Psychiatric Disorders in Drug Abusers:
Relation Between Primary Drug and Type of Disorder
A. T. McLellan; G. E. Woody; C. P. O'Brien
149
Ethnoeconomical Approach to the Relationship Between Crime
and Drug Use: Preliminary Findings
P. J. Goldstein
156
The Impact of Heroin Addiction Upon Criminality
J. C. Ball; L. Rosen; E. G. Friedman; D. N. Nurco
163
Drug Abusers:
Defeated and Joyless
J. D. Cowan; D. C. Kay; G. L. Neidert; F. E. Ross;
S. Belmore
x
170
Outpatient Treatment and Outcome of Prescription Drug Abuse
F. S. Tennant, Jr.
177
Addicts and Drugs
D. N. Nurco; N. Wegner
184
A Quantitative Method for Determining the Effects of Opiates
on Fetal Rats In Utero
M. L. Kirby
191
Differential Effects of Opioids on Flurothyl Seizure
Thresholds in Rats
A. Cowan; E. B. Geller; M. W. Adler
198
Intravenous Phencyclidine Self-Administration by Rhesus
Monkeys Leading to Physical Dependence
R. L. Balster; W. L. Woolverton
205
Effects of Chronic Treatment With Morphine, Methadone, and
LAAM on the Response to Phencyclidine in Rats
G. T. Pryor; R. A. Howd
212
Dependence Within the Opiate-Sensitive Neurone
H. O. J. Collier
219
Clonidine Detoxification: A Fourteen-Day Protocol for
Rapid Opiate Withdrawal
M. S. Gold; A. L. C. Pottash; D. R. Sweeney; H. D. Kleber. 226
Clonidine Hydrochloride: A Nonopiate Treatment for
Opiate Withdrawal
A. M. Washton; R. B. Resnick; R. A. Rawson
233
Usefulness of Propoxyphene Napsylate for Maintenance
Treatment of Narcotic Addiction
G. E. Woody; J. Mintz; F. Tennant; C. P. O'Brien;
A. T. McLellan
240
Management of Neonatal Narcotic Abstinence Utilizing a
Phenobarbital Loading Dose Method
L. P. Finnegan; T. F. Mitros; L. E. Hopkins
247
Relative Analgesic Potency of Intramuscular Heroin and
Morphine in Cancer Patients With Postoperative Pain:
A Preliminary Report
R. F. Kaiko, S. L. Wallenstein; A. Rogers; G. Heidrich, III;
254
R. W. Houde
Clinical Analgesic Assay of Oral Zomepirac and Intramuscular
Morphine
S. L. Wallenstein; A. Rogers; R . F . K a i k o ; G . H e i d r i c h , I I I ;
261
R. W. Houde
Conditioned Heroin Responses as an Indication of Readdiction
Liability
S. I. Sideroff; M. E. Jarvik
xi
268
Unreinforced Self-Injections: Effects on Rituals and
Outcome in Heroin Addicts
C. P. O'Brien; R. Greenstein; J. Ternes; A. T. McLellan;
J. Grabowski
275
Conditioned Drug Responses to Naturalistic Stimuli
J. W. Ternes; C, P. O'Brien; J. Grabowski; H. Wellerstein;
282
J. Jordan-Hayes
The Phase III Clinical Evaluation of LAAM: I. Comparative
Epidemiology of Mortality in LAAM and Methadone
D. B. Thomas; J. A. Whysner; M. C. Newmann
289
Naltrexone, 6ß-Naltrexol and 2-Hydroxy-3-Methoxy-6ß-Naltrexol
Plasma Levels in Schizophrenic Patients After Large Oral
Doses of Naltrexone
K. verebey; S. J. Mule
296
Heroin and Naltrexone Effects on Pituitary-Gonadal Hormones
in Man: Tolerance and Supersensitivity
J. H. Mendelson; J. Ellingboe; J. Kuehnle; N. K. Mello
302
Histopathologic and Clinical Abnormalities of the Respiratory
System in Chronic Hashish Smokers
F. S. Tennant, Jr
309
SATELLITE SESSION ON KHAT: PHARMACOLOGY AND ABUSE POTENTIAL
Assessment of Public Health and Social Problems Associated
With Khat Chewing
I. Khan; P. H. Hughes
316
Khat--The Problem Today
H. Halbach
318
Research on the Chemical Composition of Khat
0. J. Braenden
320
Studies on the Central Effects of (-)Cathinone
J. Knoll
322
Behavioral Studies of Cathinone in Monkeys and Rats
C. R. Schuster; C. E. Johanson
324
Studies on Cathinones: Cardiovascular and Behavioral Effects
in Rats and Self-Administration Experiment in Rhesus Monkeys
T. Yanagita
326
Discriminative Stimulus and Neurochemical Mechanism of
Cathinone:
A Preliminary Study
J. A. Rosecrans; 0. L. Campbell; W. L. Dewey; L. S. Harris. 328
xii
PROGRESS REPORTS
Annual Report:
Dependence Studies of New Compounds in the
Rhesus Monkey (1979)
M. D. Aceto; L. S. Harris; W. L. Dewey; E. L. May
330
Annual Report: Biological Testing Program of the Committee
on Problems of Drug Dependence, Inc. (1979)
A. E. Jacobson
351
Annual Report: Evaluation of New Compounds for Opioid
Activity (1979)
H. H. Swain; J. H. Woods; F. Medzihradsky; C. B. Smith;
C. L. Fly
356
PAPERS READ BY TITLE BUT NOT PRESENTED
Effects of Alcohol Abuse on Progression of Liver Disease in
Methadone-Maintained Patients
C. L. Beverley; M. J . K r e e k ; A . O . W e l l s ; J . L . C u r t i s .
399
Modification of Treatment Compliance as a Function of
Contingent Payment Manipulations
J. Grabowski; C. P. O'Brien; R. Greenstein; M. Long;
S. Steinberg-Donato; J. Ternes
402
The Effect of l-Alpha Acetyl Methadol in Morphine-Dependent
Rats
A. L. Riley; D. S. Etherton; R. M. Shapiro
409
Outcome for Structural Family Therapy With Drug Addicts
M. D. Stanton; T. C. Todd; F. Steier
415
General Cardiovascular Pharmacology of 1- -Acetylmethadol
(LAAM)
J. L. Stickney; D. C. Eikenburg; J. D. Keedy
422
On the Relative Efficacy of LAAM and Methadone
J. A. Whysner; D. B. Thomas; W. Ling; C. Charuvastra
429
Lack of Toxicity of High Dose Propoxyphene Napsylate When
Used for Maintenance Treatment of Addiction
G. E. Woody; F. S. Tennant; A. T. McLellan; C. P. O'Brien;
435
J. Mintz
Subject Index
441
Author Index
477
List of Monographs
480
xiii
Papers Presented
at the 41st Annual
CPDD Meeting
Hooked for Thirty Years: Tales of
an Investigator
Way, E. L.
It is with deep gratitude and humility that I acknowledge the
great honor bestowed upon me today. It is also with considerable
pride that I accept the Nathan B. Eddy Award because my peers,
rightly or wrongly, have placed me in a niche with such distinguished pioneer investigators as Seevers, Isbell, Wikler, Martin
and Kosterlitz, all of whom were or are dear friends.
I first met Nathan Eddy in 1944 and from that time on and until
his death in 1973 our paths crossed many times not only at our
annual CPDD meetings but also on numerous other occasions. I
remember particularly one incident back in the 50's when we were
members on an analgetic evaluation committee for the VA. Since
we were meeting in San Francisco, I, of course, had to arrive a
little late. As soon as I entered the meeting room, Dr. Eddy
came up to me and said, "Eddie, I have 60,000 dollars for you,"
whereupon he reached into his pocket and handed me an ounce of
heroin. Since that quantity is equal to about three thousand
10 mgm fixes, at $20 per bag the price would be about right. The
integrity of Dr. Eddy was such that he had the complete confidence
and trust of the Bureau of Narcotics. As their consultant, he
was allowed to push to whomever he wished extraordinary amounts of
controlled drugs. To have heroin today, investigators need to
have a license registration number and the approval of a joint
FDA/NIDA Committee. Although progress appears to dictate the
need for more rigid security measures and red tape, I do not know
of a single investigator who violated Dr. Eddy's trust.
Before I start discussing some of our investigative work, let me
pay tribute to my many colleagues and, in particular, to former
students and post-doctoral fellows, with whom I have had the good
fortune to have been associated. It will not be possible to name
them all but each one has played a significant role to enrich my
life by helping me solve problems in opiate research and becoming
steadfast loyal friends. Suffice it to say the conditioning I
received in their environment is such that if I had a life to live
again, my free choice for a career would still be in pharmacology
and I would bar press actively for opiates.
1
314-300 0 -80 - 2
My interest in narcotics started with an undergraduate course in
pharmacology taught by Chauncey Leake at San Francisco but it was
two of my former bosses at George Washington University who
"hooked" me. Under George Roth I studied the local anesthetic
and cardiac effects of meperidine (known in those days as
isonipecaine) but when P.K. Smith succeeded him in 1946 I became
interested in drug metabolism. At George Washington together
with my first graduate student C.Y. Sung (who will head a
pharmacology delegation from the People's Republic of China this
coming fall) we found that meperidine was metabolized by the liver
to an unknown basic metabolite. Based on these preliminary data
I applied for and was awarded a research grant in 1948 from NIH to
study the biologic disposition of morphine and its surrogates. I
transferred the grant when I moved to San Francisco and with subsequent renewals held it for more than 20 years until I shifted to
working on tolerance and dependence mechanisms.
The proximity of San Francisco to Berkeley facilitated the
acquisition of N-14CH3 labelled isotopes of meperidine, morphine
and codeine and this gave us a running head start over other
investigators in this area. N-demethylation was found to be a
common metabolic pathway for the surrogates of morphine. In
actuality this turned out to be a relatively minor pathway for
opiates but it provided a major stimulus for studies on microsomal
metabolism. N-demethylation also paved the way for two imaginative
hypotheses. Beckett developed a theory of analgesia based on Ndemethylation and Axelrod and Cochin postulated N-dealkylation as
a mechanism for tolerance. I thought Terry Adler and I had pointedly rejected both hypotheses but I note recently that Fishman
et al. have found that N-demethylation of opiates occurs in the
brain and as a consequence they have resurrected the early postulates.
I was rather proud of the study on the metabolic fate of meperidine
carried out by Nick Plotnikoff as a graduate student because he was
able to outline several metabolic pathways without the actual isolation of any of the metabolites and he used a non-specific dye
technique for his estimations. By combining the Brodie methyl
orange procedure for organic bases with countercurrent distribution,
Plotnikoff identified meperidine and normeperidine in the urine by
their partition behavior. He then showed that hydrolyzed metabolites of these two substances were biotransformation products by
demonstrating that under esterification conditions with ethanol
the yields of meperidine and normeperidine in the urine could be
substantially increased. Furthermore, evidence that meperidinic
acid and normeperidinic acid were also excreted in the urine as
conjugated products was indicated by the fact that if he subjected
the urine to hydrolytic conditions before esterification, the yield
of meperidine and normeperidine could be further enhanced.
Another pathway established for some opiates was 0-dealkylation.
Terry Adler first demonstrated in 1951 that codeine could be 0demethylated to morphine. To establish this point 014CH3 labelled
morphine was shown to yield 14CO2 after parenteral administration
2
of codeine and morphine was unequivocally identified as a urinary
metabolite of codeine by X-ray diffraction studies. Together
with Jim Fujimoto, Adler also found that codeine and morphine were
N-demethylated to their respective nor derivatives, and norcodeine
and normorphine would then be excreted in the urine as conjugates
of glucuronic acid.
In those days it was not so simple to demonstrate glucuronide products of opiates because their high water solubility made their
purification and isolation from urine by solvent extraction
techniques difficult. Oberst at Lexington first demonstrated that
the yield of morphine in the urine could be increased substantially
by acid hydrolysis but it was not until almost 20 years later that
Lauren Woods then at Michigan showed that the "bound" morphine in
dog urine was a glucuronide. Shortly thereafter, Fujimoto demonstrated that morphine glucuronide was the chief metabolite of morphine excreted in the urine by humans.
With Sung and Peng we found that methadone is N-demethylated but
we had difficulty isolating and identifying the des-methyl metabolites, and it remained for Pohland and associates to demonstrate
that following mono- and di- demethylation, the products undergo
rearrangement to form cyclic metabolites. In studies on l-acetylmethadol, Sung and I reported in 1954 that 1-acetylmethadol undergoes
extensive biotransformation and that much of its activity results
from the formation of an active metabolite. This conjecture has
only recently been validated by Mule, Misra and associates.
Taking a sabbatical leave at Berne with Walther Wilbrandt to study
the disposition of heroin, we were able to confirm that heroin was
rapidly hydrolyzed to morphine. Later with John Kemp and others
we found that the biologic half-life of heroin was less than 3
minutes and that the sequence of hydrolysis involved deacetylation
first to 6-monoacetylmorphine which was then hydrolyzed to morphine
Based on toxicity studies of heroin, 6-monoacetylmorphine and
morphine after subcutaneous, intravenous and intracerebral
injection, we found that morphine was least potent by the
parenteral routes but most potent after intracerebral injection.
We concluded from these findings that the primary effects of
heroin are due to the formation of morphine. The greater potency
of heroin over morphine by the parenteral routes could be explained
by the lipid solubility conveyed by the acetyl groups which are
than rapidly removed by esterases in the brain. Thus hydrolysis
of heroin to morphine in the central nervous system represents an
activation process but when it occurs outside the brain in the
liver and other organs and tissues, hydrolysis, reflects a detoxification process.
The results of these studies led us to a consideration that the
enhanced sensitivity of the newborn to morphine might be attributable to disposition factors. The toxicity of morphine in the
rat was studied from birth to one month of age with Kupferberg.
The LD50 remained relatively constant for 16 days but between days
3
16 and 32 it increased abruptly by 4-fold. After developing a
sensitive spectrophotofluormetric technique for measurements of
brain morphine levels in the newborn, we found that with equal
doses of morphine the brain levels in the 16-day-old rat were
usually more than twice those in the 32-day-old and in order to
attain comparable brain levels with the two age groups it was
necessary to administer a dose three times as high in the 32-dayold mice. Thus the results provided an explanation for the
difference in toxicity of the two age groups and indicated that
the decreased sensitivity to morphine in the maturing animal is
due in large part to the development of a blood-brain barrier to
morphine. Subsequent studies with heroin and meperidine further
revealed that this process was peculiar to morphine. Virtually
no CNS barrier development to heroin or meperidine could be demonstrated with increasing age and this was reflected by only small
variations in toxicity between different age groups.
With Kaul, Lin, El Mazati, Afifi, Nayak, Berkowitz and others we
studied also the disposition of apomorphine, anileridine, noscapine,
methotrimeprazine and pentazocine and made generalization concerning
the disposition characteristics of basic compounds. Basic drugs
are in general more potent than acidic ones because at body pH
proportionately more base exists in the unionized form. This
property favors their gaining access to target sites for eliciting
pharmacologic effects promptly and sequestering in indifferent
organs for later release to prolong drug action. By and large,
organic bases, including the opiates, have a high apparent volume
of distribution because they rapidly leave the blood and concentrate in parenchymatous tissues. Tissue levels can be decreased
and excretion facilitated by lowering body pH. These conclusions
were summarized and published in a 1962 monograph, Biologic
Disposition of Morphine and Its Surrogates, co-authored with
Terry Adler.
We took our second sabbatical leave in 1962 and went to Hong Kong
to assess the unique modes of inhaling heroin. Addicts there use
two techniques: one is by smoking heroin inserted into a cigarette
("ack ack") and the other procedure is by inhaling the fumes resulting from heating a mixture of heroin and barbital ("dragon
chasing"). We were informed that dragon chasing was a more
effective way of inhaling heroin than ack ack. To find an
explanation for this difference, Ben Mo and I decided to compare
the urinary excretion of morphine by these two inhalation techniques
with that after intravenous administration. Our urinary excretion
values of total morphine were consistent with the practice in the
field. Based on the percent of the dose that could be accounted
for in urine, the efficiency of dragon chasing was found to be twofifths that of intravenous injection and twice that of ack ack.
Under laboratory conditions simulating the two modes of administratior
we found that the temperature for volatilizing heroin was critical.
At a high temperature such as that of a burning cigarette (746oC),
availability of heroin is poor because of extensive decomposition.
The addition of barbital to the heroin minimizes the loss of heroin
by facilitating the volatilization of heroin at a lower temperature
4
(244oC). Perhaps, the Hong Kong junkies had a “connection” who
was a pharmacist with a sophisticated knowledge of delivery systems!
Although most of our initial work centered on drug disposition
studies some of my associates involved me in characterizing sites
of opiate action. There is much current interest in the hypothalamic effects of -endorphin and these studies relate back to
some early work on morphine and hypothalamo-pituitary-adrenal function. Bob George and I reported in the 50's that the hypothalamus
is an important intermediary for pituitary-adrenal activation by
analgetic agents and that their effects could be blocked by a
lesion in the median eminence. Subsequently Bob George and
Norio Kokka further noted that growth hormone and gonadotrophin
release are also altered by morphine. More recently Eddie Wei
(my "friends" identify him as the young good-looking one) found
that several mesodiencephalic areas of the brain, the medial
thalamic region in particular, are important for mediating opiate
antinociception and certain withdrawal signs. Also Edgar Iwamoto
has demonstrated that nigrostriatal pathways are much involved in
the expression of abstinence.
In 1966 we were invited to attend an International Symposium on
Analgetics in Santiago. There I met Professor F. Huidobro and
observed his morphine pellet implantation techniques for producing
morphine tolerance and physical dependence in mice. In his
earlier writing Nathan Eddy has mentioned that tolerance and
physical dependence were not characteristic responses in rodents,
but as it turns out the earlier workers simply did not administer
morphine frequently enough. I was fascinated by the simplicity
of the pellet procedure and reflected that I could now study
tolerance and physical dependence mechanisms without interfering
with my week-end golfing activities.
The pellet made by Professor Huidobro did not quite suit our needs
because only limited quantities could be made by a hand press. I
consulted Bob Gibson in the School of Pharmacy and he formulated
a tablet that could be mass produced and this pellet is now in wide
use.
The implantation of this pellet subcutaneously in a mouse for three
days produces a high degree of tolerance and physical dependence.
A quantitative measure of the degree of tolerance development is
given by an increase in the dose of morphine required to produce
analgesia and this is generally between 7-and 20-fold. The degree
of physical dependence can be quantified by determining the naloxone
ED50 to precipitate withdrawal jumping, the greater the dependence
the lower the naloxone ED50. Alternatively, Takemori uses the
total number of jumps in a group of animals as an index.
Applying these procedures together with some pharmacologic probes
we initiated studies in the mechanisms involved in tolerance and
physical dependence development. We obtained considerable evidence
supporting the biochemical nature of these processes. Like others,
5
Loh, Shen and I were able to demonstrate the blockade of tolerance
development with inhibitors of protein synthesis. We found that
cycloheximide not only inhibits the development of tolerance but
the development of physical dependence as well. It was also
possible to achieve this effect without altering the acute action
of morphine and we postulated, therefore, that the macromolecule
involved in tolerance and dependence development may be different
from the receptor concerned with acute effects and likely was
turning over at a more rapid rate.
Inasmuch as the inhibitors of protein synthesis have widespread
effects, identifying the macromolecule possibly involved with the
development of morphine tolerance and dependence has been a
formidable task. Virtually every known putative neurotransmitter
has been assessed with respect to its effect on the acute and
chronic action of morphine. We (including Shen, Loh, Ho, Bhargava,
Friedler, Iwamoto and others) have used various pharmacologic tools
to affect as selectively as possible the synthesis storage, release, or degradation of acetylcholine, dopamine, norepinephrine,
and serotonin, and the consequences of such maneuvers on the
tolerant-dependent state and on the development of tolerance to
and dependence on morphine were evaluated.
Based on these experiments, we concluded that acetylcholine,
norepinephrine, and dopamine may participate in the mediation of
acute pharmacologic responses to morphine as well as certain withdrawal signs in dependent animals but they seem less directly involved with the development of tolerance to and physical dependence
on morphine. Although our findings seem to implicate 5-HT to a
greater degree, a causal relationship for 5-HT could not be conclusively established, and although our findings have been largely
verified by Herz's laboratory they dispute our conclusions.
Moreover, Kalant's laboratory note that a selective role for 5-HT
in opiate tolerance development can be challenged on the grounds
that decreasing serotonin functional activity also reduces alcohol
tolerance development and it has been pointed out that a
correlation does not appear to exist between brain 5-HT turnover
and development of tolerance to other opiates.
There are other pharmacologic tools which can be used to alter
tolerance and dependence. Although the same caveat can be applied
with respect to interpreting the significance and implication of
such maneuvers, it is important to note that the rate of development
of tolerance and physical dependence may be reduced or accelerated
to varying degrees by pharmacologic agents acting by diverse
mechanisms. For example, tolerance can be inhibited by agonist
receptor blockade with antagonists such as naloxone or by inhibiting
protein synthesis. Although there is evidence less impressive, it
appears that reducing serotonin functional activity,
-adrenergic
blockade, or reducing
-aminobutyric acid activity with antagonists
such as bicuculline can also reduce tolerance and dependence
development. It is of interest to note that tolerance and
dependence can be accelerated with agents which oppose the effects
of the latter three classes of compounds. Examples are,
6
respectively: a stimulator of serotonin synthesis (tryptophan),
and its analogs, and inhibitors of GABA transamination.
Again, there is no evidence that these manipulations affect
directly the causal processes related to tolerance and dependence.
CAMP
Despite the inability to solve the precise mechanism involved in
opiate tolerance and physical dependence, some essential basic
information has resulted from the studies. The biochemical
nature of the processes was clearly established in that tolerance
and physical dependence could be demonstrated to be reduced or
accelerated by pharmacologic manipulation. Moreover, the fact
that the immediate pharmacologic response to morphine can be
modified greatly without significantly altering tolerance and
physical dependence development indicates that it is possible to
dissociate selectively the process involved in the immediate
pharmacologic effects of opiates from those which might be concerned
with the development of tolerance and dependence. The converse
fact that the development of tolerance and dependence can be
blocked without modifying the acute pharmacologic action of morphine
also supports this view.
We went back to the drawing board and decided to assess the role
of Ca++ in opiate analgesia, tolerance and physical dependence.
There were compelling reasons that prompted our interests.
Takemori first demonstrated in 1962 that morphine inhibits
respiration in depolarized brain slices and later Kokka, Elliott
and I found that the effect occurred only in the presence of low
Ca++. Kaneto reported that Ca++ antagonized the analgetic actions
of morphine and concluded that opiates may be mediating their
effects by altering Ca++ flux. Subsequently, Ross found that
opiates acutely lowered the Ca++ content at nerve endings. In the
meantime we had initiated our studies of Ca++-morphine interactions
with Harris and confirmed the findings by Kaneto and by Ross. We
found that in addition synaptosomal Ca++ content increased with
tolerance and dependence development. We have since carried out
extensive studies on Ca++-opiate interactions.
I should like to present now a personal view concerning the possible
mode of action of opiates. Although there are many gaps, the
operational model that I am proposing appears to offer a more complete explanation than existing ones with respect to the acute and
chronic effects of opiates. Based on the data generated thus
far by our laboratory I should like to postulate that the nociceptive
state is subject to regulation by the intraneuronal Ca++ level.
A lowering of the Ca++ results in analgesia while elevating Ca++
causes hyperalgesia. Thus, morphine and other opiates have been
well established to lower neuronal Ca++; however, other agents
such as lanthanum, which reduces Ca++ uptake, and EGTA, which
chelates Ca++, also exhibit antinociceptive activity. On the
other hand, the intraventricular injection of Ca++ produces hyperalgesia and antagonizes morphine analgesia. Ca++ also reduces
greatly the agonist effects of normorphine and B-endorphin on the
guinea pig ileum. Moreover, the ionophore X537A, which facilitates
Ca++ entry’, augments Ca++ antagonism of morphine analgesia, whereas
7
La+++ reverses the antimorphine action of Ca++. These studies were
mostly carried out by Harris, Iwamoto, Huidobro-Toro and Hu.
The acute lowering of Ca++ by opiates initiates a homeostatic response to prevent Ca++ loss. This counteradaptive process requires
the presence of morphine and becomes increasingly effective with
each successive dose of morphine. Yamamoto, Harris, and GuerreroMunoz have found that the development of tolerance to morphine is
accompanied by an accumulation of synaptosomal Ca++ and the subcellular components involved in this increase include the inner
synaptic plasma membrane and vesicles. They also found that the
increase in synaptosomal Ca++ is proportional to the degree of
tolerance developed. Since Ca++ antagonizes acute morphine action,
the accumulated Ca++ would oppose opiate effects and more morphine
would be required for reducing Ca++ to produce analgesia. However,
the higher dose of morphine would further enhance the Ca++ retention process and render acute lowering of Ca++ even more difficult.
Thus, a mechanism is provided to explain tolerance.
The proposed cumulative enhancement of Ca++ retention by morphine
also provides a mechanism to explain cross-tolerance. The elevated
Ca++ and its increased retention capacity should not only reduce
the effects of other opiates but also those of other agents that
reduce Ca++. Thus, tolerance to morphine has been demonstrated to
result in cross-tolerance to La+++ and to EGTA. It could be further argued that since these agents tend to augment opiate effects,
they should facilitate the development of opiate tolerance. Consistent with this notion, Schmidt found on comparing the analgetic
response to morphine in mice rendered tolerant by morphine pellet
implantation and infused either with EGTA or saline that a dose of
morphine, which produced analgesia in 50 percent of the saline
treated animals, was ineffective in the EGTA group. Conversely,
Kaneto and others have reported that repeated Ca++ administration
inhibits tolerance development.
The development of an enhanced Ca++ storage process after sustained
morphine administration also offers explanations for physical dependence and the abstinence syndrome. Physical dependence is an
invariable accompaniment of tolerance and the two states appear to
be closely linked. Under such conditions cytosol Ca++ may be maintained at a higher steady state by the enhanced retention process
which requires the continual presence of morphine. The need for
morphine to support this retention process is indicated by
Yamamoto's finding that administration of naloxone to precipitate
withdrawal results also in a marked fall in synaptosomal Ca++.
Abrupt discontinuance of morphine or antagonist precipitated abstinence results in an increase in cytosol free Ca++ at the expense of
the retention process and the abstinence syndrome would reflect
hyperirritable responses to Ca++ that ordinarily are masked by morphine. Hence, when morphine is administered during this state,
abstinence would be suppressed because the free Ca++ becomes reduced not only by decreased cellular uptake but also by enhanced
intraneuronal removal at amplified storage sites. If this be the
case, then maneuvers designed to lower free Ca++ should suppress
8
abstinence and elevating it should exacerbate the syndrome. Thus,
Harris has shown that La+++ decreases the incidence of withdrawal
jumping in morphine-dependent mice and increases the dose of naloxone needed to precipitate withdrawal jumping. Conversely, Schmidt
has shown that hyperalgesia occurs during abstinence and can be
considered to be a withdrawal sign. It is detectable in a dependent animal shortly after discontinuance of morphine and during
this state the hyperalgesia can be further enhanced by Ca++ administration. Thus, we have qualitative data to support our hypotheses
and this provides the framework for validation with more definitive
experiments.
Not all of our approaches have been made from the bench. The conceptualization of an operational receptor with molecular models
by Cho and Loh has yielded fruitful data beyond expectations.
Models of the glycolipids indicate that they might be suitable
candidates for binding opiates. In particular cerebroside sulfate
yielded excellent correlation between binding affinity and agonist
activity. The agreement was obtained not only on the guinea pig
ileum with respect to inhibition of electrically induced contractility but also on analgetic potency in mice and humans. To our
surprise and delight, the opiate "receptor" isolated from mouse
brain by Goldstein's laboratory was found to consist essentially of
cerebroside sulfate. Loh's group has persevered in their efforts
to validate cerebroside sulfate as an integral part of the opiate
receptor and their more recent findings are truly exciting. In collaboration with Bauman's laboratory in Paris, an antibody to cerebroside sulfate has been made which displaces morphine from its
central nervous system binding sites and antagonizes its pharmacologic actions. Moreover, the incorporation of cerebroside sulfate
by a neuroblastoma cell culture appears to initiate prostaglandin
activity in the preparation. Almost certainly there will be increasing activity in the future to assess the role of glycolipids
in interaction with drugs.
Thus, our approach towards combating the problems of drug dependence
has been essentially pharmacologic and directed towards ferreting
the basic mechanisms involved. Although I would without qualification concede that misuse and abuse of chemical substances reflect
signs and symptoms of individual and societal maladjustment, I
firmly believe that the pharmacologic approach offers, if not the
cure, certainly the facilitation that makes psychologic, psychiatric
and rehabilitative measures possible. Success with the latter
approaches in the past without drug intervention has been notoriously lacking, at least in terms of reaching the major population
of addicts.
To a pharmacologist, all drugs are merely chemical substances which
ultimately must act on biologic processes. Irrespective of environmental factors, the use of adequate amounts must effect pharmacologic
responses by either stimulating or inhibiting cellular activity
after their combination at specific sites. It seems reasonable to
presume, therefore, that compulsive drug use may be associated with
9
aberrations in these processes and if this be the case, it should
be possible to block or reverse these changes with pharmacologic
agents. There are already modest indications that pharmacologic
intervention offers good chances for success.
The use of disulfiram for alcohol dependence and methadone for
maintenance have not attained universal cures but this should not
be expected. Although the successes attained with these agents
have been relatively limited, they were achieved with less expenditures of governmental resources in time, effort and money than nondrug approaches. Further studies to dissociate the processes
involved with acute opiate effects from those concerned with tolerance and physical dependence offer hope that more effective
therapeutic agents can be developed and indeed some are already
appearing on the immediate horizon.
In conclusion, I wish to again express my deepest gratitude for
honoring me today and for providing me a forum to summarize
approximately 30 years of labor described in approximately 300
publications in approximately 30 minutes. I hope that some day
(< 30 years) I will again be afforded equal time that will
reflect more efficient utilization of my efforts.
AUTHOR
E. Leong Way, Ph.D.
Department of Pharmacology
University of California San Francisco
San Francisco, California 94143
10
The Prescription of Controlled Substances:
What’s Right and What’s Wrong
Cohen, S.
The remark that we live in a drug-oriented society has
been repeatedly made. If this is true, it is in part because our
citizens have come to expect rapid relief from discomfort, unease and other forms of real or imagined psychophysical distress. Especially, but notexclusively, young people seek
chemical solutions for whatever shyness, boredom, or
tensions of everyday life they may encounter. Beyond the
amelioration of noxious feeling tones, increasing numbers look
to drugs to provide them with positive mood states. They
search out euphoriants to procure pleasure, ecstatants for joy,
and deliriants to deliver them from themselves. Is their
demand for pharmacologic surcease a sign of societal decadence,
individual failure of nerve, or something else? Whatever it is,
the latter day ability to supply chemical configurations that do
what is desired with considerable specificity is at hand. And
this precision tooling of molecular arrangements inevitably
increases demand. It’s not better, but easier living through
chemistry.
It should be made clear that the physician's contribution
to hedonic drug-taking represents only a fraction of the consumer
market. The cocaine, heroin, the hallucinogens, the volatile
solvents, the cannabis and the array of other psychobotanicals
are acquired without benefit of a prescription. Add to these
the tobacco and alcohol products, the proprietary medicaments,
and we are left with the prescription narcotics, sedatives and
stimulants. The supplies of these substances seen on the street
are often obtained by theft, highjacking or illegitimate manufacture. Nevertheless, the fraction contributed by the medical
profession is important because, for some people, it may
initiate or maintain a career of drug dependence, it might
cause accidental overdose, or can become a means of suicide.
It was the increased preoccupation with psychochemical
consciousness-alteration during the 1960s that provoked the
Drug Abuse Prevention and Control Act of 1970. As a result
the prescribing of narcotics, sedatives and stimulants became
more restricted than previously with criminal penalties available to those convicted of violating the various statutes.
Although they make the practise of medicine somewhat more
onerous, these controls seem justified. Increasing the pool
of abusable drugs simply makes them more readily accessible
to users, old and new. The story of the six physicians who
11
were responsible for the outbreak of heroinism in London has
been amply described. We have had similar mini-epidemics
in this country. For a while a single doctor was prescribing
2.5 percent of the national supply of methylphenidate. Quick
corrective action must be taken against the script doctor or
the impaired physician who becomes a supplier of large
quantities of mind-altering drugs. A gullible doctor may become
overinvolved in writing for narcotics, and then blackmailed into
continuing to write. Sometimes, the physician is not even involved -- just his prescription pad.
A second reason for the Drug Control Act was the
expectation that patients on dependency-producing drugs would
receive closer supervision. No longer could prescriptions for
sleeping pills be renewed interminably. This was certainly a
worthy goal, and perhaps this hope has been realized in part.
Medication supervision is certainly not what it should be at the
present time.
There is an ancient German proverb that translated, says:
"No soup is ever eaten as hot as it is cooked." Unfortunately,
the regulatory broth does not conform to the adage. Certain
States have not only adopted the Federal legislation, they have
gone far beyond it. They have enacted laws that are considerably more constrictive and their enforcement borders on the
inane on occasion. Some states have defined the package insert
and the PDR as the basis for medical practise. Deviations
from the approved indications or the recommended doses turns
out to be illegal, or at least, unethical. For example, the
prescribing of a stimulant for an atypical depression unresponsive to conventional therapies can lead to investigations,
administrative hearings and a variety of penalties. When the
administrative judge, who is not a physician, does not understand the great variability of human responses to psychotherapeutic drugs, things can go very badly for the clinican
who tries to do as much as he can for his patient. Unfortunately,
judges do not assume responsibility for seriously ill patients.
The prescribing of meperidine for intractable, recurrent,
one-sided headaches is probably poor medicine, but what is the
alternative by the time the desperate patient has become overtly
suicidal. Or consider the case of the busy doctor practising in
a poor part of town. A young man (who later turns out to be
an undercover investigator) comes in complaining of a running
nose, nausea and vomiting, sweating and back pains. A prescription for codeine and aspirin is prescribed after a rather
routine history and physical examination. The doctor is charged
12
with prescribing narcotics for an addict in withdrawal. He had
diagnosed a viral infection.
These are actual cases from a single State. I hope that
this sort of thing is not the fallout of the Drug Control Act
because I confess, I had something to do with its genesis.
So the practise of medicine in some places has become
rigidified, frozen in the problematic mold of the package insert.
I must remind you that this piece of paper is an agreed upon
statement between the FDA and some pharmaceutical firm.
I know of no legal stature that it may have involving physicians.
Nevertheless, it is being used in courts, not as a guide but as
some absolute decree that must not be transgressed. Unfortunately, there are a few patients whose needs do not happen to
conform to the arcane pronouncements of the package insert.
Meanwhile, the following situation is taking place, spilling
hundreds of dosage units every four minutes onto the black
marketplace. A long line of young people extending back over
a hundred yards from a doctor’s office are awaiting a script
for amphetamines or barbiturates or both (slide). It took 14
months to close this operation down.
So what starts out as a landable effort to deter the diversion
of psychochemicals into non-medical channels, culminates as
a nit-picking effort to fit the practise of medicine into some
committee-constructed Procrustean bed. It may be that those
doctors who had the temerity to prescribe amphetamines for an
atypical depression, Demerol for migraine-type headache,
and codeine for what appeared to be influenza deserved whatever
punishment was inflicted. Although they were not particularly
contributing to our drug abuse problem, the brand of medicine
they practised was not the best. But what of the conscientious
doctor who did not want to give a month’s supply of sleeping
pills or of tricyclic antidepressants to a depressed, indigent
person on Medical or Medicaid? If he wanted to provide such
a person with a sublethal amount of these drugs, a one week’s
supply would be proper. But the rules restrict the number of
patients visits, in some instances to one a month. So while
the bureaucracy frowns upon what may or may not be poor
medicine on one hand, it promotes terrible medicine on the
other.
As we look at the changes in the drug schedules since
1970, it is clear that the trend is in the direction of up scheduling.
The barbiturate hypnotics have been moved from III to II.
13
The amphetamines have been similarly treated. Propoxyphene,
pentazocine, pemoline, the weight control drugs and the benzodiazepines, previously unscheduled, are now in IV. Methaqualone and phencyclidine jumped from an unscheduled status
to II. The only drugs that have gone in the opposite direction
are apomorphine and the narcotic antagonists. These changes
are probably reasonable in view of the known pharmacology and
the recent abuse history of the agents involved.
Specific Drug Classes
1.
Stimulants
Cocaine is in Schedule II and retains some occasional
usefulness as a topical anesthetic and decongestant. On rare
occasions physicians have misprescribed it for its antidepressant
or stimulating actions for themselves or for patients. In even
rarer instances they provided cocaine prescriptions for profit.
The amphetamines, methylphenidate and phenmetrazine are
also in Schedule II, and their indications have become more
restricted than previously. Narcolepsy and the hyperkinetic
behavioral disorders are accepted indications for stimulant
Use. Their antiobesity effects are in dispute but short courses
are permitted. Their use for mild depressive or fatigue states
is much more controversial. An occasional patient with an
atypical depressive reaction that is intractable to other
therapeutic attempts, has benefited from the amphetamines
according to a number of clinicians. The amphetamine-related
drugs have been the prime agents prescribed by unscrupulous
doctors for profit. Weight control substances like fenfluramine
(Pondimen) and diethylproprion (Tenuate) are listed in Schedule
IV. They have a lesser abuse potential and have rarely been
abused in this country.
2.
The Hypnosedatives and Anxiolytics
The hypnotic barbiturates and methaqualone
(Quaalude) are located in Schedule II. The non-barbiturate
sedative-hypnotics are either in III: methylprylon (Noludar)
glutethimide (Doriden) and butabarbital (Butisol); or, in IV:
phenobarbital, chloral hydrate, paraldehyde, ethchlorvynol
(Placidyl) and ethinamate (Valmid). The benzodiazepines and
meprobamate also are in IV. These drugs may be overused
by patients or diverted into non-medical channels.
3.
Narcotics
Opium, morphine, codeine, oxycodone (Percodan),
14
Pantopon, dihydromorphinone (Dilaudid), methadone and meperidine (Demerol) are all to be found in Schedule II. Codeine
combinations with analgesics and paregoric are located in III.
Propoxyphene (Darvon) and pentazocine (Talwin) are in IV and
the codeine-containing cough mixtures are in V. All of these
opioids have been misused by health care professionals or
their spouses or diverted to the black market at one time or
other. Recently, a large number of Dilaudid tablets was
obtained from the UCLA outpatient pharmacy by the forgery of
blank triplicate prescriptions.
An organized effort has been underway to reschedule
heroin from I to II so that it can be used for severe pain,
particularly in the terminally ill cancer patient. In England
and Belgium heroin is used for this purpose. Most of it is
taken orally. When taken in equivalent oral doses (heroin:
morphine = 1:1.5) morphine is at least as effective as heroin
according to the studies at St. Christopher’s Hospital. Patients
given the drugs by the subcutaneous route (usually a 1:3 ratio)
cannot distinguish morphine from heroin. When it is given
intravenously the somewhat more rapid action of heroin is an
advantage. On the other hand, morphine is a bit longer acting.
When enormous amounts of a narcotic are needed, heroin has
the advantage of greater solubility. Until additional data are
acquired, heroin cannot be said to have a distinct medical
advantage over morphine, and rescheduling it does not seem
to be indicated now.
In addition to what has already been said, a listing of the
problem areas encountered in the prescribing of controlled
drugs should be mentioned. They include:
1. The diversion of leftover prescription drugs.
2. Patient non-compliance in using amounts of the
drugs larger or smaller than ordered.
3. Tolerance development in the insufficiently supervised patient.
4. Poor prescription security such as careless control
of prescription pads, pre-signed prescription blanks, erasable
prescriptions and improper prescription writing.
5. The failure to do periodic reviews of the drugs
the patient is taking.
15
6. Physician deception by drug-dependent patients.
7. The management of patients with chronic pain or
insomnia, and dealing with anxiety in the abstinent addict.
These are all physicians responsibilities, Better
education and training are needed to correct poor habits of
prescribing and supervising patients on controlled drugs.
Author :
Sidney Cohen, M.D.
Neuropsychiatric Institute
UCLA Center for the Health Sciences
Los Angeles, CA 90024
16
Effects of Scheduling on the
Economics of Drug Development
Cavallito, C. J.
"Controlled Substances," in the context of the present discussion,
refers to those substances covered by the "Comprehensive Drug
Abuse Prevention and Control Act of 1970" (Public Law 91-513, 9lst
Congress, October 27, 1970) and regulations pertinent to the Act
beginning with and subsequent to the April 20, 1971 regulations
issued by the Federal Bureau of Narcotics and Dangerous Drugs
(BNDD) of the U.S. Department of Justice and July, 1971 pertinent
regulations of FDA within H.E.W. The BNDD was the predecessor
agency to the Drug Enforcement Administration (DEA). The Statutory amendment to the Public Health Service Act repealed and replaced the old Harrison Antinarcotic Act and the 1965 Drug Abuse
Control Amendments. Essentially, the Act regulates the manufacture, distribution and dispensing of narcotics and/or dangerous
drugs through Federal registration of all those involved in this
legitimate chain, excepting the ultimate patient user. Research
and development activities also are encompassed.
The substances or drugs controlled by the Act are placed in five
categories or "Schedules." These are briefly described and illustrated. by the following:
Schedule I. This covers certain opiates (including some
isomers, derivatives and synthetics) and hallucinogenic substances
(such as LSD, marijuana, etc.) for which there is a high abuse potential. These also differ from substances in other Schedules by
having no current acceptable medical use in treatment.
Schedule II. Includes certain opiates and opium alkaloids;
most narcotics of the former Class A group; stimulants such as
straight amphetamine and methamphetamine and some of their combinations, phenmetrazine, methylphenidate, etc. These drugs have
a high abuse potential.
Schedule III. Covers depressants, including certain barbiturates; nalorphine; straight paregoric and narcotics of former
Class B, etc. These drugs have less potential for abuse than
those in II.
Schedule IV. Includes certain depressants such as chloral
hydrate, meprobamate, certain long acting barbiturates and such
17
314-300 0 -80 - 3
drugs having a lower potential for abuse than those in Schedule
III.
Schedule V. Preparations which contain limited quantities
of narcotic drugs and include one or more non-narcotic medicinal
ingredients (such as paregoric combination products) for which
there is lower potential for abuse than Schedule IV.
Schedule V at present largely relates to some older combination
products. Deterrents to the development of new products that
might enter Schedule V include the FDA regulatory hurdles to obtaining approval of efficacy claims for combination products, and
manufacturing and record controls required for certain ingredients--such as codeine. New combination products of old drugs
become new drugs and the difficulties in satisfying regulatory
requirements for combinations are likely to make it economically
less attractive to develop new products of this class.
Schedule I substances importantly differ from other Scheduled
materials in having no current accepted medical use in treatment.
The scheduling of pharmacologically active substances in this
category also makes it less likely that legitimate medical uses
will be sought and developed. Limited access to materials and increased risks and potential liabilities for sponsors and investigators would constrain investigations of such agents in human subjects. There also are ethical problems involved in the use of
some of these substances except in very serious conditions.
Schedule I at present may be too broad and heterogeneous a category. Should LSD and marijuana, for example, be in the same
Schedule? The first has a much greater known potential for harm,
the latter has a much greater incidence of use. Although substances in this Schedule have no current accepted medical use,
does such classification virtually foreclose investigations of
possible uses of all substances in this class? Should there be
subschedules within I so that certain present or future substances
within the broad category would be differentiated on such bases
as degree of possible harm from infrequent use, ease of access by
abusers, and extent of the abuse problem, and the like? At least
one substance in Schedule I, tetrahydro-canhabinol from marijuana,
is under consideration as a possible therapeutic agent. If a substance in Schedule I were shown to have merit in serious or terminal illnesses, it might be rescheduled in II. However, this would
require some sponsor to assume a number of unappealing risks with
little potential for reward.
An indirect deterrent of scheduling to the development of new
drugs, particularly with Schedule I substances, relates to the constraints on the use of such substances or related materials as
chemical components in the synthesis of other possibly useful products. Prototype substances in Schedule I obviously are pharmacologically active. However, constraints associated with compounds
categorized by broad Scheduling definitions inhibit the traditional
inclinations of medicinal chemists to use these substances as ingredient starting points or even as models for molecular
18
modifications in the search for new useful medicinal agents. For
example, under Scheduled tetrahydro-cannabinols there are included synthetic substances with similar chemical structure and
pharmacological activity. Pharmacological activity often appears
as a multicomponent profile within which all components are not
expressed equally among different compounds of purportedly similar structures. Furthermore, among molecular analogs, homologs
or isomers, a chemist often, with equal logic, can relate important points of similarities or dissimilarities among so-called
similar compounds, and make equally fallible predictions as to
pharmacolgically anticipated properties. Class scheduling language that covers as yet unstudied "related" substances can unnecessarily constrain the use of such substances either as starting ingredients or as models in the search for new drugs.
A new drug comes into use through three broad stages--discovery,
development and delivery (1,2). Drug discovery encompasses those
activities that result in identification of a new drug candidate
or new use of a known drug. Drug development covers the range of
activities from point of discovery or selection of a new drug
candidate that appears to merit clinical evaluation, to release
of the product for commercialization. Drug delivery includes
manufacture, distribution, purchase, and conveyance of the drug
product to the patient. Although science and economics had been
the dominant influences on the relationship among these components, in recent years political considerations also have assumed
a major role. In examining the economics of any new drug development, the associated economics of discovery and delivery must
be concurrently considered before a decision can be reached as to
the merits of entering the field to begin with. The impact of
Scheduling would become more visible on economics as one moves
from discovery through development to delivery. If the economics
of delivery are unfavorable, a mission-oriented discovery program
would not be justified. An accidental or serendipitous discovery
might, of course, change the picture. In any event, the economics
of delivery would likely compel a decision as to whether or not
to try to develop a product regardless of how the new drug candidate was discovered, With drugs likely to be scheduled, the econonics of delivery are just that much more complicated.
The effects of Scheduling should be evaluated not only in terms
of current drugs and their categories and the likelihood of similar new drugs falling into the same category, but one also should
do some speculating as to how impending regulatory changes and
attitudinal trends that may create new regulations might affect
the economics of new drug development and delivery. Since the
development track is likely to be a long one for a potentially
classifiable new drug, the anticipation of changed ground rules
and uncertainties surrounding such can serve as a deterrent.
There are already so many uncertainties associated with the development of any new drug, that the likelihood of more strigent new
regulations or interpretations of existing regulations in the
area of Classification of drugs can only be inhibitory to new
development.
19
A substance that is considered as a candidate for entry into a
new drug development track and which presently can be anticipated
to be subject to Classification should be examined in terms of
the kinds of contraints associated with Schedule IV as a minimum
and Schedule II as a possibility. Schedule IV drugs require
registration, a narcotic permit, additional record keeping,
greater security in storage areas, and certain limits on refills;
Schedule II additionally demands more stringent record keeping,
uses of special order forms, more elaborate security in storage,
no refills, and imposes manufacturing quotas. Deterrents to development increase in major quantum leaps as one moves from a nonscheduled to a Schedule IV to a Schedule II drug. The intermediate Schedule III appears closer to IV than to II in its economic
impact.
Any new drug having some effect on higher centers of the central
nervous system is potentially a candidate for classification.
Inhalation anesthetics are not included. Non-drug substances such
as volatile solvents (as in sane glues) are subject to hazardous
abuse by inhalation, but regulation here would be virtually unenforceable. Alcohol and tobacco also are outside the Classification system, but subject to widespread abuse. For that matter,
how about coffee and caffeine? Imposed regulations frequently
are less related to the magnitude of the target problem than to
the social-political acceptance of the regulations.
Any strong analgesic, sedative, hypnotic or stimulant becomes a
certain candidate for Classification. It will become increasingly difficult to exclude any centrally acting analgesic from future
Classification as such products are likely to fail FDA efficacy
requirements unless their effects are substantial, in which event
they become almost certain candidates for Classification. Propoxyphene was placed in Schedule IV in 1977, and recently has
been the subject of consumer activist pressure to place it in
Schedule II. Pentazocine, first marketed some 10 years ago with
clinical evidence of relatively low abuse potential, has more
recently been subject to abuse and entered into Schedule IV.
The rationale for scheduling becomes further complicated when one
considers that abusers of drugs frequently practice polypharmacy.
Pentazocine is being taken along with the antihistamine pyribenzamine as a substitute for heroin. Almost any CNS depressant becomes a more dangerous drug when taken with alcohol. Should a
drug be Classified as dangerous largely because its abuse is promoted by combination with other substances? In the recent report
by the Institute of Medicine entitled, "Sleeping Pills, Insomnia
and Medical Practice" (3) it is suggested that control of the
availability of drugs should take into account the hazards of combination with other drugs or with alcohol. Secretary of H.E.W.
Califano a month ago on May Day told the National Council on Alcoholism that, "We are increasingly concerned about the dangers of
alcohol used in combination with certain other drugs" and that
H.E.W. "will take major steps to protect the public against the
special dangers of combining alcohol with other drugs." He has
20
asked FDA to compile a list of commonly prescribed drugs that may
present health hazards when used with alcohol. This could be
quite a list. Further, since public access to alcohol and its
consumption is even beyond H.E.W. control, the likely target for
further controls are drug products. We may even have a new basis
for Classification anticipated on the potential for abuse in
combinations.
An impending regulatory change with economic repercussions would
derive from sections of the latest (1979) version of a proposed
"Drug Regulation Reform Act" originating with Senator Kennedy and
his Staff. Senator Kennedy considers the post-marketing surveillance provisions a most important feature of the proposed
Bill. Pertinent to the issue of controlled drugs, the Bill proposes that additional scientific investigation also might be required if the drug has known or suspected (emphasis added) risks
or is subject to abuse. The drug sponsor would bear the cost.
It is generally recognized that we need better means for examination of the performance of certain kinds of drug products in the
period immediately following their market introduction--particularly from the perspective of safety. There is a Joint Commission
for Prescription Drug Use presently investigating the possible
means for improving post-marketing surveillance of new prescription drugs. Post-marketing or so-called Phase IV studies are
nothing new for the pharmaceutical industry, and do consume significant resources. This is likely to increase. Greater regulatory formalization of such studies with inclusion of extensive
industry surveillance of use by physicians will, of course, add
considerably to over-all costs of new drug development and early
delivery and particularly so with drugs suspected of an abuse
potential. There also can be a self-defeating aspect to highly
formalized requirements for post-marketing surveillance. The
busy physician will tend to refrain from using a new drug for
which he will have to spend additional time with reporting forms
or other formalities covering use of the drug--with the result
that the incidence of use will be restricted and much more time
would be required to gain experience with patient numbers. These
several points only illustrate the uncertainties deriving from
future changes in regulations which will add to the complexities
of development and delivery of new drugs that might be subject
to abuse.
Many factors contribute to the economic profile of discovery, development and delivery of any new drug. The likelihood of Scheduling only adds to or complicates this, particularly with such
drugs as analgesics, sedatives, tranquilizers, stimulants (antidepressants?), certain antihistamines--or almost any CNS-active
drug.
Discovery
Since the mid-1950's, the search for new leads among compounds
with possible CNS effects has included screening programs involving a battery of presumptive tests, frequently beginning with
21
response profiles in the mouse and progressing to more elaborate
tests in other animal system. In more recent years, screening
approaches also have involved mechanistically presumptive biochemical tests. Screening methodologies for hypnotic and analgesic propensities go back further in time. Since lab animal
model systems usually are developed around responses observed in
these animals from drugs with established properties in humans, a
limitation of most such laboratory presumptive tests is that they
tend to uncover leads to candidate drugs with properties rather
similar to those drugs already available. Novel leads among
many kinds of drugs have arisen in the course of observing the
performance of new drugs in man while using them for same other
purpose. This "discovery in man" applies equally to unexpected
undesirable as well as desirable properties. Among such undesirable properties have been characteristics leading to abuse.
Although animal pharmacological profiles suggesting abuse potentials can be derived from certain drug categories such as
opiate related analgesics, other CNS active agents such as minor
tranquilizers and moderately potent analgesics have not been as
readily assessable. Even more difficult is the prediction of
abuse potential for drugs directed to replacement for abuse drugs
in the course of treatment. The drug discovery process lacks
adequate lab animal model systems for early detection of abuse
potential in the laboratory--except among drug categories already
established to have distinct abuse potentials. Among these latter, such as strong analgesics, there has been an understandable
growing reluctance in the pharmaceutical industry to initiate or
continue exploratory new drug discovery programs.
Drug Development to Delivery
If certain programs in drug discovery are inhibited, this obviously will spill over by providing fewer new drug candidates for
development. The feed-back relationship also mans that the more
complicated the development track and less rewarding the delivered result, the less will be the motivation for such missionoriented discovery programs.
There are considerable differences in development tracks among
categories of drugs aside from questions of abuse potential. A
new antibiotic, anti-cancer drug, certain diagnostic agents, and
the like, can be developed with investment of less time and resources than for example a new anti-inflamatory agent or cardiovascular drug. A new drug to be used infrequently in individual
patients, or for use in serious illnesses for which other treatment modalities are of limited value, or for debilitating conditions for which no drug is available-is likely to require a less
lengthy development time than a drug requiring chronic administration in a condition for which other drugs are available, or
for a drug which perhaps may be considered only to improve
quality of life. Drugs with suspected abuse potential, of
course, can be expected to have long development tracks.
22
Certain regulatory trends are likely to further increase the
development complexities for all new drugs, and especially CNSactive drugs. The FDA has taken positions implying that we don't
need certain new drugs, or don't need them expeditiously, unless
they provide a distinct advance in therapy. Although FDA does
not have a statutory base enabling it to issue regulations requiring evidence of greater relative efficacy of a new drug in
reference to available drugs as a basis for approval of the new
drug, there are informal modes for practicing such a philosophy.
FDA credits itself--and in a couple of cases with justification-with expediting regulatory approval for marketing of new drugs
which it considers to-constitute substantial advances in therapy.
The other side of the coin is that new drugs which The FDA considers to be minor modifications of existing drugs or to provide
little improvement, will languish further in the approval process.
Often, the ultimate value of a new drug cannot be assessed until
that Product has had more widespread evaluation under conditions
of practice. Although one might sympathize in principle with the
selective expedition of approval of certain drugs, there is little
comfort in permitting such a judgment to rest with a government
regulatory agency. Certainly, any new drug under a shadow of
abuse potential is unlikely to be expedited and would be assured
to require a Phase IV surveillance.
As noted earlier in the mention of Class I substances, there are
likely to be regulatory constraints--both from FDA and DEA--on
new drugs with purported similarity of chemical-structure or
pharmacological activity with that of an abused drug. Purported
similarities and differences usually involve value judgments.
Examples abound of chemically similar compounds with markedly
different pharmacological properties and dissimilar chemicals
with comparable pharmacology. Each substance ideally should be
evaluated on its specific properties; however, individual regulatory attitudes on this subject will vary widely and unpredictably.
Laboratory research programs oriented toward some discovery mission may take as little as three years or as long as ten or more
years. Although discovery research is highly risky in terms of
yield, it is more controllable in terms of resource commitments.
Development introduces less controllable economic risks. Perhaps no more than one in ten of new substances launched in a
development track becomes a deliverable drug product, and with no
assurance of its commercial success. Following discovery, development time in the laboratory may begin from one to two years
before submission of an IND and preliminary testing in humans.
With a CNS-active drug, or with most drugs involving chronic administration, development activities are likely to occupy eight
to twelve or even more years including the period an NDA is pending. Development costs rarely will be less than $l million per
year per drug candidate and be appreciably higher during certain
development phases. This excludes the prior costs of research
leading to the discovery and research that did not yield drug
development candidates.
23
There are many component activities in a drug development that
have increased in terms of unit costs and in elaborateness of implementation.
A constructive derivative of the 1962 Drug Amendments was the improvement in the design and implementation of
clinical studies and the quality of the resultant data. The time
and costs for conducting such studies and processing the results
have grown rapidly and continually. Too frequently these have
been extended or complicated by conflicting value judgments as to
what comprised adequate and well controlled clinical studies, or
the statistical interpretation of what might be considered significant, or changes in demands arising from changes in regulations
or of regulatory personnel. With certain drugs, such as analgesics, difficulties in clearly establishing efficacy and assessing
the potential for habituation, addiction, or other level of abuse,
substantially can complicate clinical assessment and materially
increase development time and costs. In addition to increases in
resources required for support of clinical studies are increased
costs of concommitant laboratory safety studies. This of course
applies to all new drugs. The so-called Good Laboratory Practices regulations have further increased costs for drug development, with a dubious cost-benefit relationship. Among new drugs
with a potential for abuse, further developmental burdens are imposed by DEA regulations governing registration of researchers,
security requirements of manufacturers, etc.
Prospective development time and cost estimates for any new drug
are made and modified at periodic intervals during a development.
This is necessary as the properties of the new drug candidate become better defined and as unforeseen events change the economics
of the development. Acceptable development burdens for any new
product will vary with time and the perceived needs and opportunities of the development sponsor. Opportunities and costs constitute such a shifting relationship that development cost estimates
become subject to frequent changes. A most difficult decision to
make and implement is that of terminating a project for economic
reasons. Scientists in particular will accept termination of a
development if the product appears to be ineffective or has unacceptable adverse effects, but may find it difficult to accept
a termination based on anticipated economic deficiencies. With
any new drug candidate, major variables contributing to the economics of development include:
a.
b.
c.
d.
e.
f.
Unit costs of clinical studies in phases I, II, and III.
Investment in material and facilities for preparation of
investigational drug supplies (and later for manufacture of the commercial product).
Any special laboratory safety studies in addition to
usual requirements.
Opportunities for introduction of the new product outside the U.S.
Time required to develop marketing in the U.S.
Probability of competitors earlier entries with similar
products.
24
For a drug with recognized abuse potential, the first three
are likely to require a greater economic commitment and have an
overall effect of increasing development time. Increased time
results in a compounding of the accumlating economic investment. For example:
a.
Costs incurred prior to delivery (drug marketing) become cumulatively compounded in the order of 12% per
year and may be higher as costs for money can rise.
An investor would be foolish to place money in a development venture in which his past costs are compounded
in double digit figures, his chances are appreciable of
losing his past investments, and his potential return
limited to a short period of time. One could more
prudently direct new product development to a field
with less risk, or just invest in commercial paper.
b.
The return on investment must be adequate during the
period the innovator has a sole-source market presence.
This usually means during life of the patent. The
longer the development time, the shorter the residual
patent life. The profitable patent life is further subject to erosion for any drug requiring a Phase IV postmarketing surveillance. Any new drug with a shadow of
abuse potential is likely to carry a Phase IV requirement. As abuse potential becomes suspect with more
categories of drugs, this Phase IV shadow will lengthen.
A post-marketing stricture of three to five years (or
more superimposed on a long development time could consume the patent life of the new drug.
c. The post-patent entry of non-innovative manufacturers
would reduce the innovator's income with multi-source
competition at about the time the expensive risks already had been assumed by the innovator. Non-innovative
manufacturers can enter if it appears the drug is becoming successful, or avoid it if it is not, and have
assumed no prior risks in the process. contributing to
this has been FDA's practice of facilitating multisource entries, largely as apolitical expediency purportedly in the public interest. With drugs in Class
II, there also are manufacturing quotas established by
regulation.
With a successful Class II drug product,
the entry of manufacturers in addition to the innovator
would result in a fragmentation of quotas and a further
reduction in the innovator's return.
d.
Long development time in the U.S. can reduce market penetration abroad. It has become increasingly difficult
for American companies to introduce products in some
foreign markets prior to obtaining FDA approval for use
in the U.S. Regulatory strictures in this country on
export of products from the U.S. prior to U.S. NDA approval, and FDA dictation of labeling for products going
25
overseas further place U.S. companies at a disadvantage
in worldwide competition. This can be a greater problem
for drugs more likely to be subject to abuse in a U.S.
culture than in other countries.
At any one time, an innovative pharmaceutical company will
have access to more potential new drug candidates for development
than it has reources to develop. This is as it should be and it
does require its management to make selections with considerations
of the economics of product development and delivery. Placing
new categories of drugs in Class IV or escalating Class IV prototypes to Class II, will tend to be an economic disincentive to
selection of analagous substances for development. Further, as
the strictures of Classification require the assumption of greater economic risks both in development and delivery, there is a
further shrinkage in the base of numbers of companies with the
resources to assume such risks.
In 1976 and 1977, in the U.S., there was a two-year total of 36
new single drugs, diagnostic agents and biologicals marketed for
the first time (4). Of these, new single drugs comprised 7 in
1976 and 8 in 1977. With an industry R. and D. expenditure of
the order of $1 billion in each of those years, the U.S. marketed
new product output appears small. This reflects on the resources
required to bring a new drug or related health product to market,
the resources to maintain existing drug products, and expended
resources that have not yet or will not yield marketed products.
By the time a new drug is released for marketing in the U.S., that
drug product usually will have had several years of use experience
in sane other countries. That experience helps to anticipate the
success or failure of the new drug in the U.S. in terms; of medical
performance relative to existing drugs and may detect adverse
reactions of such incidence that can be observed only from wider
use than experiences in development. Successful use abroad, however, is no guarantee of success in the U.S. for a variety of
reasons, often hinging on differences in medical practice concepts. Particularly limited may be the value of prior use abroad
in assessing the potential for abuse of anew drug. The U.S.
appears to have a particularly large, active, and imaginative
drug abuse sub-culture. There also appears to be a gray-area of
transition of abuse from "legitimate" prescription-inflicted to
illegal self-inflicted. This brings about changes in specific
drug abuse preferences. In the recent report by the Institute
of Medicine(3) the impression is left that benzodiazepines are
replacing barbiturates as abuse culprits. With abuse of a new
drug, the regulatory solutions usually involve changes in product labeling from FDA and drug Classification by DEA. The
economic consequences on the innovative manufacturer can then be
quite substantial. If this solves the problem, let the chips
fall where they may. Unfortunately, such solutions may be shortlived as the immaginative abuser will turn to something else.
26
The Institute of Medicine report, for example, acknowledges that
controls have reduced the incidence of suicides from barbiturates,
but with little effect on the numbers of drug-induced suicides.
Concluding
Remarks
During the past twenty years costs of doing business of all kinds
have markedly increased. This is particularly true of businesses
and industries subject to considerably increased regulations, of
which the innovative prescription drug industry is one of the
most affected. Present society is far too complex to live without regulations. Regulations, like medicine, should be prescribed
within effective dose ranges; over-medication and over-regulation
both are dangerous to someone's health. Clinical pharmacology
has made more sophisticated the evaluation of optimum dosages of
our medicines. We have yet to enter the threshold of objective
evaluation of optimum dosages in regulations.
With the human propensity for self-abuse, it is unrealistic to
propose that certain drugs with abuse potential not be controlled
by regulations. With human ingenuity in discovering new routes
to self-abuse, it also should be recognized that there are
limits as to how far a government can go in protecting people
from themselves. Regulators also can be self-serving and can
rationalize the need for more regulations. What would have
seemed ludicrous in 1962 as future regulatory extensions of the
1962 New Drug Amendments, in 1979 are regulatory realities. It
would be challenging to speculate on the scope of regulations in
1987 based on the Drug Abuse Prevention and Control Act of 1970.
The discovery of opioid peptides such as -endorphin and
enkephalins and their possible madiator roles is suggesting an
ultimate common or similar receptor route for analgesic effects
of as diverse a group of agents as opiates, acupuncture needles
and placebos (5). Taking regulatory innovation to logical conelusions, will we see new abuse classifications proposed to
cover needles, placebos, and then just as logically, psychiatrists?
In the development of new drugs subject to possible abuse, the
burden of classification added to that resulting from new drug
regulations in general may become the economic straw that broke
the development camel's back. A productive approach at this
time could be to resolve regulatory disincentives to the development of new drugs in general and caution prudence in the extension and implementation of regulations governing drug classification. Disincentives derive not only from known regulatory
restraints, but perhaps even so from concern with the uncertainties of threatened further regulations.
References
1.
Cavallito, C. J., "Interactions of Science, Economics and
Politics in Drug Discovery, Development and Delivery," Drug
Development Communications, 1, 259-285 (1974-1975).
27
2.
Beyer, K. H., "Discovery, Development and Delivery of New
Drugs," Spectrum Publications, Jamaica, N. Y., 1978.
3.
"Sleeping Pills, Insomnia, and Medical Practice," Report of a
Study, Institute of Medicine, N.A.S., Washington, D. C.,
1979.
4.
de Haen, Paul, "New Drug Parade, 1976-7," Drug and Cosmetic
Industry, 123, 68, 123 (1978).
5.
Levine, J. D., Cordon, N. C., and Fields, H. L., "The
Mechanism of Placebo Analgesia," The Lancet, Sept. 23, 1978,
654-657.
AUTHORS
C. J. Cavallito, Ph.D.
Adjunct Professor
School of Pharmacy
University of North Carolina
Chapel Hill, North Carolina 27514
28
The Impact of Regulations on the
Development of Psychoactive Drugs
Lasagna, L.
Dr. Richard Crout, the capable Director of the Bureau of Drugs
of the Food and Drug Administration, said four years ago that regulation must inevitably "cut down on innovation" in the development
of new drugs. It is hard to envision a facilitatory role for most
regulation. Furthermore, I believe that it is important for people
to recognize that regulations are really more important than laws
these days. It has been said that we have become a nation governed
by men rather than by laws, and I believe there is a great deal in
that. This is true for a variety of reasons. To begin with, laws
are more general than regulations. Second, one doesn't need to have
laws passed in order to have regulations promulgated. Third, regulations can be invoked at many different layers. For instance, one
can have regulation at the level of institutional review boards
(IRB'S). Such IRB's vary considerably in makeup, functioning, and
toughness, but they can at times provide major obstacles to research
and new drug development, even if only at the level of delaying
research. Considerable mischief is possible if an institution
decides, in an act of self-flagellation, to appoint "public" representatives of the kind who believe that the only fun in life comes
from using dental floss three times a day, jogging, and drinking
Perrier water, and who love dogs and cats but hate doctors and
research.
Another layer of regulation comes from the Department of
Health, Education and Welfare, as exemplified recently by the regulation that information would have to be given when informed consent
was being obtained, concerning the availability of compensation
for physical. injuries suffered by research subjects. There are also
regulations that can he promulgated by the Drug Enforcement Administration, or by the states. For instance, my own state of New York
is about to repeal. the Hatch-Metcalf Act, which in the past has
allowed a few dogs and cats to be diverted from pounds to research
laboratories. The future consignment of all these animals to the
gas chamber will in all likelihood triple tie cost of large animal
research.
Regulations may also result as the consequence of the deliberations and recommendations of such groups as the National Commission
for the Protection of Human Subjects of Biomedical and Behavioral
Research, or the Institute of Medicine.
Finally, and most important in regard to new drug development,
the Food and Drug Administration represents an extremely influential
source of regulations.
29
To exemplify the interrelationship between several of these
layers, let me discuss some recent happenings as a result of recommendations made by the National Commission for the Protection of
Human Subjects and the Food and Drug Administration.
The Commission made a number of recommendations in regard to
IRB'S. One was that the Department of Health, Education and
Welfare should be the single agency for the promulgation of regulations relating to the protection of human research subjects. A
second recommendation took up the composition, procedures, authority
and facilities of IRB's, in most instances merely describing what
is currently the case. Still another recommendation described what
should be considered in deciding whether a protocol was acceptable
or not, and a final recommendation defined in fairly permissive
terms what should constitute a quorum for an IRB to make decisions
at a meeting.
The FDA, in turn, came up with recommendations which were much
more stringent in regard to the matter of quorum, which asked
IRB's to assure the validity or reliability of scientific data,
which assigned to the FDA authority to copy records of human subjects, and which limited the ability of IRB's to review and approve
the work of any investigator who had participated in the selection
of an IRB member for the panel.
As Dr. Robert Levine, a distinguished clinical pharmacologist
and member of the National Commission said in an article on this
problem:1 "The FDA has proposed to establish regulations that are
contrary to the letter and the intent of the Commission's recommendations. The FDA proposal expects the IRB to perform some
functions for which it is incompetent - e.g. assure the validity or
reliability of scientific data. It instructs the IRB to collaborate
in such dubious activities as facilitating access to patients'
medical records. It burdens the IRB with the requirement to perform
various tasks of dubious value. And it prescribes heavy penalties
for noncompliance with its requirements."
Santayana long ago recommended that we learn from history lest
we repeat the errors of the past. What does a survey of the past
show?
A lot of unfortunate things have been happening to drug development in recent years, and I believe that many of them can be
attributed to excess regulatory zeal. For instance, a short time
ago our Center for the Study of Drug Development at the University
of Rochester estimated that it took about eight years of human
testing and about $54 million to bring a new chemical entity to
market. Other estimates have put forth a lower dollar figure, but
I believe these are in error because they have not taken into
account the considerable amounts of money spent on chemicals that
never do make it to market. If one simply looks at the R D
expenditures of American pharmaceutical firms over the years and
divides this by the number of new chemical entities brought to
30
market, I think one will come up with a figure that is close to
our estimates.
The most recent data available to us, namely those for the
year 1976, show that the total time has now gone up to nine years
for the human development phase. About six and a half years of
this is the time spent from the filing of the IND to the filing
of the NDA, and the rest of the time is spent in processing the
NDA. The latter phase has remained fairly static at about two
and a half years for some time. It might be argued by the FDA
that they are not responsible for the increasing length of time
spent in the first phase, but I believe that it is foolish to
assert that expectations about what will be required in the NDA
phase do not have an impact on how much work is done during the
earlier phases. This long duration of gestation obviously means
a considerable decrease in the effective patent life for compounds
that finally make it to market.
It has also been said that an increased amount of R D money
is spent in nonproductive, so-called "defensive", research, but
since I don't have any hard data on that point, I shall say no more
about it.
I also sense that in conjunction with this increased duration
and expense of drug development, many firms have shown a decreased
adventuresomeness in research. This is not unique to the drug
industry. It is also being seen at the National Institutes of
Health, and in both cases is a reflection of the decreased amount
of funds available for research. It used to be said that the NIH
peer review system was one of the noblest developments of American
science. We used to believe that the system worked beautifully
in deciding priorities. In fact, it seemed to work well because
there was enough money available to eliminate the need for priorities. Now that the need is there, one Finds a good many deficiencies. It is not at all infrequent to hear of study sections
turning down research because it looks "chancy", and not predictable in its outcome.
A special side issue is the decreasing likelihood that any
company will pursue so-called "orphan drugs", i.e. drugs intended
for the treatment of patients with diseases that afflict so few
individuals that commercial return will never be adequate enough
to pay for their development.
Our data also show a decrease in the rate of new chemical
entities being taken into man. For about a decade the number
remained static at about fifty per year, but in the last two years
of our survey, i.e. 1975 and 1976, this number dropped to about
half of the former plateau. The number of IND filings has gone
down from a level of forty to fifty per year to about twenty,
and it is particularly distressing to note that whereas most of
the new chemical entity IND filings by U.S. firms used to be for
chemicals originated by these firms themselves, in 1976, for the
31
first time, more than one third of the filings were for NCEs not
originated by these firms.
More and more new chemical entities are being studied abroad
for the first time. This number used to be minuscule a decade ago.
It has risen gradually to a high of 44% in 1976, and my guess is
that it has risen still higher during the years since then.
All these trends might not be so depressing if one could look
forward to a counterbalancing of regulatory zeal by external advice.
This is unlikely to happen, however, not through any fault of the
FDA, but because the current administration has vowed to cut back
on advisory committees, and because discussions between HEW and the
Justice Department have defined conflict of interest in a manner
unlikely to encourage the use of the best advisors.
So much for the past. What about the future? One can foresee
developments that are likely to add to the burdens already described.
To begin with, there will probably be an increasing interest in
developing patient package inserts for drugs prior to their marketing. This will almost certainly delay still further the advent
of new chemical entities on the market.
The advent of the so-called "fast track" and "slow track"
systems in the FDA poses new problems. First of all, the judgment
as to whether a drug is really a major advance is hardest to make
at just the point when it is being made -- when it first enters
the FDA evaluative system. Second, however, directing the attention
of reviewers in the FDA to certain favored drugs will almost
certainly mean a slowdown in the evaluation of the chemicals unlucky
enough not to be so judged.
There will almost certainly be more post-marketing surveillance
studies, which will add to the expense of drug development. I have
long argued in favor of post-marketing surveillance, but not of
the kind which is currently going on. There are many things about
a drug's usage that can only be determined after it is marketed,
such as appropriateness of use, degree of misuse, drug abuse,
results of gross overdose, etc. What is being measured, however,
is primarily the adverse drug reaction performance of a drug, with
a view towards checking out suggestions of trouble in the premarketing phase, lest the regulators be embarrassed at the approval of
a drug that turns up unpleasant surprises later on in its history.
Such studies are extraordinarily expensive and have thus far
yielded little of novel interest.
There will certainly be more "gumshoeing" by FDA investigators
who, despite the fact that they are not supposed to be engaged in
"fishing expeditions", but only examining records where there is
good reason to expect fraud, will be in fact looking for whatever
they can find unless halted by investigators or institutions.
Furthermore, this problem will be compounded by the inclination
of certain pharmaceutical firms to ask investigators to sign
32
general release forms about patients' records, providing even
greater authority than is stipulated in the regulations. If a
firm takes this attitude, and only awards contracts or grants to
investigators who are willing to sign such releases, it will
penalize those investigators who quite properly are more concerned
about the privacy of patients’ records.
Finally, there is the extra obstacle involved in demands by
the FDA that a new drug be evaluated for all sorts of indications
other than ones of major interest to the manufacturer. It can be
argued, quite correctly, that an interesting new anti-inflammatory
analgesic will likely be used not only for rheumatoid arthritis
but for osteoarthritis, ankylosing spondylitis, and juvenile rheumatoid arthritis even if the drug has only been well worked up for
adult rheumatoid arthritis and the manufacturer only wants to
promote it for that purpose. Yet, to demand that all of these
studies be done before a drug is marketed will mean a delay in access
of patients with rheumatoid arthritis to the drug, as well as penalties for the manufacturer, who cannot possibly begin to earn back
any money on his investment until all of the studies are done.
What are the roots of all these troubles? One root is
stupidity. The FDA is no different from the university world or
the industrial world in this regard. There is much more incompetence in this world than there is unadulterated evil, regardless of
what romantic people would like to think. I am at least part of
the time a university bureaucrat, and honestly believe that my own
mistakes are almost invariably the result of stupidity.
But there are also other motivations. There are individuals
in regulatory agencies who are ambitious, arrogant, or motivated
by a psychotic hate of industrial producers. Some believe that
they are better equipped to tell people what is good for them than
are people themselves able to judge this on their own behalf.
This
is depressing to those of us who believe that government should
act as an umpire and not as a dictator.
Perhaps most important of all, however, is the absence of any
real feeling in the FDA for cost-benefit analyses. It is all too
easy for a regulator to promulgate regulations without assessing
fully the implications of his moves. If one looks, for example,
at the "good laboratory practices" that were prescribed for toxicity testing in animals by, or on behalf of, industrial sponsors,
it is clear that the extra work and expense involved in meeting
these regulations would spell the doom of any such activities in
most universities, since universities do so little of this work
that most of them would give up the opportunity to do it rather than
shoulder the considerable expense involved in meeting the rather
arbitrary requirements.
An especially depressing aspect of bad regulations is that
they are very hard to undo. The advice by some that one repeatedly take the government to the legal mat is not really appealing.
33
314-300 0 -80 - 4
It is just not very realistic to engage in litigation every time
one runs across a foolish or even dangerous regulation.
More sensible would be an opportunity to have impact on those
formulating regulations before the latter are issued for a first
view by the general public. Although the preliminary publication
of regulations in the Federal Register in theory allows for their
change on the basis of comments received by the government such
changes are probably harder to achieve than would be the case if
the regulations had not yet been published. That is only common
sense and human nature.
The government quite correctly would argue back that they
cannot show such drafts to a few people because then they would have
to show them to everyone. I do not, however, see why our society
cannot set up advisory committees of people representing all
strata of opinion about regulation who would have a chance to
express their opinions on proposed FDA regulations before they
were ever published in the Federal Register.
In conclusion, therefore, I believe that our current "drug
lag" is attributable to excessive regulation, and that on
balance this is not in the interest of the American public,
although I would admit that I cannot easily quantify in toto
the benefits and the risks that have resulted from this drug lag.
I acknowledge that there are others who say that we don’t have a
drug lag, but a "death lag", and that the public is better off
because drugs are so expensive to develop and take so long to
reach the market. I am sure that they believe that as devoutly
as I am convinced of the opposite.
On the other hand, I believe that the most parsimonious explanation of what has been going on is that the drug lag both exists
and is deleterious, that regulation is at the base of the changes,
and that a reversal of the present trend would reverse these
untoward effects.
It has been said that a pessimist is someone who says that
things can't possibly get any worse than they are, and that an
optimist is a person who says, "Oh yes they can!".
I am an optimist, but not really that kind of optimist. I
agree that things can get worse than they are, but don't believe
that they need to get worse. They will, however, never improve
unless influential segments of our society demand that they change.
On balance, despite heroin and thalidomide and other untoward
results of drug development, the development of psychotropic
drugs and of drugs in general have been fantastically beneficial
for our society. I see no evidence that we have come to the end
of that road unless as a society we insist on putting insuperable
obstacles in our own way.
34
1.
Levine, Robert J. Changing Federal Regulation of IRBs: The
Commission’s Recommendations and the FDAs Proposals. IN :
IRB Vol. 1, No. 1, pp. 1-3. March, 1979.
AUTHORS
Louis Lasagna, M.D.
Department of Pharmacology and Toxicology
University of Rochester School of Medicine
35
The Influence of the Mode of
Morphine Administration on
Tolerance and Dependence
Cochin, J.; Miller, J. M.; Rosow, C. E.; Grell, R.;
Poulsen, J. L.
For the past several years, we have, with the support of the
Committee on Problems of Drug Dependence, been exploring the
effects of implantation of morphine pellets on the development
and loss of tolerance and dependence in the rat and comparing
this method of drug administration with a series of injections
designed so as to approximate the amount of morphine delivered
by the pellets. We have also compared the effects of injections
and pelleting on both the analgesic and temperature responses
in the mouse. Because this is the last report we will make to
the Committee about the work that it has supported, we are taking
the liberty of summarizing some of the experiments that have been
described at previous meetings of the Committee before reporting
some new findings obtained in the past year. Figure 1
LOSS OF TOLERANCE IN THE RAT
PELLET vs INJECTION
Analgesic response to a single injection of 15 mg/kg MS at
the days indicated an the abcissa.
36
(Cochin et al, 1978a) shows the comparison of the effects of a
series of injections, pellet-retention and pellet-removal on
tolerance to the analgesic hot-plate response in the rat as elicited by the injection of a 15 mg/kg test dose of morphine sulfate at the indicated intervals. Although the degree of tolerance after three days of injections or after three days of
pellet in situ is maximal, this tolerance disappears significantly more rapidly in the group of animals in which the pellets
were removed than in the groups of animals that received injection or in which the pellets were retained. However, four weeks
after pellet removal or termination of injections, the degree of
tolerance is identical for all three groups, although even that
long after pellet removal or termination of injection the animals are still slightly tolerant. We believe, therefore, that
although there are quantitative differences in the rate of
recovery of drug sensitivity, probably related to the amount of
drug released by the pellets over time, pellet implantation is
not qualitatively different from other forms of drug administration.
We also investigated the onset and disappearance of physical
dependence using the three-hour weight loss after naloxone-precipitated withdrawal as an index of the presence of and severity
of physical dependence. Although we observed other signs of
physical dependence such as ptosis, wet-dog shakes, jumping,
diarrhea and tooth chattering, we found weight loss to be the
most easily quantifiable and very sensitive as well.
Figure 2
WEIGHT LOSS AFTER PRECIPITATED WITHDRAWAL
PELLET vs INJECTION
Onset and disappearance of physical dependence in the rat as
measured by 3-hour weight Loss after a nuloxone (10 mg/kg) challenge given at the indicated times.
* = P < 05 compared to placebo-pelletted group.
37
summarizes the results obtained in those experiments. Three
days after the beginning of treatment, all groups of animals
were profoundly dependent on morphine, but the injected group
(broken line) demonstrated less physical dependence than the two
pelleted groups and lost that dependence more rapidly. By three
days after the termination of the injections, there was no significant weight loss after naloxone challenge in the injected
This rapid loss of dependence is probably caused by the
group.
patterns of drug administration and the levels of drug administered during the three days of injections. The group of animals
from which the pellets had been removed three days after implantation also showed rapid loss of dependence, significant weight
loss no longer being detectable a week after the pellets had been
removed (solid line). The group of animals in which the pellets
were allowed to remain (slashed line) showed a much slower return to control values with significant weight loss observed for
at least 12 days longer than the group in which the pellets had
been removed.
We also compared the development and loss of tolerance in the
mouse with respect to analgesia as measured by the hot-plate
Earlier work
assay and by morphine-induced temperature changes.
in our laboratory has shown that it is difficult to induce tolerance in mice to the analgesic effects of morphine by giving
multiple daily injections.
Pelleting has made the demonstration
of the development of tolerance in this species much easier.
Figure 3 shows that mice pelleted with a single 75 mg morphine
LOSS OF TOLERANCE IN THE MOUSE
HOT-PLATE
Loss of tolerance to the analgesic effect of morphine sulfate
(20 mg/kg) in mohphine-pelleted mice. Solid line: single group
of mice tested repeatedly. Broken line: data for separate groups
of mice, each group tested, on only one of the indicated days.
38
pellet will show a significant degree of tolerance for as long
as 35 days after pellet implantation and that animals tested
repeatedly with a 20 mg/kg morphine injection (solid line)
showed a greater degree of tolerance than those that were tested
only once. However, even the pelleted animals that were given
only one morphine injection (broken line) showed residual tolerance 28 days after pellet implantation (Cochin et al, 1978a).
We still have to look more systematically at the degree of
residual tolerance with respect to analgesia in animals in which
pellets are removed after three days. Attempts to show residual
tolerance after a single morphine injection in an unpelleted
mouse have not been successful thus far.
The effect of morphine on body temperature in the mouse is an
assay system which we have used very extensively in our laboratory and which we have described at several previous meetings.
It is possible to show tolerance to the hypothermic effect of
morphine after a series of injections or after morphine pelleting (Miller et al., 1977, 1978; Cochin et al., 1978b). Figure 4 shows
T MORPHINE 160 mg/kg
Temperature response of mice to 160 mg/kg of mohphine at three
anbient temperatures.
the effects of twice-daily injections of 160 mg/kg of morphine
for 50 days at three different ambient temperatures. As can be
seen, the hypothermic effect almost disappears at 20 degrees and
is converted to hyperthermia at 25 and 30 degrees. In pelleted
mice, one can see a more striking reversal of the hypothermic
39
effect and indications of the loss of tolerance a month after
pelleting. The temperature effect can also be used to measure
cross-tolerance either after injections or pelleting.
The studies described above concern themselves with tolerance
to the hypothermic effect of the opioids and opiates. In the
past year we have turned to a study of tolerance to the hyperthermic effect of morphine. It has long been believed that no
tolerance developed to the hyperthermic effect of morphine and
one sees many references to this in the literature. We have
not understood this because even if hyperthermia is a stimulatory effect some tolerance should develop to it and it should
be reversible by the antagonists. At this time we will address
ourselves only to the first point, that of the development of
Since we were never able to see any indication of
tolerance.
tolerance development to hyperthermia in mice that received 160
mg/kg of morphine twice a day for 50 days, we decided to pursue
this further by using morphine-pelleted animals rather than injected animals (Miller et al., 1979). Groups of mice were
implanted with either morphine or placebo pellets and were then
tested at various intervals after implantation. Figure 5 shows
ONE DAY AFTER PELLET IMPLANTATION
Tolerance to the hyperthermic effect of morphine (40 mg/kg) in
mice one day after pellet implantation.
the results obtained one day after the implantation of a 75-mg
morphine base pellet and after a test dose of 40 mg/kg of morphine was administered.
It is evident that there is a significant decrease in morphine hyperthermia at 30° ambient temperature although there is still a discernible effect. Four days
40
after pellet implantation an injection of a 40 mg/kg test dose
demonstrates almost complete tolerance to the hyperthermic effect (Figure 6). We do not believe that these results are
TOLERANCE TO MORPHINE HYPERTHERMIA
FOUR DAYS AFTER PELLET IMPLANTATION
Tolerance to the hyperthermic effect of an injection of morphine
(40 mg/kg) in mice four days afterpellet implantation.
different than those seen after a water or saline injection.
It is, of course, a well known fact that tolerance is a function
of dose as well as time. Figure 7 shows the results obtained
in animals implanted four days previously after receiving a dose
of 160 mg/kg of morphine rather than 40 mg/kg and it is obvious that there is incomplete although measurable tolerance
to the larger dose. The difference between the placebo-pelleted
and the morphine-pelleted mice is much smaller than that in the
groups given 40 mg/kg. Figure 8 shows a return of drug sensitivity in morphine-pelleted animals that received a 40 mg/kg
test dose one week after pellet implantation. One still sees
an attentuated response but it is nowhere near as marked as the
response to the same test dose observed in animals four days
after pellet implantation (Figure 6).
This assay system can also be used to study cross tolerance to
opiates other than that in the implant. When mice implanted
with either morphine pellets or placebo pellets for one week
are given 30 mg/kg of levorphanol there is significant attenuation of levorphanol hyperthermia in the morphine-pelleted
group (Figure 9). The difference between the two levorphanol
curves is almost as great as is the difference between the two
41
TOLERANCE TO MORPPHINE HYPERTHERMIA
FOUR DAY AFTER PELLET IMPLANTATION
Tolerance to the hyperthermic effect of morphine (160 mg/kg) in
mice four days after pellet implantation.
TOLERANCE TO MORPPHINE HYPERTHERMIA
ONE WEEK AFTER PELLET IMPLANTATION
Tolerance to the hyperthermic effect of morphine (40 mg/kg)
one week after pellet implantation.
42
CROSS TOLERANCE TO LEVORPHANOL HYPERTHERMIA
ONE WEEK AFTER MS PELLET IMPLANTATION
Cross tolerance to the hyperthermic effect of levorphanol
(30 mg/kg) in mice one week after morphine pellet implantation.
morphine curves a week after implantation (Figure 8). This is
not surprising since 30 mg/kg of levorphanol is approximately
the equivalent of 40 mg/kg of morphine in this assay system.
The differences between the two curves can also be measured
precisely as shown in Table 1 which lists the areas under the
curves in minute-degrees for the experiments shown in figures
5-9.
It is apparent that both hypo- and hyperthermia are excellent
assays for tolerance and cross tolerance and that one can get a
more quantitative estimate of the degree of tolerance by measuring the differences in response between two groups of animals.
We have also demonstrated that hyperthermia is an opiate
effect to which tolerance develops and some preliminary experiments in our laboratory also demonstrated that hyperthermia can
be blocked by naloxone (Miller et al., 1979).
Finally, we would like to describe experiments using a
technique developed in E. Leong Way's laboratory. We had been
having some problems in removing the pellets because they were
either heavily encapsulated or were in a form whose outline was
very difficult to difine. Dr. William Schmidt, a student of
Dr. Way's, told us about a tecnique in which pellets were
wrapped in small nylon bags cut from a larger piece of pantyhose. Although the exact brand of panty hose is not important.
43
Table 1
THE USE OF AREA UNDER CURVE OF HYPERTHERMIC EFFECT
TO MEASURE TOLERANCE AND CROSS TOLERANCE
IN MICE
Drug Dose
(in mg/kg)
Pretreatment
Area After Drug Injection
(min/degrees)
One Day After Pellet Implantation
MS 40
Placebo Pellets
MS Pellets
128.85
75.75
Four Days After Pellet Implantation
MS 40
Placebo Pellets
MS Pellets
140.85
18.25
MS 40
Placebo Pellets
MS Pellets
175.95
95.40
One Week After Pellet Implantation
MS 40
Placebo Pellets
MS Pellets
120.70
47.57
Levorphanol
30
Placebo Pellets
MS Pellets
121.70
70.70
the mesh probably is. We used the upper part of the garment
which is made up of heavier material than is the stocking
part. We proceeded to wrap a number of pellets and then repeated that part of our earlier experiments in which the pellet was allowed to remain in the rat. To our surprise, we
were able to detect significant dependence as measured by 3-hour
weight loss after naloxone challenge for 52 days after the
implantation of a wrapped pellet. It took 59 days for the
animals to become indistinguishable from controls. This contrasted with the results with implantation of unwrapped pellets
after which it took only 17 days to return to control values
(Figure 2). We then decided to undertake a new series of
experiments which would compare in a systematic fashion the
delivery of morphine via unwrapped pellets or via nylon-enshrouded pellets, using the disappearance of dependence as the measure of drug effect.
44
The animals used in these experiments were adult male WistarLewis rats weighing 250 to 300 grams. All were housed in general animal quarters with food and water freely available.
Three groups of animals were used. One group was implanted
with two 75-mg morphine-base wrapped pellets, another with
two 75-mg morphine-base unwrapped pellets, the third group was
implanted with two placebo pellets. The animals were tested
for dependence at weekly intervals from 7-71 days after implantation of the pellets. Half the animals in each of the pelleted
groups were given a challenging dose of 10 mg/kg of naloxone to
precipitate abstinence, the other half received 30 mg/kg. On
day 50 the group that had received 30 mg/kg of naloxone was
given a dose of 60 mg/kg and on day 57 and thereafter all rats
received a dose of 60 mg/kg of naloxone. The results are shown
in Figure 10. The open squares and circles represent the
WEIGHT LOSS AFTER PRECIPITATED WITHDRAWAL
WRAPPED vs UNWRAPPED PELLETS
Thee-hour weight Loss after naloxone challenge in rats
implanted with morphine pellets either unwrapped or nylonwrapped. The naloxone challenge dose (in mg/kg) is indicated
in the key.
unwrapped pellets, the closed circles, squares and triangles
the wrapped pellets. As can be seen, rats with the unwrapped
pellets return to control values within 14 to 21 days after
implantation, while the animals with the wrapped pellets showed
significant weight loss as compared to the controls through day
50 with both 10 and 30 mg/kg of naloxone, and on day 64 after
a 60 mg/kg naloxone dose (triangle). Except for the first two
test days there is no difference between the effects of 10
45
and 30 mg/kg naloxone challenge doses. One can speculate that
had we given 60 mg/kg instead of 30 all the way along, the difference between these two lines in the graph would have been
exaggerated, but this is something that would have to be shown
experimentally.
With respect to signs of physical dependence other than threehour weight loss our results are as follows: In the animals in
which the pellets were not encased, the only signs seen two
weeks after pellet implantation were diarrhea and ptosis and by
three weeks after implantation, diarrhea and ptosis were seen in
only 20% of all the experimental animals regardless of the challenging dose of naloxone. In the animals which were implanted
with nylon-wrapped pellets, however, the results were quite
different. Nine out of 17 animals demonstrated jumping behavior
42 days after implantation, and this behavior was seen in a small
number of animals for as long as 71 days. A significant number
(6 out of 17) had diarrhea on day 64, not severe enough to
result in weight loss after the 42nd day, but present, nevertheless. Ptosis was also observed in 4 out of 17 animals 64 days
after pellet implantation. Wet-dog shakes were not remarkable
except for the first week and we do not believe that they
constitute a very sensitive indication of the presence or
absence of physical dependence.
It is clear that encasing the pellet in a nylon mesh bag is a
way of ensuring that there is steady release of small amounts
of morphine throughout a period of several weeks. It is also
clear that this is an inexpensive and stable delivery system
which depends on passive diffusion at a rather constant rate for
its effectiveness. If the tie of the bag in which we put the
pellet is, for some reason or another, forced open, then the
results resemble those seen with unwrapped pellets. Several
animals in the wrapped-pellet group gave results that were
similar to those observed in rats in which unwrapped pellets were
implanted and recovery of the nylon bag showed that much of the
morphine base had already been extruded and that the walling off
of the pellet was like that which would be seen with the unwrapped
pellet. It is obvious then that the bag serves to protect the
morphine pellet as much as it serves as a vehicle to deliver the
morphine to the animal.
ACKNOWLEDGEMENTS
The research reported in this paper was supported in part by then
National Institute on Drug Abuse grants DA00016 and F32DA05091 and
in part by a grant from the Committee on Problems of Drug Dependence. We would also like to thank Dr. Robert Willette, Division
of Research, NIDA for the morphine sulfate used in many of these
experiments.
46
REFERENCES
Cochin, J., Miller, M.J., Grell, R. and Poulsen, J.L. Morphine
tolerance and dependence following multiple injections or pellet
implantation in rodents. Proceedings of the 40th Annual
Scientific Meeting of the Committee on Problems of Drug
Dependence. (1978a) pp. 112-128.
Cochin, J., Rosow, C., and Miller, J. Ambient temperature and
morphine action. In: Adler, M., Manara, L., and Samanin, R.,
eds. Factors Affecting the Actions of Narcotics. New York:
Raven Press, (1978b) pp. 631-41.
Miller, J.M., Grell, R., Poulsen, J.L., and Cochin, J. The
comparison of pellet implantation with multiple injections of
morphine sulfate in rodents. Proceedings of the 39th Annual
Scientific Meeting of the Committee on Problems of Drug
Dependence. (1977) pp. 93-100.
Miller J., Rosow, C., Grell, R., and Cochin, J. Rectal temperature as a measure of both tolerance and physical dependence in
the morphine-pelleted mouse. Fed. Proc. 37: 310, 1978.
Miller, J.M., Rosow, C.E., and Cochin, J. Antagonist blockade
of morphine-induced hypothermia and hyperthermia in the mouse.
Fed. Proc. 38: 681, 1979.
AUTHORS
Joseph Cochin, M.D., Ph.D.
Joel M. Miller, AB, BS (Pharmacy)
Carl E. Rosow, M.D.
Rachelle Grell, B.S.
Janet L. Poulsen, B.A.
Department of Pharmacology
Boston University School of Medicine
Boston, Massachusetts 02118
47
Biosynthesis of the Enkephalins in the
Myenteric Plexus of the Guinea Pig Ileum:
Further Analysis of the Interaction of the
Enkephalins and Their Analogues With the
Opiate Receptors
Kosterlitz, H. W.; McKnight, A. T.; Corbett, A. D.; Gillan, M. G. C.;
Paterson, S. J.; Robson, L. E.; and Sosa, R. P.
In this paper, we are reporting on the research of the Unit for
Research on Addictive Drugs during the past year. The results
which were obtained have been submitted for publication elsewhere
in more detailed form.
BINDING SITES OF VARIOUS OPIATES AND OPIOID PEPTIDES IN HOMOGENATES OF GUINEA-PIG BRAIN1
The binding of a number of tritiated agonists to opiate receptors
was studied in homogenates of guinea-pig brain by a modification
of the method of Pert and Snyder (1973). The compounds could be
divided into a group with low numbers and another group with high
numbers of binding sites (Gillan, Kosterlitz and Paterson, 1979a;
Gillan, Paterson and Kosterlitz, 1979b). To the first group belonged ligands which in an earlier investigation (Kosterlitz et
al., 1979) had been assigned to interact preferentially with
receptors, e.g. {3H)-D-Ala2-D-Leu5-enkephalin or the µ-receptors,
e.g. {3H}-dihydromorphine. Their maximal number of binding sites
were 7.4 ± 0.3 pmol/g brain tissue (n = 5) and 4.26 ± 0.36 pmol/g
brain tissue (n = 4), respectively. On the other hand, the
number of binding sites of {3H}-D-Ala2-L-Leu5-enkephalin amide
(n = 5) were 12.4 ± 0.9 pmol/g and of {3H}-etorphine 15.4 ± 2.5
pmol/g (n = 3).
It may be concluded that the latter two ligands
combine with both the
and µ-binding sites. When cold ligands
were tested against their respective labelled ligands, it was
found that for the displacement of {3H}-D-Ala2-D-Leu5-enkephalin
84 times more cold morphine was required than for the displacement of {3H}-dihydromorphine. On the other hand, for the displacement of {3H}-dihydromorphine only 3.7 times more cold D-Ala2D-Leu5-enkephalin was required than for the displacement of {3H}D-Ala2-D-Leu5-enkephalin. Thus, considerable cross reactivity
was found for D-Ala2-D-Leu5-enkephalin. D-Ala2-L-Leu5-enkephalin
amide, which has similar affinities to both receptors, was equally
effective in displacing {3H)-dihydromorphine and {3H}-D-Ala2-DLeu5-enkephalin.
48
SPECIFIC PROTECTION OF THE BINDING SITES OF D-ALA2-D-LEU5-ENKEPHALIN ( -RECEPTORS) AND DIHYDROMORPHINE (µ-RECEPTORS)
Although there is now considerable evidence in favour of the existence of more than one receptor with which the opioid peptides
interact (Lord et al., 1977; Gillan et al., 1979a,b; Kosterlitz
et al., 1979), it was thought desirable to obtain a more direct
proof by examining whether or not appropriate ligands specifically
protect the binding sites against inactivation by alkylating agents
(Robson and Kosterlitz, 1979). Phenoxybenzamine was chosen as an
alkylating agent because it has been shown that it inhibits the
specific binding of {3H}-naloxone irreversibly (Cicero, Wilcox and
Meyer, 1974; Spiehler, Fairhurst and Randall, 1978). It was
found that, in homogenates incubated at 37°C for 15 min, phenoxybenzamine inactivated µ- and -receptors to the same extent, the
IC50 values varying between 0.8 and 1.3 nM. To obtain an inactivation of 70-80%, a concentration of 2.4 µM of phenoxybenzamine
was required. The principles of the experimental procedure in
the protection experiments were based on preincubation with varying concentrations of the cold ligands for 10 min at 37°C whose
protecting power was to be investigated before the homogenates
were exposed to the action of phenoxybenzamine for 15 min at 37°C.
The cold ligands were removed from the homogenates by centrifuging,
reconstituting the homogenate from the pellet and incubating it
for 15 min at 37°C. This procedure was repeated once before
testing the achieved protection by binding assays with either {3H}dihydromorphine or {3H}-D-Ala2-D-Leu5-enkephalin (40 min, 25°C).
The results showed that the binding of {3H}-dihydromorphine was
protected about 6 times better by cold dihydromorphine than by
cold D-Ala2-D-Leu5-enkephalin and that the binding of {3H}-D-Ala2D-Leu5-enkephalin was protected about 20 times better by cold
D-Ala2-D-Leu5-enkephalin than by cold dihydromorphine.
No such
selectivity was found when D-Ala2-L-Leu5-enkephalin amide was used
for the protection of either the µ- or the -binding sites. The
results of these experiments constitute so far the best evidence
for the existence of µ- and -binding sites because the cross-over
design excludes metabolic effects.
ENKEPHALIN PRECURSORS IN THE MYENTERIC PLEXUS OF GUINEA-PIG ILEUMl
It has been shown previously that, in the myenteric plexus of the
guinea-pig ileum, the enkephalins originate from unknown precursors produced locally by ribosomal synthesis (Sosa et al., 1977;
McKnight et al., 1978). It has further been found (Lewis et al.,
1978) that, in the striatum of various species, peptides of
40,000-100,000 daltons occur and, on tryptic digestion, yield
fragments that bind to the opiate receptors of brain homogenates.
It has been suggested that these peptides may be precursors in the
biosynthesis of enkephalins.
Analogous putative precursors have now bean isolated from the
myenteric plexus of the guinea-pig ileum (McKnight et al., 1979).
Preparations were homogenised in 5 volumes of 10% (v/v) acetic
49
314-300 0 -80 - 5
acid containing 0.01% (w/v) dithiothreitol and centrifuged at
49,000 g for 30 min. The supernatants were applied to 1.5 x
50 cm columns of Sephadex G75 and eluted in the same solution
used for extraction but containing 0.02% (w/v) sodium azide.
In the early experiments, 2 ml fractions were collected, dried
and re-dissolved in 200 µl of Krebs solution without bicarbonate.
Generally, a 100 µl aliquot was taken with 100 µl of a 1 mg/ml
solution of trypsin treated with diphenyl carbamyl chloride
(Sigma) in 0.1 M Tris hydrochloride (pH 7.8 at 37°C) for incubation at 37°C. The remaining 100 µl was used for a control
incubation without trypsin. Digestions were terminated by
acidifying to pH 2 with HCl. The digested and non-digested
samples were transferred to 10 x 0.5 cm columns of Amberlite
XAD-2 with 0.1 M HCl. After washing with distilled water the
columns were eluted with methanol.
The eluates were evaporated
and the dried samples were dissolved in the modified Krebs
solution for bioassay on the mouse vas deferens.
When the effects of electrical stimulation were examined, control
and stimulated (10 Hz) preparations were incubated for 2.5 h in
Krebs solution containing a mixture of amino acids (1 µg/ml)
(Sosa et al. 1977). When synthesis of proteins and enkephalins
was to be inhibited, the Krebs solution of both the unstimulated
and stimulated preparation contained cycloheximide (0.1 mM). In
these experiments, 8 ml fractions of eluate from G75 columns were
collected, freeze dried and dissolved in 1 ml modified Krebs
solution and digested with 400 µg of trypsin in 1 ml 0.1 M Tris.
After a 2 h digestion the samples were purified and assayed as
before. In certain cases, the active fractions after digestion
were purified by thin layer chromatography.
The elution patterns of materials causing a naloxone-reversible
depression of the contractions of the mouse vas deferens showed
one area of activity in the total volume and another area which
eluted generally between 30 and 60 ml from the G75 column, which
corresponded to material of a higher molecular weight of between
10,000 and 20,000 daltons. No activity was ever observed which
corresponded to material larger than 20,000 daltons even after
tryptic digestion for 16 h. The total activities of the high and
low molecular weight materials after digestion were approximately
100 and 200 ng methionine-enkephalin equivalents per gram of
tissue, respectively; in control samples incubated without trypsin only the activity due to the low molecular weight material
was found. Since this was unchanged by tryptic digestion, it
was assumed that the low molecular weight material probably consisted of enkephalins.
The possibility that the active products after tryptic digestion
of the high molecular weight material might be enkephalin-like was
supported by pharmacological tests using both the vas deferens
and the myenteric plexus assay tissues. The active fractions
were more potent in the former tissue in producing naloxonereversible inhibitions, confirming that the activity was "enkeph-
50
alin-like" rather than "
1977).
-endorphin-like" (Waterfield et al.,
The proposal that the crude extract of the 10,000-20,000 daltons
material might include peptides which were the precursors of the
enkephalins was tested by examining the effects of electrical
stimulation and cycloheximide on the levels of the putative precursors. Control tissues had a mean content of naloxone-reversible activity after tryptic digestion of the high molecular
weight peptide of 140 ± 27 ng/g (n = 3). Stimulation alone or
cycloheximide alone did not significantly alter this value.
When tissues were stimulated in the presence of cycloheximide
the content of enkephalins was reduced by about 70% (P < 0.005).
Although the exposure of myenteric plexus preparations to cycloheximide reduced the incorporation of {3H}Tyr into proteins by
93% after only 1 h, the mean content of the naloxone-reversible
activity after tryptic digestion in preparations stimulated for
2 h in the presence of cycloheximide was not significantly different from the unstimulated control value.
Preliminary attempts to identify the active products of tryptic
digestion of the 10,000-20,000 daltons material were performed by
thin-layer chromatography of pooled active fractions. In each of
four experiments, unstimulated or stimulated, in the absence or
presence of cycloheximide, the activity patterns were similar.
Activity was present at the origin and in the band preceding the
band due to standard methionine-enkephalin , which itself contained
only little active material, but no activity was found in other
areas of the plate. No activity corresponding to leucine-enkephalin was detected.
The results from our experiments on the effects of stimulation
and cycloheximide may be taken as evidence against the view that
all of the "enkephalin-like activity" generated by tryptic digestion can be related to original precursor molecules. After
stimulation in the presence of cycloheximide, the total enkephalin
content of the myenteric plexus preparation fell. Since previous
work had shown that this depleting effect was maximal after this
time (Hughes, Kosterlitz and Sosa, 1978; McKnight et al., 1978)
we might have expected to see at least a similar reduction in the
level of the putative precursors. Since this was not the case,
it would appear that not all the large peptides yielding on
tryptic digestion fragments interacting with opiate receptors are
precursors of the enkephalins. It has been shown that the incorporation of {3H}-tyrosine into proteins of preparations of
myenteric plexus is virtually abolished by 0.1 mM cycloheximide
(Sosa et al., 1977) but whether any residual capability of the
cell for protein synthesis might exist and whether this might be
able to maintain sufficient stores of precursor is not known.
The possibility that cycloheximide may inhibit the enzymes responsible for conversion of precursor to enkephalin or prevent
their synthesis must also be considered.
51
ACKNOWLEDGEMENTS
The work was supported by the Medical Research Council, the U.S.
National Institute on Drug Abuse (DA 00662) and the U.S. Committee on Problems of Drug Dependence.
REFERENCES
Cicero, T.J., Wilcox, C.E. and Meyer, E.R. Effect of -adrenergic blockers on naloxone binding in brain. Biochem Pharmacol,
23:2349-2352, 1974.
Gillan, M.G.C., Kosterlitz, H.W. and Paterson,S.J. Comparison
of the binding characteristics of tritiated opiates and opioid
peptides. Brit J Pharmacol, 66:86-87P, 1979;.
Gillan, M.G.C., Paterson,S.J. and Kosterlitz, H.W. Comparison
of the binding characteristics of opiates and opioid peptides.
In: Way, E.L., ed. Endogenous and Exogenous Opiate Agonists and
Antagonists. Oxford: Pergamon Press, 1979b, in press.
Hughes, J., Kosterlitz, H.W. and Sosa, R.P.
Enkephalin release
from the myenteric plexus of guinea-pig small intestine in the
presence of cycloheximide.
Brit J Pharmacol, 63:397P, 1978.
Kosterlitz, H.W., Lord, J.A.H., Paterson, S.J. and Waterfield,
A.A. Effects of changes in the structure of enkephalins and
narcotic analgesic drugs on their interactions with µ-receptors
and -receptors. Brit J Pharmacol, in press, 1979.
Lewis, R.V., Stein, S., Gerber, L.D., Rubinstein, M. and Udenfriend, S. High molecular weight opioid-containing proteins in
striatum. Proc Natl Acad Sci USA, 75:4021-4023, 1978.
Lord, J.A.H., Waterfield, A.A., Hughes, J. and Kosterlitz, H.W.
Endogenous opioid peptides: multiple agonists and receptors.
Nature, London, 267:495-499, 1977.
McKnight, A.T., Sosa, R.P., Corbett, A.D. and Kosterlitz, H.W.
Enkephalin precursors from guinea-pig myenteric plexus. In:
Way, E.L., ed. Endogenous and Exogenous Opiate Agonists and
Antagonists. Oxford: Pergamon Press, 1979, in press.
McKnight, A.T., Sosa, R.P., Hughes, J. and Kosterlitz, H.W.
Biosynthesis and release of enkephalins. In: Van Ree, J.M. and
Terenius, L., eds. Characteristics and Function of Opioids.
Amsterdam: North-Holland Biomedical Press, 1978, pp. 259-270.
Pert, C.B. and Snyder, S.H. Properties of opiate receptor binding in rat brain. Proc Natl Acad Sci USA, 70:2243-2247, 1973.
Robson, L.E. and Kosterlitz, H.W. Specific protection of the
binding sites of D-Ala2-D-Leu5-enkephalin ( -receptors) and
dihydromorphine (µ-receptors). Proc Roy Soc B, 205:425-432, 1979.
52
Sosa, R., Mcknight, A.T., Hughes, J. and Kosterlitz, H.W.
Incorporation of labelled amino acids into the enkephalins.
FEBS Lett, 84:195-198, 1977.
Spiehler, V., Fairhurst, A.S. and Randall, L.O.
The interaction of phenoxybenzamine with the mouse brain opiate receptor. Mol Pharmacol, 14:587-595, 1978.
Waterfield, A.A., Smokcum, R.W.J., Hughes, J., Kosterlitz,
H.W. and Henderson, G. In vitro pharmacology of the opioid
peptides, enkephalins and endorphins. Eur J Pharmacol, 43:
107-116, 1977.
AUTHORS
H.W. Kosterlitz, M.D., D.Sc.
A.T. Mcknight, Ph.D.
A.D. Corbett, B.Sc.
M.G.C. Gillan, Ph.D.
S.J. Paterson, B.Sc.
L.E. Robson, B.Sc.
R.P. Sosa, M.D.
Unit for Research on Addictive Drugs
University of Aberdeen
Marischal College
Aberdeen AB9 1AS
Scotland
FOOTNOTE
1. The sections on Binding Sites of Various Opiates and Opioid
Peptides in Homogenates of Guinea-Pig Brain and on Enkephalin
Precursors in the Myenteric Plexus of Guinea-Pig Ileum appear in
somewhat modified form in Endogenous and Exogenous Opiate Agonists
and Antagonists, E. Leong Way, editor, copyright 1980, Pergamon
Press, Inc., Elmsford, New York. They are used with permission of
Pergamon Press and may not be further reproduced without their
specific permission.
53
The Binding of LAAM and Its
Metabolites to Blood Constituents
Toro-Goyco, E.; Martin, B. R.; Harris, L. S.
INTRODUCTION
A diversity of reports indicate that in vivo the narcotic analgesic LAAMl, which shows an opiate-like profile (Fraser and Isbell
1952) is converted to two major metabolites, namely
-acetylnormethadol (McMahon, Calp, and Marshal 1965) and
-acetyldinormethadol (Billings et al. 1973). Both metabolites have been found
to remain in the circulation for prolonged periods (Billings,
McMahon, and Blake 1974) and there is existing evidence that a
significant portion of the activity of LAAM is due to its metabolites (Billings et al. 1973; Nickander, Booher, and Miles 1974).
LAAM and its metabolites have been found to bind to the opiate
receptors of rat brain (Horng, Smits, and Wong 1976).
Despite the fact that the binding of drugs to plasma proteins is
well established as an important parameter in the pharmacological
and therapeutic activities of medicinal agents, no studies, to our
knowledge, have been reported on the binding and distribution of
LAAM and its major metabolites to blood constituents.
In this work, we report the distribution of LAAM between RBC and
plasma proteins. By using the techniques of gel filtration and
equilibrium dialysis, we studied in vitro the nature, extent and
reversibility of the binding of LAAM and its metabolites to plasma
proteins. We also identified a LAAM binding fraction in plasma
and characterized it as a high molecular weight -globulin present
in low (about 1 mg/ml) concentration.
MATERIALS AND METHODS
Drugs: LAAM, tritiated in carbon 2 of the heptyl chain, specific
activity 38.06 mCi/mmole, (Batch No. 1634-88); nor-LAAM, tritiated
in the o,o' carbon atoms of the phenyl rings, specific activity
1
Abbreviations used: LAAM, (-)
acetylmethadol; nor-LAAM,
(-) -acetyl-N-normethadol; dinor-LAAM, (-) -acetyl-N,N-dinormethadol; CsCl, cesium chloride; SDS, sodium dodecyl sulfate.
54
1.40 Ci/mmole (Batch No. 2014-lB-2); dinor-LAAM, tritiated in the
o,o' carbon atoms of the phenyl rings, specific activity 94
mCi/mmole, (Batch No. 2150-2) and methadone, tritiated in the o,o'
carbon atoms of the phenyl ring, specific activity 16.7 Ci/mmole,
(Batch No. 1709-148B-8) were obtained as their hydrochloride salts
from Research Triangle Institute (Research Triangle Park, N.C.) as
authorized by the National Institute on Drug Abuse.
All the compounds were over 95% purity as determined by radioscan after chromatography.
The above named unlabelled compounds were also supplied
in crystalline form by the same organization.
Chemicals: Optical grade ultrapure CsCl was from Nutritional Biochemicals. All other chemicals were CP or reagent grade.
Materials: Sephadex G-2OO, 40-120 µ, 30-40 ml bed volume/gm dry
gel was obtained from Pharmacia.
We used Glenco gravity flow columns 1.5 x 100 cm, 1.5 x 60 cm, and
5.0 x 100 cm for gel filtration chromatography. Experiments were
done at a room temperature of 20 + 3°C. Absorbancies were detected
with a IsCOUA-5 absorbance monitor and recorder (Instrumentation
Specialties Co., Lincoln, Nebraska). The eluent was collected in
tubes in an automatic fraction collector. Radioactivity was counted in a Beckman liquid scintillation counter. Quench was corrected,
whenever necessary, by external standardization. Blood was collected into evacuated blood collection tubes (vacutainers) from nonfasting, apparently healthy individuals with no current or past
history of narcotic abuse. When sera was desired, blood was collected in the absence of anticoagulants, allowed to clot at room temperature and centrifuged immediately thereafter. The sera was removed and stored at 4°C. For larger amounts of plasma, outdated blood
from the institution's Blood Bank was used.
The time course of binding of the different drugs to serum proteins
was determined by dialysis. Equilibrium dialysis was used to determine percent. binding of drugs to protein. Bound/free ratios were
calculated at various concentrations of drug for Scatchard's plots
(Scatchard 1949).
The basic apparatus for the dialysis has been described before
(Judis 1976). The dialysis tubing was prepared by heating for 1 hr
at 80° in the presence of 1% EDTA and soaking in water with 0.1%
EDTA until used. Dialysis was carried out at 20° ± 3°. The electrophoretic mobility of the LAAM-binding fraction was determined by
Sepraphore polyacetate electrophoresis and estimation of its molecular weight by SDS gel electrophoresis. Gels were prepared as suggested by Maizel (1966) and molecular weights were estimated as suggested by Weber and Osborn (1969). Proteins of known molecular
weights (Sigma Chemical) were used as standards in the calibration
curve for molecular weight determination. Quantitative protein determinations were made by Sutherland's (Sutherland et al. 1949)
modification of the Folin reaction. Spectrophotometric measurements
were done in a Model 635 Varian UV Vis spectrophotometer.
55
RESULTS
Distribution of LAAM in blood constituents. The results presented
indicate that in whole blood, LAAM is nearly evenly distributed between RBC's and plasma proteins. The results were-consistent for
the six subjects studied. It must be emphasized, however, that the
subjects used for this study had not been recently exposed, to our
knowledge, to LAAM or any other opiate-like drugs and significant
differences could occur in individuals exposed to LAAM or analogous
drugs. Evidence of the weak nature of the binding of LAAM to plasma protein was obtained by Sephadex G-200 gel filtration. The elution pattern indicated that even when the serum proteins were allowed to equilibrate for 18-24 hr with this drug, almost all the drug,
as shown by the radioactivity used to trace its presence, was eluted
after the proteins. The radioactivity coincided with the elution of
other small molecules present in plasma which absorb at 280 nm and
that elute with the total volume (or volume accessible for diffusion) of the chromatographic columns. This chromatographic behavior is in marked contrast to highly lipophilic drugs such as the
cannabinoids, that are strongly bound to plasma proteins and elute
from the column together with the proteins1. Since the metabolites
of LAAM (nor-LAAM and dinor-LAAM) have been found to last periods
of over 48 hr in plasma, we also performed a gel chromatographic
study of these drugs after equilibration with plasma to ascertain
whether their chromatographic behavior was different and might be
a clue for their long lasting presence in plasma. Their elution
behavior did not differ from that of LAAM.
Equilibrium dialysis. Our experimental approach to equilibrium
dialysis was to allow the plasma proteins to accumulate the drug
until saturation. The time taken to attain saturation was determined by removal of aliquots from the dialysis bag (and dialysing
buffer) at various time intervals until the ratio of bound/free
drug reached a plateau. This plateau was attained 24 hr after
start of the dialysis. Bound/free ratios were calculated from
samples removed at 36 hr or longer.
Reversibility of the binding of LAAM. Our data indicates that the
binding of LAAM was readily reversible. When the drug was incubated
with plasma, and the ratio-of labelled:unlabelled drug was 1:5
serum proteins bound a significant higher amount of radioactivity
than when lower ratios (1:25 and 1:50) were used. After the addition of a 10-fold excess of unlabelled drug, thus decreasing the
labelled to unlabelled ratio from 1:5 to 1:50, the amount of radioactivity bound per ml of protein diminished reaching the same values
of radioactivity bound when the dialysis was started with a labelled
to unlabelled ratio 1:50. An identical effect was observed when
LAAM (labelled:unlabelled ratio 1:5) was incubated with serum protein and the ratios were decreased 1:25 and 1:50 by the addition of
unlabelled nor-LAAM and dinor-LAAM. It can be inferred from these
results that the binding of LAAM is highly reversible and that the
1
B. R. Martin and E. Toro-Goyco - unpublished data.
56
metabolites compete for the same binding sites. The reversal of
the situation, the displacement by LAAM of one of its metabolites
(dinor-LAAM) and the opiate methadone from their binding sites was
studied also. After 24 hr equilibration of serum with the drugs,
addition of an excess of unlabelled LAAM (50 x) caused their displacement from the binding sites as shown by a decrease in the
amount of bound radioactivity per ml plasma.
The results of our equilibrium dialysis experiments show that the
binding affinity for LAAM and its major metabolites nor-LAAM and
dinor-LAAM, and methadone is of the same order of magnitude when
their respective concentrations in plasma are identical (1 nmole/ml
or 1 µM). We also found that for any particular one of the above
drugs in serum at the concentrations used, a 5- to 10-fold excess of
any other of the drugs studied causes a displacement of the binding
of the same order of magnitude. These results are also consistent
with the fact that binding is weak and reversible and that the four
drugs studied here compete for the same binding sites.
Identification of the LAAM binding fraction. Our failure to isolate
and identify a serum-protein-LAAM complex by gel filtration led us
to simulate conditions that favor an equilibrium between drug and
protein. Equilibration of a chromatographic column with a buffer
containing a given concentration of drug (in this case LAAM) favors
the presence of a LAAM-protein complex no matter how weak it may be.
This is true for any ligand provided appropriate concentrations of
the ligand are found in the eluting buffer. This approach enabled
us to identify a specific plasma fraction with affinity for LAAM.
This fraction eluted between the first and second protein peak of
the chromatogram. Neither the immunoglobulins nor albumin showed
any appreciable binding of LAAM.
Further characterization of the LAAM binding fraction. Further
characterization of the LAAM binding protein indicates that it has
the electrophoretic mobility of an µ-globulin. On SDS gel electrophoresis, because of dissociation of polypeptide chains in the
several proteins comprising this fraction, several different bands
of varying molecular weights were observed. However, two of the
sharpest bands in the gel correspond to particles of molecular
weights close to 400,000.
A Scatchard plot traced to determine specific binding indicate that
one ml of plasma binds close to 3 nmoles of LAAM. These results
corroborate the data which indicates that albumin plays an insignificant role in the binding of LAAM and suggests that the drug must
be bound by a protein of low concentration in plasma.
DISCUSSION
Several factors determine the rate at which a drug leaves the circulation. Among these are the drug's partition coefficient, or ratio
of solubility in lipid to solubility in water, molecular weight and
state of aggregation in plasma. For drugs like LAAM and its metabolites, which are of low molecular weight and water soluble, these
57
factors alone would favor their rapid disappearance from plasma.
The remaining factor, state of aggregation, is very important in
determining their long lasting presence. Our results show that at
drug levels found in humans treated with these drugs (100-1000 ng/ml
serum) (Billings, McMahon, and Blake 1974; Kaiko and Inturrisi 1975),
the fractional binding and the partition coefficient could be important parameters in determining their continuous presence in plasma.
In the absence of a renal active process for the clearance of the
drug from plasma, only glomerular filtration will account for their
removal in urine. If the fractional binding is high, as shown by
our results, the amount of drug available for glomerular filtration
rate is significantly diminished. Despite a high fractional binding, strength of binding is weak. This last factor favors rapid
removal from plasma. Unfortunately, there is no information available as to what the fate of LAAM and its metabolites is after
glomerular filtration. The indirect evidence at hand (long duration in spite of weak plasma binding) suggest that reentry of the
drug into the circulation by reabsorbtion cannot be discarded as a
possibility.
It has been reported (Toffaletti, Savory, and Gittelman 1977) that
in subjects receiving LAAM, 24 hr plasma levels show the simultaneous presence of LAAM and its two major metabolites, but the bulk
consist of the metabolites. Our results suggest that this may be
accounted for by the displacement of LAAM from its binding sites
by its metabolites.
Probably the higher lipid:water partition
ratio of LAAMl contributes to its removal from plasma in preference to its metabolites.
We must conclude that the evidence presented here cannot support a
statement asserting that the long lasting presence of LAAM and its
metabolites in plasma can be explained on the basis of the strength,
nature and magnitude of their binding to plasma proteins.
An unexpected finding in this work has been the weak role played by
albumin in the binding of these drugs. Albumin plays the most important role in drug binding by plasma proteins and is usually taken
as a model protein for drug studies. It has been previously reported that methadone binds mostly to a globulin fraction (Judis 1976).
Being aliphatic amines, LAAM and its metabolites are protonated at
physiological pH. It would be logical to expect the binding of
these drugs to the albumin molecule, which contains over 100
carboxyl groups available to form salt like linkages. This is not
the case and in turn, the binding occurs to another molecular entity.
The suggestion is made that another negatively charged group (possibly a sulfate) may be forming a salt-like linkage with the amine.
The experimental approach used to identify a protein-drug complex
is very helpful in cases like this where protein drug complexes
are difficult to identify because of the weakness of the association. This approach has been used before to identify plasma
1
2. Toro-Goyco - unpublished data.
58
protein calcium complexes in human serum (Toffaletti, Savory, and
Gittelman 1977). The results obtained from the Scatchard plot are
very significant. It is shown that 1 ml of serum (or plasma) is
capable of specifically binding about 3 nmoles of LAAM. If we assume a minimum of one binding site per protein molecule, we conclude that one ml of plasma contains three nmoles of the binding
protein. The same volume of plasma contains close to 600 nmoles
of albumin, making the binding by albumin a very unlikely possibility. On the other hand, if we suppose the binding globulin to be
a very scarce protein in plasma, as suggested by our data, and this
protein to be high molecular weight entity of around 400,000 as
calculated from SDS gel electrophoresis experiments, we can safely
conclude that a protein with a concentration of 1-2 mg/ml plasma
could very well be the binding protein. Small changes in the concentration of this binding protein, without a significant change
in total plasma proteins could account for marked changes in the
LAAM binding capacity of the blood. We have found (work in progress) differences as high as l0-fold in the specific binding
affinity for LAAM in the serum of individuals. By the same reasoning these differences could explain the marked differences in
dosages required by individuals to react therapeutically.
ACKNOWLEDGEMENTS
The work reported here was carried out with grant (DA 00490) and
contract (271-77-3404) support from the National Institute on
Drug Abuse and a grant from the Committee on Problems of Drug
Dependence, Inc.
REFERENCES
Fraser, H.F., and Isbell, H. Action and addiction liabilities of
alphaacetyl methadol in man. J Pharmacol Exp Ther, 105:458-465,
1952.
McMahon, R.E., Calp, H.W., and Marshal, F.J. The metabolism of
-d, 1 acetyl methadol in the rat: The identification of a probable active metabolite. J Pharmacol Exp Ther, 149:436-445, 1965.
Billings, R.E., Booker, R., Smits, S., Pehland, A., and McMahon,
R.E. Metabolism of acetyl methadol. A sensitive assay for nor
acetyl methadol and the identification of a new active metabolite.
J Med Chem, 16:305-306, 1973.
Billings, R.E., McMahon, R.E., and Blake, D.A.
-Acetyl methadol
(LAAM) treatment of opiate dependence; plasma and urine levels of
two pharmacologically active metabolites. Life Sciences, 14:
1437-1446, 1974.
Acetyl methadol and
Nickander, R., Booher, R., and Miles, H.
its demethylated metabolites have potent opiate action in the
guinea pig isolated ileum. Life Sciences, 14:2011-2017, 1974.
59
Horng, J.S., Smits, S.E., and Wong, D.T. The binding of the optical isomers of methadone, -methadol, -acetyl methadol and
their N-demethylated derivatives to the opiate receptors of rat
brain. Res Comm Chem Path Pharmacol, 14:621-629, 1976.
Scatchard, G, The attraction of proteins for small molecules and
ions. Ann N Y Acad Sci, 51:660-672, 1949,
Judis, J. Binding of codeine, morphine and methadone to human
serum proteins. J Pharm Sci, 66:802-806, 1976.
Maizel, I.V, Acrylamide-gel electropherograms by mechanical
fractionation: Radioactive adenovirus proteins. Science, 151:
988-990, 1966.
Weber, K. and Osborn, H. The reliability of molecular weight determinations by dodecyl sulfate polyacrylamide gel electrophoresis.
J Biol Chem, 244:4406-4412, 1969.
Sutherland, E.W., Cori, C.F., Haynes, R., and Olson, N.S. Purification of the hyperglycemic glycogenolytic factor from insulin and
from gastric mucosa. J Biol Chem, 180:825-837,1949.
Kaiko, R.F., and Inturrisi, C.E.
Disposition of acetyl methadol
in relation to pharmacologic action. Clin Pharmacol Ther, 18:
96-103, 1975.
Toffaletti, J., Savory, J., and Gittelman, H.J. Use of gel filtration to examine the distribution of calcium among serum proteins. Clin Chem, 23:2306-2310, 1977.
AUTHORS
Efrain Toro-Goyco, Ph.D.
University of Puerto Rico
Medical Sciences Campus
San Juan, Puerto Rico
Billy R. Martin, Ph.D.
Louis S. Harris, Ph.D.
Medical College of Virginia
Department of Pharmacology
Richmond, Virginia 23298
60
Progress Report From the NIDA
Addiction Research Center
Jasinski, D. R.; Cone, E. J.; Gorodetzky, C. W.; Risner, M.
E.; Shannon, H. E.; Su, T. P.; Vaupel, D. B.
ARC PROGRAM
By September of this year the ARC clinical research
program will be relocated into temporary quarters at
Baltimore City Hospital (Please I). The animal and
chemical research programs will remain in Lexington
for two to three years. In 1981 or 1982, the entire
ARC will relocate into refurbished laboratories at
Baltimore City Hospitals (Phase II). In the Phase I
unit, the ARC will reinstitute clinical abuse potential
studies to complement the animal and chemical abuse
potential studies. The ARC will maintain its relationship with the CPDD) in regard to abuse potential
studies. It is doubtful that the ARC will ever be able
to) clinically assess the number of drugs that it did in
the past. For this reason, the ARC will assist the
CPDD in developing alternate clinical facilities for
these studies.
PCP STUDIES
For approximately the last year and half, the ARC has
had an extensive program concerning the problems associated with the abuse of phencyclidine (PCP). As a
disease-oriented laboratory, our perspective is to conduct studies to understand the causes, diagnosis,
treatment and prevention of PCP abuse.
The research strategy concerning PCP abuse was addressed
to the following issues:
1.
Reports that indicated PCP showed effects similar
to other drugs of abuse including the ability to
serve as a reinforcer on self-administration
studies.
2.
The appearance of PCP precursors as Well as PCP
homologues and their precursors in street samples.
61
To date, the ARC scientists have generated an extensive
body of data. This progress report will summarize some
of these data and some of the conclusions reached by
ARC scientist. Because of both space and time limitations, other program activities will not be presented.
Current homologues of phencyclidine consist of substitutes for the phenyl and piperitline rings on the
cyclohexane moiety (Table 1). Five homolocucs of PCP
have been identified in illicit samples (TCP, PCN, PCPY,
PCE, NPPCA). Three homologues (TCM, PCDEA, NMPCA) were
produced as legitimate research drugs. The synthesis
of PCP involves the reaction of a carbonitrile precursor
with a Grignard reagent such that an incomplete reaction
produces a product contaminated by the toxic carbonitrile, PCC (Table 1). PCC, as well as MCC, PYCC,
DEACC, was synthesized at the ARC. The two hydroxylated
metabolites have also been studied.
Analytic methods for Identification of PCP Homologues
Thin-layer chromatography (TLC), gas liquid chromatography (GLC) and chemical ionization-mass spectrometry
(CI-MS) were investigated as methods for identification
of PCP and its homologues, precursors and metabolites.
In general Rf values for these compounds in various
TLC systems overlap such that PCP cannot be distinguished from its analogues. GLC was somewhat more
specific but no one column or condition tested could
resolve the various PCP analogues. On the other hand,
with CI-MS all compounds were readily identified.
Street Sample Analysis
Small portions of eleven confiscated PCP) samples
(tablets and powder) were evaluated with GLC and CI-MS.
Nine samples contained PCP; the other two contained PCE
and TCP. One sample was contaminated by PCC, the toxic
precursor.
Opiate Receptor Binding (ORB) Studies
The PCP analogs were studied utilizing: standard ORB
assays prepared from guinea pig brain. PCP analogs
bind sterospecifically but on a much less order than
morphine. The potencies of the analogs relative to PCP
were similar to those obtained in whole animal assays,
suggesting this preparation can be used for studies of
structure activity relationships among this class of
compounds.
62
R1
Table 1.
R2
Structures of Phencyclidine Homologs
and Metabolites
1
1
Name
R1
R2
PCP
l-(l-phenylcylohexyl)
piperdine
Ph
Pi
1-piperidinocyclohexanecarbonitrile (PCC)
TCP
1-[l-(2-thienyl) cyclohexyl) piperidine
2-Th
Pi
PCC
PCM
1-(l-phenylcycloheyl)
morpholine
Ph
M
1-morpholinocyclohexanecarbonitrile (MCC)
TCM
1-[1-(2-thienyl) cyclohexyl)
morpholine
2-Th
M
MCC
PCPY
1-(l-phenylcyclohexyl)
pyrrolidine
Ph
Py
1-pyrrolidinocyclohexanecarbonitrile (PYCC)
PCDEA
N,N-diethyl-l-phenylcyclohexylamine
Ph
N(C 2 H 5 ) 2
NMPCA
N-methyl-l-phenylcyclohexylamine
Ph
NHCH3
Compound
Precursor
1-methylaminocyclohexanecarbonitrile
PCE
N-ethyl-l-phenylcyclohexylamine
Ph
NHC2 H5
NPPCA
N-prop l-l-phenylcyclohexylamine
Ph
NHCH2 CH2 CH3
KET1
2-(0-chloroplenyl)-2(methylamino)-cyclohexanone
Ph
4-HO-Pi
l
PPC
4-phenyl-4-piperidinocyclohexanol
PCHP
1-(1-phenylcyclohexyl)4-hydroxypiperidine
1-diethylaminocyclohexanecarbonotrile (DEACC)
1-propylaminocyclohexanecarbonitrile
Chronic Spinal Dog Studies
This preparation allows concurrent analysis of both
infra- and supra- spinal drug effects, behavioral effects,
and autonomic effects. Data obtained with this preparation include: (1) pharmacologic profiles after
acute administration, (2) alteration of drug response
by specific antagonists, (3) tolerance and crosstolerance studies, and (4) dependence and crossdependence studies. Such data for PCP will allow the
determination of similarity of action with other prototypic drugs of abuse. To date, only acute administration
studies have been completed.
In doses of 0.125, 0.25, 0.5 and 1.0 mg/kg, PCP was
infused over 40 min to five chronic spinal dogs. These
doses depressed the flexor reflex, increased heart
rate, dilated pupils, retracted the nictitating membrane,
increased the latency of the skin twitch and pupilloconstrictor reflexes, and elevated body temperature.
The dogs remained quiet but exhibited nystagmus,
staring, tracking, and sterotypic head movements. Loss
of lateral and medial canthal reflexes and lack of
attention to external stimuli indicated anesthesia with
the 1.0 and 0.5 mg doses. Opisthotonic posturing and
hypersalivation were also produced by these two doses.
This single dose pharmacologic is distinct from
that of LSD, d-amphetamine, delta-9-tetrahydrocannabinol,
morphine and pentobarbital although PCP does share some
properties in common with each.
The profile does resemble that of SKF-10,047, a prototypic hallucinogenic opioid.
Dog Self-Administration Model
The reinforcing properties of PCP, as well as its
analogs and netaholites, are being studied. Intravenous infusions of PCP (5.135, 6.25, 12.5, 25.0 and
50 µg/kg/infusion) were available to the dogs on a FRI
schedule during daily 4 hour sessions. Access was
given to each unit dose for five daily consecutive
sessions with treatments presented in random order.
All five unit doses maintained responding at rates
greater than those of saline. The number of infusions
decreased as the unit dose increased from 6.25 through
5.00 µg indicating the ability of the dogs to adjust
their responses to the magnitude of reinforcement,
thereby obtaining approximately the same amount of drug
each session. When the unit dose was 3.125 µg/kg/
infusion, the dogs failed to respond at a rate to
maintain this total drug dose. Preliminary results
indicate that dogs respond for ketamine in a similar
manner.
64
Thus, the dog self-administration model appears useful
for studying the reinforcing; properties of PCP and
analogs.
Rotarod Studies
Experiments to determine both the relative potencies
and durations of action for phencyclodine-like compounds
and their precursors by measuring ataxia were designed
to provide information on a nontoxic pharmagcological
action of these drugs for future comparisons to their
lethal effects in mice as well as to aid in selecting
dose levels for studies in the rat and dog.
Male Swiss Webster mice were tested for their ability
to remain on the rod rotating at 5 RPM for a 120 second
trial. Following two control trials, each mouse was
given an intraperitoneal injection anti was tosted at 6
minute intervals for 1 hour after injection. Ten mice
were used for each dose. Relative potencies were
determined from bioassays using peak effect values and
with doses doses expressed as pmole/kg. The following drugs
were employed:
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)
(12)
(13)
(1-phenylcyclohexyl) piperidine HCL (phencyclidine,
PCP)
1-[1-(2-thienyl) cyclohexyl] piperidine HCL (TCP)
1-piperidinocyclohexanecarbonitrile free base (PCC)
1-[1-phenylcyclohexyl] pyrrolidine HCL (PCPY)
1-[1-(2-thienyl) cyclohexyl] pyrrolidine HCL (TCPY)
1-pyrrolidinocyclohexanecarbonitrile
HCL
(PYCC)
1-[1-phenylcyclohexyl] morpholine HCL (PCM)
1-[1-(2-thienyl) cyclohexyl] morpholine HCL (TCM)
1-morpholinocyclohexanecarbonitrile
HCL
(MCC)
N-ethyl-1-1-phenylocyclohohexylamine HCL (PCE)
N,N-diethyl-1-phenylcyclohexylamine (PCDEA)
N-(n-propyl)-1-phenylcyclohexylamine HCL (NPPCA)
2-(o-chlorophenyl)-2-(methylamine)
cyclohexanone
(ketamine, KET).
All drugs were dissolved in saline except for PCC which
was made up in saline having: a pH of 4. The injection
volume was 0.01 ml/g of body weight.
The first compounds studied were the cyclohexylpiperidines which included PCP. Setting the potency of PCP
equal to 100, it was found that its precursor PCC was
only .31 times as potent than PCP.
A comparison of the cyclohexylpyrrolidines, again
letting the potency of PCP equal to 1 1.00, showed that
PCPY was 1.08 times more potent and TCPY 1.54 times
more potent. The precursor for this series PYCC was
the least potent having a ratio of 0.22.
65
314-300 0 -80 - 6
The cyclohexylmorpholine
were equal to each other
only one-fifth as potent
were: MCC-0.21, PCM-0.18,
derivatives and precursors
in potency although they were
as PCP. Thc actual potencies
and TCM-0.17.
The most potent series of compounds investigated was
the amine-substituted phenylcyclohexylamines. Compared
to PCP, their relative potencies were 2.15 for PCE,
1.52 for PCCEA and 0.82 for NPPCA. A close analogue of
the phenylcyclohexylamines is ketamine which is a
phenylcyclohexanone. Ketamine was 0.31 times as potent
as PCP.
A synopsis of the potencies between these families of
PCP analogues showed the phenylcyclohexylamines to be
more potent than the equally potent cyclohexylpiperidines
and cyclohexylpyrrolidines. Least potent were the
cyclohexylmorpholines.
Lethal Dose Studies
Acute lethal dose effects of the carbonitrile precursors
and the parent phenylcyelohexyl derivatives of the
piperidine, pyrrolidine and morpholine series were
determined in order to predict, with respect to the
illicit synthesis of these drugs, how contamination
with an intermediate precursor might affect the
potential toxic effects of the phencyclidine analogue.
These studies were conducted in male Swiss Webster mice
two weeks after they had been previously used in the
rotarod study. Drugs (see rotarod studies) were administered by i.p. injection and 4 hour LD) 50s anti potency
estimates were determind using the method of Litchfield
and Wilcoxon. Ten mice were used for each dose.
Each of the precursors was shown to be more toxic than
the parent compound. Using doses expressed as pmole/kg
the following potencies relative to the parent derivative were calculated: PCC 1.83 X PCP; PYCC 1.27 X
PCPY; and MCC 7.88 X PCM.
Within this group of three precursors, their potencies
were almost-equivalent: PCC (1.00) - PYCC (.95) > MCC
(.80).
Among the other derivatives the relationship of their
potencies to PCP as determined from the lethal dose
studies was as follows: PCPY (1.37) + PCE (1.27) > PCP
(1.00) > KET (0.22) > PCM (.19).
66
Lastly using data from the lethal close and rotarod
studies, the therapeutic index (TI) was calculated for
eight compounds using the ratio of the LD50 value to
the ED50 value for ataxia in order to provide a measure
of their safety. The data broke out into three groups.
The precursors possessed the lowest TI‘s: PCC 3; PYCC
2; and MCC 3 . A second group having larger TI's
included: PCP 18; PCPY 14; anti PCM 1.8. The highest
TI’s were those for KET 25.1 and PCE 30.3.
Discriminative Stimulus Properties
The discriminative stimulus properties of phenecyclidine
were evaluated in rats using a two-choice, discrete
trial avoidance: task in which rats were injected i.p.
with either saline or phencyclidine 1.0 or 3.0 mg/kg 30
minutes prior to the Start of thc session. Rats were
trained until their performance on the appropriate
level was 95% correct for 10 consecutive sessions. It
was found that rats discriminate PCP from saline in a
dose-related manner but the slope in rats trained to
the 3.0 mg dose was steeper.
In order to further evaluate the the discriminative stimulus
properties of PCP, a number of PCP analogs were tested.
Studies of PCP and two piperidine analogs, the thienyl
derivative (TCP) and the carbonitrile synthetic intermediate (PCC) indicate that TCP produced dose-relaed
PCP-like discriminative stimuli. A (lose of 20 mg/kg of
T C P was required to product greater than 90% responding
on the PCP-appropriate lever. On the other hand, PCC
failed to produce any PCP-appropriate responding even
with a dose 3-fold higher than the 3 mg/kg training
close of PCP. Higher doses could not be tested due to
toxicity.
In the morpholine chemical family, three similar analogs
were tested Both thc phenyl analog (PCM) and the
thienyl analog (TCM) produced dose-related PCP-like
discriminative, stimuli. Doses of 30 mg/kg of PCM and
56 mg/kg of TCM were required to procedure greater than
90% responding on the PCP-appropriate lever. Thus,
these two compounds were one-tenth to one-twentieth as
potent, respectively, as PCP. As in the previous
series, the carbonitrile derivative (MCC) failed to
produce any PCP-appropriate responding. However doses
as low as 20 mg/kg of MCC produced convulsions.
Within the pyrrollidine chemical family, three similar
analogs were tested. The phenyl derivative (PCPY) was
approximately equipotent to PCP in producing PCP-like
discriminative stimuli. In addition, the thienyl
67
derivative (PCPY) is equipotent to PCP and PCPY in
producing PCF-like discriminative stimuli. As with
the two previous carbonitriles, PYCC also failed to
produce any PCP-appropriate responding at non-toxic
doses.
Scveral additional PCP derivatives have also been found
to produce PCP-like discriminative stimuli. PCE, the Nethyl analog, is thc most potent compound tested to
date; a dose of only 1.0 mg/kg of PCE being required to
procduce at least 90% PCP-appropriate responding.
However, the slope of the dose-response curve for PCF
appears to be more shallow than that for PCP and this
compound is being more extensively tested. The Npropyl analog, which also has appeared on the street,
generalizes to PCP and is essentially equipotent to
PCP. In addition, ketamine was also found to generalize
to PCP and was approximately one-tenth as potent as
PCP. Further, the N-diethyl compound has also now been
tested and it is approximately equipotent to PCP in
producing PCP-like discriminative stimuli.
SKF 10,047 is not a PCP derivative, but is an analog
of cyclazocine, a narcotic antagonist with psychotomimetic properties. Interestingly, this compound
produced dose-related PCP-like discriminative stimuli
and was approximately one-third as potent as PCP. The
pharmacologic properties of the discriminative stimulus
effects of PCP were further chracterized by testing
several standard psychoactive drugs from other classes
(ketocyclazocine, d-amphetamine, pentbarbital, chlorpromazine, delta-9-THC, morphine, MDA, scopolamine,
LSD, physotigmine). None of these drugs produced
appreciable levels of responding on the PCP-appropriate
choice lever, although each of them produces one or
more actions in common with PCP.
Summary and Conclusions of PCP Studies
1.
PCP preparations may be contaminated with precursors
which are used for synthesis of PCP homologues.
2.
Chromatographic methods tested for identification
of PCP and homologues showed the following:
specificity: CI - MS > GLC > TLC
3.
Opiate receptor binding (OEE) assay data on PCP
homologues correlate well with pharmacologic tests
in mouse and rat.
4.
Two PCP metabolites are approximately 1/7 as
potent and equipotent in the ORB assay.
68
5.
Rotarod studies in the mouse have shown differences
in potencies between families of PCP analogues
but the magnitude of these differences is not
extreme.
6.
Acute toxicity studies have demonstrated that the
precursors are more toxic than the parent compound.
7.
Therapeutic indices indicated that the precursors
were less safe than the PCE drugs and that PCE
was the safest of the analogues tested.
8.
Studies in the chronic spinal dog show PCP to be a
drug with diverse actions. Within the hallucinogens,
PCP most closely resembles a hallucinogenic opioid.
9.
PCP can serve as a positive reinforcer in dog
self-administration studies, indicating this model
may be used to study relative reinforcing properties
of PCP homologues.
10.
In studies of its discrimanative stimulus properties
PCP can produce stimulus control of behavior in
the rat.
11.
Nine analogues generalized to PCP with clear
orders of relative potencies. The precursors did
not generalize.
12.
Except for the hallucinogenic opioid SKF-10,047,
other psychoactive drugs failed to generalize.
13.
PCP and analogues are a unique class of drugs.
14.
Chronic spinal dog, dog self-administration, and
discriminative studies of the rat are useful for:
(1)
Conducting specific studies of the mode of
action, the toxicity, and the treatment of
PCP abuse, and
(2) Judging the potential of compounds for PCPlike abuse.
AUTHORS
D.R. Jasinski, M.D.; E.J. Cone, Ph.D.; C.W. Gorodetzky, M.D., P.h.D.; M.E. Risner, Ph.D.; H.E. Shannon, Ph.D.;
T.P. Shu, Ph.D.; D.B. Vaupel, Ph.D.
NIDA/Division of Research; Addiction Research Center;
Lexington, Kentucky
69
Drug Dependence Programme of
the World Health Organization
Khan, I.
It is a pleasure for me to be given the opportunity to inform
1.
you of the developments within WHO which I consider will be of
interest to this meeting.
Since your last meeting in Baltimore, approximately one year
ago, interesting developments have taken place. WHO, having
benefitted in the past of the very useful collaboration with the
Committee on Problems of Drug Dependence (CPDD), as a body as well
as with individual members, has moved a step forward by establishing a more "formal working relationship with the Committee."
2.
Drug Evaluation for International Control
It is the United Nations Commission on Narcotic Drugs who has
the final authority to decide on recommendations of WHO for
scheduling substances under the international drug control
treaties. At the 28th Session of the Commission on Narcotic Drugs
held in Geneva, 12-23 February 1979, the Commission approved
rescheduling the status of methaqualone from Schedule IV to
Schedule II of the 1971 Convention. This body also noted with
satisfaction the view of WHO that the status of phenobarbital and
lefetamine need not be changed.
Nicocodeine (6-nicotinoylcodeine) was approved to be added to
the list of drugs in Schedule III of the Single Convention on
Narcotic Drugs. This change was requested by the Government of
Austria.
Plans for 1979
We have selected for review the following substances for
scheduling/rescheduling under the international drug control
treaties:
70
d-Propoxyphene, Tilidine and Sufentanil under the Single
Convention on Narcotic Drugs;
Phencyclidine and Mecloqualone under the 1971 Convention on
Psychotropic Substances.
3.
Some challenges posed to WHO and its Member States by the
Convention on Psychotropic Substances, 1971.
(i) Article 2 of the Convention on Psychotropic Substances,
1971, describes briefly the data required for recommending psychotropic substances for international and national control. The
21st Report of the WHO Expert Committee on Drug Dependence1 gives
more details of the methods required to obtain data for this
purpose.
I wish to refer to certain aspects of those studies
where attention is required in a coordinated way by the scientific
community, WHO and its Member States.
There is a need for coordinated investigations of the major categories of psychotropic
substances with respect to:
Self-administration and reinforcement properties, development of CNS tolerance and physical dependence in animals and
the development of cross tolerance and cross dependence
between new psychotropic substances and substances
already controlled.
These studies will provide baseline data against which data
I am
obtained with new and similar compounds can be compared.
aware of the long and valuable role the CPDD has had in screening
narcotic substances and antagonists. Would the Committee be
willing to undertake a coordinating role in the establishment of
agreed procedures for carrying out such tests in psychotropic
substances and the allocation of specific testing to the laboratories of individual members? Cooperation with WHO in this venture would be highly appreciated.
(ii) Long-term effects of psychotropic substances on the
social and personal functioning, their impact on physical health
and the extent to which they positively and/or negatively reinforce other forms of treatment. The 1971 Convention makes it
obligatory for WHO, its Member States and the United Nations
Commission on Narcotic Drugs, that data on the public health and
social problems associated with the use of psychotropic substances
be identified, quantified and considered along with data on
psychopharmacological tests and the therapeutic usefulness of
these substances. Thus, WHO plans to address itself to the
assessment of the public health and social problems in an Expert
Committee scheduled to meet in September 19802.
1
WHO Technical Report Series, No. 618,(1978).
WHO Expert Committee on Drug Dependence, Geneva,
15-20 September 1980.
2
71
(iii) As many as half of the patients in general medical
practice are prescribed psychotropic drugs in many environments.
It is suspected that a significant proportion of these patients
are unknowingly dependent on these drugs and it is believed that
physicians, including psychiatrists, are often unaware of the
"hidden psychotropic drug dependence."
The reason is that the
symptoms of drug dependence (i.e. anxiety, insomnia, restlessness)
are often the target symptoms for which some psychotropic drugs
are prescribed. With the increasing use of psychotropic drugs in
medical practice there is an urgent need to develop methodological
tools to:
(a) differentiate drug dependent patients from those
who are not, and once these tools are available it will then be
possible to (b) assess the true extent of hidden psychotropic
drug dependence and to (c) develop collective clinical methods for
its management.
4.
WHO continues its collaboration with its Member States,
especially in developing countries, to develop and strengthen
further the programmes on drug dependence. The major activities
of these programmes are:
(a)
(b)
(c)
(d)
Manpower development and training of personnel.
Strengthening of services and facilities involved
in the prevention, treatment and rehabilitation of
drug dependent persons.
Development of technology for effective demand
reduction of illicit drugs.
Promotion of cooperation between countries in the
implementation of drug dependence programmes.
WHO has carried out the above activities in Afghanistan, Burma,
Egypt, Iran, Malaysia, Pakistan, Peru, Thailand, and Vietnam.
A study on "drug dependence in socio-cultural context" is
also presently being carried out in order to provide guidelines
for planning suitable and effective programmes for the treatment
and rehabilitation of drug dependent persons.
5.
The WHO Research and Reporting Project on the Epidemiology of
Drug Dependence is now in its fourth year and is finalizing the
methodology development phase. A series of publications are now
in preparation which will describe a variety of data collecting
methodologies in this field. The methodologies have been tested
in a network of collaborating centres, primarily in developing
countries and the following reports are expected to be published
in 1979 and 1980:
(a)
(b)
(c)
A Methodology for Student Drug Use Surveys
Core Data Items in Epidemiological Studies of Drug
Dependence.
The Use of Reporting Systems on Drug Abuse.
72
(d)
(e)
(f)
(g)
(h)
General Population Surveys on Drug Abuse
Intensive Case Finding and Monitoring of Drug
Drug Use Surveys of Special Populations at Risk,
including Unemployed and Working Youth.
Evaluation of Drug Dependence Treatment Methods
WHO Guidelines for Collecting Existing Information on
Dependence Producing Substances.
At the meeting of collaborating investigators in April of
this Year in Malaysia, the project was evaluated and the future
directions proposed, including the application of these methodologies on the country level.
AUTHORS
Dr. Inayat Khan, M.B., B.S. (Punjab), Ph.D. (Edinburgh)
Senior Medical Officer
Drug Dependence Programme
Division of Mental Health
World Health Organization
Geneva, Switzerland
73
Fifty Years of International Control
of Dependence-Producing Drugs
Kaymakcalan, S.
It is my pleasure and honour to greet you as the representative of
the International Narcotics Control Board (INCB) of the United
Nations.
Your Committee
drug addiction
Council. It is
narcotic drugs
was born 50 years ago as an advisory Committee on
of the National Academy of Sciences-National Research
a happy coincidence that international control of
was also established exactly 50 years ago.
The first international organ concerning the control of legitimate
use of narcotics which was the Permanent Control Board, was created
by the Geneva Opium Convention of 1925 and started to work in 1929.
It was primarily concerned with monitoring manufacture of, and trade
in, narcotic drugs through the establishment of a statistical reporting system.
Over the years it became necessary to enlarge the scope of the 1925
Convention to place under control some new substances and also to
combat illicit use and traffic of psychoactive substances. Seven
additional treaties were signed in the years of 1931, 1936, 1949,
1953, 1961, 1971, and 1972. The last three are the most important
and are known as the 1961 Single Convention on Narcotic Drugs, the
1971 Convention on Psychotropic Substances, and the 1972 Protocol
Amending the Single Convention.
At present the number of States which are parties are 110 for the
Single Convention, 57 for the Convention on Psychotropic Substances, and 66 for the 1972 Protocol. The INCB, which was created by
the Single Convention, is the successor to the Permanent Control
Board and the Drug Supervisory Body. The latter had been established by the 1931 Convention to ensure control over future legal
national requirements of narcotic drugs. This became the "estimates" system.
As it is presently composed, the INCB has thirteen members who are
elected by the United Nations Econonomic and Social Council and who
act in their personal capacity. Within the legal framework of the
74
treaties, the Board's main duties are:
1) to monitor the international trade in both narcotic and
psychotropic substances through the administration of the
estimates (applicable to narcotic drugs only) and the statistical systems with a view to preventing any country from
becoming a center of illicit traffic;
2) to endeavour, on the other hand, to ensure that there is a
balance between the licit supply of, and demand for, narcotic drugs:
3) to recommend, in the event of important breaches of the
relevant treaties, an embargo on the import of drugs,
export of drugs, or both, from or to the country or territory concerned; I am glad to say that this has never been
fully invoked because all countries are normally ready to
cooperate.
4) to recommend assistance to countries which need it to help
them comply with their international treaty obligations.
5) to address itself to public opinion world-wide through the
publication of its annual report.
The INCB works in close cooperation with the Commission on Narcotic
Drugs, the Division of Narcotic Drugs of the U.N., the United Nations
Fund for Drug Abuse Control and the WHO.
In spite of these combined efforts it is a fact that there is a
growing problem of abuse of dependence-producing substances in
many parts of the world. However, it should not be forgotten that
if international treaties and endeavours did not exist, the world's
situation would be much worse.
A few examples may clarify this situation. Between 1925 and 1929
evidence documented by the Secretariat of the League of Nations
showed that at least 100 tons of morphine-type dependence producing drugs passed into the illicit traffic by diversions from duly
authorized licit manufacture. The total world legitimate needs were
then approximately 39 tons of morphine equivalent per year. The
huge amounts of narcotics had been obtained by illicit traffickers
from authorized manufacturers. During 1927 and the first three
months of 1928 a single factory in Europe had exported 860 kg. of
morphine, 2.711 kg. of heroin and 40 kg. of cocaine to a single
country for illicit purposes.
Since international treaties became progressively operative there
have been no, or negligible, leakages of narcotics from licit sources
to the illicit traffic.
During the last decade we have seen an almost similar situation
with amphetamines. Although many industrialized countries are still
not parties to the 1971 Convention, there have been considerable
reductions in the manufacture of amphetamines in many countries
75
following the terms of this Convention.
Before closing my remarks I may say that in the struggle against
the abuse of dependence-producing substances we are not pessimistic.
At least one may think that international efforts have had some
positive effects in reducing the supply of these drugs. However,
as regard the etiology, treatment and rehabilitation of drug dependence there are still many things to be learned. Therefore the
scientific contributions of your Committee are very important to
the international community, and I am sure that your achievements
will help to reduce the suffering of mankind.
AUTHOR
Sukru Kaymakcalan, M.D.
Professor and Chairman, Department of Pharmacology, Medical School
of Ankara University, Ankara, Turkey, and Vice-President of the
International Narcotics Control Board, Geneva, Switzerland
76
A New Synthetic Codeine
Substitute: (-)-3-Phenoxy-NMethylmorphinan
Mohacsi, E.; Leimgruber, W.; Baruth, H.
INTRODUCTION
In recent years, there has been a growing concern in the United
States that a serious shortage of analgesics prepared from
opium may develop in the event of a major national emergency1.
Consequently, there has been considerable interest to provide
alternate sources for these drugs or to complement and possibly
replace them with synthetic substitutes. In connection with this
latter approach directed at the search for a synthetic codeine
substitute with reduced addiction liability, we undertook a
number of years ago the synthesis of 3-O-t-butylmorphine (3 )
and (-)-3-t-butoxy-N-methylmorphinan (6)2. Our rationale for
preparing this novel codeine and levomethorphan analog was
based on the expectation that a tertiary butyl group on phenolic
oxygen would prevent their in vivo metabolic conversion to
morphine (1) and levorphanol (4), respectively, thus eliminating
the pharmacological effects of these metabolites.
Pharmacological evaluation revealed that 3-O-t-butylmorphine
(3) is active in the writhing but not in the tail-flick test, whereas
(-)-3-t-butoxy-N-methylmorphinan
(6) shows activity in both
tests. The virtual lack of analgesic activity in the case of the
codeine analog 3 has been explained in terms of its blocked
However, any interpretation
metabolic pathway to morphine3.
must take into account the subsequent finding4 that both analogs,
despite the presence of a bulky tertiary butyl group, show
similar binding to the opiate receptor when compared to
codeine (2) and levomethorphan (5), respectively.
Since the potentially interesting levomethorphan analog 6 was
77
1
R = -H
4
R = -H
2
R = -CH
5
R = -CH
3
R
6
R
=
3
-C(CH3)3
7
R
=
-C6H5
=
3
-C(CH3)3
unsuitable for development in view of its instability in acids, we
shifted our synthetic efforts towards the preparation of aryl
ethers of levorphanol (4 ) such as (-)-3-phenoxy-N-methylmorphinan (7) which had not been previously reported. We
hoped to find within this class of compounds a codeine-like
analgesic with reduced addiction liability because the presence
of a lipophilic phenyl group was expected to facilitate transport
to narcotic receptor sites while preventing metabolic conversion
to levorphanol. An additional attractive feature of these aryl
ethers was their anticipated chemical stability under conditions
which cause degradation of codeine to morphine, thus providing
a safeguard against abuse.
METHODS
CHEMISTRY
Ullmann reaction5 of levorphanol with bromobenzene in pyridine
in the presence of potassium carbonate and copper gave (-)-3phenoxy-N-methylmorphinan (7).
The
substituted
O-aryl-Nmethylmorphinans
8-19
were prepared by this method from 4
and the appropriate aryl halides
When 7 was treated with O-dealkylating agents commonly
employed in the morphine and morphinan series, such as
pyridine hydrochloride7 at 220° for 25 minutes, 48% hydrobromic acid in refluxing acetic acid8 for 6 hours, or boron tribromide in chloroform9 at room temperature, only starting
material was isolated. Attempted ether cleavage with sodium in
liquid ammonia10 also resulted in the recovery of the starting
78
material 7 in high yield.
PHARMACOLOGY
Analgesic measures
Phenylquinone-writhing test. The writhing test described by
Siegmund et al.11 as modified by Hendershot and Forsaith12
was used to test the compounds for analgesic activity in mice.
The ED50 and their 95% confidence limits were determined by
the method of Litchfield and Wilcoxon13. The test results are
shown in Tables 1 and 2.
Tail-flick method. The antinociceptive potency of the compounds was assessed using the tail-flick method of D'Amour and
Smith14 as described by Dewey and Harris15 in mice and rats.
The ED50 and 95% Fiellers' limits were computed by the
Berkson Minimum Logic Chi-Square method16. The test
results are presented in Tables 1 and 2.
Binding assays. Interaction of the compounds with the opiate
receptor in whole rat brain homogenates was measured by
assaying the displacement of [3H] naltrexone from specifically
bound sites as described before17.
The concentration of the test compound necessary to displace
one-half of the stereospecific [3H] naltrexone binding (IC50)4
is shown in Table 2.
RESULTS AND DISCUSSION
Tables 1 and 2 summarize the results obtained in various test
p r o c e d u r e s 1 1 - 1 7 with the new aryl ethers (compounds 7-19).
Activities of these compounds were compared with those of
morphine (1), codeine (2), levorphanol (4), and levomethorphan
(5). As Table 1 indicates, (-)-3-phenoxy-N-methylmorphinan
(7) has about twice the analgesic potency of codeine in mice.
When the phenoxy group in 7 was replaced by a pyridyloxy group
(compound 8), a moderate increase in analgesic activity was
observed. Except for a p-hydroxy group (compound 12), substituents on the phenyl ring did not significantly alter analgesic
potency.
As shown in Table 2, compound 7 interacts with the opiate
receptor with an affinity comparable to codeine and levomethorphan4, 17. The analgesic potency of 7 is about twice that of
codeine when administered subcutaneously in both the phenylquinone writhing11,12 and tail-flick assays14,15 in mice, but 7
is about 10 times more potent than codeine in the writhing and-
79
Table 1.
Analgesic
Activities
Analgesic
7
b
C6H5-
8b
9c
act.a,
1.25(0.78-2.00)
2-pyridylI
0-Arylmorphinans
Writhing
R
Comp
of
4-CH3OC6H4-
I
ED50,
mg/kg
Tail-flick
g
19.71(17.28-22.16)
1.1(0.61-1.98)
10.08(8.95-11.35)
2.1(1.08-4.10)
24.98(21.99-28.96)
10 d
3-CH3OC6H4-
2.5(1.43-4.38)
39.74(33.21-51.54)
11d
2-CH3OC6H4-
0.49(0.26-0.93)
24.40(21.27-30.17)
12 c
4 - H O C
6
H
4
-
1.3(0.65-2.60)
6.69(4.88-8.17)
13 b
3 - H O C
6
H
4
-
9.0(4.50-18.00)
80.14(56.17-159.14)
14 b
2-HOC6H4-
1.8(0.90-3.60)
11.44(10.95-12.06)
15 c
4-CH3C6H4-
16 c
2-O2NC6H4-
2.8(1.65-4.48)
17 C
4 - F C 6 H4 -
1.0(0.38-2.65)
37.26(33.15-42.76)
18 b
3-FC6H4-
1.85(1.00-3.00)
71.00(58.36-92.13)
l9 d
2-FC6H4-
3.0(1.36-6.60)
23.31(20.49-26.98)
1e
Morphine
0.46(0.26-0.83)
2f
Codeine
2.3(1.21-3.91)
23.0(13.94-37.95)
4.06(3.78-4.41)
38.97(35.31-42.79)
a) Tested SC in mice. b) Tartrate.
c) Hydrochloride.
d) Oxalate. e) Sulfate. f) Phosphate g) Numbers in
parenthesis are the 95% confidence limits.
80
Table 2. Analgesic Activities and Opiate Receptor Affinities
act.a,
Analgesic
Compound
Morphineb
Codeinec
Route
Levomethorphan e
7
d
mg/kg
Tail-flick
f
s c
0.46(0.26-0.83)
p o
2.5(1.40-4.45)
31.20(26.30-35.73)
s c
2.3(1.21-3.91)
38.97(35.31-42.79)
po
Levorphanold
Writhing
ED50,
24.0
4.06(3.78-4.41)
Binding
affinitiesg’h
3
[ H] Naltrexone (1O-9)
IC50x1O6 (tris buffer)
0.027
10.0
(13.71-42.00) 119.03(105.16-132.21)
s c
0.11(0.06-0.22)
1.21(1.13-1.31)
po
1.4
8.50(7.22-10.25)
s c
0.64(0.34-1.22)
po
1.5
sc
1.25(0.78-2.00)
19.71(17.28-22.16)
p o
2.3
51.68(43.72-62.41)
(0.70-2.80)
(1.32-1.71)
(1.22-4.32)
6.78(6.23-7.43)
0.004
2.0
5.27(4.49-6.17)
5.0
a) Tested SC and po in mice. b) Sulfate. c) Phosphate. d) Tartrate. e) Hydrobromide f) Numbers
in parenthesis are 95% confidence limits. g) Binding was performed using rat brain homogenate.
h) Expressed as the concentration of compound required to inhibit stereospecific [3H] naltrexone
binding by 50%.
approximately twice as active in the tail-flick assay when
administered orally. In the rat tail-flick test14,15 it is equal
to codeine (ED50 12.2 mg/kg, vs. 12.3 mg/kg) by the subcutaneous route, whereas it is approximately five times more
potent than codeine upon oral administration (ED50 25.68
mg/kg and 126.03 mg/kg respectively). As expected, the
analgesic action of 7 in the rat tail-flick test (25 mg/kg SC) is
inhibited by pretreatment with naloxone (2 mg/kg SC). The
duration of analgesic activity observed for 7 was at least twice
that of codeine when administered at equiactive doses in both
the mouse and rat tail-flick assays. An additional important
feature of 7 is the finding of Dewey et al.18 that it has considerably less physical dependence liability than codeine. This
is evidenced by substitution experiments in rats in which
codeine, but not 7, substituted for morphine in morphinedependent rats, while 7 substituted only partially for codeine in
codeine-dependent rats. These studies also showed that 7 is
devoid of primary physical dependence in rats in contrast-to
codeine and morphine18. Finally, preliminary metabolic
studies of 7 in rats identify compound 12 as the major metabolite while levorphanol and 3-phenoxynormorphinan were detected as the minor metabolites19.
In conclusion, (-)-3-phenoxy-N-methylmorphinan (7 ) is an
orally effective analgesic comparable to codeine except for its
decreased physical dependence liability and its longer duration
of action. Although this compound is a levorphanol ether it
cannot be converted by conventional reactions to levorphanol,
thus providing a safeguard against abuse. Furthermore, since
it is prepared by total synthesis, adequate supplies can be
assured at reasonable cost, Preclinical studies of this
potential codeine substitute are under way in preparation for
clinical trials in man.
Acknowledgment. We are indebted to Dr. E.J. Simon,
Department of Medicine, New York University Medical Center,
New York 10016, for the binding affinity data. We are also
grateful to Mr. T. Hayes, Mrs. D. Kelly, Mr. R. Marino and
Mrs. J. Ploski for their technical assistance and to Dr. J.
Sepinwall for providing analgesic data. Finally, the authors
wish to thank Mr. L. Berger for his stimulating suggestions
and valuable discussions.
82
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Greentree, L.B. New England J. of Medicine, 291, 1411
(1974).
Mohacsi, E. and Leimgruber, W. Unpublished results.
Kamm, J.J., Bastone, V.B., Mohacsi, E. and Vane, F.
M. Xenobiotica, 1, 273 (1971).
Simon, E.J. Private communication.
Ullmann, F. and Sponagel, P. Ann., 350, 83 (1906).
Mohacsi, E . U.S. Patent 4,113,729 (Sept. 12, 1978).
Rapoport, H., Lovell, C.H. and Tolbert, B.M. J. Amer.
Chem. Soc., 73, 5900 (1951).
Bentley, K.W., Bower, J.D. and Lewis, J.W. J. Chem.
Soc. (C), 2569 (1969).
Rice, K.C. J. Med. Chem. 20, 164 (1977).
Sawa, Y.K. Tsuji, N. and Maeda, M. Tetrahedron 15,
154 (1961).
Siegmund, E., Cadmus, R. and Lu, G. Proc. Soc. Exp.
Biol. Med. 95, 729 (1957).
Hendershot, L.C. and Forsaith, J. J. Pharmacol. Exp.
Ther. 125, 237 (1959).
Litchfield, Jr., J.T. and Wilcoxon, F. J. Pharmacol.
Exp. Ther. 96, 99(1949).
D'Amour, F.E. and Smith, D.L. J. Pharmacol. Exp.
Ther. 72, 74 (1941).
Dewey, W.L. and Harris, L. S. in "Methods in Narcotic
Research" (Ed., S. Ehrenpreis & A. Neidle) Vol. 5, pp.
101-108, Marcel Dekker, Inc., New York (1975).
Berkson, J. J. Amer. Stat. Assoc., 48, 565 (1953).
Simon, E.J. in "Methods in Narcotics Research" (Ed., S.
Ehrenpreis & A. Neidle) Vol. 5, pp. 349-360, Marcel
Dekker, Inc., New York (1975).
Dewey, W. L., Aceto, M.D., Harris, L.S. and May, E.L.
Reported at the 39th Annual Scientific Meeting of the
Committee on Problems of Drug Dependence (1977) p. 111.
Kamm, J.J. and Leinweber, F. Private communication.
AUTHORS
Emo Mohacsi, Ph.D., and Willy Leimgruber, Ph.D., Chemical Research
Department; and Herman Baruth, B.S., Pharmacology Department;
Hoffman-La Roche Inc.; Nutley, New Jersey 07110
83
Stereospecific and Potent
Analgetic Activity for NantradolA Structurally Novel, CannabinoidRelated Analgetic
Milne, G. M.; Koe, B. K.; Johnson, M. R.
SUMMARY
Nantradol is a structurally novel, cannabinoid-related analgetic
with two to seven times greater potency than morphine across a
battery of analgetic tests. Despite this morphine-like analgetic
profile, nantradol is devoid of interactions at the opiate receptor. Nantradol has a total of five asymmetric centers and has
heretofore been studied as a 50:50 mixture of two diastereomers,
both of which possess the trans 6a, 10a stereochemistry and have
-oriented substituents at positions 6 and 9. Evidence is provided
that, in common with the opiates, the analgetic actions of nantradol are stereospecific, the majority of the activity residing in a
single levorotatory isomer. The stereospecificity and potency of
the analgetic effects of the nantradol series suggests a highly
specific interaction at an as yet unidentified receptor.
INTRODUCTION
Despite long-standing anecdotal evidence suggestive that marijuana
preparations have analgetic properties in man (Li 1974; Rossi 1970),
reports of the analgetic activity of the natural cannabinoids can
best be described as equivocal (Mechoulam 1973; Hill et al. 1974;
Milstein et al. 1975). However recently it has been reported that
oral 9-tetrahydrocannabinol ( 9 -THC, Figure 1), the proposed active
constituent of Cannabis satavia, at 10 and 20 mg provides pain reduction equivalent to codeine (60 and 120 mg) with marked sedation
9
being a primary side effect at the higher doses of
-THX (Brunk
et al. 1975; Noyes et al. 1975; Noyes et al. 1976). Certainly in
laboratory animals, a number of investigators have reported that
8
- and 9-THC exhibit analgetic properties, in some cases comparable to morphine (Sofia et al. 1973; Buxbaum 1972; Chesher et al.
1973; Kaymakcalan, Turker, and Turker 1974). However, Dewey et al.
9
(1972) could not show a significant antinociceptive effect for
THC in the mouse tail flick test.
It is perhaps fitting that one of the most revealing probes into the
analgetic activity of cannabinoid molecules was carried out in the
84
laboratories of Everette May, an acknowledged leader in the field
of opiate analgesics. In 1974, May and Wilson (1974) postulated
- and
-THC was due to their llthat the analgetic activity of
hydroxy metabolites. They supported this conclusion by the observation that the 9-nor derivatives, which cannot be transformed into
the 11-hydroxy metabolites, lack significant analgetic activity but
exhibit dog ataxia and cardiovascular profiles nearly identical to
- and
-THC (Wilson and May 1974; 1975). During these studies
(-)-9-nor-9 -hydroxyhexahydrocannabinol (HHC) was prepared and
found to be analgetic with activity in the mouse hot plate test
nearly equal to that of morphine (Wilson et al. 1976). Their finding that analgetic activity was a discrete, dissociable feature of
the cannabinoid molecule considerably buttressed the historical
case for cannabinoid analgesia.
Recently, we have reported (Milne et al. 1978) on the analgetic
activity of an even more potent and structurally distinct cannabinoid related analgetic, nantradol, with activity two to seven-fold
greater than morphine across a variety of animal tests. Despite an
opioid-like spectrum of analgetic activity, nantradol does not bind
to the opiate receptor in vitro. In distinction to
-THC, nantrado1 exhibits reduced analgetic tolerance development and an improved
ratio of analgetic to cannabinoid-like behavioral activity.
Nantradol has a total of five asymmetric centers; however, owing
to its defined stereochemistry at positions 6, 6a, 9 and 10a, it
is an approximately equal mixture of only four of the possible 32
85
Figure 1. Stereoisomers comprising nantradol
isomers. Nantradol has heretofore been studied only as a 50:50
mixture of the two racemic diastereoisomers indicated in Figure 1,
both of which possess the trans 6a, 10a stereochemistry and have
oriented substituents at positions 6 and 9.
In the present paper,
we will provide evidence that the analgetic actions of nantradol
are stereospecific, both with respect to the nucleus and the C-3
side chain.
METHODS
Subjects: Mice used in most of the studies were Charles River males,
Swiss CD strain (17-21 g). Mice in the 2-phenyl-4-benzoquinone abdominal stretching experiment were Carworth males, albino CF-1
strain, weighing 11-15 g. Rats were Charles River males, SpragueDawley CD strain weighing 180-200 g unless otherwise noted.
Materials:
-Tetrahydrocannabinoid (
-THC) was supplied courtesy
of Ms. Jacqueline R. Porter of NIDA. Nantradol [(±)-1-acetoxy-5,6,
6a ,7,8,9,10,10a -octahydro-9 -hydroxy-6- -methyl-3-(5'-phenyl-2'pentyloxy)-phenanthridine hydrochloride)] and its stereoisomers
(Figure 1) are a product of Pfizer Central Research.
Pentazocine
was graciously donated by Winthrop Laboratories.
Except where otherwise noted, nantradol,
-THC and comparative
standards were dissolved and administered to rodents in a vehicle
consisting of 5 percent ethanol, 5 percent Emulphor-620 and 90 percent saline. This vehicle alone. served as the control treatment.
Doses of salts were calculated from weights of the salt and not of
the base. Solution concentrations were varied to allow a constant
injection volume of 10 ml/kg of mouse and 5 ml/kg of rat.
Statistics:
In several analgesic and other studies, data were first
calculated as the "% maximal possible effect," or % MPE. For most
studies, this datum was calculated as follows:
% MPE =
mean test value - mean control value
x 100
maximum possible value - mean control value
For the PBQ study, it was calculated as follows:
% MPE =
mean control stretches - mean test structures
x 100
mean control stretches
In either case, % MPE may be interpreted as the mean degree of analgesic or other effect on a given test. As it approaches 100 percent,
it indicates that the drug produced the maximum effect possible; as
it approaches 0 percent, it indicates that the drug produced no effect.
In many studies, mean % MPE data were subjected to a linear
least squares regression analysis, from which an "MPE50" was determined. MPE50 may be interpreted as the best estimate of the dose
of a substance at which 50 percent of the maximum possible effect
could be observed on a given test.
Tests of analgesia. Blockade of abdominal stretching after phenylbenzoquinone (PBQ test): Pairs of Carworth CF-1 mice were injected
87
with 2 mg/kg of PBQ i.p. and placed in a lucite box maintained at
40°C by a thermostatically controlled water bath. Drug pretreatment
times were 1 hr unless otherwise specified. Starting 5 min later
the animals were observed for 5 min and the number of abdominal
stretching responses per animal was recorded. A stretch was considered to represent an intermittent contraction of the abdomen,
hind limb extension, pelvic rotation or opisthotonos. The degree
of analgesic protection was calculated on the basis of the suppression of writhing relative to control animals run on the same day
(% MPE), as described above.
Mouse tail-flick test: Tail-flick testing in mice was modified after the D'Amour and Smith (1941) procedure.
Haffner tail-pinch test: A modification of the procedure of Haffner
(1929) was used to ascertain drug effects on the aggressive attacking responses elicited by a pressure stimulus pinching the tail.
Flinch-jump test: A modification of the flinch-jump procedure.
(Evans 1961; Tenen 1968) was used for determining pain thresholds
following drug administration.
THE COMMITTEE ON
PROBLEMS OF DRUG DEPENDENCE, INC.
announces its
42nd ANNUAL SCIENTIFIC MEETING
June 17-19, 1980
Dunfey Hyannis Hotel
West End Circle
Hyannis, MA 02601
For further information, contact:
Dr. Leo E. Hollister, Veterans Administration Hospital, 3801 Miranda Ave., Palo Alto, CA 94304
88
Table 1.
Compound
Comparative Doses Producing 50 Percent of the
Maximum Possible Analgetic Effect
MPE50 (mg/kg sc) at Time of Esimated Peak Activity (95%
Confidence Limits
PBQ Writhingb
Tail Flickb Rat Tail Pinchc Flinch Jumpc
Morphine a
0.9
(0.4-1.3)
2.9
(1.4-7.0)
4.3
(3.5-5.8)
10.3
(6.6-13.8)
-THC
9.1
(5.4-12.3)
55
(32.4-218.2)
-133
83
(47.8-122)
CP-44,001-1
0.4
(.33-.56)
0.7
(.47-1.1)
1.0
(.57-1.6)
1.4
(.89-3.1)
Diastereoisomer A
0.2
(.11-.34)
0.2
(.17-.31)
0.7
(.53-.91)
.30
(.22-.38)
Diastereoisomer B
1.7
(.79-4.5)
2.4
(1.7-4.2)
14.2
(8.3/46.8)
2.4
(1.5-5.1)
CP-50,556-l
0.1
(.05-0.1)
0.2
(0.1-0.4)
0.3
(0.07-.34)
0.3
(0.2-0.5)
CP-53,870-1
6.5
(6.4-6.6)
>10
>10
NA
7.4
(1.3-13)
>56
>56
>56
>100
>100
>100
Pentazoctinea
Aspirin (po)
123
(106-132)
a
All test results at 0.5 hr post dose
Values at 1 hr post dose
Values at 2 hr post dose
b
c
89
RESULTS
Analgetic effects in rodents. Nantradol exerted analgetic effects
against each of the nociceptive challenges exemplified in Table 1.
The pattern of antinociceptive activity seen for nantradol was
similar to that found for morphine but quite distinct from that of
the antiinflammatory and narcotic antagonist standards. Nantradol
was from 20 to 100 times more potent than
-THC, the higher ratios
reflecting superior activity in the more stringent tests for
analgesia.
Comparison of the two diastereomeric components of nantradol (isomers A and B) indicated that most, but not all, of its analgetic
activity resides in the A diastereomer. The levorotatory isomer
of diastereoisomer A (CP-50,556) was likewise shown to account for
the preponderance of both isomer A and nantradol analgetic activity.
DISCUSSION
Nantradol has a number of structural and pharmacological features
which distinguish it from both the opiates and cannabinoids. 'The
most notable structural differences are the absence of a pyran
oxygen, the presence of a weakly basic nitrogen and the introduction of an oxygen-containing C-3 side chain. Nantradol is considerably more potent (20 to 100-fold) than
-THC as an analgetic,
and as previously reported, nantradol also has substantially reduced tolerogenic activity relative to
-THC (Milne et al. 1978).
The substantial potency exhibited by these compounds suggests that
they are acting rather specifically to produce their analgetic effects, and in fact, Wilson and May (1976) had previously found
that the activity of HHC is stereospecific. However, the C-3 side
In the case of nanchain of HHC contains no asymmetric centers.
tradol, we have introduced an asymmetric center in the C-3 side
chain. The results reported herein demonstrate that stereospecificity of action also extends to this region of the molecule.
Since as tested nantradol is a mixture of four isomers - a pair of
racemic diastereomers present in essentially equal amounts, the
first step toward identifying the major active isomer was the separation of nantradol into its component diastereomers - herein
designated diastereoisomers A and B. Diastereomer A is at least
10-fold more potent than its C-3 side chain counterpart diastereomer B in analgetic tests. These results clearly suggest that
isomer A contains the enantiomer responsible for the majority of
nantradol's analgetic activity. Separation of isomer A into its
two optically active components demonstrates that the levorotatory
isomer, CP-50,556-l, possesses the largest portion of the analgetic
activity of nantradol, being four- and two-fold more potent than
nantradol and diastereoisomer A, respectively.
The demonstration that CP-50,556-1 produces opiate-like analgesia
stereospecifically without binding to the opiate receptor suggests
that these new derivatives act stereospecifically at a novel, as
yet unidentified, site of action.
90
ACKNOWLEDGEMENTS
Technical assistance was provided by Werner Kappeler, Maureen A.
Leahy, Charles B. Matylewicz, Gwendolyn Robinson, Lorraine Wagner
and Hans Wiederman. We thank Mrs. J. R. Porter of NIDA and the
various companies cited in the methods section for donations of
standard agents.
REFERENCES
Brunk, S.F., Noyes, R., Jr., Avery, D.H., and Carter, A. The
analgesic effect of
-tetrahydrocannabinol. J Clin Pharmacol,
15(7):554,
1975.
Buxbaum, D.M. Analgesic activity of
-tetrahydrocannabinol
in
the rat and mouse. Psychopharmacologia, 25(3):275-280, 1972.
Chesher, G.B., Dahl, C.J., Everingham, M., Jackson, D.M., MarchantWilliams, H., and Starmer, G.A. The effect of cannabinoids on intestinal motility and their antinociceptive effect in mice. Br J
Pharmacol, 49:588-594, 1973.
D'Amour, F.E., and Smith D.L. A method for determining loss of pain
sensation. J Pharmacol Exp Ther, 72:74-79, 1941.
Dewey, W.L., Harris, L.S., and Kennedy J.S. Some pharmacological
and toxicological effects of 1-trans-tetrahydrocannabinol and
1-trans-tetrahydrocannabinol in laboratory rodents. Arch Int
Pharmacodyn Ther, 196(1):133-145, 1972.
Evans, W.D. A new technique for the investigation of some analgesic
drugs on a reflexive behavior in the rat. Psychopharmacologia,
2:318-325, 1961.
Haffner, F. Experimentelle prüfung schmerzstillender. Deutsch
Med Wschr, 55:731-732, 1929.
Hill, S.Y., Schwin, R., Goodwin, D.W., and Powell, B.J. Marijuana
and pain. J Pharmacol Exp Ther, 188(2):415-418, 1974.
Kaymakcalan, S., Turker, R.K., and Turker, M.N. Analgesic effect
of
-tetrahydrocannabinol in the dog. Psychopharmacologia, 35(2):
123-128, 1974.
Li, H.C. An archeological and historical account of cannabis in
J Economic Botany, 28:437-448, 1974.
China.
Mechoulam, R., ed. Marijuana. New York: Academic Press, 1973.
220, 253, 274, 294 pp and references cited therein.
91
Milne, G.M., Weissman, A., Koe, B.K., and Johnson, M.R. CP-44,001
a novel benzo(c)quinoline analgesic. Pharmacologist, 20(3):243,
1978.
Milstein, S.L., MacCannell, K., Karr, G., and Clark, S. Marijuana
produced changes in pain tolerance experienced and nonexperienced
subjects. Int Pharmacopsychiatry, 10(3):177-182, 1975.
Noyes, R., Jr., Brunk S.F., Avery, D.H., and Canter, A. The analgesic properties of
-tetrahydrocannabinol and codeine. Clin
Pharmacol Ther, 18(1):84-89, 1975.
Noyes, R., Jr., Brunk, S.F., Baram, D.A., and Canter, A. The
Pharmacology of Marijuana. Braude, M.C., and Szara, S., eds.
New York, Raven Press, 1976. 833-836 pp.
Rossi, G.V. Antihypertensive drugs--a review. Amer J Pharm,
142(5):197-207, 1970.
Sofia, R.D., Nalepa, S.D., Harankal, J.J., and Vassar, H.B.
Antiedema and analgesic properties of
-tetrahydrocannabinol.
J Pharmacol Exp Ther, 186(3):646-655, 1973.
Tenen, S.S. Antagonism of the analgesic effect of morphine and
other drugs by p-chlorophenylalanine, a serotonin depletor.
Psychopharmacologia, 12(4):278-285, 1968.
Wilson, R.S., and May, E.L. Analgesics based on the cannabinoid
structure. Abst papers, Amer Chem Soc, 168:Medi 11, 1974.
-tetrahydrocannabinol, a
Wilson, R.S., and May, E.L. 9-Norcannabinoid of metabolic interest. J Med Chem 17(4):475-476,
1974.
Wilson, R.S., and May, E.L. Analgesic properties of the tetrahydrocannabinoids, their metabolites and analogs. J Med Chem,
18(7):700-703, 1975.
Wilson, R.S., May, E.L., Martin, B.R., and Dewey, W.L. 9-Nor-9hydroxyhexahydrocannabinols synthesis, some behavioral and analgesic properties and comparison with the tetrahydrocannabinols.
J Med Chem, 19(9):1165-1167, 1976.
AUTHORS
George M. Milne
B. Kenneth Koe
M. Ross Johnson
Pfizer Central Research
Groton, Connecticut 06340
92
8 -Alky-N-CycloalkyI-DihydroCodeinones and -Morphinones as
Analgesic Narcotic Antagonists
Kotick, M. P.; Leland, D. L.; Polazzi, J. O.; Schut, R. N.
The finding of potent analgesic activity in a series of tertiary
alcohols derived from Diels-Alder adducts of thebaine prompted the
proposal of a lipophilic site on the opiate receptor (Lewis, Bentley,
and Cowan 1971). This new lipophilic site was in addition to the
previously proposed anionic site, the cavity for C-15 and C-16 and
a flat surface for the aromatic A ring. This lipophilic site was
proposed to extend from the vicinity of C-7 and C-8 in the C ring
of the morphine nucleus. This site must be of great importance in
the binding of 6,14-endo-ethenotetrahydrooripavines to the opiate
receptor as demonstrated by the high analgesic potency of this series
and the affinity with which these compounds bind to isolated receptors. We wished to utilize this site in the design of novel, potent
analgesic narcotic antagonists.
In order to utilize this site on the opiate receptor, we initiated
a study to determine the effect of lipophilic alkyl substitution
in this region of the morphine nucleus. At the onset of our work,
it appeared that carbon-carbon bond formation in the C ring could
be most easily accomplished at carbon 8 using a 1, 4- conjugate
addition reaction. In particular, the use of lithium organo copper
reagents (Posner 1972) attracted our attention as an efficient
method for introducing various alkyl groups at this position of
opiate derived
-unsaturated ketones.
We also knew that a narcotic antagonist component of action could
be incorporated into the newly synthesized molecules by replacement
of the N-methyl group with moieties such as cyclopropylmethyl,
cyclobutylmethyl or allyl (Eddy and May 1973). This paper describes
our work on the conjugate addition of alkyl groups to codeinone.
Codeinone (1) was easily prepared from thebaine by modification of
a reported method (Gavard et al. 1965). Addition of a benzene
solution of codeinone (1) to 1.25 equivalents of lithium dimethyl
cuprate in ether gave a mixture of products. The major product,
identified as 8 -methyl-7,8-dihydrocodeinone (2) was obtained in
crystalline form from the reaction mixture in ~ 50 percent yield.
Additional 2 was obtained as the fastest migrating component on
93
chromatography of the mother liquors. The next product eluted was
thebainone-A (3), a 4,5-epoxy cleaved product, identified by comparison with an authentic sample (Sawa, Horiuchi, and Tanaka 1965).
The most polar product, obtained only in small amounts, was identified as the 8 -methyl isomer 4.
The structures of the alkylated products 2 and 4 were proven by mass
spectrometry and nmr studies. The mass spectral fragmentation of
both isomers showed a parent ion peak followed by loss of a methyl
radical. The remainder of the mass spectra were similar to those
reported for codeinone. The configuration of the methyl group in
isomers 2 and 4 were definitively proven by nmr spectroscopy. The
methyl group of 4 was observed at 0.40 in CDCl3 solution.
This
position is upfield by about 0.6 from the methyl group signal of
the major product 2.
The upfield shift in 4 may be attributed to
the anisotropic effect of the aromatic A ring which can occur only
if the methyl group occupies the axial or a orientation.
Having
established the configuration of the methyl group in the minor
product as , and hence, in the major product as
, we observed
94
several other differences in these spectra. The singlet for the
H5 proton of the minor a product was observed at a position slightly
downfield from that of the major product. Secondly, the aromatic
region of 2 was observed as a singlet whereas the aromatic region
of 4 was a sharp narrow doublet with a coupling of 1 Hz. This
difference in the aromatic region was also observed in other
In cases where we isolated only one
pairs which we have isolated.
isomer, the shape of the aromatic region was used to confirm the
stereochemistry at C-8.
The series of 8-alkyl-7,8-dihydrocodeinones we have prepared are
listed in Table 1. We obtained in pure form both the and
isomers of 8-methyl, 8-ethyl- and 8-propyl-dihydrocodeinone, the
isomers in each case being the predominant product. For the
remaining compounds listed in Table 1, we isolated only the
product. Yields for this isomer ranged from a low of 50 percent to a
high of
90 percent. The yields in the conjugate addition reaction
appear to be highly dependent on the purity of the alkyl lithium
compound used to prepare the organo copper complex and in the formation and thermal stability of the lithium diorganocuprate.
CMPD
2a
2b
2c
2d
2e
2t
2g
2h
2i
2j
2k
2l
2m
4a
4b
4e
5a
5b
MOUSE
WRITHING
R
Methyl
Ethyl
Vinyl
Cyclopropyl
-Probyl
-Propyl
-Propenyl
-Butyl
-Butyl
-Butyl A
-Butyl B
-Octyl
Phenyl
Dihydrocodeinone (R=H)
Methyl
Ethyl
-Propyl
1.7
0.64
5.0
15.8
6.6
8.2
> 20
10.6
6.9
5.0
> 10
11.6
> 20
1.06
RAT TAIL
FLICK
>
<
>
>
>
3.6
7.4
47.0
10
20
20
190
10
2.35
0.71
0.98
> 10
1.32
> 10
> 10
0.08
0.13
0.08
0.53
0.35
0.43
Methyl
Ethyl
Digydromorphinone (R=H)
Several of these 8 alkyl-dihydrocodeinones were O-demethylated to
the correspnding morphinones. The transformation of 2 to 5 was
accomplished by heating 2 with pyridine hydrochloride at 200° for
1 to 2 hours.
95
The compounds prepared were tested in both the acetic acid mouse
writhing (Whittle 1964) and heat-induced rat tail flick (Harris and
Pierson 1964) assays for analgesic activity. The results of these
assays are indicated in Table 1. The 8-alkyldihydrocodeinones (2a-b
and 4a-b) and the 8 -alkyldihydromorphinones (5a-b), where the 8
alkyl group is methyl or ethyl, have about the same potencies as
dihydrocodeinone (2, R = H) or dihydromorphinone (5, R = H). Unexpectedly, introduction of a side chain larger than ethyl, for example
n-propyl (2e), or the introduction of unsaturation (2c) or an aromatic group (2m) at the 8 position cause a drop in potency. One of
the stereoisomers of the secondary butyl compounds (2j) was active,
whereas the other was inactive. The 8 -dihydrocodeinones (4a-b) were
also as active as the reference dihydro compounds, but the activity
again rapidly falls off when the 8 group is larger than ethyl.
These data indicate that incorporation of a small alkyl group at the
C-8 position of morphine does not substantially alter the analgesic
effect of the N-methyl compounds.
We next determined the effect of short 8 -alkyl-substituents in Nsubstituted dihydro-codeinones and -morphinones. The agonists 2
were converted to N-cycloalkylmethyl compounds as outlined in Scheme
2. Treatment of 2 with cyanogen bromide gave the N-cyano compounds
6 which were hydrolyzed to the nor-compounds 7 by refluxing in 2 N
HCl. Alkylation with the appropriate bromide gave 3-methoxy-N-antagonists 8. These substituted codeinones were converted to morphinones 9 by pyridine hydrochloride treatment. The corresponding 8hydrogen antagonists (R = H) were prepared as reference compounds
by a similar N-demethylation-alkylation route from dihydrocodeinone.
96
Analgesic data for compounds 8 and 9 are presented in Table 2. Thc
data given are the ED50’s for analgesia in the mouse writhing assay
(Whittle 1964) and for narcotic antagonism against morphine in the
rat tail flick test (Harris and Pierson 1964). Also included are the
agonist-antagonist ratios (MW/AD). Numbers in this column greater
than 1 indicate the compound is more antagonistic than analgesic
while ratios less than 1 indicate compounds which are more analgesic.
In general, N-cyclopropylmethyl (CPM) compounds are strong antago nists while the N-cyclobutylmethy (CBM) compounds are more analgesic.
In the 3-methoxy series 8 CPM, the 8 -alkyl substituent has the
effect of increasing the potency of both the analgesic and antagonist
activities for R equal methyl or ethyl. As seen with the agonists
2, the potency drops off sharply when R is propyl. We therefore
did not prepare any other antagonists where R is other than methyl
or ethyl. For the 3-hydroxy series, 9 CPM, the 8 -methyl group decreases the analgesic potency over the reference 8-hydrogen compound.
The 8 -ethyl group restores antagonist potency but without a similar
increase in analgesia.
In the 3-methoxy-N-cyclobutylmethyl series 8 CBM, the effect of 8substitution is unpredictable. None of the compounds are, however;
of sufficient potency to warrant further investigation. The introduction of an 8 -alkyl substituent in the corresponding 3-hydroxy
series 9 CBM at first. results in a decrease in analgesia while retaining antagonist potency. The 8 -ethyl function further decreases
the analgesic activity while boosting the antagonist potency by a
moderate amount.
97
314-300 0 -80 - 8
On the basis of potency considerations, the 3-methoxy-8 -ethyl CPM
and 3-hydroxy-86-methyl CBM compounds have been studied further in
other pharmacological models. The pharmacological properties of
the 3-methoxy-8 -ethyl CPM compound, TR-5109, are the subject of
another presentation at this meeting (Howes et al. This volume).
To summarize, we have shown that introduction of a small alkyl group
in the
position at C-8 can affect the agonist to antagonist ratios
of N-substituted dihydrocodeinones and dihydromorphinones. The
activity of these novel compounds is clearly dependent on both the
8-alkyl and nitrogen substituents. In addition to further pharmacological studies with 17-cyclopropylmethyl-8 -ethyl-7,8-dihydronorcodeinone (TR-5109), we have also extended this work to the morphinan-6-one series. This continuing work will form the basis of
future communications from these laboratories.
This study has led to the synthesis of a novel analgesic narcotic
antagonist. But, have we succeeded in our goal of utilizing the
proposed lipophilic area on the opiate receptor? The compounds prepared in this study do not have analgesic potency in the range of
ring C bridge tetrahydro-oripavines. We have, however, found a site
which does modify the narcotic agonist-narcotic antagonist profiles
of opiate derivatives. We have succeeded in the practical goal of
obtaining a useful analgesic agent - TR-5109.
REFERENCES
Eddy, N.B., and May, E.L. Origin and history of antagonists. In:
Braude, M.C., et al., ed. Narcotic Antagonists. New York, Raven
Press, 1973. pp. 9-11.
Gavard, J.P., Krauz, F., Rüll, T., and Delfly, M. Sur une nouvelle
method de preparation de la codeinone partir de la thebaine. Bull
Soc Chim France, 486-490, 1965.
Harris, L.S., and Pierson, A.K. Some narcotic antagonists in the
benzomorphan series. J Pharmacol Exp Ther, 143:141-148, 1964.
Lewis, J.W., Bentley, K.W., and Cowan, A.H. Narcotic analgesics and
antagonists. Annu Rev Pharmacol, 11:241-270, 1971.
Posner, G.H. Conjugate addition reaction of organocopper reagents
Organic Reactions, 19:1-113, 1972.
Sawa, Y.K., Horiuchi, M., and Tanaka, K. Synthesis of 3-methoxy-Nmethyl-isomorphinan derivatives. Tetrahedron, 21:1133-1139, 1965.
Whittle, B.A., The use of changes in capillary permeability in mice
to distinguish between narcotic and nonnarcotic analgesics. Br J
Pharmacol, 22:246-253, 1964.
AUTHORS
Michael P. Kotick, Ph.D.; David L. Leland, M.S.;
Joseph O. Polazzi, M.S.; Robert N. Schut, Ph.D.
Chemistry Department, Corporate Research Division
Miles Laboratories, Inc., Elkhart, Indiana 46515
98
The Pharmacology of TR5109, a New
Narcotic Agonist/Antagonist Analgesic
Howes, J. F.; Osgood, P. F.; Razdan, R. K.; Moreno, F.; Castro, A.;
and Villareal, J.
The search for a reliable analgesic without physical dependence
liability led to the development of the narcotic agonist antagonist
analgesics.
While these compounds are not without problems, useful
analgesic activity has been obtained. Pentazocine (Talwin) is the
most successful compound of this series to date.
The criteria desirable for a compound in this series are that it
should be reasonably potent with good narcotic antagonist activity.
The compound should not cause constipation and should be free of
dependence liability.
METHODS
a) Mouse Acetic Acid Writhing Test
Male albino CD-l mice (18-22 g) were used for this study. A modification of the Whittle (1964) procedure was used. The test drug
was given by subcutaneous injection 15 minutes prior to an intraperitoneal injection of 0.5% acetic acid (0.4 ml). The number of
writhes per group of five mice were counted for 20 minutes starting
five minutes after the acetic acid injection. Analgesic potency was
calculated from the difference between the test groups and their
controls.
b) Rat Tail-flick Procedure (for Narcotic Antagonist Activity)
The
Male Albino Wistar rats (100-150 g) were used for this study.
method described by Harris and Pierson (1964) was used.
Two control reaction times were determined thirty minutes apart and
Ten minutes
prior to intraperitoneal injection of the test drug.
later an ED80 dose of morphine was administered subcutaneously and
reaction times were then determined twenty minutes later. The narcotic antagonist activity was determined from the difference between
the groups and control groups which received morphine alone.
c) Estimation of Physical Dependence Liability in the Rat
The method described by Teiger (1974) was used. Male Albino Wistar
rats (200-240 g) were implanted with a polyethylene cannula from the
peritoneal cavity, and subcutaneously to an exit between the ears.
99
This cannula was connected to an infusion pump via a swivel arrangement which allows the animal freedom of movement. Morphine or the
test drug was infused for six days (see Table 3 for schedule). At
the end of 6 days the infusion was stopped and symptoms of withdrawal
were observed for up to 96 hours.
In some experiments at the end of a six-day morphine infusion a 24hour infusion of the test drug was substituted. The animals were observed for signs of withdrawal during this 24-hour period and for a
further 48 hours.
d) Mouse Charcoal Meal Test
The method of Rodriquez and Villarreal (1974) was used. Mice were
given a bolus of charcoal and tragacanth 15 minutes after a dose of
the test drug. 15 minutes later the animals were sacrificed and the
distance that the bolus had travelled along the gastro-intestinal
tract was determined.
Inhibition of gastro-intestinal motility was determined by comparison
with untreated animals.
e) Guinea Pig Ileum
Guinea pig ilea were dissected according to the method of Kosterlitz
and Watt (1968). The segments were incubated overnight in a medium
containing the test drug.
The following day these segments were challenged with a dose of naloxone (300 nM). The spontaneous contraction induced by naloxone was
measured.
f) Respiratory Depressant Studies
Male Wistar rats (300-500 g) were anesthetized with sodium pentobarbital (50 mg/kg ip) and placed on a warming plate. Rectal temperature was monitored and maintained at 37° throughout the experiment. An external jugular vein and a carotid artery were cannulated.
A tracheotomy was made and a short cannula was inserted.
The following variables were measured using a Grass polygraph: Mean
arterial blood pressure, ECG, heart rate, tidal volume, respiratory
rate and minute volume.
RESULTS
TR5109 was selected from a series of 8 ethyl dihydrocodeinones and
dihydromorphinones, based on its pharmacological profile (See Table
1). TR5109 had the best combination of narcotic agonist and antagonist activities in this series.
TR5109 had a duration of action in rodents similar to pentazocine
and produced no overt symptomology in rodents at doses well above
the analgesic dose.
TR5109 did not cause severe effects on gastro-intestinal motility.
TR5109 was similar to pentazocine in this preparation. Its effects
were at doses well above the analgesic doses. (Table 2).
100
Table 1 - Analgesic and narcotic antagonist activities of 8
dihydrocodeinone and dihydromorphinones.
#
R
R'
ethyl
ED50 Mouse Writhing
(mg/kg, SC)
AD50 Rat Tail Flick
(mg/kg, ip)
CH 3
-CH 2
2.1 (0.3 - 13.6)a
0.78 (0.31-1.96)
H
-CH 2
7.8 (4.4 - 13.9)
0.25 (0.08 - 0.80)
CH3
-CH 2
9.6 (3.7 - 24.6)
Iab @ 3.0
IV
H
-CH 2
9.2 (2.5 - 33.9)
0.52
V
CH3
-CH2 CH=CH2
> 10.0
5.6 (1.9-17.0)
H
-CH2 CH=CH2
Ia @ 10.0
0.58 (0.05 - 6.6)
CH3
-CH 2
H
-CH 2
I
TR5109
II
III
VI
VII
VIII
>10.0
(0.18-1.53)
> 10.0
1.06 (0.25 - 4.54)
1.80 (1.24 - 2.62
Pentazocine
3.7 (2.45 - 5.50)
10.4 (3.9 - 28.7)
Cyclazocine
0.11 (0.03 - 0.45)
0.22.(0.13-0.39)
Morphine
0.79 (0.42 - 1.5)
Codeine
4.2 (1.1 - 16.2)
a
b
95% Confidence limits
Inactive
Table 2 - Inhibition of gastrointestinal motility in mice
Compound
TR5109
Pentazocine
Morphine
Cyclazocine
Maximum
Inhibition
67%
71%
100%
39%
Dose for Maximum Dose for 1/2 Maximum
hg/kg , SC)
(mg/kg, SC)
100.0
100.0
10.0
3.0
101
10.0
10.0
1.0
0.1
Table 3 - Physical Dependence Liability Study - Weight Changes
% Change in Weight from Day Oa on
Day
Drug
Infusion
R
Schedule
50 mg/kg/day for 1 day
100 mg/kg/day for 1 day
200 mg/kg/day for 4 days
8
Pentazocine
200 mg/kg for 6 days
4
TR5109
200 mg/kg for 6 days
6
TR5109
400 mg/kg for 6 days
2
Morphine
Control
Saline for 6 days
+ 1
+ 2
-16.8*
-12.7*
+ 4
- 7.8*
- 1.6
±1.9
± 2.3
± 4.6
3.6
2.7
4.9
4.8
+ 3.7
± 5.0
+11.9
± 4.3
+ 3.8
± 6.5
+13.6
± 7.3
- 0.5
+ 3.8
+ 9.7
+11.5
+ 2.7
± 1.5
+ 7.1
± 1.51
+ 8.8
± 2.2
+ 9.6
± 3.8
± 1.3
8
+ 3
±
±
±
7.7*
3.9
5.1
2.5
a
Cessation of Infusion
*
P < 0.05
+
±
+
±
Table 4 - Induction of Withdrawal Signs by TR5109 and Naloxone in
Morphine-Dependent Rats
Symptom
Teeth Chatteringa
Tremors
Chewinga
Wet dog shakesb
Irritability
Aggression
Vocalizationc
DiarrheaC
4 hr Weight loss (%)
TR5109
Naloxone
(10.0mg/kg ip) (2.0mg/kg ip)
1.17
8.67
8.17
15.50
± 0.17
± 0.99
± 0.31
± 3.87
6/6
3/6
4/6
2/6
7.67 ± 1.38
3.20
7.20
3.40
8.20
± 1.01
± 1.61
± 1.12
± 2.67
5/5
1/5
1/5
3/5
6.22 ± 1.01
Saline
0.00
0.00
0.00
0.00
1/5
0/5
1/5
1/5
2.14 ± 0.71
a
Mean number of 3 minute periods/hour that animals showed response
b
Mean number of wet dog shakes per hour
c
Ratio of animals showing responses at 1 hour
d
Expressed as mean % loss at 4 hours
Table 5 - Guinea Pig Ileum Data
Response in GMS (Tension) to
Naloxone (300 nM)
Compound Incubated with Ileum
2.80
2.42
0.43
0.64
0.27
0.44
0.71
Levorphanol (64 nM)
Morphine (480 nM)
Pentazocine (1715 nM)
Nalorphine (156 nM)
Cyclazocine (24 nM)
TR5109 (480 nM)
Fresh Ilea
103
±
±
±
±
±
±
±
0.40
0.07
0.02
0.10
0.07
0.30
0.18
Table 6 - The effects of intravenously injected TR5109 on the
respiration of the anesthetized normotensive rat
Dose
mg/kg
Respiratory
Rate
(per minute)
Minutes after Injection
0
5
30
No.
Rats
1.0
5
5.0
5
10.0
5
100
±9.6
%
105
±3.2
%
97
±9.7
%
40.0
5
104
±10.9
%
Tidal
Volume
(me)
1.0
5
5.0
5
10.0
5
40.0
5a
(0
1.89
±0.138
%
1.93
±0.065
%
1.88
±0.199
%
1.90
±0.146
%
Minute
Volume
(me/min)
1.0
5
5.0
5
10.0
5
40.0
5a
(0
200
±23.2
%
220
±26.7
%
182
±24.6
%
191
±15.5
%
88
±7.2
-12
94
±9.2
-10
86
±8.1
-11
79
±7.7
-24
10
2.02
±0.240
+7
2.02
±0.207
+13
2.65
±0.840
+41
2.09
±0.328
+10
5
181
±24.4
-10
209
±35.6
-5
247 b
±92.3
+36
161
±24.5
-16
104
±10.8
+4
101
±3.7
-4
94
±12.5
-3
110
±12.4
+6
30
1.82
±0.251
-4
1.82
±0.099
+5
2.26
±0.497
+20
1.85
±0.295
-3
30
207
±36.7
+4
216
±31.6
-2
229
±72.8
+26
191
±24.5
0
a
2 other rats died shortly after this dose was injected
b
Effect at 10 minutes. Minute volume was consistently elevated
at this dose (10.0 mg/kg) with the maximum increase occurring
at 10 minutes.
104
Using the rat infusion procedure TR5109 was shown not to produce
physical dependence in rodents. At the termination of the procedure
TR5109 showed no symptoms of withdrawal and weight changes were not
significantly different from controls (Table 3). This was in marked
contrast with pentazocine which caused a significant weight loss and
other signs of withdrawal following termination of infusion, TR5109
did not substitute for morphine in this procedure and appeared to
exacerbate the withdrawal (Table 4). Further, in physically dependent monkeys TR5109 did not support morphine addiction (A. Jacobsonpersonal communication).
Incubation of TR5109 with guinea pig ilea did not induce a state of
physical dependence as defined by the subsequent response to a test,
dose of naloxone. The results are presented in Table 5.
The response to a test dose of naloxone was smaller after incubation
with TR5109 than with pentazocine.
TR5109 had no significant effects on the cardiovascular system of
the dog nor did it cause any respiratory depressant effects in the
rat (Table 6).
CONCLUSIONS
TR5109 represents a logical chemical modification of established
analgesic structures to yield an interesting compound. TR5109 shows
analgesic activity in animals in the same ranges as both morphine
and pentazocine.
It is a more potent narcotic antagonist than pentazocine.
TR5109 is similar to pentazocine in mouse charcoal meal
test.
The rat infusion procedure and the guinea pig ileum data indicate that TR5109 is superior to pentazocine, TR5109 causing no
"physical dependence" in the rat and a much smaller effect on the
guinea pig ileum preparation.
TR5109 is free of cardiovascular and respiratory depressant effects
in animals.
REFERENCES
Harris, L.S. and Pierson, A.K. Some narcotic antagonists in the
benzomorphan series. J. Pharmacol. Exp. Ther. 143(2) 141-148, 1964.
Kosterlitz, H.W. and Watt, A.J. Kinetic parameters of narcotic agonist and antagonists with particular reference to N-allylnoroxymorphone (Naloxone). Brit. J. Pharmacol. Chemother. 33:266-276,1968.
Rodriquez, R. and Villarreal, J.E. Graded quantition of morphine tolerance and dependence on the same physiological system in the mouse.
Committee on Problems of Drug Dependence, Annual Report 453-459 (1974).
Teiger, D.G. Introduction of physical dependence on morphine, codeine and nependine in the rat by continuous infusion. J. Pharmacol. Exp. Ther. 190 (3):408-415, 1974.
Whittle, B.A. The use of changes in capillary permeability in mice
to distinguish between narcotic and nonnarcotic analgesics. Brit.
J. Pharmacol., 22:246-253, 1964.
AUTHORS John F. Howes, Ph.D., Patricia F. Osgood, Ph.D., Raj K.
Rasdan, Ph.D., SISA Inc., 763 Concord Ave., Cambridge, MA 02138, and
Facundo Moreno, Antonio Castro, Julian Villarreal, Ph.D., Institute
Miles de Terapeutica Experimental, Mexico City, Mexico
105
Dependence Potential of
Loperamide Studied in Rhesus
Monkeys
Yanagita, T.; Miyasato, K.; Sato, J.
Loperamide is an antidiarrhetic similar to diphenoxylate that has
been recently developed by Janssen Pharmaceutical Co. It is water
soluble up to only 0.1 percent at room temperature. The pharmacodynamic profile of loperamide is similar to that of diphenoxylate
(Shoji et al 1978a & 1978b); however it is believed that loperamide
has a more potent therapeutic effect with less frequent systemic
side effects in humans than diphenoxylate because of its low absorbability from the gastro-intestinal tract. Since diphenoxylate is
known to possess a morphine-like dependence potential (Fraser &
Isbell 1961), the dependence potential of loperamide was tested by
9 experiments using rhesus monkeys.
METHODS
1.
Gross Behavioral Observation of Acute Central Nervous System
Effects in Normal Monkeys
Twenty-two normal adult male and female monkeys were housed 4 to 6
Single doses of loperamide were administered,
monkeys per cage.
and the monkeys' gross behavioral manifestations of drug effects were
observed prior to and after administration until the disappearance
of the drug effects. Doses used were: 0.25, 0.5 and 1 mg/kg i.v.;
0.25, 1, 4, and 8 mg/kg s.c.; and 0.25, 1, 4, and 16 mg/kg p.o.
For i.v. and low-dose S.C. use, the drug was prepared by first dissolving in distilled water and then adjusting the solution to isotonicity with NaCl. For high-dose S.C. and p.o. use, the drug was
prepared with a 0.5 percent sodium carboxymethylcellulose-water
suspension.
2.
Suppression of Withdrawal Signs by Single Dose Administration
of Loperamide to Morphine Dependent and Withdrawn Monkeys
Monkeys were made physically dependent by repeated S.C. administration of 3 mg/kg of morphine HCl 4 times daily for longer than 8
weeks. The drug was then withdrawn for about 10 hours and when
the animals manifested morphine withdrawal signs, single doses of
106
loperamide at 0.25, 1, and 4 mg/kg were given S.C. to 2 or 4 monkeys
each, with observation for changes in the signs continued for 7
hours. For comparison, saline, morphine HCl at 3 mg/kg, and codeine
phosphate at 16 mg/kg were used.
3.
Development of Physical Dependence on Loperamide by Repeated
Administration to Normal Monkeys
The experiment consisted of 3 parts using different subjects.
Part 1. Subcutaneous administration of loperamide.
Five normal male and female monkeys were administered loperamide
S.C. at doses of 1 mg/kg 4 times daily for 31 days. On days 14 and
28 the naloxone precipitation test was conducted by single dose administrations of naloxone HCl at 1 mg/kg S.C. The natural withdrawal test was conducted from day 32 for 5 days. During the administration period, gross behavior was observed regularly with body
weights determined weekly. Withdrawal observations were conducted
blind and severity of the withdrawal signs were graded according to
Seevers' criteria (Seevers 1936).
Part 2. Oral administration of relatively high doses of loperamide.
Five normal male and female monkeys were orally administered loperamide by gavage at a dose of 2 mg/kg twice daily for 31 days.
The
naloxone tests, natural withdrawal test, and all other observations
were conducted as described in part 1.
Part 3. Oral administration of relatively low doses of loperamide.
Based on the fact that the blood level of loperamide in humans
reaches 10 ng/ml at the highest even after the maximally ingestable
experimental doses (Weintraub et al 1977), the possibility of
development of physical dependence on the drug was studied in
rhesus monkeys at around these blood levels.
Since oral administration of the drug to rhesus monkeys at 2 mg/kg every 12 hours brought
their blood level to approximately 100 ng/ml, in this test each dose
was 0.2 mg/kg. The experiment was started in 6 normal monkeys following the procedure described above. Two weeks later, the blood
levels were determined and it was found that the levels were relatively high (average 15.9 ng/ml) in 3 of the monkeys and low
(average 7.2 ng/ml) in the other 3 (Suzuki et al 1978). The low
group was continued with the same doses for another 4 weeks and 5
days. The doses for the high group were reduced to 0.05 mg/kg for 2
weeks, and then increased to 2.0 mg/kg for the remaining time up to
the 47th day of the experiment.
The blood level of the high group
was determined again at the end of the 0.05 and 2.0 mg/kg administration periods. All monkeys were subjected to the naloxone test on the
14th, 28th, and 42nd days, and to the natural withdrawal test for 5
days at the end of the 47-day administration period.
4.
Intravenous Cross Self-Administration of Loperamide with
Lefetamine and Saline
Six monkeys that had been trained by a method described elsewhere
(Deneau, Yanagita and Seevers 1969) to intravenously self-administer
lefetamine, a standard reinforcing agent, were tested with lefetamine, saline, and loperamide for 3 successive days each, at 4 hours
per day using an FR 1 schedule. This procedure was repeated 3 times
for 3 unit doses of loperamide: 4, 15, and 60 µg/kg/inj. The
107
unit dose of lefetamine was always 0.01 mg/kg/inj.
5.
Continuous Self-Administration of Loperamide
Part 1. Intravenous self-administration.
Two monkeys that had previous experience with i.v. self-administration of lefetamine were tested for 1 to 2 weeks with i.v. selfadministration of saline without time limitations, after which the
animals were allowed to self-administer loperamide at a unit dose of
0.06 mg/kg. One week later the unit dose was increased to 0.25
mg/kg. This time a 2-hour time-out was scheduled after every 4
doses taken within 24 hours because in the preceeding study it had
been determined that the animals would die if allowed to overdose.
When the animals had shown active self-administration of the drug
for 3 to 4 days the unit dose was cut back to 0.06 mg/kg, the timeout schedule was cancelled, and the experiment was continued for
4 weeks. Then, after a 2-day withdrawal test, the experiment was
continued for another 4 weeks at the same unit dose, and finally
a 5-day withdrawal was conducted.
Since experienced monkeys were
found to be taking the drug in the first test, a further experiment
similar to the above was conducted using 2 naive monkeys.
Part 2. Intragastric self-administration.
Four monkeys that had previous experience with i.v. self-administration of pentazocine and/or lefetamine were allowed to intragastricly
self-administer loperamide without time or dose limitations at a unit
dose of 0.25 mg/kg for 6 weeks, and then at 0.5 mg/kg for the 4 to
6 weeks. After this, all monkeys received programmed intragastric
administration of the drug at a dose of 4 mg/kg twice daily for 2
weeks, followed by further observation of intragastric selfadministration at 0.5 mg/kg for 2 more weeks, and at 0.125 mg/kg
for another 2 weeks. Upon termination of the intragastric experiment, the intravenous experiment was conducted in the same animals
at a unit dose of 0.06 mg/kg for 2 weeks.
6.
Progressive Ratio Test for Intravenous Self-Administration of
Loperamide
Three monkeys that had been trained to self-administer lefetamine
i.v. at FR 100 were used in this test. Each trial consisted of
3 periods: a pretreatment period, an FR 100 period, and progressive
ratio period. Each monkey successively underwent 6 trials in a
counterbalanced design. In the pretreatment period, either loperamide (0.06 mg/kg), codeine phosphate (1 mg/kg), or saline (0.25
ml/kg) was administered i.v. every 20 min, 72 times daily for 7 days.
Self-administration was not available in this period. During the
FR 100 period the animals were allowed to self-administer the designated agent at the above-indicated unit dose under the FR 100 schedule for 24 hours. In the progressive ratio period the ratio started
at 100:1, increasing geometrically by a factor of
at every dose,
and continued until the number of lever presses during 48 hours
failed to reach 50 percent of that required for the next dose, upon
which the trial was terminated, with the ratio achieved for the last
administered dose being regarded as the final ratio.
Throughout
the experiment each self-administration was followed by a 15 min
108
time-out period which was indicated to the animal by a panel light.
RESULTS
1.
Gross Behavioral Observation of Acute Central Nervous System
Effects in Normal Monkeys
The acute CNS effects of loperamide were morphine-like; it produced
a decrease in awareness of fellow monkeys and the observers, drowsiness, mydriasis, and skin scratching. These effects were observed
at doses higher than 0.25 mg/kg i.v. and 10. mg/kg S.C. or p.o.
When 1.0 mg/kg was administered, the approximate times for the onset and duration of drug effects were, respectively: i.v., ¼ and
30 hours; s.c., ½ and 30 hours; and p.o., 1 and 20 hours. The
doses of 8 mg/kg S.C. and 16 mg/kg p.o. were toxic with one out of
2 monkeys in each group dying 5 and 4 hours respectively after administration due to respiratory and cardiac failure.
2.
Suppression of Withdrawal Signs by Single Dose Administration
of Loperamide to Morphine Deplendent and Withdrawn Monkeys
All monkeys manifested an intermediate grade of morphine withdrawal
signs about 10 hours after the last dose of morphine. Single doses
of loperamide did not suppress the withdrawal signs at 0.25 or 1.0,
but did so at 4.0 mg/kg S.C. The suppression was complete in 2 of
the monkeys and nearly complete in the other 2. Exactly the same
results as the above were obtained with morphine at 3.0 mg/kg S.C.
Codeine at 16.0 mg/kg S.C. also resulted in nearly complete suppression.
3.
Development of Physical Dependence on Loperamide by Repeated
Administration to Normal Monkeys
Part 1. Subcutaneous administration of loperamide.
As the repeated S.C. administration began, drowsiness was observed
in all 5 monkeys. The drowsiness weakened gradually in the 3rd and
4th weeks of administration, but motor activity was still slow.
The results of the 2 naloxone tests and the natural withdrawal test
are shown in Table 1. The development of physical dependence on
loperamide was quite evident from these results.
TABLE 1.
Development of Physical Dependence by Repeated
Subcutaneous Administration of Loperamide
C
Grade of withdrawal signs ’
Body weight (kg)
Monkey
# 613 female
# 752 male
# 770 male
# 771 male
# 787 male
Withdr
period b’
Naloxone test (mg/kg, s.c )
lnitlal
14th day
28th day
3.6
3.3
3.3
3. 4
3.2
3.3
3.0
3.3
3
3 2
3.1
Severe
Severe
3.4
2.9
3.1
3.2
2.8
2.8
Severe
Severe
Severe
2.9
3.4
3.4
14th day
a) Dosing schedule : 1 mg/kg s.c. 4 times daily for 31 days
b) Minimum body weight during a 5-day withdrawal period (32-36th day)
c) Graded by Seevers criteria.
d) Heaviest grade during the 5-day withdrawal period.
109
Withdrawal test
28th day
Severe
Severe
Intermediate
Severe
Severe
Intermediate
Intermediate
Severe
Intermediate
Severe
d
Part 2. Oral administration of relatively high doses of loperamide.
The results of the repeated oral administration experiment were
quite similar to those of the S.C. experiment, except that the development of physical dependence appeared to be somewhat slower by
this route.
Part 3. Oral administration of relatively low dose of loperamide.
No effect was observable in the monkeys treated with repeated oral
administration of loperamide at 0.2 mg/kg twice daily for 2 to 6
weeks. The naloxone test on day 14 did not precipitate any withdrawal signs in any of the 6 monkeys. The administration was further continued at the same dose in half of the monkeys (Group A)
still the naloxone tests on days 28 and 42 and the natural withdrawal test from day 48 to 52 failed to show any indication of development of physical dependence.
In Group B, definite development of physical dependence was shown by both the naloxone and natural withdrawal tests but only when treated with loperamide at 2.0
mg/kg twice daily for 2 weeks (Table 2).
TABLE 2 Development of Physical Dependence by Small Oral Doses
Body weight (kg)
Group Monkey
lnitial
A
B
Withdr.
14th day 28th day 42nd day p e r i o d b )
Withdrawal
test d)
5.3
None
None
None
None
4.2
4 5
4.4
None
None
None
None
4.2
4.4
4.1
None
None
None
None
4.0
4. 0
4.1
3. 8
None
None
Severe
Intermediate
5.0
5.2
5.1
4. 9
None
None
Intermediate lntermediate
None
None
Intermediate Intermediate
5.2
5.2
4 3
4.4
# 962
female
4.0
4.0
# 931
female
4. 2
# 959
male
# 963
female
5.0
4.6
14th day 28th day 42nd day
c)
5.3
5.2
# 938
male
# 945
female
Grade of withdrawal signs
Naloxone test (1 mg/kg s.c.)
46
4.8
4.0
4.4
a) Dosing schedule : Group A-0.2 mg/kg. po. twice daily for 47 days
Group B-Same as group A for the first 14 days, 0.05 mg/kg twice daily from 15 to 28th day and
2.0 mg/kg twice daily from 29 to 47th day.
b) Mimimum body weight during a 5-day withdrawal period (48-52nd day)
c) Graded by Seevers’ criteria. d) Heaviest grade during the 5-day withdrawal period.
4.
Intravenous Cross Self-Administration of Loperamide with
Lefetamine and Saline
During the daily 4-hour sessions, frequent intake for lefetamine
and infrequent intake for saline were observed in all 6 monkeys
(Table 3). The intake ratio of loperamide against the reference
drug significantly higher than that of saline at a unit dose of
15 µg/kg.
5.
Continuous
Self-Administration
of
Loperamide
Part 1. Intravenous self-administration.
Both experienced and naive monkeys initiated and maintained selfadministration when allowed to take the drug at a unit dose of
0.25 mg/kg. Once initiated they maintained this behavior at a unit
dose of 0.06 mg/kg (Table 4). The highest daily dose taken by any
monkey was 7.05 mg/kg/day in an average over a 2-week period.
110
TABLE 3 Intravenous Cross Self-Administration of Loperamide
with Lefetamine and Saline
Average No. of
self-administ.
Monkey
0.1 mg/kg/inj
# 648 male
# 673 male
#
#
#
#
Percent ratio of self-administration rate lefetamine as 100%
Lefetamine
4.1kg
4.0kg
758 female 4.1kg
768 male
4.3kg
798 male
3.5kg
799 male
3.7kg
Saline
(/4hrs/day)
390.5
203 4
0.004
(%)
0.06
0.015
(%)
10
6.6
8.9
53.8
2.5
(%)
7.5
6 2
6.9
5.3
0.3
36 6
13.5
40.5
41.8
33 3
14.4
15.8
37.8
9.0±3.1
14.1 ± 20 2
193.1
260.9
320 9
213 2
Mean ± S.D.
Loperamide (mg/kg/inj)
0.25ml/kg/inj
b)
(%)
11.7
38.1
12.6
c)
11.0
c)
8 7
c)
5.2
33 9 ± 10.5”
a ) l-1, 2-diphenyl-dimrthyl-aminoethane HCl
b) Overdosed and fell into coma on the 2nd day of the test at this unit dose and the test was terminated
This monkey died 4days later.
c) Self-administration was limited to shorter than 4 hours for prevention of the overdose
··P<0.01 against saline
In these animals, although CNS depression was observed, no such
toxic manifestations as paralysis, coma, respiratory insufficiency,
convulsions, or death were observed.
In the 2-day withdrawal test
conducted at the end of the 4-week self-administration period, all
monkeys manifested severe withdrawal signs and increased their
lever-pressing responses. This increase was particulary marked in
the naive monkeys. Self-administration was resumed in 3 monkeys for
an additional 2 to 4 weeks, and a further increase of the daily dose
level was observed in 2 of the monkeys. In the 5-day withdrawal
test, the withdrawal signs in monkeys #681 were very severe and a
gradual withdrawing schedule by programmed administration of loperamide had to be implemented.
Part 2. Intragastric self-administration.
During the 10 to 12-week periods none of the 4 monkeys initiated
self-administration of loperamide by the intragastric route at the
unit doses of 0.25 or 0.5 mg/kg. Programmed administration of the
drug at 4.0 mg/kg twice daily for 2 weeks also failed to result in
initiation of self-administration. Therefore the experiment was continued changing to the i.v. route in all except one monkey which died
during the programmed administration period. This time all 3 monkeys
initiated self-administration.
TABLE 4.
Continuous Intravenous Self-Administration of Loperamide
Average daily number of self-administration
Naive or
Monkey
Saline
Loperamide
0 25 for
Withdrawal 0.06
0.06 for
experienced 0.25ml/kg/inj. 0.06 mg/kg/inj
a)
for 2 w x 2
2-4days
2W x 2 periods for 2days
for 1 week
for 1 week
b)
# 669 Experienced
female
4.3kg
b)
# 681 Experienced
male
4.4kg
# 641
female
4.6kg
# 779
male
3.2kg
Withdrawal
for 5 days
0.6
1.0
15.0
44.8.
36.9 (1st d. 120) 38 2. 47.0 (1st d. 232)
(2nd d. 234)
(2nd d. 46)
2.3
2.0
7.0
29.9.
47.4 (1st d. 227) 72.7.
(2nd d. 61)
Naive
2.7
4.8
35.6, 117.5 (1st d. 405)
(2nd d. 42)
Naive
2.7
6.0
36.0,
6 5 . 0 ( 1 s t d . 4 9 3 ) 86.7.
(2nd d. 139)
(1st d. 518)
(2nd d. 68)
(1st d. 453)
(2nd d. 108)
a) Deprived for 2hours after every four intakes. The period before initiation of self-administration not included.
b) Previously experienced with intravenous self-administration of lefetamine but deprived from any experiments for
longer than 1 month.
111
6.
Progressive Ratio Test for Intravenous Self-administration of
Loperamide
In the first trial for saline the monkeys only took a few doses during the FR and PR periods, with the final ratios recorded as 140,
120, and 170 in monkeys #325, 478, and 769, respectively (Table 5).
In the trials for codeine, the number of self-administrations in 2
monkeys was fewer when pretreated than when not pretreated for all 3
monkeys (Table 6). In the trials for loperamide, the number of selfadministrations during the FR and PR periods tended to be lower than
was the case for codeine regardless of whether or not the animals
were pretreated. The final ratio was also generally low, particularly in monkeys #325 and 769 when pretreated. When pretreated with codeine or loperamide, mild to intermediate grades of withdrawal signs
were observed during the FR and/or PR periods.
TABLE 5 Final Ratios in the Progressive Ratio Test
Saline
Monkey
0.25ml
/kg/inj.
Codeine phosphate
Loperamide HCI
1.0mg/kg/inj.
0.06mg/kg/inj.
Pretreated
a)
with codeine
Control
(saline)
Pretreated
a)
with loperamide
Control
(saline)
Saline
0.25ml
/kg/inj.
# 325 female 3.6kg
140( 1)
3200(2)
2690( 3 )
140( 5 )
670( 4 )
# 478 female 3.65kg
120( 1)
12800( 3 )
6400(2)
1350( 4)
670( 5 )
170( 6 )
# 769 male
170( 1)
10760( 4 )
4530(5)
0(3)
570( 2 )
340( 6 )
4.85kg
Died( 6)
a) Pretreated by programmed intravenous administration of the drug at the indicated unit doses every 20 minutes
(72 injections/day) for 7 days.
( ) : Test order of trials in each monkey.
TABLE 6 Number of Self-administration in the Progressive Ratio
Test
Agent
Monkey
Saline
Unit dose
(mg/kg/inj.,j.v.)
a)
Codeine phosphate
Loperamide HCl
1.0
0.06
0.25ml
Salien
0.25ml
Pretreated
None-pretreated
Pretreated
Non-pretreated
FR period
b)
PR period
4(1)
3
0(2)
21
53(3)
20
7(5)
3
16(4)
12
Died(6)
FR
P R
4 ( 1 )
2
80(3)
29
64(2)
2 5
12(4)
16
25(5)
1 2
8 ( 6 )
4
No. 769
F R
P R
6 ( 1 )
4
1(4)
28
19(5)
23
0(3)
male 4.85kg
0
3(2)
11
4 ( 6 )
8
No. 325
female 3.6kg
No. 478
female 3.65kg
a) The 24-hour fixed ratio 100 period.
b) The progressive ratio period.
( ) : Test order of trials in each monkey.
DISCUSSION
The pharmacological profile of loperamide observed in this study was
very similar to that of morphine or the many morphine-like narcotics
in such aspects as the acute CNS effects, the tolerance-and physical
dependence-producing properties, antagonization by naloxone, and the
positive reinforcing effect of i.v. self-administration. However,
loperamide differed from morphine-like narcotics in that it failed to
produce physical dependence at oral doses of one-tenth the maximum
tolerable dose, it showed no reinforcing effect with the intragastric
route of self-administration, and the intensity of its i.v. reinforcing effect as assessed by the progressive ratio test was substantially
112
weaker than that of codeine even after the development of physical deBased on these findings and taking the
pendence prior to the test.
dose-blood level relationships of rhesus monkeys and humans into account, it was concluded that the development of dependence on this
drug is unlikely to occur in humans because the low water-solubility
and oral bioavailability may be self-limiting so that any use of the
drug will still fail to increase the blood level to the point that
dependence may be developed.
REFERENCES
1.
Deneau, G.; Yanagita, T.; and Seevers, M. H. Self-administration
A measure of psychoof psychoactive substances by the monkey.
logical dependence.
Psychoparmacologia (Berl), 16:30-48, 1969.
Fraser, H. F.; and Isbell, H. Human pharmacology and addictive2.
ness of ethyl l-(3-cyano-3, 3-phenylpropyl)-4-phenyl-4-piperidine
carboxylate hydrochloride (R-1132, Diphenoxylate). Bull Narcot,
13:29-43, 1961.
3. Seevers, M. H.
Opiate addiction in the monkey. I. Methods of
study.
J Pharmacol Exp Ther, 56:147-156, 1936.
4. Sohji, Y.; Kawashima, K.; and Shimizu, M. Pharmacological
studies of loperamide, an anti-diarrheal agent.
II. Effects on
peristalsis of the small intestine and colon in guinea pigs.
Folia Pharmacol Japon, 74:155-163, 1978a. (in Japanese)
5. Sohji, Y.; Kawashima, K.; and Shimizu, M. Pharmacological studies
III.
Interaction between
of loperamide, an anti-diarrheal agent.
loperamide and various agonists in the guinea pig intestine.
Folia Pharmacol Japon, 74:213-223, 1978b. (in Japanese)
6. Suzuki, H.; Iwaisaki, M.; Sekine, Y.; Minaki, Y.; and Hashimoto,
m. Blood levels of loperamide in monkeys. The Clinical Report,
12:3429-3438, 1978. (in Japanese)
AUTHORS
T. Yanagita, K. Miyasato, J. Sato
Preclinical Research Laboratories
Central Institute for Experimental Animals
1433 Nogawa, Takatsu-ku
Kawasaki, Japan 213
113
314-300 0 -80 - 9
Opioid Self-Administration and
REM Sleep EEG Power Spectra
Steinfels, G. F.; Young, G. A.; Khazan, N.
INTRODUCTION
An
animal model of self-maintained drug dependence became available in 1961 when a technique was established which permitted a
rat to press a lever switch in order to self-administer norphine,
via an indwelling intravenous (iv) cannula (Weeks, 1961); and in
this way, the rat resembled a drug addict by maintaining itself
in a state of dependence. Meanwhile, studies of the electroencephalogram (EEG) had demonstrated that various states of consciousness such as wakefulness, drowsiness, or sleep were associated with distinct EEG patterns (Morruzzi and Magoun, 1949).
Thus, the experimental self-administration model of Weeks was incorporated with a method for chronic recording of cortical EEG;
(Khazan, Weeks and Schroeder, 1967; Khazan and Weeks, 1968). The
resulting experimental model allows continuous recording of ongoing EEG changes during morphine self-administration and provides
a basic model for simultaneous study of behavioral and electrophysiological correlates during self-maintained dependence in the
rat (see review, Khazan, 1975).
Self-injections of morphine in dependent rats produced a biphasic
response consisting of a brief episode of behavioral stupor with
EEG; slow bursts that was followed by behavioral and EEG arousal
(Khazan et al, 1967; Khazan and Weeks, 1968). Sleep and REM sleep
episodes then predominated until immediately before the next selfinjection.
These morphine-dependent rats with free access to an
operant lever for self-administration usually took single iv injections (10 mg/kg) every 2 to 3 hours (Weeks and Collins, 1968;
Moreton, Roehrs and Khazan, 1976).
We have used this experimental self-administration model study
electrophysiological and behavioral correlates during the selfadministration of other narcotics such as methadone,
-alphaacetylmathadol (LAAM),nor-INN (NLAAM), and dinor-IAAM (DNLAAM)
(Moreton et al., 1976; Young, Steinfels and Khazan, in press).
Although the average intervals between methadone self-injections
were shorter than those with morphine (1.5 to 2 hours), similar
114
biphasic EEG and behavioral responses were seen. Unlike morphine
or methadone, however, after LAAM self-injections a few sleep and
rapid eye movement (REM) sleep episodes did sometimes emerge before the stuporous phase. Self-administration of NLAAM also produced a biphasic EEG and behavioral response similar to that seen
with morphine and methadone. In contrast, there were no apparent
relationships between DNLAAM self-injections and distribution of
sleep-awake activity.
Recently, power spectral analysis has been used in our laboratory
to quantitate EEG parameters not readily discernible by visual
observations.
The EEG recordings during the three behavioral
states of wakefulness, sleep, and REM sleep in the rat demonstrated
characteristic power spectra (Young, Steinfels, Khazan and Glaser,
1978a). We have recently found that as time progressed from one
morphine self-injection in a dependent rat toward the next injection a significant spectral shift of the EEG to slower frequencies
OCCurred during successive REM sleep episodes (Young, Steinfels,
Khazan, and Glaser, 1978). Each morphine self-injection reinstated
the predominance of faster frequencies in the REM sleep EEG spectra. We have also found similar changes in EEG frequency during
methadone self-administration in the rat (Steinfels, Young, and
Khazan, 1978). In the present study we report on comparative
changes in EEG power spectra derived from successive REM sleep
EEG episodes during self-administration of five narcotics: morphine, methadone, LAAM, and the active N-demethylated metabolites of LAAM, NLAAM and DNLAAM.
METHODS
Animals and Experimental Preparation
Eighteen adult female Sprague-Dawley rats weighing 250-275 grams
were prepared with chronic EEG and EMG (electromyographic) electrodes (Khazan, 1975). Stainless steel screws served as bipolar
cortical electrodes and were implanted over the frontal
and ipsilateral parietal cortices. For EMG recordings, stainless
steel wires were sewn into the left and right temporalis muscles.
Wire leads from the EEG and EMG electrodes were soldered into a
miniature connector which was secured to the skull with dental
acrylic. For drug administration a silicone rubber cannula was
implanted in the right jugular vein (Weeks, 1972).
During the experimental procedures, all animals were housed in
individual chambers. To permit unrestrained movement of the rat
during EEG and recordings, each cage was equipped with a
swivel connector with concentric mercury pools which served as
noise-free sliding contacts. A feed-through cannula for drug
administration extended through the center of each swivel. An
eight-hour lights-off period was maintained from 10 p.m. to
6 a.m., and room temperature was kept at 72-78°F.
115
Drugs Used
The drugs use were: morphine sulfate (Mallinckrodt, Inc., St.
Louis, MO.), methadone HCl (Eli Lilly and Go., Indianapolis, IN.),
-alpha-acetylmethadol HCl (NIDA, Bethesda, MD.), noracetylmethadol
HCl (NIDA, Bethesda, MD.),and dinoracetylmethadol (NIDA, Bethesda,
MD.). All drugs were dissolved in isotonic saline (0.9%) and doses
are expressed as the salt. A 0.1 ml volume administered over
6 seconds utilized during intravenous drug administration.
Drug Self-administration
Pats were first made tolerant to and physically dependent on morphine by a series of electronically-controlled automatic hourly iv
injections.
During the firstdayrats received 1.25 mg/kg/hr of
morphine . The dose was increased to 2.5, 5.0, 10.0, and 20.0 mg/
kg/hr on successive days. Fifteen of the rats were then trained
to lever press on a fixed ratio (FR) schedule of reinforcement to
receive morphine (10 mg/kg/injection). An FR of one lever press
was initially required per injection, which was gradudlly increased
to FR-20. After one week of stabilized responding for morphine,
the rats were divided into five groups of three rats each. One
group continued to self-administer morphine. In each of the other
four groups, methadone (2 mg/kg/injection), LAAM (1 mg/kg/injection), NLAAM (1 mg/kg/injection), or DNLAMM (1 mg/kg/injection)
was substituted for morphine. These doses were selected based
upon previous dose-response studies in our laboratory (Moreton et
aL, 1976; Young et al., in press). At least one week was allowed
for restabilization self-administration patterns and then data
were collected for further analysis. The remaining morphinetolerant rats were not trained to lever press but were given automatic morphine injections every 2.5 hours foratleastoneweek.
This interinjection interval of 2.5 hours approximated the average
interinjection interval reported earlier during morphine selfadmimistration (Khazan and Weeks, 1968; Moreton et al., 1976).
Data Collection and Analysis of REM Sleep EEG
Continuous EEG and EMG activities were recorded on a Grass model
7D polygraph. The EEG was filtered to pass frequencies between
1 and 35 Hz. The EEG activity was also recorded on FM tape with
a Hewlett-Packard model 3960-A recorder.
REM sleep onset was determined by the corresponding changes in
gross behavior and the appearance of theta waves with a coincident
drop in integrated EMG activity (Khazan et al., 1967; Khazan and
Weeks, 1968; Khazan, 1975; Moreton et al., 1976). The EEG of the
successive REM sleep episodes occurring between drug interinjections were analyzed as follows. Using a Nicolet MED-80 system,
power spectra were derived from the EEG during each REM sleep episode. The EEG was digitized at a sampling rate of 54 samples per
second, and power spectral densities from zero to 27 Hz were estimated at 0.1 Hz intervals and weighted geometric smoothing over
three neighboring frequencies was used.
116
RESULTS
Figure 1 shows a sample of theta waves recorded during a REM sleep
episode.
The resulting power spectrum from an entire REM sleep
episode is shown on the right. It can be seen that the majority
of the spectral power occurred beween 5 and 9 Hz(theta band).
FIGURE 1
FAST SPEED TRACING
POWER SPECTRUM
Fast-speed tracing of EEG theta waves during REM sleep
in a naive rat is displayed in the left-hand box. A
power spectrum derived from REM sleep EEG is shown in
the right-hand box. In this example, the majority of
the spectral power is in the 5-9 Hz bandwidth and the
peak EEG frequency is 7.2 Hz.
Changes in peak EEG: frequencies of REM sleep episodes during selfadministration of morphine, methadone, LAAM,NLAAM,and DNLAAM are
shown in Figure 2 as best-fit linear regression lines. The length
of each regression line relative to the x-axis reflects the average durationof the interinjection intervals for that narcotic.
Analyses of variance (all p < .05) indicated that the changes in
mean peak EEG frequencies during morphine [F(5,10)=17.97], methadone [F(7,14)=12.59], LAAM [F(8,16=6.82], NLAAM [F(7,14)=21.72],
and DNLAAM [F(9,18=13.64] interinjection intervals were significant. Analyses of the same data for linear trends were also significant.
When the data for all five narcotics were compared in
an analyses of covariance, significance was found [F(5,35=8.65].
Further analyses of covariance indicated that the linear regressions associated with morphine and methadone were not different
from one another, but were different from those associated with
LAAM, NLAAM, and DNLAAM. Furthermore, the linear regressions
associated with LAAM, NLAAM, and DNLAAM were all significantly
different from one another.
In order to determine whether lever pressing activity per se was a
significant factor in producing the changes in mean peak EEG frequencies, morphine-tolerant rats were studied while receiving automatically delivered morphine injections. The results were analogous to those obtained during morphine self-administration. As
time progressed from one automatic morphine injection toward
another injection, a linear decline in man peak EEG frequencies
occurred during successive REM sleep episopdes.
117
FIGURE 2
Mean EEG peak frequencies (Hz) of successive REM sleep
episodes during narcotic interinjection intervals are
The length of each
shown as best-fit regression lines.
line relative to the x-axis indicates the average duration between setf-injections of the respective drug
(interinjection interval). The slopes of the linear
regression lines expressed in Hz/hour ± s.d. are:
morphine (.72 ± .25), methadone (.53 ± .35), LAAM
(.03 ± .02), NLAAM (.21 ± .04), and DNLAAM (.11 ± .07).
DISCUSSION
In a previous report from this laboratory we compared the EEG frequency spectra derived from the first REM sleep EEG episodes after
self-injections of morphine independent rats with those derived
from the last REM sleep episodes just prior to the next injections
(Young et al, 1978b). It was foundthatthe average mean peak frequency associated with the first REM sleep EEG episodes was significantly faster than that during the last REM sleep episodes. The
presentstudyhas extended those findings by demonstrating the existence of linear declines in FEM sleep EEG peak frequencies during
morphine, methadone, LAAM, NLAAM, and DNLAAM self-administration in
dependent rats.
The differences seen in linear regression slopes among the five
narcotic drugs (Figure 2) were probably related to differences in
their pharmacodynamic properties. Compared to morphine or methadone, LAAM's longer duration of action has been postulated to result from the formation of its active N-dmthylated metabolites,
NLAAM and DNLAAM. Evidence for this arises from the fact that its
two N-demethylated metabolites have been shown to accumulate in the
118
plasma (Billings, McMahon, and Blake, 1974; Henderson, Weinberg,
Hargreaves, Lau, Tyler, and Baker, 1977a; Henderson, Wilson, and
Lau, 1977b), and to have relatively long plasm half-lives (Kaiko
and Inturrisi, 1975). Therefore, in the present study the smaller
Slopes of LAAM, NLAAM, and DNLAAM, compared to morphine and methadone, are presumably related to their longer half-lives.
REFERENCES
Billings, R.E., McMahon, R.E. and Blake, D.A. Alpha-acetylmethadol
(LAM) treatment of opiate dependence: Plasma and urine levels of
two pharmacologically active metablites. Life Sci, 14:1437-1446,
1974.
Henderson, G.L., Weinberg, J.A., Hargreaves, W.A., Lau, D.H.M.,
Tyler, J. and Baker, B. Accumulation of 1-alpha-acetylmethadol
(LAAM) and active metabolites in plasma following chronic administration. J Anal Toxicol, 1:1-5, 1977a.
Henderson, G.L., Wilson, B.K. and Lau, D.H.M. Plasma 1-alphaacetylmethadol (LAAM) after acute and chronic administration.
Clin Pharmacol Therap, 21:16-25, 1977b.
Kaiko, R.T. and Inturrisi, C.E. Disposition of acetylmethadol in
relation to pharmacological action. Clin Pharmacol Therap, 18:96103, 1975.
Khazan, N. The implication and significance of EEG and sleepawake activity in the study of experimental drug dependence on
morphine.
In: Ehrenpreis, S. and Neidle, A.,eds. Methods in
Narcotics Research. Vol. 5, Modern Pharmacology-Toxicology.
New York : Marcel Dekker, Inc., 1975, pp. 173-215.
Khazan, N. and Weeks, J.R. The electroencephalogram (EEG) and
the electromyogram(EMG) of self-maintained morphine addicted rats
in relation to injections. Phamamlogist, 10:189, 1968.
Khazan, N., weeks, J.R. and Schroeder, L.A. Electmencephalographic, electromyographic, and behavioral correlates during a cycle of
self-mintained morphine addiction in the rat. J Pharmacol exp
Ther, 155:521-531, 1967.
Moreton, J.E., Roehrs, T. and Khazan, N. Drug self-administration
and sleep-awake activity in rats dependent on morphine, methadone,
or
-alpha-acetylmethadol. Psychopharmacologia, 47:237-241, 1976.
Morruzzi, G. and Magoun, H.W. Brain stem reticular formation and
activation of the EEG. Electroenceph clin Neurophysiol, 1:455473, 1949.
Steinfels, G.F., Young, G.A. and Khazan, N. Morphine and methadone self-administration independent rats: Associated EEG spectral changes. Fed Proc, 37:310, 1978.
119
Weeks, J.R. Self-maintained morphine addiction. A method for
chronic programmed intravenous injections in unrestrained rats.
Fed Proc, 20:397, 1961.
Weeks, J.R. Long-term intravenous infusion. In: Myers, R.D.,
ed. Methods in Psychobiology. Vol. II. New York : Academic
Press, 1972, pp. 155-168.
Weeks, J.R. and Collins, R.J. Patterns of intravenous selfinjection by mophine-addicted rats. In: Myers, R.D., ed.
The Addictive States. Baltimore : Williams and Wilkins Co.,
1968, pp. 288-298.
Young, G.A., Steinfels, G.F. and Khazan, N. (in press). Pharmacodynamic profiles of
-alpha-acetylmethadol (LAAM) and its Ndemthylated metabolites, nor-LAAM and dinor-LAAM, during selfadministration in the dependent rat. J Pharmacol exp Ther.
Young, G.A., Steinfels, G.F., Khazan, N. and Glaser, E.M. Cortical
EEG; power spectra associated with sleep-awake behavior in the rat.
Pharmacol Biochem Behav, 8:89-91, 1978a.
Young, G.A., Steinfels, G.F., Khazan, N. and Glaser, E.M. Morphine
self-administration and EEG power spectra in the rat. Pharmacol
Biochem Behav, 9:525-527, 1978b.
ACKNOWLEDGMENT:
This study was supported by NIDA Grant DA 01050.
AUTHORS
George F. Steinfels, M.S.
Gerald A. Young, Ph.D.
Naim Khazan, Ph.D.
Department of Pharmacology and Toxicology
University of Maryland School of Pharmacy
636 West Lombard street
Baltimore, Maryland 21201
120
Motor Activity and Learning Ability
in Rats Perinatally Exposed to
Methadone
Zagon, I. S.; McLaughlin, P. J.
INTRODUCTION
Methadone is a synthetic narcotic analgesic that is commonly
utilized in detoxification and maintenance programs for narcoticaddicted pregnant women (Blinick et al. 1976). In spite of its
widespread clinical use, the short-term and long-term consequences
of methadone exposure on perinatal development have not been elucidated. However, in the limited number of clinical studies that
have been conducted, children delivered by methadone-exposed
mothers have been reported to be retarded in body growth (Ting,
Keller, and Finnegan 1975; Wilson 1975) and to exhibit behavioral
abnormalities (Ting, Keller, and Finnegan 1975).
The developing nervous system of laboratory animals appears to be
particularly sensitive to methadone. Previous studies (McLaughlin,
Zagon, and White 1978; Thompson, Zagon, and McLaughlin 1979; Zagon
and McLaughlin 1977a; 1977b; 1977c; 1978a; 1978b) in our laboratory,
using different schedules of maternal methadone treatments, reveal
that drug-exposed rat offspring have morphological and biochemical
alterations in brain and cerebellar development as well as disturbances in somatic growth and preweaning behavior. The present investigation was undertaken in order to determine the effects of perinatal methadone exposure on motor activity in young rats and to
establish whether adult learning ability is impaired.
METHOD
Subjects and Drug Treatment:
Female (180-200 g) and male (250-300 g) Sprague-Dawley rats (Charles
River Labs, Wilmington, MA) were utilized in this study and housed
under controlled conditions (Zagon and McLaughlin l977b). Females
were treated daily with an i.p. injection of either 5.0 mg/kg
dl-methadone hydrochloride (Dolophine), or an equivalent volume of
saline.
Five days after initiating drug treatment, females were
mated. Within 4 hr of birth, 4 groups of animals based on treatment schedule (i.e. exposure to methadone during gestation,
121
lactation, or gestation-lactation, as well as controls) were established (Zagon and McLaughlin 1977b; 1977c; 1978a; 1978b). All
offspring were weighed at birth and on days 21, 45, 60, and 120.
Eight males and 8 females from
were tested for activity levels
4 females from each group were
days, 6-9 female rats comprised
each of the 4 treatment schedules
at 21 days of age, and 4 males and
tested at 45 and 60 days. At 120
each of the treatment groups.
Apparatus and Procedures:
Activity cage. A cylindrical activity cage (Lehigh Valley Electronics, Model 145-03), 60 cm in diameter and 38 cm high, which
contained 6 banks of infrared photobeams was utilized to assess
locomotor activity in a darkened area. An animal’s movement was
measured as the total number of photobeam interruptions during a
5 min period.
Open field. The open field was constructed of masonite with a 52.5
cm x 52.2 cm surface divided by painted lines into 25 squares; the
walls were 20 cm high. Illumination was provided by standard
fluorescent ceiling lights and all lights were turned on throughout the test period. During testing each rat was placed in the
center square of the field and allowed to explore the area for 5
min. Locomotion was scored as the total number of squares entered
with all four paws.
Animals were tested at three age periods: days 21, 45, and 60. On
day 21, rats were removed from their home cages, marked for identification, placed in plastic holding cages (5 rats per cage), and
allowed one hr to acclimate to the testing location. Each test
required approximately 5 min, with a minimum interval of 50 min
between tests. Test order was randomized for all animals in order
to control for effects of order of presentation. Rats were returned
to their home cages at the end of each test day. This procedure
was replicated at each age.
Active avoidance. The apparatus for conducting active avoidance
tests was a standard 2-way shuttle box (Lafayette Instrument Co.).
A 6 W light bulb, suspended from the ceiling; was used as the conditioned stimulus and a 1 ma shock passed through a Lehigh Valley
model 1531 scrambler was the unconditioned stimulus.
Tests were designed to measure the ability of an animal to respond
to a visual signal within 5 sec by crossing a barrier in order to
avoid receiving a footshock. On day 1, rats were habituated to the
shuttle box for a 15 min period. On each of the next 5 days, 20
avoidance training trials (total 100 trials) with 45 sec intertrial
Illumination of the test compartment
intervals were conducted.
signalled that shock would be administered in 5 sec.
If the rat
crossed to the alternate compartment within this interval, no footIf an avoidshock occurred and an avoidance response was recorded.
ance was not made, a 1 ma footshock was administered and terminated
when the animal crossed to the other compartment (escape).
122
Footshock was terminated and the trial ended if the rat did not
successfully cross to the other compartment within 10 sec.
Discrimination learning. Animals were tested in a 4-unit discrimination box (Krechevsky 1932). Pats were habituated by allowing
them to freely explore the discrimination apparatus for 15-min
sessions on each of 5 days. During the entire testing period, rats
were maintained on a one hr per day feeding schedule, with food
available for one hour immediately following each test session;
a palatable wet mash was also present in the goal box. During
actual training, one randomly chosen alleyway was illuminated and
a barrier was positioned across the darkened exit on the opposite
side. The rat was placed in the start box and allowed to find its
way to the goal box. The guillotine doors of each compartment were
lowered after the animal passed into the next compartment in order
to prevent the rat from returning to the start box. Each rat made
5 runs (20 discriminations) per day for 5 days; a one-minute interval in the goal box was allowed between runs. A wrong choice was
recorded if the rat's head and forefeet passed through the opening
of a blocked alley. The sequence of lighted and darkened choicepoints was randomized for each of the 25 runs.
Data analysis. Body weights were evaluated by analysis of variance
with Treatment Schedule and Sex considered as between-groups variables and Age as a repeated measure; subsequent analyses were made
using Dunnett's procedure (Winer 1971).
Performance on each of the activity measures was evaluated by analysis of variance. At 21 days, two-factor analyses of variance
were used to evaluate the number of squares entered in the open
field and number of photobeam interruptions in the darkened
activity cage. Sex and Treatment Schedule were treated as betweengroups variables. Because group size differed, data obtained at
45 and 60 days were evaluated using a three-factor analysis of
variance with Sex and Treatment Schedule as between-groups variables and Age (45 or 60 days) as a within-groups variable. Subsequent comparisons involving groups were made using Dunnett's
procedure (Winer 1955).
RESULTS
Body Weights:
Pats that were perinatally exposed to methadone tended to weigh
less than controls prior to sexual maturity, but differences were
reliable only at certain ages for males. Males exposed to methadone during lactation weighed less than controls at 45 and 60 days
of age, and those exposed to drug only during gestation had body
weights that were less than controls at 60 days. Body weights of
animals in the gestation-lactation group did not differ from controls at any age. By 120 days, female rats perinatally exposed to
methadone had body weights that were comparable to controls.
123
Motor Activity Behavior:
Methadone-treated animals were generally less active than controls
at 21 days in the activity cage and open field tests (Tables 1 and
2). Animals in the gestation, lactation, and gestation-lactation
groups made fewer photobeam interruptions than controls and entered
fewer squares in the open field. In contrast to the reductions in
activity observed at weaning, methadone-exposed offspring were more
active than controls at 45 and 60 days of age. Rats treated with
methadone only during lactation were significantly more active than
controls in both activity cage and open field tests. Furthermore,
rats in the gestation group entered more squares in the open field
and animals exposed to methadone during both gestation and lactation recorded more photobeam interruptions in the darkened activity
cage than controls. In general, males were more active than females
at 45 and 60 days, and males became more active with increasing age
in comparison to female counterparts.
Table 1.
The effect of perinatal methadone exposure on activity
cage performance of young rats
Treatment Schedule
Age
Control
Gestation
Lactation
Gestation-Lactation
21
132.40
99.12*
107.08*
115.40*
45
97.80
90.68
134.96*
119.18*
60
104.56
128.43
189.50*
138.31*
Values represent mean number of photobeam interruptions in the
darkened activity cage in 5 min. N = 16 at 21 days; n = 8 at 45
and 60 days. Significantly different from controls at p<0.01 (*).
Table 2.
The effect of perinatal methadone exposure on
performance in the open field on young rats.
Treatment Schedule
Age
Gestation-Lactation
Control
Gestation
Lactation
21
38.23
20.85*
29.31*
18.29*
45
26.78
35.25*
43.79*
24.78
60
23.90
26.78*
34.96*
27.18
Values represent mean number of squares entered in the open field
in 5 min. N = 16 at 21 days; n = 8 at 45 and 60 days. Significantly different from controls at p<0.01 (*).
124
Learning Behavior:
Active avoidance. Group differences in the numbers of animals
successfully meeting the criterion of 5 consecutive avoidances
within 100 test trials were analyzed using the Fisher Exact Probability test (Winer 1971). When data from the three experimental
groups were combined and compared with controls, a significantly
smaller proportion of methadone-treated rats met criterion (43.5
percent methadone and 87.5 percent controls, p = 0.037). Comparisons of control animals with rats from individual methadone
treatment schedules revealed that only 33.3 percent of the animals
in the gestation and gestation-lactation groups met the criterion
of 5 consecutive avoidances in comparison to 87.5 percent of the
controls (p = 0.031 in both comparisons). Sixty-two percent of
the rats in the lactation group met the criterion within 100 trials,
and this proportion did not differ significantly from control.
levels. No significant differences between groups were found for
total number of avoidances, footshocks, or crossings from one
compartment to another.
Discrimination learning. Group differences in the number of
animals successfully meeting the criterion of 9 correct discriminations within 10 consecutive choices were analyzed using the Fisher
Exact Probability test. In comparison to controls, a smaller proportion of females exposed to methadone met the criterion (87.5
percent and 36.4 percent, respectively). Only 33 percent of animals in the gestation group and 25 percent of rats in the lactation
group met the criterion in comparison to 87.5 percent controls
(p = 0.047 and p = 0.01, respectively). Sixty percent of animals
in the gestation-lactation group met the criterion. When the total
number of correct discriminations out of 100 were evaluated by
analysis of variance, no group differences were detected. Differences between the actual number of correct responses and the expected chance levels were analyzed for each of the four groups
using the t-test for single means. On the last 50 discriminations,
the percentage of correct responses for each group were as follows:
gestation, 53 percent; lactation, 54 percent; gestation-lactation,
64 percent; controls, 62 percent; these percentages differed from
chance levels only for animals in the control and gestationlactation groups (both p's <0.05).
DISCUSSION
The results of a previous investigation on the ontogeny of gross
motor development and the maturation of sensory and motor behaviors
(Zagon and McLaughlin 1978b) revealed that the ages of initial appearance and 50 percent and maximal appearances of a particular behavior were often delayed several days for methadone-treated offspring in comparison to controls. However, these behavioral responses were eventually achieved by all rats, indicating only
transient retardation in preweaning behavioral development. The
present results demonstrate that rats treated with methadone in
utero and/or during lactation were less active than controls at
weaning, but more active by postnatal days 45 and 60. Moreover,
125
in adulthood, female rats maternally exposed to methadone had an
impairment in learning ability. Thus, methadone exposure during
gestation and/or lactation has a profound effect on activity levels
prior to sexual maturity and cognitive abilities in adulthood, with
the magnitude of behavioral alterations related to the schedule of
opioid treatment.
The cognitive deficits in adult rats that were perinatally exposed to methadone may be a function of the inability to overcome initial learning deficits, retarded rate of acquisition,
and/or failure to maintain attention to appropriate cues. Although
the two tests employed in the present study were designed to define
learning capabilities, it must be recognized that a number of factors (e.g., emotionality, motivation, physical impairments) may
have influenced the results. However, in the present study, drugtreated rats were not found to be blind, undernourished, physically
retarded, or unmotivated.
It appears that perinatal methadone
exposure may not totally disrupt normal behavior but rather exerts
a selective influence upon certain aspects of behavioral development and learning abilities, with the degree of functional loss
differing among the treatment schedules.
The results of the present investigation may be correlated with
clinical observations on children delivered by mothers subjected
to methadone. These children tend to have electroencephalographic
and behavioral changes consistent with increased central nervous
system irritability and lowered overall alertness (Lodge, Marcus,
and Ramer 1975; Ramer and Lodge 1975), as well as behavioral patterns characterized by hyperactivity (Ting, Keller, and Finnegan
1975; Wilson 1975) and a high intensity of response (Ting, Keller,
In view of these clinical findings, and our
and Finnegan 1975).
results suggesting that methadone alters both somatic and neurobiological development, it appears that further research is needed
to define the long-term consequences of perinatal methadone exposure.
ACKNOWLEDGMENT
This research was supported by National Institute on Drug Abuse
grant DA 01618.
REFERENCES
Blinick, G., Wallach, R.C., Jerez, E., and Ackerman, B.D. Drug
addiction in pregnancy and the neonate. Am J Obstet Gynecol, 125:
135-142, 1976.
Krechevsky, I. "Hypothesis" versus "chance" in the presolution
period of sensory discrimination learning. University of California
Publications in Psychology, No. 3, 1932. pp. 27-44.
Lodge, A., Marcus, M.M., and Ramer, C.M. Behavioral and electrophysiological characteristics of the addicted neonate. Addict Dis, 2:
235-255, 1975.
126
McLaughlin, P.J., Zagon, I.S., and White, W.J. Perinatal methadone
exposure in rats: effects on body and organ development.
Biol Neonate, 34: 48-54, 1978.
Ramer, C.M., and Lodge, A. Clinical developmental characteristics
of infants of mothers on methadone maintenance. Addict Dis, 2:
227-234, 1975.
Thompson, C.I., Zagon, I.S., and McLaughlin, P.J. Impaired thermal
regulation in juvenile rats following perinatal methadone exposure.
Pharmac Biochem Behav, 10: 551-556, 1979.
Ting, R.Y., Keller, A., and Finnegan, L.P. Physical, neurological,
and developmental assessment of infants born to methadone dependent
mothers. Proc Second Natn Drug Abuse Conf, New Orleans, 1975.
Wilson, G.S. Somatic growth effects of perinatal addiction. Addict
Dis, 2: 333-345, 1975.
Winer, B.J. Statistical Principles in Experimental Design. New
York: McGraw Hill, 1971, 907 pp.
Zagon, I.S., and McLaughlin, P.J. Effect of chronic maternal
methadone exposure on perinatal development. Biol Neonate, 31:
271-272, 1977a.
Zagon, I.S., and McLaughlin, P.J. The effects of different schedules of methadone treatment on rat brain development. Exp Neurol,
56: 538-552, 1977b.
Zagon, I.S., and McLaughlin, P.J. Methadone and brain development.
Experientia, 33: 1486-1487, 1977c.
Zagon, I.S., and McLaughlin, P.J. Perinatal methadone exposure and
brain development: a biochemical study. J Neurochem, 31: 49-54,
1978a.
Zagon, I.S., and McLaughlin, P.J; Perinatal methadone exposure and
its influence on the behavioral ontogeny of rats. Pharmac Biochem
Behav, 9: 665-672, 1978b.
AUTHORS
Ian S. Zagon, Ph.D.
Associate Professor of Anatomy
The Milton S. Hershey Medical Center
of The Pennsylvania State University
Hershey, Pennsylvania 17033
Patricia J. McLaughlin, M.S.
Research Assistant in Anatomy
The Milton S. Hershey Medical Center
of The Pennsylvania State University
Hershey, Pennsylvania 17033
127
Narcotic Drug Discriminations by
Rhesus Monkeys and Pigeons
Woods, J. H.; Herling, S.; Valentino, R. J.; Hein, D. W.;
Coale, E. H., Jr.
Drug discrimination procedures, which reinforce responding differentially in the
presence and absence of drug administration, have demonstrated several important
aspects of the behavioral pharmacology of narcotics. Using these techniques it has been
shown that morphine-like compounds have discriminable effects that are similar across
chemically different classes of narcotics (e.g., Colpaert, 1978). The discriminative
effects of morphine-like drugs are easily differentiated from those of a variety of other
behaviorally active classes of drugs such as major tranquilizers and sedative hypnotics
(e.g., Shannon and Holtzman, 1976). More important, perhaps, is the fact that differences among narcotic analgesics have been shown. Rats and squirrel monkeys trained
to discriminate morphine from saline do not generalize completely to cyclazocine, and
vice versa (Holtzman et al., 1977). Since marked differences in the interoceptive effects
of these drugs in humans have been reported, Holtzman and his colleagues (e.g.,
Schaefer and Holtzman, 1978) have suggested a strong correspondence between the
discriminative effects of these drugs in animals and the subjective effects of the drugs
in man.
We were interested in describing the discriminative effects of a variety of narcotics
in the rhesus monkey, chosen because of the vast information available on narcotics
in this species, and the pigeon, chosen on the basis of convenience for comparative
purposes. In terms of drug classification, we were interested in whether we could
find distinctive drug classes, based on drug-induced discriminative effects, that would
correspond to Martin’s hypothesis (Martin et al., 1976) that three receptors mediate
the agonist effects of narcotics. In addition, we have investigated the discriminative
actions of systemically active narcotic peptides in an attempt to establish a correspondence between structural analogues of enkephalin and Martin’s classificatory
scheme. Finally, we have studied the discriminative properties of naltrexone in pigeons
that were otherwise drug naive. The direct actions of naltrexone responsible for its
discriminative effects appear to be different from those of other narcotic agonists and
mixed agonist-antagonists.
METHODS
Subjects. White Cameaux pigeons, obtained from Palmetto Pigeon Farm, Sumter,
South Carolina, were reduced to approximately 80 percent of ad libitum feeding
weight and maintained at this weight by reduced feeding supplemental to that earned
in the experiments. Rhesus monkeys, obtained from Primate Imports, New York, N.Y.,
or Mol Enterprises, Portland, Oregon, were reduced to approximately 85 percent of
128
free feeding weight. They were fed sufficient Purina Monkey Chow after each session
to maintain their reduced weights; fresh fruit was provided following most sessions.
The monkeys were also given isoniazid (20 mg/day) on sugar cubes. All animals were
housed individually and water was freely available in the home cages.
Discrimination training. The discrimination training procedure used in these experiments is similar to that described by others (e.g., Colpaert et al., 1976). The experimental chambers were fitted with two keys and a food receptacle. Programming and
recording were accomplished by a Texas Instruments 960A computer and cumulative recorders. The animals were trained to operate the keys by the method of successive approximation, and initially each response was reinforced. Responses on the right
or left key were reinforced on successive days depending upon whether drug or saline
administration occurred before the session; responses on the inappropriate key had no
programmed consequence. The number of responses required for reinforcement was
gradually increased across successive sessions until 20 consecutive responses (fixed ratio
20) were required. Responses on the inappropriate key reset the fixed-ratio requirement on the appropriate key. Responding by the monkeys was reinforced by the
delivery of a 300 mg banana-flavored Noyes food pellet, while responding by the
pigeons was maintained by 4 sec access to a hopper containing mixed grain. Training
sessions ended after either 32 (for the pigeons) or 75 (for the monkeys) reinforcer
deliveries, or after 1 hour, whichever occurred first.
Animals continued on the training procedure 6 days/week until they met the criteria
of emitting less than 40 responses before the first reinforcer delivery and distributing
at least 90 percent of the total session responses on the appropriate key for 5 consecutive sessions during which drug and saline injections alternated and then for 4
consecutive sessions during which drug and saline pretreatments were administered
in a double alternation sequence.
Dose-effect determinations for training drugs. Following acquisition of the drug/saline
discrimination, various doses of the training drug were evaluated for their ability to
produce drug-appropriate responding. Throughout these sessions, 20 consecutive
responses on either the drug-appropriate or saline-appropriate key were reinforced.
In general, testing with different doses of the training drug was conducted on Tues.,
Thur., and Sat., while further drug/saline discrimination training continued during
the remaining daily sessions. If an animal failed to achieve the discrimination criteria,
described above, on a given training session, further testing was postponed until these
criteria were met on at least two consecutive training sessions.
Cross-drug evaluations. Dose-effect evaluations for a variety of drugs were conducted
to establish the ability of these drugs to produce discriminative effects similar to
those of the training drugs. Testing was conducted as described above for the training drugs. Single observations per dose were obtained at a variety of doses for each
test drug, and in most cases, in each of at least three animals.
Several measures of the discriminative control of behavior exerted by the drugs were
obtained. We report here the average dose of each test drug which was required to
produce more than 90 percent of the total session responses on the drug-appropriate
key.
Drugs. Naltrexone hydrochloride and naloxone hydrochloride were generously supplied by Endo Labs. Ethylketazocine methane sulfonate, pentazocine (base), cyclazocine (base), ketazocine methane sulfonate and meperidine hydrochloride were
provided by Dr. W. Michne (Sterling Winthrop). FK 33824 (Tyr-D-Ala-Cly-MePheMet(0)-ol) was generously supplied by Dr. D. Roemer (Sandoz). Etorphine hydro129
314-300 0 -80 - 10
chloride was provided by Dr. R. Willette (NIDA). Dextrorphan tartrate and UM 1046
(3-cyclopropylmethyl-1,2,3,4,5,6-hexahydro-8-hydroxy-6-methyl-3-benzazocine
hydrochloride) were gifts from Hoffmann LaRoche. UM 979 ((-)-5,9-dimethyl-2(3-furylmethyl)-2'-hydroxy-6,7-benzomorphan), UM 1072 ((+)-(1R/S, 5R/S, 9R/S,
2"R/S)-5,9-dimethyl-2'-hydroxy-2-tetrahydrofurfuryl-6,7-benzomorphan
hydrochloride) and quatemary naltrexone were kindly provided by Dr. H. Merz (BoehringerIngelheim). Apomorphine hydrochloride was a gift from Merck & Co. Cyclorphan
hydrochloride was donated by Dr. M. Gates (University of Rochester). SKF-10,047
was provided by Dr. A. Jacobson (NIH). D-amphetamine sulfate was a gift from Smith,
Kline and French. Nalorphine hydrochloride was provided by Lilly. Codeine phosphate
and sodium pentobarbital were obtained from University Hospital, Ann Arbor, MI.
Morphine sulfate was purchsed from Mallinckrodt (St. Louis); thyrotropin releasing
hormone (TRH) from Sigma (St. Louis); and bemegride from Aldrich (Milwaukee).
RESULTS
Assessment of morphine-like and ethylketazocine-like drugs in rhesus monkeys and
pigeons. Rhesus monkeys were trained to discriminate either etorphine (0.001 mg/kg,
i.m., 40 min before session) or ethylketazocine (EKC; 0.01 mg/kg, i.m., 10 min before
session) from saline. Table 1 shows that drugs that produced drug-appropriate responding in monkeys trained to discriminate etorphine from saline, i.e., morphine, meperidine, codeine and the systemically active. analogue of methionine enkephalin, FK
33824, did not produce drug-appropriate responding in animals trained to discriminate
EKC from saline. Conversely, EKC and SKF-10,047, drugs which produced doserelated EKC-appropriate responding, were inactive as cues in etorphine-trained monkeys.
Pentazocine, at behaviorally active doses, did not produce drug-appropriate responding
in either group of animals. In the monkey, the following drugs were also fully equivalent
to EKC (doses, mg/kg, given in parentheses): cyclazocine (0.02); ketazocine (0.04);
cyclorphan (0.05); nalorphine (0.32); and UM 1072 (0.01) and UM 909 (1.0) (two
furyl N-substituted benzomorphans that fulfill some of the criteria for kappa-receptor
agonist activity, Woods et al., 1978). In addition to the narcotic agonists listed in
table 1 which -failed to produce EKC-appropriate responding, apomorphine (0.030.32 mg/kg), pentobarbital (3.2-17.8 mg/kg), and dextrorphan (1.0-5.6) were not
equivalent to EKC.
Table 1
Average dose, mg/kg, of compounds required to produce at least 90 percent of the total session responses on the drug-appropriate key in rhesus monkeys.
Training Drugs, Dose (mg/kg)
Compound
(dose range tested, mg/kg)
morphine
meperidine
codeine
FK 33824
EKC
SKF-10,047
pentazocine
(0.1 - 10.0)
(0.1 - 1 .8
(0.32 _ 10.0)
(0.1 - 3.2)
(0.003 - 0.03)
(0.1 - 1.8)
(0.32 - 3.2)
a
b
etorphine, 0.001
(n=2)
EKC, 0.01
(n=3)
1.0
0.7
3.2
2.1
inactive as cue
inactive as cue
inactive as cue
inactive as cuea
inactive as cue
inactive as cue
inactive s as cue
0.01 b
0.4
inactive as cue
The majority of responses following the administration of drugs which were “inactive as cues” were
made on the saline-appropriate key.
n=5
130
Pigeons were trained to discriminate either morphine (10 mg/kg , i.m., 10 min before
session) or EKC (0.32 mg/kg, i.m., 5 min before session) from saline. The pattern of
cross-drug evaluation in the pigeon (table 2) was markedly different from that seen in
the monkey. Morphine-trained pigeons showed drug-appropriate responding following
injections of EKC and vice versa. EKC was five times more potent than morphine in
producing drug-appropriate responding in morphine-trained birds and 24 times more
potent than morphine in EKC-trained birds. In addition, drugs that were equivalent
only in EKC-trained monkeys (e.g., ketazocine, UM 909, and UM 1072) or in etorphinetrained monkeys (e.g., codeine and FK 33824) produced drug-appropriate responding
in both groups of birds. Pentazocine, which had not occasioned drug-appropriate
responding in either group of monkeys, produced both morphine- and EKC-appropriate
responding in pigeons. While the doses of these drugs needed to produce morphineappropriate responding were, in most instances, at least twice those required for EKCappropriate responding, the rank order of potencies of these compounds were virtually
identical in the two groups of birds (table 2).
Table 2
Average dose, mg/kg, of compounds required to produce at least 90 percent of the total session
responses on the drug-appropriate key in pigeonsa
Training Drugs, Dose (mg/kg)
Compound
(dose range tested, mg/kg)
morphine
EKC
ketazocine
codeine
FK 33824
UM 909
UM 1072
pentazocine
cyclazocine
SKF - 10,047
pentobarbital
dextrorphan
morphine, 10.0
(3.2 - 32.0)
(0.03 - 10.0)
(0.03 - 10.0)
(3.2 - 32.0)
(0.1 - 3.2)
(3.2 - 32.0)
(0.03 . 1 0)
(3.2 - 32.0)
(0.32 - 3.2)
(1.0 - 17.8)
(5.6 . 17.8)
(3.2 - 32.0)
7.4
1.4
5.8
21.4
2.5
10.0
0.5
19.4
inactive as cueb
inactive as cue
inactive as cue
inactive as cue
EKC, 0.32
4.8
0.2
1 .4
17.8
1.0
12.6
0.3
10.0
inactive as cue
inactive as cue
inactive as cue
inactive as cue
a
Each compound was studied in at least three subjects.
The majority of responses following the administration of drugs which were “inactive as cues”
were made on the saline-appropriate key.
b
Behaviorally active doses of cyclazocine, SKF-10,047, pentobarbital, and dextrorphan
were not equivalent to either morphine or EKC in the pigeon. The inability of cyclazocine and SKF-10,047 to produce EKC-appropriate responding in the pigeon is in direct
contrast to the effects of these drugs in EKC-trained rhesus monkeys.
Assessment of the discriminative effects of naltrexone in pigeons. Pigeons were trained
to discriminate naltrexone (32 or 56 mg/kg i.m., 10 min before session) from saline.
Each of ten pigeons acquired the discrimination. The results of cross-testing with a
variety of agents in an attempt to characterize the naltrexone cue are shown in table 3.
Naloxone produced more than 90 percent drug-appropriate responding (i.e., complete
generalization) in 4 of 5 birds. In these birds naloxone was equipotent to naltrexone.
On the other hand, EKC produced less than 10 percent naltrexone-appropriate responding in each of the pigeons tested. Cyclazocine, amphetamine, bemegride,
131
Table 3
Drugs evaluated in pigeons trained to discriminate naltrexone (32 or 56 mg/kg) from saline.
Drug (dose range tested, mg/kg)
Number of Birds
Tested
Numbers of Birds Showing Various Degrees
of Naltrexone-Appropriate Responding
Complete
> 90%+
naltrexone (3.2 - 56.0)
naloxone (10.0 - 56.0)
UM 979 (3.2 - 32.0)
UM 1046 (3.2 - 17.8)
cyclazocine (0.32 - 5.6)
EKC (0.32 - 10.0)
quarternary naltrexone (10.0-56.0)
TRH (3.2-32.0)
bemegride (1.0 - 10.0)
amphetamine (0.32 - 3.2)
10
5
5
5
5
3
5
3
3
4
10 (28)**
4 (25)
2 (7)
2 (8)
1(32)
1(10)
Intermediate
11-89%*
1
2
2
3
1
1
1
1
Absent
< 10%*
1
1
2
3
3
1
2
3
*Values refer to the percentage of the total responses during the session which were distributed on
the naltrexone-appropriate key.
**Given in parentheses is the average dose, mg/kg, required to produce at least 90% naltrexoneappropriate responding.
quaternary naltrexone, and TRH caused little or only intermediate amounts of
naltrexone-appropriate responding in most of the birds, although quatemary naltrexone
(32 mg/kg) and TRH (10 mg/kg) each produced complete generalization in one pigeon.
UM 1046, a compound that produces a syndrome resembling narcotic abstinence in
narcotic-naive monkeys (Valentino et al., 1978), and UM 979, a drug with narcoticantagonist properties, both produced more than 90 percent naltrexone-appropriate
responding in 2 of 5 pigeons, and intermediate levels of drug-appropriate responding
in two others.
DISCUSSION
The data reported here support the general proposition that drug discrimination techniques may be used to distinguish among different types of narcotics. Our results with
EKC and etorphine in the rhesus monkey are similar to those of Holtzman and his
colleagues (Holtzman et al., 1977; Schaefer and Holtzman, 1978) who studied the
discriminative effects of morphine and cyclazocine in the squirrel monkey. There is
general agreement between our data and theirs where there are direct comparisons;
they found that cyclazocine-trained squirrel monkeys showed drug-appropriate responding to ketazocine but not tomorphine. We have used EKC as a training drug
rather than cyclazocine because EKC does not appear to be an antagonist of morphine,
and yet, the discriminative effects of cyclazocine, ketazocine, and EKC are similar in
these two species of primates. Of considerable importance to us was the fact that two
n-furyl substituted benzomorphans, UM 909 and UM 1072, which were predicted to
be compounds with EKC-like activity (Woods et al.. 1978), produced EKC-appropriate
responding in the rhesus monkey. It is quite possible that we can use the distinctiveness of the EKC cue to specify the structure-activity characteristics of drugs with
EKC-like agonist activity. Drugs classified in this way can then be used to examine the
substrates of behavioral actions associated with EKC-like compounds. The fact that the
pigeon appears to lack the ability to discriminate morphine-like from EKC-like compounds under these conditions (table 2; Herling et al., 1979) may reflect the absence
132
of a necessary substrate. It is obvious that further drug and substrate differences
between the pigeon and the rhesus monkey may be helpful in determining mechanisms
of action for these drug classes.
The pigeon is able to distinguish the administration of naltrexone from saline, although
doses required to establish this drug discrimination are quite high (e.g., 32 mg/kg). At
these doses, the antagonism of morphine by narcotic antagonists may be limited by
the antagonist’s direct action on behavior (e.g., Downs and Woods, 1976). Thus while
it may be appealing to invoke interference with an endorphin system as the basis
of the discriminability of naltrexone, only further pharmacological analysis will delineate drugs that share common discriminative properties with naltrexone and drugs
that might block its discriminative effects. Nevertheless, the discriminative effects of
the naltrexone cue appear clearly distinct from other narcotic cues that have been
established in the pigeon.
Our findings with FK 33824 are of considerable interest; the initial subjective reports
of its effects in man indicated that it appeared somewhat unlike morphine (von
Graffenried et al., 1978). Nevertheless, the behavioral pharmacology of the peptide in
animals suggests strong morphine-like effects (e.g., Roemer et al., 1977; Hill et al..
1978), and the discriminative effects of the drug in the rhesus monkey and pigeon
suggest common discriminative elements with morphine (tables 1,2). We have, on the
other hand, found that FK 33824 was self-injected by rhesus monkeys at rates considerably below codeine and morphine and only slightly above saline (Woods et al.,
1979). An examination of factors which dissociate the discriminative and reinforcing
effects of narcotic-like neuropeptides is an interesting subject for further research.
In terms of our overall objectives we have found strong evidence in the rhesus monkey
for distinctive discriminative cues for mu (morphine-like) and kappa (EKC-like) compounds, in accord with Martin’s classification. The sigma agonist, SKF-10,047, was
EKC-like in the monkey. In the pigeon, morphine and EKC appear to share common
discriminative effects; and neither cyclazocine nor SKF-10,047 is a member of this
class, although both drugs are EKC-like in the rhesus monkey. It is possible that in the
pigeon the bases for the discriminative effects of cyclazocine and SKF-10,047 are
related to the mechanism of action responsible for the sigma-like effects of these drugs
described in the dog by Martin and his colleagues.
Our findings with naltrexone in the pigeon establish this drug as a cue for the first time
in a naive subject. A full characterization of the discriminative effects of pure antagonists will have important theoretical implications for the classification of narcotic
drugs in both the naive and dependent state. The initial findings with FK 33824
suggest that the combined use of a discriminative and reinforcing stimulus analysis of
enkephalin analogues (Woods et al., 1979) may be helpful in establishing the similarity
of neuropeptide actions to those of other narcotic drugs.
REFERENCES
Colpaert, F. C. Discriminative stimulus properties of narcotic analgesic drugs. Pharmacol Biochem
Behav, 9:863-887, 1978.
Colpaert, F. C., Niemegeers, C. J. E., and Janssen, P. A. J. Theoretical and methodological considerations on drug discrimination learning. Psychopharmacology, 46: 169-177, 1976.
Downs, D. A., and Woods, J. H. Morphine, pentazocine and naloxone effects on responding under a
multiple schedule of reinforcement in rhesus monkeys and pigeons. J Pharmacol Exp Therap, 196:
298-306, 1976.
133
Herling, S., Hein, D. W., Valentine, R. J., Winger, G. D., and Coale, E. Narcotic drug discrimination in
pigeons. Fed Proc, 38:740, 1979.
Hill, R. C., Roemer, D., and Buescher, H. H. Some pharmacological properties of FK 33824, a stable
orally active analogue of methionine enkephalin. In: Costa, E., and Trabucchi, M., eds. The Endorphins. New York: Raven Press, 1978. pp. 211-215.
Holtzman, S. G., Shannon, H. E., and Schaefer, G. J. Discriminative properties of narcotic antagonists.
In: Lal,H.,ed.Discriminative Stimulus Functions of Drugs. New York: Plenum Press, 1977.pp.47-72.
Martin, W. R., Eades, C. G., Thompson, J. A., Huppler, R. E., and Gilbert, P.E. The effects of morphineand nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J
Pharmacol Exp Therap. 197:517-532,1976.
Roemer, D., Buescher, H. H., Hill, R. C., Pless, J., Bauer, W., Cardinaux, F., Closse, A., Houser, D.,
and Hueguenin, R. A synthetic enkephalin analogue with prolonged parenteral and oral analgesic
activity. Nature, 268:547-549, 1977.
Schaefer, G. J., and Holtzman, S. G. Discriminative effects of cyclazocine in the squirrel monkey. J
Pharmacol Exp Therap, 205:291-302, 1978.
Shannon, H. E., and Holtzman, S. G. Evaluation of the discriminative effects of morphine in the rat.
J Pharmacol Exp Therap, 198:54-65, 1976.
Valentino, R. J., Smith, C. B., and Woods, J. H. Release of acetylcholine in the guinea pig ileum by a
benzazocine which produces effects similar to the narcotic abstinence syndrome. Comm Prob Drug
Dependence: Proc of the 40th Scientific Meeting, 1978. pp. 753-767.
von Graffenried, B., del Pozo, E., Roubicek, J., Krebs, E., Poldinger, W., Burmeister, P., and Kerp, L.
Effects of the synthetic enkephalin analogue FK 33824 in man. Nature, 272:729-730, 1978.
Woods, J. H., Fly, C. L., and Swain, H. H. Behavioral actions of some n-furyl benzomorphans and
ketazocines in rhesus monkeys and mice. In: Van Ree, J. M., and Terenius, L., eds. Characteristics
and Functions of Opioids. New York: Elsevier/North Holland, 1978. pp. 403-411.
Woods, J. H., Hein, D. W., Herling, S., Young, A. M., and Valentino, R. J. Discriminative and remforcing effects of some systemically active enkephalin analogues. In: Way, E. L. et al., eds, Endogenous and Exogenous Opioid Agonists and Antagonists. New York: Plenum Press, 1979. In press.
ACKNOWLEDGEMENTS
This research was supported by USPHS Grants DA 00154 and DA 00254. We would like to thank Dr.
Alice Young whose helpful comments vastly improved the manuscript.
AUTHORS
James H. Woods, Ph.D.
Seymore Herling
Rita J. Valentino
David W. Hein and
Edward H. Coale, Jr.
Departments of Pharmacology and Psychology
M6322 Medical Science Building I
University of Michigan
Ann Arbor, Michigan 48109
134
Effects of Closing the Bakersfield
Methadone Clinic
McGlothlin, W. H.; Anglin, M. D.
In California, methadone maintenance programs have come under pressure in the wake of Proposition 13, and two programs, with a total of
920 clients, have recently closed. Earlier, in September 1976, the
only methadone clinic in Bakersfield was closed. Since the nearest
continuing clinic was in Tulare at a distance of 70 miles, this provided an opportunity to measure the individual and social impact of
involuntary termination of methadone maintenance.
The communities and clients served were quite similar. The male samples were approximately 50% white and 50% Chicano (white of Mexican
descent); the female samples were approximately 80% white. An average of 6 years elapsed between postaddiction (N) and initial methadone maintenance entry (M) for the males, and 5 years for the female
samples. The mean time from M to methadone discharge (D) (July,
August or September 1976) was 28 months for the Bakersfield males
and 12 months for the female sample. For comparison, a dummy discharge date of August 31, 1976 was chosen for the Tulare sample. The
mean number of months from M to D for the Tulare male and female samples were 30 and 36 respectively. Thus, the only significant predischarge difference between the Bakersfield and Tulare samples was
the length of time on methadone for the female groups.
Followup interviews1 were conducted between August 1978 and March
1979--an average of 26 months after the methadone discharge or dummy
discharge date. Of the combined samples, 95% were located and interviewed. Two of the Bakersfield sample were deceased--both from drug
overdoses--and one of the Tulare sample died from nondrug causes.
There were three refusals and four not located.
Of the 94 Bakersfield respondents interviewed, only 11 had reentered
a methadone program by the time of interview (I)--some two years after
the clinic closure. Eight individuals transferred directly and three
entered at a later date. Seven were enrolled at I.
Of the 83 Tulare respondents interviewed, 42 (51%) were on methadone
maintenance continuously from September 1976 to I, and another 2 were
enrolled at I after a period off the program. During the period, D-I,
135
the Tulare sample spent 73% of its nonincarcerated time on methadone
compared to 8% for the Bakersfield group.
The first half of Table 1 compares the status and behavior of the
Bakersfield and Tulare samples for the period D to I. The data are
shown in terms of the percent of the sample involved in the status or
behavior at sometime during D to I; and, for daily narcotic use and
employment, the mean percent of the nonincarcerated time so involved.
The latter is the mean of the individual percentages, including those
with zero time involved.
Overall, the percentages of Bakersfield respondents arrested, incarcerated and on parole or probation is about twice that for the Tulare
sample. Probably the most relevant variable is the number of Bakersfield clients who became readdicted to heroin, and the percent of time
spent in this state. Slightly over one-half of both the male and female samples reported addiction at sometime after termination. If the
eight who transferred directly to other methadone programs are excluded, 60% of the male and 56% of the female samples became readdieted subsequent to discharge. Of the combined Tulare sample of 83,
26 (31%) reported some daily illicit narcotic use during D to I. Of
these, 22 were discharged from the methadone program prior to I; and,
for 13 all daily use was subsequent to discharge. Of the 41 discharged from the Tulare program, 3 were incarcerated the entire period
to I, and 39% of the remainder used narcotics daily at sometime subsequent to discharge.
The second half of Table 1 presents the status at the time of interview. Self-reported use of narcotics and other illicit drugs in the
four weeks preceding I was only marginally higher for the Bakersfield
sample; self-reported daily use was quite low for both groups. Urine
specimens were obtained from all but seven of the 154 respondents not
incarcerated. Analysis was only for morphine (heroin), using immunoassay techniques substantially more sensitive than those of the routine commercial laboratory tests (cutoff was 30 ng. morphine per ml.)
(Catlin 1973). There was 91% agreement between the urine results and
self-reported opiate use within the seven days prior to I. The Bakersfield rate of positive urines plus refusals was about twice that for
the Tulare samples, indicating more frequent use for the former. Of
the 14 Tulare respondents testing positive--or refusing a specimen-only two were from individuals currently on methadone maintenance.
There is some indication of greater stability among the Tulare samples
as evidenced by the higher percentages supporting dependents and living
in the same residence for the past 12 months.
The Bakersfield respondents reported their own assessments of the effect of the clinic closing on various areas of their lives. Seventytwo percent stated that they increased heroin use--at least as an aid
to detoxification from methadone. Twenty percent said they substituted
other drugs, mainly tranquilizers and barbiturates, and 15% increased
alcohol consumption. Twenty-six percent reported employment dislocation, 30% health problems (prolonged withdrawal), 18% marital or social
difficulties, and 28% increased criminal activity. Fifty-six percent
felt the Program closure was the indirect cause of one or more arrests.
As an overall assessment of their methadone experience, 81% of the
136
Table 1
Status or Behavior Subsequent to Methadone Discharge
Females
Males
Bak.
N=55
Status or Behavior
Discharge to interview (D-I)
% arresteda
% incarcerated >30 days
% on legal supervision
% using narcotics daily
Mean % time using daily
% abusing alcohol
% dealing drugs
% reporting property crime
Mean % time employed
% receiving welfare
Tulare
N=56
Bak.
N=39
Tulare
N=27
73*
65*
60*
55*
30*
64*
62*
22
51*
15
43
32
34
32
13
43
32
16
68
23
74*
54*
67*
54
20
44
41
26
32
44
33
22
15
30
9
22
30
41
26
48
15
4*
14
56
10
14*
11
71
49
40
9
50
35
6
37
31
9
33
25
8
30
4
15
4
31
9
21
0
Reported use; refused or
positive urine
51
42
51
33
>40 oz. 85 proof alcohol
in last 7 days
26
19
9
0
Supporting dependents
43
60
41
54
Living in current residence
>12 months
21*
44
20*
46
Status at time of interview (%)
Incarcerated
On methadone maintenance
Drug use last 4 weeks (exc. mari.)
Any use
Any narcotic use
Daily narcotic use
Urinalysis results
Positive (morphine)
Refused specimen
Mean % times using daily and employed are based on nonincarcerated time from discharge to interview; and all status-atinterview percentages except that for incarceration are based
on the nonincarcerated samples.
*Difference between Bakersfield and Tulare samples significant
(P<.05).
a
Arrest data are for period methadone discharge to April 1978.
b
Alcohol abuse is defined as drinking at least seven drinks or
equivalent over a six-hour period two or more times per week.
Note:
137
Bakersfield sample stated they were glad they enrolled in the program
compared to 88% for the Tulare group.
Social costs during D to I were calculated for those variables which
could be readily measured in economic terms. The entries in Table 2
are the aggregate costs for treatment, incarceration, etc. divided by
the number of respondents in the sample. Treatment costs are $200
per month for methadone maintenance and $600 for therapeutic communities--detoxification and other treatment costs are not included. Arrest and court processing is estimated at $900 per arrest. Jail,
civil commitment center and prison costs are $480, $600 and $910 per
month respectively. Probation, civil addict parole and prison parole
costs are $50, $175 and $130 per month. The cost of forgeries and
robberies is the amount of money realized by the respondent. The reported income from burglaries and thefts is multiplied by three to
adjust for the discounting associated with the disposal of stolen
goods. Welfare income is that reported by the respondent.
Table 2
Social Costs ($00) Per Respondent from
Methadone Discharge to Interview
Males
Females
Costs
Bak.
N=55
Tulare
N=56
Bak.
N=39
Tulare
N=27
Treatment
Arrests and court processinga
Incarceration
Legal supervision
Property crime
Welfare
Total
Mean annual costs
6
16
16
8
62
8
134
62
31
10
30
5
35
7
116
53
6
19
19
9
12
16
81
37
39
6
6
1
38
41
132
63
Note:
The data in this table are the aggregate costs divided by the
number of respondents--not the means of individual costs.
a
Arrest data were collected from methadone discharge to April 1978,
but are prorated to the time of interview.
b
Excludes crime data for one Tulare male and one Tulare female.
The higher treatment costs for the male Tulare sample are offset by the
greater criminal justice and crime costs for the Bakersfield group.
The Tulare female sample exhibits higher treatment, crime and welfare
costs than that for the Bakersfield group, and the total annual costs
per respondent are some $2600 higher. The female income was augmented
by prostitution. Twenty-three percent of the Bakersfield and 26% of
the Tulare female samples reported prostitution during the period,
D-I, and the average annual income across all female respondents was
$2200 and $1300 respectively.
It should be noted that the crime costs are based on the reports of a
138
small number of persons (for the female samples, 9 Bakersfield and
11 Tulare respondents reported property crimes). In a previous
study employing a much larger sample, both property crime arrest and
self-reported crime were strongly related to the proportion of time
addicted to heroin (McGlothlin, Anglin, and Wilson 1978).
The data presented in Tables 1 and 2 have focused on the interval D to
I. Similar data were collected for the average interval of 5-6 years
from first daily narcotic use (N) to initial entry into a methadone
program (M); and from M to D--an average interval of 2.5 years for the
male samples and 1-3 years for the female groups. The mean percent of
nonincarcerated time using narcotics daily during N-M was 80 for the
combined male and female Bakersfield sample, and 76% for the Tulare
sample. The corresponding percentage for M-D was 13 for both samples.
Annual social costs were calculated in the same manner as in Table 2
for periods N-M and M-D. For Bakersfield, the values were $12,200 and
$6100 respectively; and for the Tulare sample, $17,600 and $8200.
Thus, while the results presented in Table 2 do not show a social cost
advantage for continuing methadone for clients already in treatment
for an average of 2-3 years, the pre- to during-methadone cost data do
show a large improvement.
In summary, the results presented in Table 1 clearly show that the
Bakersfield clients performed worse than the Tulare sample subsequent to the clinic closure. Even in the absence of a corresponding
social cost advantage for the Tulare sample during the D to I period,
the maintenance approach would appear preferable to one requiring such
extensive criminal justice intervention--not to mention the possible
prevention of the two drug overdose deaths that occurred in the Bakersfield sample. Had the extent of postdischarge heroin addiction and
associated criminal behavior in the Bakersfield sample returned to a
point approaching the premethadone level, the social cost would have
exceeded that for the Tulare group by a substantial margin. Why did
this not occur? The most favorable interpretation is that the beneficial effects of treatment continued to limit the rate of addiction
after the involuntary termination of methadone. On the other hand,
the apparent large declines in addiction rates found in followups of
untreated samples would suggest that other factors are also involved
(NIDA 1977; Simpson, Savage and Sells 1978).
One explanation is the existence of an especially active Bakersfield
Heroin Impact Project (HIP) at the time of the clinic closure. The
Bakersfield HIP force was initiated in May 1976--five months before the
clinic closure--and during the next 12 months, made 852 arrests compared to a total of 166 misdemeanor drug arrests in 1975 (Bureau of
Criminal Statistics 1978). The arrest records for the Bakersfield
clients show that 18 were arrested on under-the-influence charges for
the 6-month period during and immediately following the clinic closure (July-December 1976). Thus, the threat of arrest, incarceration
and subsequent probation supervision may well have limited the amount
of time addicted.
A second factor which may have limited the return to heroin addiction
after discharge is the current very low purity and high price of street
heroin. Heroin overdose deaths and other indices of use have shown a
sharp decline since mid-1976 (Drug Enforcement Administration and NIDA
139
1978), and the poor quality of heroin is thought to be a major reason.
Responses obtained in the present study support this hypothesis. Of
the 57 Bakersfield respondents indicating recent experience in acquiring heroin, 52% said that as a result of the very poor quality
they were less interested in using, or that it wasn't worth it.
parenthetically, 19% of the 86 Bakersfield and Tulare respondents enrolled in treatment in the two years prior to interview indicated that
these considerations were partly responsible for their Continuing
treatment.
In summary, it seems reasonable to conclude that
Bakersfield clinic closing, as reflected by the
associated behavior, is a minimum estimate. The
pressure, and the poor quality and high cost of
mized the extent of readdiction to heroin.
the impact of the
readdiction rate and
additional police
heroin, probably mini-
whatever the causes of the relatively low postdischarge rate of heroin
addiction among the Bakersfield sample, it raises the question of the
extent to which methadone programs may be unnecessarily prolonging the
addiction to a narcotic--albeit one licitly obtained. In spite of a
general bitterness about the closure of the clinic, 27% of the respondents stated that, in retrospect, they felt they had benefited
since it enabled them to discontinue methadone maintenance as well as
heroin. Only 26% indicated they would enroll in methadone maintenance
if it were available; although a larger number would undoubtedly do SO
if they became readdicted to heroin. At the time of the interview,
73% of the Bakersfield sample were not incarcerated, and did not admit
addiction to either a licit or illicit narcotic. The comparable percentage for the Tulare group was 28.
On the other hand, 54% of the Bakersfield sample became readdicted to
heroin; 73% were arrested; 61% were incarcerated for more than 30
days; and 2 died of drug overdoses. Certainly, there were a number
of instances where an individual who was leading a stable life on
methadone was thrust back into the chaotic life of the street addict.
In considering whether or not to force a stable methadone client to
detoxify, the clinic director must weigh these risks against the treatment costs and the possible benefits which may result to the individual
from terminating methadone dependence. Interestingly, comparing those
who did and did not become readdicted during D to I showed virtually
no difference with respect to sex, age, time on methadone or methadone
dose level prior to detoxification (mean=38 mg.). Those becoming readdicted were more likely to be Chicano and to have an earlier and
more extensive pretreatment criminal justice involvement. Those reporting little or no illicit narcotic use while on methadone were
significantly more likely to avoid addiction after discharge.
Given the dilemma of whether to maintain a stable client indefinitely,
or risk serious detrimental effects from involuntary termination, an
approach of encouraging detoxification with an accompanying flexible
readmission policy may be the best solution.
FOOTNOTE
1.
The interview was adapted in part from a schedule developed by
Nurco and colleagues (Nurco et al. 1975).
140
REFERENCES
Bureau of Criminal Statistics. Criminal Justice Profile - 1977 Kern
county. Sacramento, California: Bureau of Criminal Statistics, 19%.
Catlin, D.H. Urine testing: A comparison of five current methods
for detecting morphine. Amer J Clin Path, 60:719-728, 1973.
Drug Enforcement Administration and NIDA. DAWN Quarterly Report
January - March 1978. Washington, D.C.: Drug Enforcement
Administration and NIDA, 1978.
McGlothlin, W.H., Anglin, M.D., and Wilson, B.D. Narcotic addiction
and crime. Criminology, 16:293-315, 1978.
National Institute on Drug Abuse. Drug Treatment in New York City
and Washington, D.C. Followup Studies. Services Research Monograph
Series. Washington, D.C.: Superintendent of Documents, U.S.
Government Printing Office, 1977.
Nurco, D.N., Bonito, A.J., Lerner, M., and Balter, M.B. The natural
history of narcotic addiction: A first report. Paper presented at
the Meeting of the Committee on Problems of Drug Dependence,
Washington, D.C., May 1975.
Simpson, D.D., Savage, L.J., and Sells, S.B. Followup study of
1969-1972 admissions to the Drug Abuse Reporting Program (DARP).
Ft. Worth Texas: Texas Christian University, Institute of
Behavioral Research, 1978.
Votey, H.L. Which drug policy is least cost: Addict control or
control of supply. J Calif Law Enforcement, 10:148-153, 1976.
ACKNOWLEDGEMENTS
Supported by National Institute on Drug Abuse grants DA01890 and
Research Scientist Award DA70182; and Contract No. 77-61245 from the
California Department of Health. Dr. Donald Catlin of the UCLA
Department of Pharmacology performed the urinalysis. Ms. Ann
Hubbard, Director of the Tulare County Substance Abuse Program,
provided valuable cooperation.
AUTHORS
William H. McGlothlin, Ph.D.
M. Douglas Anglin, Ph.D.
Department of Psychology
University of California, Los Angeles
Los Angeles, California 90024
141
An Improved Evaluation
Instrument for Substance Abuse
Patients: The Addiction Severity
Index
McLellan, A. T.; Luborsky, L.; O’Brien, C. P.; Woody, G. E.
INTRODUCTION
The mental health field has traditionally profited from attempts to
divide patients into homogeneous groups based upon relevant symptomatology. As in the examples of psychosis and especially affective
disorders, such diagnostic classifications have added focus to research efforts, and improved the specificity and effectiveness of
treatments. However, within the field of substance abuse treatment,
efforts to evaluate and classify the patient population have been
far less useful. In our view, these less than satisfactory attempts
are due in part to a somewhat restricted view of addiction, and in
part to failure in developing a standardized, reliable and valid
evaluation instrument which would be suitable for use with both
alcoholic and drug addicted patients. The design for such an instrument was first proposed in an NIDA conference on Treatment
Efficacy (O’Brien 1975; Fonaroff et al. 1978) and has led to the
development of a multi-dimensional clinical research instrument for
addicted clients, the Addiction Severity Index (ASI) (McLellan et al.
1979a,b). The present paper reports the results of reliability,
validity and patient classification studies using the ASI.
DESCRIPTION OF THE ADDICTION SEVERITY INDEX
Design: The design of the ASI is based upon the premise that ad% must be considered in the context of those treatment problems which may have contributed to and/or resulted from the chemical
abuse. The objective of the ASI is to produce a problem severity
profile of each patient through an analysis of six general areas
which commonly result in treatment problems. These include: (1)
Chemical Abuse, (2) Medical, (3) Psychological, (4) legal, (5)
Family/Social, and (6) Employment/Support. The severity of each of
the treatment problem areas is assessed individually and independently through two types of information.
Objective Information: The data collected within the objective section detail the number, intensity, and duration of problem symptoms
in each of the six areas. Verifiable data from objective questions
142
as well as test results, laboratory reports, physical examinations,
and psychological interviews are collected to develop a factual
representation of the patient’s life pattern in each of the six
areas.
Patient’s Judgments of Severity: The second section of each problem area is designed to measure the subjective intensity of problem
symptoms. The patient is requested to rate, using a five-point
scale, the extent to which he has been bothered by problems in each
of the six areas, and the extent to which he feels that treatment
for those problems is important. The time frame for these evaluations is the previous 30 days.
SEVERITY RATINGS
The data from the objective information and patient-report section
of each problem area are integrated by the interviewer to produce
the severity ratings, These six severity ratings form the basis
for the clinical profile of each patient, providing a diagnostic/
evaluative summary of the patient’s treatment needs. In this respect the ASI has utilized the approach taken by the Health-Sickness
Rating Scale (Luborsky 1962; Luborsky 1975; Luborsky and Bachrach
1974). Roth instruments rely on objective information and analyses
of problem components as a means toward developing clinical ratings
of severity. While the HSRS uses a 100-point scale anchored by
descriptions, the ASI uses a ten-point (0-9) unanchored scale.
ADMINISTRATION
The ASI may be administered to all types of substance abuse clients
by an easily trained technician in an average time of 25-30 minutes.
The interview was designed for initial use shortly after admission
to treatment, and then for repeated administrations at subsequent
followup periods. The ASI is administered most effectively under
conditions of privacy and confidentiality where the interviewer
maintains an atmosphere of professional concern and warmth. A
brief introduction to the interview explaining the design of the
ASI, and the use of the patient rating scale, is considered necessary
to the developmont of a productive and valid interview.
The results of 750 admission interviews from 421 alcoholics and
329 drug addicts, indicate that the ASI is applicable to, and often
appreciated by, the majority of patients. Many have reflected positively upon the patient-estimate sections, commenting that they have
been able to focus upon the individual aspects of their addiction.
Only 11 of these 750 interviews were discarded for invalid information, and only 14 others were eliminated due to inadequate comprehension.
VALIDITY
We have performed preliminary assessments of validity for each of
the problem severity scales by correlating the scale scores with
other independent items having clear relationships to the particular
143
problem area. These correlation coefficients are presented in table
I. As can be seen, each of the severity scales correlates with the
comparison items at mid range or higher levels, and in the expected
direction, with the comparison items. Although these early results
are encouraging it should be clear that these data are only indicative of presumptive or face validity.
RELIABILITY
TESTING
The reliability of the Addiction Severity In&x was initially assessed
during the performance of our evaluation study (McLellan et al. 1977)
and was reassessed periodically during that study and in two others
(Woody et al. 1977; McLellan et al. 1979). In the basic design one
research technician has conducted an interview while three others
rated the videotaped presentation. The results to be reported are
based upon the judgments of these four bacculaureate level research
and rehabilitation technicians with little previous interviewing
experience. The data for 25 male veteran patients rated by these
judges are presented in table II.
The first line of table II shows the mean per-judge reliability coefficients (Spearman-Brown formula; see Winer 1962) calculated for
the first 16 patients interviewed. As can be seen, the coefficients
are particularly high given that the judges had had very little experience with substance abuse patients or the AST. While it seems
likely that the forced uniformity of the procedure (one interview
instead of four) may have artificially enhanced the reliability, we
were mainly concerned that the high coefficients were the result of
a systematic bias developed over the course of training in the inexperienced judges. To test for this possibility, we repeated the
reliability assessment procedure following a two-month, and then a
four-month period of independent on-the-job interviewing experience
by the four judges. The results for these additional reliability
tests are presented in the second and third lines of table I, and
as can be seen, no significant decrements were observed in the
average reliabilities for each scale.
Given the generally high level of reliability demonstrated, we attempted to determine if there were significant differences in reliability between several obvious subgroups of our substance abuse
clients. The second section of table II presents reliability coefficients for these 25 patients divided into alcoholic (n=14)
and drug addict (n=11) subgroups. Again the reliability results for
each group are quite high. These 25 subjects were then divided on
the basis of age, and by their total (sum of six scales) severity
scores, to determine the extent of difference in reliability of
severity estimates. The results of these comparisons are presented
in the third and fourth (respectively) sections of table II, and
again the coefficients remain high, with no significant differences
between the groups on any of the scales.
One important issue raised by the uniformly high reliability across
the six problem scales is the extent to which the problem areas are
interrelated. If the problem areas and their severity estimates are
144
highly related to each other then the determination of one severity
estimate (i.e., substance abuse severity) might exert a controlling
influence upon the other scales, thereby accounting for their high
reliabilities. In order to determine the nature and extent of the
relationships between the scales, correlation coefficients were
calculated on the ASI's of 524 male veteran substance abuse clients.
As can be seen in table III, the intercorrelations are generally
quite low with the exception of the psychological and family/social
scales (.41), indicating a considerable degree of independence between the scales. Ibis result was much different from our experience
with the Health-Sickness Rating scale where the components of mental
health tended to be highly intercorrelated and highly correlated individually with the global rating (Luborsky 1962). As a further test
of these relationships we performed the same analysis with several
obvious subgroups of the population. These included alcoholics, drug
addicts, those over 45 years old, those less than 45 years old,
blacks and whites. While several small differences in the interrelationships of these ratings were noticed between the subgroups, the
majority of the coefficients remained quite low.
The independence of the six problem areas indicates that the treatment problems presented by addicted patients are not necessarily
related to the severity of their chemical abuse. This result suggests that the proposed method of analyzing a patient's total condition by the severity of his component problems is both reasonable
and necessary for the development of an effective treatment plan,
UTILITY OF THE ASI
The findings from our analysis of ASI scale intercorrelations suggested that our substance abuse population may be composed of
several subgroups of patients, each with a somewhat different
pattern of treatment problems. As a test of this possibility, and
as a means of assessing the utility of the ASI in differentiating
patients into relatively homogeneous subgroups, we performed a
cluster analysis on 150 randomly selected patients (75 alcohol, 75
drug), using their six ASI scale values as independent variables.
In the particular type of cluster analysis selected (Hartigan 1975;
Brown and Dixon 1977) groups (clusters) of patients are formed by
minimizing the differences (Euclidean distance) between values on
each of the scales within the clusters and maximizing the differences
in mean values of the scales between clusters. Since we had no theoretical or mathematical rationale for variable weighting of the
scale values, all six scales were treated equally in the analysis.
The results of this analysis are presented in table IV, which shows
the resulting six, statistically different (p < .01), clusters and
the mean values for their six problem severity scales. The differences between clusters in the scale severity scores explain, in large
part, the low intercorrelations between the scales when the data are
ungrouped (table IV). Analyses of scale intercorrelations within
each of these clusters indicate rather high (.75-.90) relationships
between three or four scales within each cluster.
The mean severity profiles of the clusters are interesting since
145
314-300 0 -80 - 11
they correspond with several "types" of patients which are commonly
seen during treatment. For example, cluster #4 corresponds to the
"medical model" of addiction as a progressive syndrome. The average
profile for this group is demonstrative of patients with significant
problem severity in all aspects of their condition. In contrast,
cluster #3 depicts patients with a high substance abuse severity,
but few additional problems. Cluster #5 is especially noteworthy
since the mean profile of this group indicates that while substance
abuse may be their presenting complaint, it is not their most severe
treatment problem.
In summary, the results of this cluster analysis do suggest the
utility and effectiveness of the Addiction Severity Index as an
evaluative method for differentiating clients into subgroups with
different patterns of treatment problems. It should be clear that
the particular clusters presented here may not be indicative of
groups found in other clinics, especially programs with adolescents,
women, nonveterans, etc. However, they suggest that the ASI scales
can be effective in differentiating a substance abuse population
into whatever appropriate subgroups exist.
CONCLUSIONS
We have attempted to show the need for a standardized clinical research instrument, suitable for general use in the study and treatment of substance abuse. This instrument should have the capacity
to analyze the total addiction profile into its component treatment
problems, and to reliably and validly estimate the severity of each
of these problems. Our early results with the Addiction Severity
Index suggest that it may have the potential for being such an
instrument.
Clearly, much work is still required to further establish the reliability and validity of the instrument with other patient populations, and other teams of judges. Despite the considerable work
remaining, we expect that the ASI should fill the need for an instrument to assist the clinician in integrating and summarizing the
background and current status of patients. In addition we feel the
ASI may be of special assistance in determining a treatment plan
for the individual client.
We are also encouraged by the potential benefit of the ASI to research in the field of addiction. After proper standardization we
expect the ASI to be suibable for general use in clinical research
and thus facilitate greater comparability of results (Rittenhouse
1978). In addition the ASI may permit more effective matching of
patients at the start of experimental treatments, and a more comprehensive evaluation of posttreatment outcome.
REFERENCES
Due to space constraints references are available from the senior
author.
146
TABLE I
VALIDITY OF ASI SCALES
524 MALE VETERAN SUBSTANCE ABUSE CLIENTS
SCALE
INDEPENDENT
VARIABLES
CORR. COEFF.
ABUSE
TIMES O.D., BLACKOUT, SEIZURE
TOTAL YRS. REGULAR USE ALC/DRUGS
AMOUNT SPENT ON ALC/DRUGS PER WEEK
MEDICAL
NUMBER OF CURRENT MEDICAL SYMPTOMS, VA REVIEW SYSTEM .69
AMOUNT OF MEDICAL DISABILITY/PENSION
.60
NUMBER OF PREVIOUS HOSPITALIZATIONS
.58
EMP-SUP
RATIO OF EARNED TO UNEARNED INCOME, PAST MONTH
MONTHS OF CONTINUOUS FULL TIME WORK
HOLLINGSHEAD S.E.S. RATING
FAM-SOC
PROPORTION OF FRIENDS W/ABUSE PROBLEM
PROPORTION OF FAMILY W/ABUSE PROBLEMS
NUMBER OF CLOSE FRIENDS
.52
.48
.43
LEGAL
TOTAL CONVICTIONS
TOTAL MONTHS INCARCERATED
PROPORTION OF INCOME GAINED LEGALLY
.71
.68
.62
PSYCHOLOGICAL
MAUDSLEY N SCALE
BECK DEPRESSION INVENTORY
HAMILTON DEPRESSION SCALE (N=111)
.64
.61
.58
.72
.66
.54
-.64
-.62
.56
TABLE II
INTER-RATER RELIABILITY COEFFICIENTS
ON PROBLEM SEVERITY RATINGS*
SUB.
ABUSE
EMP./
SUP.
MED
LEGAL
FAM./
SOC.
PSYCH
AVE.
(Sept.) Subjects 1-16
(Nov.) Subjects 17-19
(Jan.) Subjects 20-25
All Subjects 1-25
.90
.89
.91
.90
.89
.90
.91
.90
.92
.92
.90
.92
.88
.89
.90
.89
.85
.86
.86
.86
.92
.91
.32
.92
.898
.905
.906
.918
Alcoholics
N=14
Drug Patients N=11
.90
.91
.91
.88
.93
.91
.88
.90
.85
.87
.92
.91
.908
.905
Age < 35 N=11
Age > 35 N=14
.90
.91
.89
.91
.91
.91
.90
.88
.84
.87
.89
.93
.S85
.912
Cumulative Sev. Score
> 30 N=15
Cumulative Sev. Score
< 30 N=10
.90
.91
.93
.89
.86
.94
.915
.89
.88
.91
.89
.85
.90
.886
TEST
* Ratings were based upon 4 judges; per-judge reliability coefficiently were calculated by
the formula:
MSB - MSW
MS5 + (K-l) MSW
= R
(Winer, 1962)
147
TABLE III
ASI SEVERITY RATINGS
CORELATION
COEFFICIENTS
524 MALE, VETERAN, SUBSTANCE ABUSE PATIENTS
MEDICAL
ABUSE
EMP/SUP
LEGAL
FAM/SOC
PSYCH
.19
.09
.14
.18
.26
.06
.16
.34
.27
.21
.17
.15
.11
.10
MEDICAL
EMP/SUP
LEGAL
FAM/SOC
.41
TABLE IV
ASI SEVERITY RATINGS
ANALYSIS OF PATIENT SUB-TYPES
IN
150 MALE, VETERAN, SUBSTANCE ABUSE PATIENTS
(75 ALCOHOLIC - 75 DRUG ADDICTED)
CLUSTER N
ABUSE
MEDICAL
EMP/SUP
LEGAL
1
40
6.5
1.5
5.5
3.5
2
32
7
2
4.5
1
3
27
6
2
2
4
25
7
5
6.5
1.5
5
FAM/SOC
5
5
PSYCH
2
5.5
1.5
2
6
7
5
14
5
1
2.5
4
5.5
6.5
6
12
5
4.5
2
5
5
5
ACKNOWLEDGMENTS
This work was supported by HSR&D Projects #284 and #525 from the
Veterans Administration. The cooperation of the Substance Abuse
Treatment Unit at the Coatesville VA Medical Center is gratefully
acknowledged. Much of this work was developed from the PADAT study
by the Veterans Administration.
AUTHORS
A. Thomas McLellan, Ph.D.; Lester Luborsky, Ph.D.; Charles P. O'Brien,
M.D., Ph.D.; George E. Woody, M.D. Drug Dependence Treatment and
Research Service, Philadelphia VA Medical Center, and Department of
Psychiatry, University of Pennsylvania, Philadelphia, PA 19104
148
Development of Psychiatric
Disorders in Drug Abusers:
Relation Between Primary Drug
and Type of Disorder
McLellan, A. T.; Woody, G. E.; O’Brien, C. P.
INTRODUCTION
In the course of evaluating the long term effectiveness of our drug
abuse treatment program, we discovered a sample of substance abuse
patients who had been initially admitted to inpatient drug-free
treatment at this facility during 1971-1972, and had demonstrated a
pattern of virtually continuous drug abuse since that time, punctuated only by their multiple readmissions for further treatment.
The readmission records of these patients provided information on
intake status, psychiatric assessments, psychological testing and
within-treatment progress over the course of the past six years,
offering an opportunity to examine the longitudinal relationships
between patterns of prolonged substance abuse and the development
of psychiatric disorders.
METHOD
Subjects - Subjects were 51 male veterans who had been admitted to
inpatient drug abuse treatment at the Coatesville VA Medical Center
during 1971-1972, and who had been readmitted for treatment at that
facility a minimum of six times since 1972. These subjects were of
course selected retrospectively during 1978, and while this sample
of chronic readmissions represents only 9% of the total patients
admitted to treatment at that facility during the period July 1971
through June 1972 it represents all of the patients who met the readmission frequency criterion.
These subjects were divided into three groups based upon their primary drug preferences in 1971-1972. Subjects in group I (n=11) had
reported primary use of psychostimulants including hallucinogens,
amphetamines and inhalants. Subjects in group II (n=14) had reported
primary use of psychodepressants including barbiturates, benzodiazepines, and sedative hypnotics. Group III subjects (n=23) had
reported primary use of narcotics, such as heroin, methadone, and
synthetic opiates.
Procedure - The purpose of the present research was to examine the
149
course of change in drug problems and psychological status within
these three groups over the course of their six year treatment history.
1978 COMPARISONS
An examination of the 1978 admission data for these subjects indicated significant generalized deterioration within groups, as well
as significant specific changes in psychological status between
groups (table I).
Group I - Psychostimulants - Although the subjects in this group
could still be characterized as psychostimulant users generally,
there was evidence of significant and pervasive change in their
patterns of abuse by 1978. For example, the majority (79%) of these
subjects reported regular use of amphetamine or methylphenidate
injected intravenously (see table II), and little regular use of
psychedelics or hallucinogens (with the exception of marijuana).
In addition, 28% reported irregular use of psychophysiologically
dissimilar chemicals (i.e., barbiturates, benzodiazepines) in addition to amphetamine. This pattern of change in drug preference
away from psychedelics to amphetamine has been reported by Smith and
his colleagues (Smith and Fisher 1969; Shick et al. 1972) and
appears to represent a legitimate change in preference rather than
a change in availability. These subjects reported very little
(2.3%) narcotic use, and no period of physical addiction.
As can be seen in the comparison of 1972-1978 psychological testing
for these subjects (table I), the group results showed significant
increases in psychological symptoms (F=12.12, df 1, 274, p .001)
between the years. Although no decrements in intellectual or conceptual function were evident, the MMPI data demonstrated pervasive
differences, especially in the areas of general pathology (F), hysteria (Hy), Paranoid (Pa), Schizophrenia (Sc), and Mania (Ma).
High scores on these scales suggest the presence of psychotic
symptomatology, especially paranoid form (Gilberstadt and Duker
1965; Dahlstrom et al. 1972). Significant also in this regard is
the fact that the modal MMPI profiles in this group by 1978 were
2-8-9 (31%) and 4-8-9 (14%), which are again indicative of psychotic
symptoms.
The results of the psychological testing were mirrored by the results of the psychological interviews (table II) perfonned by the
staff physician and psychologist at each readmission. These interviews in 1977-1978 indicated the presence of psychological symptomatology sufficient to warrant a primary or secondary psychiatric
diagnosis in 71% of the subjects and referral to primary psychiatric
treatment in 45% of the cases. The diagnosis of schizophrenia
(Paranoid or Undifferentiated) was rendered in 63% of the cases and
8% were characterized as having sociopathic personalities. Seventytwo percent of the subjects reported visual or auditory hallucinations (during drug-free periods) and 18% suicidal ideation.
Group II - Psychodepressants - The group II subjects remained pri-
150
TABLE I
PSYCHOLOGICAL TESTING 1972-1978
GROUP I
PSYCHOSTIMULANTS
N
MEAN I.Q.
MEAN C.Q;
MMPI
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
L
F
K
Hs
D
HY
Pd
Mf
Pa
Pt
SC
Ma
Si
PREVIOUS PSYCH.
TREATMENT
+ = P< .05
* + P < .01
GROUP II
PSYCHODEPRESSANTS
GROUP III
NARCOTICS
BET. GROUPS
SIG. IN 1973
1972
1978
1972
1978
1972
1978
11
11
14
14
26
26
101
93
103
94
102
93
94*
81*
104
92
102
91
52
64
56
61
55
60
70
64
63
56
66
64
48
54
96*
58
67+
58
71+
76+
70
84*
57
98*
87*
55
54
58
53
61
60
54
68
60
57
58
60
63
55
51
78*
58
72+
94*
58
74+
58
55
62
63
66
59
56
62
51
59
60
54
72
72
59
58
64
65
56
55
66
56
61
66
54
78
78
61
62
61
59
58
4%
63%*
0%
24%+
4%
8%
+
+
+
*
*
+
*
+
*
*
TABLE II
ADMISSION STATUS 1978
GROUP I
PSYCHOSTIMULANTS
N
11
MAJOR DRUGS
1st
2nd
3rd
GROUP II
PSYCHODEPRESSANTS
26
14
%
Amphetamine
Cocaine
Phencyclidine
BETWEEN
GROUPS
SIG.
GROUP III
NARCOTICS
%
%
41
20
Barbiturates
82
Benzodiazepines 78
Alcohol
44
Methadone
Synth. Opiate
Heroin
86
59
52
Psychopathic
Personality
Sociopathic
Personality
Other
16
PSYCH. DIAGNOSES
1st
Schiz. Paranoid
36
Dep.
2nd
Schiz.
27
Anxiety Reaction 21
3rd
Undifferentiated
Sociopath.
Personality
ADMISSION
SYMPTOMS
Suicidal Ideation
Suicide Attempts
Hallucinations
Memory Change
Problems Concentrating
PERCENT REFERRED FOR
PSYCHIATRIC TREATMENT
+ = P<.05
* =p
< .01
8
Neurosis
Organic
syn
brain
34
14
12
12
%
%
%
18
72
77
35
6
9
35
16
8
8
4
0
45
21
8
marily psychodepressant users, although a significant proportion
(34%) of these subjects reported abuse of alcohol instead of, or in
addition to, barbiturate and benzodiazepine abuse.
Again, like the group I Psychostimulant users, the group II subjects
evidenced significant changes in their psychological status by the
1978 admission. However, unlike the psychostimulant users, this
group showed virtually no evidence of psychotic symptoms. As can
be seen in the table I data, the most significant changes in the
MMPI test results were found in the general pathology (F) and especially the depression (D) scales, although the entire group profiles were found to differ between 1972 and 1978 (F=3.99, df 1, 349,
p<.05). Again, these testing results were reflected in the patients’
1977-1978 readmission symptoms, and in the diagnostic impressions
of the admitting staff (table II). Anxiety and Depressive disorders
were diagnosed in 55% of the group II subjects, and 21% were referred to primary inpatient psychiatric treatment. Especially significant is the fact that by 1978, fully 77% of this group reported
suicidal ideations, and over 35% had actually attempted suicide. In
addition, the incidence of drug overdoses was four times higher than
in either of the other two groups.
Finally, the data from the Shipley Institute of Living Scale indicated a significant (t=6.34, df 13, p<.001) reduction in the mean
conceptual quotient scores of this group between 1972 and 1978. Although this test provides only a rough index of conceptual impairment (i.e., brain damage), it is noteworthy that while all subjects
in this group were within normal limits in 1972, and repeated administrations typically produce improved scores (Shipley 1940),
fully 15% of this group showed worse results on the test and presumptive evidence of brain damage by 1978.
Group III - Narcotics - The subjects in group III remained primarily
narcotic users with only slight evidence of regular nonopiate drug
u s e . However, there was a clear shift in primary drug problems
from heroin in 1972 to methadone (licit and illicit) and synthetic
o p i a t e s b y 1 9 7 8 . This shift may have been more a function of reduced quality and availability of heroin than a change in drug
p r e f e r e n c e . An additional problem which was increasingly reported
b y t h i s g r o u p i s a l c o h o l a b u s e . While only two subjects had changed
their primary abuse problem to alcohol, all subjects had reported
considerably greater day-to-day use of alcohol than at the time of
their 1972 admission.
Results of psychological testing within this group indicated very
low levels of symptom change, and no significant differences between
years. Data from the 1978 SILS indicated no significant changes
in group I.Q. or conceptual quotient (brain damage) scores, both of
which were within normal population ranges (Shipley 1940; Simes and
Simmons 1958). S i m i l a r l y , r e s u l t s o f p e r s o n a l i t y t e s t i n g w i t h t h e
MMPI showed no between-years effect (F=1.06, df 1,649, p>.10), and
indicated only moderate levels of depression, and low levels of
psychotic symptoms. Modal profiles for this group were comparable
to those found in 1972; 2-4 (31%), 2-4-9 (11%), again suggesting
153
little systematic change in psychological status over the six year
period.
Summaries of readmission interviews tended to support the results
of the psychological testing. Comments from ward physicians and
psychologists indicated a general group trend toward moderate increases in symptoms of depression, but little suggestion of psychotic
symptomatology. By 1978, only. two subjects had been referred for
primary psychiatric treatment, both due to prominent suicidal ideation and recent attempts. Despite these two serious cases, the
narcotic group generally showed the least change in psychological
status over the six year period of drug use.
SUMMARY AND DISCUSSION
Two explanations are possible for the observed increases in psychological symptoms of groups I and II. First, it is possible that
the patients in these groups may have already developed underlying
symptoms of their subsequent disorders by 1972. While these symptoms were below the threshhold for detection at that time, they may
have influenced the subjects’ selection and pattern of drug use.
That is, these patients may have required or responded preferentially
to particular combinations of chemical agents due to the influence
of their underlying symptoms. Thus, while these drugs did not prevent the subsequent expression of the disorders, they may have pmvided a particular form of relief. This "medication" view does explain the well documented (McLellan and Druley 1977; MacGahan and
McLellan 1979; McLellan et al. 1979; Zuckerman et al. 1975; Smith
and Fisher 1969) tendency for patients to select combinations of
chemical agents having similar psychophysiological effects and to
often reject other available types of drugs. This pattern of use
suggests that many patients attempt to induce a particular effect,
rather than simply "get high."
A second plausible explanation for the psychological symptom increases in groups I and II is that the prolonged abuse of the specific
combination of street drugs had a direct role in the development
and expression of the resulting disorders. This "developmental"
view would suggest that while these subjects may have had undetected,
borderline symptoms in 1972, and that they would have eventually
developed a form of psychiatric illness regardless of drug use,
the data presented here and elsewhere (McLellan and Druley 1977;
MacGahan and McLellan 1979) argue that regular use of particular
street drugs may hasten the development! and determine the nature
of the subsequent disorder. The mechanism(s) by which the particular drug combination could determine the nature of a psychiatric
disorder might include state dependent learning (Overton 1972) or
even biochemical changes, through the prolonged alteration of CNS
monoamine systems (Snyder 1972; Wyatt et al. 1972; Stein and Wise
1971). Regardless of the mechanism(s) involved, this view does
suggest how many of the short term, toxic reactions to these drugs
could develop the longer duration and manifestations of overt
psychiatric syndromes following years of continued abuse.
154
If prolonged abuse of psychoactive chemical agents is associated
with specific psychological disorders, then why are there no significant increases in psychological symptoms in the narcotics group?
The answer to this question, we feel, lies in the specific psychopharmacological effects of the narcotic drugs. For example, in
chemical structure morphine resembles the phenothiazine family
(Goodman and Gillman 1945), and it has been used in this country
(with some success) as an antipsychotic (Comfort 1977). It is our
clinical impression that methadone, morphine, and to some extent
heroin, may function to medicate underlying psychological problems,
and to reduce symptoms of anxiety, depression, and paranoia.
Again, the data reported have been collected posthoc, on a relatively
small sample of male, veteran drug abuse clients. Although the
relationships reported are significant and distinct, the nature of
the problem and the limitations of the data require continued,
rigorous examination of this most intriguing area.
REFERENCES
Due to space constraints references are available from the senior
author.
ACKNOWLEDGEMENTS
This work was supported by HSR D Project 284 from the Veterans
Administration. The cooperation of the Substance Abuse Treatment
Unit of the Coatesville VA Medical Center is gratefully acknowledged.
AUTHORS
A. Thomas McLellan, Ph.D.
George E. Woody, M.D.
Charles P. O'Brien, M.D., Ph.D.
Drug Dependence Treatment Service
Philadelphia VA Medical Center
and
Department of Psychiatry
University of Pennsylvania
Philadelphia, PA 19101
155
Ethnoeconomical Approach to the
Relationship Between Crime and
Drug Use: Preliminary Findings
Goldstein, P. J.
Issues related to the economic behavior of narcotics addicts have
never been satisfactorily resolved in the social scientific literature . This is because there has never been an adequate data
base from which to address these issues. This paper constitutes
a preliminary report on an attempt to construct such a data base.
The study has two principal foci; one substantive and the other
methodological. The substantive focus is on the economic behavior
of street level opiate addicts. Where does street addicts' income come from and where does it go? How much of that income comes
from crime? How much of it is spent on drugs? The methodological
focus revolves around the problems of trying to collect valid and
reliable data on these issues. If addicts were able to accurately
recall their income-producing and income-expending activities over
long periods of time, then a retrospective interview type design
would be adequate for collecting the sort of data that we are interested in. If, however, the ability of addicts to accurately
recall their economic activities proved to be unreliable, then a
different type of methodology would be required.
METHODOLOGY
Previous empirical research on the drug-crime relationship has mainly employed the survey approach among captive populations (i.e.
those in prison or drug treatment facilities). Subjects in such
studies engage in retrospective self-reporting that may span several decades. These studies have been essentially static in character, considering such variables as age of first drug use, age
of first criminal activity, age of first arrest.
The intent of this study was to illuminate the processual aspects
of the relationship between drug use and criminal activity. Ethnographic data collection techniques appeared best suited to this
end. A storefront was rented, two indigenous field workers were
hired, and information about the nature of our study was passed
via word-of-mouth on the streets.
156
Once a subject had been recruited for the study he or she was
given a Life History Interview (LHI). Each LHI session lasted
one hour. Subjects typically received 2 or 3 LHI sessions. These
had two principal purposes. The first was to engage in a protracted dialogue with respondents in order that we could get to
know them and they could get to know us; in other words, to enhance feelings of trust and rapport. The second purpose of the
LHI sessions was to enable us to establish parameters of the sample. Basic demographic data (e.g. age, race), the prior nature
and scope of subject's drug-using and criminalistic activities,
employment histories, etc. were all recorded.
We also attempted to record subjects' econanic behavior (i.e. all
income and expenditures) for the year preceding the LHI. The results of this latter effort were disappointing. Few subjects were
able to recall their economic activities for the prior year with
any degree of accuracy. It was not uncommon for subjects to estimate expenditures 500 percent in excess of incone. When this was
pointed out to them they might reply, "Well, maybe I stole a lot
more than I thought". Or, "Well, maybe I didn't use quite as much
drugs as I thought". Or, "I don't know". Thus, while retrospective self-reporting may be an adequate technique for eliciting information about bi events in subjects' lives (e.g. first heroin
use, first arrest) it was inadequate for collecting data on the
daily minutiae of everyday living that best express the routine
on-going relationship between drug use and crime.
The core of our methodological approach thus became the daily
follow-up of subjects. Subjects reported to the storefront 5 days
a week and were debriefed on their previous days' activities in a
15-20 minute interview. Subjects were followed for at least 30
consecutive days and then replaced with new subjects from the
pool who had already received life-history interviews.
About 50 percent of the subjects who began reporting on a daily
basis completed the 30 day cycle. Three subjects were terminated
because we learned they had broken into our storefront and stolen
some tape recorders and typewriters. Several subjects failed to
complete the thirty day cycle because of arrest and incarceration.
Others just disappeared from the street and their whereabouts were
unknown. This report is based upon the first eight subjects to
complete the initial daily follow-up cycle. Table 1 provides some
demographic data on these subjects.
Subjects' ages ranged from 24 to 39. Two were employed on a full
time basis, one as a taxi driver and the other as a porter. Subjects had addiction histories besides heroin that included alcohol
(n=2), methadone (n=1) and barbiturates (n=1). In addition, three
subjects claimed that they had been addicted to cocaine.
157
TABLE 1
Demographic Characteristics of Research Subjects (N=8)
32.5
Mean Age:
Race:
Hispanic
Black
White
Enployed full-time:
Yes
No
Education:
Some High School
High School Grad
Some College
4
2
2
(50%)
(25%)
(25%)
2
6
(25%)
(75%)
4
2
2
(50%)
(25%)
(25%)
17.9
Mean Age of first Heroin use:
Addicted to Heroin:
Yes
Mean Number of Arrests:
Mean Number of Convictions:
8
(100%)
5.6
1.5
FINDINGS
Income derived from criminal activity was the largest single category of cash income for the group, constituting 40 percent of
total income. However, this is misleading in that a single subject, Steven H., accounted for about 65 percent of-the group's
total criminal income. In fact, Steven H.'s criminal income
($2,968) was more than 26 percent of the group's total income
from all sources.
For all subjects the major portion of the category "Other Income"
consisted of payments that they received from us for being research subjects. Only one of the 8 subjects received public support and this contributed negligibly toward his total income. Income from family, from wives or girlfriends, from public sources,
from friends or from panhandling failed to contribute substantially
to any subject's total income.
Most subjects were actively engaged in either legitimate employment or in criminal activity or in various aspects of the drug
business. One half of the group earned more than 40 percent of
their cash income through legitimate employment. Two subjects
earned the majority of their income through legitimate employment.
Three subjects earned 40 percent or more of their cash income from
criminal activity, but only one subject earned the majority of his
income in this manner. Only one subject reported no cash earnings
from criminal activity.
158
TABLE 2
Subject
Steven H.
Mike S.
Keith D.
Frenchy S.
Kerwin T.
Keith H.
Bobby H.
Tito C.
TOTAL
Employment
Crime
31%
1%
--
45%
45%
19%
8%
7%
--
25%
11%
3%
14%
33%
--
-42%
-7%
59%
45%
8%
76%
SUBJECETS' SOURCES OF CASH INCOME
Wife or
Public
Girlfriend
Family
Support
Drug
Business
1%
1%
2%
7%
1%
1%
5%
8%
Friends
-1%
6%
--
5%
3%
-_
--1%
-------
2%
5%
4%
2%
3%
3%
2%
--
$3,270
$4,538
$728
$226
$75
$224
$267
(29%)
(40%)
(7%)
(2%)
(0.6%)
(2%)
(2%)
Other
Total Income
$3,522
20%
19%
25%
15%
29%
45%
15%
$ 850
$ 795
$2,321
$1,198
$1,186
$1,884
$11,212
(17%)
(100%)
Working within the drug business was the least important of the
three major sources of cash income. Only 7 percent of the group's
total cash income was raised in this fasion. One subject earned
one-third of his income working in the drug business, and another
earned one quarter. The remainder of the subjects earned little
or no cash in this manner. However, many drug transactions involved pay-offs in drugs rather than in cash.
For 7 of the 8 subjects, more than 50 percent of their total expenditures involved the purchase of drugs. No subject reported
any expenditures for gambling or legal fees. Less than half of
the subjects reported expenditures for clothing, recreation (i.e.
movies, ball games, shooting pool, discos, etc.) or savings. The
expenditures that were reported in these categories, in all cases,
were negligible. Subjects spent on the average about 6 percent
of their cash income for food; 6 of the 8 subjects spent less than
$1 per day on food, mainly as snacks. They obtained their main
meal from mothers, girlfriends, or wives for no cash expenditure
(table 3).
Expenditures for drugs clearly dominated the economic lives of
these 8 subjects. Heroin was the principal drug used by respondents. Six of the eight subjects used more heroin (in terms of
cash value) than any other drug. The predominant drug used by the
remaining two subjects was cocaine. Only one subject consistently
purchased less than half of the drugs that he consumed. Approximately 22 percent of the total amount of heroin consumed by the
group was obtained as a gift or an in-kind payment.
Fluctuations in heroin consumption were far more pronounced in
some subjects than in others. Table 4 reveals the mean dollar
value of heroin used per day by each subject, the standard deviation of heroin use, and, also, the estimated daily dollar value of
heroin that respondents reported during the LHI that they used for
the previous year.
Several trends appear in table 4, The 4 subjects with the highest mean heroin use per day also have the highest standard deviations. Heroin addiction clearly is not the monolithic daily constant that some sources suggest. Heroin use by subjects in this
group fluctuated considerably from day to day and it would be inaccurate to refer to them as $50/day or $30/day addicts. A similar situation was found in earlier research with prostitutes
where it would be similarly inaccurate to refer to them as $100
call girls or $10 street hookers (see Goldstein, 1979). Prices
for individual "tricks" were found to fluctuate widely. References to addicts as having specific dollars-per-day habits, or to
prostitutes as having specific dollars-per-trick fees, are part
of an everyday verbal shorthand that make our perception of the
world simpler and make "reality" easier to grasp. But it must be
remembered that this conceptual shorthand simplifies reality, and
in doing so obscures the many complexities that characterize reality.
160
TABLE 3
SUBJECTS' CASH EXPENDITURES
SUBJECT
TOTAL
EXPENDITURES
DRUGS
ALCOHOL
LIVING 1
FOOD
FAMILY
CLOTHING
CIGARETTES
OTHER
Steven H.
$3,732
83%
-O-
2%
7%
4%
-O-
2%
2%
Mike S.
$
826
59%
6%
-O-
6%
16%
-O-
2%
10%
Keith D.
$
851
90%
3%
-O-
3%
3%
-O-
1%
1%
Frenchy S. $ 827
86%
1%
-O-
7%
-O-
-O-
1%
5%
Kerwin
$2,304
65%
4%
21%
6%
-O-
-O-
1%
3%
Keith H.
$1,272
53%
5%
9%
9%
-O-
3%
3%
18%
Bobby H.
$
540
23%
14%
-O-
5%
36%
4%
5%
13%
Tito C.
$1,093
74%
-O-
-O-
5%
12%
-O-
1%
8%
T.
1.
Includes rent, utilities, telephone, etc.
TABLE 4
SUBJECT'S HEROIN USE
Mean Dollar Value of
Heroin Use per Day
Subject
Steven H.
Mike S.
Keith D.
Frenchy D.
Kerwin T.
Keith H.
Bobby H.
Tito C.
Estimated
Standard
Heroin Use For
Deviation Previous Year
$49
13
32
25
11
8
18.52
11.74
22.42
19.64
9.32
10.44
9
20
8.66
25.47
$60
50
50
60
30
Information not
available
10
100
All 7 of the subjects for whom complete data were available estimated their average daily heroin use for the previous year to be
higher than what was found in the current daily follow-up. The
average mean daily cost of heroin use reported on our daily followup was $22.7 per day. However, the same 7 subjects estimated their
average daily heroin cost for the previous year to be $51.4 per day.
While it is possible that each subject used less heroin this year
than last year, we believe that these data indicate that our daily
follow-tip technique is eliciting more accurate data than is gathered through the more typical method of doing a single interview with
a subject and asking him to recall specific activities occuring
over extended periods of time.
The daily follow up of narcotic addicts has enabled us to produce
econanic data with a clarity, richness and depth not previously
available. It appears clearly superior to data gathered via retrospective interview techniques. This paper constitutes only -the
preliminary analysis of the first group to complete the daily reporting cycle. As the number of cases accumulate, we should be
able to typologize addicts according to their economic lifestyle
and to utilize that typology for purposes of hypothesis testing
and theory building.
REFERENCES
Goldstein, P.J. Prostitution and Drugs. Boston: Lexington Books,
1979.
AUTHOR
Paul J. Goldstein, Ph.D.
Narcotics and Drug Research, Inc.
2 World Trade Center
New York, New York 10047
162
The Impact of Heroin Addiction
Upon Criminality
Ball, J.C.; Rosen, L.; Friedman, E.G.; Nurco, D.N.
STATEMENT OF THE PROBLEM
There is rather general agreement among criminologists that an
increase in criminality commonly occurs following the onset of
heroin addiction in the United States (Chein et al. 1964;
O'Donnell, 1966 and 1969; Ball and Snarr, 1969; Nash, 1973;
McGlothlin, Anglin and Wilson, 1978). Despite this overall
consensus, however, the dynamics of the relationship between
opiate addiction and crime continues to be a matter of controversy. Among the questions which remain unresolved, two seem
especially crucial: (1) What are the frequency and types of
crimes comitted by heroin addicts? (2) What impact do postonset periods of heroin addiction or periods of abstinence have
upon criminality?
A NEW MEASURE OF CRIMINAL BEHAVIOR
In the present paper, a new measure of criminal behavior is
described and employed in an on-going research project. The
new measure has been termed Crime-Days Per Year At Risk. A
crime-day is a 24 hour period in which an individual commits one
or more crimes. The number of crime-days per year at risk
refers to the number of days per year that an individual has
comitted crimes, from 0 to 365. Years at risk refers to tiMe
when the subject was not incarcerated; risk is time "on the
street".
This new measure, crime-days per year at risk, is found to have
unique analytical power as it permits the calculation of uniform
crime rates by years at risk and it is not confounded by multiple
crimes committed on a given day. Furthermore, the term crimedays per year at risk. appears to be an effective procedure for
explaining and understanding the extent of persistent criminal
behavior because it relates the number of crimes committed by
individuals to a common frame of reference -- times per year.
The discovery of the average crime-days per year concept was
163
made by the senior author while analyzing detailed life history
data pertaining to heroin addictsas part of an on-going followup study in Baltimore.
THE SAMPLE OF ADDICTS
This paper is based on interview data obtained from 243 Baltimore
opiate addicts (most were heroin addicts). The 243 male addicts
Were a stratified randon sample drawn from 4,069 persons listed
by the Baltimore Police Department between 1952 and 1971 as known
addicts. Analysis of cohort and race differences has been undertaken elsewhere (Nurco and DuPont, 1977).
Although comprehensive institutional data was collected with
respect to the addict sample, the main source of data for the
present analysis was obtained through personal interviews.
Each of the 243 addicts was interviewed during 1973 or 1974 by
specially trained interviewers who were familiar with the
Baltimore addict subculture. The interview lasted some three
hours and the questions were focused upon six topics: drug use,
criminal behavior, work, living arrangements, drug selling and
other sources of income. The validity of the interview data
was found to be satisfactory in a separate study (Bonito, Nurco
and Shaffer, 1976).
ADDICTION STATUS AND CRIMINALITY SINCE ONSET
After the number of crime-days since the onset of regular
opiate use had been coded for each subject, it was possible
to classify both his addiction status and criminality during
his years at risk. Thus, the following data was coded for each
subject: (1) total crime-days while addicted, (2) total crimedays off opiates while "on the street", (3) crimeless days while
addicted and (4) crimeless days while off regular opiate use.
These four statuses were mutually exclusive.
For the entire sample, the most frequent addiction-crime status
during their entire risk years was that of being addicted and
comitting crimes on a daily basis; this occurrerd during 41.7
percent of the risk period (Table 1). Next most common was being
off regular opiates and not committing daily crimes; this occursed for 34.5 percent of the risk period. The remainder of the
risk period was accounted for by addicted time when crimes were
not committed (19.9 percent) and abstinent time when crimes were
committed (3.9 percent of days).
164
Total Time at Risk by Addiction Status and Criminality
for 237 Addicts
Days in
Percent of
Each Status
Days in Each Status
Status While At Risk
TABLE 1
1.
2.
3.
4.
Crime-Days on Opiates
Crime-Days off Opiates
Crimeless Days on Opiates
Crimeless Days off Opiates
Total Days at Risk:
432,947
40,791
206,082
358,304
41.7
3.9
19.9
34.5
1,038,124
100.0
The total amount of time that this Baltimore male sample spent
addicted to opiate drugs since onset of regular opiate use was
61.6 percent of their risk years. Since their average years at
risk was 11.3, they were addicted to opiates almost two-thirds
of the time and abstinent somewhat over a third of the time.
Two further points are pertinent about their addiction or abstinence status. First, with regard to the abstinence from regular
opiate use classification, this status included periods of occasional use of opiates as well as periods of frequent use of nonopiate drugs. Second, it is significant that 85 percent of the
sample had such abstinence periods.
NUMBER OF CRIMES COMMITTED BY THE 243 ADDICTS
The total number of crime-days during
addicts is tabulated in Table 2. The
the sample was fron 0 to 9,450. That
ed by six addicts to 9,450 crime-days
during his risk years.
the risk years for the 243
range in crime-days within
is, from no crimes committaccumulated by one addict
The total number of crime-days amassed by these 243 addicts
during their years at risk was 473,738. This total may be regarded as an underestimate of the total number of crimes committed, as multiple crimes during a crim-day were common. It is
also pertinent to note in this context that most of the crimes
reported were for theft and that drug use or possession was not
classified as a crime. The mean number of crime-days per addict
during their years at risk was 1,998.9.
165
TABLE 2
Total Crime Days for 243 Addicts
Crime Days
0 (None)
1-99
100-499
500-999
l,000-1,999
2,000-2,999
3,000-3,999
4,000-4,999
5,000-5,999
6,000-9,450
Total
Number of
Addicts
Percent of
Addicts
2.5
8.2
12.8
12.8
22.2
18.9
11.1
4.9
4.1
2.5
100.0
6
20
31
31
54
46
27
12
10
6
243
Total crime-days since onset of addiction: 473,738
In order to control for years at risk, crime-days were computed
for each person by years at risk (Table 3). This measure Crime-Days Per Year At Risk - indicates the average number of
crime-days per year during the risk years for each of the 243
addicts. The mean number of Crime-Days Per Year At Risk for
the sample was 178.5. Thus, the total amount of time that these
addicts spent engaged in daily criminal behavior since their
onset of addiction was almost half of their risk years. To
he exact, they committed crimes during 45.6 percent of their
days at risk.
TABLE 3 Crime-Days Per Year at Risk for 243 Addicts
Crime-Days
Per Year at Risk
No Crime-Days
Less than 1 per yr.
1-49
50-99
100-149
150-199
200-249
250-299
300-349
350-365
Total
Number of
Addicts
6
11
35
26
31
32
25
26
28
23
243
166
Percent of
Addicts
2.5
4.5
14.4
10.7
12.8
13.2
10.3
10.7
11.5
9.5
100.0
THE IMPACT OF ADDICTION UPON CRIMINAL CAREERRS
Each of the 243 addicts was classified as to the common criminal
career which he had followed since onset of regular opiate use
(Table 4). The extent of criminality among all nine career types
was affected by their addiction status. Thus, there Was an overall six-fold increase in the number of crime-days per year during
addiction as contrasted with the crime rate when abstinent.
Although the extent of criminality within this addict sample Was
notably increased when the subjects were addicted to opiate drugs,
the non-addicted trim rate was still quite high. Thus, two of
the career types had more than 100 crime-days per year while not
addicted to opiates.
TABLE 4
Crime-Days Per Year At Risk By Addiction Status
Crime Career Type
1.
2.
3.
4.
5.
6.
7.
8.
9.
Number of
Addicts
Theft-daily
Sale of Drugs-daily
Other Crimes-daily
Weekly Theft
Weekly Sale of Drugs
Weekly, other crimes
Infrequent Theft
Infrequent Sales
Infrequent, other crimes
No Crime
Total:
Crime-Days
Per Year at
Risk
Crime-Days Per
Year at Risk:
addicted abstinent
41
13
7
58
18
7
57
14
22
6
330.3
328.0
319.4
189.6
181.1
201.9
72.4
102.4
46.8
---
347.7
353.2
341.4
280.9
284.0
297.0
140.7
260.9
108.2
---
109.7
88.3
151.0
23.3
27.6
70.1
7.4
10.5
2.3
---
243
178.5
248.0
40.8
INTERPRETATION AND CONCLUSTION
In this study of male heroin addicts in Baltimore, it has been
found that most of the subjects were deeply enmeshed in criminal
careers on a daily basis wer a period of many years. Secondly,
it has been found that the vast majority of these crimes were
committed While the subjects were addicted to opiates. Converse
ly, the rate of criminal activity was greatly reduced when these
subjects were abstinent.
167
With respect to criminality, it was found that each of the 243
addicts committed an average of 1,999 crimes (i.e. had 1,999
trim-days) and that together this sample was responsible for
committing at least 473,738 offenses. (These figures do not
include drug use or 'drug possession offenses). On an annual
basis, this sample of male addicts committed 178 crimes per
year since their onset of regular opiate use.
The association of this high level of criminal behavior with
active addiction to opiates was striking. Thus, the rate of
criminal offenses committed increased six times during their
addiction pariods as contrasted with their abstinence pariods.
With respect to years at risk, 91.4 percent of their crimedays were also days during which the subjects were addicted;
conversely, only 8.6 percent of their crime-days were abstinent days.
These research findings concerning the impact of addiction
upon criminality are consistent with those of various other
studies. (Sutter, 1966; Ball and Snarr, 1969; Preble and
Casey, 1969; DeLeon et al. 1972; Inciardi and Chambers, 1972;
Nash, 1973). At the same time, employment of a newmeasure of
criminality (crime-days per year at risk) prwides a more meaningful and statistically valid procedure for analyzing the crimedrug relationship than has previously been available. For it is
now feasible to compare rates of criminality and relate these
differential rates to various aspects of drug addiction.
REFERENCES
Ball, J.C., and Snarr, R.W. A test of the maturation hypothesis
with respect to opiate addicts. Bull Narc, 21 (4): 9-13, 1969.
Bonito, A.J., Nurco, D.W., and Shaffer, J.W. The veridicality
of addicts' self-reports in social research. Int J Addict, 11
(5): 719-724, 1976.
Chein, I., Gerard, D.L., Lee, R.S., and Rosenfeld, E. The Road
to H. New York: Basic Books, 1964.
DeLeon, G., Holland, S., and Rosenthal, M.S. Phoenix house:
criminal activity of dropouts. JAMA, 222: 686-689, Nov. 6,
1972.
Inciardi, J.A., and Chambers, C.D. Unreported criminal involvement of narcotic addicts. J Drug Issues, 2: 57-64, 1972.
McGlothlin, W.H., Anglin, M.D., and Wilson, B.D. Narcotic
Addiction and Crime. Criminology, 16 (3): 293-315, 1978.
168
Nash, G. The impact of drug abuse treatment upon criminality.
Report, State of New Jersey, Division of Narcotic and Drug Abuse
Control, December, 1973.
Nurco, D.N., and DuPont, R.L. A preliminary report on crime and
addiction within a community-wide population of narcotic addicts.
Drug Alcohol Depend, 2: 109-121, 109-121, 1977.
O'Donnell, J.A. Narcotic addiction and crime. Social Problems,
13 (4): 374-385, 1966.
O'Donnell, J.A. Narcotic Addicts in Kentucky. Washington, D.C.:
U.S. Government Printing Office, 1969.
Preble, E. and Casey, J.J. Taking care of business - the heroin
user's life on the street. Int J Addict, 4: 1-24, March, 1969.
Sutter, A.G. The world of the righteous dope fiend. Issues in
Criminology, 2 (2): 177-222, Fall, 1966.
ACKNOWDGEMENT
This project was supported, in part, by NIDA Research Grant
ROI DA 01375, Principal Investigator David N. Nurco. Special
appreciation is due Dr. John A. O'Donnell for his careful review
of this paper.
AUTHORS
John C. Ball, Ph.D., Department of Psychiatry
Temple University School of Medicine
3401 N. Broad street
Philadelphia, PA 19140
Lawrence Rosen, Ph.D., Department of Sociology
Temple University
Berks St. between 11th and 12th
Philadelphia, PA 19122
Ellen G. Friedman, M.P.H., Maryland Psychiatric
Research Center, Department of Psychiatry
University of Maryland School of Medicine
1229 W. Mt. Royal Ave.
Baltimore, MD 21217
David N. Nurco, D.S.W., Maryland Psychiatric
Research Center, Department of Psychiatry
University of Maryland School of Medicine
1229 W. Mt. Royal Ave.
Baltimore, MD 21217
169
Drug Abusers: Defeated and
Joyless
Cowan, J. D.; Kay, D. C.; Neidert, G. L.; Ross, F. E.;
Belmore, S.
INTRODUCTION
It has long been recognized that individuals who abuse one psychoactive drug are likely to abuse others. Such an association is
especially strong between opiates and sedative-hypnotics, including
alcohol. It is our thesis that this indiscriminate urge to take
drugs is supported (and possibly initiated) by a common drug effect
that improves feelings and/or produces amnesia for unpleasant feelings.
This study is an extension of a new approach to identifying pathological feeling states in alcohol and opiate abusers. Martin,
Hewett, Baker, and Haertzen (1977) postulated that alcoholics and
opiate addicts are characterized by high basic needs, impulsivity,
egocentricity, sociopathy, and hypophoria. Various definitions of
hypophoria have included elements of lack of confidence, low energy,
joylessness, and self-perceived unpopularity. Martin, Haertzen, and
Hewett (1978) hypothesized that hypophoria was a feeling state that
occurred with increased frequency or intensity in drug abusers.
Since trait measures such as the MMPI or ARCI psychopathy scales
were known to be insensitive to acute drug effects or withdrawal
from drugs, new instruments with a more current time frame were
developed.
Martin et al. (1977) devised a short questionnaire
(Maturity Scale) which contains rationally derived subscales to
measure five of the characteristics which they postulated for drug
abusers. Haertzen, Martin, Hewett, and Sandquist (1978) constructed a long instrument, The Social Experience Questionnaire (SOEX),
and then short pychopathic state scales (Haertzen et al., in press).
This study is concerned with describing more precisely the pathological feelings common to many alcoholics and opiate addicts. The
rather broad focus of Martin's initial conceptualization of hypophoria led us to hypothesize that such a feeling state might consist
of more than one independent canponent. Accordingly, in Experiment
I we reanalyzed the data fran the SOEX, starting with new, rationally constructed marker scales for four canponents of hypophoria:
lack of confidence, low energy, joylessness, and unpopularity.
170
EXPERIMENT 1
Methods
Subjects
Three male groups were studied: Control subjects (n = 54) consisted of students, faculty, and staff fran a religious college
and seminary. Participation was restricted to those who had never
been treated for alcohol or drug problem. Alcoholic subjects
(n = 53) had been treated for alcoholism by an agency in the Lexington area. Opiate addicts (n = 28) were Federal prisoners with
a documented history of repeated opiate use who had volunteered
for studies at the Addiction Research Center.
Data Analysis
LONG SCALES: Initial rational scales were derived from the SOEX
items by using the judgment of two raters. Four long scales
resulted: Lack of Confidence, Low Energy, Unpopularity, and Joyless. There were high correlations (all but one above .45) between
the long Lack of Confidence, Unpopularity, and Low Energy scales.
However, none of these scales were strongly related to the Joyless
scale. The 128 item of three correlated scales were therefore
combined into a scale labeled Defeated. Overlapping items that
could be appropriate to both the Joyless and Defeated scales were
eliminated.
These two scales were then scored and intercorrelated
in the three criterion groups. Their correlation was significantly positive: r = .201; (.01 < p < .05).
SHORT SCALES: Two short scales were selected fran the items that
were originally members of the long Defeated or of the long Joyless scales. Basically, the 15 items with the largest correlations
between that item score and the appropriate long scale were selected. All items on the short Defeated scale marked true are scored
positively. In contrast, the Joyless scale measures denial of
positive feelings. It is a euphoria scale with the items scored
positively when the answers are false. These scales are available
fran the authors upon request.
Results
SHORT SCALES: The 15-item Defeated and Joyless scales produce patterns that are similar to the long scales. Each short scale correlates strongly with its parent long scale, .865 and .953, respectively, but is slightly less powerful in differentiating the
three clinical groups. The correlation between these two short
scales is not significant in these population samples.
The short Defeated scale clearly segregates-alcoholics fran normals
(p < 10-6 ) and addicts from normals (p < 10-9 ), but the two drugabusing groups do not differ significantly. The possible diagnostic usefulness of this scale is indicated by the fact that if a
cutoff score of 5 (T score = 59.05) is established, none of the
171
normals' scores exceed this level. However, 41.5% (n = 22) of the
alcoholics and 57.1% (n = 16) of the addicts had scores above this
limit.
The short Joyless scale does not distinguish between alcoholics
and normals, but does differentite addicts fran both alcoholics
(p = .0018) and normals (p < 10-5).
HYPOPHORIA SCALE: The 15-item Hypophoria scale developed by
Haertzen et al. (1979) from the SOEX appears to combine aspects of
both the Defeated and Joyless scales. Hypophoria correlates significantly with both these scales (.680 and .406, respectively).
It clearly differentiates alcoholics fran both addicts (p = .00015)
and nomals (p = 10-6).
The Defeated and Joyless scales were derived from differences
between criterion groups, whereas ARC Inventory scales were validated using drug-induced states. In order to establish that both
types of measures are also senstiive to naturally occurring changes
in feelings, Experiment 2 was conducted.
EXPERIMENT 2
Methods
College students, 24 men and 24 women, participated in Experiment
2 for credit in an introductory psychology course.
As part of a
larger study, the subjects were shown the TV film Christmas in
Appalachia. The extent of the change in their feelings was measured by two tests, the Profile on Mood States (POMS) and the
Present Affect Rating (PAR), given before and after the film.
Instruments
P O M S : This instrument contains 65 adjectives relating to feelings,
and is divided into six scales: Tension-Anxiety, DepressionDejection, Anger-Hostility, Vigor, Fatigue, and Confusion-Bewilderment. The subjects were asked to rate adjectives on an intensity
scale ranging from 0 ("not at all") to 4 ("extremely"). Raw scale
scores were calculated by adding these item ratings.
PAR: This test consists of 106 sentences relating to feelings,
attitudes, and opinions. Short (14-17 items) versions of four
drug-effect scales fromn the ARC Inventory were included: the
Morphine-Benzedrine Group (MBG), Pentobarbital-ChlorprorazineAlcohol Group (PCAG), LSD, and Tired scales. The other four scales
on the PAR were derived from the SOEX that was used in Experiment
1. The short scales for Hypophoria and Sociopathy, as well as
Defeated and Joyless, were utilized to sample a range of feelings
and attitudes possibly associated with addiction and psychopathic
states.
Each subject responded to PAR items by using one of four responses:
strongly agree, mildly agree, mildly disagree, or strongly disagree,
172
and these responses were numerically weighted. Raw scale scores
were calculated by adding these weighted items.
FILM: Christmas in Appalachia is a half-hour black and white
movie that was originally broadcast as a CBS News Special Report
in the mid-1960s. Charles Kuralt narrates his visit to a small
community in the mountains of southeastern Kentucky. Extreme
poverty is evident in all the families of unemployed coal miners
that Kuralt interviews. The celebration of Christmas only serves
to emphasize their sadness, unhappiness, futility, and despair.
Procedures
The subjects completed the POMS and the PAR before the film (Test
1). Immediately after the film, the participants again completed
the POMS and PAR (Test 2) with respect to their feelings during
the film. To permit the scores on the various scales to be compared with one another, the raw scores were converted to standardized T scores with a mean of 50 and a standard deviation of 10,
by using the means and standard deviations for the pre-film test
as the basis of adjustment.
RESULTS
Film Effects
The effects of the film on feelings varied greatly (Table 1).
The largest effect was an increase in Depression-Dejection, p = 2
x 10-6 (two-tailed). Changes on four interrelated scales were
also highly significant: increases in Joyless (p = .0001) and
Hypophoria (p = .0008), and decreases in Vigor (p = .00001) and
MBG (p = .0002). In contrast, no significant changes were produced
in Defeated or Fatigue; there was a relatively small (though significant) increase in Confusion-Bewilderment (p = .017). The difference between the large increase in Joyless and the small change
in Defeated was significant (p = .0089).
So, despite the fact that the film depicted a number of defeated
people, the Defeated scale was not significantly elevated in the
college students who watched it. In contrast, scores on the Joyless scale were strongly increased. It is apparent that the
Defeated scale is a more stable, requiring a more intense stimulus
or more personal involvement than that provided by the poverty
film to change this aspect of these nonaddict subjects.
DISCUSSION
Hypophoria
Both experiments in this study demonstrate that two separate components, Joyless and Defeated, can be identified which were
previously subsumed within Martin et al's. (1977) concept of hypophoria.
173
Joyless
The data from Experiment 1 suggest that joyless feelings may be a
canponent of a pathological state that is greater in opiate addicts.
Experiment 2 found that the Joyless scale is strongly and inversely
correlated with the MBG scale, a well-validated treasure of euphoria
induced by the opioids and other drugs of abuse. This finding is
consistent with the idea that opioids my be used to relieve feelings of joylessness. However, the greater Joyless feelings in
addicts my also be due to the fact that they were prisoners,
while the other groups were not.
Defeated
Defeated appears to be particularly important in understanding
pathological feeling states, since it differentiates both alcohol
and opiate abusers fran normals. Prior explanations of antisocial
behavior might be related to defeated feelings: for example,
anomie, hopelessness, alienation and apathy. Several previous
studies support the idea that drug abusers have low self-esteem
(Vanderpool, 1969; Berg, 1971). It is noteworthy that there is no
substantial correlation between Tension-Anxiety and Defeated in
Experiment 2. This would suggest that prior equivocal experimental
data regarding tension-reduction models of alcoholism are not necessarily related to hypotheses about feelings of defeat in drug
abusers.
Psychopathic
State
We think that drug abusers might suffer from some distinctive pattern of pathologic feelings--particularly defeated ones--which can
lead to and/or result fran chronic drug intake. This has been
termed a pychopathic state, to differentiate it fran a stable
psychopathic trait. It is not yet clear whether feelings of defeat
or other elements of a psychopathic state are relatively constant,
or if they occur in episodes similar to anxiety (or panic) states.
This underlying disease process, or psychopathic state, may occur
in drug abusers even when they are not using drugs.
Drugs and Defeated Feelings
Psychoactive drugs (for example, alcohol and opioids) my be used
to relieve persistent or episodic feelings of defeat. Several
studies in which the experimental manipulation threatened the
subject's self-image produced an increase in alcohol consumption
(Nathan and Lisman, 1976). Although two studies report that drinking alcohol directly improves the current self-concept of alcoholics (Berg, 1971), three others do not support this conclusion
(Pollack, 1965; Vanderpool, 1969; Vanicelli, 1972).
Drugs that counteract feelings of defeat do not necessarily have
to do so by producing opposite feelings, such as success; aiding
the users to forget or suppress fran consciousness the unwanted
feelings my be quite sufficient to provide relief. Both alcohol
174
(Cowan, 1978) and marijuana (Cowan, Neidert, and Miller, in preparation) produce an amnesia for feelings of Fatigue and Confusion.
These POMS scales were related to the Defeated scale in Experiment
2. It would, therefore, appear profitable to test psychoactive
drugs for their ability to induce amnesia for defeated feelings.
One can, then, generate viable hypotheses which specify that sane
psychoactive drugs act to produce amnesia for defeated feelings,
to suppress their episodic occurrence, or to temporarily counteract them. These hypotheses could account for the repetitive use
of drugs such as alcohol or heroin, even though there is considerable evidence that these drugs do not produce consistently euphoric
states.
Instruments such as the Defeated and Joyless scales may
prove of value in the assessment of the underlying disease process
in drug abusers, and its modification by the efforts of treatment
programs.
REFERENCES
Berg, N.L. Effects of alcohol intoxication on self-concept:
Studies of alcoholics and controls in laboratory conditions. Q
J Stud Alcohol, 32:442-458, 1971.
Cowan, J. Testing the escape hypotheses: Alcohol effects on
memory for feelings. Proceedings of the Committee on Problems of
Drug Dependence, 1978. pp. 491-510.
Haertzen, C.A., Martin, W.R., Hewett, B.B., and Sandquist, V.
Measurement of psychopathy as a state. J Psychol, 100:201-214,
1978.
Haertzen, C.A., Martin, W.R., Ross, F.E., and Neidert, G.L.
Psychopathic State Inventory (PSI): Development of a short test
for measuring psychopathic states. Int J Addict, in press.
Martin, W.R., Haertzen. C.A., and Hewett, B.B. Psychopathology
and pathophysiology of narcotic addicts, alcoholics, and drug
abusers. In: Lipton, M.A., DiMascio, A., and Killam, K.F., eds.
Psychophamacolgy: A Generation of Progress. New York, Raven
Press, 1978. pp. 1591-1602.
Martin, W.R., Hewett, B.B., Baker, A.J., and Haertzen, C.A.
Aspects of the psychopathology and pathophysiology of addiction.
Drug Alcohol Depend, 2:185-202, 1977.
Nathan, P.E., and Lisman, S.A. Behavioral and motivational patterns of chronic alcoholics. In: Tarter, R.E., and Sugarman, B.A.,
eds. Alcoholism. Reading, Mass., Addison-Wesley, 1976. pp. 479577.
Pollack, D. Experimental intoxication of alcoholics and normals:
Sane psychological changes (Doctoral Dissertation, University of
California, Los Angeles, 1965). Dissertation Abstracts International. Part 1, 73838 (University Microfilm No. 65-5707), 1965.
Vanderpool, J.A. Alcoholism and the self-concept. Q J Stud
Alcohol, 30:59-77, 1969.
Vanicelli, M.L. Mood and self-perception of alcoholics when
sober and intoxicated. Q J Stud Alcohol, 33:341-357, 1972.
175
TABLE 1
Changes in Feelings Produced by the Film(a)
Mood Scale
Mean Raw
Scores
T score
difference
Pre-Film
Post-Film
8.62
7.08
5.13
15.31
6.27
7.08
7.48
13.35
7.92
11.65
6.92
7.87
-2.28
+8.81****
+5.37***
-5.91****
+1.21
+2.34*
21.85
20.31
13.58
26.67
18.04
22.23
14.98
29.31
-5.29***
+2.83**
+2.71*
+4.06***
19.58
22.15
17.73
12.83
20.27
25.94
20.42
12.69
+1.14
+4.88****
+4.09***
+0.28
POMS(b):
Tension-Anxiety
Depression-Dejection
Anger-Hostility
Vigor
Fatigue
Confusion-Bewilderment
ARCI(c):
MBG(e)
PCAG(f)
LSD
Tired
SOEX(d):
Defeated
Joyless
Hypophoria
Sociopathy
(a) A positive difference indicates that the film increased the
average intensity of that feeling in the 48 subjects (T scores).
(b) Scales fran the Profile on Mood States (POMS).
(c) Scales on the Present Affect Hating (PAR) derived fran the
Addiction Research Center Inventory (ARCI).
(d) Scales on the PAR derived fran the Social Experience Questionnaire (SOEX).
(e) Morphine-Benzedrine-Group scale.
(f) Pentobarbital-Chlorpranazine-Alcohol-Group scale.
*p < .05 (Two-tailed t test); **p < .01; ***p < .001; ****p < .0001.
AUTHORS
Jonathan D. Cowan, Ph.D., Department of Phamacology, Catholic
University of Puerto Rico, Ponce, Puerto Rico.
David C. Kay, M.D., Gary L. Neidert, M.S., and Frances E. Ross,
B.A., National Institute on Drug Abuse, Division of Research,
Addiction Research Center, Lexington, Kentucky.
Susan Belmore, Ph.D., Department of Psychology, University of
Kentucky, Lexington, Kentucky.
176
Outpatient Treatment and Outcome
of Prescription Drug Abuse
Tennant, F. S., Jr.
SUMMARY-ABSTRACT1
Forty-six consecutive patients who voluntarily sought outpatient
treatment for abuse of one or more prescription drugs were studied.
Barbiturates, amphetamines, and diazepam were the most common
drugs abused. Desired treatments by patients included counseling,
medical withdrawal, or medical maintenance with the drug of abuse
or a chemically related drug. Twenty-two (47.8 percent) patients
left treatment and relapsed within one month; another eight (17.4
percent) patients relapsed between one and three months after
entering treatment. Only 13 (28.3 percent) reported abstinence
90 days after entering treatment. This experience suggests that
a wide range of medical, social, and psychologic resources are
required to treat prescription drug abuse, and that long-term
drug abstinence is difficult to achieve with all patients.
INTRODUCTION
Treatment of prescription drug abuse has dealt primarily with
drug complications such as overdose, toxic reactions, and techniques for medical withdrawal.1-5 Other reports describe behavior
patterns of prescription drug abuse and often refer to it as polydrug abuse, since many persons frequently abuse more than one
drug.6-8 Some reports emphasize the clinical complexity of polydrug abuse and particularly note the severity of multiple medical
and psychiatric complications.9-11 Few attempts have been made
to describe treatment and outcome of prescription drug abuse.12
Reported here is a series of 46 consecutive patients who voluntarily
sought outpatient treatment for prescription drug abuse. Type of
treatment desired, concomitant medical and psychiatric conditions,
treatment given, and outcome are described.
METHODS
Forty-six consecutive patients voluntarily sought outpatient treatment for prescription drug abuse between January 1 and June 30,
1977. All patients stated that they used their prescribed drug(s)
177
314-300 0 -80 - 13
compulsively one or more times a day for at least 60 days. When.
admitted, a patient's complete history was taken and a physical
examination was done, including necessary laboratory and urine
drug-screening Procedures.13 Part of the history taking included
a written checklist of the following psychiatric symptoms and
conditions: anxiety, depression, hallucinations, insomnia, and
nervousness. Patients also completed, in writing, the following
questions that were answered yes or no to help screen for psychosis
and suicidal thoughts:
I am depressed at this time.
Have you ever tried to commit suicide?
Right now I feel as though I want to injure myself or someone
else.
Right now I feel I do not particularly want to live.
I sometimes hear noises or see things that aren't really there.
I sometimes think that part of my body disconnects and leaves
for a short time.
I sometimes think I do not have total control over my mind.
I think that most of the people I know are against me.
Depression and suicidal tendency were further assessed and documented by an elevated score (above 16 on a scale of 0 to 39) on
the Beck Depression Inventory. No patients were admitted to the
study who exhibited evidence of delirium, intoxication, or dementia. Patients were specifically asked the reason the drugs were
prescribed, which drug(s) they used, and whether they perceived an
adverse drug effect on health, mind, work, social function, and
marriage, or whether they were physically addicted to their drug(s).
The patients were also asked the type of treatment(s) desired, including medical withdrawal, counseling, or medical maintenance with
the same drug or one chemically related to it. Following intake
procedures, the patient was assigned to an experienced drug treatment team that consisted of a physician, registered nurse, psychiatric technician, and licensed marriage and family counselor.
If the patient desired medical withdrawal, a medical detoxification
regimen was prescribed, which usually required that the patient
attend clinic on a daily basis. Although amphetamines and methylphenidate hydrochloride do not apparently cause physical dependence,
some patients requested medical withdrawal for dependence on these
drugs; this was provided.2 The following drugs were used for detoxification and withdrawal purposes: hydroxyzine pamoate for
barbiturate or other sedative-hypnotic dependence; hydroxyzine for
amphetamine or methylphenidate dependence; and propoxyphene napsylate or diphenoxylate hydrochloride for codeine, pentazocine hydrochloride, oxycodone hydrochloride, and propoxyphene hydrochloride
dependence. Hydroxyzine was chosen as a withdrawal agent since it
is a sedative with antihistamine properties that has low abuse and
overdose potential, and it has been found effective in alcohol
withdrawal.15-17 Propoxyphene napsylate and diphenoxylate were
chosen because they are compounds with relatively low abuse potential that can effectively suppress narcotic withdrawal.18-22 Withdrawal agents were administered in a declining dose fashion over
a two- to three-week period. Following detoxification, each
patient entered an ongoing counseling program in which the patient
attended the clinic at least once a week. Counseling sessions
178
lasted 15 to 45 minutes and were primarily supportive in nature,
with attention particularly directed at the patient's marital,
employment, health, or financial problems. Special focus was
directed on guiding the patient to find alternatives to taking a
prescribed drug(s) when he/she experienced a symptom such as nervousness, lethargy, or depression, although no specific relaxation
technique such as biofeedback, hypnosis, or meditation was used.
Sessions often included family members, and they were continued
weekly until. the patient dropped out of treatment. Medical maintenance was done by substituting a drug chemically related to the
one of abuse. It was done when the patient desired it and when no
treatment alternative was deemed viable. Each patient was interviewed by telephone or by face-to-face contact approximately 90
days after admission to solicit a self-report and determine outcome. Longer follow-up was obtained for patients who remained in
treatment more than 90 days,
RESULTS
Most patients were under age 27 years (mean, 26.1 years). There
were a few more men (25 of 46 or 53.3 percent) than women. The
majority were neither married nor employed (Table 1). Most patients
(34 or 73.9 percent) desired counseling (6 or 13.0 percent) for
treatment, although others requested medical withdrawal (11 or
23.9 percent) or medical maintenance (6 or 13.0 percent) with the
same or related drug. Some patients wanted more than one type of
treatment. The most common drugs of complaint were barbiturates,
amphetamines, and diazepam (Table 1). Patients stated they had
used their drugs from one to 14 years, with a mean of 4.5 years.
Some patients used more than one drug obtained by prescription.
Every patient stated that he used his drugs in excess to what was
prescribed by his physician. Patients had usually obtained their
drugs for depression, insomnia, anxiety, "nervousness," weight
control, or minor pain problems such as headache. All patients
except one perceived that their drug use had developed into a
"problem" and had an adverse effect on their mind, health, social
and work functions, marriage, or that they were addicted (Table 2).
These patients had numerous medical and psychiatric complaints.
Anxiety or nervousness, depression, insomnia, chronic pain, suicidal thoughts, and obesity were the most common (Table 3).
Twenty-two (47.8 percent) patients left treatment within one month
and reported relapse at 90-day followup (Table 4). Eight (17.4
percent) patients left treatment between one and three months and
relapsed. Thirteen (28.3 percent) patients remained in treatment
and reported abstinence at 90-day followup. Urine that did not
contain a detectable, abusable drug was obtained from these patients
and supported their claim of abstinence. Two of the 13 patients
relapsed, however, shortly after the 90-day followup. Six (13.0
percent) patients requested medical maintenance with their chosen
drug of abuse or a chemically-related drug, and this was provided
in four of these patients. Three of the four were still in maintenance treatment at the 90-day followup. One patient relapsed
shortly after three months, one continued maintenance after one
year, and one achieved abstinence after almost one year of
maintenance.
179
COMMENT
The patients studied here excessively abused one or more prescribed
drug and volunteered for treatment. None was referred by the judicial system for mandatory treatment, which is frequently done
with casual drug users.10 Patients perceived that prescribed drugs
had a variety of adverse effects when used to excess. The three
predominant treatments requested were counseling, medical withdrawal, and medical maintenance with their drugs of abuse or chemically-related drugs. Patients had many medical and psychiatric
complaints and conditions, as has been previously reported with
groups of polydrug abusers.9-ll The numerous medical and psychiatric conditons, variety of drugs abused, and different forms of
treatment desired by these patients made treatment a complex endeavor that required a well-trained, multidisciplinary clinical team
with considerable clinical resources. All patients were similar
in that they knowingly exceeded the prescribed dosages intended by
the initial prescribing physician.
Anderson et al. attempted to treat a group of patients with amphetamine, barbiturate, and hallucinogen problems on an outpatient basis
and encountered dismal treatment outcomes. Only eight of their 83
patients even returned for a second clinic visit.l2 Outcome in
the patients studied here appeared better in that patients almost
always returned to the clinic for followup treatment visits, but
only 13 of 46 (28.3%) reported abstinence 90 days after entering
treatment. A different treatment program that uses more frequent
counseling, medical maintenance, or other techniques may have improved outcome. If patients had been mandated by the judicial
system to accept treatment in lieu of incarceration, treatment outcome may have been better.25 Although medical maintenance with
methadone is an accepted treatment for heroin addiction, the concept of medical maintenance for prescription drug abuse has not
been well explored. Six of 46 (13%) patients specifically requested this form of treatment, which suggests that this approach to
prescription drug abuse deserves further study. Despite difficulty
in achieving long-term abstinence with most outpatients studied
here, there is no reason to conclude that inpatient treatment would
have produced better outcome.
TABLE 1. Drugs of Complaint Among
46 Prescription Drug Abusers
No. of Patients*
%
19
18
10
41.3
39.1
21.7
Barbiturates
Amphetamines
Diazepam
*Total is more than 46 since some patients complained about more
than one drug.
180
3
3
3
2
1
1
1
1
Codeine
Methaqualone
Propoxyphene hydrochloride
Pentazocine
Methylphenidate
Chlordiazepoxide
Meprobamate
Oxycodone
TABLE 2.
6.5
6.5
6.5
4.3
2.2
2.2
2.2
2.2
Patients' Perceptions of Adverse Drug Effects
No. of Patients*
Work/social function
Health
Mind
Physically addicted
Marriage
No adverse effects
24
19
15
7
3
1
%
52.2
41.3
32.6
15.2
6.5
2.2
*
Total is more than 46 since some patients perceived that drug use
had multiple adverse effects.
TABLE 3. Psychiatric-Medical Complaints and
Problems Found in 46 Prescription Drug Abusers
No. of Patients*
Anxiety or nervousness**
Depression * * +
Insomnia
Chronic pain
Suicidal thoughts
Obesity
Seizure disorder
Psychotic disorder
Arteriosclerotic heart disease
Congestive heart failure
Hypertension
Regional Enteritis
Thyroid nodule
Endometriosis
Peptic ulcer
Amenorrhea
35
25
24
8
1
1
1
1
1
1
1
1
1
1
1
1
*
%
76.1
54.3
52.2
17.4
15.2
8.7
4.3
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
Total is more than 46 since some patients had more than one
complaint or problem.
**
Presence based on patient self report and/or screening questionnaire.
+
Presence based on screening questionnaire and Beck Depression
Inventory. 14
181
TABLE 4.
Outcome of Treatment
No. of Patients
Left treatment within 1 mo. and
reported relapse at 90-day
followup
Left treatment between 1 and 3 mo.
and reported relapse at 90-day
followup
Remained in treatment and reported
abstinence at 90-day followup
Medical maintenance over 90 days
Totals
%
22
47.8
8
17.4
13
28.3
3
46
6.5
100
Nonproprietary Name and Trademarks of Drug
Methaqualone - Quaalude, Sopor, Tuazole.
REFERENCES
1. Smith , D.E., and Wesson, D.R. Phenobarbital technique for
treatment of barbiturate dependence. Arch Gen Psychiatry, 24:
56-60, 1971.
2. Fischman, V.S., Kramer, J.C., and Littlefield, D.C. Amphetamine abuse. JAMA, 201:305-309, 1967.
3. Tennant, F.S., Jr. Complications of propoxyphene abuse. Arch
Intern Med, 132:191-194, 1973.
4. Tennant, F.S., Jr. Complications of methaqualone-diphenhydramine abuse. Br J Addict, 68:327-330, 1973.
5. Mays, J.A. Psychopharmacological roulette: A follow-up study
of patients hospitalized for drug overdose. Am J Public Health
64:616-617, 1974.
6. Gould, L.C., and Kleber, H.D. Changing patterns of multiple
drug use among applicants to a multimodality drug treatment program. Arch Gen Psychiatry, 31:408-413, 1974.
7. Duncan, D.F. The acquisition, maintenance and treatment of
polydrug dependence. J Psychedelic Drugs, 7:209-213, 1975.
8. DuPont, R.L., Greene, M., and Nightengale, S. Evolving patterns
of drug abuse. Ann Intern Med 83:402-411, 1975.
9. Grant, I., Mahns, L., and Miller, M., et al. A neuropsychological study of polydrug users. Arch Gen Psychiatry, 33:973-978,
1975.
10. Bloom, E.S. An Approach for Casual Drug Users. DHEW Pub. No.
(ADM) 77. Rockville, Md., 1977. p. 533.
11. National Polydrug Collaborative Projects. National Institute
on Drug Abuse. DHEW Pub. No. (ADM)77. Rockville, Md., 1977,
p. 515
12. Anderson, W.H., Lazare, A., and O'Malley, J.E. Failure of outpatient treatment of drug abuse: amphetamines, barbiturates,
hallucinogens. Am J Psychiatry, 128:122-125, 1972.
13. Mule, S,J. Identification of narcotics, barbiturates, amphetamines, tranquilizers, and psychotomimetrics in human urine.
J Chromatogr, 39:302-311, 1969.
182
14. Beck, A.T., and Beck, R. Screening depressed patients in family practice: a rapid technique. Postgrad Med, 52:81-85, 1972.
15. Kaim, S.C., Klett, C.J., Rothfield, B. Treatment of the acute
alcohol withdrawal state: a comparison of four drugs. Am J
Psychiatry, 125:1640-1646, 1969.
16. Dilts, S.L., Hoge, G., Keleher, D.L., et al. Hydroxyzine in
the treatment of alcohol withdrawal. Am J Psychiatry, 134:9293, 1977.
17. Tennant, F.S., Jr. Ambulatory alcohol withdrawal. J Family
Pract, 8:3:621-623, 1979.
18. Casas, S.K., Russell, B.A., Tennant, F.S., Jr., et al. Heroin
detoxification: a comparison of propoxyphene and methadone.
JAMA, 232:1019-1022, 1975.
19. Clark, S.C., Jasinski, D.R., Pevnick, J.S., et al. Therapeutic
usefulness of propoxyphene napsylate in narcotic addiction.
Arch Gen Psychiatry, 34:227-233, 1977.
20. Goodman, A. Use of diphenoxylate hydrochloride in the withdrawal of narcotic addiction: a preliminary report. South Med
J, 61:313-316, 1968.
21. Fraser, H.F., Isbell, H. Human pharmacology and addictiveness
of ethyl 1-(3-cyano-3,3-phenylpropyl)-4-piperidine carboxylate
hydrochloride (R-1132, diphenoxylate). Bull Narc, 13:29-43,
1961.
22. Glatt, M.M. The treatment of the withdrawal stage in narcotic
addicts by diphenoxylate and chlormethiazole. Int J Addict,
7:593-596, 1972.
23. Lasagna, L. Propoxyphene napsylate. Ann Intern Med, 85:619621, 1976.
24. Blachly, P.H. Naloxone for diagnosis in methadone programs.
JAMA, 224:334-335, 1973.
25. Vaillant, G.E. Outcome research in narcotic addiction: problems and perspectives. Am J Drug Alcohol Abuse, 1:25-36, 1974.
ACKNOWLEDGEMENTS
This study was supported in part by the California and Los Angeles
Offices of Narcotic and Drug Abuse, contract 28757.
Carmel Marti Day, M.A., M.S., gave technical assistance in the
preparation of the manuscript.
AUTHOR
Forest S. Tennant, Jr., M.D., Dr.P.H., Executive Director, Community Health Projects, Inc., 336½ South Glendora Avenue, West Covina,
California, 91790.
FOOTNOTE
1. This article originally appeared in Tennant, F.S., Jr., Outpatient treatment and outcome of prescription drug abuse, Archives
of Internal Medicine, Vol. 139, pp. 154-156, copyright 1979,
American Medical Association, Chicago, Illinois.
It is used with
permission of the American Medical Association and may not be further reproduced without their specific permission.
183
Addicts and Drugs
Nurco, D. N.; Wegner, N.
This paper, a retrospective study in the anthropological oralhistory tradition, presents an overview of drug addiction in
Baltimore City from 1950 through 1977. Interviews were conducted
with male addicts and ex-addicts who served as research informants
to describe the conditions prevailing on the narcotic drug scene in
Baltimore during that period.
Each addict was considered as a
participant observer, and the interview focused on his observations
of the conditions that prevailed in Baltimore during his periods
of addiction and not upon his own activities or habits.
In addition to the interviews, data were drawn from available police
statistics and from the Maryland State Drug Abuse Administration.
METHODOLOGY
The formal design of the sample of addict informants called for
the selection of persons who could report on two or more of the
arbitrarily defined time periods during which their own addiction
was of substantial duration. To be eligible for interview, each
addict must have had at least two periods of addiction in Baltimore, separated by a period of time when he was not addicted.
In order to keep the interviews at manageable length, each addict
was asked about two of the time periods during which he was
addicted, regardless of the number of time periods for which he
might have provided information. In general, almost all of the
interviews were based on the addict's initial period of addiction
and the second period of addiction following remission.
In all, 48 interviews were conducted with addict informants (24
blacks and 24 whites). Twenty of the addict informants were
chosen from the sample used in an earlier study of a communitywide population of addicts. The remainder were recruited from
among nominees suggested in early interviews. Respondents
received $15 for a one-session interview lasting one and one-half
hours, conducted by trained and experienced interviewers; 80 percent of the respondents were previously known to the staff, or
to the principal investigator, who has been engaged in drug
184
research in this area for more than a decade.
THE ADDICTS
In the early 1950's, the addict population of Baltimore was relatively small, largely black and almost entirely male. The number
of narcotic addicts, according to police files, did not exceed a
few hundred (Nurco et al. 1975). Between 1951 and 1959, most of
the individuals who were entering the drug scene were largely from
black inner-city neighborhoods, primarily in west Baltimore, and
were raised in working-class families. During the ensuing years
the major changes have been in the direction of an increase in the
total number as well as an increase in the proportion of whites
and of females. By 1970, the addict population had increased more
than ten-fold, and the trend toward increasing proportions of whites
and of women (particularly among blacks) continued.
In the 1950's and earlier 1960's, the black and white addict populations tended to form rather disparate and non-interacting groups
(apart from necessary drug-buying transactions) but with the
passage of time and the advent of social changes such as urban
renewal and trends toward integration, there has been a slight
decline in the separation of black and white addicts. However,
over time, there has been a continued tendency for the existence
of two separate drug subcultures, black and white, differing in
kinds of drugs preferred, methods of supporting habits, location
of "hangouts," and visibility of drug use (blacks tending to be
more visible).
An analysis of the geographical origins of Baltimore City narcotic
addicts has revealed a discernible concentration of narcotic
abusers in the inner city.
In existence in our first time period
(1950-1954), this concentration near the center of the city has
increased with time, and has also spread to adjacent areas. In
addition, new pockets of concentration have appeared in other areas
of the city, which, by the 1970's, were not only isolated from one
another but also seemed to differ in ethnic and sex characteristics
of addict members, although the majority have been black males.
In the early 1950's, an individual's use of narcotic drugs typically
began in the late teens, often coinciding with the end of his
schooling. Through the 1950's and early 1960's, there was a
gradual decline in the age of starting to use narcotic drugs; this
may have occurred originally as a result of greater availability
and popularity of pharmaceutical narcotics such as liquid codeine.
There is some evidence indicating that starting ages have reverted
to those characteristic of the early 1950's, although older addicts
have tended to perceive the addicts of the 1970's as very young
(possibly an impression resulting from being middle-aged).
In the period of the early 1950's when the addict population was
small, addicts of each race tended to be known to one another,
i.e., to be "like a small family," characterized by feelings of
mutual trust and dependency, as well as willingness to share or
185
provide help with drugs, skills, and information. In the 1960's,
and certainly more recently, these group feelings declined markedly,
so that by the late 1960's and early 1970's relations among addicts
have deteriorated to a climate described as "cut-throat." Within
addict groups of the 1950's and early 1960's, there was often some
community of interests extending beyond the shared use of drugs, and
embracing recreational activities such as music, as well as in-group
customs. With the increase in numbers of young addicts, there was
some tendency toward a polarization of younger and older addict
populations in association and behavior. In fact there appeared to
be two separate cultural orientations. The younger generation of
addicts has been described as the "now generation," looking for a
quick and easy way to get money for drugs.
When we explored with our addict informants how social changes may
have affected the drug scene, their awareness of the world around
them seemed to be extremely narrow and restricted; they made
virtually no comments about wars, economic changes, political
events, urban development, technological and industrial changes,
etc. Their detachment was further evidenced by their ignorance
and lack of interest in foreign sources of heroin.
Pathways to addiction did not reveal marked changes during the
period from 1950 through 1977. Reported first experiences with
narcotic drugs have been, for the most part, similar over time.
Addicts were first introduced to narcotics by an older friend or
acquaintance, a relative of a friend, a family member, or someone
encountered in the neighborhood or at a social occasion. Explanations for having started and having continued to use narcotic
drugs are also similar throughout our time period. Some of the
most frequently cited reasons in our study have included curiosity,
peer pressure, escape from boredom, ego support, and pleasure.
Perhaps the most significant of these was peer pressure.
THE DRUGS
In the early 1950's, the clearly preferred drug in the Baltimore
black addict community was heroin. At that time, heroin was
easily obtained, reasonably priced, and considered to be of very
good quality by the standards of 1977. Since cutting agents were
relatively safe dilutants, there was little likelihood of health
hazards such as abscesses resulting from chemical contamination.
Because the strength of the drugs was fairly consistent, the chance
of overdosing was not great for those addicts of relatively stable
tolerance levels. Because of heroin's fairly high strength and
low cost, a heroin habit of even long standing could be well
supported with little money.
Another popular narcotic drug was liquid codeine, obtainable in
the 1950's in the form of over-the-counter (non-prescription)
cough remedies known in the addict community as "syrup." Each
four-ounce bottle could be used as a narcotic agent and could
produce euphoria and addiction. They were often "drunk" by
younger teenagers, and were frequently cited as the "path to
186
addiction" by addicts who started using "syrup" and later went on
to heroin. In the 1950's, "syrup" was obtainable with little
restriction at all drugstores.
In this period of the early 1950's, the quite small population of
white addicts typically preferred "drugstore dope," i.e., pharmaceuticals, to heroin, although white users of heroin did exist.
The category of "drugstore dope" included Dilaudid (one of the
most favored), morphine, codeine, Dolophine, Demerol, and Pantopon.
Some white addicts also used non-narcotic drugs such as amphetamines, barbiturates, and cocaine. Pharmaceuticals were perceived
as "safer" narcotics; because they were not cut and the strength
and composition of the drugs were known, they provided "safe
highs." "Drugstore dope" was obtained primarily from drugstore
burglaries, thefts of physicians' medical bags, and often through
forging prescriptions or "conning" physicians.
In the later 1950's, the kinds of narcotic drugs available had not
changed greatly. Heroin was still the major narcotic used by
blacks. Cutting agents were the same as in the early 1950's. Any
illness, infections, abscesses, etc. resulting from heroin use in
this period tended to stem primarily from using unsterilized
"works" (syringe, etc.). Codeine syrups had become very popular
and were used extensively. "Syrup" was often used by heroin addicts
to avoid or relieve withdrawal symptoms when heroin was unavailable to them. Some also turned to the very inexpensive "syrup"
when they needed to use their money for other expenses. "Syrup"
also attracted many addicts who wished to avoid the necessity of
injecting a drug, and those unwilling to resort to criminal
activities to support a heroin habit. The threat of prosecution
applied also to heroin purchase and use, while at this time purchase
and use of codeine syrups were still entirely legal. Pharmaceuticals
were still relatively popular with whites. In "panics" (periods
when heroin was scarce), blacks might turn to alcohol or barbiturates. Combinations of drugs were used and indeed preferred by
many addicts.
During the 1960's, the purity of heroin gradually declined, with a
greater variety of synthetic chemicals being used as cutting agents.
By this period, overdosing occurred with some frequency since
addicts could not be certain of the drug's strength, or might use
too much in an attempt to get a reaction from the weaker substance.
Also, many of the chemical contaminants used to dilute heroin caused
itches, rashes, and abscesses, the latter in part because addicts
injected the weaker drugs more frequently. In this period pharmaceuticals became increasingly difficult to obtain because of
intensified security measures instituted by pharmacists and
physicians as sophistication about narcotics developed. One of the
greatest changes in the 1960's was the removal of codeine syrups
from the over-the-counter category. By the later 1960's, liquid
codeine had become scarce, and obtainable primarily on the black
market at high prices. Another great change occurring in the late
1960's, related to the proliferation of therapeutic programs providing methadone maintenance, was the appearance on the streets of
187
methadone, first in tablet or powdered form, later as liquid.
The trends of the 1960's continued into the 1970's. Heroin became
steadily more costly, and was cut with many chemical substances
and household materials. The heroin was considered rather unsafe
and "firing" frequently resulted in itching, swellings, infections,
and illness. A decline in the quality began in 1971 and continued.
Prices varied greatly, according to quantity and quality, but a
daily heroin habit in the most recent years of our study required
from $50 to $150. Many addicts felt that the heroin had become
so diminished in quality that it was not worth the effort involved
in trying to obtain it. In the last few years, there has been a
gradual return to the use of pharmaceuticals? as addicts forged
prescriptions for use in pharmacies in counties around Baltimore
City. By the end of our study, methadone was widely used; it was
sometimes used in combination with Valium or cocaine.
OBTAINING
DRUGS
Before 1950, the addict community of Baltimore City was small and
intimate. Addicts and the few dealers who supplied them were well
known to one another. There were feelings of mutual trust between
buyers and sellers. Dealers were typically found in certain
locations; there were in fact only a limited number of "pockets"
in Baltimore where narcotics were sold. Traditionally, some of
the most popular hangouts for black addicts were located along
and surrounding Pennsylvania Avenue; In the early 1950's, dealers
carried their stock of narcotics with them, selling "out of their
pockets," so that a purchase usually involved a direct and immediate exchange of money and drugs. At this time, most of the
dealers working the streets were themselves addicts and their
reputations as dealers were usually known to other addicts; also
any addict might at some time also sell drugs. In this period,
drugstores freely sold "paraphernalia" which could be used for
"firing" (injecting) heroin, such as syringes, as well as empty
capsules (used as containers for heroin) and commonly used cutting
agents. Relations between dealers and addicts tended to be smooth
and amicable. At this time there was little contact with the
police; although the Narcotic Squad had been organized early in
1951, addicts of that era perceived the police as little threat
to them. Investigations, arrests, and convictions were more
likely to be responses to the petty larcenies in which the addicts
engaged than to any direct violation of narcotics laws. The
general public was comparatively naive and uninvolved in matters
of drugs.
In the early 1950's, almost all dealers were black. The small
minority of white addicts had to locate a black dealer; most
typically, they would use a black go-between to buy drugs for them.
Occasionally a white addict might gradually develop a relationship of familiarity and trust with a black dealer and might therefore become the buyer for other white addicts, thereby supporting
his own habit. White buyers were usually charged higher prices
than blacks were, often for drugs of lesser quality. Addicts
188
using codeine rather than heroin were not involved with dealers.
Many white addicts avoided problems of purchasing drugs through
the more common white preference for pharmaceuticals, typically
obtained through thefts, burglaries, forgeries, and "conning,"
rather than by commercial transactions.
In the later 1950's and early 1960's, the following changes
occurred in the process of obtaining narcotic drugs: activity of
the police increased; consequently, dealers stopped "carrying"
narcotics, rather "stashing" them nearby. As numbers of addicts
increased, buyers had to travel some distance to find dealers;
this, as well as increase of public awareness, led to the rise
of "shooting galleries"; these gradually decreased in the late
1960's and early 1970's. Areas of selling proliferated and
spread; although the original center-city location persisted as
a core of drug traffic, areas of drug traffic also spread to
the city's periphery and surrounding suburbs. The 1960's also
saw the rise of the "profiteer" dealer, who was less likely to be
an addict himself; the increase of profiteer dealers paralleled
a decrease of trust in dealers. Also the number of dealers and
their mobility increased. Baltimore dealers regularly travelled
to New York for sizeable quantities of heroin to sell on the
streets of Baltimore.
Addicts pursued both legitimate and illicit activities to obtain
narcotic drugs. In the early 1950's, it was possible to support
a habit by legitimate sources of income, such as employment, funds
from parents, pawning possessions, gambling, or funds from welfare.
These techniques became increasingly inadequate for supporting a
habit in the 1960's and 1970's. Even in the 1950's, however,
many black addicts supported their habits by petty crimes, usually
non-violent in nature, and white-addicts typically obtained
pharmaceuticals by illicit means, i.e., theft, burglary, and
forgery. As the cost of heroin rose and competition for supplies
increased, illicit activities for obtaining funds to support a
heroin habit tended to involve more serious crimes of less skill
and more violence, the latter often directed to others within the
addict community.
Addicts' major perception of available help for problems associated with narcotic addiction focused on methadone maintenance
programs which originated in the mid-1960's and proliferated
fairly rapidly. Addicts' opinions of the value and contributions
of methadone maintenance therapy covered a broad spectrum, ranging
from enthusiastic support to bitter opposition. Positive reactions
often stressed the advantages of methadone maintenance over heroin
addiction in its elimination of the necessity for criminal activities, and for searching for the drug, as well as the fact that
tolerance to methadone does not increase as is true of heroin.
Major criticisms of methadone maintenance focused on beliefs that
methadone created a new addiction, and was also damaging to health,
as well as sapping initiative.
189
Addicts who have sought help from drug abuse treatment programs
have been motivated by legal pressures (an alternative to imprisonment), family pressures, or the desire to change their lives.
Some addicts are apparently also obtaining methadone simply as
a substitute for heroin, or to sell on the streets.
An interesting finding characterizing the outlook of a majority of
the addict and ex-addict informants is the almost unanimous opinion
that conditions during the early years of addiction were far
better than those of later years, irrespective of the specific
decade which they described. This we think of as the "good old
days" phenomenon, which appears to stem from several conditions:
the dramatic quality of the first experience with narcotics; the
easier life of the addicts' youthful years; the fact that there
is often a period of a few years before the addict is identified
by the authorities (a period of relative freedom); the increase
in drug tolerance over time, diminishing the impact of the drug;
and the fact of the difficulty of the addict’s life which causes
him to "burn out."
REFERENCES
Nurco, D.N., Bonito, A.J., Lemer, M., and Balter, M.B. Studying
addicts over time: Methodology and preliminary findings. Amer.
J. of Drug and Alcohol Abuse, 2(2):183-196, 1975.
ACKNOWLEDGEMENTS
This research was supported by the Services Research Branch,
National Institute on Drug Abuse and was supported by-Friends
Medical Science Research Center, Incorporated. We gratefully
acknowledge the cooperation and assistance given to us by
Commissioner Pomerleau of the Baltimore City Police Department
and his staff, and our Chief of Field’ Work, Philip Stephenson.
AUTHORS
David N. Nurco, D.S.W.
Maryland Psychiatric Research Center
Department of Psychiatry
University of Maryland School of Medicine
1229 West Mount Royal Avenue
Baltimore, Maryland 21217
Norma Wegner, Ph.D.
Friends Medical Science Research Center, Inc.
1229 West Mount Royal Avenue
Baltimore, Maryland 21217
190
A Quantitative Method for
Determining the Effects of Opiates
on Fetal Rats In Utero
Kirby, M. L.
INTRODUCTION
Morphine's ability to modify movement in adult animals is well
documented (Wikler, 1945; 1950). Its effects include depression
of spontaneous activity, depressed simple somatic polysynaptic
reflexes and enhanced extensor thrust. With small doses of
opiates the monosynaptic reflexes are unchanged; however, with
larger doses these too are depressed. McGinty and Ford (1976)
treated pregnant rats with opiates and found that the offspring
exhibited decreased spontaneous movement and whole-body-startle
response to touch.
Fetal rat behavior has been studied in utero by several investigators (Angulo y Gonzales, 1932; Narayanan, Fox and Hamburger,
1971; Raney and Carmichael, 1934; Windle et al, 1935). Fetal
rats exhibit two types of activity: spontaneous movement and
reflexes. Spontaneous movement begins late on day 15 of gestation (Angulo y Gonzales, 1932) and peaks at day 18 when the fetus
is active almost 50% of the observed time (Narayanan, Fox and
Hamburger, 1971). Reflexes can be elicited from the vibrissal
region and the palmar surface of the forepaw on day 16, and by
day 18 all areas of the body are sensitive to stimulation
(Narayanan, Fox and Hamburger, 1971).
Because the effects of opiates on fetal movement have not been
observed the present investigation was undertaken to determine
the feasibility of quantifying the effects of opiates and their
antagonists on fetal spontaneous activity and reflexes in utero.
MATERIALS AND METHODS
Pregnant Wistar rats (Charles River) were obtained on the sixth
day of gestation. On the 18th day of gestation each dam was
anesthetized with ether. An incision was made on the dam's
back at approximately the level of the midthorax. The fascia
and dorsal musculature were dissected away from the vertebral
column and the dorsal arch removed. The exposed spinal cord
was transected completely with a pointed scalpel and the incision
191
closed with suture. The cord transection was at the T6-T9
spinal level (Gelderd and Chopin, 1977). The dam was immobilized
on a plexiglass board and a laparotomy was performed just above
the inguinal region. The dam's hindquarters and abdomen were
immersed in a bath of physiological saline maintained at 37°C,
and the uterine horns were allowed to float outside the abdominal
cavity submerged in the warm saline. Fifteen to twenty minutes
was allowed for the dams to recover from the ether and the
fetuses to acclimatize to the saline bath.
Spontaneous activity was observed through the uterine wall with
a magnifying lamp or dissecting microscope. At 18 days of
gestation the uterine wall is translucent, and even subtle
fetal movements can be observed. Spontaneous activity was
recorded by the observer by pressing event markers wired into a
Grass Model 3 Polygaph. Activity was monitored continuously
in a single fetus for periods ranging from 45 to 90 minutes.
In one rat, fetal activity was recorded for 45 minutes and
observed 3 hours later. Activity did not change during 3 hours
of observation. Three uninjected fetuses served as controls.
For each of the other fetuses observed, a control record was
obtained for 20 minutes before any drugs or saline were injected.
After 20 minutes, saline, morphine or naloxone was injected
subcutaneously into the dam's pectoral region. After fetal
activity was recorded for an additional 20 minutes, saline,
morphine or naloxone was injected into the opposite side of the
dam and fetal activity was recorded during a third 20-minute
period. Morphine and naloxone were injected in various concentrations in physiological saline. Naloxone was injected in
appropriate concentrations to reverse visibly the effects of
morphine on the dam within 2 minutes after Injection.
The
amount of time each fetus spent in spontaneous movement was
calculated as a percentage for each one-minute interval of the
record. The percentages derived from each fetus studied were
plotted for each minute of the record on standard 1/10 inch
grid graph paper. The points were connected to obtain a timeactivity curve (fig. 1). The area under a 15-minute interval
of the time-activity curve after administration of each drug
was determined using a planimeter (fig. 1). A similar period
of time under the time-activity curve was measured prior to
any drug administration. The areas measured after each injection were calculated as a percentage of the area measured
during the control period (fig. 1). A time-activity curve was
constructed for each control fetus and each of the curves was
subdivided into three 15-minute periods. The area under each
period of the curve was measured and areas under the second two
periods calculated as a percentage of the first period. These
percentages were compared with the percentages derived from
saline-naloxone treated fetuses and were found to be not statistically different. The saline treated fetuses were compared with
the pooled morphine treated fetuses by a 2-tailed t test and a
significant variation was found. Finally, the naloxone periods
were compared to the morphine periods in a paired t-test and
found to be significantly different.
192
Figure 1
Figure 1. Time-activity curve constructed as described in the
text. The curve is divided into three periods as shown by
stippled areas. These areas are measured with a planimeter.
Period
% of A
Area
A.
5 to 20 minutes
3.39 in.2
B.
28 to 43 minutes
1.02 in.2
43 to 48 minutes
2
C.
2.06 in.
30
61
Reflexes were studied in additional animals. For these tests
the uterine wall was cut at the antimesometrial border and the
fetuses allowed to float in saline with the amnion intact.
Reflexes were elicited with a sharpened probe or a probe heated
in boiling water to 50-60°C (measured with a thermister coupled
to an ohmmeter calibrated for the appropriate temperature
range). Ten stimuli of each type were applied to the snout,
dorsum of paw, or shoulder region at 30-second intervals.
Three or 4 fetuses were tested in each dam. Ten mg/kg of
morphine was injected into the dam as described above and
reflexes retested after 20 minutes. Naloxone was injected in
an appropriate concentration to reverse the effects of the
morphine on the dam and the fetal reflexes were tested again 5
minutes after injection. The number of positive responses for
10 stimuli was recorded. A one-way analysis of variance was
performed to determine significance of the differences in the
response level after various drug treatments.
193
314-300 0 -80
- 14
RESULTS
The control fetuses showed bursts of spontaneous activity for
2-to-4 minute intervals followed by short periods of relatively
little activity throughout the record. The same pattern was
observed after 3 hours. The same type of control record was
obtained for all the animals studied which were not chronically
injected with morphine. The level of activity was unchanged by
the injection of saline or naloxone (table 1). When morphine
was injected at concentrations between 0.3 mg/kg and 20 mg/kg
there was a depression of activity (table 1). The amount Of
depression showed a trend of dose-dependence with 0.3 mg/kg
causing the least depression and 20 mg/kg causing the most
severe depression of activity (table 1). In general this
represents a dose-related depression of activity. However, it
should be emphasized that the sample for each dose is not large
enough to confirm this trend. With the present data it can be
stated conclusively that morphine administration causes a
depression in fetal spontaneous activity. The injection of
naloxone alone caused no significant change in spontaneous
activity (table 1). The fetal response to naloxone following
morphine injection was not uniform. In 5 out of 8 fetuses
Table 1
Acutely Injected Animals
Animal
1.
2.
3.
4.
5.
6.
7.
8.
9:
10.
11.
Morphine
(mg/kg)
106
125
114
86
22
60
45
58
30
23
18
0(Saline)
0(Saline)
0(Saline)
0.30
1.25
1.25
5.00
5.00
10.00
10.00
20.00
Naloxone
(mg/kg)
12.
Activity*
Activity*
1.00
129
Naloxone
(mg/kg)
0.5
0.5
117
114
0.08
0.16
0.16
0.23
0.23
0.34
0.34
0.64
36
53
177
81
165
61
23
20
Morphine
3.5
*Expressed as % of control activity
194
Activity*
Activity*
104
naloxone caused an increase in activity after morphine injecIn 3 of these the activity did not attain control levels
tion.
(53%, 81%, 61%) while in 2 cases activity was increased over
control activities (177% and 165%). A paired t-test revealed a
significant increase in activity after naloxone treatment
following acute morphine administration.
The average number of reflexes for control periods varied
depending on which area was stimulated. Snout was most sensitive
to stimulation and responses were consistently 9-10 responses
for 10 stimuli (table 2). Paw and shoulder were less sensitive
and averaged 5 and 6 responses for 10 stimuli. Paw was eliminated
from consideration in the heated probe test because it could
not be stimulated discretely. The number of responses decreased
significantly for each area after morphine injection and returned
to control levels after naloxone injection. Paw and shoulder
reflexes tended to be more localized than snout reflexes which
occasionally started mass movements in the fetuses.
Table 2
The effects of acute morphine and naloxone injection on
reflexes of 18-day fetal rats.
A.
Pin Prick
Control
Morphine (10 mg/kg)
Naloxone (.12 mg/kg
B.
Snout
Paw*
Shoulder
9.3
3.5
9.8
5.0
2.0
6.3
6.0
2.0
7.0
Heated Probe (50-60°C)
Control
Morphine (10 mg/kg)
Naloxone (.12 mg/kg)
Snout
Shoulder
9.6
8.7
5.0
1.0
5.2
Table 2. The average number of fetal responses elicited by 10
stimulations with a pin prick (A) and heated probe (B). Testing
was done prior to drug treatment (control), 20 minutes after injection of 10 mg/kg morphine subcutaneously in the dam, and 5
minutes after injection of .12 mg/kg of naloxone to reverse the
effects of the morphine. The differeces in responses are significant at the p < . 01 level except for column marked * which
is significant at p < .05 level
195
DISCUSSION
This study demonstrates the feasibility of quantitatively evaluating the effects of morphine on fetal spontaneous activity and
reflexes in utero. The effects of acute morphine injection on
18-day fetal rats are similar to that of adult animals (Wikler,
1945; 1950). In all cases there is a decrease in spontaneous
activity and polysynaptic reflexes after an acute injection of
morphine is given to the dam. Naloxone following acute morphine
injection reverses the morphine effect on both activity and
reflexes.
Placental transfer of opiates has been measured in pregnant rats
from day 11 to day 21 of gestation (Blanc and Dobbs, 1967; Kirby,
1978; Sanner and Woods, 1965; Yeh and Woods, 1970). Morphine
traverses the placenta with increasing facility as gestation
progresses (Kirby, 1978). Peak concentrations of morphine are
found in the fetus 1 hour after subcutaneous injection of the
mother (Kirby, 1978)., The changes in fetal activity following
morphine injection occurred within 20 minutes. It is possible
that the depression of fetal activity would be more remarkable by
one hour after injection. However, since the fetuses are metabolically stable in in utero studies for an indeterminate amount
of time, all the experiments should be carried out as rapidly as
possible. Therefore, the effective dose of morphine in fetal
studies must be related to a predetermined time period. The
latency period of the lowest doses of morphine appeared to be
about 13 to 16 minutes. Hence 20 minutes seems a reasonable
predetermined time period.
In conclusion, it is possible to quantitatively assess the effects
of morphine and naloxone on fetal activity and reflexes and it
appears that the effects on 18-day rat fetuses are similar to
those seen in adult animals.
REFERENCES
Angulo y Gonzalez, A. W. The prenatal development of behavior in
the albino rat, J Comp Neurol, 55:395-442, 1932.
Blanc, G. F., and Dobbs, H. E. Distribution of tritium-labelled
etorphine (M99) and dihydromorphine in pregnant rats at term, Br
J pharmacol, 30:166-172, 1967.
Gelderd, J. B., and Chopin, S. F. The vertebral level of origin
of spinal nerves in the rat, Anat Rec, 188:45-47, 1977.
Kirby, M. L. Enhanced placental transfer of morphine with increasing gestational age, Neurosci Abstr 4, 134, 1978.
McGinty, J. F., and Ford, D. H. The effects of maternal morphine
or methadone intake on the growth, reflex development and maze
behavior of rat offspring. In: Ford, D. H., Clouet, D. H., eds.
Tissue Response to Addictive Drugs. New York: Spectrum Publ
Inc, 1976. pp 611-629.
196
Narayanan, C. H., Fox, M. W., and Hamburger, V. Prenatal development of spontaneous and evoked activity in the rat (Rattus
Norwegicus albinos), Behavior, 40:100-134, 1971.
Raney, E. T., and Carmichael, L. Localizing responses to tactual
stimuli in the fetal rat in relation to the psychological problem
of space perception, J Genet Psychol, 45:3-21, 1934.
Sanner, J. H., and Woods, L. A. Comparative distribution of
tritium-labeled dihydromorphine between maternal and fetal rats,
J Pharmacol Exp Therap, 148:176-184, 1965.
Wikler, A. Effects of morphine, nembutal, ether, and eserine on
two-neuron and multineuron reflexes in the cat, Proc Soc Exp Biol
Med, 58:193-196, 1945.
Wikler, A. Sites and mechanisms of action of morphine and related
drugs in the central nervous system, J Pharmacol Exp Therap, 2:
435-506, 1950.
Windle, F. W., Minear, W. L., Austin, M. F., and Orr, D. W. The
origin and early development of somatic behavior in the albino
rat, Physiol Zool, 8:156-185, 1935.
Yeh, S. Y., and Woods, L. A. Maternal and fetal distribution of
3
H-dihydromorphine in the tolerant and nontolerant rat. J
Pharmacol Exp Therap, 174:9-13, 1970.
ACKNOWLEDGEMENT
Supported by NM Grants RR-05365 and ROl DA02060-01. My sincere
thanks to Drs. Martin Adler, Stephen Holtzman, Dale Bockman and
Thomas Rosenquist for their help in data analysis and preparation
of this manuscript.
AUTHOR
Margaret L. Kirby, Ph.D.
Department of Anatomy
Medical College of Georgia
Augusta GA 30912
197
Differential Effects of Opioids on
Flurothyl Seizure Thresholds in
Rats
Cowan, A.; Geller, E. B.; Adler, M. W.
INTRODUCTION
Morphine and related compounds have recently been subdivided into
at least three different classes on the basis of diverse subjective
effects in man (Jasinski, 1977), different sensitivities towards
naloxone (Takemori, 1973), and dissimilar pharmacological profiles
both in vitro (Lord et al. 1977) and in viva (Martin et al. 1976).
We have extended the in vivo profile approach to include altered
seizure threshold as a measure and have classified twenty opioids
by comparing qualitative effects, dose-response curves of enantiomers, sensitivities towards naloxone, and by conducting tolerance
and cross-tolerance studies. In light of these experiments, we now
report that opioids can be classified into at least four groups in
vivo. Three of the groups show good correspondence with a classification obtained using the chronic spinal dog preparation (Martin
et al. 1976). The fourth group represents a new category; meperidine and pentazocine are the prototype analgesics.
MATERIALS AND METHODS
Animals
The animals used were male Sprague-Dawley albino rats (Zivic-Miller
Laboratories) weighing 300-350 g. They were housed in groups of
4-6 per cage at 22 ± 1°C; food and water were available ad libitum.
A standard light-dark cycle was maintained with a timer-regulated
light period from 6 a.m. to 7 p.m.
Flurothyl-Induced
Seizures
Groups of 10-20 rats received vehicle or test agent by S.C. injection 30 min before being exposed to flurothyl (Indoklon), a volatile convulsant (Adler, 1975). When appropriate, naloxone was
injected S.C. at the same time as the test agent. The flurothyl
was given as a 10% solution in 95% ethanol (v/v) to rats placed
individually in one-gallon glass jars. The flurothyl was infused
onto a gauze pad which was positioned in a perforated metal basket
198
attached to the underside of the screw cap. A constant rate of
infusion of 0.10 ml/min was maintained by a Harvard pump. The
time interval between the start of the infusion and the onset of a
clonic convulsion was considered the seizure threshold. Testing
took place between 10 a.m. and 1 p.m. Mean seizure thresholds for
rats injected acutely with saline were routinely in the range of
350-380 sec.
Tolerance and Cross-Tolerance Studies
Groups of 12-16 rats were injected S.C. twice daily (at 8 a.m. and
5 p.m.) for 11 consecutive days with vehicle or one of the test
compounds listed in table 1. The last injections took place at
midnight on day 11. At 9 a.m. on day 12 the rats received the
vehicle, the same test compound (tolerance studies), or a second
test compound (cross-tolerance studies) S.C. and were exposed to
flurothyl 30 min later.
Table 1
Doses of test compounds used in the multiple-injections schedules
Compound
Cyclazocine
Levorphanol
Meperidine
Pentazocine
Test
Day/Dose (mg/kg) per Injection
Day 1
Day 2
1.25
2.5
6.25
6.25
2.5
10
6.25
12.5
Days 3-11
5
20
12.5
25
Compounds
Most compounds were dissolved in saline and the doses calculated
in terms of the particular salt (see acknowledgements). Sparingly
soluble benzomorphans were dissolved in a few drops of glacial
acetic acid, the pH adjusted to 5 with NaHCO3,
and the solution
made up to volume with saline. Each compound was injected S.C. in
a volume of either 1 or 2 ml/kg body weight.
RESULTS
The opioids could be subdivided into the 4 groups shown below.
Group 1
The sigma ( ) receptor agonists (Martin et al. 1976), SK
F
10,047 (N-allylnormetazocine) (10-40 mg/kg) and cyclazocine (1-5
mg/kg) (figure 1A) , raised the seizure threshold in a dose-related
manner. These psychotomimetic benzomorphans caused behavioral
activation and side-to-side head movements in the rats during the
period of flurothyl challenge. Both enantiomers of cyclazocine
raised the seizure threshold; (-)-cyclazocine was 1.6 times more
199
potent than (+)-cyclazocine. Naloxone (1 and 10 mg/kg) had no
significant influence on the anticonvulsant effects of either
cyclazocine or SK
F 10,047. Reverse tolerance developed to the
anticonvulsant action of cyclazocine. Specifically, the mean
seizure threshold (± s.e.m.) was 330 ± 11 sec in rats pretreated
for 11 days with vehicle and subsequently challenged with vehicle;
the corresponding values were 447 ± 20 sec and 481 ± 23 sec in rats
pretreated with vehicle and cyclazocine, respectively, and subsequently challenged with cyclazocine (5 mg/kg).
Group 2
Several mu (µ) receptor agonists raised the seizure threshold
(table 2). The dose-response curve for etorphine is presented in
figure 1B. In contrast to our observations with SK F 10,047 and
cyclazocine, behavioral depression was associated with the anticonvulsant effects of the µ receptor agonists. Unlike (+)- and
(-)-cyclazocine, only (-)-methadone possessed anticonvulsant
properties; (+)-methadone slightly lowered the seizure threshold.
Interadtional studies with naloxone further differentiated the
compounds in Groups 1 and 2. Thus, very low doses of naloxone
(10-100 µg/kg) could attenuate the anticonvulsant effects of the
three µ receptor agonists tested: etorphine, morphine, and (-)methadone. Importantly, (-)-naloxone (100 µg/kg) antagonised the
anticonvulsant effect of etorphine whereas the same dose of (+)naloxone had no marked effect (figure 2). Finally, tolerance
developed to the anticonvulsant effect of levorphanol (20 mg/kg)
in rats pretreated for 11 days with levorphanol. Rats from this
study were also cross-tolerant to the anticonvulsant effect of
morphine (50 mg/kg).
Table 2
The effects of several µ receptor agonists on seizure
threshhold in rats challenged with flurothyl
Compound
Etorphine
Morphine
(-)-Methadone
Phenazocine
Levorphanol
Buprenorphine
Dose range
(mg/kg, s.c.)
0.005-0.02
12.5-64
1.25-5
0.5-5
2.5-20
0.004-12.5
Max. % change in S.T.
relative to controls
+28.6
+25.6
+22.8
+18.0
+17.5
+15.2
Group 3
The following compounds had no clear (or dose-related) effects on
seizure threshold: cyclorphan (1-80 mg/kg); ethylketocyclazocine
(0.5-50 mg/kg); ketazocine (0.5-20 mg/kg); moxazocine (12.5-50 mg/
kg); nalbuphine (5-20 mg/kg); nalorphine (25-100 mg/kg); naloxone
(0.01-10 mg/kg); norcyclazocine (6.25-25 mg/kg) and normorphine
(50-100 mg/kg).
200
Figure
201
1
Group 4
Dose-related proconvulsant effects were obtained with meperidine
(12.5-50 mg/kg), pentazocine (12.5-50 mg/kg), and normeperidine
(1.56-50 mg/kg). The maximum percent changes in seizure threshold
(relative to controls) were 19.2%, 31.5%, and 46.8%, respectively.
Both enantiomers of pentazocine lowered the seizure threshold; (+)pentazocine was 5.6 times more potent than (-)-pentazocine. The
proconvulsant effects of meperidine and (-)-pentazocine were potentiated by naloxone. At 10 mg/kg (but not at 1 mg/kg) naloxone displaced, in a parallel, downward direction, the dose-response lines
of both analgesics. Naloxone (10 mg/kg) had no marked influence on
the already substantial proconvulsant effects of (+)-pentazocine
(figure 3) . Although the naloxone-normeperidine interaction gave
a trend towards potentiation, no statistically significant differences were obtained. Tolerance did not develop to the proconvulsant
action of meperidine. There was no cross-tolerance between meperidine and etorphine. In other words, etorphine (0.02 mg/kg) still
had a marked anticonvulsant action in rats that had received multiple injections of meperidine. Reverse-tolerance developed to the
proconvulsant action of pentazocine. Specifically, the mean seizure
threshold (± s.e.m.) was 359 ± 11 sec in rats pretreated with vehicle and subsequently challenged with vehicle; the corresponding
values were 281 ± 9 sec and 232 ± 22 sec in rats pretreated with
vehicle and pentazocine, respectively, and subsequently challenged
with pentazocine (30 mg/kg).
Figure
3
Dose-response curves for (+)-pentazocine ( ) and (-)-pentazocine
( ) in the absence. (closed symbols) and presence (open symbols)of
naloxone (10 mg/kg).
Vehicle control ( ); naloxone (10 mg/kg)
202
DISCUSSION
In the present study, twenty opioids have been separated into four
groups using the conventional in vivo approaches of dose-response
relationships, stereospecificity, naloxone-sensitivity, and tolerIt seems that analgesics classified as µ
ance/cross-tolerance.
receptor agonists in the chronic spinal dog preparation (Martin et
al. 1976) are likely to raise seizure threshold in our model. The
receptor mediating this effect has the classical features of stereospecificity, sensitivity towards (-)-naloxone, and susceptibility to
tolerance. A second receptor mediates the anticonvulsant actions of
SK
F 10,047 and cyclazocine, two
receptor agonists that cause
bizarre behavioral effects in rats. This receptor is only weakly
stereospecific, the Levo-rotatory enantiomer of cyclazocine being
the preferred ligand. Naloxone insensitivity and resistance to
tolerance are further features of this receptor.
Several compounds have no pronounced effect on the flurothyl-induced
seizure threshold. Present in this group are four analgesics (ethylketocyclazocine, ketazocine, nalbuphine, nalorphine) that possess
only low physical dependence capacities in withdrawn, morphinedependent monkeys. It remains to be seen if this classification is
fortuitous or is indeed an additional characteristic of certain
receptor agonists.
Our finding that meperidine and pentazocine are not grouped with
the prototype µ,
and
agonists is in keeping with the difficulties experienced by others in trying to define the position of
these analgesics relative to other opioids (e.g. Martin et al. 1978).
We are unable to state, unequivocally, that the proconvulsant actions
of meperidine and pentazocine are mediated by a subclass of opioid
receptors as opposed to being merely a reflection of non-specific,
stimulant effects. There seems to be a naloxone-sensitive link in
the mechanism of action of (-)-pentazocine and meperidine since the
proconvulsant effects of these analgesics were enhanced. The fact
that such enhancement was not obtained with compounds possessing
minimal narcotic analgesic activity (normeperidine, (+)-pentazocine)
may indicate that further subdivision within Group 4 is possible.
In this regard, Gilbert and Martin (1975) view meperidine and normeperidine as having different modes of action in producing convulsions in mice.
In conclusion, our data support current theories of multiple opiate
receptor types. Furthermore, the model may well be suited for detecting novel narcotic antagonists since the receptors involved
mediate effects that are (a) antagonized, (b) enhanced, or (c) unaffected by naloxone, the standard narcotic antagonist. Antagonists
with profiles different from naloxone have been a recurring need;
their availability will most likely prove critical in the discrimination of opiate receptors just as the advent of specific antagonists was associated with major advances in the areas of, say,
adrenergic and histaminergic pharmacology.
203
REFERENCES
Adler, M.W. Pharmacology of flurothyl: laboratory and clinical
applications. In: Essman, W., and Valzelli, L., eds. Current
Concepts in Psychopharmacology. Vol. 2. New York: Spectrum
Publications, 1975. pp. 30-61.
Gilbert, P.E., and Martin, W.R. Antagonism of the convulsant effects
of heroin, -propoxyphene, meperidine, normeperidine and thebaine
by naloxone in mice. J Pharmacol Exp Ther, 192:538-541, 1975.
Jasinski, D.R. Assessment of the abuse potentiality of morphinelike
drugs (methods used in man). In: Martin, W.R., ed. Drug Addiction.
New York: Springer-Verlag, 1977. pp. 197-258.
Lord, J.A.H., Waterfield, A.A., Hughes, J., and Kosterlitz, H.W.
Endogenous opioid peptides: multiple agonists and receptors.
Nature, 267:495-499, 1977.
Martin, W.R., Eades, C.G., Thompson, J.A., Huppler, R.E., and
Gilbert, P.E. The effects of morphine- and nalorphine-like drugs
in the nondependent and morphine-dependent chronic spinal dog.
J Pharmacol Exp Ther, 197:517-532, 1976.
Martin, W.R., Gilbert, P.E., Thompson, J.A., and Jesse, C.A. Use
of the chronic spinal dog for-the assessment of the abuse potentiality and utility of narcotic analgesics and narcotic antagonists.
Drug Alc Dependence, 3:23-34, 1978.
Takemori, A.E. Determination of pharmacological constants: use
of narcotic antagonists to characterize analgesic receptors. In:
Braude, M.C. et al., eds. Narcotic Antagonists. New York: Raven
Press, 1973. pp. 335-344.
ACKNOWLEDGEMENTS
It is a pleasure to thank Dr. R.E. Willette (NIDA) for samples of
buprenorphine HCl, etorphine HCl, (+)- and (-)-methadone HCl, and
nor-morphine HCl, and Dr. A.E. Jaconson (NIAMDD) for (+)- and (-)naloxone. The various companies are thanked for generous samples
of the following compounds: phenazocine HBr, SK F 10,047 (Smith,
Kline
French); ethylketocyclazocine and ketazocine methanesulfonates; meperidine, normeperidine and pentazocine hydrochlorides;
cyclazocine, norcyclazocine (Sterling-Winthrop); cyclophan HCl,
levorphanol tartrate (Hoffmann-LaRoche); moxazocine tartrate (Bristol
Labs); nalbuphine HCl, naloxone HCl (Endo Labs); morphine sulfate,
nalorphine HCl (Merck, Sharp
Dohme).
This work was supported by Grant DA 00376 from NIDA.
AUTHORS
Alan Cowan, Ph.D., Ellen B. Geller, M.A. and Martin W. Adler, Ph.D.
Department of Pharmacology;
Temple University School of Medicine,
Philadelphia, Pennsylvania 19140.
204
Intravenous Phencyclidine SelfAdministration by Rhesus
Monkeys Leading to Physical
Dependence
Balster, R. L.; Woolverton, W. L.
Phencyclidine (PCP) has been shown to reinforce i.v. drug selfadministration behavior in rhesus monkeys (Pickens et al., 1973;
Balster et al., 1973). Self-administration studies can by used as
an animal model to study both the reinforcing properties of PCP and
the consequences of self-administered doses of PCP. Previous
research ( e.g. Deneau et al., 1969; Yanagita and Takahashi, 1970;
Winger and Woods, 1973; Johanson et al., 1976) has shown that unlimited access i.v. self-administration can result in high levels
of drug intake with characteristic toxicities for various classes of
abused drugs. In the cases of opioids, barbiturates and ethanol,
amounts sufficient to produce physical dependence are self-administered. This paper summarizes the results of i.v. PCP self-administration in rhesus monkeys given continuous access for an extended
period of time. Very high PCP intakes were observed which led to
the development of physical dependence.
METHODS
The subjects were five adult male rhesus monkeys. Each monkey was
housed in an individual self-administration cubicle and fitted with
a stainless steel tubular harness (Deneau et al., 1969) and connecting arm. Under anesthesia the animals were prepared with venous
catheters. The catheter exited through the skin on the back and
connected through the harness and arm to a peristaltic infusion pump.
Self-administration sessions were conducted beginning at noon each
day. At the beginning of the session two white lights were illuminated over each lever and each left lever press response resulted
in a 10 sec infusion of the drug or vehicle solution. During infusions the left lever lights changed from white to red. Responses
on the right lever produced the same stimulus changes over the right
lever but no infusion resulted. At 11:00 a.m. the subsequent morning the session was terminated, the data recorded, the equipment
checked, the cages cleaned, and the food intake over the preceding
23-hour period determined.
205
The experimental design was as follows. For the first 7 sessions,
left lever responses resulted in saline injections. For the next
30 sessions, responses resulted in 0.01 mg/kg injections of PCP.
Following access to 0.01 mg/kg PCP, the unit dose of PCP was increased to 0.05 mg/kg/inj. for 20 sessions, after which time saline
was again made available. In most cases the subjects were returned
to PCP and a second withdrawal period was studied.
In addition to food intake other observations were made of the subjects' general behavior. During withdrawal, a symptom checklist was
used to score withdrawal signs every 4 hours until recovery. Plasma
PCP concentrations were determined by Dr. B.R. Martin using a GC/MS
method substantially the same as that described by Lin et al. (1975).
RESULTS
TABLE 1 summarizes the results of unlimited access to PCP in all
animals. The data are divided into the periods of access to saline
and 10-day segments of access to PCP at both the low and high dose.
Table 1
INTRAVENOUS PHENCYCLIDINE SELF-ADMINISTRATION IN RHESUS M0NKEYS
Daily Injections, Drug Intake, Incorrect Responding and Food Intake
in Different Phases of the Study
Monkey
Injections
Session
Mean Range
Mg/Kg/
Day
Mean
Incorrect Rs/
Session
Mean Range
Food Intake (g)
Mean
Range
Sessions 1-7 1.0 ML/INJ Saline
3147
Ml55
Ml93
M258
M266
23
111
4
4
37
22
44
17
9
25
1-103
65-199
0-17
1-9
13-63
4-37
14-108
0-55
0-31
5-64
200
142
180
190
192
200-200
65-200
170-200
170-200
170-200
Sessions 8-17 0.01 MG/KG/INJ PCP
3147
Ml55
Ml93
M258
M266
211
283
77
36
406
9-514
47-473
O-336
3-181
167-693
2.1
2.8
0.8
0.4
4.1
37
64
26
7-123
13-157
0-71
135
119
200
212
31-548
113
30-200
50-180
O-180
200-200
15-200
Sessions 18-27 0.01 MG/KG/INJ PCP
3147
Ml55
Ml93
M258
M266
578
484
21
88
554
8-851
288-734
3-137
l-305
4-1003
5.8
4.8
0.2
0.9
5.5
86
86
7
19
260
206
11-247
20-224
2-19
O-70
l-678
99
58
174
195
95
200-195
20-130
125-200
145-200
O-200
Table 1 (continued)
Monkey
Injections/
Session
Mean
Range
Mg/kg/
Day
Mean
Food Intake (g)
Mean
Range
Incorrect Rs/
Session
Mean
Range
Sessions 28-37 0.01 MG/KG/INJ PCP
3147
Ml55
Ml93
M258
M266
744
513
113
89
400
138-1211
67-827
25-315
0-214
8-807
7.4
5.1
1.1
0.9
4.0
20
101
13
7
67
1-57
1-390
5-47
O-25
0-155
176
124
129
123
80
60-200
O-200
O-200
20-185
O-200
137
118
49
136
75
55-180
25-185
O-200
30-200
50-130
148
164
43
163
125
125-195
120-185
O-190
55-200
80-175
141
130
115
70-180
50-135
30-190
Sessions 38-47 0.05 MG/KG/INJ PCP
3147
Ml55
Ml93
M258
M266
238
222
151
164
258
62-331
116-282
7-206
86-237
171-298
11.9
11.1
7.6
8.2
12.9
28
42
44
91
34
O-96
6-138
O-110
9-255
l-95
Sessions 48-57 0.05 MG/KG/INJ PCP
3147
Ml55
Ml93
M258a
M266
294
163
180
233
131
207-340
130-202
93-276
61-398
71-168
14.7
8.1
9.0
11.7
6.6
27
42
63
64
149
3-118
8-125
O-167
2-183
6-365
Readdiction 0.05 MG/KG/INJ PCP
b
3174
M258 b
M266b
a
288
163
284
Sessions 48-59
183-372
175-286
190-387
14.4
12.1
14.2
b
10
83
52
Sessions 63-75
O-46
25-343
3-149
c
Sessions 61-72
During the first seven sessions of access to saline, few injections
were administered, usually averaging less than 50 injections per
session. The exception was Ml55 who had prior experience with drug
self-administration. Incorrect lever responding was about as frequent as correct lever responding, again with the exception of Ml55.
Food intake usually exceeded 170 rams during this period. During
the initial 10 day access to PCP (0.01 mg/kg) average drug intake
ranged from 0.8-4.1 mg/kg/day. Three of 5 animals (3147, M155,
M266) readily initiated responding for this dose of PCP and achieved substantial levels of intake. Self-administration was more
erratic in the other two monkeys. Incorrect lever responding also
increased somewhat, though not as much as responding on the correct lever. Food intake was markedly decreased, particularly during sessions in which PCP intake was highest. Over the next 20
sessions of access to this dose of PCP, intake gradually increased
207
in all animals, with one animal achieving an average daily intake
of 7.4 mg/kg between sessions 28 and 37. In spite of increasing
PCP intake, food intake returned toward baseline levels, evidence
for tolerance to this effect of PCP. During this period, the animals that reliably self-administered PCP maintained virtually continuous intoxication. They were able to sit but only by supporting
themselves with their arms. Legs were often splayed in an uncharacteristic manner and vertical nystagmus and tongue movements were
prominent.
When the dose per injection of PCP was increased to 0.05 mg/kg PCP,
all animals self-administered the drug readily with less daily
variability in intake than at the low dose. For the animals that
had reliably responded for 0.01 mg/kg PCP (3147, M155, M266), injections/session decreased but not in proportion to the change in
dose. Consequently, overall intake increased, frequently resulting
in total daily intakes greater than 10 mg/kg. For animals that were
less reliable in their self-administration of 0.01 mg/kg PCP (M193,
M258), the 5-fold increase in unit dose resulted in an increase in
the average number of injections per day and roughly a 10-fold increase in mean total intake. Incorrect lever responding did not
change in a systematic manner with the changes in unit dose. Concurrent with the increased drug intakes at the higher dose, food
intake once again decreased and failed to return to baseline levels
during this period. When animals again had access to PCP after the
first withdrawal period (the readdiction phase) all animals promptly
resumed responding at or above previous levels.
At the higher unit dose, all monkeys maintained an even more pronounced intoxication than at the lower dose. Typically they would
be found lying in awkward positions on the cage floor in the vicinity
In one case
of the response lever, unable to support themselves.
(M193), lying in awkward positions and inability to move apparently
reduced blood flow to various parts of the body resulting in gangrenous extremities. This animal died before withdrawal data could
be obtained.
On session 58 (and again after the readdiction phase) saline was
substituted for PCP and the behavior of the animals scored on an observational rating scale every 4 hours. A summary of the observations is presented in TABLE 2.
Table 2
INCIDENCE OF PCP WITHDRAWAL SYMPTOMS
Symptom
Vocalizations
Fearfulness
Bruxism
Oculomotor Hyperactivity
Diarrhea
3147
X
X
X
X
X
208
M155
X
X
X
X
X
Monkey
M258
X
X
X
X
X
M266
X
X
X
X
X
TABLE 2 (continued)
INCIDENCE OF PCP WITHDRAWAL SYMPTOMS
Symptom
3147
Monkey
M155
M 2 5 8
Refuse Preferred Food
Piloerection
Tremors
"Nodding Off"
Ear and Facial Twitches
Priapism
Abdominal Contractions
Emesis
Convulsions
Most Intense Episode
Severe
Moderate
Mild
M266
Severe
Although the spectrum of symptoms varied somewhat between animals,
generally the following observations were made. By 4 hours the
animals had substantially recovered from PCP intoxication, were
eating and less ataxic. At 8-12 hours, animals became markedly
hyperresponsive with a distinctive conjugate oculomotor hyperactivity
that was not the same as nystagmus characteristic of the intoxication.
The animals usually refused preferred foods. At its maximum
(12-16 hours) several of the following abstinence symptoms were present: piloerection, tremor, diarrhea, continuous vocalizations,
hyperresponsitivity, oculomotor hyperactivity, priapism, bruxism and
ear and facial twitches. Abdominal contractions and emesis were observed in one animal, while convulsive activity could be elicited
in another. Characteristically, food intake was reduced by about
50% during withdrawal. Over the next 24 hours the symptoms gradually
diminished. The entire spectrum could be immediately reversed by
the i.v. administration of PCP (0.25 mg/kg). I.V. naloxone (0.1
mg/kg) failed to precipitate withdrawal.
Blood samples were taken at various times during the readdiction
phase and during the second withdrawal period in two monkeys (M258
and M266) for determination of plasma levels of PCP. These levels
ranged from 105 to 280 ng/ml, and decreased to O-12 ng/ml within
24 hours of saline substitution.
DISCUSSION
The conclusions of this experiment may be summarized as follows:
(1) Rhesus monkeys will respond for intravenous PCP delivery at
doses of 0.01 and 0.05 mg/kg. The reinforcing properties of PCP
have been shown previously Pickens et al 1973; Balster et al.,
1973). This study confirms and extends those previous reports.
(2) The rate and pattern of responding with continuous access to
PCP is in part related to the unit dose. At the lower dose (0.01
mg/kg) generally higher response rates could be obtained than with
209
314-300 0 -80 - 15
the higher dose (0.05 mg/kg), however response rates were more varAlthough
iable, both from session to session and within-sessions.
response rates were lower at the higher unit dose they were not
proportionately lower, thus daily drug intake increased with unit
dose.
(3) Unlimited access to PCP self-administration results in dose
levels producing marked intoxication. Since drug intake was higher
during access to the higher unit dose, the intoxication was more pronounced during this phase. In most cases this constant severe intoxication led to effects on food intake, sleep and body positioning
which resulted in a deterioration of the health of the animals.
(4) Food intake was always suppressed by PCP. For some monkeys,
tolerance to this effect was evident.
(5) Unlimited access to PCP self-administration at 0.05 mg/kg/inj.
leads to intakes producing plasma levels of PCP in the range of
100-300 ng/ml.
(6) Unlimited access to PCP self-administration can result in
continuous intakes of PCP sufficient to produce physical dependence
as evidenced by a withdrawal syndrome. This is perhaps the most
novel observation in this experiment and requires some comment.
PCP has not previously been reported to produce physical dependence,
although studies designed to evaluate this phenomenon have not been
carried out. On the other hand, McCarthy and Harrigan (1976), also
using unlimited access self-administration as well as continuous intravenous infusion in rhesus monkeys, found evidence that ketamine
produced physical dependence. The symptoms observed were very similar to what we observed with PCP. They included piloerection, tremors, irritability, preconvulsive activity and a single episode of
clonic convulsions.
Seven instances of PCP withdrawal were observed in this study.
The most consistent finding was the time course for this syndrome
following abrupt discontinuation of i.v. self-administration. The
onset was between 4-8 hours, with a peak from 12 to 16 hours and
recovery by 24-48 hours. The severity and specific symptom complex
differed somewhat from subject to subject, although separate episodes in the same animal were generally quite similar. Neuromuscular symptoms were prominent in all animals. Bruxism and vocalizations were common and in some cases very striking. Gastro-intestinal symptoms included diarrhea in most cases, apparent abdominal pain,
and emesis in one case. All the animals refused highly preferred
foods during withdrawal and normal food intake was often disrupted.
Other signs and symptoms occassionally seen included piloerection,
priapism and in one monkey on two occasions convulsions. Some of
the animals appeared exhausted during withdrawal, frequently closing their eyes and apparently falling asleep even while being watched by an observer (what we termed "nodding off").
On three occasions we were not able to precipitate the syndrome with
i.v. naloxone. On the other hand, it was possible to completely
reverse the symptoms of withdrawal immediately with i.v. PCP. In
210
short, PCP appears capable of producing physical dependence in the
rhesus monkey. This dependence is not of the morphine-type, but
may be common to other arylcycloalkylamines (e.g. ketamine).
ACKNOWLEDGEMENTS
The authors are indebted to Earl Dowdy for his expert technical
assistance. We thank Dr. B.R. Martin for performing the plasma
level determinations. The research was supported by N.I.D.A. grant
DA-01442. William L. Woolverton was a postdoctoral trainee supported by N.I.D.A. grant DA-07027.
REFERENCES
Balster, R.L., Johanson, C.E., Harris, R.T. and Schuster, C.R. Phencyclidine self-administration in the rhesus monkey. Pharmacol
Biochem Behav, 1:167-172, 1973.
Deneau, G., Yanagita, T. and Seevers, M.H. Self-aministration of
psychoactive substances by the monkey. Psychopharmacologia (Berl.),
16:30-48, 1969.
Johanson, C.E., Balster, R.L. and Bonese, K. Self-administration
of psychomotor stimulant drugs: The effects of unlimited access.
Pharmacol Biochem Behav, 4:45-51, 1976.
Lin, D.C.K., Fentiman, Jr., F., Foltz, R.L., Forney, Jr., R.D. and
Sunshine, I. Quantification of phencyclidine in body fluids by gas
chromatography chemical ionization mass spectrometry and identification of two metabolites. Biomed Mass Spectrom, 2:206-214, 1975.
McCarthy, Jr., D.A. and Harrigan, S.E. Dependence-producing capacity of ketamine in Macaca mulatta. Excerpta Medica International
Congress Series No. 399 Anaesthesiology. Proceedings of the VI
World Congress of Anaesthesiology, Mexico City, April 24-30, 1976.
pp. 160-168.
Pickens, R., Thompson, T. and Muchow, D.C. Cannabis and phencyclidine self-administration by animals. In Goldberg L. and Hoffmeister, F. (eds.) Psychic Dependence. Bayer-Sympogium IV. New York,
Springer-Verlag, 1973. pp. 78-86.
Winger, G.D. and Woods, J.H. The reinforcing property of ethanol
in the rhesus monkey: I. Initiation, maintenance and termination
of intravenous ethanol-reinforcing responding. Annals of the New
York Academy of Sciences, 215:162-175, 1973.
Yanagita, T. and Takahashi, S. Development of tolerance to and
physical dependence on barbiturates in rhesus monkeys. J Pharmacol
Exp Ther, 172:163-169, 1970.
AUTHORS: Robert L. Balster, Ph.D. and William L. Woolverton, Ph.D.,
Pharmacology Department, Medical College of Virginia, Richmond, Va
23298
211
Effects of Chronic Treatment With
Morphine, Methadone, and LAAM
on the Response to Phencyclidine
in Rats
Pryor, G. T.; Howd, R. A.
Many people regularly taking narcotics that they obtain on the
street or during maintenance therapy are known to use other drugs
for recreational or therapeutic reasons (Du Pont 1976). The passibility that chronic narcotic use may alter the response to or
disposition of other drugs has received only limited attention.
Recently we have been engaged in a survey of the effects of chronic
treatment with morphine, methadone, and LAAM on the response to
and disposition of a number of commonly used or abused drugs.
We
found that in addition to pentobarbital the response to thiopental,
phenobarbital, and barbital were all enhanced and prolonged after
chronic treatment with morphine by Pellet inplantation (Howd and
Pryor 1979).
Moreover, we found that the response to diazepam and
ethanol were similarly enhanced and prolonged, all of which suggest
that chronic treatment with morphine significantly affects systems
other than the hepatic drug metabolizing enzymes. We recently
examined phencyclidine, because of the increase in street abuse
of this drug (Petersen and Stillman 1978) and the fact that it is
often misrepresented as a number of other drugs such as LSD,
mescaline, and
-tetrahydrocannabinol.
METHODS
Male Fischer strain rats were used. The apparatus and procedures
for establishing a multisensory conditioned pole-climb avoidance/
escape response (CAR) have been described (Pryor et al. 1977).
Briefly, the rats were taught to escape a 1.0 mA foot shock by
climbing or pulling an aluminum pole suspended from the ceiling of
the test chamber. This response terminated the trial. Then they
were taught to avoid the foot shock by responding in the presence
of a pulsating change (2.5 per minute) in the intensity of the
house light or a 4 kHz tone or a nonaversive current (120 µA) on
the floor. Each stimulus was presented separately on a given trial
and preceded the aversive foot shock by 10 seconds.
If the rat
failed to respond (avoidance failure), the stimulus and the aversive
foot shock remained on for 20 seconds. An escape failure was
recorded if the rat did not respond throughout the trial.
212
Placebo- or morphine-pelleted rats were tested
after ip injection of saline or phencyclidine
on Day 8 (N = 9 per group, total N = 72).
Placebo or morphine-pelleted rats were tested
again after ip injection of saline or phencyclidine on Day 16.
Placebo- or morphine-pelleted rats were tested
again after ip injection of saline or phencyclidine on Day 32.
Rats treated daily with saline or methadone were
tested after ip injection of saline or pentobarbital on Day 16 (N = 9 per group, total N = 72).
Rats treated daily with saline or methadone
were tested again after ip injection of
saline or phencyclidine on Day 44.
Rats treated daily with saline or LAAM were
tested after ip injection of saline or phencyclidine on Day 24 (N = 9 per group, total
N = 72).
For morphine the pellet-implantation technique was used (Gibson
and Tingstad 1970). One placebo or morphine (75-mg base) pellet
was implanted subcutaneously on the nape of the neck under light
ether anesthesia. Two additional pellets were implanted 3 days
later. The pellets were not removed. For methadone and LAAM the
drugs were dissolved in 2 ml/kg saline and given daily by oral
intubation. The initial dose of 5 mg/kg of methadone was increased
by 2.5 mg/kg on days 6, 11, 18, 25, 36, 47, and 59. The initial
dose of 1 mg/kg of LAAM was increased by 1 mg/kg on days 6, 8, 10,
14, 18, and 22. For each test the rats were given nine warm-up
trials to reinstate the avoidance response. Then they were injected
ip with saline or 1 of 3 doses of phencyclidine HCl (Phillips
Roxane, Inc., St. Joseph, Missouri, 2 ml/kg) and given a 60-trial
test.
RESULTS
Figure 1 shows that when tested on the 8th day, 1 and 2 mg/kg
phencyclidine had no significant effects on the CAR performance
of placebo-pelleted rats and 4 mg/kg had only minimal and shortlasting effects, whereas both avoidance and escape responses were
severely impaired by all doses of phencyclidine in morphine-pelleted
rats throughout the 60-trial test session. The impairing effects
of phencyclidine on CAR performance 12 days after the last placebo
or morphine pellets were slanted were still clearly enhanced and
prolonged in the morphine-pelleted rats compared with placebopelleted controls (Figure 2). However, this effect was not as great
as it was the week before, indicating some recovery from the chronic
treatment with morphine. The effects of chronic treatment with
morphine on the response to phencyclidine had dissipated completely
when the rats were tested 28 days after the last pellets were
implanted (Figure 3).
As shown in Figure 4, chronic treatment with methadone decreased
the duration of the impairing effect of pentobarbital on CAR performance when tested on the 16th day. Similar results were obtained
when the test with pentobarbital was repeated on the 30th day. The
effects of phencyclidine were tested on the 44th day. Chronic
treatment with methadone did not, like chronic treatment with
morphine, increase the potency or duration of action of phencyclidine
(figure 5). The trend at all doses was toward less effect of phencyclidine after chronic treatment with methadone than with saline.
The effects of phencyclidine were tested after 24 days of treatment
with LAAM. Figure 6 shows that LAAM, like methadone, did not
increase the potency or duration of action of phencyclidine. Also,
like methadone, there was less effect of the 4 mg/kg dose of phencyclidine after chronic treatment with LAAM than saline. We tested
the rats with pentobarbital on the 51st day of the experiment.
Chronic treatment with LAAM, like methadone, clearly and markedly
shortened the duration of action of this barbiturate (data not
shown).
216
DISCUSSION
Cur results show that chronic treatment with morphine markedly
enhanced and prolonged the impairing effects of phencyclidine in
our test system. Phencyclidine is metabolized in rats primarily
by ring oxidation (Munch 1974; Wong and Biemann 1976). Therefore,
because chronic treatment with morphine decreases the activities
of other ring oxidative enzymes (Kato and Onoda 1966; Clouet and
Ratner 1964; Masten, Price, and Burnett 1978), it probably also
decreases phencyclidine metabolisn to some extent. However, the
magnitude of the enhanced phencyclidine response was surprisingly
large and other mechanisms may be involved.
In contrast to chronic treatment with morphine, the effects of
phencyclidine were not enhanced after chronic treatment with
methadone or LAAM. Instead, there was some evidence for the
opposite response. Indeed, the duration of the effects of pentobarbital was shortened appreciably by chronic treatment with both
methadone and LAAM. This latter effect was probably related to
the induction of hepatic microsomal enzymes reported by others
(Masten et al. 1974; Masten, Price, and Burnett 1978) for these
narcotics. In view of the clear effect on the response to pentobarbital, it was somewhat surprising that a similar effect on the
response to phencyclidine was not observed.
Chronic treatment with morphine appears to enhance and prolong
the pharmacological effects of a variety of psychoactive drugs.
Along with our present results with phencyclidine, the list of
such drugs now includes amphetamine, several of the barbiturates
(hexobarbital, pentobarbital, phenobarbital, thiopental, and
barbital), the minor tranquilizers meprobamate and diazepam, and
ethanol. Although chronic treatment with morphine has been shown
to decrease the metabolism of some of these drugs, this mechanism
alone cannot account for all the interactive effects observed (e.g.
barbital). Other dispositional effects such as changes in absorption, distribution, and elimination may be involved to a greater
or lesser extent. However, it is also possible that chronic
treatment with narcotic agonists causes neurochemical or neurophysiological changes in the brain such that the pharmacological
response to these drugs is enhanced. Failure to see such an
enhanced response after methadone and LAAM may have been due to
the metabolic cross tolerance caused by these narcotics that
masked the cerebral changes or prevented their development.
REFERENCES
Clouet, D. H., and Ratner, M. The effect of altering liver microsomal N-demethylase activity on the development of tolerance to
morphine in rats. J Pharmacol Exp Therap, 144:362-372, 1964.
Du Pont, R. E. Polydrug abuse and the maturing national drug abuse
data base. Ann NY Acad Sci, 281:311-320, 1976.
217
Gibson, R. D., and Tingstad, J. E. Formulation of a morphine implantation pellet suitable for tolerance-physical dependence studies
in mice. J Pharmaceut Sci, 59:426-427, 1970.
Howd, R. A., and Pryor, G. T. Effect of chronic morphine on the
response to and disposition of other drugs. Pharmacol Biochem
Behav, 1979. In Press.
Kato, R., and Onoda, K. I. Effect of morphine administration on
the activities of microsomal drug-metabolizing enzyme systems in
the liver of different species. Japan J Pharmacol, 16:217-219, 1966.
Masten, L. W., Peterson, G. R., Burkhalter, A., and Way, E. L.
Effect of oral administration of methadone on hepatic microsomal
mixed function oxidase activity in mice. Life Sci, 14:1635-1640,
1974.
Masten, L. W., Price, S. R., and Burnett, C. J. Microsomal
enzyme induction following repeated oral administration of LAAM.
Res Commun Chem Pathol Pharmacol, 20:1-20, 1978.
Munch, J. A. Phencyclidine: pharmacology and toxicology. Bull
Narcotics, 26(4):9-17, 1974.
Petersen, R. C., and Stillman, R. C. Eds. Phencyclidine (PCP)
Abuse: An Appraisal. National Institute on Drug Abuse Research
Monograph 21. DHEW Pub. No. (ADM) 78-728. Washington, D C.:
Superintendent of Documents, U.S. Government Printing Office,
1978. 313 pp.
Pryor, G. T., Husain, S., Larsen, F., McKenzie, C. E., Carr, J. D.
-tetrahydrocannabinol and
and Braude, M. C. Interactions between
phencyclidine hydrochloride in rats. Pharmacol Biochem Behav,
6:331-341. 1977
Wong, L. K., and Biemann, K. Metabolites of phencyclidine. Clin
Toxicol, 9:583-591, 1976.
ACKNOWLEDGEMENTS
This work was supported by NIDA Contract HSM-42-72-182. The methadone was a gift from Eli Lilly and Co., Indianapolis, Indiana, and
the LAAM was supplied by the NIDA. We thank Ms. Julie Dickinson for
her technical assistance, and Dr. Monique M. Braude of the NIDA for
her continuing support and encouragement of this research.
AUTHORS
Cordon T. Pryor, Ph.D., and
Robert A. Howd, Ph.D.
Life Sciences Division
SRI International
Menlo Park, California 94025
218
Dependence Within the OpiateSensitive Neurone
Collier, H. O. J.
Abstract
The basic principle is proposed that the neurone possessing specific
opiate receptors (opiate-sensitive neurone) is the primary and sufficient site of opiate dependence and associated tolerance (ODT).
The lines of experimental evidence that support this principle are:
(a) in the dependent rat, drugs, such as atropine, that block transmission between neurones lessen some signs of withdrawal, intensify
others and leave yet others unchanged, whereas opiates suppress and
specific opiate antagonists intensify all withdrawal signs; (b) in
the mouse and in the post-ganglionic myenteric plexus of the guineapig ileum, as dependence intensifies, so the effective concentration
of naloxone falls below that at which naloxone interacts only with
the opiate receptor; (c) ODT can be demonstrated in single neurones in situ in the rat cerebral cortex and the myenteric plexus
of them-pig ileum; (d) ODT can be induced in the guineapig isolated ileum by exposure to opiate in conditions of transmitter blockade, both of ganglia and of the neuromuscular junction;
(e) ODT develops in cultured opiate-sensitive neuroblastoma x
glioma cells, which are functionally separate. The principle that
the opiate-sensitive neurone is the primary and sufficient sit
of ODT eliminates about half of the hypotheses that have been
advanced to explain the mechanism of ODT and points towards a
small group of hypotheses that postulate intracellular mechanisms.
Introduction
Several hypotheses of the mechanism of opiate dependence and associated tolerance (ODT) imply that this condition occurs within the
neurone that responds directly to opiates through specific opiate
219
receptors (opiate-sensitive neurone). Such hypotheses include
those involving (a) changes in the opiate receptor (Axelrod,
1956; Collier, 1966; Snyder, 1975), (b) hypertrophy of the cyclic
AMP mechanism inhibited by interaction between opiate and receptor
(Collier and Roy, 1974; Sharma, Klee and Nirenberg, 1975; Traber,
Gullis and Hamprecht, 1975), and (c) damming up of unreleased transmitter (Crossland and Slater, 1968; Paton, 1969). Long after these
hypotheses were first proposed, the evidence has accumulated to the
point of conviction that ODT does indeed occur within the opiatesensitive neurone. This evidence will be discussed under four heads:
(a) paradoxical effects of transmitter blockade; (b) increased
responsiveness to naloxone; (c) ODT in individual neurones in situ;
and (d) ODT in neuroblastoma x glioma cells.
Paradoxical Effects of Transmitter Blockade
Attempts to determine whether any endogenous substances that convey
messages between neurones were intimately involved in the mechanism
of dependence have provided one of the first pieces of evidence that
dependence occurs within the opiate-sensitive neurone, although this
interpretation was overlooked at the time the experiments were done.
In 1972, we showed that, in the morphine-dependent rat, heroin, given shortly before naloxone challenge, lessened all the ten signs of
precipitated abstinence then being recorded (Collier, Francis and
Schneider, 1972). In contrast, substances, such as atropine, indomethacin and para-chlorophenylalanine , which block the action or formation of putative messengers between neurones, inhibited some signs
of abstinence, intensified others and left still other signs unaffected. For example, when atropine was given 30 min before withdrawal was precipitated with naloxone, it significantly decreased
the incidence of jumping, diarrhea and chewing, but significantly
increased that of irritability to touch and of paw tremor, and it
did not change the incidence of squeak on handling, teeth chattering,
ptosis, head shakes and body shakes. Essentially similar results
were obtained when the withdrawal syndrome was modified with an
inhibitor of the synthesis of serotonin or of prostaglandins.
That all withdrawal signs are suppressed by opiates and precipitated by opiate antagonists, whereas inhibitors of transmission between neurones have paradoxical effects on the expression of abstinence, argues that the site of dependence in the whole animal is
the opiate-sensitive neurone.
Increased Responsiveness to Naloxone
Whole animals. In opiate-naive mice, naloxone does not normally
elicit the jumping response, characteristic of withdrawal behavior; but, as exposure to opiate continues and dependence deepens, this response is elicited by increasingly smaller doses of
naloxone (Cheney and Goldstein, 1971; Way, Loh and Shen, 1969).
Thus, the dose needed to elicit jumping in a highly dependent animal is less than 1/70 of that required at an early stage in the induction of dependence. Because low doses of naloxone probably act
220
only at the opiate receptor this suggests, although it does not
prove, that dependence occurs in the neurones possessing such receptors. For stronger evidence, we must turn to the post-ganglionic
part of the myenteric plexus of the guinea-pig ileum.
Post-ganglionic myenteric plexus of ileum. More or less prolonged
incubation of the quinea-pig isolated ileum in Krebs solution containing opiate, at 4°C, 26°C or 37°C produces ODT, in the form of
a contractant response to a low concentration of naloxone, coupled
with a reduced inhibition by morphine of the response to neurally
evoked stimulation (Paton, 1957; Hammond, Schneider and Collier,
1976; Villarreal, Martinez and Castro, 1977; North and Karras,
1978; Villarreal and Castro, 1979; Collier, Cuthbert and Francis,
1979). This is a specific effect, since responsiveness to naloxone
is not induced by another inhibitory substance -- adrenaline -- and
withdrawal is not precipitated by (+)naloxone. This condition in the
myenteric plexus resembles in essential characteristics the ODT that
has for long been studied in whole animals. Thus, its induction is
specific, since it is blocked by (-)- but not by (+)- naloxone (Collier, Cuthbert and Francis, 1979). It is also stereospecific, since
it is brought about by (-)-morphine, but not by (+)-morphine (Collier, Cuthbert and Francis, 1979), and by levorphanol, but not by
dextrorphan (Hammond, Schneider and Collier, 1976; North and Karras,
1978). Moreover, the degree of ODT produced by incubating the ileum
with opiate is related to the concentration of opiate and to the
duration of exposure to it (Collier, Cuthbert and Francis, 1979;
Hammond, Schneider and Collier, 1976). Furthermore, induction of
tolerance in the ileum, as in the whole animal, is blocked by the
protein synthesis inhibitor, cycloheximide. That this induction
occurs in the presence of hexamethonium (Hammond, Schneider and
Collier, 1976), and that hyoscine blocks the contracture elicited by
naloxone challenge of the dependent ileum (Collier, Cuthbert and
Francis, 1979) indicate that tolerance and dependence here occur in
the post-ganglionic part of the myenteric plexus.
In ilea made in this way highly dependent on normorphine, we find
that a withdrawal contracture can be elicited by as little as 30nM
naloxone (Collier, Cuthbert and Francis, 1979), a concentration that
acts only by blocking the opiate receptors of the plexus. Hence,
these observations on the ileum lead to the conclusion that the
opiate-sensitive neurone is the site of this heightened responsiveness-to naloxone and of the dependence that it characterizes.
The
parallelism between ODT in the myenteric plexus and that in the whole
animal argues that the same conclusion applies in vivo.
Individual Neurones in situ
Rat cerebral cortex. Continuous exposure to morphine for 30 min of
individual neurones of the rat cerebral cortex in situ induces
tolerance and a state of excitation (Satoh, Zieglgänsberger, and
Herz, 1976). Likewise, induction of ODT by continued treatment of
the whole animal with morphine results in a lessened response to
opiate and a heightened response to stimulant substances and to
221
naloxone of the individual cortical neurone prepared for electrical
recording of its nerve impulse production (Satoh, Zieglgänsberger,
and Herz, 1976).
Myenteric plexus of guinea-pig ileum. Nerve impulse production by
single neurones of the myenteric plexus, made tolerant and dependent by 24 h exposure to morphine, normorphine or levorphanol at
room temperature in vitro has been recorded by North and Karras
(1978). Such neurones were less responsive to normorphine, but
when treated with naloxone, fired impulses at high frequency.
Neither hexamethonium nor hyoscine prevented the induction of this
state of morphine tolerance and dependence in vitro. These observations demonstrate directly that ODT occurs in the post-ganglionic
neurones of the myenteric plexus.
Neuroblastoma x Glioma Hybrid Cells
Neuroblastoma x glioma hybrid cells (strain NG108-15), cultured in
the presence of an opiate, develop a form of tolerance and dependence expressed as an increased capacity to produce cyclic AMP
(Sharma, Klee and Nirenberg, 1975, 1977; Traber, Gullis and Hamprecht, 1975). Although these cells possess opiate receptors, and
the affinity of opiates for these receptors is correlated with their
ability to inhibit adenylate cyclase (Sharma, Nirenberg and Klee,
1975); the extent to which induction of tolerance and dependence in
NG 108-15 cells resembles that in normal neurones is uncertain, for
three reasons. First, it has not been possible directly to connect
increases in cyclic AMP level in normal, opiate-inhibited neurones
with increased impulse production or transmitter release (Takagi and
Takayanagi, 1972; Hayashi, Mori, Yamada and Kunitomo, 1978; Karras
and North, 1979; Duggan and Griersmith, 1979). Second, the NG 108-15
cells are not arranged in a stable inter-communicating system, as
are neurones of the CNS or myenteric plexus. Third, the NG 108-15
cells are of malignant origin and, unlike neurones, reproduce themselves. There is good evidence, however, that they still develop
ODT when their reproduction is inhibited (W.A. Klee, personal communication). Despite these objections, there is no doubt that, after
exposure of the culture to opiate, tolerance and dependence occurs
within cells that possess specific opiate receptors.
Discussion and Conclusion
Each of the lines of evidence that I have discussed points to the
conclusion that ODT occurs within the opiate-sensitive neurone.
Since this is the only neurone known to be sensitive to low concentrations of naloxone, the nanomolar sensitivity to naloxone that
accompanies the development of dependence in the post-ganglionic
part of the myenteric plexus of the guinea-pig ileum leads to the
proposition that the opiate-sensitive neurone is the main and sufficient site of ODT.
222
Table 1
Proposed mechanisms of tolerance (T) and/or dependence (D) compatible with its occurrence within the opiate-sensitive neurone.
1.
Enzyme expansion or contraction (Goldstein and Goldstein,
1968; Shuster, 1961); e.g. increased enzyme destroying enkephalins
(Malfroy, et al., 1978) (T/D).
2.
Supersensitivity to excitatory or subsensitivity to inhibitory transmitter (Grumbach, 1961; Collier, 1966, 1968; Jaffe and
Sharpless, 1968) (T/D).
3.
Damming up of transmitter release (Crossland and Slater, 1968;
Paton, 1969) (T/D).
4.
Change in number (density) or efficiency (affinity and
intrinsic activity) of receptors for opiate (Axelrod, 1956;
Collier, 1966) (T), or for endogenous messengers (Collier,
1966; 1972) (T/D).
5.
Hypertrophy of cyclic AMP system (Collier and Roy, 1974;
Sharma, Klee and Nirenberg, 1975, 1977; Traber, Gullis and Hamprecht,
1975) (T/D).
6.
Development of cellular immunity to opiates (Cochin and Kornetsky, 1968) (T).
7.
Dual receptors: (a) Agonist and antagonist (Snyder, S.H.,
1975) (T/D); (b) Excitatory and inhibitory agonist (Jacquet,
1978; Jacquet, et al., 1977) (D).
This proposition does not exclude the possibility that, in nervous
systems, other changes, such as supersensitivity to transmitter in
a neurone downstream of the opiate-sensitive neurone may also contribute to ODT. Indeed, there is now some experimental evidence for
this (Llorens, et al., 1978).
This principle affects both the theory and practice of investigating
the opiate dependence mechanism. It appears to be incompatible with
six of the thirteen or so hypotheses that have been put forward in
recent decades to explain the mechanism of ODT. Among the remaining
seven hypotheses (Table 1), this principle particularly favours those
that involve changes in the responsiveness of the neurone, such as
those of super- and subsensitivity (No. 2) and hypertrophy of the
cyclic AMP system (No.5).
223
Acknowledgments
I am grateful to Mr. D.L. Francis, Dr. W.A. Klee, Dr. J.R.
Lovely and Prof. M. Ginsburg for useful discussions and to
Dr.K.C. Rice for (+)-morphine and (+)-naloxone.
References
Axelrod, J. Science, 124:263-264, 1956.
Cheney, D.L. and Goldstein, A. Nature (Lond), 232:477-478, 1971.
Cochin, J. and Kornetsky, C. In The Addictive States, ed. Wikler,
A. pp. 268-279, Williams & Wilkins, Baltimore, 1968.
Collier, H.O.J. Adv Drug Res, 3:171-188, 1966.
Collier, H.O.J. Nature (Lond), 220:228-231, 1968.
Collier, H.O.J. Br J Addict, 67:277-286, 1972.
Collier, H.O.J., Cuthbert, N.J. and Francis, D.L. In Endogenous and
Exogenous Opiate Agonists and Antagonists, ed. E.L. Way, Pergamon, Oxford, 1979. In press.
Collier, H.O.J., Francis, D.L. and Schneider, C. Nature (Lond.),
237:220-223, 1972.
Collier, H.O.J. and Roy, A.C. Nature (Lond.), 248:24-27, 1974.
Crossland, J. and Slater, P. Br.J.Pharmacol., 33:42-47, 1968.
Duggan, A.W. and Griersmith, B.T. Br.J.Pharmacol., 1979. In press.
Goldstein, A. and Goldstein, D.B. In The Addictive States, ed.
A. Wikler, pp. 265-267. Williams & Wilkins, Baltimore, 1968.
Grumbach, L. In Minutes of the 23rd Meeting of the Committee
on Drug Addiction and Narcotics, Appendix 16. National Academy
of Science - National Research Council, Washington, DC (1961).
Hammond, M.D., Schneider, C. and Collier, H.O.J., In Opiates and
Endogenous Opioid Peptides, ed. Kosterlitz, H.W., pp. 169-176.
Elsevier, Amsterdam (1976).
Hayashi, E. Mori, M. Yamada, S. and Kunitomo, M. Europ J Pharmacol,
48:297-307, 1978.
Jacquet, J.F. Klee, W.A., Rice, K.C., Iijima, I. and Minamikawa,
Science, 198:842-845, 1977.
Jaffe, J.H. and Sharpless, S.K., In The Addictive States, ed.
Wikler, A., pp. 226-246, Williams & Wilkins, Baltimore, 1968.
Karras, P.J. and North, R.A., Br J Pharmacol, 65;647-652, 1979.
Llorens, C., Martres, M.P., Baudry, M. and Schwartz, J.C., Nature
(lond), 276:523-526, 1978.
Malfroy, B., Swerts, J.P., Guyon, A., Roques, B.P. and Schwartz,
J.C., Nature (Lond), 276:523-526, 1978.
North, R.A. and Karras, P.J., Nature (Lond), 272:73-75, 1978.
Paton, W.D.M., Br J Pharmacol, 12:119-127, 1957.
Paton, W.D.M., In Scientific Basis of Drug Dependence, ed. Steinberg, H., pp. 31-41. Churchill, London, 1969.
Satoh, M., Zielglgänsberger, W. and Herz, A., Brain Res. 115:99-110,
1976.
Sharma, S.K., Klee, W.A. and Nirenberg, M., Proc Natl Acad Sci USA,
72:3092-3096, 1975.
Sharma, S.K., Klee, W.A. and Nirenberg, M., Proc Natl Acad Sci USA,
74:3365-3369. 1977.
Sharma, S.K., Nirenberg, M. and Klee, W.A., Proc Natl Acad Sci USA,
72:590-594, 1975.
224
Shuster, L. Nature (Lond), 189:314-315, 1961.
Snyder, S.H., In Opiate Receptor Mechanisms, ed. Snyder, S.H., &
S. Matthysse, pp. 137-141. MIT Press, Cambridge, Massachusetts,
1975.
Takagi, K. and Takayanagi, I., Japan J Parmacol, 22:33-36, 1972.
Traber, J., Gullis, R. and Hamprecht, B., Life Sci, 16:1863-1868,
1975.
Villarreal, J.E. and Castro, A., In Mechanisms of Pain and Analgesic compounds, ed. Beers, R.F. & E.G. Bassett, pp. 407-428.
Raven, New York, 1979.
Villarreal, J.E., Martinez, J.N. and Castro, A. In Problems of
Drug Dependence, 1977, pp. 305-314. Committee on Problems of
Drug Dependence Inc., 1977.
Way, E.L., Loh, H.H. and Shen, F.-H., J Pharmacol Exp Ther, 167:1-8,
1969.
AUTHOR
Harry 0. J. Collier
Miles Laboratories Limited
Stoke Poges
Slough, SL24LY, England
225
314-300 0 -80 - 16
Clonidine Detoxification: A Fourteen-Day
Protocol for Rapid Opiate Withdrawal
Gold, M. S.; Pottash, A. L. C.; Sweeney, D. R.; Kleber, H. D.
INTRODUCTION
Last year at this meting, in Baltimore, we reported that a single
dose of 5 ug/kg of clonidine but not placebo caused a rapid and
significant decrease in opiate withdrawal signs and symptoms in
patients addicted to methadone (2). More recently, we confimed
these findings for other synthetic opiates and heroin (3). These
initial studies suggested a new use for clonidine, an imidazoline
drug widely used in the treatment of hypertension (4). We suggested after an open outpatient study, that a nonopiate treatment
like clonidine, which could control symptoms during the acute
phase of opiate withdrawal and allow the patient to have symptomatic relief while detoxifying, could enable patients to switch to
other treatment modalities, especially maintenance on the longacting opiate antagonist naltrexone. In allowing patients who
dish to be opiate free to make it to zero mg of methadone, clonidine detoxification appeared to be superior to the usual treatment of opiate withdrawal (2). During clonidine detoxification
the patients experience a few mild opiate withdrawal symptoms
which may allow a large number of patients to discontinue their
While our previous studies (2,3,4) offered considermethadone.
able promise they were complicated by the failure of patients to
follow the outpatient protocol for clonidine administration and
refrain from use of other drugs after their hospital discharge.
Studies in rodents and primates have suggested that the neurotransmitter, norepinephrine, is involved in opiate withdrawal (4,5,7,8,
11). Our early experience with the alpha-2 adrenergic agonist
clonidine (2,3) which reduces brain noradrenergic activity, provided pharmacological support in man for a noradrenergic hyperactivity mediation of opiate withdrawal. We now have given clonidine acutely in a dose of 6 ug/kg and chronically in a dose of
17 ug/kg/day in an inpatient setting to thirty opiate addicts
after withdrawal from 10-60 mg or chronic methadone treatment.
226
SUBJECTS AND METHODS
Subjects were members in good standing of methadone maintenance
treatment programs for at least six months prior to admission.
These thirty patients had been addicted to opiates for up to fifteen years. Average methadone dose was 40 mg/day. Twenty-five of
the patients were employed. They all expressed interest in discontinuing methadone and gave informed consent to a study which required an abrupt withdrawal from methadone three days after admission to the Evaluation and Research Unit and at least 36 hours
with no opiate administration. All patients had previous unsuccessful attempts at detoxifying from opiates. All had objective signs
of opiate withdrawal. Patients were observed for the presence or
absence of withdrawal signs and symptoms by a research nurse
clinician every hour from 8:00 a.m. while the patients were at bed
rest during the day of clonidine administration (4). The nurse
rated twenty-one items associated with withdrawal (4) as present (1)
or absent (0); the total score being added to give a measure of
withdrawal severity. The symptoms and signs were opiate craving,
anxiety, yawning, perspiration, lacrimation, rhinorrhea, yen sleep,
mydriasis, goose flesh, tremors, hot and cold flashes, aching bones
and muscles, anorexia, increased blood pressure, insomnia, increased temperature, increased respiratory rate and depth, increased
pulse rate, restlessness, nausea and vomiting, diarrhea and spontaneous orgasm. All patients completed self-rating Addiction Research Center Inventory (ARCI) WOW scales (4) every hour from
9:00 a.m. to assess for self-rated opiate withdrawal symptomatology.
After the first day of clonidine administration, the patients were
administered clonidine 17 ug/kg/day in divided doses and rated three
times a day before clonidine administration for opiate withdrawal
symptoms by a research nurse clinician. In addition, all patients
completed self-rating analog scales. These analog rating scales
were utilized to assess for changes in nervousness, being high,
unpleasantness, energy, irritability, fear and anger. They were
completed every hour from 9:00 a.m. during the first day of clonidine administration and thereafter completed three times a day prior
to clonidine administration. On the first day, the patients took
6 ug/kg of clonidine or placebo orally in matching vehicles to demonstrate the effect of clonidine on opiate withdrawal signs and symptoms and to assess the changes in blood pressure produced by this
dose of clonidine. After the initial clonidine and placebo administration, patients without precipitous blood pressure declines were
given clonidine 17 ug/kg/day for at least nine days. Clonidine dose
was gradually decreased to zero by day fourteen. All patients were
excluded who had a previous history of cardiac arrhythmias, hypotension, vasomotor instability, psychiatric illness or hospitalization (6).
RESULTS
Acute First Dose Study
The number of opiate withdrawal signs increased during the baseline
period to a peak of 14.0 ± 0.5 S.E.M. Clonidine 6 ug/kg produced a
rapid and significant decrease in opiate withdrawal signs and symptoms to 5.7 ± 0.8 at 90 minutes and 0.6 ± 0.2 at 120 minutes and 0.6
± 0.2 at 120 minutes (paired t Test p< .01). An example of this
227
acute effect is shown in Figure 1.
Opiate withdrawal ratings remained unchanged for an additional 240
minutes.
Systolic blood pressure was significantly reduced (p<0.01)
from a pretreatment mean of 130.9 ± 3.2 to 102.4 ± 4.4; as was
diastolic blood pressure from a pretreatment mean of 91.4 + 2.2 to
69.7 ± 2.9 at 120 minutes after clonidine administration (p< 0.01).
Blood pressure was not significantly changed over the next 240
minutes. In two patients, systolic blood pressure was reduced to
<60 mm hg at 180 minutes after the first dose of clonidine. This
decrease persisted for an additional 120 minutes. ARCI ratings
were also significantly (p< 0.01) reduced from a pretreatment mean
of 12.5 ± 1.3 to 6.4 ± 0.5 at 120 minutes after clonidine administration. Relief of subjective and objective distress was significant (see Figure 2).
On self-rating analog scales where 70 is the highest score, there
were significant (p< 0.01) decreases in self-rated nervousness
from 54.5 ± 1.4 before clonidine to 31.3 ± 0.8 at 120 minutes
and irritability from 48.3 ± 2.6 to 24.6 ± 1.7 at 120 minutes.
228
There were no significant
changes noted in self-rating
analog scales for energy or
feeling "high". There was a
significant (p<0.01) decrease
in scores reported for the
"uninvolved" and "angry"
scales. All patients stated
that they needed their methadone
and that they were "kicking"
immediately prior to clonidine
administration.
At 120 minutes
after clonidine administration,
none of the patients stated that
they felt the need for methadone
or like they were "kicking".
Placebo had no significant
effects on any of the above
measurements or ratings. The
effect of clonidine was not
significantly different for
those patients addicted to
15 or 50 mg of methadone.
Ten Day Study
All 30 patients were continued on clonidine in an inpatient hospital setting. None of the patients chose a return to methadone
after their first dose of clonidine. On the first day of clonidine administration, the patients were given 6 ug/kg as a test dose
and then 6 ug/kg at bedtime. For the next 9 days patients were
given 17 ug/kg of clonidine in divided doses of 7 ug/kg at 8:00 a.m.
and 3 ug/kg at 4:00 p.m. and 7 ug/kg at 11:00 p.m. Each day vital
signs and nurses' abstinence ratings and self-ratings were done as
described previously (4). Clonidine doses were held in some cases
due to severe hypotension. There were no significant changes in
the abstinence ratings durinq this ten-day inpatient trial. Twentyone patients, however, complained of difficulty in falling asleep.
Dry mouth, sluggishness, depression and occasional bone pain were
more infrequent complaints. Mean twelve noon opiate withdrawal
symptoms and signs were 1.1 ± 0.3 on day two, 0.6 ± 0.2 on day three,
0.5 ± 0.2 on day four, 0.3 ± 0.1 on day five and 0.3 ± 0.1 on day
six.
229
Systolic and diastolic blood pressure remained significantly decreased throughout the nine days of 17 ug/kg of clonidine administration. Therewere no significant increases or decreases in
self-rated nervousness, irritability, uninvolved, angry, fear,
"high" or energy. On fourteen occasions clonidine dose was decreased to compensate for oversedation or hypotension. On days
11,12 and 13 the clonidine dose was decreased by 50%. On day 14,
the patients received no clonidine whatsoever. None of the patients showed any increase in opiate withdrawal signs or symptoms
or had the emergence of clonidine withdrawal symptoms using this
protocol. On day 14 all patients were given Naloxone (1.2 mg)
intravenously to assess for residual opiates or dependence. All
Naloxone tests were negative. All of the 30 patients completed
the 14-day inpatient study.
DISCUSSION
As compared to our previous studies (2,3,4) the data reported here
were not confounded by difficulties in compliance and other drug use.
All patients in this study were successfully detoxified from chronic
methadone addiction and all were fourteen or more days without any
opiate administration at the time of discharge from the hospital.
This detoxification success rate is much greater than our experience
with methadone detoxification groups. In addition, significant
and potentially serious decreases in systolic and diastolic blood
pressure were successfully managed in the hospital without the
patient incurring additional opiate withdrawal symptoms by frequent
vital signs and bed rest.
In this inpatient detoxification study, we have shown that clonidine
is a safe and effective non-opiate treatment for opiate withdrawal
which suppresses the symptoms and signs of opiate withdrawal as well
230
as the affective changes associated with opiate withdrawal. Affects
associated with withdrawal such as anxiety, irritability and anger
were rapidly reduced after clonidine administration. Clonidine is
therefore extremely useful as a treatment for detoxification. This
14-day inpatient clonidine detoxification protocol could be useful
in the treatment of selected opiate addicts. For example, clonidine
detoxification could be linked to maintenance on long-acting opiate
antagonists such as Naltrexone. As we demonstrated in the last
group of ten patients - clonidine, being a nonopiate, allows the
patient to abruptly discontinue opiate administration and be opiatefree long enough to initiate maintenance treatment with Naltrexone.
Clonidine detoxification may allow the detoxification of patients
maintained on methadone who have had previous unsuccessful attempts
to detoxify due to the morbidity of current slow detoxification
practices.
Clonidine is also potentially useful in the treatment
of iatrogenic addictions and the protracted abstinence syndrome
where the risk of exposure to opiates might be reduced.
We tested the efficacy of clonidine in opiate withdrawal as a result
of studies of the major noradrenergic nucleus, the locus coeruleus
(LC), in monkeys. The effects of electrical or pharmacological
activation of this nucleus were demonstrated to produce changes
which resembled those seen in opiate withdrawal (5-8). Morphine
and clonidine blocked the effects of the electrical and phamacological activation of the IC in primates (5-7). This suggested
that opiate withdrawal my be due, in part, to increased noradrenergic neural activity in seas such as the LC which are regulated
by both opiates through opiate receptors and clonidine through
alpha-2 adrenergic receptors (2). This hypothesis is also supported by the similarity of clonidine and opiate withdrawal with respect
to vital signs and mood and the noradrenergic hyperactivity reported
in clonidine withdrawal (11). These and other data (1,7-10) have
suggested that opiate interactions with noradrenergic areas such as
the LC, regulated by both alpha-2 adrenergic and opiate receptors,
may become activated in opiate withdrawal-related panic states and
possibly naturally-occurring panic states.
In summary, the effects of clonidine on opiate withdrawal in man
(2-4) and rodent (1) provide pharmacological support for a noradrenergic hyperactivity hypothesis for opiate withdrawal (2,7,8) and
suggest that clonidine reverses opiate withdrawal by replacing
opiate-mediated inhibition with alpha-2 adrenergic inhibition of
brain noradrenergic activity. Additional basic and clinical tests
of this noradrenergic hyperactivity hypothesis are necessary. However, our studies and the studies of Washton and Resnick reported
in this monograph suggest that clonidine detoxification is a safe
and rapid procedure which may add additional treatment options to
the current and standard treatment of the opiate addict. Our data
suggest that clonidine detoxification allows 100% of the addicts to
become opiate-free and clonidine-free within fourteen days but that
maintenance with Naltrexone and group therapy may be necessary to
maintain this state.
231
REFERENCES
1.
Aghajanian, G.K. Tolerance of locus coeruleus neurons to
morphine and suppression of withdrawal response by clonidine.
Nature, 276:186-188, 1978.
2.
Gold, M.S., Redmond, D.E., Jr., and Kleber, H.D. Clonidine
in opiate withdrawal. Lancet I, 929-930, 1978.
3.
Gold, M.S., Redmond, D.E., Jr., and Kleber, H.D. Noradrenergic
hyperactivity in opiate withdrawal supported by clonidine reversal of opiate withdrawal. Am J Psychiatry, 136:100-102, 1979.
4.
Gold, M.S., Redmond, D.E., Jr., and Kleber, H.D. Clonidine
blocks acute opiate withdrawal symptoms. Lancet 2, 599-602,1978.
5.
Gold, M.S., Redmond, D.E., Jr, Pharmacological activation and
inhibition of noradrenergic activity alter specific behaviors
in nonhuman primates. Neurosci Abs, 3:250, 1977.
6.
Cold, M.S., Pottash, A.L.C., Sweeney, D.R., Kleber, H.D., and
Redmond, D.E.; Jr. Rapid opiate detoxification: clinical
evidence of antidepressant and antipanic effects of opiates.
Am J Psychiatry, 136:982-983, 1979.
7.
Gold, M.S., Byck, R., Sweeney, D.R., and Kleber, H.D.
Endorphin-locus coeruleus connection mediates opiate action
and withdrawal. Biomedicine, 30:1-4, 1979.
8.
Gold, M.S., Kleber, H.D. A rationale for opiate withdrawal
symptomatology. Drug and Alcohol Dependence, 4:419-424, 1979.
9.
Gold, M.S., Sweeney, D.R., Pottash, A.L.C., and Kleber, H.D.
Decreased serum prolactin in opiate withdrawal and dopaminergic
hyperactivity. Am J Psychiatry, 136:849-850, 1979.
10.
Kuhar, M.J. Opiate receptors: some anatomical and physiological aspects. NY Acad Sci, 311:35-48, 1978.
11.
Svensson, T.H., and Strombom, U. Discontinuation of chronic
clonidine treatment: evidence for facilitated brain noradrenergic neurotransmission. Naunyn-Schmeidberg's Arch Pharmacol,
299:83-87,
1977.
12.
Washton, A., Resnick, R., and LaPlaca, R. Clonidine hydrochloride - a nonopiate treatment for opiate withdrawal.
American College of Neuropsychopharmacol, Maui, Hawaii, 1978.
AUTHORS
Mark S. Gold, M.D.; A.L.C. Pottash, M.D.; Donald R. Sweeney, M.D.,
Ph.D.; and Herbert D. Kleber, M.D.; Yale University School of
Medicine, Department of Psychiatry and Substance Abuse Unit; and
Research Facilities, Fair Oaks Hospital; and Psychiatric Diagnostic
Laboratories of America, Summit, New Jersey 07901
232
Clonidine Hydrochloride: A Nonopiate
Treatment for Opiate Withdrawal
Washton, A. M.; Resnick, R. B.; Rawson, R. A.
Interest in clonidine hydrochloride as a treatment for opiate withdrawal has been stimulated by the recent findings of Gold, Redmond
and Kleber (1978). These investigators found that a single oral
dose of .005 mg/kg clonidine produced a rapid and significant decrease in acute withdrawal symptoms, subjective distress, and blood
pressure in 11 hospitalized addicts following abrupt discontinuation
of 5-50 mg chronic methadone.
It was suggested that a new use for
clonidine, a nonopiate imidazoline drug widely used in the treatment
of hypertension, might be to reduce the morbidity of current opiate
detoxification procedures.
Various symptoms that emerge during opiate withdrawal discourage attempts to detoxify and contribute to the large number of patients
who are unable to achieve abstinence. A nonopiate medication which
could suppress withdrawal symptoms might improve the prognosis for
achieving abstinence and allow more patients the option of other
treatment modalities, such as the long-acting opiate antagonist, naltrexone (Resnick et al. 1974). The applicability of naltrexone treatment has been limited by the-fact that-before receiving the first dose
of naltrexone patients must detoxify and then remain opiate free for
at least several days to avoid a precipitated withdrawl reaction. A
potentially important role for clonidine would be to bridge the gap
between opiate dependence and naltrexone treatment by providing symtomatic relief during detoxification and the subsequent opiate-free
period when relapse rates are extremely high.
Critical questions about clonidine's efficacy as a treatment for
opiate withdrawal concern its suitability for use in an outpatient
clinical setting. During the past year at the Division of Drug Abuse
Research and Treatment of New York Medical College, the present
authors conducted a series of preliminary clinical trials which included upwards of 70 outpatients who attempted detoxification from
opiates with the aid of clonidine.
In preparation for a carefully
controlled investigation, these open clinical trials sought to replicate the single-dose findings of Gold et al. and obtain preliminary
information concerning clonidine's efficacy in facilitating outpatient
233
detoxification from opiates, its side effects and acceptability to
patients, and to determine a daily dosage regimen that would maximize clonidine's therapeutic benefit.
I.
SINGLE-DOSE
TRIALS
Subjects and Methods
A single oral dose of .005 mg/kg clonidine was administered to 12
opiate-dependent individuals-experiencing acute withdrawal discomfort from heroin and/or methadone. All subjects were free of serious medical and psychiatric illness and signed an informed consent
after the nature of the experimental procedures had been fully explained. Blood pressure measurements and subjective ratings of
withdrawal symptoms were taken immediately before clonidine ingestion and again at 2 hours postclonidine. Each of 17 withdrawal
symptoms were rated by the subjects on a 4-point scale as either
absent (0), mild (1), moderate (2), or severe (3).
Results
The withdrawal rating scores were totalled to give a composite measure of withdrawal severity both pre and postclonidine for each subject, as shown below in Table 1.
Table 1
WITHDRAWAL RATING SCORE TOTALSl BEFORE AND AFTER .005 mg/kg CLONIDINE
Subject #
1
2
3
4
5
6
7
8
9
10
11
12
Preclonidine
40
12
29
25
23
13
38
24
38
31
25
45
22.75
Mean
2 Hours
Postclonidine
9
2
9
6
5
0
6
11
16
2
4
15
6.25*
1
The highest possible withdrawal rating score total is 51.
*Mean pre and postclonidine scores differ significantly:
t = 9.8648, df=11, p<.001.
These data show that clonidine produced a marked and significant
reduction in withdrawal ratings from a mean of 22.75 preclonidine
to 6.25 at 2 hours postclonidine. All subjects reported dramatic
relief of their withdrawal discomfort. The symptoms reduced most
by clonidine were chills, lacrimation, rhinorrhea, nervousness,
stomach cramps and muscle/joint pains. Clonidine side effects consisted of dry mouth, drowsiness, and a decrease of 10-15 mmHg in
234
systolic and diastolic blood pressure. These findings closely resemble the results of Cold et al. and provide further evidence of
clonidine's ability to suppress ongoing withdrawal symptoms.
II.
CLINICAL TRIALS
Two methods of clonidine detoxification were employed: one involved
a gradual reduction in methadone with simultaneous administration
of clonidine and the other involved an abrupt switch from methadone
and/or heroin to clonidine.
1.
Gradual Detoxification Procedure
Subjects and Methods
The subjects were 20 methadone maintenance patients who requested
detoxification to an opiate-free state. After a thorough explanation of the experimental procedures, all subjects signed an informed
consent for clonidine and naltrexone treatments. The detoxification
procedure involved induction onto clonidine followed by gradual decrements in methadone at a rate of 5 or 10 mg per week with continued
daily administration of clonidine. Clonidine was started at .005
mg/kg per day in divided doses and then increased by 0.1 mg steps
as needed to a maximum of .010 mg/kg per day. The rate of clonidine
dosage increments was tailored for each patient so as to maximize
therapeutic benefit and minimize the occurrence of adverse side effects such as sedation and orthostatic hypotension. The maximum
daily dose of clonidine ranged from 0.2 to 0.9 mg, with a mean of
0.8 mg/day. At the point where clonidine was introduced, level of
methadone dependence ranged from 5-40 mg with a mean of 17 mg. Time
on clonidine plus methadone ranged from 2-6 weeks. Upon reaching a
Subjects who
zero methadone dose, placebo methadone was introduced.
reached a zero methadone dose and remained opiate free for 10 days
were given an intravenous injection of 1.2 mg naloxone to confirm opiate-free status in preparation for immediate induction onto naltrexone. After the first dose of naltrexone, clonidine was discontinued at varying rates. At each clinic visit the subjects were
seen for withdrawal ratings (as described earlier) blood pressure
measurements, and adjustment of medication.
2.
Rapid Detoxification Procedure
Subjects and Methods
The subjects were 50 opiate-dependent individuals who requested detoxification and gave their written consent to treatment with clonidine and naltrexone after a thorough explanation of the experimental
procedures.
Twenty-two of the 50 subjects were on methadone maintenance and the remaining 28 subjects were "street addicts" using
illicit methadone or heroin. For the methadone maintenance patients,
level of dependence ranged from 5 to 40 mg methadone per day, with
a mean of 19 mg. Street addicts using illicit methadone were stabilized on 5-30 mg methadone (mean of 19 mg) for approximately two
weeks prior to starting detoxification while those using heroin
235
(range: $10-150 per day; mean: $52 per day) were switched directly
to clonidine without iterim stabilization on methadone.
From the levels of dependence specified above there was a simultaneous abrupt discontinuation of opiates and introduction of clonidine. For the methadone-dependent subjects, placebo methadone was
introduced on the first day of clonidine treatment and administered
daily for the remainder of the detoxification procedure. For all
subjects, the method of clonidine induction was the same as that
described above for the gradual detoxification procedure. The maximum daily dose of clonidine ranged from 0.2 to 0.9 mg, with a mean
of 0.5 mg/day. Ten days after opiates were discontinued, a naloxone
challenge of 1.2 mg i.v. was administered to confirm opiate-free
status in preparation for immediate induction onto naltrexone.
After the second day on naltrexone, clonidine was discontinued gradually by 0.1 or 0.2 mg decrements per day until a zero dose was
reached.
RESULTS
Clinical Outcome
A major aim of these clinical trials was to obtain a preliminary assessment of clonidine's efficacy as a transitional treatment to
bridge the gap between opiate dependence and naltrexone, and the
relevant outcome data are presented below in Table 2.
Table 2
DETOXIFICATION SUCCESS RATES FOR SUBJECTS IN THE GRADUAL AND RAPID
DETOXIFICATION GROUPS
NonNaltrexone
Starters
Starters
I. GRADUAL DETOXIFICATION GROUP (N=20)
10/20(50%)
10/20(50%)
II. RAPID DETOXIFICATION GROUP (N=50)
A.
B.
Methadone patients (N=22)
Street Addicts (N=28)
1. On Heroin (N=ll)
2. On Methadone (N=17)
35/50(70%)
15/50(30%)
18/22(82%)*
17/28(61%)
4/11(36%)
13/17(76%)**
4/22(18%)
11/28(3%)
7/11(64%)
4/17(24%)
* Street addicts vs methadone maint. patients: x2=2.61, df=1, p > .10
** Heroin vs methadone street addicts: x2 =4.46, df=1, p<.05
Subjects who completed detoxification and received at least one dose
of naltrexone are categorized as "naltrexone starters" and those who
failed to complete detoxification are categorized as "nonstarters".
Table 2 shows that of the 20 subjects who underwent the gradual detoxification procedure, 50 percent started naltrexone. In light of
the earlier findings of significantly attenuated withdrawal symptoms
after a single dose of clonidine, this 50 percent success rate was
Although the adjunctive clonidine suppressed
somewhat disappointing.
withdrawal symptoms that emerged from successive decrements in meth236
adone, when daily methadone doses finally reached zero milligrams,
clonidine's ability to suppress symptom seemed markedly reduced.
The procedure in Which methadone was abruptly discontinued appeared
to circumvent this problem as reflected by the greater success rates,
as shown in Table 2. Among the 50 subjects in the Rapid Detoxification group, 70 percent started naltrexone and only 30 percent
failed to complete the detoxification procedure. A breakdown of
these 50 subjects revealed a greater success rate for methadone
maintenance patients (82%) as compared With street addicts (61%),
although this difference was not statistically significant.
A further breakdown of the street addict subgroup into heroin vs
methadone users reveals that 76 percent of the methadone users started
naltrexone as campared With only 36 percent of the heroin users, a
statistically significant difference.
In an attempt to account for these outcome differences, a retrospective analysis of mean level of opiate dependence was performed
for naltrexone starters vs nonstarters in each of the subject groups
and the results are presented in Table 3.
Table 3
MEAN PREDETOXIFICATION LEVEL OF OPIATE DEPENDENCE FOR
NALTREXONE STARTERS AND NONSTARTERS
Naltrexone
Starters
Nonstarters
I.
Gradual Detoxification
16 mg
18 mg
26 mg
$21
23 mg
$70*
II. Rapid Detoxification
A.
B
On Methadone
On Heroin
* Wilcoxon Rank Sum Test: W=12, p<.05.
These data show no significant differences in level of dependence
between naltrexone starters and nonstarters except for heroin users
where a high level of dependence was associated with poor outcome.
Clonidine
Effects
Most subjects reported that clonidine reduced but did not completely
eliminate their withdrawal symptoms. The symptoms reduced most effectively and consistently by clonidine were chills, lacrimation,
rhinorrhea, yawning, stomach cramps, sweating and muscle/joint
aches. Marked reductions in anxiety and restlessness were also reported. Although clonidine substantially alleviated withdrawal distress, none of the 70 subjects reported that clonidine induced euphoria
or any of the other subjective effects of opiates.
Clonidine's lack
of opiate-like subjective effects was reflected by the fact that
subjects on clonidine easily detected the blind transfer from active
to placebo methadone prior to the emergence of withdrawal symptoms.
237
Clonidine side effects consisted of sedation, dry mouth, and decreased blood pressure. Sedation from clonidine had both positive
and negative aspects. Nighttime doses helped alleviate insomnia
but morning and afternoon doses exacerbated symptoms of anergia
and weakness leading to complaints of interference with daytime
functioning. After at least several days of daily administration,
tolerance developed to clonidine's sedative effect and additional
nighttime sedation was required in approximately 50 percent of subjects who went on to complete the detoxification process. Blood
pressure values decreased from a mean of 120/80 preclonidine to
105/68 at the maximum daily dose (X=0.7 mg). Only 6 subjects reported symptoms of orthostatic hybotension such as dizziness or
lightheadedness upon standing.
Abrupt discontinuation of clonidine after 2-6 weeks of daily administration and at least 2 days on naltrexone produced complaints
of headaches and exacerbated withdrawal symptoms of chills, sweating, nervousness and muscle/joint aches. In some subjects, blood
pressure values temporarily increased above preclonidine levels but
there was no evidence of a clinically significant rebound hypertension. Experience with varying rates of clonidine dosage decrements indicated that the least problerratic method consisted of 0.1
or 0.2 mg decrements per day until a zero dose was reached. This
method resulted in no headaches, re-emergence of withdrawal symptoms, or abnormally elevated blood pressure values.
DISCUSSION
The present study confirms the single-dose findings of Gold et al.
(1978) and demonstrates the safety and feasibility of clonidine detoxification in an outpatient clinical setting. Although conclusions about clonidine's efficacy in these preliminary open
clinical trials are limited by the absence of an appropriate control group, comparison with reports of other investigators using
routine detoxification procedures suggests that clonidine enabled
patients to abruptly discontinue opiates and remain opiate free
long enough to initiate treatment with naltrexone. For example,
the 1978 report of the National Research Council Committee on Clinical Evaluation of Narcotic Antagonists shows that only 21 percent
of methadone maintenance patients and 17 percent of street addicts
reached zero methadone and retrained opiate free long enough to begin
naltrexone treatment. Senay et al. (1977) reported that 53 percent
of methadone maintenance patients detoxified by gradual methadone
decrements reached a zero dose and remained abstinent for at least
one week. These figures are substantially lower than the success
rates of 82 percent for methadone maintenance patients and 61 percent for street addicts in the present investigation.
It can also
be said on the basis of clinical experience that abrupt discontinuation of as much as 40 mg chronic methadone would have had little
chance of a successful outcome without the aid of clonidine.
Although it was expected that the use of clonidine in normotensive
outpatients might be seriously hampered by problems of orthostatic
hypotension, this was not the case. The low incidence of such untoward side effects can be attributed primarily to our conservative
238
dosing practices and close daily monitoring of each patient's clinical course. Clonidine's lack of opiate-like subjective effects
limits its abuse potential among addicts, but it might be abused in
attempts at self-medication for withdrawal symptom. Ibis could result in severe hypotension from clonidine overdose or rebound hypertension from discontinuing clonidine abruptly.
Clonidine's paucity of adverse side effects, lack of euphorogenic
properties, and significant attenuation of Withdrawal symptoms,
point to its potential usefulness as a safe and effective treatment
for opiate withdrawal. However, the present experience indicates
that controlled clinical trials are needed before definitive conclusions can be drawn about clonidine's efficacy in opiate detoxification. A study of this type is currently in progress at New
York Medical College. If these controlled trials confirm the current
optimism about clonidine, a greater number of addicted individuals
might be successfully withdrawn from opiates and given the option
of other treatment modalities such as naltrexone.
REFERENCES
Gold, M.S., Redmond, D.E., and Kleber, H.D. Clonidine in opiate
withdrawal. Lancet I:929-930, 1978.
Report of the National Research Council Committee on Clinical Evaluation of Narcotic Antagonists. Clinical evaluation of naltrexone
treatment of opiate-dependent individuals. Arch Gen Psychiat,
35:335-340, 1978.
Resnick, R.B., Volavka, J., Freedman, A.M., and Thomas, M. Studies
of EN-1639A (Naltrexone): a new narcotic antagonist. Am J Psychiat,
131(6):646-650, 1974.
Senay, E.C., Dorus, W., Goldberg, F., and Thornton, W. Withdrawal
from methadone maintenance: rate of withdrawal and expectation.
Arch Gen Psychiat, 34:361-367, 1977.
AUTHORS
Arnold M. Washton, Ph.D.
Richard B. Resnick, M.D.
Richard A. Rawson, Ph.D.
Department of Psychiatry
Division of Drug Abuse Research & Treatment
New York Medical College
Five East 102nd Street
New York, N.Y. 10029
239
Usefulness of Propoxyphene
Napsylate for Maintenance
Treatment of Narcotic Addiction
Woody, G. E.; Mintz, J.; Tennant, F.; O’Brien, C. P.;
McLellan, A. T.
Recently several studies have examined the use of propoxyphene
napsylate (Darvon-N) in the detoxification and maintenance of
narcotic addicts. Tennant (1974) reported that three programs in
Los Angeles had succeeded in detoxifying 280 heroin addicts with
propoxyphene napsylate, while maintaining 92 others on an outpatient basis for periods up to 240 days. In a doubleblind
detoxification study comparing propoxyphene napsylate and methadone, he found that propoxyphene patients were more likely than
methadone patients to be opiate abstinent at one month followup
(Tennant, Russell, Casas, 1975).
However, in this doubleblind study, Tennant found propoxyphene
to be less effective than methadone in suppressing withdrawal
complaints. He also noted side effects from propoxyphene, such
as mild visual hallucinations, slurring of speech and seizurelike symptoms (Tennant, 1974, 1973). Jasinski (1977) reported
that propoxyphene napsylate used in maximum non toxic doses
(about 1200 mg per day) produced narcotic-like activity equal to
that of only 20 to 25 mg of subcutaneously administered morphine,
or 10 mg of orally administered methadone. Again, he found that
propoxyphene napsylate doses greater than 700 mg produced disturbing side effects in many subjects.
This paper will report the results from two studies, one
carried out in Los Angeles and one in Philadelphia. Both were
designed to evaluate the usefulness of propoxyphene napsylate in
the maintenance treatment of opiate addiction. In both studies,
propoxyphene was prescribed in divided doses. This allowed
patients to receive the higher amounts required for maintenance
that would have been toxic in a single dose. The protocols
followed by the two clinics were similar, thus allowing data to
be pooled.
METHODS
At each location, addicts applying for methadone maintenance
240
treatment between the ages of 19 and 55 with "mild to moderate"
opiate habits were selected. Those with larger habits, who were
expected to require more than 30 mg methadone, were excluded. An
ample number of patients was available, because the average daily
methadone dose was 35 mg in each clinic. Current physical dependence was verified by signs of abstinence and use. Patients with
psychoses, seizure disorders, hepatitis, severe liver disease, or
any other serious illness were excluded. Approval from the Food
and Drug Administration (FDA) was obtained for a waiver of the
two year minimum addiction requirement for methadone maintenance,
so that patients who had been addicted for six months or more
were eligible for treatment in the experimental programs. Individuals were allowed to remain in the study for a maximum of six
months.
A double blind format insured that neither patients nor
therapists were informed about the individual's experimental group.
Both medications were prepared in capsules that were identical in
taste and appearance. Medicines were prescribed in divided doses,
to be taken in the clinic, and at home approximately 12 hours
later. The maximum dose of methadone was 36 mg per day, all of
which was ingested at the clinic (takehome doses for the methadone group were placebo). This design was arranged by consultation with the FDA, the Drug Enforcement Administration (DEA), the
National Institute on Drug Abuse (NIDA), and both research groups.
It was a compromise intended to prevent methadone diversion while
allowing propoxyphene to be prescribed in divided doses, in order
to minimize its side effects and maximize its therapeutic effectiveness.
The protocol was explained to all prospective candidates and
informed consent was obtained. All had the option of choosing
any other form of treatment offered at the clinic. In Philadelphia, before signatures were accepted a short quiz was given to
assure full understanding of all items included in the consent
form.
Patients in each study were given a complete physical examination,
including chest x-ray, CBC, urinalysis, SMA-6/12, EEG and EKG. A
Beck Depression Inventory, a symptom check list, and a narcotic
withdrawal scale were also done. The physical examinations, including laboratory tests, were repeated at two weeks, and monthly,
until termination. The EKG was administered at three months and
six months. The chest x-ray and EEG were repeated at termination.
Vital signs and urinalyses for drug screening were collected
weekly. Patient and counselor reports of employment, personal
adjustment, and criminal activity were given weekly. The Philadelphia group also gave a Brief Psychiatric Rating Scale, Hamilton
Anxiety and Depression ratings. Gordon Personality Profile, Wonderlic I.Q. test, anxiety checklist, and a sentence completion test
at intake, one month, three months, and six months (or termination).
All physical and psychological measures taken during the study
were done 24 hours after the patient received his last medication.
241
314-300 0 -80 - 17
One hundred and twenty-seven patients received propoxyphene (79
in Philadelphia, 48 in L.A.) and 103 patients were treated with
methadone (68 in Philadelphia, 35 in L.A.). Methadone patients
who reached the maintenance state of treatment were stabilized
on an average of 32 mg per day, while propoxyphene patients
stabilized on 1000 mg per day.
RESULTS
The characteristics of the Los Angeles and Philadelphia samples
at intake are summarized in Table I. As can be seen, the samples
differ significantly with regard to racial and sexual composition
and in terms of educational and legal status at intake. Differences in background and drug history were also compared between
medication groups for each of these samples, and no statistically
significant differences were found.
Physical examinations were completed on all patients at the start
of treatment. Results indicated no significant differences between the two medication groups. Serial EEGs and laboratory
analyses were performed during the study. EEG results for both
groups showed the increases in high frequency, lower voltage
activity typically found in people taking psychotropic drugs, and
no patient had an epileptic seizure during treatment. Laboratory
test results indicated that SGOT levels in the methadone clients
were elevated at intake and decreased to normal levels during the
study. In the propoxyphene group bilirubin values decreased from
high normal to mid normal levels during treatment. Serious toxicity was absent in both groups despite relatively long treatment
duration (average six weeks) and is discussed in more detail elsewhere (Woody, Tennant, McLellan, this volume).
Duration of treatment is summarized in Table II. Patients
were divided into short term (less than one month) and long term
(more than one month). In both studies, methadone patients
tended to stay in treatment longer than propoxyphene patients.
In Philadelphia this finding was significant at the .01 level. In
Los Angeles, although results were not significant, they were in
the same direction.
Treatment was divided into three periods: Induction (first four
weeks), Maintenance (from week five until detoxification or
termination), and Detoxification (until detoxification was complete
or allotted treatment time ran out). A wide variety of physical
symptoms and drug side effect data were examined and analyzed
for each patient. Propoxyphene patients reported more symptoms,
and greater symptom severity, than methadone patients during
the Induction period, but these results were only significant for
the Induction period in the Philadelphia study, although the Los
Angeles results were in the same direction. These physical
symptoms were usually related to withdrawal rather than side
effects of propoxyphene itself. For example, in the Philadelphia
study propoxyphene patients reported more difficulty sleeping,
242
greater anxiety or nervousness, and heightened irritability.
During the Maintenance period, overall indices of symptoms and
their weighted severity scores did not distinguish between medication groups in either study. So few patients reached Detoxification stage (4 propoxyphene and 8 methadone patients in Los
Angeles; 2 propoxyphene and 11 methadone patients in Philadelphia)
that statistical tests were not meaningful.
One of the most important measures taken from each patient was
the weekly urinalysis. Urine was tested for the presence of
various illicit street drugs, and especially for evidence of
morphine. Among short term patients in both studies, propoxyphene
and methadone groups did not differ in frequencies of positive
urines. Among long term patients, however, an examination of the
pooled data shows that 64% of the propoxyphene patients had
positive urines for at least half of the weeks tested, while
among methadone patients, the comparable proportion was 41%.
These results are significant at the p < .05 level (X2 = 4.0,
df = 1). Use of amphetamines and barbiturates was infrequent and
did not differ between medication groups.
Counselor reports of social adjustment were also analyzed and no
differences were found between medication groups in either study.
The most important factor in predicting vocational adjustment was
pretreatment employment status; those employed before treatment
tended to remain employed. Ratings of psychological adjustment
were obtained for long term patients in both studies. Medication
groups differed only on ratings of apathy (propoxyphene patients
showed more apathy).
Reasons for termination were coded into categories based upon
their positive (completion of treatment, detoxification), negative
(medications not working, extended absence), or neutral (jail,
scheduling problems) implications for effectiveness of the treatment medication. The distribution of patients' reasons for
termination are presented by these codes for both the propoxyphene
and methadone patients in Table III. The data for both the Philadelphia and Los Angeles samples are combined in the table as there
were no statistically significant differences between them. Thirty
percent of the methadone patients terminated for positive reasons,
57% for negative reasons, while 13% terminated for reasons unrelated to the medications. The comparable figures for the propoxyphene groups were 13%, 75%, and 12%. These distributions of
answers differ significantly (p< .01) between the two groups.
Followup interviews were scheduled for both samples at one month
following treatment and additionally at six months in the Philadelphia sample only. Patients were interviewed extensively concerning drug use, living arrangements, physical and psychological
well being, vocational and crime data, and benefits from treatment.
Patients' urine samples were also collected.
243
An average of 85% of the eligible patients were contacted in
both clinics at the one month interval and results were examined
separately for the two samples. No significant differences
between methadone and propoxyphene patients were found in either
sample, although patients in both treatment groups reported less
drug use than at intake. Results of the six month followup at
Philadelphia produced similar findings, showing no significant
differences in posttreatment adjustment between the two groups.
Approximately 22% of the patients in each treatment group were
drug free (by urine and interview) at that time.
COMMENTS
Our findings indicate that propoxyphene is a less satisfactory
medication than methadone for maintenance treatment of narcotic
addiction. Propoxyphene patients tended to drop out of treatment
earlier, and those who did remain in treatment one month or longer
were more likely to terminate for a reason which indicated poor
progress. Propoxyphene patients tended to drop out early. Those
who stayed in treatment longer than one month were more likely to
abuse heroin. The early dropout rate of propoxyphene patients
usually was related to higher withdrawal symptom complaints during
the first four weeks of treatment. A small number of propoxyphene
patients dropped out due to signs and symptoms of CNS irritability.
This finding is consistent with the reported side effects of high
dose propoxyphene (Tennant, 1973; Jasinski, Pernick, Clark, 1977).
However, side effects were relatively minor due to the divided
dose schedule for propoxyphene used in both studies.
We note that to some degree the validity of these conclusions may
be a function of local conditions, such as the availability of
methadone treatment. In the Philadelphia study, patients had
immediate access to methadone treatment after termination from
the study. In that setting, about three-fourths of the patients
treated with propoxyphene dropped out within one month. Some
patients left the clinic, while others switched to methadone
maintenance.
However, despite these short term differences, followup data indicated that posttreatment adjustment between treatment
groups did not differ.
244
TABLE I
Intake Data
Philadelphia
Los Angeles
Sig.
Males
99%
85%
*
Mean Age
28.6
29.8
N.S.
71%
29%
0%
0%
44%
56%
H. S. Graduates
71%
43%
Unemployed
59%
70%
N.S.
Current Legal Problems
43%
28%
*
Race
% Black
% White
% Mexican-American
Mean Years Addicted
Prior Drug treatments
*= p < .01
*
7.3
8.3
N.S.
2.1
1.5
N.S.
2
.01 (x )
TABLE II
Duration of Treatment
Philadelphia
Propox.
Meth.
Propox.
Meth.
N (%)
N (%)
N (%)
N (%)
38 (55)
36 (78)
30 (88)
30 (45)
10 (22)
4 (12)
LONG TERM
(1 month or more) 22 (28)
SHORT TERM
(Less than
1 month)
Los Angeles
57 (72)
x2 = 11.9 p < .01
245
x2= 1.34 p < .10
TABLE III
Termination Reasons
(Philadelphia & Los Angeles Combined)
Propoxyphene
Methadone
Positive reasons
Completion
Detox
16 (13%)
6
10
31 (30%)
21
Negative reasons
Transfer to Meth. Maint
Side effects
Meds not holding
Absence
94(75%)
4
15
20
55
59 (57%)
5
14
14
26
16 (12%)
10
6
N = 126*
13 (13%)
8
5
N = 103
Unrelated to Med.
Jail
Schedule Probs.
x2 = 11.2 df = 2 p<.01
*Reasons for termination on one propoxyphene patient were not known.
REFERENCES
Jasinski, D.R., Pernick, J.S., Clark, S.C., Griffith, J.D.
Therapeutic Usefulness of Propoxyphene Napsylate in Narcotic
Addiction. Arch Gen Psych 34:227-233, 1977.
Tennant, F.S. Propoxyphene Napsylate (Darvon-N) Treatment of
Heroin Addicts. J of the Nat Med Assoc 66(1):23-24, 1974.
Tennant, F.S., Russell, B.A., Casas, S.K., Bleich, R.N. Heroin
Detoxification: A Comparison of Propoxyphene and Methadone. JAMA
232(10):1019-1022, 1975.
Tennant, F.S. Propoxyphene Napsylate for Heroin Addiction. JAMA
226(8):1012, 1973.
Woody, G.E., Tennant, F.S., McLellan, A.T., O'Brien, C.P. Lack of
Toxicity of High Dose Propoxyphene Napsylate When used for
Maintenance Treatment of Addiction. (This volume)
ACKNOWLEDGMENT
This research was supported by NIDA Contract ADM-45-74-152.
AUTHORS
George E. Woody, M.D.; Jim Mintz, Ph.D.; Forest Tennant, M.D.;
Charles P. O'Brien, M.D., Ph.D.; A. Thomas McLellan, Ph.D.
Department of Psychiatry, University of Pennsylvania, Philadelphia,
PA 19104; and Drug Dependence Treatment & Research Service,
Philadelphia Veterans Administration Medical Center
246
Management of Neonatal Narcotic
Abstinence Utilizing a Phenobarbital Loading Dose Method
Finnegan, L. P.; Mitros, T. F.; Hopkins, L. E.
The suggested therapy for the neonatal abstinence syndrome has
been phenobarbital, paregoric, chlorpromazine, and diazepam. The
choice of a particular agent and its dosing regimen has been based
on individual clinical experience and subjective clinical assessment of symptomatology (Nathenson, Golden, and Litt 1971; Reddy,
Harper, and Stern 1971; Zelson, Rubio, and Wasserman 1971). At
present, little information is available about the dose response
curves, pharmacokinetics, or inter-, intra-individual patient
variability of pharmacokinetics when these agents are administered to the newborn.
It was our intent to examine the feasibility of administering an
oral loading dose of phenobarbital, to observe the consistency of
serum levels obtained from such an oral loading dose, and to test
the possible clinical application of such a regimen.
Of these four agents, phenobarbital has been most extensively
studied in the newborn during management of seizures and prophylaxis of hyperbilirubinemia (Jalling 1975; Pearce, Sharman, and
Forster 1977).
Several studies have reported a correlation between a loading dose administered either orally or parenterally
and the peak serum concentration (Brachet-Liermain, Goutieres,
and Aicardi 1975; Viswanathan, Booker, and Welling 1978). The
amount of phenobarbital measured in the serum at the time of
maximum concentration has been found to be roughly 1.3 times the
dose administered parenterally, and this peak concentration was
somewhat lower in relation to the dose administered orally
(Viswanathan, Booker, and Welling 1978). Further, the time of
peak serum concentration has been found to occur from 30 minutes
to 4 hours after administration of a loading dose (BrachetLiermain, Goutieres, and Aicardi 1975; Jalling 1975; Pearce,
Sharman, and Forster 1977; Viswanathan, Booker, and Welling 1978).
We postulated that these results may have direct application to
the treatment of neonatal abstinence due to in utero exposure to
psychotropic drugs. In our preliminary studies, more rapid
control of withdrawal symptomatology could be attained by the
247
administration of an oral loading dose of phenobarbital, when
compared with the conventional dosing method, in order to achieve
a therapeutic serum level of this agent within four hours of
administration. The therapeutic serum level recommended in the
control of neonatal seizures has been 15 to 40 micrograms per
milliliter.
This paper will describe the use of an oral phenobarbital loading
dose approach in conjunction with a clinical scoring system used
to monitor and manage withdrawal symptomatology as seen in the
neonatal narcotic abstinence syndrome.
METHODS
Nineteen consecutive neonates with the narcotic abstinence syndrome were studied. There were 13 males and 6 females. Birth
weights ranged from 1.96 to 3.99 kg. These neonates were born to
mothers maintained on methadone but who also occasionally took a
variety of psychotropic agents in various quantities throughout
their pregnancy. Neonates were admitted to the Intensive Care
Nursery and evaluated for narcotic abstinence symptoms using a
scoring system developed at our hospital which has been patterned
after our initial scoring system which has been previously
presented (Mac New, Mitros, and Finnegan 1978) and published
(Finnegan et al. 1975) [Table 1].
The abstinence score is comprised of twenty-one of the most commonly seen symptoms in the passively addicted neonate. Signs are
recorded as single entities or in several categories if they
occur in varying degrees of severity.
Each symptom and each degree of severity of each symptom has been
assigned a score. The higher scores were given to signs or
symptoms which are associated with increased morbidity and
mortality. The total score for the specified time interval of
measured infant behavior is added and recorded at the bottom of
the scoring sheet.
It should be emphasized that the scoring system is dynamic rather
than static, that is, all of the signs and symptoms observed
during the two or four hour time intervals in which infant
symptomatology is monitored are point-totalled for that interval.
The infants were assessed for withdrawal symptomatology at twohour intervals for the first forty-eight hours of life, then
every four hours thereafter. If, at any point, the infant's total
score was 8 or greater, every two-hour scoring was initiated and
continued for twenty-four hours from the last total score of 8 or
greater. If the two-hour scores continued to be 7 or less for
twenty-four hours, then four-hour scoring intervals were resumed.
The need for pharmacologic intervention was indicated when the
total abstinence score was 8 or greater for three consecutive
scorings or when the average of any three consecutive scores was 8
248
Table 1
NEONATAL ABSTINENCE SYNDROME ASSESSMENT AND TREATMENT
SIGNS AND SYMPTOMS
SYSTEM
SCORE
Excessive High Pitched (Or Other) Cry
Continuous High Pitched (Or Other) Cry
2
3
Sleeps < 1 Hour After Feeding
Sleeps < 2 Hours After Feeding
Sleeps < 3 Hours After Feeding
3
2
1
Hyperactive Moro Reflex
Markedly Hyperactive Moro Reflex
2
3
Mild Tremors Disturbed
Moderate-Severe Tremors
1
2
Disturbed
Mild Tremors Undisturbed
Moderate-Severe Tremors Undisturbed
3
4
Increased Muscle Tone
2
Excoriation (Specify Area):
1
Myoclonic Jerks
3
Generalized
5
Convulsions
Sweating
1
Fever < 101 (99-100.8°F./37.2-38.20C.)
Fever > 101 (38.4 C. and Higher)
1
2
Frequent Yawning (> 3-4 times/interval)
1
Mottling
1
Nasal Stuffiness
1
Sneezing (> 3-4 times/interval)
1
Nasal Flaring
2
Respiratory Rate > 60/Min.
Respiratory Rate > 60/Min. with Retractions
1
2
Excessive Sucking
1
Poor Feeding
2
Regurgitation
Projectile Vomiting
2
3
Loose Stools
Watery Stools
2
3
TOTAL SCORE
249
or greater. If the infant's total score was 12 or greater for
two consecutive intervals or the average of any two intervals was
12 or greater, therapy was initiated. Therefore, all infants who
met the scoring criteria for pharmacologic intervention were
treated with phenobarbital no longer than 4-6 hours following the
onset of significant symptomatology.
Eighteen of nineteen infants met the criteria for initiation of
therapy, and therefore were given an oral loading dose of 16 mg/kg
of sodium phenobarbital to rapidly achieve an expected therapeutic
serum level of 18 mcg/ml. The sodium phenobarbital was in 60%
propylene glycol solution containing 20 mg/ml to decrease the
volume of solution and to maintain solubility and stability.
Doses were administered with no relation to feedings. Serum
samples were drawn by heel stick at 3, 12, and 24 hours after the
initial loading dose and daily thereafter. Serum analysis was
accomplished using the EMIT technique--an enzyme-multiplied
immunoassay which is highly specific, rapid, and requires small
volumes of serum.
If the total withdrawal score was less than 8 after the desirable
therapeutic serum level was achieved, that level was maintained
for 72 hours. Subsequent dosing was considered as "maintenance."
A daily maintenance dose of 4-6 mg/kg/day was initiated 24 hours
following the loading dose. The infants were started with 5
mg/kg/day for maintenance and then the dose was adjusted as
necessary to maintain the desired serum phenobarbital level.
After 72 hours of maintenance, detoxification was begun; that is,
the phenobarbital serum levels were allowed to decline at a rate
of 10-2O%/day, by administering phenobarbital 2 mg/kg/day. If
serum phenobarbital levels indicated that detoxification was too
rapid (that is, greater than 20%/day), the maintenance dose was
increased to 3 mg/kg/day. If detoxification was too slow (that
is, less than lO%/day), the maintenance dose was decreased by 1
mg/kg/day.
Once the serum levels fell below 14 mcg/ml and the total withdrawal score was still less than 8, the detoxification dose was
decreased by 1 mg/kg/day. Once the serum level fell below 10
mcg/ml, and the total withdrawal score was less than 8, the
phenobarbital was discontinued. The infant was observed for withdrawal symptomatology for 72 hours following discontinuation of
therapy, then discharged if no symptoms reappeared.
If the total withdrawal score was greater than 8 after
therapeutic level was achieved, an attempt was made to
the phenobarbital serum levels by 10 mcg/ml increments
hour period until: (1) the total withdrawal score was
8 or, (2) the serum level reached 50 mcg/ml.
our desired
increase
per 24
less than
If the total serum phenobarbital level reached 50 mcg/ml or
greater and the total withdrawal score was still greater than 8,
then the choice of detoxicant therapy was reevaluated before
250
attempting to exceed the level.
Detoxification was carried out in the same manner as described
previously. All infants had vital signs (heart rate and
respiratory rate) taken every hour for six hours following the
initial loading dose of phenobarbital. After six hours, the vital
signs were taken at four-hour intervals until 24 hours following
the loading dose, then routine monitoring was resumed.
Once the infant was controlled (that is, the total withdrawal
score less than 8), then the phenobarbital serum levels were
drawn daily immediately preceding the daily phenobarbital dose
until therapy was discontinued (that is, when the total serum
level fell to less than 10 mcg/ml).
RESULTS
Analysis of the data revealed that: seventeen of the eighteen
infants were controlled when phenobarbital levels were between
20 and 30 mcg/ml. The loading dose of 16 mg/kg of sodium phenobarbital produced average daily blood levels at 24 hours of 17.4
mcg/ml with a standard deviation of 3.15 mcg/ml. No infant had
blood levels above 25 mcg/ml with the loading dose while two
infants had subtherapeutic levels of 11.5 and 12.8 mcg/ml 24
hours after the dose. No infant exhibited signs of toxicity or
undue depression during the administration of the loading dose.
The range of maintenance doses necessary to deal with metabolism
and pharmacologic response aspects varied between 2 and 8 mg/kg/
day.
In comparison to a conventional three times per day dosing
regimen used previously, it was evident that therapeutic levels
were obtained 15 to 24 hours earlier. In those infants not controlled by the usual 20-30 mcg/ml, the aggressive approach proposed allows higher serum levels to be obtained 40 to 72 hours
sooner than under the conventional system.
One infant was not controlled with serum levels of 50 mcg/ml of
phenobarbital. This infant's mother was on the largest methadone
maintenance dose of 80 mg/day. Three of the four infants, born
to mothers on doses of methadone greater than 35 mg/day, demonstrated an initial control of symptoms by phenobarbital in the
first week of therapy only to relapse with higher scores that
indicated more severe abstinence.
The latter four infants were hospitalized for an average of 43
days with a range of 22-55 days. The fourteen infants exposed
in utero to methadone doses of 20 mg/day or less were hospitalized
for an average of 26 days with a range of 13-46 days.
An advantage of this regimen is the maintenance dose approach
whereby the daily mg/kg dose approximates the drug eliminated by
metabolism, therefore maintaining the lowest efficacious serum
level. We also feel that detoxification based on gradually
251
declining serum levels with monitoring of patient withdrawal
symptomatology is a pharmacologically sound and clinically efficacious method of treating the neonatal abstinence syndrome which
avoids the problem of relapses from premature discontinuation of
therapy while defining an endpoint when therapy is no longer
required.
CONCLUSION
A group of eighteen infants which experienced the neonatal
abstinence syndrome due to prenatal maternal use of methadone
responded adequately to phenobarbital with control of symptoms.
By administering the phenobarbital as an initial single loading
dose and closely monitoring the-blood levels, maintenance dosing
could easily tie adjusted for variables in infant metabolism and
pharmacologic effect. By use of a multifactoral abstinence
scoring system, the pharmacologic effects on clinically observed
abstinence symptomatology could be closely monitored and correlated with the blood levels. Serum levels of 20-30 mcg/ml were
adequate to control all but one infant. Tapering the blood level
of phenobarbital to 10-12 mcg/ml and observing no scores over 8
for 72 hours identified the place in time where abstinence was no
longer significant and the infant could be discharged without
medication.
REFERENCES
Brachet-Liermain, A., Goutieres, F., Aicardi, J. Absorption of
phenobarbital after the intramuscular administration of single
doses in infants. J Pediatr, 87:624-626, 1975.
Finnegan, L.P., Kron, R.E., Connaughton, J.F., Emich, J.P.
Assessment and treatment of abstinence in the infant of the drugdependent mother. Int J Clin Pharmacol Biopharm, 12:19-32, 1975.
Jalling, B. Plasma concentrations of phenobarbital in the treatment of seizures in newborns. Acta Paediatr Scand, 64:514-524,
1975.
Mac New, B.A., Mitros, T.F., Finnegan, L.P. An innovative approach to clinical assessment and pharmacotherapeutic detoxification of the passively drug dependent neonate. In: Proceedings
of the 40th Annual Scientific Meeting of the Committee on
Problems of Drug Dependence of the National Research Council,
Baltimore, Maryland, June 3-6, 1978, pp. 312-321.
Nathenson, G., Golden, G.S., Litt, I.F. Diazepam in neonatal
narcotic withdrawal syndrome. Pediatrics, 48:523-527, 1971.
Pearce, J.L., Sharman, J.R., Forster, R.M. Phenobarbital in the
acute management of febrile convulsions. Pediatrics, 60:569-572,
1977.
Reddy, A.M., Harper, R.G., Stern, G. Observations on heroin and
252
methadone withdrawal in the newborn. Pediatrics, 48:353-358,
1971.
Viswanathan, C.T., Booker, H.E., Welling, P.G. Bioavailability
of oral and intramuscular phenobarbital. J Clin Pharmacol, 18:
100-105, 1978.
Zelson, C., Rubio, E., Wasserman, E. Neonatal narcotic addiction:
Ten year observation. Pediatrics, 48:179-189, 1971.
AUTHORS
Loretta P. Finnegan, M.D., Department of Pediatrics, Thomas
Jefferson University Hospital, 1025 Walnut Street, Philadelphia,
Pennsylvania 19107.
Thomas F. Mitros, R.Ph., Department of Pharmacy, Thomas Jefferson
University Hospital, 111 South 11th Street, Philadelphia,
Pennsylvania 19107.
Leigh Hopkins, Pharm.D., Department of Pharmacy, Thomas Jefferson
University Hospital, 111 South 11th Street, Philadelphia,
Pennsylvania 19107.
253
Relative Analgesic Potency of
Intramuscular Heroin and
Morphine in Cancer Patients With
Postoperative Pain: A Preliminary
Report:
Kaiko, R.F.; Wallenstein, S. L.; Rogers, A.; Heidrich, G., Ill;
Houde, R. W.
Heroin (Diacetylmorphine; 7,8-Didehydro-4,5 alpha-epoxy-17-methylmorphinan-3,6 alpha-diol diacetate ester), although not employed in
the United States, has been used in some countries as the treatment
of choice in controlling pain in patients with advanced cancer.
Heroin has been judged to produce more intense euphoria than morphine (Ross 1944; Seevers and Pfeiffer 1936; Elliott et al. 1971),
an attribute which has been considered a reason for its being the
preferred drug of narcotic addicts and for having particular virtues
in the management of intractable pain and suffering of terminal illness (Twycross 1974; Twycross 1975). Apart from differences in
relative potency and time action (Reichle et al. 1962), morphine and
heroin have been shown to be similar in most respects, so that the
uniqueness of heroin's attributes has been questioned (Lasagna,
Von Felsinger, and Beecher 1955; Smith and Beecher 1962; Fraser et
al. 1961; Martin and Fraser 1961). Indeed, there is considerable
evidence to suggest that heroin is rapidly hydrolyzed to monoacetylmorphine and morphine after drug administration (Jaffee and Martin
Controlled comparisons of intramuscular heroin and morphine
1975).
have been previously carried out in postoperative patients (Reichle
et al. 1962), but controlled intramuscular assays have not yet been
carried out in patients with chronic pain due to cancer.
The study reported here is the first in a series intended to provide
more substantial information as to whether heroin has any unique
attributes which morphine may not have in the treatment of patients
with advanced cancer. The purpose of this initial study is to determine the relative analgesic potency of intramuscular heroin compared
to morphine and to compare the treatment-related changes in mood and
side effects at equianalgesic doses in cancer patients with postoperative pain.
METHODS
Intramuscular doses of heroin of 2 and 4 mg and 4 and 8 mg were compared with 8 and 16 mg doses of morphine in two series of double
blind, twin crossover relative analgesic potency assays. The method
of the assay has been previously described in detail (Houde,
Wallenstein, and Rogers 1960; Wallenstein and Houde 1975). The
254
method and modifications employed in this particular study are
briefly described below.
Study Design
Each twin crossover assay consists of a series of four treatment
studies incorporating a lower and upper dose of the standard and
the test drug. The ratio of doses of standard to test drug are
varied from study to study. Each patient receives two doses, a
lower dose of one drug and an upper dose of the other. Each block
of four patients is balanced for drug, dose and order, and the
assignment of patients to treatments within the block is randomized.
On completion of each block, a sequential decision-making process
is instituted to determine whether the next block should incorporate
a lower or higher dose ratio of standard to test drug. The objective of this process is to obtain as much data as possible in the
equianalgesic effect range of the two drugs.
Collection of Data
Patients with postoperative pain are selected on the basis of an
evaluation of the cause of pain, the appropriateness of treatment
with the study drugs and the ability of the patients to communicate
with the observer. Patients are seen at hourly intervals and questioned about the severity of their pains. If the patient requests
medication for pain and has not received an analgesic for at least
three hours, and if the pain is reported as moderate or severe, a
study drug is given by the nurse observer. Observations are then
made at one half hour and continued at hourly intervals for six hours
or until pain has returned to the premedication level. At each observation time, the patient is questioned as to the severity of pain,
degree of pain relief, whether or not the pain has been at least
half relieved and whether or not he considers the drug acceptable.
Volunteered and observed side effects are also recorded.
Patients are also asked to complete visual analog scales (VAS) and
mod questionnaires. VAS data are obtained at the same observation
times as categorical (CAT) data. The patient is asked to mark 100
mm scales at the point on the line which best reflects how he feels
between "Worst I Could Feel" and "Best I Could Feel" for the mood
VAS, between "Least Possible Pain" and "Worst Possible Pain" for the
pain VAS and between "No Relief of Pain" and "Complete Relief of
Pain" for the relief VAS. The mm distance from the origin to the
point marked is measured and taken as the VAS score in each case.
At the time of drug administration and at 2 hours after drug, patients are requested to estimate their mods more specifically by
use of a set of 15 contrasting word pairs. Patients are instructed
to circle either a neutral, "O", point or a "1", "2" or "3" in the
direction of either word of the pair. Negative feelings are later
assigned negative signs and positive feelings, positive signs. The
number is taken as the mod questionnaire score for each pair of
words.
255
RESULTS AND DISCUSSION
Data from the first 36 patients who provided both complete CAT and
VAS pain and pain relief scores are presented here. Analyses of
variance for twin crossover assays were carried out with modifications for sequential study design (Finney 1964). The use of both
CAT and VAS measurements allowed the calculation of eight estimates
of relative potency: estimates based on peak CAT and VAS pain intensity difference, total CAT and VAS pain intensity difference
and the four sets of corresponding pain relief data. Table 1 shows
the results of the analyses in terms of relative potency
, upper
and lower 95 percent confidence limits and lambda, a measure of the
experimental efficiency of a bioassay. Lambda is derived by dividing the standard error by the common slope. The lower the value
of lambda the greater the sensitivity of the assay.
Table 1.
Relative analgesic potency of IM heroin vs. morphine.
PAIN INTENSITY DIFFERENCE
Total
Peak
CAT VAS
CAT VAS
2.2 2.9
2.1
2.4
10.5
95%
limits..<0.1
Lambda
5.2
1.9
0.62 0.36
PAIN RELIEF
Peak
Total
CAT
VAS
CAT
VAS
2.5
2.9
2.1
2.3
3.3
1.1
5.3
1.0
3.0
1.6
5.1
1.8
0.38
0.48
0.34 0.36
2.9
1.5
3.3
1.5
0.26
0.31
Potency estimates based on peak effects were consistently higher
than those based on total effects, an indication that heroin has a
shorter duration of action than morphine at equianalgesic peak effects. Estimates using VAS data were consistently higher than the
corresponding CAT data estimates. The use of pain relief data provided more efficient estimates than use of pain intensity data.
Comparable limits and efficiency were obtained with analyses using
CAT and VAS data. These results show intramuscular heroin hydrochloride to be between 2.1 and 2.4 times as potent as morphine
sulfate in tern of total analgesic effect and between 2.2 and 2.9
times as potent in terns of peak effect. Thus, approximately 4 mg
of heroin and 10 mg of morphine are judged to be equianalgesic in
relieving postoperative pain.
Time effect curves for heroin and morphine (not shown) also suggest
that heroin has a shorter duration of effect than morphine. Table
2 shows the mean time (minutes ± standard error) of the peak intensity of VAS pain relief compared to the time of peak VAS mood
for both drugs, and also shows the level of significance (two tailed,
paired t-test) associated with the difference between the two means.
A significant time lag is observed between peak pain relief and
peak mood for both heroin and morphine. This may suggest that
changes in mood may not be determined solely by the analgesic effect of these drugs.
256
Table 2. Time of peak intensity of pain relief and mood after IM
heroin and morphine.
Heroin
Morphine
DOSE (mg)
4.6
ll.l
RELIEF
69 ± 7
86 ± 10
MOOD
90 ± 9
120 ± 13
P<
0.025
0.005
Attempts were made to calculate estimates of relative potency in
terms of mood, but it was observed that both the direction and degree of mood change after drug were highly dependent upon the initial mood of the patient. For example, the total VAS mood change
(sum of the differences between hourly VAS mood scores and initial
score) after 8 mg of heroin was inversely related to initial mood
with a linear correlation coefficient of -0.84 (P<0.001). The linear regression line crossed the abscissa at an initial mood score
of approximately 50 mm. That is, patients who initially report
relatively low mood scores report positive changes after drug,
whereas those patients who initially report high scores report negative mood changes after drug. Qualitatively similar results were
obtained for the other doses of both drugs and examination of the
word pair mood questionnaire data yielded similar results. The
influence of initial mood requires further evaluation by covariance
and multiple regression analyses before any quantitative and definitive statements can be made concerning the relative effects of
heroin and morphine on mood.
When the patient population as a whole is considered, however, both
heroin and morphine provide significantly improved moods. Table 3
lists the word pairs from the mood questionnaire each arranged according to negative mood on the left and positive mood on the right.
To the right are the mean mood scores at the time of drug administration and at two hours after drug and the level of significance
(two tailed, paired t-test) associated with the difference between
the two means for both heroin and morphine. The word pairs are
separated according to several categories. Prior to drug administration, patients report being somewhat restive; both heroin and
morphine result in significant shifts toward feelings of tranquility.
Prior to drug, patients reported being somewhat more euphoric than
dysphoric; drug administration results in some significant shifts
Initially, patients were optimistic
toward feelings of euphoria.
and these feelings were improved somewhat after drug. Drug administration also results in some positive shifts toward enthusiasm and
feeling less serious.
Table 4 shows the side effect occurrence after heroin and morphine
in all patients having received a test drug. The percentage of
patients with side effects appears to be dose related for both
drugs. The incidence of side effects is consistent with the relative
analgesic potency estimates. The most prominent side effect observed
or reported after both drugs was drowsiness. This effect and
"relaxed" feelings were observed somewhat more frequently after
morphine, whereas feelings of "high" and "euphoria" were reported
slightly more frequently after heroin. However, the difference in
occurrence of these effects were small and are of doubtful significance.
257
314-300 0 -80 - 18
Table 3. Word pair mood questionnaire scores before and after IM
heroin and morphine.
FACTORS
I Agitation-Serenity
Shaky- Serene
Restless-Peaceful
Uneasy-At ease
Nervous-Calm
II Dysphoria-Euphoria
Blue-Cheerful
Angry-Contented
sad-Happy
Alone-Sociable
Don't care-Interested
Pessimistic-Optimistic.
III Pessimism-Optimism
Pessimistic-Otimistic.
Apprehensive-Confident.
Apathetic-Enthusiastic.
IV Apathy-Enthusiasm
Heavy-Bouyant
Lethargic-Peppy
Apathetic-Enthusiastic.
V Serious-Amused
HEROIN, 4.5 mg
O Hr 2 Hr P<
-0.1 0.9 0.02
-0.2 0.6 0.05
-0.5 0.9 0.001
0.4 1.3 0.01
MORPHINE, 11.9 mg
0 Hr 2 Hr P<
-0.8 1.3 0.001
-0.6 0.9 0.005
-0.4 1.1 0.005
-0.2 1.3 0.001
0.5
0.9
0.7
0.0
1.4
1.2
1.2
1.4
1.1
0.8
1.7
1.4
0.01
0.05
0.2
0.05
0.4
0.4
0.0
0.8
0.1
-0.4
1.8
1.4
0.6
1.4
0.7
0.6
1.5
1.6
0.02
0.005
0.05
0.02
0.3
0.7
1.2
0.9
0.3
1.4
1.1
1.1
0.4
0.6
0.02
1.4
0.4
0.9
1.6
1.2
1.1
0.7
0.01
0.6
-1.3 -0.6
-1.4 -1.3
0.9 1.1
-1.1 -0.3
0.05
0.8
0.6
0.02
-1.0 -0.1 0.001
-1.2 -1.0 0.6
0.3 1.1 0.02
-1.2 -0.7 0.2
In summary, the results of this study in postoperative patients
have, thus far, revealed little that was not expected from a review of the literature. Heroin hydrochloride appears to be about
two to three times more potent than morphine sulfate as an analgesic, to act more promptly and to have a slightly shorter duration
of action. There is a suggestion that heroin may have a somewhat
different spectrum of side effects and mood effects compared to
morphine, but the effects of both drugs on mood were inversely
correlated with the patients' feelings at the time of drug administration. Regardless, as a group, patients responded to both drugs
with significantly improved moods. A lag time between the peak intensity of analgesic and mood effects of both heroin and morphine
suggest a dissociation between these effects. Whether or not these
early impressions will be reinforced as this study proceeds, and
whether or not the effects of the drugs in patients with chronic
pain due to advanced cancer will be any different than in these
patients with postoperative pain, remains to be seen.
258
Table 4.
Side effect occurrence after IM heroin and morphine.
MORPHINE
SIDE EFFECTS
8 mg 16 mg
Pain Injection Site. 1
2
Nausea
Vomiting
4
Dry Mouth
5
2
Sweating
2
18
Sleepy (Drowsy)
13
1
Groggy (Dopey)
1
3
Lightheaded
2
2
Dizzy
2
2
Weak (Tired)
1
Nervous
6
6
Relaxed
1
Palpitation
Headache
1
Increased Pain
1
1
Floating Feeling
1
Feeling of Unreality.
Disoriented (Confused).
1
High (spacey)
1
Apathetic
1
Carefree
1
Unsteady
1
Diplopia
Increased Appetite
Euphoria
Hot
Calm
1
Vivid Dreaming
Difficulty
1
concentrating
N (patients, meds.)
27
Pts. with side effect 18
% with side effect
67
27
22
81
2 mg
HEROIN
4 mg
1
2
5
4
1
11
1
1
1
3
1
2
1
1
1
8 mg
1
1
4
13
1
1
3
1
1
4
1
1
1
1
8
5
63
1
1
1
1
2
1
1
1
1
1
24
16
67
21
16
76
REFERENCES
Elliott, H.W., Parker, K.D., Wright, J.A., and Nomof, N. Actions
and metabloism of heroin administered by continuous intravenous infusion to man. Clin Pharmacol Ther, 12:806-814, 1971.
Finney D.J. Statistical Method in Biological Assay. New York:
Hafner Publishing Co., 1964. pp. 266-272.
Fraser, H.F., Van Horn, G.D., Martin, W.R., Wolbach, A.B., and
Isbell, H. Methods for evaluating addiction liability. (A) "Attitude" of opiate addicts toward opiate-like drugs. (B) A short-term
"direct" addiction test. J. Pharmacol Exper Ther, 1-3:371-387,1961.
Houde, R.W., Wallenstein, S.L., and Rogers, A. Clinical Pharmacology of analgesics: 1. A method of assaying analgesic effect. Clin
259
Pharmacol Ther, 1:163-174, 1960.
Jaffee, J.H., and Martin, W.R. Narcotic analgesic and antagonists.
In: Goodman, L.S., and Gilman, A., eds. The Pharmacological Basis
of Therapeutics. New York: Macmillan Publishing Co., 1975. pp.256.
Lasagna, L., Von Felsinger, J.M., and Beecher, H.K. Drug-induced
mod changes in man. 1. Observations on healthy subjects, chronically ill patients and postaddicts. J Am Med Assoc 157:1006-1020,
1955.
Martin, W.R., and Fraser, H.F. A comparative study of the physiological and subjective effects of heroin and morphine administered
intravenously in postaddicts. J Pharmacol Exp Ther, 133:388-399,
1961.
Reichle, C.W., Smith, G.M., Gravenstein, J.S., Macris, S.G., and
Beecher, H.K. Comparative analgesic potency of heroin and morphine
in postoperative patients. J Pharmacol Exp Ther, 136:43-46, 1962.
Ross, J. Heroin during labour (Correspondence). Brit Med J 1:59,
1944.
Seevers, M.H., and Pfeiffer, C.C. A study of the analgesia, subjective depression and euphoria produced by morphine, heroine, Dilaudid
and codeine in the normal subject. J Pharmacol Exp Ther, 56:166,
1936.
Smith, G.M., and Beecher, H.K. Subjective effects of heroin and morphine in normal subjects. J Pharmacol Exp Ther, 136:47-52, 1962.
Twycross, R.G. Clinical experience With diamorphine in advanced malignant disease. Intl J Clin Pharmacol, 7:184-198, 1974.
Twycross, R.G. The use of narcotic analgesic in terminal illness.
J Med Ethics, 1:10-17, 1975.
Wallenstein, S.L., and Houde R.W. The clinical evaluation of analgesic effectiveness. In: Ehrenpreis, S., and Neidle, A., eds.
Methods in Narcotic Research. New York: Marcel Dekker, Inc., 1975.
pp. 127-145.
ACKNOWLEDGEMENTS
This work is supported in part by NIDA Grant No. DA-01707 and by
NCI Core Grant No. CA-08748.
AUTHORS
Robert Kaiko, Ph.D.; Stanley Wallenstein, M.S.; Ada Rogers, R.N.;
George Heidrich III, R.N., M.A.; Raymond Houde, M.D.
Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 95,
New York, New York 10021
260
Clinical Analgesic Assay of Oral
Zomepirac and Intramuscular
Morphine
Wallenstein, S. L.; Rogers, A.; Kaiko, R. F.; Heidrich, G., III;
Houde, R. W.
dimethylZompirac (McN-2783-21-98), sodium 5-(p -chlorobenzoyl)-1,4
1H-pyrrole-2-acetate dihydrate, is a close analog of tolmetin sodium, a
compound currently marketed for the treatment of rheumatoid arthritis.
Its pharmacological profile indicates antiinflammatory, antiarthritic and analgesic activity. In the rat, it antagonizes kaolin and carrageenin-induced edema. While zomepirac is inactive in
the "tail-clip" analgesic assay, it is effective in blocking acetylcholine-induced writhing in mice. On the basis of both animal data
and early studies in man, zomepirac appears to be well tolerated and
more effective than aspirin and other antipyretic and nonsteroidal
antiinflammatory drugs for the control of pain (McNeil Laboratories
1977). This report represents preliminary data in a clinical analgesic assay of oral zomepirac and intramuscular morphine.
METHODS
Study Design
Two parallel assays of orally administered zomepirac and intramuscular morphine are being carried out in two patient groups, one
assay in patients with post-operative pain, and one in patients with
chronic pain due to cancer. The assay in post-operative pain is
designed as a series of sequentially related twin crossover studies
comparing 50 and 100, or 100 and 200 mg of oral zomepirac with 4
and 8, or 8 and 16 mg of intramuscular morphine sulfate. Utilizing
the same doses, a complete crossover comparison of the two drugs
is being carried out in patients with chronic cancer pain. Each
assay consists of series of studies of four treatments each, in
which a lower and upper dose of zomepirac is compared with a lower
and upper dose of the standard, morphine. In the twin crossover
assay each patient receives a lower dose of one drug and an upper
dose of the other in a randomized order. In the complete crossover
assay, each patient receives all four medications to be included
in the analysis. Periodic decisions are made, based on the patients'
reports of pain relief, to adjust the doses of either the standard
or test medication up or down in order to obtain most of the data
in the equianalgesic range of the two drugs.
261
Data Collection
Observations are made on patients by full time trained nurse-observers who question the patients about their pain and degree of relief
after medication and record the patients' verbal subjective reports.
Patients are seen hourly and the nurse observers administer the coded randomized test medications when pain is either moderate or
severe. Patients are seen hourly for up to six hours by the observer and the patients' verbal reports of severity of pain and degree
of relief are recorded by the observer on standardized forms.
Patients axe not questioned directly about side effects, but all
observed and volunteered drug effects are recorded. Detailed
descriptions of the methodology have been previously reported (Wallenstein and Houde 1975).
In addition to the conventional verbal reports, subjective measurements of pain and pain relief utilizing visual analogue scales (VAS)
were obtained in most patients so that direct comparisons of assay
sensitivity utilizing verbal and visual scales could be made. In
particular, it was felt that VAS measurements might be found to be
more sensitive for the measurement of peak drug effects than the
more limited categorical verbal scales. The VA3 consisted of 100 mm
horizontal lines labelled from "least possible" to "worst possible"
pain and from "no" to "complete" relief of pain. Patients were
asked to mark in pencil the place on the scale that reflected how
they felt at the moment. Measurements were made in millimeters
from the left edge of the scale to the patient's mark. VAS data
were obtained by the nurse observers at hourly intervals immediately
after the verbal reports.
That narcotics in appropriate circumstances are capable of affecting
mod is well accepted. The extent of the effects in hospitalized
patients when the drugs are administered therapeutically for pain,
however, remains an open question. The current study of zomepirac
and morphine was employed as a vehicle for developing mood scales
that would be brief and simple enough to administer repeatedly to
sick patients with pain, and to provide a comparison of mood effects
after a narcotic (morphine) and a nonnarcotic analgesic (zonepirac).
A VAS scale and a 15 item self scoring word-pair questionnaire were
employed for this purpose. The mood VAS was obtained hourly, and
the questionnaire was completed prior to, and at two hours after
drug administration.
RESULTS
Conventional Relative Potency Assay:
Crossover comparisons have been obtained thus far in 132 post-operative patients and 17 chronic pain patients. The analgesic results,
in terms of total relief scores utilizing our traditional categorical
scales, are summarized in Table 1. Our original expectations,
based on animal and early clinical pharmacology, was that analgesic
equivalence might be obtained in the range of doses of 4 and 8 mg
of IM morphine and 100 and 200 mg of PO zomepirac and both the
post-operative and chronic pain patients were initiated using these
262
doses. Results in the first series, as illustrated in Table l, show
zomepirac to be more effective, relative to morphine, than expected.
Doses of the drugs were subsequently adjusted in both patient populations, and it was not until a third series in the post-operative
patients, in which the zomepirac doses were lowered to 50 and 100
mg, that its analgesic effects were in the same range as 8 and 16
mg of IM morphine.
Table 1. Summary of total relief scores for 6 hours after morphine
IM and zompirac PO on all series for patients with postoperative
pain and chronic cancer pain.
POSTOPERATIVE
PATIENTS:
I
Dose(mg)
SERIES
Relief
Dose(mg)
II
Relief
III
Dose(mg) Relief
Morphine,
IM
Zomepirac, PO
4
200
5.2
8.5
4
100
3.3
9.9
8
100
9.4
10.4
Zomepirac, PO
Morphine,
IM
100
8
9.4
6.8
50
8
8.6
6.8
50
16
6.4
8.5
Relief
Dose(mg)
4.1
5.0
7.5
5.7
8
16
100
200
CHRONIC PAIN PATIENTS:
I
Dose(mg)
SERIES
Morphine,
Morphine,
Zomepirac,
Zomepirac,
IM
IM
PO
PO
4
8
100
200
II
Relief
4.7
5.7
5.0
7.5
Relative potency analyses (Finney 1964) for both populations were
carried out eliminating the first series in each in which the drugs
were obviously not in the equipotent range (Table 2). A valid
analysis was obtained for the post-operative patients indicating
morphine IM to be about 5x as potent as zomepirac PO in terms of
verbal total relief estimate although the confidence limits are
rather wide. A valid relative potency estimate could not be calculated due to the small amount of data in the chronic patients.
The time effect curves for the post-operative patients are quite
similar for the two drugs, (Figure 1) although there is some indication of a slower onset for zomepirac. In the chronic pain patients,
zomepirac appears to have a longer duration of action than morphine
which may be due to narcotic tolerance in these patients. The
overall incidence of side effects was roughly the same for both
drugs (Table 3). Sleepiness, nausea, dry mouth and feelings of
weakness were observed after both drugs, but more patients were
groggy, lightheaded and dizzy after morphine while dyspepsia
and sweating were observed after zomepirac.
263
Figure 1. Time-effect curves for
oral zomepirac and intramuscular
morphine in a twin crossover
comparison in patients with
post-operative pain. Mean
categorical pain relief
(ordinate) is plotted against
time in hours (abscissa).
Table 2. Relative potency analysis of oral zomepirac and intramuscular morphine in patients with postoperative and chronic pain
in terms of total categorical relief.
POST-OPERATIVE
PAIN:
SOURCE
df
Drugs
Slope
Days
Days x Parellelism
Within Pt. Error
1
1
1
1
76
60.3
151.0
75.1
7.0
26.6
Parallelism
Days x Drug
Days x Slope
Between Series
Among Pts. Error
1
1
1
1
76
7.0
17.2
14.8
96.3
35.1
6.77
0.76
F
MS
2.267
5.677*
2.823
2.744
1.320
0.19
*p<0.05
95% limits = 0.11, 1.5
CHRONIC PAIN:
F
SOURCE
df
MS
Among Patients
Drugs
Slope
Parallelism
PxD Error
5
1
1
1
15
39.7
18.4
7.0
3.4
8.6
2.91
0.55
0.12
95% limits =
*P<0.05
264
4.616*
2.140
Table 3. Side effect occurrence after intramuscular morphine given
with an oral lactose placebo and after oral zomepirac given with
an intramuscular saline placebo.
SIDE EFFECTS
Injection Site Pain
Nausea
Vomiting
Dyspepsia
Dry Mouth
Sweating
Tremors
Flushed
Itching
Sleepy
Groggy
Lightheaded
Dizzy
Weak
Cold
Nervous
Relaxed
Depressed
Crying
Dyspnea
Headache
Marked Increased Pain
Visual Hallucinations
Disoriented
Blurred Vision
Dreaming
Euphoric
More Alert
Lethargic
singultus
Diarrhea
Stomach Pain
Hot
shaky
Tingling Head
MORPHINE,I.M.
4
8
16
6
14
3
7
4
5
2
2
6
4
1
2
1
1
1
1
13
36
19
3
3
4
2
3
3
5
4
3
3
2
5
50
2
6
1
1
2
11
2
2
ZOMEPIRAC, P.O.
100
200
4
2
2
3
3
3
19
3
2
1
8
1
25
1
3
4
6
5
1
4
1
5
2
1
3
2
1
1
1
1
2
3
1
1
3
4
1
2
1
1
4
4
1
2
1
1
1
1
2
1
1
1
1
1
1
1
1
1
Number of Patients
52
105
45
52
103
54
Patients with side
effects
24
55
30
25
43
32
%Pts. with side effects...46
52
67
48
42
59
The confidence limits of the relative potency estimates are quite
wide at this time, but this study is still in progress. At this
point zomepirac would appear to be a surprisingly effective oral
analgesic, capable of serving as a substitute for usual clinical
doses of intramuscular morphine.
265
Visual Analogue Scales:
In order to compare the sensitivity and efficacy of the VAS with
the standard categorical measures, analysis of variance and relative potency estimates in terms of peak and total relief were carried out in the twenty patients in Series III in whom both types of
measures were obtained. The results of these analyses are summarizobtained with
ed in Table 4. The estimates of relative potency
both the verbal and visual scales were in reasonably good agreement;
however, significant slopes and finite confidence limits were obtained in this small patient sample only with the measures of total
, an estimate of the
and peak VAS relief. In terms of lambda
efficiency of the assay arrived at by dividing the standard error
by the slope, the analyses utilizing VAS were superior to those
employing the categorical measures in this study. This limited
data provides some evidence that VAS may be superior to categorical
measures in small patient groups and, particularly, in terms of
peak effect where the restrictions of a limited categorical scale
may mask drug differences.
Table 4. Relative potency assays in the same patients employing
either standard categorical or VAS relief scales.
PEAK RELIEF
TOTAL RFLIEF
MS
MS
Z
Z
8
16
50
100
IM
IM
PO
PO
N
CATEGORICAL
8.4
8.4
5.8
10.8
VAS
227.0
232.0
133.7
324.2
20
325.2
0.43
0.16
0.01, 1.6
20
8.3
0.67
0.16
95% limits
CATEGORICAL
2.7
2.6
1.9
3.0
20
1.7
0.56
0.12
VAS
72.4
64.8
45.6
88.4
20
58.5
0.36
0.15
0.05,0.35
Measurement of Mood
The mood VAS, given hourly, and the questionnaire, given before and
at two hours after drug, were found to be acceptable to the patients.
Measurement of mood in patients taking medication for pain is
complicated by the fact that the patient's pre-drug mood may vary,
and the post-drug score is significantly influenced by the patients'
starting mood. Nevertheless, analysis of covariance of the mood
VAS indicates a significant positive drug effect with a relative
potency of zomepirac to morphine of 0.18 (95% confidence limits =
0.08 to 0.93), which is in the same range as that obtained for pain
relief. The mood VAS reflects a global patient response, and
whether mood as measured using this parameter is a result of drug
action or secondary to pain relief remains to be determined.
In
terms of the questionnaire, preliminary analysis indicates that
selected word pairs(restless-peaceful, shaky-serene, and sad-happy)
are most affected in the direction of improved mood by both drugs.
Whether or not there is a differential drug effect remains to be
266
seen as additional data is obtained.
SUMMARY
Zomepirac appears to be an unexpectedly effective oral, non-opioid
analgesic. The relative potency of oral zomepirac is roughly 1/5
to 1/8 that of intramuscular morphine. Visual analogues of pain
relief offer a reliable alternative to verbal categorical scales,
and may provide some advantages in assays of peak drug effect, and
in relatively small patient populations.
REFERENCES
Finney, D.J., Statistical Method in Biological Assay, Chapt. 10,
New York, Hafner 1964.
MC Neil Laboratories.
Investigative Drug Brochure, 1977.
Wallenstein, S.L. and Houde R.W.: The Clinical Evaluation of
Analgesic Effectiveness, Chapter 7, In S. Ehrenpreis and A. Neidle.
eds. Methods in Narcotics Research. New York, N.Y., Marcel Dekker,
Inc. 1975, pp.127-145.
ACKNOWLEDGEMENTS
This work is supported in part by NIDA Grant DA-01707, by NCI
Core Grant CA-08748 and by a contribution from the MC Neil
Laboratories.
AUTHORS
Stanley L. Wallenstein, M.S.
Ada G. Rogers, R.N.
Robert Kaiko, Ph.D
George Heidrich III, R.N., M.S.
Raymond W. Houde, M.D.
Memorial Sloan-Kettering Cancer Center
1275 York Avenue, Box 95, New York, New York 10021
267
Conditioned Heroin Responses as
an Indication of Readdiction
Liability
Sideroff, S. I.; Jarvik, M. E.
This study presents data on responses by drug addicts to stimuli
associated with their drug-taking behavior. It also suggests a
promising approach in developing an objective measure of a patient’s
likelihood of readdiction. The premise behind establishment of what
we call a "Readdiction Liability Test" is the theory that conditioned
responses by ex-addicts to heroin-related stimuli in the environment
are a major cause of relapse (Wikler 1973). According to this thesis,
encountering a person or place previously associated with drug-taking
behavior will produce conditioned responses in ex-addicts similar to
abstinence signs or craving. (The exact nature of these conditioned
responses has not been precisely determined at this point). Evidence
of this effect includes animal studies (Goldberg, Woods, and Schuster
1969; Goldberg and Schuster 1970; and Wikler 1965), anecdotal reports
(Wikler 1973), and responses conditioned in the laboratory (O'Brien
et al. 1976). When the symptoms are elicited "in vivo" however, they
are likely to lead to drug-seeking and-taking behavior. If this premise is correct, then one might expect addicts demonstrating the largest conditioned response or responding most readily to the appropriate heroin-related stimuli to have the greatest probability of readdiction. Finally, if these stimuli can be sufficiently isolated and
recreated in the laboratory, where patients' responses (both psychological and physiological) can be monitored and quantified, then an
objective measure of their responsivity can be established, and used
as a guide to their readdiction liability.
In our laboratory we have begun to examine psychological and physiological responses in addicts to stimuli associated with their drugtaking behavior. The goal of our research has been to approximate
the actual stimulus situation within the laboratory setting, and thus
we hope to develop a "Readdiction Liability Test". Obstacles have
included the inability or unwillingness of the addicts to participate
in "guided imagery" as a method of recreating their own environment as
well as our desire to have the subjects remain motionless to accurately monitor physiological responses.
In a previous study (Sideroff and Jarvik, in press) we described our
initial procedures in obtaining conditioned responses in addicts
268
detoxifying from opiates.
It was found that during a videotape (VT)
showing heroin-related stimuli, the subjects (unlike control subjects]
demonstrated a significant increase in heart rate and in number of
galvanic skin responses (GSR). In addition, they had an increase in
level of craving for opiates and increases in levels of anxiety and
depression as measured by the Multiple Affect Adjective Checklist
(MAACL).
The present study was designed to improve on the procedures and look
at additional physiological response systems. In the procedure, we
now allow for instantaneous indication of level of craving versus
previously asking for level before and after the entire experiment.
If the conditioned responses elicited in the laboratory are of a
reduced level and shorter duration than on the street (due to the
inappropriate context) a more immediate measure of craving is important.
METHOD
Subjects
Twelve volunteers from the Substance Abuse Service were used as experimental subjects. At the time of their participation nine were
detoxifying from heroin (five were at 0 mg. methadone, two were at
2 mg., and two were at 5 mg.) and three were on methadone maintenance (one at 30 mg., and two at 60 mg. of methadone). Ten control
subjects were volunteers from the nursing service of the Brentwood
Veterans Administration Medical Center. They were used to control
for the shock of viewing needles and injections. After being read
the procedures, all subjects gave their written informed consent
and were told they could withdraw from the experiment at any time.
Procedure
Subjects were asked to sit in a chair in front of a television
monitor. They were then connected to a Beckman Dynograph via
electrodes to record heart rate and GSR, as well as thermocouplers
attached under the nose to monitor respiration and to the thumb for
skin temperature. They were then given the MAACL; a brief drug
history, and the Profile of Mood States (ROMS). They were also
given blank paper and a black magic marker and asked to draw a person. This was a projective technique we hoped would yield a sensitive measure of change in mood state; one that the subject would
be unable to manipulate. This same series of tests was again administered to the subject at the conclusion of the experiment.
After completion of the questionnaires, the subjects were asked to
relax. At this point they were shown a dial next to their right
arm with the numbers 1 - 10 inscribed on the circumference. They
were asked to dial the knob to their level of craving for heroin,
with '0' indicating "no desire" and '10' being "total desire".
Additional instructions helped the subjects establish a frame of
reference to determine their craving level. They were instructed
to change that level any time during the experiment at which their
269
level of craving actually changed. In addition, they were asked to
check the dial just prior to each trial to ascertain whether it was
set correctly. Trials were preceded by a three-second tone as a cue.
The actual VT material was presented in five two-minute trials, with
one-minute intervals between trials. There were two VT's: an experimental VT showing various drug-related scenes including people preparing heroin and shooting-up, and a control VT showing neutral material. The two VT's were presented in a counterbalanced design on
two successive days.
Upon completion of the second set of questionnaires, the experimenter
talked with subjects, answering their questions and making observations on their physical appearance. Follow-up meetings were made to
assure that there were no long-lasting effects from the videotape.
RESULTS
Figure 1 presents mean levels of craving during trial periods and
intertrial rest periods (indicated with an 'R') for control and drug
groups. The data points were derived by choosing the level that was
observed at the end of each interval. Control subjects, without exception, set their dial at "0" during the entire experiment. Looking
at the mean baseline or "pre" data for the drug group it can be seen
that the level of craving was basically the same at the start of the
two videotapes, and that this level was maintained throughout the
control stimulus presentation, actually dropping slightly over the
session. On the other hand, during the experimental videotape,
craving level increased during each of the trial periods as compared
to the immediately prior intertrial interval; in fact, craving levels were higher during each trial than during any rest period.
Mann-Whitney comparisons indicated significant differences between
the two videotapes for the drug subjects for all but the fourth
trial period (p<0. 05).
Figure 1.
Mean level of craving for each of the four conditions: *
270
* DE
DC
CE
CC
-----
Drug group, experimental VT
Drug group, control VT
Control group, experimental VT
Control group, control VT
Levels of anxiety, depression and hostility as measured on the
MAACL showed no significant change as a consequence of viewing
either videotape, unlike results from the previous study
(Sideroff and Jarvik, in press). It should be noted, however,
that prevideotape scores were highly variable from subject to
subject as well as within subjects from one session to the next.
Similarly, the POMS yielded no significant changes with high
inter- and intra- subject variability. On the other hand, a
double blind examination of the "Draw-a-Person" test by an outside judge with experience in this projective technique, showed
some interesting results. The judge was given the drawings in
pairs: before and after videotape, in a random sequence for the
four conditions, and asked to select those pairs which showed
an increase in confusion, anxiety, disorientation or decompensation. She picked out a total of 15, of which eight were from
the DE group, two were from the CE group, two were from the DC
group, and three were from the CC group. In addition, the judge
pointed out that in several other cases (all by the drug group)
the first drawing was so regressed (e.g. "stick" figures) that
it was impossible to detect an increase in the factors we were
looking for. Thus, while the results were not statistically significant, they do indicate a trend toward the DE group effect.
Figure 2 presents percent heart rate changes from baseline for
the four experimental conditions over the five trial periods.
Figure
2.
Percent heart rate change from baseline.
HEART RATE CHANGE FROM BASELINE
271
It should be noted that there were no significant differences in
heart rate baseline for the four conditions. From the figure, one
can see a consistent increase in heart rate during the DE condition,
with all other groups showing primarily a heart rate decrease.
Analysis of variance of scores summed across trials showed significant differences between the DE and DC conditions (p<.001) and
between the DE and CE conditions (p<.05). Of the 12 drug subjects,
eight showed heart rate increases, while the other four were either
flat or a deceleration during the experimental videotape.
Respiration data showed the same pattern, i.e., eight experimental
subjects showing increases and four showing basically a decrease.
Significant differences between groups, however, were not found.
This, as with our earlier study, appears to be due to extreme variability. Mean respiration changes as a percent change from baseline
were: 9.5 for DE; 5.8 for DC; -0.9 for CE; and -2.7 for CC.
Looking at the GSR we found the DE group had a significant increase
in number of responses to the VT, with no comparable change in the
other groups.
Pre-VT response levels did not differ between groups.
Skin temperature yielded variable results. To begin with, due to
problems with our equipment during the running of some of our subjects we have skin temperature data for only eight of the experimental subjects and six control subjects. What we found was that
four of the subjects, during the DE condition demonstrated systematic decreases in temperature of between 0.3 and 1.3 degrees centigrade on at least three of the five trials. The only other change
noted was an increase in temperature during some trials for the CC
condition.
DISCUSSION
In this study we have attempted to obtain conditioned psychological
and physiological responses in drug addicts to stimuli associated
with their drug-taking behavior. In doing so we wanted to replicate
our earlier research and to extend the findings in order to better
characterize these responses. Furthermore, we believe that the elicitation of the conditioned responses in the laboratory setting might
be a first step in determining a patient's "Readdiction Liability".
The data clearly demonstrated that the addicts differentially responded to the drug-related stimuli, and that the responses were
unique to the addicts when compared with an appropriate control
group. These differences were notable in the craving responses,
where a sharp elevation was found during each drug-related stimulus
trial. In addition, heart rate and GSR showed increases consistent
with the expectation of a conditioned withdrawal response. The other
physiological measures, respiration and skin temperature, while not
significantly different from controls, were still in the expected
direction of change. The data is also consistent with the results of
O'Brien et al. (1976)) where responses were conditioned within the
laboratory.
272
It was difficult to analyze some of the data of the present study.
To begin with, not all drug addict subjects demonstrated a responsivity to the experimental videotape, and tended to deny any negative feelings (as indicated in the questionnaire responses) both
before and after its presentation.
In a sense we seemed to have
a dichotomy in the experimental population that we tested. On the
one hand were the drug addicts who seriously were interested in
becoming drug free, or at least were very concerned with their
drug problem. These subjects consistently were affected by the
videotape as indicated in our psychological and physiological
data. The second group of drug addicts we tested were very "cool".
Nothing was going to affect them; their drug habit really wasn’t a
problem, and they were participating in the experiment because it
was good money. These subjects, as measured by the MAACL and POMS
tended to deny their feelings, responded to a minimum number of
feeling states, and, in general, appeared to be unaffected by the
experimental procedure.
To at least partially deal with this problem we explored the use of
a projective test in which the subjects were not as facile in hiding
their emotions. This test, "Draw-a-Person", was at least partly successful in demonstrating increases in anxiety, confusion, as well as
regressive tendencies in the drug addicts to the experimental videotape. As mentioned in the results section, some subjects were difficult to detect in this manner since their pretest pictures demonstrated
what might be expected in the posttest picture. This, as well as other
responses, might be a function of their status in the detoxification
program. Since most of the subjects were just finishing detoxification
from opiates, it might be expected that their baseline levels would be
somewhat erratic.
The physiological data also showed a dichotomy mentioned above, with
some experimental subjects demonstrating clear responses, particularly
heart rate and GSR, and to a lesser extent in skin temperature and respiration. The fact that some subjects show consistent conditioned responses while others do not respond at all has important implications
for a test of "Readdiction Liability". It would be important to be
able to discern beforehand if a low response level is an indication
that that person is less likely to develop conditioned withdrawal in
his home environment, or if he simply is denying during the test presentation. In our current research procedure we are preceding the
videotape presentation with questionnaires that we hope will discriminate between these two populations (such as the Lykken Activity Preference Questionnaire). Our readdiction liability test procedure,
therefore, might only be applicable to the subpopulation that responds
in some way to the conditioned stimuli, or the subpopulation that does
not deny their problem.
The variability in some of our data points to the possibility that the
detoxifying subjects were still experiencing abstinence effects that
at times masked the effects of the drug-related stimuli. Thus it would
be important in future studies to employ subjects not encumbered by, or
at least minimally affected by, protracted abstinence.
273
314-300 0 -80 - 19
REFERENCES
Goldberg, S.R., and Schuster, C.R. Conditioned nalorphine-induced
abstinence changes: persistence in post morphine dependent monkeys.
J Exp Anal Behav, 14:33-46, 1970.
Goldberg, S.R., Woods, J.H., and Schuster, C.R. Morphine: conditioned increases in self-administration in rhesus monkeys.
Science, 166:1306-1307, 1969.
O'Brien, C.P., Testa, T., O'Brien, T.J., and Greenstein, R.
Conditioning in human opiate addicts. Pavlov J Biol Sci, ll(4):
195-202, 1976.
Sideroff, S.I., and Jarvik, M.E. Conditioned responses to a videotape showing heroin-related stimuli. Int J Addict, in press.
Wikler, A. Conditioning factors in opiate addiction and relapse.
In: Miller, D.M., and Kassebaum, G.G., eds. Narcotics. New York:
McGraw-Hill, 1965. pp. 85-100.
Wikler, A. Dynamics of drug dependence, implication of-a conditioning theory for research and treatment. Arch Gen Psychiat,
28:611-616, 1973.
ACKNOWLEDMENTS
This research was funded in part by USPHS Biobehavioral Research
Support Grant No. RR 05756-04.
AUTHORS
Stephen I. Sideroff, Ph. D., and
Murray E. Jarvik, M. D., Ph. D.
Department of Psychiatry
School of Medicine
The Neuropsychiatric Institute
University of California
Los Angeles, California 90024
and
Psychopharmacology Unit
Veterans Administration Medical Center Brentwood
Los Angeles, California 90073
274
Unreinforced Self-Injections: Effects on
Rituals and Outcome in Heroin Addicts
O’Brien, C. P.; Greenstein, R.; Ternes, J.; McLellan, A. T.;
Grabowski. J.
The work of Abraham Wikler (1973, 1974) over the past three decades
has focused attention on the conditioning aspects of the addiction
process, and provided a theoretical foundation for some of the
clinical approaches to opiate addiction, particularly the use of
narcotic antagonists (Wikler 1974). While a patient is receiving
an antagonist such as naltrexone, he can be exposed to stimuli
which provoke opiate use and even use opiates with little or no
reinforcement. However, urinalysis results and patients' selfreports (Kleber et al. 1974) indicate that most patients who are
maintained on narcotic antagonists rarely test naltrexone by
injecting heroin. The patients report that once they are convinced
that opiate effects will be blocked by the antagonists, they do not
wish to waste their money by using heroin.
While a few "test" injections are generally enough to convince the
maintained client that the naltrexone will block primary reinforcement of the narcotic, these "test" trials are usually not sufficient
to extinguish the associated drug-seeking and ritual injection
behavior which have been shown to elicit drug-craving and even
physical withdrawal. (O'Brien et al. 1975, 1977). Thus, when the
naltrexone client terminates his antagonist therapy, he is once
again susceptible to conditioning aspects of his environment which
may promote readdiction. Studies by Meyer and his colleagues
(1976) and our own group (Greenstein et al. 1976) confirm this
impression, indicating that while heroin injection was quite low
among active naltrexdne patients (even when heroin was readily
available at minimal cost), readdiction may occur in many clients
following termination of naltrexone maintenance.
We have postulated (O'Brien, et al. 1975; O'Brien and Greenstein,
1976) that the effectiveness of naltrexone treatment could be
enhanced and prolonged in combination with a supplemental regimen
of behavioral extinction trials designed to reduce the conditioned
effects of pre-injection drug rituals and self-injection behavior.
In the present study, former addicts maintained on naltrexone were
given opiate (hydromorphone) or saline to self-inject on a
regularly prescribed basis in the laboratory. This paper compares
275
the six-month follow-up status of clients who received extinction
trials, with those remaining naltrexone patients who did not
participate in the procedure.
METHOD
Subjects
Subjects were 94 male veterans admitted to outpatient naltrexone
treatment at the Drug Dependence Treatment Service of the Philadelphia Veterans Administration Medical Center. All subjects
had been determined to be physically dependent on heroin or other
opiates at the time of admission to treatment and all were then
detoxified and stabilized on naltrexone (350 mg. per week), in a
standard manner. A full description of this program has been
provided elsewhere (Greenstein, et al. 1976; O'Brien, et al. 1978).
After discharge to outpatient status, twenty-one patients volunteered to perform self-injections in the laboratory according to
experimental schedule. Patients were randomly assigned to one of
three conditions. The Massed Trials Hydromorphone (Dilaudid)
group (n=6) injected 2 mg hydromorphone at a frequency of four
trials per day. The Spaced Trials Hydromorphone group (n=6)
injected 2 mg hydromorphone at a frequency of three trials per
week. The Spaced Trials Saline group (n=9) injected saline on a
schedule identical to that of the Space Trials Hydromorphone group.
Subjects in the Spaced Trials groups were run under double-blind
conditions.
Seventy-three additional patients receiving naltrexone
but no behavioral treatment served as a "No Extinction" (NO EXT)
comparison group.
General Extinction Procedure
Experimental sessions took place in a subject chamber equipped
with audio speakers, a chair, table, syringe switch box, drug
paraphernalia box (containing syringe, water, cotton, cooker,
matches, bags of lactose, and belt), ash tray, sterile prepared
syringe containing hydromorphone or saline, two TV cameras, a
video pupillometer, thermistor, and TV monitor. Laboratory equipment included a Grass Polygraph, two video tape recorders, monitor,
cassette player, switch for syringe box, videotape and cassette
with music and instructions.
Skin temperature was recorded continuously throughout each session,
and two-minute sessions of continuous pupil measurements were
taken by video pupillometer periodically. Each trial was videotaped for subsequent ethological analysis in which independent
observers scored the frequency of a number of behavioral responses.
Subjective measures were verbal self-reports (VSR) to various taperecorded questions which were presented five times during each
session. Experimental sessions lasted about one hour depending
on the length of the individuals' pre-injection ("cook-up") ritual
and the ease with which each patient was able to self-inject.
276
After signing an informed consent, the patient entered the
experimental chamber, a temperature sensor (thermistor) was taped
to his finger, and the pupillometer head brace was adjusted.
Baseline measures were recorded and the patient was then instructed
to begin cooking-up. The patient cooked-up and prepared a syringe
using the paraphernalia provided for him. The "drug" was powdered
lactose packed in glassine bags to look like heroin. The patient
typically would empty the contents of one or more bags into a
cooker, add water, heat the solution to boiling, draw it into his
"works," and then place the syringe into a black box on the table
while waiting for the instruction to "shoot-up." The box contained
an identically prepared syringe on a revolvable turntable. During
the brief interval between "cook-up" and "shoot-up," the electrically
operated mechanism silently rotated 180 degrees. This substitution
procedure insured that the patient always injected with a sterile
syringe. Subjects were informed that the syringe would be switched
for the purpose of sterility and all willingly accepted the substitution. When the syringe box was activated and the sterile
syringe became accessible, the patient was instructed to begin
"shooting up." He then removed the sterile syringe from the box,
tied his arm with the belt, and self-injected. Following "shootup" the patient sat quietly for another 15 minutes until the
session ended.
All subjects were eligible for the standard clinical
follow-up procedure by an independent interviewer six months
following treatment. An 84 percent contact rate was maintained
for all patients, with no significant (p> .10) between-group
difference.
Spaced Trials Procedure
Subjects in the Spaced Trials group attended sessions three times
per week (usually Monday, Wednesday, and Friday) either 48 hours
after a 100 mg. dose of naltrexone, or 72 hours after a 150 mg.
dose. Patients received $2.50 per trial with payment at the end
of each week. Patients were offered a $25 bonus if they completed
18 trials, however they were allowed to drop out of the study
whenever they wished. Spaced Trials subjects were randomly assigned
to either the hydromorphone or the saline group, and were tested
under double-blind conditions throughout.
Massed Trials Procedure
Subjects in the Massed Trials group attended sessions on three
consecutive days each week and were given four trials per day.
The first syringe each day contained saline while the remaining
three syringes contained hydromorphone. Naltrexone was administered approximately one-half hour prior to the-start of the
session each day, in order to eliminate the reinforcing effects of
the accumulated hydromorphone. Patients received $50 upon completion of the twelfth trial and $25 for participating in a
follow-up interview.
277
RESULTS
Admission Status
Subjects in each of the four groups were compared across nine
admission status variables to determine the extent to which they
differed at the outset of naltrexone treatment. Since no significant differences were found between the three extinction groups,
they were combined into a single extinction (EXT) group (n=21)
for subsequent comparisons with the NO EXT group (n=73). Chi-square
comparisons (p > .10) show that groups were essentially equal in
terms of admission status prior to the start of naltrexone treatment.
Within-Treatment
Changes
Both subjective and physiological responses to the self-injections
changed markedly over the course of trials. While the entire
injection procedure (including pre- and post-injection rituals)
was reported as mildly pleasant after the first few trials, subsequent trials were reported as being increasingly aversive.
This change in affective responses replicates similar results
reported by our group under similar conditions (O'Brien, 1975).
For the majority of subjects in all extinction groups, the preinjection rituals of "cooking-up" and "tying-off" produced physiological signs of craving and withdrawal. While the early selfinjections (either saline or hydromorphone) relieved the withdrawal and produced weak opioid effects, the later self-injections
served to increase the withdrawal response. These changes in the
physiological signs of craving are illustrated by the graphs in
Figure 1 which plot one of these measures (skin temperature) over
sessions 1 through 4 for a typical massed trials subject. The
switch from pleasurable effects to withdrawal effects occurred
regardless of whether saline or hydromorphone was self-injected.
The self-injection procedure grew increasingly aversive over the
course of trials and this was especially pronounced in the Spaced
Trials Saline group. Several patients became angry and refused
to continue the injections desnite cash inducements. While the
Massed Trials Hydromorphone and the Spaced Trials Hydromorphone
groups each completed an average of nine self-injections, the
Spaced Trials Saline group averaged only five trials (F< 1, p >.10).
The NO EXT group averaged 58 days of naltrexone treatment, while
the Massed Trials Hydromorphone and Spaced Trials Hydromorphone
averaged 53 and 56 days of treatment respectively. However, the
Spaced Trials Saline group completed an average of only 31 days of
treatment, significantly (t=4.16, p <.05) less than the other
three groups .
278
Figure 1: In trial 1, the pre-injection ritual and self-injecttion produced elevated skin temperature (an opiate effect
associated with pleasure). However, in trials 2, 3, and 4 temperature became progressively lower and this was correlated with
reports of opiate withdrawal feelings and increased drug-craving.
Post-Treatment
Changes
The overall effectiveness of naltrexone treatment alone was examined
through a comparison (chi-square) of nine performance criteria at
admission and six months following treatment in the NO EXT group.
Results indicated that there had been improvement in all nine
criteria, and four of these were significant (p <. 05), including
drug use (especially heroin), illegal activity, and employment.
As expected, comparisons of admission and follow-up performance
criteria for the EXT group also showed similar improvement across
all nine measures, signficantly so (p<.O5) in five of them.
The clinical effectiveness of the extinction procedures was assessed
by comparing the follow-up status of the four groups. Since previous analysis of the admission status and demographic variables
had indicated no significant (p >. 10) differences among the four
groups at the outset of treatment, we felt at liberty to analyze
outcome data directly. Ten performance criteria as well as three
additional measures which were collected only at follow-up, were
compared among the four groups. Results of these comparisons
279
indicated no significant (p>.05) differences among groups, although
the extinction groups, particularly the Massed Trials Hydromorphone
group, showed the best outcome in the majority of variables examined.
There was reason to expect the lack of statistically significant
differences among the four groups when compared on any single
criterion, since we had few subjects, and the general improvement
due to naltrexone alone was quite high. However, it was still
possible that there were general improvement differences among
the groups when compared across all measures. As a test of this
possibility, four of the original performance criteria and the
combined urinalysis results were summarized into five measures,
and the groups were rank-ordered on the basis of their improvement since admission. These ratings, seized in Table I,
TABLE I
GROUP IMPROVEMENT RANKINGS ON SIX-MONTH FOLLOW-UP MEASURES
(1=Best Outcome)
GROUP
% on
DPA % Unemployed % Arrested
MASSED HM
1
Positive
Follow-up # Drugs
Urines
Used
1
2.5
1.5
1
SPACED DIL
2
2
2.5
1.5
2
NO-EXTINCTION
3
3
4
4
4
SPACED SAL
4
4
1
3
3
x2 = 29.4 df 12, p<.01
demonstrate the differential effects of the extinction procedures
after six months. As can be seen, subjects in the hydromorphone
extinction groups (especially the massed trials group) showed
the greatest general improvement while NO EXT subjects and the
Spaced Trials Saline group showed the least (X2=29.4 df 12, p<.01).
No significant differences were detected between the two hydromorphone gropus (p>.12) or between the Spaced Trials Saline and
the NO EXT group (p >.25).
DISCUSSION
The results of this study suggest that naltrexone is an effective
treatment plan for narcotic-dependent clients, particularly when
it is combined with behavioral extinction procedures. The comparison of pre-treatment and six months post-treatment status in
those clients who received naltrexone for at least two weeks,
indicates clear improvement which appears to be directly related
to the treatment modality. Furthermore, these improvements were
manifest across the full range of outcome variables studied,
including the important areas of drug use, crime, employment,
280
and psychological status (data not presented here). In addition to
the general improvement in all groups treated with naltrexone,
those subjects who received supplemental blocked self-injections
of hydromorphone showed improvement above that shown in the NO EXT
and the saline extinction groups.
The pre-injection rituals were effective in producing withdrawal
as measured both by subjective reports and physiological changes.
This withdrawal was partially relieved or even reversed by the
first one to three injections, but subsequent self-injections only
increased the signs and symptoms. These changes in the effects of
self-injection were more rapid and more aversive for subjects
receiving saline than for those who recieved hydromorphone. The
difference may be partially explained by mild opiate effects caused
by hydromorphone even in the presence of naltrexone.
Our results are also of interest because they are the first indication that changes in self-injection behavior during treatment may
be associated with effects on clinical outcome at follow-up. Those
who received saline improved less, and those who received massed
trials actually did better than expected. Neither group turned
out to be an optimal test of the extinction hypothesis because both
had persistent conditioned withdrawal responses as a result of
self-injections even in the final trials, indicating that extinction
was not complete.
We cannot be sure whether the poorer outcome in the saline group
was a cause or a result of their shorter treatment duration. We
were struck by the aversiveness created by the saline injection
procedure, and it may be that the frustration and anger associated
with these trials had a negative clinical effect. Had we been
able to retain these patients in treatment and to convince them
to complete the full course of self-injections, the conditioned
withdrawal responses may have diminished, producing a better
clinical outcome.
These findings must be considered preliminary due to the small
sample size and the fact that idividuals in the extinction groups
were self-selected. Still the data suggest that attempts to
"extinquish" putative conditioned responses in opiate addicts can
have either beneficial clinical effects or detrimental effects,
depending on how these procedures are applied. We are now testing
a more gradual extinction procedure which will be preceded by
systematic desensitization of the pre-injection stimuli. It is
our hope that this gradual procedure will lead to a more thorough
extinction and ultimately a better clinical outcome.
ACKNOWLEDGMENT
This research was supported by NIDA grants 00586 and 01218.
REFERENCES
Due to shortage of space, references are not presented here.
can be obtained from the senior author upon request.
AUTHORS - See author index.
281
They
Conditioned Drug Responses to Naturalistic
Stimuli
Ternes, J. W.; O’Brien, C. P.; Grabowski, J.; Wellerstein, H.; JordanHayes, J.
Research with both animals and humans has demonstrated that
conditioned drug reactions can be produced in the laboratory when
neutral stimuli are paired with narcotic drugs. Two different
and apparently opposite types of conditioned responses have been
One, a positive affective reaction, mimics the
identified.
agonistic effects of the drug US. Schuster and Woods (1968),
for example, have shown in monkeys that a stimulus paired with
injections of morphine acquired secondary reinforcing properties
which were capable of maintaining an operant for drug infusion
even after the subjects were completely withdrawn from morphine.
Roffman, Reddy and Lal (1973) reported that a tonal stimulus
could delay rectal temperature changes in addicted rats being
withdrawn from morphine. The occurrence of conditioned drugpositive reactions in humans has also been reported. Levine
(1974), for example, found that some addicts report pleasure from
self-injection of inactive substances. O'Brien (1975) observed
that positive affective and physiological changes occur in some
drug addicts when stimuli previously associated with drug attainment or relief of withdrawal are present.
The second and more common type of conditioned drug response is
a negative affective reaction which mimics the effect of an
opiate antagonist. Wikler (1965) showed that environmental
stimuli could evoke withdrawal reactions in rats previously withdrawn from opiates in the presence of those stimuli. Goldberg
and Schuster (1969) found that monkeys could be conditioned to
show withdrawal symptoms to stimuli associated with nalorphine
(a narcotic antagonist) administration. Siegel (1976, 1977)
argued that tolerance to morphine-induced analgesia and hypothermia
is a Pavlovian conditioned compensatory response.
Clinical evidence for conditioned responses in human addicts was
reported by Wikler (1948). He described the process as follows:
when the drug-free "ex-addict" returns to the environment (the
CS) in which he formerly used drugs (the US) he develops strong
craving and autonomic changes (the CR) which are similar to the
withdrawal state (the UR). Teasdale (1973) reported that slides
282
of drug-related scenes arouse anxiety in addicts. O'Brien et al.
(1974, 1975) found that negative affective and physiological
changes occurred both in drug-free former addicts and in patients
maintained on methadone when they were presented with drug-related
stimuli.
Recently Sideroff and Jarvik (1978) have also reported that heart
rate changes can be elicited in addicts undergoing detoxification
when they are allowed to view videotapes of drug administration
procedures. While these results are suggestive of the naturally
conditioned responses which we hypothesize, no systematic demonstration of such responses has been reported either in maintained
addicts or in drug-free exaddicts.
Our group has had considerable experience eliciting both conditioned and unconditioned withdrawal reactions (O'Brien et al.
1975, 1977). Unconditioned withdrawal has been elicited by
administering naloxone to patients in methadone maintenance.
Generally the result observed is a standard withdrawal syndrome,
including skin temperature decrease, pupillary dilatation, heart
rate increase, respiration increase, and an elevation of the skin
resistance response. We also have observed an increase in objective withdrawal signs, such as stomach cramps, nausea, yawning,
lacrimation, sweating, and nasopharyngeal congestion. Finally,
our patients' subjective reports indicate an increase in craving
for drugs and in feelings of withdrawal.
Conditioned withdrawal (O'Brien et al. 1977) was produced in
methadone maintenance patients by pairing neutral stimuli (sounds
and odors) with a narcotic antagonist (naloxone). After 12
pairings we found that these CSs presented alone elicited withdrawal reactions. In addition we have found (Ternes and O'Brien,
in preparation) that when drug-free patients blocked on naltrexone
perform a cook-up ritual and then self-inject either saline or
hydromorphone, the pattern of physiological, subjective and
behavioral responses is similar to the standard withdrawal
pattern. We have also observed this withdrawal pattern in response
to drug preparation rituals and saline injections in both drugfree former addicts (not blocked on naltrexone) and in methadone
maintenance patients.
We have now obtained further evidence of conditioned drug responses
to naturalistic drug-related stimuli. We have tested the effects
of the placebo (saline injections) and ineffective drug doses
(e.g., hydromorphone challenge during naltrexone blockade), in
addition to effects of rituals preceding drug administration
("cook-up"), videotapes of these procedures, slides of drugrelated scenes, and drug objects ("works"). We have found that
the most realistic and powerful drug CSs are embedded in the
drug-preparation ritual and act of self-injection. In this
paper we will primarily be concerned with the demonstration
of conditioned withdrawal responses to slides, videotapes, and
objects. Presented alone, these stimuli are not as powerful as
drug rituals and placebo administrations; however, the demonstra-
283
tion of their effects, that is, their ability to evoke withdrawallike responses, is an important step toward the development of
a behavioral model of addiction.
METHOD
This experiment involved presenting naturalistic stimuli to three
different groups of subjects: patients in methadone maintenance
(MM), drug-free patients who had been detoxified for at least
two weeks (DF) and normal controls who had never used heroin (CC).
Stimuli were presented in six separate sessions. Three different
stimulus modes were used: slides, videotapes, and objects. Two
types of stimuli (neutral and drug) were presented in each modality.
Data was also recorded during two baseline sessions in which no
stimuli were presented.
Each session consisted of thirty minutes of baseline followed by
ten minutes of stimulus presentation. Dependent measures included
the autonomic variables of skin temperature, and heart rate (HR).
Withdrawal was measured with the Weak Opiate Withdrawal (WOW) scale
and mood was measured with the Profile of Mood Scale (POMS). Both
POMS and WOW were administered before and after each session.
RESULTS
All physiological data were normalized by dividing each minute
during the 10-minute stimulus period by the mean of the 10-minute
baseline which preceded it. Analysis of variance (ANOVA) for
each variable was performed on the transformed scores. The design
was a 3 x 2 x 3 in each case.
Temperature
The effect of Groups was highly significant (p <.005) and indicated
that temperature was generally lower in the MM and DF groups. The
main effect for Type of stimulus was also highly significant
(p < .005), as was that for Modality (p <.001). The Groups by
Type interaction was also significant (p < .025). Figure 1 shows
the groups' mean skin temperature scores plotted as a function
of stimulus type. Appropriate two-group comparisons between
neutral and drug stimuli have indicated that drug stimuli produced
reliable decreases in skin temperature in both the MM and the DF
groups but not in the CC group.
Heart rate
The main effect for Groups was highly significant (p <.005).
The HR was higher in the MM and DF groups than in the CC group.
The main effects for Type of stimulus and Modality were also
significant (p <.001 and p <.05 respectively). Figure 2 shows
the group mean HR plotted as a function of stimulus type. The
Groups by Type interaction was also significant (p <.05). Appropriate two-group comparisons indicated that the drug stimuli
produced reliably higher HR in the MM and DF groups relative to
284
the CC group. However, only the MM group's HR was significantly
higher during drug stimulus presentations relative to neutral
stimulus presentations.
Figure 1:
Group mean skin temperature scores
WOW Scale
This scale provided a measure of subjective withdrawal reactions.
None of the changes in the pre- and postsession WOW scores were
significant for any group. Although the MM and DF subjects did
not report a high level of withdrawal, their scores tended to
be higher after drug as opposed to neutral stimulus presentation,
whereas the CC scores tended to be lower. This trend is reflected
in Figure 3, which shows the sum of the rank order differences
between neutral and drug postsession scores for the three groups.
POMS
We calculated scores for each of the Depression (D), Anger (A),
Tension (T), Vigor (V), Fatigue (F), and Confusion (C) subscales
of the POMS. For purposes of analysis, the POMS presession scores
were subtracted from the postsession scores. No significant
differences were found between pre- and postsessions for drug or
neutral stimulus presentations for any of the three groups. However, some individuals in both the MM and DF groups did show large
postsession changes in mood after the drug stimulus presentations.
285
Figure 2:
Group mean heart rate scores.
Figure 3: The sum of the rank order differences
between neutral and drug post-session WOW scores
for MM, DF and CC groups for each stimulus modality
286
An arousal score was derived from the T, V, F, and C subscales
of the POMS. Figure 4 shows the mean pre- and postarousal scores
for each group across the eight experimental sessions. Although
Figure 4: Mean pre-and postarousal scores for
each group across the eight experimental sessions.
The arousal score is derived by subtracting the
sum of the F and C scores from the sum of the
T and V scores.
there was no systematic effect of drug stimuli upon general arousal
in any of the groups, the figure indicates that the CC group was
consistently less aroused than the DF and MM groups after both
It also indicates that
drug and neutral stimulus presentation.
physiological changes reported above are not due to general
arousal, since the MM and DF groups were aroused on all sessions
both before and after the stimuli were presented.
DISCUSSION
We have found (Ternes and O'Brien, in preparation) that when
drug-free patients blocked on naltrexone perform a cook-up ritual
and then self-inject either saline or hydromorphone, the resulting
pattern of physiological, subjective and behavioral responses is
similar to the standard withdrawal pattern. We have also observed
this withdrawal-like pattern in responses to drug preparation
rituals and saline injections in both drug-free former addicts
(not blocked on naltrexone) and in methadone maintenance patients.
We believe that the patterns of responses reported in the present
287
experiment are components of the naturally conditioned withdrawal
response.
However, because the CSs were presented in a novel
context the CR was attenuated.
The amount of associative. strength that a CS or any component of
a CS complex has attained can be demonstrated empirically by
presenting each component by itself (that is in the absence of
the US). This procedure is known as Pavlovian extinction. In
general, any CR is said to have both specific and general or
supportive components. These components may be acquired at
different rates and likewise may also have differential extinction
rates. Stimulus-specific instrumental responses are usually
acquired more rapidly and are more susceptible to extinction.
A number of investigators have found that while the stimulusspecific response to a CS may extinguish rapidly, one or more of
the supporting components of the CR may be highly resistant to extinction. These may be elicited even when there is no remaining
overt evidence that the CS is effective. For example, a dog
which no longer salivates to the sound of a bell may still experience tachycardia when the bell is rung although there is no
overt mortor behavior to indicate that the bell still has any
associative strength.
Our data suggest that conditioned drug responses are complex combinations of subjective, behavioral, and physiological responses.
Most accounts of conditioned drug reactions emphasize the subjective (drug craving) and instrumental (drug-seeking) response
components of the CR. We recognize the primacy of these components,
however, our definition of the nature of Pavlovian conditioned drug
responses leads us to measure the general physiological components
of these responses as well. We believe that these supportive
components are highly resistant to extinction and persist long
after the subjective and motor components have dropped out.
Generally these supportive components represent a pattern of
autonomic responses which partially mimic withdrawal and which
may be elicited when naturalistic drug-related stimuli are presented.
This pattern of supportive responses may in turn evoke the more
stimulus-specific instrumental responses which initially led to
redosing and eventually to readdiction.
ACKNOWLEDGEMENT
This research was supported by NIDA grants 00586 and 01218.
REFERENCES
Due to shortage of space, references are not presented here. They
can be obtained from the senior author upon request.
AUTHORS
J. W. Ternes, Ph.D.; C. P. O'Brien, M.D., Ph.D.; J. Grabowski, Ph.D.;
H. Wellerstein; J. Jordan-Hayes; Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104; and Drug Dependence
Treatment and Research Service, Philadelphia Veterans Administration
Medical Center
288
The Phase III Clinical Evaluation of
LAAM: I. Comparative
Epidemiology of Mortality in LAAM
and Methadone
Thomas, D. B.; Whysner, J. A.; Newmann, M. C.
Since its development in the early 1950's, levo-alphaacetylmethadol, or LAAM, a derivative of methadone, has
been established as safe and efficacious for maintainence
therapy of heroin addicts (Blaine and Renault, 1976).
As LAAM is able to prevent and relieve opiate withdrawal
symptoms for up to 72 hours, it need only be administered
three times a week, thus freeing the patient from a daily
round of clinic attendence and all of the implications
of take-home doses.
The current Phase III study of LAAM is a large-scale
cooperative trial, involving 86 clinics nationwide.
This article reviews mortality patterns among LAAM patients in this study and compares the data with
findings on methadone maintenance patients, taken from
the DARP and CODAP data sets. The clinical implications
of these findings, for the management of patients on LAAM,
will also be discussed.
PATIENT
POPULATION
Subjects are inducted into an open protocol, or randomized to LAAM or methadone. Both groups include men new
to drug maintenance therapy and those previously stabilized on methadone.
Each patient is given a pretreatment evaluation consisting of a laboratory workup, physical exam, and medical
and personal history. During the study, weekly urine
screens, possible adverse reactions and a variety of
other findings are reported. Upon completion of the
trial (40 weeks or upon premature termination), each
patient is again fully worked-up.
If a patient dies, the clinic follows a formal Autopsy
Protocol. The protocol first directs the clinic to con-
289
314-300 0 -80 - 20
tact, and gain cooperation from local coroners, and then
obtain a copy of the coroner's autopsy report. Also,
clinics submit samples of blood, urine, and other tissues
to Dr. Brian Finkle at the University of Utah, Salt Lake
City, for analysis of LAAM and its metabolites. A broad
screen for other drugs of abuse is also performed.
Thus, for the Phase III study, extensive and high-quality
data are available, such that the specific cause of death
can be determined for almost every case. Our only real
problems have been obvious homicides; in these cases,
coroners are under legal restriction, which limits
their ability to release information.
CHARACTERISTICS OF THE SAMPLE
Intake for the Phase III LAAM study began in July 1976
and closed in April 1979. To date, 3,042 patients have
been formally logged into the study for treatment on
LAAM. Approximately 74% were crossed over from methadone, and 26% entered LAAM treatment directly. One protocol randomized patients to LAAM or methadone, and 524
patients received methadone. This last group of patients
is too small for stable estimates of mortality rates,
so only data on LAAM patients will be presented here.
To provide a comparative data base for LAAM vs. methadone as a maintenance drug, two sets of data on methadone maintenance patients will be used. The earliest
of these is the DARP (Sells and Simpson, 1976) data on
patients inducted from June 1, 1970 to May 31, 1973 and
followed up to March 31, 1974. During year 1 of DARP,
24 agencies provided data; this increased to 36 and 52
in the next two years. The reporting clinics are fairly
well distributed nationally, but the 11,529 methadone
maintenance patients included are not a probability
sample, and their representativeness to the national
universe has not been established. The DARP study population was broken into annual cohorts, defined as
anyone in treatment on June 1 of a given year or entering during the following 12-month period. An individual
remaining in treatment could be counted again in subsequent cohorts, SO that the DARP population is aging
in terms of exposure to treatment to some unknown extent.
The CODAP data, collected directly by NIDA from clinics
receiving federal funds, provide the other body of
methadone maintenance data. CODAP receives client data
on about 90% of the nation's clinics: again, it is not
a strict national sample, but its coverage should ensure
representativeness. Data from a cohort of methadone
maintenance patients inducted between July 1, 1976 and
August 31, 1977 which provides a cohort of 23,111 patients
will be used.
290
While both the DARP and CODAP data have been criticized
for various reasons, by Glenn and Hartwell (1976) and
Richman (1977), among others, they are sufficiently accurate to furnish useful estimates of the parameters to
be described. They are also the only readily available
data of a scale sufficiently large to compare with LAAM
data. Both the CODAP and DARP data must be used, since
neither has all the data required for a full comparison.
COMPARISON
OF
SAMPLES--BACKGROUND
VARIABLES
The comparisons of distributions of available background
variables across studies are summarized by P-values,
relating to comparisons among groups, as shown in Table
1. Only age and race/ethnic status are available for
the DARP cohort, so the rest of the variables only compare the Phase III LAAM and CODAP groups.
Variable
TABLE 1
P-Value
Age (DARP, CODAP, PH III)
P >.0521
Race (DARP, CODAP, PH III)
P <.012
Marital Status (CODAP, PH III)
P >.05
P <.0522
Employment Status (CODAP, PH III)
Educational Status (CODAP, PH III)
P >.052
P >.05
Current Educational Status (CODAP, PH III)
Length of Heroin Addiction (CODAP, PH III)
P >.0512
Arrests Prior to Admission (CODAP, PH III)
P<.005
1) Continuous variable analyzed by the Analysis of Variance; 2) Catagorical variable analyzed by the Chi-square
test.
Briefly, review of these distributions indicates that
LAAM patients are slightly older, more often married,
employed, more likely to have no arrests, tend to have
shorter histories of addiction, and have somewhat more
education than the DARP and CODAP patients. There are
also fewer black and more white patients in the LAAM
population than the methadone maintenance groups.
The previous analysis of DARP mortality (Watterson, et
al., 1976) shows that mortality rates increase with age,
but racial composition has no influence. Given the slight
tendency for LAAM patients to have some social advantages
over the other two cohorts, we might expect some reduction in mortality. However, the limited number of events
upon which this analysis is based does not allow for partitioning of mortality rates for these background variables.
Therefore, parameters to be estimated below must be considered with some caution and the results taken as preliminary pending the accumulation of further data.
291
RESULTS
Over the initial 40-week trial, 17 LAAM patients died.
To compare experiences among studies, for each cohort,
the number of patient days were summed and man-years of
exposure computed. The death rate per 1,000 per manyear was then calculated, as shown in Table 2.
CODAP doesn't cite cause of death, but we can sub-divide
these rates into the various categories used in DARP
reporting. Overdose deaths are those secondary to direct
drug effects, or reactions such as anaphylactic shock.
Deaths secondary to the consequences of prolonged drug
abuse, such as alcoholism, cirrhosis, or hepatitis are
also included. Violent deaths encompass those due to
traumatic events, such as homicide, suicide, auto accidents, etc. Medical deaths are those caused by a medical
problem unrelated to drug abuse. Unknown deaths are
those for which the data available are insufficient to
assign a cause.
Mortality experience in the three cohorts has been fairly
similar. The LAAM Phase III trial has had the lowest
mortality rate (13.35 per 1,000 man-years), followed
closely by the DARP cohort (15 per 1,000 man-years);
the CODAP data, however, show somewhat higher rates
(20 per 1,000 man-years). Interpreting these data,
several potential influencing factors must be balanced.
The LAAM population is somewhat older, so we would expect some elevation of mortality. The apparent advantages of LAAM patients, in terms of social adjustment
may tend to move these rates in the opposite direction.
The continual aging of the DARP cohort might tend to
lower estimated rates. As will be seen below, this factor has a strong influence upon the probability of mortality.
TABLE 2
COMPARATIVE MORTALITY OF MALE DRUG MAINTENANCE PATIENTS
(man-years per 1,000)
LAAM
METHADONE
DARP
Phase III
CODAP
(1976-1979)
(1976-1977) (1970-1973)
DEATH CATEGORY (n = 3,042)
(n = 23,11l)(n = 11,529)
Overall Mortality
Overdose Deaths
Violent Deaths
Medical
Unknown
13.35
5.50
5.50
1.57
.78
20.28
15
4.55
6.24
3.46
.75
The breakdown of deaths in treatment by cause, as shown
in the rest of the table (for the Phase III LAAM and DARP
data only) is quite similar for both studies, given the
292
limited number of events which constitute the basis
for these calculations in either study. These distributions by cause of mortality are graphically displayed in
Figure 1, which reflects the excess of "medical" deaths
in the DARP sample and more overdose-related deaths among
the LAAM patients. As shown at the bottom of this figure,
the distributions do not differ statistically from each
other by the chi-square test).
Reviewing the temporal distribution of deaths over the
40 weeks of the Phase III LAAM trial (Figure 2), there
is a notable tendency for deaths due to all causes to
occur soon after induction. Comparable data is not
available for DARP patients, but is available for our
CODAP cohort though it is only available aggregated
for all causes. These data were used to calculate the
probability of death for each two-week interval across
the 40 weeks as shown in Figure 3. As with the LAAM
data there is a striking tendency for mortality to be
more frequent soon after induction.
This pattern may occur as a legacy of patients' previous
drug abuse history and life-style. Also, patients at the
highest risk of dying probably terminate early from
treatment so that there is a lowering of aggregate risk
of mortality over time. It is evident from these data
reviewed here that the length of participation in a
maintenance program has a strong effect upon the probability of dying. This implies that comparative analyses
of mortality would do well to standardize this parameter
in order to avoid misleading conclusions.
DISCUSSION
Since five of the overdose deaths occurred in the first
week of therapy, very close observation, on a daily basis,
seems indicated when a patient is beginning treatment
with LAAM. In addition, strong psychological support
and repeated admonition against the use of alcohol and
other drugs, especially diazepam, should be prominent
aspects of early LAAM therapy. However, two of these
early deaths were due to a dosage of LAAM administered
in amounts greater than the protocol allowed in conjunction with evidence of use of other drugs. Thus, three
patients were treated properly in the early-death group.
Methadone maintenance patients, as well as street patients, have probably developed a keen sense of just how
much alcohol or tranquilizer they can tolerate while
taking heroin or methadone. LAAM, however, has a slow
onset and prolonged time-course of action, due to active
metabolites; this drug therefore may make established
patterns of ethanol and tranquilizer use obsolete, and
occasionally lethal. Time and experience are required
for the individual to learn how to accommodate himself
293
to this drug. However, the distribution of mortality
among methadone patients reported to CODAP suggests
that these admonitions might well be applied generally.
Metabolic findings on these drug deaths and possible
drug interactions will be reviewed in a future paper.
In conclusion, two essential points can be made:
1. Mortality experience in the LAAM Phase III trial
follows closely the experience of methadone maintenance
though these data should be considered preliminary.
2. Generally, the influence of time in treatment on
the probability of mortality is strong enough to warrant avoiding comparisons between mortality rates
where this parameter is not controlled.
REFERENCES
1. Blaine, J.D. and P. Renault, Eds., RX = 3x/Week
LAAM Alternative to Methadone. National Institute on
Drug Abuse Research Monograph 8. DHEW Pub. No. (ADM)
78-347. Washington, D.C.: Superintendent of
Documents, U.S. Government Printing Office, 1977.
2. Glenn, W.A., Hartwell, T.D. Review of methods of
estimating numbers of narcotic addicts. Research
Triangle Park, N.C.
Research Triangle Institute, 1975.
3. Richman, A. The contribution of treatment data to
epidemiologic perspectives of narcotic addiction. In
Rittenhouse, J.E. (ed.) The Epidemiology of Heroin and
Other Narcotics. National Institute on Drug Abuse
Research Monograph 16. DHEW Pub. No. (ADM) 78-559.
Washington, D.C.: Superintendent of Documents, U.S.
Government Printing Office, 1977. pp. 183-191
4. Sells, S.B., and Simpson, D., eds. Studies of the
Effectiveness of Treatment for Drug Abuse, Volume 5.
Cambridge, Mass: Ballinger Publishing Co., 1977.
5. Watterson, O., Simpson, D.D., and Sells, B.B.
Death rates and causes of death among opiod addicts
in community treatment programs during 1970-1973.
Am J Drug Alcohol Abuse, 2 (1): 99-111, 1975.
AUTHORS
David B. Thomas, John A. Whysner, and Mary Carol Newmann
Medical Research Applications, Inc., 821 Clinton Place,
McLean, Virginia 22101
294
FIGURE 1
DISTRIBUTIONS OF TYPE OF DEATH:
DARP AND PHASE III LAAM STUDIES
295
FIGURE 2
TYPE OF DEATH AND DURATION IN THE STUDY:
PHASE III
295a
FIGURE 3
PROBABILITY OF DEATH (ALL CAUSES) OVER THE INITIAL 40 WEEKS OF TREATMENT:
CODAP METHADONE COHORT
Naltrexone, 6 -Naltrexol and 2Hydroxy-3-Methoxy-6 -Naltrexol
Plasma Levels in Schizophrenic
Patients After Large Oral Doses of
Naltrexone
Verebey, K.; MuIe S. J.
ABSTRACT
From 100 to 800 mg daily naltrexone doses were given to six
schizophrenic patients. The plasma levels of naltrexone, its major
metabolite 6
naltrexol ( OL) and its minor metabolite 2-hydroxy3-methoxy-6
naltrexol (HMN) increased to very high levels without
therapeutic improvement, toxicity or any other undesirable side
effects. Two weeks after the discontinuation of the 800 mg naltrexone dose the plasma was free of naltrexone, 6 naltrexol and
HMN; indicating a rapid and efficient elimination of the drug from
the body. The proposed role of naltrexone is opiate receptor
blockade in narcotic post addicts to prevent readdiction to heroin.
The effective heroin blocking dose for a 72-hour period is 100 mg
of naltrexone. Even when naltrexone was used at considerably
higher doses, as in this study, no undesirable side effects were
noted; indicating a high margin of safety.
INTRODUCTION
Naltrexone, a reasonably pure narcotic antagonist, has been tested in man principally for the blockade of heroin-related euphoria
in narcotic post addicts (Martin et al., 1973). Naltrexone may
be effective in blocking the addiction-abstinence cycle by preventing re-addiction to heroin (Goldstein, 1976). In previous studies
the naltrexone doses given to narcotic post addicts varied between
20 and 200 mg perday (Resnick et al., 1974). The effectiveness
and safety of 100 mg daily oral doses. of naltrexone was evaluated
after acute and chronic administration. Naltrexone provided nearly
100% blockade of heroin-related symptoms for 48 hours and about 50%
blockade at 72 hours. Other findings indicated no undesirable side
effects; the drug was biotransformed to less active metabolites,
6 naltrexol and HMN, which were excreted mainly into the urine
(Verebey et al., 1976b).
The recent discoveries of the opiate receptor and the identification of the endogenous ligands (endorphins) in the brain provided
therapeutic rationale for the use of opiate agonists as well as
opiate antagonists in psychiatric patients (Verebey et al., 1978).
The experiments utilizing an antagonist such as naloxone, N-allyl
congener of naltrexone, in chronic schizophrenic patients were
found to be effective in eliminating auditory hallucination in
some patients (Gunne et al., 1977), while attempted replications
in similar studies were therapeutically unsuccessful (Volavka et
al., 1977, Davis et al., 1977 and Janowsky et al., 1977). Sincethe oral effectiveness and longer time action of naltrexone seemed
an advantage in chronic therapy, it was also evaluated for its
possible effectiveness in schizophrenic patients, however, mostly
without benefit (Mielka and Gallant, 1977 and Simpson et al., 1977).
In this report we present data on the plasma level of naltrexone, 6 -naltrexol and HMN in schizophrenic patients who received
up to 800 mg naltrexone daily (Simpson et al., 1977). We also
present a variation of the previously published method (Verebey
et al., 1976a) that allows quantitative measurement of naltrexone
and HMN and a separate extraction for 6 -naltrexol and HMN in
Plasma.
Materials and Methods
Subjects
Six chronic schizophrenic patients participated in the study.
The age of the subjects ranged between 32 and 54 y.(average 44.2y).
The length of hospitalization was 2 to 29 y. (average 13.3y).
Drug
Administration
Naltrexone in 50 mg tablet form and naltrexone Placebo tablets
were provided by Endo Laboratories (Garden City, New York 11530).
The patients were tapered from their psychotropic medications
to no medication, using minor tranquilizers such as diazepam when
needed. During the first week placebo capsules were given BID at
8am and 4pm. During the 2nd week 100 mg naltrexone was given (50
mg BID); 3rd week 200 mg (100 mg BID); 4th week 300 mg (150 mg BID);
the 5th, 6th and 7th week 400 mg (ZOO mg BID); 8th week 600 mg (300
mg BID) and the 9th week 800 mg (400 mg BID). Two weeks of placebo
administration followed after which the subjects received the same
medication as prior to the study.
Sample Collection
Blood samples were drawn after the patients received at least
3-4 days of the designated doses and the time of the day was just
before the administration of the next morning dose. Thus the samples represent a time 24 hours after the 1st and 16 hours after the
2nd daily dose of naltrexone. The samples were heparinized and
the plasma separated from the cells by centrifugation and frozen
until analysis. Blank samples were taken before naltrexone therapy began and samples were taken two weeks after the conclusion
of drug administration.
Method of Analysis
The Procedure for the analysis of naltrexone, 6 -naltrexol and
HMN in Plasma was based on a previously reported method (Verebey
et al., 1976a). In brief, following multiple organic-aqueous extractions of the drug, metabolite and internal standard, the puri-
297
fied bases were derivatized with pentafluoropropionic anhydride
to form electrophores for electron-capture detection by gas-liquid
chromatography. Naltrexone, 6 -naltrexol and HMN standards at
various concentrations with the internal standard (nalorphine) provided standard curves for the quantitation of unknown samples.
However, modifications were necessary for the determination of HMN
in the presence of 6 -naltrexol. The problem of quantitation occurred because the HMN and 6 -naltrexol pentofluro derivatives
were not separable by gas liquid chromatography. This problem was
solved by differentially extracting HMN without 6 -naltrexol.
This was accomplished by using a non-polar solvent, benzene, for
the first and last extractions at pH 7.5, buffering with 0.2M
tris-maleate. For the determination of 6 -naltrexol and HMN combined, the original method was used utilizing chloroform as the
extracting solvent at pH 9.8. Nalorphine was used as the internal
standard; using 12.5 ng for the chloroform procedure and 25 ng for
the benzene procedure. The retention time of nalorphine is longer
than 6 -naltrexol, HMN and naltrexone thus emerging at a locus on
the chromatogram which is free from interfering plasma peaks. In
order to facilitate reproducability, the column was conditioned
prior to injection of the samples with 40 µl of Sylil-8 solution
(Pierce Chemical Co., Rockford, Illinois 61105); this step minimizes the on column breakdown of the electrophore-drug complexes.
Results and Discussion
The results of the psychiatric evaluation of this study were
reported in an earlier communication (Simpson et al., 1977).
Briefly, the findings were that no therapeutic improvement was
achieved at any dose level in the six chronic schizophrenic patients
of whom three had auditory hallucination. Although the naltrexone
doses were increased substantially no deterioration in the condition of any of the patients or complaints of side effects were
noted.
Figure 1 shows the dosage schedule on the abscissa and the
plasma levels of naltrexone, HMN and 6 -naltrexol on the ordinate.
The levels of both drug and metabolites increased with increasing
doses of naltrexone. The average 24-hr plasma levels of naltrexone
in six subjects following 100 mg daily doses was 1.92 + 1.0 ng/ml,
which was lower than found in our earlier study (Verebzy, et al. ,
1976) using the same dose (2.98 ng/ml). Higher rate of naltrexone
biotransformation reflected by the lower than expected naltrexone
plasma levels may have resulted from the chronic administration of
large doses of phenothiazines in these patients causing induction
of the drug metabolizing enzymes. The level of 6 -naltrexol of
40 + 11 ng/ml was nearly twice that of the earlier data (24.2
ng/ml) in four narcotic post addicts (Verebey et al., 1976b).
Since 6 -naltrexol excretion was shown to be an active secretory
process (Verebey et al., 1976b), it is possible that the schizophrenic patients may have had problems with active renal clearance,
resulting in the higher than expected 6 -naltrexol plasma levels.
The highest 24 hour plasma levels of naltrexone, HMN and 6 -naltrexol at 800 mg daily doses were 9.2 ± 3.4 ng/ml, 123 ± 14 ng/ml and
298
Figure 1
Naltrexone, 6 naltrexol and HMN plasma levels determined in
plasma obtained just prior to each daily dose of naltrexone. The
incremental weekly doses are presented at the bottom of the figure.
Each point on the curve represents the mean of n=6 at O-6th week;
n=5 at 7th week and n=4 at 8th and 9th week. The two patients
who did not complete the study were dropped for medical reasons
not related to naltrexone therapy. (see Simpson et al., 1977).
299
331 ± 35 ng/ml, respectively. These
levels indicate good absorption and
large doses of naltrexone with lack
any undesirable side effects by the
high drug and metabolite
systemic distribution of the
of toxicity or complaint of
patients in this study.
In post heroin addicts optimal heroin blockade was accomplished at 100 mg daily doses of naltrexone (Verebey et al., 1976b
and Volavka et al., 1976), representing 1/8th of the highest doses
used in this study. Two weeks after the use of 800 mg daily naltrexone the levels of naltrexone, HMN and 6 -naltrexol were undetectable in the plasma, indicating that the drug is well cleared
from the body. These results provide evidence for the large margin of safety of naltrexone, observed at significantly higher
doses than the ones suggested for narcotic antagonist therapy.
Acknowledgements:
The authors thank the Rockland Research Institute: Drs. N.S.
Klein, P. Vestergaard, G.M. Simpson, Ms. J. Rogers and Mr. T. Cooper
for their collaboration in this study. The excellent technical
assistance of Ms. Ann De Pace is acknowledged. Supported by NIDA
grant No. 1 RO 1 DA-01737-O1A1.
References
1.
Martin, W.R., Jasinsky, D.R. and Mansky, P.A. Naltrexone an
Antagonist for the treatment of Heroin Dependence. Arch.
Gen. Psychiat. 28: 784-791. (1973)
2.
Goldstein, A. New approaches to the treatment of Heroin Addiction: STEPS (Sequential Treatment Employing Pharmacological
Supports). J. Psychedelic Drugs 8: 191-198. (1976)
3.
Resnick, R.B., Volavka, J., Freedman, A. and Thomas, M.
Studies of EN-1639A (Naltrexone): A New Narcotic Antagonist.
Am. J. Psychiatry 131: 646-650. (1974)
4.
Verebey, K., Volavka, J., Mule', S.J. and Resnick, R.B. Naltrexone: Disposition, Metabolism and Effects after Acute
and Chronic Dosing. Clin. Pharmacol. Ther. 20: 315-328.
(1976b)
5.
Verebey, K., Volavka, J. and Clouet, D. Endorphins in
Psychiatry: An overview and a hypothesis. Arch. Gen.
Psychiat. 35: 877-888. (1978)
6.
Gunne, L.M., Lindstrom, L. and Terenius, L. Naloxone-induced
reversal of schizophrenic hallucinations. J. Neurol.
Transm. 40: 13-19 (1977)
300
7.
Volavka, J., Mallya, A., Baig, S. et al. Naloxone in Schizophrenia. Science 196: 1227-1228 (1977)
8.
Davis, G.C., Bunney, W.E., DeFraietes, E.G. et al. Intravenous
naloxone administration in schizophrenia 'and affective illness. Science 197: 74-77. (1977)
9.
Janowsky, D.S., Segal, D.S. and Bloom, F. Lack of effect of
naloxone on Schizophrenic symptoms. Am. J. Psychiatry 134:
926-927. (1977)
10. Mielka, D.H. and Gallant, D.M. An oral opiate antagonist in
chronic schizophrenia. A pilot study. Am. J. Psychiatry
134: 1430-1431. (1977)
11. Simpson, G.M., Branchey, M.H. and Lee, J.H. A trial of naltrexone in chronic schizophrenia. Curr. Ther. Res. 22:
909-913. (1977)
12. Verebey, K., Kogan, M.J., De Pace, A. and Mule', S.J. Quantitative determination of naltrexone and beta-naltrexol in
human plasma using electron capture detection. J. Chromatogr.
118: 331-335. (1976a)
13. Volavka, J., Mallya, A., Pevnick, J., Cho, D., Reker, D.,
James, B., Bauman, J. and Dornbush, R. (in press) Naltrexone
in normal men. Science.
14. Volavka, J., Resnick, R.B., Kestenbaum, R.S. and Freedman, A.
Short-term effects of naltrexone in 155 heroin ex-addicts.
Biol. Psychiatry 11: 689-694. (1976)
Authors:
Karl Verebey and S. Joseph Mule'
New York State Alcoholism and
Substance Abuse Services
Testing and Research Laboratory
80 Hanson Place
Brooklyn, New York 11217
301
Heroin and Naltrexone Effects on
Pituitary-Gonadal Hormones in
Man: Tolerance and Supersensitivity
Mendelson, J. H.; Ellingboe, J.; Kuehnle, J.; Mello, N. K.
INTRODUCTION
A number of clinical studies have attempted to explore the relationship between opiate use and sex hormone secretion. Azizi
found a significant diminution in plasma testosterone in 8 of 16
active heroin users compared to a group of normal controls (Azizi
Cicero and co-workers (1975) found that long-term metha1973).
done administration produced a decrement in function of secondary
sex organs in adult male heroin addicts. A decreased level of
plasma testosterone was associated with these secondary sex organ
More recently, we measured plasma testosterone in
derangements.
narcotic addicts, given known doses of heroin at fixed time intervals and found a significant dose-related depression of plasma
testosterone levels (Mendelson et al. 1975a, Mirin et al. 1976).
Testosterone suppression has also been observed in street addicts
with a recent history of heavy heroin use and in patients on high
dose (80 to 150 mg) methadone maintenance (Mendelson, Mendelson
and Patch 1975).
The purpose of this study was to determine if tolerance develops
to heroin-induced suppression of testosterone and luteinizing
hormone in human opiate dependent males. A second purpose of this
study was to ascertain if naltrexone administration to heroin users
who were drug-free produced any changes in plasma levels of pituitary-gonadal hormones as a function of duration of opiate abstinence . Finally, these studies were carried out to assess tolerance
and supersensitivity of prolactin secretory activity associated
with heroin self-administration and naltrexone use during opiate
abstinence.
METHODS
Six adult male heroin addicts provided informed consent for their
participation in these studies. All six subjects (ages 23 to 28)
were in good health as determined by appropriate clinical and
laboratory examinations. All of the subjects had previously been
unsuccessful in maintaining heroin abstinence following a variety
302
of behavioral, social and pharmacological intervention programs.
The major motivation for subjects volunteering for this study was
their desire to determine if naltrexone blockade would be efficacious in suppressing their heroin self-administration behavior.
The basic research paradigm involved a five-day drug-free baseline
period, two days of acute single dose (10 mg I.V.) heroin selfadministration with an intervening drug-free day, followed by
10 days of heroin self-administration under blocked (naltrexone)
or unblocked conditions. Subjects who received naltrexone administered only one or two doses of heroin during the 10-day period
of heroin availability.
In contrast, subjects who received naltrexone placebo self-administered almost all available doses of
heroin.
Subjects who received naltrexone during the period of
heroin availability (10 days) continued to receive naltrexone for
an additional 16 days prior to their discharge. Subjects who
received naltrexone placebo were detoxified with methadone for
five days, were drug-free for the following seven days and were
subsequently placed on naltrexone (50 mg/day for four consecutive
days prior to discharge.
Plasma samples were collected from an indwelling intravenous
catheter connected to a portable non-thrombogenic pump following
an acute intravenous injection of heroin (10 mg) on the 6th and
8th days of the study. Prior to these two acute doses of heroin,
subjects were drug-free for at least 5 days. Plasma samples were
also collected on experimental day 19 after a 10-day period of
heroin self-administration when subjects could administer up to
10 mg of heroin every 6 hrs (total daily dose - 40 mg). Finally,
plasma sampies were collected on the 32nd day of the study when
subjects were administered 50 mg of naltrexone orally.
Analysis of integrated plasma samples for testosterone were car:
ried out by a double antibody radioimmunoassay modified from a
procedure used for protein normones by Niswander et al. and discussed in detail in previous publications (Mendelson et al. 1974,
Mendelson et al. 1975b).
Integrated plasma LH and prolactin concentrations were measured with a double antibody method similar
to that described by Midgley (1966) .
RESULTS
Table 1 presents mean integrated plasma testosterone and luteinizing hormone values for six subjects prior to and following acute
heroin administration (10 mg I.V.) on Day 6 and Day 8 of the experimental period. On Day 6, heroin administration was preceded
by five days of a drug-free baseline condition. Day 7 was also
a drug-free day and on Day 8 the procedures carried out on Day 6
were repeated.
303
314-300 0 -80 - 21
Table 1
INTEGRATED TESTOSTERONE AND LH LEVELS FOR 6 SUBJECTS
PRIOR TO AND FOLLOWING AN ACUTE (10 mg I.V.) OF HEROIN
LH
ng/100 ml
(LER 907)
Testosterone
ng/100 ml
X ± S.E.
Day 6
Pre Heroin
Post Heroin
1422
1005
±
±
247
168
44.5
33.2
±
±
6.7
6.9
68
82
41.8
31.5
±
±
7.8
5.2
Day 8
Pre Heroin
Post Heroin
757
669
±
±
Plasma testosterone levels were significantly higher on Day 6 when
compared with Day 8. Heroin administration on both Days 6 and 8
was followed by a suppression of plasma testosterone levels. A
10 mg intravenous dose of heroin produced suppression of integrated
LH levels on both Days 6 and 8, and the magnitude of suppression
was almost identical for each day. Thus luteinizing hormone
suppression following acute heroin self-administration appears to
be a replicable phenomenon with respect to both magnitude and time
course of LH changes.
The effects of acute naltrexone administration on plasma luteinizing hormone and testosterone levels for three subjects who selfadministered heroin during 10 consecutive days and for one subject
who was under naltrexone blockade and did not self-administer
heroin are shown in figure 1. Plasma luteinizing hormone and
testosterone levels were obtained on Day 32 of the study. Subjects
1, 2 and 3 (lHT-3, lHT-2, 1HA-2) had received no opiates for seven
days prior to Day 32. However, subject 4 had a significantly longer
period of opiate abstinence of 21 days and in addition had received
naltrexone (50 mg/day) during this period. Subjects 1, 2 and 3
showed a naltrexone-related increment in plasma luteinizing hormone
levels. Subject 4 had low basal plasma luteinizing hormone levels
prior to naltrexone administration and only a small increment
following naltrexone administration. In addition, subject 4 had
plasma testosterone levels which were significantly higher than
either subjects 1, 2 or 3.
Table 2 presents integrated testosterone and luteinizing hormone
levels for four subjects who self-administered heroin during the
10-day period of heroin availability. (These subjects received
naltrexone placebo during the period of heroin availability.)
Testosterone and luteinizing hormone levels following acute heroin
administration, and as mentioned previously, luteinizing hormone
304
Figure 1: Effects of acute naltrexone administration (50 mg)
on LH and testosterone levels in four individuals.
A= Pre naltrexone; B= 3 hrs post naltrexone;
C= 3-6½ hrs post naltrexone
Figure 2: Integrated Plasma Prolactin Values for an adult
male heroin addict.
Day 6 and Day 8: 10 mg of heroin I.V.
on an acute basis; Day 19: 2 doses (10 mg) of heroin I.V.
on the last day of a 10-day heroin self-administration
period; Day 32: naltrexone 50 mg P.O.
305
suppression appears to be a reliable and sensitive index of heroin
effects.
The lowest integrated plasma testosterone levels were observed on
Day 19 following 10 consecutive days of heroin self-administration.
However, luteinizing hormone levels on Day 19 following heroin
self-administration for 10 consecutive days were approximately the
same as observed following acute heroin self-administration on Days
6 and 8.
Table 2
INTEGRATED TESTOSTERONE AND LH LEVELS FOR 4 SUBJECTS FOLLOWING
ACUTE (Days 6 and 8) and CHRONIC (Day 19) DOSES OF HEROIN
LH
ng/100 ml
(LER 907)
Testosterone
ng/100 ml
X ± S.E.
Day 6
Pre Heroin
Post Heroin
1226 ± 176
967 ± 189
51.3 ± 8.0
38.4 ± 9.0
780 ± 83
710 ± 91
46.9 ± 7.7
34.6 ± 5.3
615 ± 72
34.2 ± 5.9
Day 8
Pre Heroin
Post Heroin
Day 19
Post Heroin
Figure 2 shows heroin-induced increments of plasma prolactin levels
for an adult male heroin addict. Acute administration of 10 mg of
heroin on Days 6 and 8 produced a prompt and sustained increment
in plasma prolactin levels. On Day 19, the last day of the 10-day
heroin self-administration period, heroin administration was also
associated with increments in prolactin levels. However, these
increments remained sustained over a much shorter time course
when compared with the acute dose reponses on Days 6 and 8.
Naltrexone administration on Day 32 produced no changes in plasma
prolactin levels.
DISCUSSION
The finding that acute heroin administration (on both Days 6 and
8) was followed by a suppression of plasma testosterone levels is
consistent with data contained in experimental animal studies reported by others (Cicero et al. 1977) and previous research carried out with humans in our laboratory (Mirin et al. 1976). The
observation that heroin-induced suppression of plasma testosterone
and luteinizing hormone levels following a 10-day period of self-
306
administration is less than the degree of suppression following
initial acute heroin dosage suggests that tolerance occurs with
respect to heroin effects on both LH and testosterone levels.
Following cessation of heroin use, an increment in the basal level
of luteinizing hormone levels was observed. At this time acute
administration of naltrexone produced a further increase in plasma
luteinizing hormone levels. These findings suggest that a "rebound"
increment in plasma luteinizing hormone levels occurs following
cessation of heroin use and that naltrexone accentuates this
effect. These observations indicate that some degree of supersensitivity occurs at the hypothalamic and/or pituitary level
regulating secretory activity of LH during opiate abstinence.
Such supersensitivity is manifest even when subjects are not
experiencing any overt opiate withdrawal signs or symptoms.
Although the lowest integrated plasma testosterone levels were
observed following 10 consecutive days of heroin administration,
luteinizing hormone levels were approximately the same as those
observed following acute heroin self-administration prior to the
10-day period of continuous heroin use. This observation suggests
development of tolerance with respect to heroin effects on LH
However, low testosterone levels per se could result in
levels.
a stimulatory effect on LH as a consequence of long-loop feedback
mechanisms which regulate LH secretory activity. A stimulating
effect on LH secretory activity as a consequence of low testosterone levels could interact with a direct inhibitory effect of
heroin at hypothalamic and pituitary sites. The relative contribution of these interacting factors on integrated plasma LH levels
during chronic heroin use remains to be determined.
The most pronounced and dramatic effects of heroin on pituitary
hormones was the prolactin response following acute and chronic
heroin self - administration. Our data indicate that the magnitude
and time course of prolactin response following heroin-self administration may provide a very useful index of assessing one aspect
of opiate tolerance.
REFERENCES
Azizi, F., Vagenakis, A.G., Longcope, C., Ingbar, S.H. and
Braverman, L.E. Decreased serum testosterone concentration in
male heroin and methadone addicts. Steroids, 22: 467-472, 1973.
Cicero, T.J., Bell, R.D., Wiest, R.G., Allison, J.H., Polakoski,
K. and Robins, E. Function of the male sex organs in heroin and
methadone users. N Engl J Med, 292: 882-887, 1975.
Cicero, T.J., Bell, R.D., Meyer, E.R. and Schweitzer, J. Narcotics
and the hypothalamic-pituitary-gonadal axis: Acute effects on
luteinizing hormone, testosterone and androgen-dependent systems.
J Pharmacol Exp Ther, 201(l): 76-83, 1977.
307
Mendelson, J.H., Kuehnle, J., Ellingboe, J. and Babor, T.F. Plasma
testosterone levels before, during and after chronic marihuana
smoking. N Engl J Med, 291: 1051-1055, 1974.
Mendelson, J.H., Meyer, R.E., Ellingboe, J., Mirin, S.M. and
McDougle, M. Effects of heroin and methadone on plasma cortisol
and testosterone. J Pharmacol Exp Ther, 195: 296-302, 1975a.
Mendelson, J.H., Kuehnle, J.C., Ellingboe, J. and Babor, T.F.
Effects of marihuana on plasma testosterone. In: Tinklenberg,
J.R., ed. Marihuana and Health Hazards: Methodological Issues
in Current Research. New York: Academic Press, 1975b, pp. 83-93.
Mendelson, J.H., Mendelson, J.E. and Patch, V.D. Plasma testosterone levels in heroin addiction and during methadone maintenance.
J Pharmacol Exp Ther, 192: 211-217, 1975.
Midgley, A.R., Jr. Radioimmunoassay: A method for human chronic
gonadotrophin and human luteinizing hormone. Endocrinol, 79:
10-18, 1966.
Mirin, S.M., Mendelson, J.H., Ellingboe, J. and Meyer, R.E. Acute
effects of heroin and naltrexone on testosterone and gonadotropin
secretion: A pilot study. Psychoneuroendocrinol, 1: 359-369, 1976.
ACKNOWLEDGEMENT
This study was supported by Grant DA 01676-03 from the National
Institute on Drug Abuse, ADAMHA.
AUTHORS
Jack H. Mendelson, M.D.
James Ellingboe, Ph.D.
John C. Kuehnle, M.D.
Nancy K. Mello, Ph.D.
Alcohol and Drug Abuse Research Center
Harvard Medical School - McLean Hospital
Belmont, Massachusetts 02178
308
Histopathologic and Clinical Abnormalities of
the Respiratory System in Chronic Hashish
Smokers
Tennant, F. S., Jr.
ABSTRACT
Thirty chronic hashish smokers (mean age-20 years) with respiratory symptoms and six control subjects who were nonhashish
smokers were evaluated by history, physical examination, bronchoTwenty-three (23) of 23 (100
scopy, and bronchial biopsy.
percent) patients who smoked hashish plus cigarettes had one or
more histopathologic abnormalities of basal cell hyperplasia,
atypical cells, or squamous cell metaplasia. Only two of seven
(28.6 percent) hashish smokers who smoked cigarettes, one of three
(33.3 percent) cigarette smokers who smoked no hashish, and zero
of three (0 percent) nonsmokers showed one or more of the same
histopathologic lesions (p<.05). Hashish smoking when combined
with cigarette smoking appeared to have more deleterious pulmonary
effects than either hashish or cigarettes smoked alone, and the
abnormal histopathologic lesions found in these smokers are identical to those frequently associated with later development of
emphysema and carcinoma of the lung.
INTRODUCTION
There is accumulating evidence that marijuana and hashish have
considerable pulmonary effects. 1-13 Acute administration of
marijuana has been found to increase bronchodilation and reduce
bronchospasms induced experimentally in asthma sufferers.4-8
Chronic administration, however, impairs lung function in otherwise healthy subjects, and there are studies which indicate that
regular smoking of marijuana may result in cellular damage with
permanent lung disease, such as interstitial fibrosis.
Clinical reports describe bronchitis and pulmonary symptoms in
hashish and marijuana smokers.1-3
An unanswered question is whether chronic marijuana or hashish
smokers may develop emphysema or carcinoma of the lung in a manner
analogous to cigarette smokers. Morphologic and cytochemical
studies of marijuana smoke on lung epithelial cells show similar
effects on deoxyribonucleic acid (DNA) and fibroblasts as does
309
cigarette smoke.9,10 Mice and dogs subjected to chronic marijuana
inhalation have been shown to produce squamous metaplasia and other
pathologic changes of bronchial epithelial cells which are precursors of emphysema and carcinoma in cigarette smokers.12,13 In
an effort to partially determine if similar changes may occur in
humans, thirty young males who chronically smoked high doses of
hashish and had respiratory symptoms were clinically evaluated by
history, physical examination, bronchoscopy, and biospy of the
tracheobronchial mucosa. Their clinical and pathologic findings
were compared to six young male subjects who did not smoke hashish
or marijuana and who volunteered for bronchoscopy and biopsy of
the tracheobronchial mucosa.
METHODS
Thirty (30) United States Army soldiers stationed in Wurzburg,
West Germany sought medical assistance for one or more respiratory
symptoms of cough, excess sputum production, chest pain, hemoptysis,
or dyspnea (Table One). Ages of hashish smokers ranged from 17 to
22 years with a mean of 20.4 years. Every patient reported a
hashish consumption of 25 to 150 grams per month for three to
24 months. Twenty-three (23) patients additionally smoked a mean
of 1.0 pack of cigarettes per day for 1.5 to 12.0 years (mean-4.9
Seven (7) hashish smokers did not smoke cigarettes.
years).
All patients completed a medical history which emphasized respiratory symptoms and smoking history. Each was given a physical
examination and bronchoscopy with biopsies of the posterior wall
of the trachea, approximately 0.5 cm. proximal to the carina and
of the right and left mainstem bronchi. Each biopsy measured
approximately 0.2 x 0.2 x 0.1 cm. and each was immediately placed
in 10 percent formalin. At least ten paraffin sections of each
were examined after staining with hematoxylin and eosin stains.
Findings were classified according to the method of Auerbach
et al.14,15 The respiratory epithelium was considered "normal"
under the following conditions: there was no loss of cilia; there
were one or two layers of basal cells; and no atypical cells were
found. An abnormality was considered present if the epithelium
appeared other than normal as defined above. Each abnormality was
(1) basal cell
classified in one of the following categories:
hyperplasia when three or more layers of basal cells were present
beneath a layer of columnar cells with or without cilia; (2) squamous metaplasia when the columnar epithelium has been replaced by
a multilayered epithelium resembling stratified squamous epithelium.
Atypical cells were defined as those whose nuclei exhibited hyperchromasia and whose nucleus cytoplasm ratios were increased.
Nuclear pleomorphism, anisonucleosis, and increased numbers of
mitoses may or may not have been present.
Findings in these patients were compared to six voluntary control
subjects who did not smoke hashish and who were males from the
same U.S. Army Post. Each of these subjects was given the same
evaluation consisting of respiratory and smoking history, physical
310
examination, bronchoscopy, and tracheobronchial biopsy. Three of
the control subjects were cigarette smokers ages 25, 32 and 26
years (mean-27.7 years) who had smoked a mean of 1.6 packs per
day for ten to twelve years (mean-11.3 years). The other three
volunteer subjects did not smoke hashish or cigarettes; their
ages were 29, 22, 31 years (mean-27.3 years).
RESULTS
Twenty-two (22) of 23 (95.7 percent) hashish plus cigarette
smokers, six of seven (85.7 percent) hashish only smokers, one of
three (33.3 percent) cigarette smokers, and zero of three (zero
percent) nonsmokers complained of a chronic cough (p<.05). No
cigarette only or nonsmokers complained of any other respiratory
symptom or showed any abnormality on physical examination or on
gross examination during bronchoscopy. All hashish smokers,
regardless of whether or not they smoked cigarettes, complained of
one or more respiratory symptoms (Table One). Hashish-cigarette
smokers reported more symptoms than hashish only smokers. Twelve
(12) of 23 (52.2 percent) hashish-cigarette smokers compared to
two of seven (28.6 percent) hashish only smokers complained of excess sputum production; 14 of 23 (60.9 percent) hashish-cigarette
smokers compared to four of seven (57.1 percent) hashish only
smokers complained of dyspnea (pNS); and five of 23 (21.8 percent)
hashish-cigarette smokers compared to zero hashish only smokers
complained of hemoptysis (p<.05). Physical examination revealed
findings of ronchi, rales, or wheezes in 20 of 23 (87.0 percent)
hashish-cigarette smokers and five of seven (71.4 percent) hashish
only smokers (pNS). Gross examination of the tracheobronchial tree
during bronchoscopy showed erythema and congestion in 13 of 23
(56.5 percent) hashish-cigarette and in zero of seven hashish only
smokers (p<.05).
Histopathologic examination of bronchial biopsies reveal atypical
cells in 23 of 23 (100 percent) hashish-cigarette smokers; two of
seven (28.6 percent) hashish only smokers; one of three (33.3 percent) cigarette smokers and zero of three (zero percent) nonsmokers
(P<.05). Basal cell hyperplasia was found in 14 of 23 (60.9 percent) hashish-cigarette smokers; one of seven (14.3 percent) hashish
only smokers, and zero of six (zero percent) cigarette smokers or
nonsmokers (p<.05). Squamous metaplasia was found in
21 of 23 (91.3 percent) hashish-cigarette smokers; one of seven
(14.3 percent) hashish only smokers; one of three (33.3 percent)
cigarette smokers, and zero of three (zero percent) nonsmokers
(p<.05).
The only patient among the six control subjects who had a respiratory complaint or histopathologic abnormality was a 32-year-old
cigarette smoker who had smoked at least two packs of cigarettes
per day for 12 years.
DISCUSSION
Patients studied here chronically smoked large quantitites of
hashish, which is known to be more irritating to the upper respira311
tory tract than is marijuana.1,2 All 30 hashish smokers related
one or more symptoms which compelled the patient to seek medical
attention. Seven hashish smokers who did not additionally smoke
cigarettes gave a history of fewer symptoms of excess sputum
production, hemoptysis, or dyspnea. Hashish only smokers also
appeared grossly normal during bronchoscopy and only two of seven
(28.6 percent) had abnormal bronchial biopsies compared to 23 of
23 (100 percent) hashish-cigarette smokers (p<.05). Hashish only
smokers, compared to three control subjects who only smoked cigarettes, appeared to exhibit no significant clinical or histopathologic differences, although hashish-cigarette smokers showed more
clinical and histopathologic abnormalities than hashish only or
cigarette only smokers. Nonsmoker control subjects showed no
clinical or histopathologic abnormalities even though they were
of slightly older ages.
It is possible that more control subjects who smoked only cigarettes may have showed one or more statistically significant
differences with hashish only smokers, but the invasiveness of
the biopsy technique limited the number of volunteer control subjects that could be recruited for study. This data, therefore, is
not sufficient to determine if hashish only smoking is more detrimental than cigarette smoking to the pulmonary system. The
findings indicate, however, that hashish plus cigarette smoking
is more deleterious than smoking either one alone since one or
more histopathologic abnormalities was found in 23 of 23 (100 percent) combination smokers compared to two of seven (28.6 percent)
hashish only and one of three (33.3 percent) cigarette smokers
(p<.05).
The histopathologic findings in these patients are compatible with
previous reports which show that chronic marijuana inhalation may
produce histopathologic changes in lung explant from mice and ma
produce squamous metaplasia in dogs and mice.10,12,13 It is unknown if these abnormalities may possibly lead to emphysema or
carcinoma of the lung,although this is a reasonable assumption
since the histopathologic abnormalities found in these patients,
particularly squamous metaplasia, have been shown to be associated
with development of emphysema and carcinoma of the lung in cigarette smokers.14,15 This study does not specifically study marijuana, but it is reasonable to assume that it too may produce
similar histopathologic lesions in humans if smoked chronically
with cigarettes.
REFERENCES
1. Preble, M., Prendergast, T.J., Tennant, E.S. et al. Medical
Manifestations Associated with Hashish. JAMA, 216: 1965-1968,
1971.
2. Guerry, R., Henderson, R.L. and Tennant, F.S. Respiratory Manifestations of Hashish Smoking. Arch Otolaryngol, 95: 248-251,
1972.
3. Waldman, M.M. Marijuana Bronchitis. JAMA, 211: 501-507, 1970.
312
4. Fitzgerald, M.X., Solliday, N.H., Vachon, L. et al. Single
Dose Effects of Marijuana Smoke; Bronchial Dynamics and Respiratory Center Sensitivity in Normal Subjects. N Engl J Med,
288: 985. 1973.
5. Frank, I.M., Shapiro, B.J., and Tashkin, D.P. Acute Effects
of Smoked Marijuana and Oral Delta 9-Tetrahydrocannabinol on
Specific Airway Conductance in Asthmatic Subjects. Am Rev
Respir Dis, 109: 420-428, 1974.
6. Frank, I.M., Shapiro, B.J., and Tashkin, D.P. Acute Pulmonary
Physiologic Effects of Smoked Marijuana and Oral Delta 9-Tetrahydrocannabinol in Healthy Young Men. N Engl J Med, 289: 336341, 1973.
7. Lee, Y.E., Shapiro, B.J., Tashkin, D.P. et al. Effect of
Smoked Marijuana in Experimentally Induced Asthma. Am Rev
Respir Dis, 112: 377-386, 1975.
8. Lee, Y.E., Shapiro, B.J., Tashkin, D.P. et al. Sub-Acute
Effects of Heavy Marijuana Smoking on Pulmonary Function in
Healthy Men. N Engl J Med, 294: 125-129, 1976.
9. Finley, T.N., and Ladman, A.J. Marijuana Smoking: A Study of
Its Effects on Alveolar Lining Material and Pulmonary Macrophages Recovered by Bronchopulmonary Lavage. J Clin Invest,
49: 60-61, 1970.
10. Leuchtenberger, C., and Leuchtenberger, R. Morphological and
Cytochemical Effects of Marijuana Cigarette Smoke on Epithelioid Cells of Lung Explants from Mice. Nature, 234: 227-229,
1971.
11. Leuchtenberger, C., Leuchtenberger, R., and Schneider, A.
Effects of Marijuana Smoke on Human Lung Physiology. Nature
241: 137-139, 1973.
12. Belleau, R., Huy, N.D., and Roy, P.E. Toxicity of Marijuana
and Tobacco Smoking in the Beagle. Int Clin Pharmacol and
Biopharm, 12: 267-276, 1975.
13. Huy, N.D., Magnan-Lapointe, F., Roy, P.E., et al. Chronic
Inhalation of Marijuana and Tobacco in Dogs: Pulmonary Pathology. Research Comm in Chem Path and Pharmacol, 14: 305-317.
1976.
14. Auerbach, O., Garfinkel, L., Hammond, E.C., and Stout, A.P.
Changes in Bronchial Epithelium in Relation to Cigarette
Smoking and in Relation to Lung Cancer. N Engl J Med, 265:
253-267, 1961.
15. Auerbach, O., Hammond, E.C., and Kirman, D. Emphysema Produced in Dogs by Cigarette Smoking. JAMA, 199: 241-246, 1967.
ACKNOWLEDGEMENTS
The author wishes to thank Oscar Auerbach, M.D., Veterans Administration Hospital, East Orange, NJ; Walter Coulson, M.D., UCLA School
of Medicine, Los Angeles, CA; and William W. Johnston, M.D., Duke
University Medical Center, Durham, NC, for reviewing and interpreting biopsy materials.
The opinions expressed here represent those of the author and not
necessarily those of the U.S. Army.
AUTHOR - For affiliation, see page 183.
313
TABLE ONE
CLINICAL AND HISTOPATHOLOGIC FINDINGS IN HASHISH SMOKERS AND CONTROL SUBJECTS
HASHISH PLUS
CIGARETTES
(N=23)
HASHISH WITHOUT
CIGARETTES
(N=7)
CIGARETTES
ALONE
(N=3)
NON-SMOKERS
STATISTICAL
SIGNIFICANCE
(N-3)
MEAN AGE IN YEARS
20.0
20.6
27.7
27.3
PNS
MEAN REPORTED
HASHISH DOSAGE PER
MONTH IN GRAMS
83.7
90.7
N/A
N/A
PNS
MEAN LENGTH OF
HASHISH USAGE
IN MONTHS
12.5
8.1
N/A
N/A
PNS
MEAN REPORTED LENGTH 1.0
OF CIGARETTE CONSUMPTION PER MONTH
IN PACKS
N/A
1.6
N/A
PNS
MEAN REPORTED
LENGTH OF CIGARETTE CONSUMPTION IN YEARS
N/A
11.3
N/A
P<.05
4.9
CHRONIC COUGH
22 (95.7%)
6 (85.7%)
1
(33.3%)
EXCESS SPUTUM
PRODUCTION
12 (52.2%)
2 (28.6%)
0 (0%)
0 (0%)
P<.005
0 (0%)
P<.05
TABLE ONE (CONTINUED)
CLINICAL AND HISTOPATHOLOGIC FINDINGS IN HASHISH SMOKERS AND CONTROL SUBJECTS
DYSPNEA
HASHISH PLUS
CIGARETTES
(N=23)
HASHISH WITHOUT
CIGARETTES
(N= 7)
14 (60.9%)
4 (57.1%)
0
(0%)
0
(0%)
P <.10
0 (0%)
0
(0%)
0
(0%)
PNS
5 (71.4%)
0
(0%)
0
(0%)
P<.05
CIGARETTES
ALONE
(N=3)
NON-SMOKERS
STATISTICAL
SIGNIFICANCE
N=3)
HEMOPTYSIS
5
RONCHI, RALES,
AND/OR WHEEZES
20
(87.0%)
ERYTHEMA AND
CONGESTION AT
BRONCHOSCOPY
13
(56.5%)
0 (0%)
0
(0%)
0
(0%)
P <.05
BASAL CELL
HYPERPLASIA
14
(60.9%)
1 (14.3%)
0
(0%)
0
(0%)
P<.01
ATYPLCAL CELLS
23
(100%)
2 (28.6%)
1
(33.3%)
0
(0%)
P <.05
SQUAMOUS
METAPLASIA
21 (91.3%)
1 (14.3%)
1
(33.3%)
0
(0%)
P <.05
(21.7%)
Satellite Session on Khat
PHARMACOLOGY AND ABUSE POTENTIAL
Assessment of Public Health and
Social Problems Associated With
Khat Chewing
Khan, I.; Hughes, P. H.
We, in WHO, are grateful to the Committee on Problems of
Drug Dependence for responding to our request to organize a
symposium on khat during its 41st Annual Meeting. We are most
gratified to note that four papers are being presented on the
pharmacological effects of cathinone, and that Dr H. Halbach,
formerly Director of the Division of Pharmacology and Toxicology
at WHO/HQ., and Dr O. Braenden, Head of the UN Narcotic Laboratory
at Geneva, are here to share with us their knowledge and longstanding experience gained in the subject over the years.
The
financial support provided to WHO by the United Nations Fund for
Drug Abuse Control and which made this research possible is
gratefully acknowledged. We look forward to working closely
with the Committee, beyond investigations into the pharmacology
of khat and into the field of epidemiology as well.
International research on khat spreads over three distinct
phases. The first related to the study of the pharmacological
effects of khat extracts and (+) cathine (norpseudephedrine) and
the comparison of their effects with amphetamine-like substances.
The second phase is related to extensive research by the UN
Narcotics Laboratory on the chemistry of khat using freshly
frozen khat leaves. This has led to the isolation of 30
substances, including cathinone, and was carried out in response
to a request from the UN Commission on Narcotic Drugs in 1971.
The availability of these substances has made it possible for
WHO to stimulate research on the biological effects, especially
its stimulant and reinforcing properties, in various countries
around the world. The third phase of the research is related to
assessing the public health and social problems associated with
khat chewing in the environments where its use is prevalent.
This type of study is a pre-requisite for decision-making by
Governments and International Organizations on whether national
and international controls are indicated for khat, and if they
are needed, the most appropriate framework for those controls.
To initiate these studies, WHO has communicated to the
concerned governments in its Eastern Mediterranean and African
316
regions to determine whether they would like to collaborate with
WHO in assessing the public health and social problems related
to khat chewing. On receiving positive responses, and with
financial support from UNFDAC, WHO will implement the
epidemiological phase of this international programme of research
on khat.
AUTHORS
Inayat Khan, M.D., B.S., Ph.D.
Patrick H. Hughes, M.D.
Drug Dependence Programme
World Health Organization
Geneva, Switzerland
317
314-300 0 -80 - 22
Khat—The Problem Today
Halbach, H.
The khat plant (catha edulis), a perennial shrub, has been cultivated for more than half a millennium in Ethiopia, Kenya, Tanzania,
North Yemen, and more recently Madagascar. The leaves are chewed,
but not normally swallowed, thus allowing for buccolingual or enteral absorption of soluble ingredients. The clinical effects of
chewing khat have been well described in the ancient Arabic literature. In the main they can be referred to a phenylethylamine-type
substance and tannins (O,1-0,2 percent and approximately 10 percent
respectively in dry leaves.
The pharmacologically active constituent named cathine was identified by WOLFES (1930) as (+)norpseudoephedrine. Its peripheral and
central effects are amphetamine-like, with greater potency of the
dextrorotatory isomer of cathine as well. The potency of cathine
was estimated to range between those of caffeine and amphetamine.
Khat users seek out the freshest possible plant material, an indication of the rapid degradation of cathine in the plant or, more likely, the existence of a more potent substance, possibly a precursor
of cathine.
Although for purposes of introducing control measures the nature of
khat effects can be satisfactorily explained as those of cathine, and
although not these effects as such, but rather their consequences
are likely to lead to public health and social problems warranting
some kind of international control - not to mention the impracticability of controlling khat under the Convention on Psychotropic
Substances- it was nevertheless decided that the active principle(s)
of khat should be fully elucidated before contemplation of control
measures.
The United Nations' Narcotics Laboratory succeeded in isolating, besides numerous inactive substances, 1) a series of so-called cathedulines (high-molecular-weight polyester-type alkaloids) one of which
is chemically related to the sedative cassinin, but unlikely to interfere with the stimulating action of khat; 2) norephedrine;
3) cathine in low quantity; 4: (-)- -amino-propiophenone "cathinone"
in larger, but varying amount. Whether the highly unstable cathinone
318
is a natural precursor of cathine is uncertain although its asymmetric carbon presents the same configuration as the corresponding
nucleus in cathine which would be compatible with its conversion
into the latter. Cathinone has been synthetized. Its N-diethylated
derivative is amfepramone. The amphetamine-like pharmacological
profile of cathinone has been studied by KNOLL and its reinforcing
properties by SCHUSTER (to be reported by the authors).
The clinical effects of khat can be fully explained by its main
constituents cathine/one and tannins. They include mydriasis,
tachycardia, extrasystoles, elevated blood pressure, transient
facial and conjunctival congestion, headaches, hyperthermia, increased respiration (through central stimulation, bronchodilatation,
counterregulation of hyperthermia), inhibition of micturition, increased diuresis (from intake of large quantities of fluids together
with khat); cerebral hemorrhage, myocardial insufficiency, pulmonary
oedema in predisposed individuals. Increased sympathicotonus is believed to be, besides psychological khat effects, the cause of anaphrodisia and spermatorrhoea. Effects on the gastrointestinal tract
include stomatitis, gingivitis, oesophagitis, gastritis, proneness
to buccal and oesophageal epitheliomas and duodenal ulcers. Very
common is constipation, sometimes with paralytic ileus. Anorexia
as a typical amphetamine effect is a strong factor in the vicious
circle khat-anorexia-malnutrition-digestive troubles-hunger-its
suppression through khat ---. Malnutrition may aggravate intercurrent disease, e.g., tuberculosis.
The reinforcing effects of khat include euphoria, logorrhoea, improvement of associations, excitement, insomnia. Toxic psychosis
occurs very rarely, if at all. This and the absence of tolerance
is obviously due to the self-limiting process of ingestion. Symptoms of withdrawal from khat are rebound phenomena rather than the
expression of a true physical dependence.
While the qualitative similarity between khat and amphetamines is
evident the quantitative differences are probably of a pharmacokinetic nature yet to be explored.
Khat problems hardly existed when its use was acculturated as, e.g.,
with the Mehru and Isiolo tribes in Kenya where only the elder herdsmen were permitted to chew khat. The major contemporary problem of
the excessive consumption of khat is the decrease of economic productivity through reduction of working hours spent on chewing khat
as well as overspending for a non-essential commodity on the expense
of food with ensuing malnutrition and proneness to disease and last,
but not least, loss of needed foreign currency.
The problem is one of today because of the easy access to khat
through air transport and because the economic development of khatconsuming countries cannot tolerate the loss of productivity from
the excessive use of khat.
AUTHOR
H. Halbach, Dr. med. Dr. -Ing., D-821o Prien - Stetten, West Germany
319
Research on the Chemical
Composition of Khat
Braenden, O. J.
At its 24th session, the Commission on Narcotic Drugs requested that
the United Nations Narcotics Laboratory should carry out research on
the chemical composition of khat, such research being fundamental
for the subsequent evaluation of the effects on health and society
caused by the chewing of khat.
Early literature on the chemistry of khat gives no information on
the degree of freshness of the material used. This is an important
factor because, in practice, khat is used only when fresh. Until
recently the only well-characterized component of khat was cathine
((+)-norpseudoephedrine). The stimulating effects obtained from the
chewing of khat were associated exclusively with the presence of
cathine, but this could not be substantiated because of marked
differences between the activities of fresh material and cathine.
The UN Laboratory therefore made an intensive study of the chemical
composition of khat, using fresh material. Staff members visited
Kenya, Madagascar, and the Yemen Arab Republic where they purchased
fresh khat and immediately extracted this with suitable solvents.
At the same time, khat material was freeze dried.
Thin layer and gas chromatographic analysis of extracts showed the
presence of a number of nitrogen-containing components that were
previously unknown in the plant. These compounds were separated
into two major groups: the phenylalkylsmine derivatives and the
weakly basic alkaloids.
A study of the phenylalkylamine fraction showed that, in fresh or
well-preserved khat material, cathine was only a minor component.
However, in each sample, a new compound was found and its chemical
structure was established as (-)- -aminopropiophenone. As this
compound had not previously been reported in nature, it was
tentatively assigned the designation "cathinone". Cathinone base is
very unstable and essily under es decomposition reactions leading
to the formation of a "dimer" (3,6-dimethyl-2,5-diphenylpyrazine)
and possibly smaller fragments such as benzaldehyde and ethylamine.
Further decomposition may lead to 1-phenyl-1,2-propanedione. Both
the "dimer" and the latter compound have been isolated from khat
320
extracts. The absolute configuration of cathinone was established
by Schorno and Steinegger 1978. The UN laboratory also synthesized
racemic cathinone using the method of Gabriel 1908, with some
modifications. From this, the optically active isomers and the "dimer"
were prepared. Other minor compounds were also identified in the
amine fraction.
The fraction containing the weakly basic alkaloids was found to have
a very complex composition. More than forty alkaloids have so far
been detected in khat by thin layer chromatography. Some of the major
components in this group were isolated. Structures were proposed for
eleven alkaloids and further structures are being established. In
this work, the UN Laboratory collaborated closely with Professor L.
Crombie and his group at the University of Nottingham, where
considerable work has been done in this field (Baxter et al. 1976,
Crombie et al. 1978). With two exceptions, all the alkaloids thus far
isolated from khat have had a common hydroxylated sesquiterpene
skeleton (euonyminol) which is esterified with various acids. The
common name "cathedulin" was proposed for this class of alkaloids.
In November 1978, the UN Laboratory convened a group of experts to
review present knowledge of the botany and chemistry of khat and to
prepare guidelines for future research in these fields. The report
of this group includes an annex listing all the substances that
have been isolated from khat together with their structural formulae.
The UN Laboratory is now concentrating its attention on the preparation of adequate amounts of certain khat components for the
pharmacological studies being carried out under the auspices of the
World Health Organization.
REFERENCES
Baxter, R.L., Crombie, L., Simmonds, D.J., and Whiting, D.A.
Structures of cathedulin-2 and cathedulin-8, new sesquiterpene
alkaloids from Catha edulis. Chem Comm, 465-466, 1976.
Crombie, L., Crombie, W.M.L., Whiting, D.A., Braenden, O.J., and
Szendrei, K. Structures of cathedulin alkaloids from Catha edulis
(khat) of Kenyan and Ethiopian origin. Chem Comm, 107-108, 1978.
Gabriel, S. Wandlungen der aminoketone. Ber dtsch chem Ges
41:1127-1156, 1908.
Schorno, X., and Steinegger, E. The phenylalkylamines of Catha edulis
Forsk: The absolute configuration of cathinone. United Nations
document MNAR/7/1978.
The botany and chemistry of khat. Report of an expert group.
United Nations document MNAR/3/1979.
AUTHOR
Olav J. Braenden, Cand.pharm., Ph.D.,
Director, United Nations Narcotics Laboratory
Palais des Nations
CH-1211 Geneva 10, Switzerland
321
Studies on the Central Effects of
(-)Cathinone
Knoll, J.
(-)Cathinone and (+) cathine are constituents of khat
which were isolated from freeze-dried khat samples.(-)
Cathinone is thought to be the major psychostimulant component in khat which might be of high importance in producing the medical effects of the chewing of khat leaves. For this reason the effect of (-)cathinone in comparison to (+) cathine and amphetamine was studied in a
battery of in vivo tests:motility (mouse), oxygen consumption (rat), food intake (rat), one way avoidance
(rat), writhing (mouse), hot plate (rat), nictitating
membrane (cat) and flexor reflex (rat); and on isolated
organs: the cat nictitating membrane, the rabbit central
ear artery, rabbit pulmonal artery, guinea pig vas deferens and rat vas deferens.
(-)Cathinone was as potent as amphetamine in increasing locomotor activity in mice, it increased oxygen
consumption like amphetamine, was more potent than amphetamine in inhibiting food intake in rats at intraventricular administration. All these effects could be antagonized by pretreatment of of -methylparatyrosine.
In the hot plate test, which is used for studying
analgesics, (-)cathinone, (+)cathinone and cathine prolonged, like amphetamine, the reaction time in high doses. These effects were antagonized by -methylparatyrosine and are apparently the consequence of overexcitataion. None of these compounds is real analgesic. Analgesics act in lower doses on the writhing test than in
the hot plate. Both isomers of cathinone acted only in
very high doses in the writhing test, showing that these
compounds are not real analgesics.
The flexor reflex of the hind limb of the spinal rat,
elicited by hind paw stimulation, is controlled by noradrenergic transmission and is regarded as a good model
322
for studying the action of drugs on central noradrenergic neurones. Amphetamine (1 mg/kg,i.v.)stimulates the
responses. Both isomers of cathinone were found to be as
potent as amphetamine in this test; cathine proved to be
less potent than cathinone.
Amphetamine (0,25-1 mg/kg, i.v.) elicits a long-lasting contraction of the nictitating membrane in the cat,
and tolerance to the effect of a single dose develops.
(-)Cathinone acts like amphetamine and cross tolerance
between these amines was observed.
In isolated organs with noradrenergic neurotransmission, (-)cathinone facilitated neuromuscular transmission like amphetamine and desmethylimipramine inhibited
these effects. On isolated rat vas deferens preparations
(-) cathinone, (+) cathine, amphetamine and phenylethylamine (PEA) were found to be about equally potent in
the facilitation of field stimulated contractions. On
the guinea pig vas deferens preparation PEA and amphetamine were found to be more potent than (-)cathinone
and (+)cathine on the perfused rabbit ear artery. (-)
Cathinone was more potent than amphetamine on the rabbit pulmonal artery strip, amphetamine and (-) cathinone
were found to be usually equally active, no tolerance
to the effects of amphetamine, (+) cathine and (-) cathinone were found on the vas deferens preparations and on
the isolated arteries. On the other hand, tolerance develped to the effect of amphetamine, (+)cathine and (-)
cathinone on the isolated medial smooth muscle of the
cat nictitating membrane and cross-tolerance between
these amines was observed. No tolerance to the effects
of PEA was observed on this organ, but on a preparation
which developed tolerance to amphetamine or to (-)cathinone, also PEA lost completely its effect.
According to the in vivo and in vitro experiments
the main acute effect of (-)cathinone and (+)cathine
is the facilitation of noradrenergic transmission. Like
amphetamine, they are taken up by the noradrenergic nerve terminals and, with high probability, release the
transmitter from extravesicular pools.
AUTHOR
Joseph Knoll, M.D.
Department of Pharmacology
Semmelweis University of Medicine
Budapest, Hungary
323
Behavioral Studies of Cathinone in Monkeys
and Rats
Schuster, C. R; Johanson, C. E.
As has been pointed out by previous speakers, it is now apparent
that the principal pharmacologically active agent in the Khat
plant is l-cathinone.
For the last year our laboratory has been investigating the
behavioral actions of dl-and l-cathinone. Because cathinone is
structurally and pharmacologically similar to d-amphetamine,
these studies have attempted to compare the effects of cathinone
to those of d-amphetamine.
To date, three behavioral procedures have been used. These are:
1) food-reinforced responding in rhesus monkeys, 2) drug selfadministration in monkeys 3) studies of tolerance and crosstolerance to the anorexic effects of cathinone and d-amphetamine
in rats.
I.
FOOD REINFORCED RESPONDING IN RHESUS MONKEYS
Three rhesus monkeys were trained to lever press under a multiple
fixed-interval (FI) 5 min. fixed-ratio (FR) 30 schedule of food
Specifically, in the presence of a red light animals
delivery.
were reinforced for the first response occuring after five
minutes had elapsed from the preceding food delivery. Following
completion of the FI component, the stimulus lights turned green
and the animals were reinforced with food after completion of
30 lever presses. The FI and FR components alternated throughout a two hour daily session.
After behavior stabilized under the multiple schedule, dose-response curves were obtained for d-amphetamine and dl-and l-cathinone. Doses of drugs were given-intravenously 5 minutes before
selected daily drugs.
All three drugs produced a dose-related decrease in responding
under both the FI and FR conditions. d1-and 1-Cathinone appeared
to be approximately equal in potency whereas d-amphetamine was
twice as potent.
II.
DRUG SELF-ADMINISTRATION STUDIES
Three rhesus monkeys surgically prepared with indwelling venous
catheters served as subjects. All animals had been previously
trained to lever press under an FR 10 schedule of cocaine delivery
during a 3-hr daily session. Various doses of d-amphetamine, dl324
and 1-cathinone as well as saline were substituted for cocaine
for 5 consecutive sessions. All drugs maintained responding
at levels significantly above those seen when saline was substituted. Both dl-and l-cathinone maintained rates of responding
significantly higher than those generated by cocaine and d-amphetamine.
Further, l-cathinone appeared to be more potent than
either dl-cathinone or d-amphetamine.
III.
TOLERANCE STUDIES
In two separate studies, cross-tolerance between d-amphetamine
and dl-cathinone was studied. In these studies, the anorexic
effects of the two drugs were studied in rats by determining
their efficacy in decreasing the animal's intake of sweetened
condensed milk made available for 15 minutes on a daily basis.
Both d-amphetamine and dl-cathinone produced a dose-related
decrement in milk intake In both studies dose-response curves
for both drugs were obtained before, during and after a period of
repeated administration of drug. In the first study, d-amphetamine (2.0 mg/kg/) was given daily. In the second study, dlcathinone was given daily. In both studies, tolerance was demonstrated by a diminution in the effect of the chronically
administered drug and as well by a shift in the dose-response
curve to the right. In the case of d-amphetamine, this shift
was approximately two-fold whereas with dl-cathinone, a much
larger shift was obtained (8-12 fold). In both studies crosstolerance between dl-cathinone and d-amphetamine was observed.
In summary, dl-cathinone shares with d-amphetamine the ability
to: 1) disrupt food reinforced lever pressing behavior in monkeys;
2) serve as a positive reinforcer in drug self-administration
experiments; 3) produce a decrement in milk intake in rats; and
4) produce tolerance to its anorexic effects. In addition, there
is cross-tolerance between cathinone and amphetamine.
AUTHORS
C. R. Schuster, Ph.D.
C. E. Johanson, Ph.D.
Department of Psychiatry
The University of Chicago
950 East 59th Street
Chicago, Illinois 60637
325
Studies on Cathinones:
Cardiovascular and Behavioral
Effects in Rats and SelfAdministration Experiment in
Rhesus Monkeys
Yanagita, T.
Three types of phannaco dynamic studies were conducted on
cathinones.
1. CARDIOVASCULAR EFFECTS IN RATS AND ISOLATED ATRIA OF GUINEA
PIGS
In intact rats, both l- and dl-cathinone produced exophthalmos,
piloerection, and sniffing at doses of 4 w/kg, S.C. or higher.
d-Amphetamine produced such effects at 1 mg/kg, S.C.
In anesthetized rats, both blood pressure and heart rate were
increased. At a single dose of 1 mg/kg, i.v., the average
pressure increases were: d-norpseudoephedrine, 24.0±5.8; lcathinone, 15.7±1.4; dl-cathinone, 11.4±4.1; dl-ephedrine, 24.8±
3.7; and d-amphetamine, 21.5±1.8 mmHg; and the heart rate
increases were: 49.5±5.1, 50.0±10.1, 41.2±10.1, 55.7±6.4 and 58.7
±8.7 beats/min respectively.
In isolated guinea pig atria, at a bath concentration of 10-5g/ml,
positive ionotropic and chronotropic effects were observed with
the cathinones. The average percent increases of the ionotropic
effects were: l-cathinone, 83.3±4.8; d-norpseudoephedrine, 52.8±
10.7; dl-cathizone, 42.4±7.6; dl-ephedrine, 36.7±9.6; and damphetamine, 50.5±9.1
2. BEHAVIORAL EFFECTS
In a spontaneous motor activity test in rats, dl-cathinone
increased the activity level markedly at a dose range of 0.25 to
4.0 mg/kg, S.C. The potency of the effect was almost comparable
to that of d-amphetamine. dl-Ephedrine did not produce such
marked effects at doses up to 16.0 mg/kg, S.C.
The operant behavioral effect of dl-cathinone was tested under a
DRL 20 sec schedule for food reinforcement in rats. Like damphetamine, this drug increased the response rate, decreased the
326
reinforcement rate and markedly shortened the interresponse
time-intervals at doses higher than 0.5 mg/kg, S.C. dlEphedrine had no such effect, excepting decrement of the
reinforcement rate which was noted at 16.0 mg/kg, S.C.
3. INTRAVENOUS CONTINUOUS SELF-ADMINISTRATION EXPERIMENT IN
RHESUS MONKEYS
Two monkeys initiated intravenous self-administration of
l-cathinone at a unit dose of 0.06 or 0.25 mg/kg/injection.
The self-administration pattern was of the spree type, like
cocaine, in which the monkeys took the drug frequently day and
night, stopping upon becoming exhausted. Such sprees continued
from several hours to 2-3 days, and during these periods the
monkeys manifested extreme restlessness, tremor, mydriasis, and
anorexia. They relapsed after a period of rest of within 24
hours. This alternation of spree and rest was repeated, but
the experiment had to be terminated within a month due to
general weakening in one monkey and edema in the other. The
duration of each spree and the average hourly doses selfadministered during each spree were as follows: monkey No. 1006:
1st spree 9 hrs, 0.8 mg/kg (0.06 mg/kg/inj); 2nd spree 32 hrs,
1.1 (0.06); 3rd spree 6 hrs, 1.0 (0.06); 4th spree 53 hrs, 1.9
(0.25); 5th spree 59 hrs, 1.4 (0.25); monkey No. 607: 1st spree
6 hrs, 1.6 mg/kg (0.25 mg/kg/inj); 3rd spree 57 hrs, 3.2 (0.25);
5th spree 11 hrs, 5.5 (0.25); 7th spree 40 hrs, 4.8 (0.25).
AUTHOR
Tomoji Yanagita, M.D.
Preclinical Research Laboratories
Central Institute for Experimental Animals
1433 Nogawa, Kawasaki, Japan 213
327
Discriminative Stimulus and
Neurochemical Mechanism of
Cathinone: A Preliminary Study
Rosecrans, J. A.; Campbell, O. L.; Dewey, W. L.;
Harris, L. S.
The major emphasis of our research conducted with cathinone involved approaches attempting to elucidate its mechanism of action.
The strategies employed involved two major studies, one
in mice and a second in rats. In the first study, l - and dcathinone were observed to increase spontaneous activity in mice
in doses ranging from 4-16 mg/kg (I.P.). The l-isomer appeared
more potent than the d-isomer in these activity procedures, and
its effects were studied further on brain catecholamine turnover
in a different group of mice. In addition, d-amphetamine's
neurochemical effects were also evaluated using a similar dose
range. l-Cathinone was observed to have little effect on norepinephrine (NE) turnover but did significantly increase dopamine (DA) turnover at 8 mg/kg (+32%). In contrast, d-amphetamine reduced NE turnover at similar doses but also. increased DA
turnover (44%) at 4 mg/kg. At higher doses, dl-cathinone (16
mg/kg) had little effect on DA turnover while d-amphetamine produced a 42% reduction. These-studies indicated that dl-cathinone produced CNS stimulant effects and did resemble d-amphetamine by increasing DA turnover at 8 mg/kg. However, l-cathinone
in the dose range studied did not appear to be as potent as damphetamine in altering catecholamine turnover.
In the second series of experiments, dl-cathinone was studied in
rats using a two-lever drug discrimination procedure.
In this
paradigm, subjects were trained to discriminate between the effects of d-amphetamine (0.9 mg/kg, I.P.) and saline in order to
In the specific experiments conobtain a Food reinforcement.
ducted, the discriminative stimulus effects of d-amphetamine
were compared to those produced by dl-cathinone. d-Amphetamine
trained rats responded as if they were given d-amphetamine when
various doses of dl-cathinone were administered (I.P.). This
generalization was dose related and dl-cathinone (ED50=0.09
mg/kg) was observed to be twice as potent as d-amphetamine (ED50=
0.19 mg/kg). Thus, dl-cathinone produced stimulus effects similar to d-amphetamine. We next set out to determine whether the
mechanism of action of both drugs was similar. The first approach used was to determine whether the DA antagonist
328
haloperidol would be effective in reducing both stimuli. Interestingly, 0.1 mg/kg of haloperidol increased d-amphetamine's
ED50 value from 0.190 (0.11-0.33) to 0.737 (0.53-l-04) mg/kg but
had no effect on the generalization of the d-amphetamine stimulus to dl-cathinone. Thus, while dl -cathinone and d-amphetamine
were indistinguishable behaviorally, their mechanism of action
appeared quite different. We studied several other antagonists
including the
-adrenergic antagonist, phenoxybenzamine, and the
serotonin antagonists, BC105/B, but none of the drugs studied
were able to antagonize either stimulus effect.
dl-Cathinone appears to be a very interesting stimulant compound.
It produces behavioral effects similar to d-amphetamine, but may
not be acting upon DA systems as does d-amphetamine. This finding, while academically important, has-some practical significance as well. The studies presented by Schuster (this Symposium) clearly indicated that dl-cathinone is self-administered
at lower doses than d-amphetamine, but was less effective than
d-amphetamine in disrupting the operant behavior of primates.
One hypothesis generated in this laboratory over the last couple
of years suggests that behavioral disruption produced by drugs
such as d-amphetamine and morphine is related to their agonist
effect on DA neurons. Taking this into consideration, the data
presented here concerning dl-cathinone's would predict that this
drug would be less able to disrupt behavior than d-amphetamine
as was demonstrated. Thus, dl-cathinone appears less disruptive
to behavior, which might explain why this drug was more potent
than d-amphetamine in our discrimination study and in self-administration research. From this, one might also predict that
individuals using this drug would be less disrupted and better
able to function under its effects. In addition, this drug
might produce fewer long term d-amphetamine-like behavioral
problems because of its apparent lack of a DA agonist action.
However, this is not to say that cathinone could not produce
psychological problems following chronic administration.
AUTHORS
J. A. Rosecrans
0. L. Campbell
W. L. Dewey
L. S. Harris
Department of Pharmacology
Medical College of Virginia
Richmond, VA 23298
329
Progress Reports
Annual Report: Dependence
Studies of New Compounds in the
Rhesus Monkey (1979)
Aceto, M. D.; Harris, L.S.; Dewey, W. L.; May, E. L.
All the test drugs were supplied by Dr. Arthur Jacobson, Medicinal Chemistry Section, NIAMDD, under the auspices of the Committee on Problems of Drug Dependence, Inc. Morphine was supplied
by Dr. Robert Willette, NIDA.
The chemical structures of the
test compounds excluding (+)-naloxone and yohimbine were unknown to us at the time that they were tested.
Three mouse tests were used in our laboratory at the Medical
College of Virginia to provide a preliminary estimate of the potency and profile of activity of each test compound. The tests
were the tail-flick agonist (TF) and the morphine antagonist
tests (TF vs M) and the phenylquinone test (PPQ)(Dewey et al,
1970; Dewey and Harris, 1971). Reference standard data for
these tests are shown in table 1.
In addition, Dr. Jacobson supplemented these data with estimated starting doses which were
based on results obtained from the mouse hot plate (HP)(Eddy and
Leimbach, 1953; Jacobson and May, 1965; Atwell and Jacobson,
1965) and Nilsen (N)(Perrine et al, 1972) tests from his laboratory. Reference data for these tests are shown in table 2.
These studies were supported by a contract (#271-77-3404) from
the National Institute on Drug Abuse, Dr. Heinz Sorer, Contract
Officer. The authors gratefully acknowledge the technical
assistance of F. Tom Grove and R. F. Jones.
330
For the most part, the procedures described by Seevers and his
colleagues (1936, 1963) and Deneau (1956) regarding the facilities and training of the monkeys were used and a brief description follows. The monkeys were injected with 3 mg/kg/sc of
morphine sulfate every 6 hours for at least 90 days before being used. This dose schedule was reported by Seevers and Deneau
(1963) to produce maximal physical dependence. Modified procedures for the precipitated withdrawal test (PPt-Withdrawal) and
single dose suppression test (SDS) were reported by Aceto and coThe PPt-Withdrawal test was iniworkers (1974, 1977 and 1978).
tiated by the injection of a test drug 2 1/2 hours after an injection of morphine and the animals were observed for signs of
withdrawal.
The SDS test was started approximately 15 hours
after the last dose of morphine at which time the animals were
showing withdrawal signs. The test compound was injected and
the animals were observed for the suppression of abstinence
signs. The onset and duration of action of the test drug were
noted. In both tests, a vehicle control and an appropriate positive control (naloxone 0.05 mg/kg or morphine sulfate 3.0 mg/kg)
along with 3 different treatments (doses) of a test compoundwere
randomly allocated to the 5 monkeys of a group. Occasionally 4
monkeys comprised a group and 2 doses of test compound were studied. Usually, 3 or 4 groups per compound were used. All drugs
were given subcutaneously in a volume, of 1 ml/kg and the vehicle
used is indicated for each compound. The observer was "blind"
with regard to the treatment given. A minimum 2-week washout
In the
and recuperation period between tests was allowed.
primary physical dependence test, the animals of a group received the drug every 6 hours for 30-45 days. They were placed in
abrupt withdrawal and challenged with naloxone periodically, and
were observed for signs of physical dependence.
Table 1
Comparative Data - ED50 Mg/Kg/Sc (95% C.L.) of Selected
Standards in 3 Mouse Agonist-Antagonist Tests
Drug
Tail-Flick
Test
Pentazocine 15% at 10.0
l.Oa
Phenylquinone
Test
1.65(1.0-2.5)
0.03(0.12-.78)
0.011(0.0046-0.3)
Cyclazocine
17%
Nalorphine
.HCl
None at 10.0 2.6(0.69-9.75)
0.6(0.25-1.44)
Naloxone
.HCl
None at 10.0 0.031(.0100.93)
NO Activity
Naltrexone
None at 10.0 0.007(0.0020.02)
No Activity
Morphine
Sulfate
5.8(5.7-5.9)
0.23(0.20-0.25)
a
at
Tail Flick Antaqonism Test
18(12.4-26)
----
Mice were ataxic at 3.0 and 10.0 mg/kg but no further increase
in reaction time was seen.
331
314-300 0 -80 - 23
Table 2
Comparative Data (ED50s Mg/Kg) (95% S.E.) from the Hot Plate
and Nilsen Test
Compound
Morphine Sulfate
Codeine Phosphate
Levorphanol
Tartrate
Meperidine .HCl
(-)-Metazocine
.HBr
Hot Plate Test
Nilsen Test
Subcutaneous
Oral
1.0(0.7-1.4)
6.3(4.7-8.3)
Subcutaneous
Oral
0.7(0.5-1.1)
8.3(6.0-11.4)
6.8(4.5-10.2)
13.5(9.7-18.7)
7.4(4.9-11.0)
14.7(9.2-23.3)
0.2(0.1-0.3)
0.2(0.16-0.3)
2.5(1.7-3.7)
4.6(3.3-6.4)
3.5(2.3-5.4)
0.6(0.5-0.9)
10.6(8.0-14.1)
0.5(0.3-0.7)
26.0(21.0-33.0)
Dihydromorphinone
.HCl
0.13(0.11-0.16)
0.9(0.7-1.2)
Nalorphine .HCl
9.9(5.7-17.1)
Cyclazocine
2.0(1.4-2.8)
0.1(0.07-0.16)
Pentazocine
9.0(6.5-12.4)
6.5(4.4-8.8)
Chlorpromazine .HCl
1.1(0.9-1.5)
3.2(2.4-4.2)
Naloxone .HCl
No Dose Response
Naltrexone .HCl
No Dose Response
0.2(0.15-0.3)
1.5(1.5-2.1)
23.0(16.2-32.7)
Phenobarbital, Amobarbital, Valium, Meprobamate and Mescaline
are inactive on the hot plate test.
332
MCV 4073-NIH 8635, 8714. 9230-UM 884, 899. 4-(p-Chloro-phenyl)-4hydroxy-N,N-dimethyl-alpha,
alpha-diphenyl-l-piperidinebutyramide hydrochloride (Loperamide)
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1) TF-28% at 10.0 at 20 min.;
92% at 10.0 with 1 hr premedication
2) TF vs M -Inactive at 1.0,
3.0, 10.0 and 30.0
3) PPQ-0.3 (0.1-0.7)
4) HP-2.6 (2.1-3.2)
MONKEY DATA
(SDS)
1
10.0
# Animals
Doses (mg/kg/sc)
3
5.0
3
2.5
2
1.25
Vehicle - 50% propylene glycol - v/v.
Results: MCV 4073 substitutes completely for morphine. The
drug appears to be as potent as morphine with a similar onset
and duration of action.
5-(3-Hydroxyphenyl)-3-azabicyclo
MCV 4075-NIH 9234.
nonane hydrobromide
(3.3.1)
MOUSE DATA-ED50 (95% C.L.)mg/kg/sc)
1) TF -Inactive at 1.0, 3.0
and 10.0
2) TF vs M -Inactive at 1.0,
3.0, 10.0; 28% at 30.0
3) PPQ-7.7 (0.5-11.7)
4) HP-15.8 (11.2-22.4)
MONKEY DATA
# Animals
(PPt Withdrawal) Doses(mg/kg/sc)
1
20.0
3
10.0
3
5.0
2
2.0
Vehicle H2O.
At 10.0 mg/kg the drug precipitated withdrawal signs. The onset
of action was rapid (< 30 min) and the duration of effect was at
least 2 l/2 hours. However, at the highest dose severe tremors
and convulsions were seen which were terminated by an injection
of 60 mg of pentobarbital. The main sign observed at the 2 lower doses was drowsiness. Drug supply was exhausted.
333
MCV 4084-NIH 9261.
7-benzomorphan
9 -Ethyl-2-hexyl-2'-hydroxy-5-methyl-6-
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1) TF-18.7 (9.5-37.0)
2) TF vs M -Inactive at 1.0,
3.0, 10.0 and 30.0
3) PPQ-5.7 (3.1-10.4)
4) HP-6.2 (4.5-8.5)
MONKEY DATA
(Primary Physical Dependence)
Five non-dependent monkeys were injected every 6 hours with MCV
The drug was dissolved in lactic acid and H20. On the
4084.
first day, the animals received 3.0 mg/kg/sc and by day 12 the
dose had been raised to 14.0.
The study terminated at this time
because severe lesions developed at the sites of injections. A
wide variety of signs designated as restlessness, scratching,
ataxia, salivation, retching, vomiting and tremors were noted.
On 2 occasions, convulsions were also seen. When the animals were
placed in abrupt withdrawal, signs designated as avoids contact,
vocalizes, restless, tremors, retching, and vocalizes when
abdomen palpated were recorded from 12-16 hours after the last
dose. A naloxone challenge of 0.5 mg/kg/sc was given and withdrawal seemed to be exacerbated. MCV 4084 appears to produce
morphine-like physical dependence.
MCV 4106-NIH 9352.
8 -Methyldihydrocodeinone
hydrochloride
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1) TF-5.9 (3.3-10.5)
2) TF vs M -Inactive at 10.0
and 30.0
3) PPQ-0.5 (0.2-1.3)
4) HP-l.2 (0.8-1.7)
MONKEY DATA
(SDS)
# Animals
Doses(mg/kg/sc)
3
2.0
3
1.0
3
Vehicle H2O.
0.5
Results: MCV 4106 substituted completely for morphine. At the
lowest dose the duration of action was approximately one hour.
At 1.0 mg/kg the duration of action was approximately 2 hrs and
at the highest dose the effect was still evident
drug. The drug appears to be as potent as morphine.
334
MCV 4107-NIH 9354.
-(-)-N-(2-Cyanoethyl)-3-hydroxymorphinan
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1) TF-5.9 (3.3-10.5)
2) TF vs M -Inactive at 10.0
and 30.0
3) PPQ-0.5 (0.2-1.3)
4) HP-0.02 (0.02-0.34)
5) N-0.05 (0.03-0.07)
(Oral=3.5 [2.3-5.3])
MONKEY DATA
(Primary Physical Dependence)
Vehicle H20
Five non-dependent monkeys were given MCV 4107 every 6 hours.
The animals were observed for overt changes and the results were
recorded as designated below.
At 0.05 mg/kg, the lowest dose,
severe drug-induced effects were noted. The animals appeared
drowsy, were frequently found lying on their sides or abdomens,
showed body sag, ataxia, wet dog shakes and tremors, moved about
slowly and had eyelid ptosis. When the dose was raised to 0.1
mg/kg the animals were nearly incapacitated and the dose was
dropped to 0.05 mg/kg each time. The drug had a prompt onset
and a short duration (2 hours) of action.
Little, if any, tolerance developed.
The animals were placed in abrupt withdrawal
on day 33 and at the end of day 44 of the study restlessness,
yawning, scratching and wet dogs were seen.
Signs such as
retching, vomiting, rigid abdomen and vocalization when abdomen
was palpated were not observed. The drug does not produce
typical morphine-like physical dependence.
MCV 4120-NIH 9264.
carbonate
1,3-Dimethyl-4-phenyl-4-piperidylethyl
MOUSE DATA-ED50 (95% C.L.) (mg/kg/sc)
1) TF-Supply exhausted
2) TF vs M 3) PPQ 4) HP-11.9 (8.7-16.4)
335
MONKEY DATA
(SDS)
# Animals
Doses(mg/kg/sc)
1
2
24.0' 16.0
2
8.0
1
4.0
Vehicle H20
At the 2 higher doses, MCV 4120 appeared to substitute completely for morphine. At 24.0 mg/kg the onset of action was rapid
(less than 30 min) and the duration of action was under 150 min.
Drug supply was exhausted. More studies are recommended.
MCV 4121-NIH 9258.
benzomorphan
2,9-alpha-Diethyl-2'-hydroxy-5-methyl-6,7-
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1) TF -Inactive at 1.0, 10.0
and 30.0
2) TF vs M -16.6 (12.2-22.6)
3) PPQ-22.9 (12.1-43.6)
4) HP-21.3 (13.4-33.9)
MONKEY DATA
(PPt-Withdrawal)
# Animals
Doses(mg/kg/sc)
1
16.0
2
8.0
2
4.0
1
2.0
Vehicle H20
MCV 4121 precipitated withdrawal signs in the dose range tested.
At the highest dose, (3 mg/kg) morphine was given to terminate
severe withdrawal. Ataxia was noted in the animal receiving
16.0 mg/kg and in 1 of 2 monkeys receiving 4.0 mg/kg. Drowsiness was also observed in most of the animals. Drug supply was
exhausted.
MCV 4130-NIH 9466-UM 1150. (-)-17-(Cyclopropylmethyl)-3-hydroxymorphinan-6-one methanesulfonate
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1) TF- Inactive up to 30.0
2) TF vs M-O.4 (0.2-0.8)
3) PPQ-0.3 (0.1-0.6)
4) HP-17.2 (13.3-22.2)
MONKEY DATA
(PPt-Withdrawal)
# Animals
Doses(mg/kg/sc)
Vehicle H20
336
2
16.0
3
8.0
2
4.0
1
2.0
MCV 4130 precipitated withdrawal. The effects were dose-related.
One monkey receiving the highest dose was found dead on the following day. The drug is approximately 1/80 as active as naloxone.
MCV 4131-NIH 9468. 4-(Methyl-n-butylamino)-4-(m-hydroxyphenyl)cyclohexanone ethylene ketal hydrochloride
MOUSE DATA-ED50
(mg/kg/sc)
1)
TF-34.6
(95%
C.L.)-
(12.7-93.9)
2) TF vs M-6.3 (1.5-26.6)
MONKEY DATA
(SDS)
3)
PPQ-8.5
4)
HP-5.5
Doses(mg/kg/sc)
Doses(mg/kg/sc)
6
8.0
6
4.0
(4.8-15.0)
(3.8-7.8)
6
2.0
Vehicle H 2 0
This compound substituted partially and briefly for morphine at
4.0 mg/kg. One monkey given the highest dose was given morphine
to terminate retching and vomiting. Possibly, the drug has a
biphasic action. More studies are recomended. Partial substitution does not necessarily imply that the drug has morphinelike
properties.
MCV 4133-NIH 9470. (±)-trans-N-Methyl-N-(2-pyrrolidinyl)
hexyl)-2-(3,4-dichlorophenyl) acetamide HCl
cyclo-
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1) TF-10.3 (2.7-40.2)
2) TF vs M - Inactive at 30.0
3) PPQ-0.8 (0.3-1.9)
4) HP-8.3 (5.7-12.1)
MONKEY DATA
(Primary Physical Dependence)
Five drug-naive monkeys were given MCV 4133 SC dissolved in H20
The starting dose was 0.5 mg/kg. At doses up to
every 6 hours.
6.0 mg/kg, which was reached by day 10, the principal signs noted in all animals were drowsiness and eyelid ptosis. When the
dose was increased to 10.0 mg/kg the animals slowed considerably
and showed body sag and salivation. They appeared ataxic and
showed tremors as the dose was raised. Because of the severe
side effects, the dose was lowered first to 7.0 and then 6.0 mg/kg
337
from days 16-29. Body sag, salivation, tremors eyelid ptosis
and drowsiness were seen regularly when the dose was again in
creased to 8.0 mg/kg from days 30-37. The signs designated
drowsiness, eyelid ptosis, tremors, body sag and ataxia were
seen consistently throughout the remainder of the study in which
the dose was gradually raised to 16.0 mg/kg by day 48. At 15 and
30 days, the animals were challenged with naloxone (0.05 mg/kg/sc)
but few signs were seen. When the animals were placed in abrupt
withdrawal at the end of the study, some restlessness, wet dogs,
fighting and coughing were seen.
Fifteen days after abrupt withdrawal the animals were challenged with naloxone (5.0 mg/kg) and
some restlessness, yawning, wet dogs and drowsiness were seen.
Weight changes throughout the study were not remarkable. The
onset action was rapid and the duration of action was from 2-4
hours. The drug does not produce a significant degree of morphinelike physical dependence. Little tolerance developed.
MCV 4137-NIH 9484.
2-(2-Cyanoethyl)-9-alpha-ethyl-2'-hydroxy-5methyl-6,7-benzomorphan
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1) TF-0.8 (0.4-1.5)
2) TF vs M - Inactive at 1.0,
3.0 and 30.0
3) PPQ-0.09 (0.04-0.2)
4) HP-O.21 (0.16-0.30)
MONKEY DATA
(SDS)
# Animals
Doses(mg/kg/sc)
2
2.4
3
1.2
4
0.6
2
0.5
1
0.3
Vehicle - Carboxymethylcellulose suspension
MCV 4137 substituted partially for morphine beginning at 1.2
mg/kg. The signs of retching, vomiting, vocalizes when abdomen
palpated, rigid abdomen and pacing were suppressed. Recommended
that additional studies be done at higher doses.
MCV 4140-NIH 9506-UM 1155.
2-Allyl-3a- m-hydroxyphenyl-2,3,3a,4,
7,7a-hexahydro-cis-isoindole
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1) TF - Inactive at 1.0, 3.0
and 10.0
2) TF vs M-O.55 (0.09-3.4)
3) PPQ-30.7 (8.7-103.0)
4) HP-Inactive
5) N-Inactive
338
# Animals
Doses(mg/kg/sc)
MONKEY DATA
(SDS)
Vehicle
-
3
8.0
3
4.0
3
2.0
carboxymethylcellulose
MCV 4140 did not substitute for morphine in the dose range tested. The drug may have exacerbated withdrawal.
MCV 4142-NIH 9508.
N-Cyclopropylmethyl-8-beta-ethylnordihydrocodeinone hydrochloride
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1)
TF- Inactive at 1.0, 3.0
and 10.0
2) TF vs M-0.2 (0.03-l.5)
3) PPQ-18.0 (7.5-43.6)
4) HP-16.8 (1.05-26.9)
5) N-50% at 50.0 and 100.0
MONKEY DATA
(PPt-Withdrawal)
# Animals
Doses(mg/kg/sc)
2
24.0
2
12.0
2
6.0
Vehicle H20
MCV 4142 precipitated withdrawal at all the doses tested. One
monkey receiving the highest dose and another receiving the intermediate dose still showed withdrawal signs 7 hours later
even though morphine had been given to them. On the second day
in another group of monkeys, all those receiving MCV 4142 were
given morphine after 20 minutes to terminate severe withdrawal.
The drug appeared to have a long duration of action.
MCV 4143-NIH 9509.
N-Cyclobutylmethyl-3-Hydroxy-8-beta-methyl6-oxomorphinan tartrate
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1) TF-24.0 (4.7-123.8)
2) TF vs M-O.4 (0.06-2.3)
3) PPQ-0.01 (0.004-0.05)
4) HP-3.05 (2-1-4.4)
MONKEY DATA
(SDS)
# Animals
Doses (mg/kg/sc)
339
3
12.0
3
6.0
3
3.0
Vehicle H20
MCV 4143 substituted partially for morphine. Salivation, jaw
sag, slowing and drowsiness were the main side effects noted at
Partial substitution does not necessarall three doses tested.
ily imply morphine-like properties.
MCV 4144-NIH 9512-UM 1158.
cinnamic acid (Baclofen)
beta-(Aminomethyl)-p -chlorohydro-
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1)
TF-Inactive
and 30.0
at 1.0, 10.0
2) TF vs M-0.06 (0.02-0.17)
3) PPQ-1.2 (0.4-3.4)
4) HP-2.1 (1.5-2.7)
5) N-6/10 at 40.0 a toxic dose
MONKEY DATA
(SDS)
# Animals
Doses(mg/kg/sc)
1
16.0
2
12.0
3
8.0
3
4.0
Vehicle; Dil HCl + H20
MCV 4144 did not substitute for morphine. At the highest dose,
a convulsion was noted which was terminated with 30 mg of pentoThe drug appeared to suppress the withdrawal signs
barbital.
retching and vomiting, Ataxia and uncoordination were noted.
One monkey receiving 12 mg/kg fell asleep.
MCV 4146-NIH 9541-UM 1170. 4-beta-( m-Methoxyphenyl)-1,3dimethyl-4-alpha-piperidinol propionate hydrochloride
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1) TF-Inactive at 1.0 and 10.0
2) TF vs M-Inactive at 1.0,
3.0 and 10.0
3) PPQ-18.7 (7.8-44.5)
4) HP-21.8 (14.6-3-2.7)
MONKEY DATA
(SDS)
# Animals
Doses(mg/kg/sc)
3
16.0
3
8.0
3
4.0; Vehicle H 2 0
At the highest dose tested, MCV 4146 appeared to substitute
completely for morphine. Additional studies are recommended.
340
l-(4-Methylphenyl)-3-azabicyclo-[3.1.0]
MCV 4147-NIH 9542.
hexane hydrochloride
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1) TF-30.9 (13.2-72.2)
2) TF vs M-Inactive at 10.0,
30.0 and 80.0
3) PPQ-4.8 (1.6-13.8)
4) HP-8/10 at 32.0; O/8 at
24.0, 16.0 and 8.0. Toxic
MONKEY DATA
(SDS)
# Animals
Doses(mg/kg/sc)
4
24.0
4
12.0
4
6.0;
Vehicle H 2 0
The drug substituted partially and very briefly for morphine
soon after it was injected. Tremors and myoclonic spasms
were prevalent especially at the 2 higher doses.
In addition,
Partial
salivation was seen in 2 animals at the highest dose.
substitution does not necessarily imply that a drug has morphinelike properties.
MCV 4152-NIH 9548.
(+)-Naloxone
hydrochloride
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1)
TF-
2) TF vs M-
MONKEY DATA
(PPt-Withdrawal)
3)
PPQ-
4)
HP-
5)
N-
# Animals
Dose(mg/kg/sc)
2
5.0
Vehicle H20
This stereoisomer did not precipitate withdrawal signs at 5.0
mg/kg/sc whereas (-)-naloxone was active at 0.05 mg/kg/sc.
341
MCV 4154-NIH 9551. 10-m-Hydroxyphenyl-2-phenethyl-cis-decahydroisoquinoline
MOUSE DATA-ED50 (95% C.L.)
(mg/kg/sc)
1) TF-12.1 (4.1-35.6)
2) TF vs M-Inactive at 1.0,
10.1 and 30.0
3) PPQ-0.2 (0.1-1.0)
4) HP-3.2 (2.5-4.2)
MONKEY DATA
(SDS)
Vehicle
# Animals
Doses (mg/kg/sc)
Carboxymethylcellulose
2
60.0
3
48.0
3
24.O
1
12.0
suspension
This drug did not substitute for morphine in the dose range
tested. Drug supply was exhausted.
MCV 4155-MCV 4183-NIH 9549-NIH 9571. 2-(2,6-Dichloro-anilino)2-imidazoline hydrochloride (Clonidine)
MOUSE DATA-ED50 (95% C.L.)
(mg/kg/sc)
1) TF-1.23 (O-23-6.65)
2) TF vs M-Inactive at 0.3,
1.0 and 30.0
3) PPO-0.005 (0.001-0.02)
4) HP-1.0 (0.7-1.5)
MONKEY DATA
A. (SDS)
# Animals
3
Doses (mg/kg/sc) 2.0
3
1.0
3
0.5
6
0.25
6
0.125
6
0.06
Vehicle H20
MCV 4155 substituted partially for morphine at all the doses
Drowsiness was a prominent sign noted at all doses.
tested.
Ataxia was seen at the highest dose and slowing was observed
at 1.0 mg/kg. Partial substitution does not necessarily imply
that the drug has morphine-like properties.
B. (Primary Physical Dependence), Vehicle H20
Five non-dependent monkeys were given MCV 4155 (MCV 4183) at the
doses indicated below SC every 6 hours. At the lowest dose (0.01
mg/kg), restlessness was noted. The dose was doubled on day 2
342
and restlessness was again noted. At 0.04 to 0.08 mg/kg, drowsiness, eyelid ptosis and slowing were seen. On day 8, the dose
was raised to 0.1 mg/kg and by day 15 the dose was 0.25 mg/kg.
The same signs noted for days 3-7 were consistently present
during this period. The animals were placed in abrupt withdrawal
on day 16 and fighting, yawning, and wet dogs developed.
Later,
a naloxone challenge (0.1 mg/kg/sc) was given and the same signs
noted during abrupt withdrawal were again observed. The dose
regimen was again increased to 3.0 mg/kg by day 30 and drowsiness, ptosis, and slowing were routinely observed, and occasionally fighting was seen. The animals were again placed in
abrupt withdrawal on day 31, but no remarkable signs were seen.
On days 32, 33 and 34 the dose was 6.6 mg/kg and drowsiness,
fighting and tremors were recorded. On day 36, the dose was
raised to 12.6 mg/kg and was raised to 14.4 the next day and
dropped to 12.6 on day 38 because, in addition to the effects
noted above, the animals stopped eating and were staring. The
animals were placed in abrupt withdrawal on day 39. The only
signs noted were residual drowsiness, fighting, avoiding contact, restlessness, wet dogs, scratching, and yawning. A naloxone challenge (1.0 mg/kg/sc) was without effect. Apparently,
a high degree of tolerance but a very low degree of physical
dependence developed with this agent. It does not appear to
produce a significant degree of morphine-like physical dependence.
MCV
4158-NIH
9580.
l-(l-Phenylcyclohexyl)piperidine
hydrochloride
MOUSE DATA-ED 5 0 (95% C.L.)(mg/kg/sc)
1) TF-Inactive at 1.0, 3.0 and
10.0
2) TF vs M-0,3 (0.1-1-O)
3) PPQ-1.4 (0.5-4.1)
4) HP-and N-(Not tested)
MONKEY DATA
(SDS)
# Animals
Doses (mg/kg/sc)
3
0.2
3
0.1
3 Vehicle H2O
0.05
This drug did not substitute for morphine. Severe dose-related
ataxia and some-body sag were seen. These effects lasted approximately 1 hour.
343
MCV 4161-NIH 9596. (-)-trans -5,6,6a,beta-7,8,9,1O,1Oa alphaoctahydro-l-acetoxy-6-beta-methyl-3-(5-phenyl-2-pentyloxy)phenanthridine hydrochloride
MOUSE DATA ED50 (95% C.L.)
(mg/kg/sc)
1) TF-1.7 (0.6-5.0)
2) TF vs M-Inactive at 3.0,
10.0 and 30.0
3) PPQ-0.1 (0.04-0.3)
4) HP-O.15 (0.13-0.19)
MONKEY DATA
(SDS)
# Animals
Doses (mg/kg/sc)
3
0.5
3
0.25
3
0.125
Vehicle Propylene Glycol-H20
This compound substituted partially for morphine at all doses
tested. The signs of drowsiness and eyelid ptosis were noted
in most of the animals, and slowing was seen in one monkey at
each dose.
Partial substitution does not necessarily imply
that the compound has morphine-like properties.
MCV 4163-NIH 9599.
N-n-Butylnormeperidine hydrochloride
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1) TF-27.5 (10.9-69.5)
2) TF vs M-Inactive at 3.0,
10.0 and 30.0
3) PPQ-7.5 (2.9-19.9)
4) HP-5.8 (4.2-8.0)
MONKEY DATA
(SDS)
# Animals
Doses (mg/kg/sc)
3
3.0
3
1.5
3
Vehicle H20
0.75
At the highest dose, MCV 4163 substituted completely and briefly
(2 hours) for morphine.
344
MCV 4164-NIH 9600.
N-sec-Butylnormeperidine
hydrochloride
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1) TF-41.6 (16.5-105.4)
2) TF vs M-Inactive at 3.0
and 10.0
3) PPQ-7.5 (4.8-11.8)
4) HP-9.0 (6.8-12.0)
MONKEY DATA
(SDS)
# Animals
Doses (mg/kg/sc)
3
10.0
3
5.0
3
2.5
Vehicle
H20
MCV 4164 substituted partially for morphine at all three doses.
At the highest dose, drowsiness, ataxia and salivation were notPartial substitution does not necessarily imply that the
ed.
drug has morphine-like properties.
MCV 4165-NIH 9579.
3-Deoxydihydromorphinone
hydrochloride
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1) TF-1.3 (0.46-3.9)
2) TF vs M -Inactive at 3.0,
10.0 and 30.0
3) PPQ-0.6 (0.2-1.8)
4) HP-0.6 (0.4-0.8)
5) N-O.9 (0.6-1.2)
MONKEY DATA
(SDS)
# Animals
Doses (mg/kg/sc)
3
3.0
3
1.5
3
0.75
Vehicle H 2 0
At the highest dose, MCV 4165 substituted completely and briefly
(first 90 minutes) for morphine.
345
MCV 4166-NIH 9607.
3,6-Dideoxydihydromorphine
hydrochloride
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1) TF-2.4 (0.9-6.6)
2) TF vs M -Inactive at 3.0,
10.0 and 30.0
3) PPQ-0.35 (0.14-0.85)
4) HP-O.37 (0.26-0.54)
5) N-l.3 (1.1-1.5)
MONKEY DATA
(SDS)
# Animals
Doses (mg/kg/sc)
2
1.2
3
0.6
3
0.3
1
0.15
Vehicle H20
At the highest dose, MCV 4166 substituted completely for morThe onset of action was prompt and the duration was apphine.
The duration of action of morphine is
proximately 1 l/2 hours.
> 3 hours.
MCV 4167-NIH 9612. (±)-9-Hydroxy-4,7-dimethyl-C-homobenzomorphan
hydrobromide
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1) TF-6.4 (3.9-10.5)
2) TF vs M-19.8 (10.5-37.2)
3) PPQ-0.5 (0.2-1.3)
4) HP-O.40 (0.25-0.62)
MONKEY DATA
(SDS)
Vehicle
# Animals
Doses (mg/kg/sc)
Carboxymethylcellulose
3
12.0
2
6.0
3
3.0
suspension
MCV 4167 did not substitute for morphine at the doses tested.
Ataxia was noted at all doses and salivation was seen at the
two higher doses.
346
MCV 4168-NIH 9613.
hydrobromide
(+)-9-Hydroxy-4,7-dimethyl-C-homobenzomorphan
MOUSE DATA -ED50 (95% C.L.)(mg/kg/sc)
1) TF-8.2 (3.1-21.8)
2) TF vs M -Inactive at 3.0,
6.0, 10.0 and 30.0
3) PPQ-0.9 (0.4-2.2)
4) HP-2.6 (2.1-3.4)
MONKEY DATA
(SDS)
# Animals
Doses (mg/kg/sc)
3
6.0
3
3.0
Vehicle H20
3
1.5
This compound did not substitute for morphine. At the highest
dose, the drug appeared to exacerbate withdrawal. Ataxia was
seen in all the animals receiving the highest dose and in 2 of
3 animals at the other doses. Tremors were also noted at the
highest dose.
MCV 4169-NIH 9614.
hydrobromide
(-)-9-Hydroxy-4,7-dimethyl-C-homobenzomorphan
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1) TF-Inactive at 3.0, 10.0
and 30.0
2) TF vs M-5.5 (1.2-25.9)
3) PPQ-9.4 (0.1-1.3)
4) HP-l.8 (1.3-2.4)
MONKEY DATA
(SDS)
# Animals
Doses (mg/kg/sc)
3
6.0
2
3.0
3
1.5
Vehicle H20
The compound did not substitute for morphine at the doses tested. The drug may have exacerbated withdrawal at the highest
dose. In addition, ataxia was noted in all animals receiving
this dose.
347
314-300 0 -80 - 24
MCV 4175-NIH 9624. 1-[(2-alpha, 6-alpha, llS)- (±)-l-(1,2,3,4,5,
6-hexahydro-8-hydroxy-3,6,11-trimethyl-2,6-methano-3-benzazocin11-yl)]-3-octanone methanesulfonate
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1)
TF-Inactive at 3.0, 10.0
and 30.0
2) TF vs M-0.03 (0.81-0.07)
3) PPQ-0.2 (0.08-0.6)
4) HP-2.4 (1.7-3.3)
MONKEY DATA
A.(SDS)
# Animals
Doses (mg/kg/sc)
3
0.5
3
0.25
Vehicle H20
3
0.125
MCV 4175 did not substitute for morphine. At the highest dose,
It was noted in the
the drug appeared to exacerbate withdrawal.
preliminary study that the animal spontaneously ejaculated semen
frequently.
MONKEY DATA
B.(PPt-Withdrawal)
# Animals
Doses (mg/kg/sc)
1
0.5
3
0.25
3
0.125
3
0.06
Vehicle H20
The drug promptly precipitated dose-related withdrawal signs.
The duration of action was approximately twice that of naloxone.
The male animals receiving MCV 4175 appeared to ejaculate semen
spontaneously, much more frequently than either the positive
One animal receiving the
control (naloxone) or vehicle control.
0.25 dose ejaculated 14 times in 3 hours.
MCV 4176-NIH 9625.
1-[(2-alpha, 6 alpha, 11S)-(±)-1-(1,2,3,4,5,
6-hexahydro-8-hydroxy-3,6,11-trimethyl-2,6-methanol-3-benzazocin11-yl)]-6-methyl-3-heptanone
methanesulfonate
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1)
TF-Inactive at 3.0, 10.0,
30.0 and 100.0
2) TF vs M-14.8 (3.7-58.6)
3) PPQ-0.002 (0.0003-0.016)
4) HP-1.1 (0.8-1.3)
Vehicle
1
3
3
2
MONKEY DATA
# Animals
H2O
2.5 1.25 0.6
Doses (mg/kg/sc) 5.0
(SDS)
In the dose range tested, MCV 41.76 did not substitute for morphine.
348
MCV 4184-NIH 9689.
Yohimbine
hydrochloride
MOUSE DATA-ED50 (95% C.L.)(mg/kg/sc)
1)
TF-Inactive at 3.0, 10.0
and 30.0
2) TF vs M-5.6 (2.7-11.5)
3) PPQ-17.1 (6.6 (44.1)
4) HP-(Not tested)
MONKEY DATA
(SDS)
# Animals
Doses (mg/kg/sc)
2
3
3
1 Vehicle
4 . 0 2 . 0 1 . 0 0.5
H20
Yohimbine did not substitute for morphine in the dose range
tested. The drug appeared to exacerbate withdrawal during the
first 1/2 hour.
One monkey at each of 3 of 4 doses masturbated
and ejaculated. At the 1.0 mg/kg, one monkey ejaculated spontaneously at least once per 1/2 hour observation period. None
Some
of the monkeys receiving vehicle displayed this behavior.
jaw sag was also noted in the monkeys receiving yohimbine.
REFERENCES
Aceto, M.D., Carchman, R.A., Harris, L.S., and Flora, R.E.
Caffeine elicited withdrawal signs in morphine-dependent rhesus
monkeys. Eur J Pharmacol, 50:203-207, 1978.
Atwell, L., and Jacobson, A.E. The search for less harmful analgesics. Lab Animal, 7:42-47, 1978.
Deneau, G. A. An analysis of factors influencing the development
of physical dependence to narcotic analgesics in the rhesus monkey with methods for predicting physical dependence liability in
man. Doctoral Dissertation, University of Michigan, 1956.
Dewey, W.L., Harris, L.S., Howes, J.F., and Nuite, J.A. The effects of various neurohumoral modulators on the activity of morphine and the narcotic antagonists in the tail-flick and phenylquinone tests. J Pharmacol Exp Ther, 175:435-442, 1970.
Dewey, W.L., and Harris, L.S. Antinociceptive activity of the
narcotic antagonists analogues and antagonistic activity of narcotic analgesics in rodents. J Pharmacol Exp Ther, 179:652-659,
1971.
Eddy, N.B., and Leimbach, D.
Synthetic analgesics. II. Dithienylbutenyl- and dithienylbutylamines. J Pharmacol Exp Ther, 107:
385-393, 1953.
349
Jacobson, A.E., and May, E.L. Structures related to morphine.
XXI. 2'-Substituted benzomorphans. J Med Chem 8:563-566,
1965.
Perrine, T.D., Atwell, L., Tice, I.B., Jacobson, A.E., and May,
E.L. Analgesic activity as determined by the Nilsen method.
J Pharm Sci, 61:86-88, 1972.
Seevers, M.H. Opiate addiction in the monkey. I. Methods of
study. J Pharmacol Exp Ther 56:147-156, 1936.
Physiological aspects of
Seevers, M.H., and Deaneau, G.A.
tolerance and physical dependence. In: Root, W.S. and Hofmann,
F.G., eds. Physiological Pharmacology. Vol. I. New York:
Academic Press, 1963. pp. 565-670.
AUTHORS
M.
L.
W.
E.
D.
S.
L.
L.
Aceto, Ph.D.
Harris, Ph.D.
Dewey, Ph.D.
May, Ph.D.
Medical College of Virginia
Department of Pharmacology
Virginia Commonwealth University
Richmond, Virginia 23298
350
Annual Report: Biological Testing
Program of the Committee on
Problems of Drug Dependence,
Inc. (1979)
Jacobson, A. E.
About 140 compounds have been examined in my laboratory at
NIH for any of several reasons over the past year. About a third
of these were submitted to either the Medical College of Virginia
(MCV) or to the University of Michigan (UM) for their examination.
A considerable number of older drugs have been included in the
UM/MCV reports in the 1979 Proceedings. These have not been
published, heretofore. Sixteen of those reports are included in
the UM folio for 1979. and one is in the MCV Addendum.
Altogether, about 43 compounds are included in the 1979
Proceedings from UM. This is the same as, or perhaps slightly
more than, the number of reports that UM printed in 1978. There
are ca. 32 reports from the laboratories at MCV. There are
several reasons for the difference in the numbers of reports from
UM and MCV. The major difference lies in the number of older
drugs reported by UM. When these are taken into consideration, we
have about 30 reports on new drugs from each group. A substantial
number of reports are being held on file in both units. These
were not released for publication in 1979; we allow a submitter
about three years before requiring release of data. Thus, about
120 compounds have been, or are being, examined and over 70 of
these are in the 1979 Proceedings. Eventually, if submitters
continue submitting and releasing data on compounds at the present
rate, we could anticipate seeing ca. 30 reports on ca. 20 to 25
compounds per year from each group in the next few years.
About 60 percent of the compounds reported on by MCV/UM, and
included in the 1979 Proceedings, have come from U.S. and foreign
universities and from research institutions, including NIH; ca.
40 percent are from the pharmaceutical industry. This is at the
low end of normal for industry. Generally, over the last few
years, industrial submissions ranged between 40 and 60 percent.
The published reports represent the work of about six industrial
firms and the same number of universities and research
351
institutions: from one to nine submissions per independent group,
It is difficult to tell, at this point, whether we are seeing the
normal yearly fluctuation in interest in analgesic research, a
sort of steady-state, or whether we have a slight decrease in
interest. The next few years may allow us to determine that
point. Certainly, however, we have not observed an increase in
interest in the field of analgesics over the past year.
At this time when we see, at best, a steady-state interest in
research on analgesics, the scientific involvement of the groups
which cooperate with the Committee, that is, UM and MCV. has
increased considerably. The scientific investigation of drugs
received by the Committee is still weighted towards a study based
on single-dose suppression, precipitated withdrawal and,
occasionally, primary dependence experiments, in the rhesus
monkey. However, at MCV, compounds are being examined by rat
infusion techniques because there is reason to believe that some
of these compounds act differently in different species. Further,
all compounds, no matter where they are sent for the initial
single-dose suppression (SDS) study, will be examined in rodent
antinociceptive and antagonist assay systems at MCV (tail flick,
tail flick antagonist and phenylquinone writhing [PPQ] tests). if
the submitted sample is in sufficient supply. All samples will be
examined biochemically for their binding affinity to the opiate
receptor in rat brain homogenates, in electrically stimulated
guinea pig ileum and in mouse vas deferens, at UM. Also,
self-administration experiments with these drugs will be done more
frequently, and reported in the Proceedings. Attempts will be
made to correlate the results from these studies - to try to
assign a drug to a previously known class, or to state differences
from the known classes of drugs with various types of abuse
potential.
Last year, the CPDD authorized joint meetings of involved
personnel of UM and MCV at times other than the Annual Meeting.
The meetings which the UM and MCV testing groups are holding to
discuss their programs will result, in the near future, in the
publication of a considerable amount of in vitro and in vivo data
on analgesic compounds. These groups are now considering the way
these data will be reported. It remains to be seen whether the
increased data will help us predict whether a drug is likely to
have dependence-producing properties of one sort or another. At
the least, we will have obtained composite data on a reasonable
number of compounds which will be most helpful to researchers in
the field. I think that these joint UM/MCV meetings will be
exceedingly valuable for the correlation of data on a drug, and
for the solution of many other types of problems which are of
common interest to these groups. One such problem which was
discussed at the last joint meeting related to the FDA’s recently
promulgated Good Laboratory Practice (GLP) Regulations. The MCV
and UM labs will work in compliance with the GLP. I am now
requesting sufficient data from all submitters to allow these
laboratories to remain in compliance with GLP regulations. Thus,
all samples which are submitted through the CPDD will, henceforth,
352
either come with the necessary data, or they will not be accepted.
Although the GLP regulations are an added burden to me and the UM
and MCV laboratories, they can, it is hoped, serve to eliminate
the examination of impure or improperly characterized compounds.
Although this did not occur very often in the past, it did happen
occasionally.
As can be noted from the UM and the MCV Annual Reports, we
tested a considerable number of analogs of recognizable
benzomorphans, piperidines, etc., for their abuse potential this
year. Some of the benzomorphans and some of the morphinan-like
compounds which were tested had unpredictable (a priori)
properties.
Among the benzomorphans, we saw an antinociceptively weak
N-ethyl compound which precipitated withdrawal (NIH 9258, MCV
4176). There were two N-methyl benzomorphans with very long
side-chains at the C-9 beta position which, contrary to what would
have been predicted, had essentially morphine-like antinociceptive
activity and did not substitute for morphine in SDS (NIH 9624 and
9625, MCV 4175 and 4176 - the NIH 9624 precipitated withdrawal).
Continuation of work. begun in 1978, with N-cyanoalkyl
normetazocines and morphinans showed that they had narcotic
antagonist properties in the monkey (NIH 9364A and 9369A, UM 1130A
and 1133A - the NIH 9364A was 30 times more potent than morphine
as an antinociceptive). NIH 9364A and its dextro enantiomer (NIH
9365B, UM 1131B) may prove biochemically useful. The levo
compound has binding affinity for the opiate receptor 100,000
times that of its enantiomer. Enantiomeric differences of this
magnitude have not been noted before. A number of racemic and
enantiomeric C-homobenzomorphans (7-membered nitrogen-containing
ring) were examined and found to be quite interesting. These were
N-methyl compounds which did not have morphine-like properties in
SDS (NIH 9612, 9613, 9614, 9560, 9561, 9562, 9563, 9564, and 9565;
MCV 4167, 4168. 4169, UM 1174, 1175, 1176, 1177, 1178, and 1179.
UM has found them to be biochemically intriguing
respectively).
compounds. It might be noted that I cannot explain why NIH 9612
(a racemic compound) is four times more potent in the hot plate
assay than its levo enantiomer (NIH 9614).
Although ketobemidone-like compounds are not generally known
for their narcotic antagonist activity (only a few have been
observed to have antagonist activity, heretofore), three
ketobemidones with antagonist activity were examined this year
(NIH 9636, 9649 and 9650, UM 1191, 1197, 1198). Other types of
substituted piperidines were also noted not to substitute for
morphine in SDS (NIH 9559 and 9356, UM 1181 and 1147 - the NIH
9356 was meperidine-like in antinociceptive activity and had
narcotic antagonist properties).
An unusual morphinan, substituted on the C-ring (NIH 9466, UM
1150 and MCV 41301, had potent narcotic antagonist activity, and a
6-oxamorphinan (NIH 9539, UM 1168) where the C-6 carbon atom in
the C ring was replaced by oxygen, had four times the potency of
353
morphine as an antinociceptive, even in the hot plate assay, and
had naloxone-like, long-lasting narcotic antagonist activity.
Evidently, substituents on the C-ring of morphinans. unlike most
substituents on the C-ring of morphine-like compounds, can be
advantageous.
The heteroatom replacement noted in NIH 9539 has
not been attempted with morphine-like compounds, insofar as I am
aware.
A structurally interesting opiate, without the phenolic
hydroxyl group or the ally alcohol moiety of morphine, proved to
be more potent than morphine as an antinociceptive. It
substituted completely for morphine in SDS (NIH 9607, MCV 4166).
and its binding affinity for the opiate receptor was about
one-third that of morphine. Thus the phenolic hydroxyl group in
morphine-like compounds does not appear to be essential for
morphine-like antinociceptive activity, or for inducing physical
dependence in monkeys.
A considerable number of compounds were examined which can
only be classified under a "miscellaneous" heading.
An acyclic
tertiary amine on. a cyclohexane ring, with an aromatic ring on the
carbon alpha to the nitrogen atom (NIH 9468, MCV 4131 and UM
1152). was not morphine-like in SDS, but was codeine-like in the
hot plate assay for antinociceptive activity. An isoindole (NIH
9506, UM 1155 and MCV 4140) appeared to be a potent long-acting
antagonist, with little antinociceptive activity. The isoindole
is a ring-contracted (and unsaturated) relative of
decahydroisoquinoline, many of which have been examined in the
last few years. Most such compounds (except for NIH 9551, MCV
4154) substitute for morphine in SDS. However, NIH 9551 is
meperidine-like in actinociceptive activity and did not substitute
for morphine. A phenanthridine (NIH 9513, UM 1159), with a
structure reminiscent of THC, was a potent antinociceptive, and
was not morphine-like in SDS. Its physical dependence capacity
was rated as very low. This compound, which will be the subject
of a paper at this meeting, was noted to cause dysphoria,
confusion and catatonia in the monkey. An odd-looking amide (NIH
9470, MCV 41331, reminiscent of fentanyl, does not produce
morphine-like physical dependence, nor is much tolerance developed
to it. It has codeine-like antinociceptive activity.
Lastly, I would like to mention the work done on Baclofen
(LIORESAL), NIH 9512, MCV 4144 and UM 1158), which has been stated
In the Investigator Brochure on
to be a GABA-like inhibitor.
Baclofen, it was noted that the compound suppressed all of the
abstinence signs in morphinized animals when administered one hour
before naloxone administration (ca. 2.5mg/kg p.o.). A 20mg/kg
p.o. dose blocked naloxone-precipitated symptoms. Baclofen was
also noted to reduce the willingness of rats to self-administer
morphine without reducing morphine's analgesic effect or tolerance
to morphine. Thus, the compound was said to reduce physical
dependence and to suppress drug-seeking behavior with doses which
do not induce marked overt behavioral effects. These claims were
brought to my attention by Dr. Heinz Sorer, at NIDA. Certainly,
354
if the claimed effects were duplicable in our laboratories, it
would be of great interest to the Committee. Thus, the company
most kindly provided us with a sufficient supply of NIH 9512, and
the drug was examined at both MCV and UM.
In the tail flick
antagonist test it appeared to be a potent (naloxone-like)
antagonist. In the hot plate assay it was noted to have about
half of the potency of morphine; it was somewhat less potent in
PPQ, and inactive in the tail flick assay.
In monkeys, in SDS, it
did not substitute for morphine. MCV noted that it appeared to
block accessive withdrawal signs of retching and vomiting. At UM,
at 8mg/kg, bizarre behavior was noted suggesting disorientation.
Normal animals, with 8mg/kg of NIH 9512, exhibited incoordination
and catatonia. Ataxia and incoordination were noted at MCV at
16mg/kg in morphinized animals, at which dose convulsions were
observed.
UM believed that the drug was not morphine-like, and
had a very low estimated physical dependence capacity. I think
that it would be of interest for UM and MCV, at their joint
meeting, to attempt to relate their results to the notion that
Baclofen reduces physical dependence and suppresses drug seeking
behavior. Perhaps further work is needed with the compound.
In conclusion, if one looks closely at the compounds being
prepared, it might be deduced that there is a trend towards
moderately potent agonist-antagonist types (codeine-like
antinociceptively). Admittedly, there would be a considerable
market for these drugs. However, it is quite conceivable, if not
likely, that the new "super aspirins" which are coming on the
market may displace them. Neither the "super aspirins” nor the
codeine-like agonist-antagonists will meet what I believe to be a
major need for a potent analgesic for the treatment of severe
chronic pain. More research is needed to find non-dependence
producing compounds with morphine-like (or better) analgesic
properties.
Perhaps butorphanol or nalbuphine will help fill that
gap. It is possible that some of the drugs which we have
discussed, or their relatives, will be able to meet that need.
From the biochemical viewpoint, a search is underway in several
laboratories to find an antagonist for the kappa or, in Dr.
Kosterlitz's nomenclature, delta receptor. Evidently, compounds
like the prototypic ethylketocyclazocine cannot be effectively
antagonized by naloxone. It is possible that UM, through its
biochemical work with the receptor assays, will find such an
antagonist among the compounds received under Committee auspices.
I would, once again, like to thank our colleagues at MCV and
UM for the fine work which they have done under the auspices of
the Committee . We are grateful to them.
AUTHOR
Arthur E. Jacobson, Biological Coordinator, CPDD, Inc.
Medicinal Chemistry Section, Laboratory of Chemistry, National
Institute of Arthritis, Metabolism, and Digestive Diseases,
National Institutes of Health, Bethesda, Maryland 20014
355
Annual Report: Evaluation of New
Compounds for Opioid Activity
(1979)
Swain, H. H.; Woods, J. H.; Medzihradsky, F.; Smith, C. B.;
Fly, C. L.
The flow of new compounds through the evaluation programs at The
University of Michigan (UM) and the Medical College of Virginia
(MCV) is coordinated by Dr. Arthur E. Jacobson, Medicinal Chemistry Section, NIAMDD, National Institutes of Health, Bethesda,
MD. The drugs, which come originally from pharmaceutical companies, universities and government laboratories, are submitted to
Dr. Jacobson, who performs the MOUSE ANALGESIA tests (see below).
At the UM and MCV laboratories, drug samples arrive from Dr. Jacobson
with only the following information:
(1) an identifying NIH number,
(2) molecular weight, (3) solubility information, and (4) a recommended starting dose. Only after-the evaluation is complete and
the-report submitted back-to Dr. Jacobson are the chemical structure and the muse analgesia data released to the evaluating laboratory.
In the present report, all the new data related to a particular
drug are placed in a single location. Thus, the first eight compounds are those which have been studied in all four UM laboratories.
Thereafter are presented several substances which have
been evaluated by two techniques and finally those drugs which have
been studied by a single method. Listed below are brief descriptions
of the techniques which are employed in these several evaluations.
PHYSICAL DEPENDENCE EVALUATION IN RHESUS MONKEYS
The single dose suppressions test (SDS) determines the ability of
a drug to suppress the signs of abstinence in monkeys which have
been made physically dependent by the chronic administration of
morphine (3 mg/kg every six hours). Compounds suspected of having
morphine-antagonist properties are tested for their ability to
precipitate the abstinence syndrome in non-withdrawn (NW) morphinedependent monkeys. Non-dependent monkeys (Normals) are used to
determine whether the acute effects of the test drug are reversible
by nalorphine or naloxone.
In a primary addiction study (PAS) nondependent monkeys receive the test drug every six hours for 30 days
to determine whether abstinence signs will appear when the animals
356
are challenged with an antagonist or when drug administration is
discontinued.
Details of these techniques have been presented in the ANNUAL REPORT to the Committee in 1963 (Minutes of the 25th Meeting).
SELF-ADMINISTRATION BY MONKEYS
The compounds examined in monkeys which had been conditioned
to self-inject codeine. Each of at least three monkeys was studied with saline as a negative control and a number of doses of
the test compound until a maximum rate of responding was obtained
or until, in the absence of evidence of a reinforcing effect, directly observable changes in behavior were elicited by the com
pound.
The schedule of intravenous drug delivery was a fixed-ratio 30;
when a light above a lever was illminated, the 30th response in
its presence turned off the fixed-ratio light and delivered a
five-second intravenous drug injection in the presence of another
light that was illuminated during drug delivery. After each injection, a ten-minute timeout condition was in effect during which
responses had no programmed consequence amd no lights were illuminated. Each of the two daily sessions consisted of 13 injections
or 130 minutes, whichever occurred first. Other details of the
procedure and initial findings of a variety of narcotics are given
in a previous report (woods, 1977, Committee Report, pages 420437). Additional background material is available from Dr. Woods.
Doses of the drugs are described in terms of moles/kg/injection, to
facilitate direct comparisons among drugs. Duplicate observations
of codeine (7.5 x 10-5 mol/kg/injections; 0.32 mg/kg/injections)
and of saline were obtained for each monkey. A saline substitution
was conducted before and after the series of observations on a
the rates of codeine-reinforced responding were obtest drug;
tained by a random sampling of two sessions interpolated between
the drug-substitution sessions. These data are represented in
the following graphs with individual symbols for each of the monkeys; in addition, using the same symbols, the mean of duplicate
observations is given for the doses studied in each monkey. There
are two additional types of average data presented.
The closed
circles indicate the averaged data for observations on the subset
of monkeys used to study each drug under each of the experimental
conditions.
The open circles indicate the codeine and saline
rates of responding of 20 monkeys studied under the same conditions.
The brackets indicate + 3 standard errors of the mean for codeine
In all cases, the
and + 3 standard errors of the mean for saline.
rates of responding given are those calculated during the fixedratio portion of each session.
DISPLACEMENT OF STEREOSPECIFIC
3
H-ETORPHINE BINDING
Details of the binding assay were described in the 1978 ANNUAL
REPORT. Briefly, aliquots of a membrane preparation from rat
357
cerebrum were incubated with 3H-etorphine in the absence and
presence of 150 mM NaCl, and in the presence of different concentrations of a given opioid drug under investigation. Stereospecific, i.e., opioid-receptor related, binding of etorphine was
determined and the inhibitory potency of the drugs was obtained
from log-probit plots of the data. Values obtained with this
meabrane preparation for some representative opioid drugs are
as follows:
DRUG
EC50 (nM)
+NaCl
-NaCl
+Na/-Na
Naltrexone
2.0
7.9
0.25
Naloxone
9.1
31.6
0.29
20.0
51.3
0.39
Cyclazocine
3.6
6.4
0.56
Levallorphan
5.5
7.0
0.79
Nalorphine
Dextrorphan
Levorphanol
Codeine
1-Pentazocine
d-Pentazocine
Morphine
18400
14000
21.4
15.4
34700
17800
85.1
174.0
6190
8660
142.0
60.2
1.32
1.39
1.95
2.04
0.71
2.36
NOTE: Binding data for an extensive number of compounds is
included in the 1978 ANNUAL REPORT
DEPRESSION OF TWITCH IN ELECTRICALLY DRIVEN GUINEA PIG ILEUM AND
MOUSE VAS DEFERENS PREPARATIONS
Submitted drugs were evaluated on two smooth muscle preparations,
the details of which were described in the 1978 ANNUAL REPORT.
Shown on the following pages are the EC50's (+ standard error) for
the tested drug alone, for the drug in the presence of naltrexone
(a pure opioid antagonist which is more effective against socalled "mu" agonists than against so-called "kappa" agonists),
and for the tested drug in the presence of UM 979 (an antagonist
which seems to be more effective against "kappa" than against "mu"
drugs). The maximum depression (+ standard error) of the electrically induced twitch in each of these preparations is shown.
The type of opioid receptor upon which a drug acts has been inferred from the relative potencies of the drug in the muse vas deferens and guinea-pig ileum preparations. Lord et al. (Nature 267:
495-499, 1977) have reported that kappa agonists such as ethylketazocine, UM 1070, UM 1072, UM 909 and UM 911 are more potent
upon the guinea-pig ileum than upon the muse vas deferens. The
EC50's for a series of drugs upon the two preparations are shown
358
in the figure below. Drugswhich were found to be equipotent upon
the two preparations include kappa agonists such as ethylketazocine,
UM 1070 and UM 1072, and mu agonists such as morphine. UM 909 and
UM 911 were more potent upon the mouse vas deferens than upon the
guinea pig ileum. Drugs with marked differences in their EC50's
upon the two preparations included pentazocine and buprenorphine.
The differences between the present findings and those of Lord
et al. may be due to a difference in the strain of mouse which
was used. Nevertheless, in the present studies the relative potencies upon the two preparations do not distinguish between the
actions upon mu and kappa receptors.
By the use of appropriate antagonists it may be possible to differentiate between the two types of opioid receptors in the muse
van deferens (Smith, in Characteristics and Functions of Opioids
eds. Van Bee and Terenius, Elsevier, North Holland Biomedical
Press, p. 237-238, 1978). Drugs which are antagonized to a
greater degree by UM 979 than by naltrexone appear to have more
selectivity for the kappa receptor. Such drugs include UM 1070,
UM 1072 and UM 911.
It is interesting that meperidine, which has
low potency upon both smooth muscle preparations, is not antagonized by either UM 979 or by naltrexone upon the muse vas deferens.
Other drugs which seem to be meperidine-like (e.g., UM1170) also
are not blocked by either antagonist. Thus, antagonists seem
to be useful for the classification of opiates.
359
MOUSE ANALGESIA.
Compounds were evaluated by Dr. Arthur Jacobson, who used the mouse hot-plate test and, in
some cases, the Nilsen test. Below are reference values for these tests on several standard opioid drugs.
HOT PLATE
NILSEN
Compound
Morphine sulfate
Codeine phosphate
Levorphanol Tartrate
Meperidine.HCl
[sc,
mg/kg]
[oral,
mg/kg]
[sc, mg/kg]
[oral, mg/kg
[sc,
umol/kg]
[oral,
umol/kg]
[sc, umol/kg]
[oral,
umol/kg]
1.0 (0.7-1.4)
6.3 (4.7-8.3)
0.7 (0.5-1.1)
8.3 (6.0-11.4)
3.0 (2.1-4.2)
18.9 (14.1-24.9)
2.1
24.9 (18.0-34.1)
6.8 (4.5-10.2)
13.5 (9.7-18.7)
7.4 (4.9-11.0)
14.7 (9.2-23.3)
17.1 (11.3-25.7)
34.0 (24.4-47.1)
18.6 (12.3-27.7)
37.0 (23.2-58.7)
0.2 (0.1-0.3)
0.2 (0.16-0.3)
2.5 (1.7-3.7)
0.5 (0.2-0.7)
0.5 (0.4-0.7)
6.2 (4.2-9.l)
(1.5-3.3)
4.6 (3.3-6.4)
16.2 (11.6-22.5)
(-)-Metazocine.HBr
Dihydromorphinone.HCl
0.6 (0.5-0.9)
10.6 (8.0-14.1)
0.5
(0.3-0.7)
26.0 (21.0-33.0)
1.9 (1.4-2.8)
34.1 (25.7-45.3)
1.6
(1.0-2.3)
83.6 (67.5-106.1)
0.13 (0.11-0.16)
0.9 (0.7-1.2)
0.2 (0.15-0.3)
1.8 (1.5-2.1)
0.4 (0.3-0.5)
2.8 (2.2-3.7)
0.6
5.6 (4.7-6.5)
(0.5-0.9)
Nalorphine.HCl
Cyclazocine
Pentitzocine
9.9 (5.7-17.1)
23.0 (16.2-32.7)
28.4 (16.4-49.1)
66.1
2.0 (l-4-2.8)
0.1 (0.07-0.16)
7.4 (5.2-10.3)
0.4 (0.3-0.6)
9.0 (6.5-12.4)
6.5 (4.4-8.8)
31.6 (22.8-43.5)
22.8
Naltrexone.HCl
No dose response
Naloxone.HCl
No dose response
No antinociceptive activity in hot plate assay:
mescaline.
Chlorpramzine.HCl
1.1 (0.9-l-5)
3.2 (2.4-4.2)
(46.6-94.0)
(15.4-30.9)
Phenobarbital, armbarbital, valium, meprobamate, and
UM 1177 NIH 9563
MOUSE ANAXESIA, ED50 (mg/kg)
Hot Plate:
Nilsen:
1.2 (0.9-1.6)
---
dl-7,12 beta-Dimethyl-9-hydroxy-4-methyl-C-homobenzomorphan
PHYSICAL DEPENDENCE EVALUATION IN RHESUS MONKEYS
This drug so alters the behavior of the animals that abstinence signs cannot be graded accurately. It causes motor incoordination, apparent confusion and marked alteration in the animals'
response to their environment. Doses tested: SDS, 0.6-2.4;
normals, 2.4 mg/kg. Vehicle: water
SELF-ADMINISTRATION
BY
MONKEYS
UM 1177 maintained rates of self-administration slightly
below the control rates for codeine. In this respect, the
compound resembles a variety of other morphine-like drugs. It
is comparable to codeine in potency.
362
UM 1177 NIH 9563 (continued)
DISPLACEMENT OF STEREOSPECIFIC
EC50 (nM)
3
H-ETORPHINE BINDING
+Na
-NA
1381
632
+Na/-Na
2.18
DEPRESSION OF TWITCH IN ELECTRICALLY DRIVEN GUINEA-PIG ILEUM
Maximum
Depression
EC50
Drug alone
5.54 (±0.45) x 10-7M
After naltrexone, 10-7M
(No response to any dose of UM 1177)
After UM 979, 10-7M
(No response to any dose of UM 1177)
55.12 (±2.56)%
DEPPESSION OF TWITCH IN ELECTRICALLY DRIVEN MOUSE VAS DEFERENS
Maximum
Depression
EC50
6.22 (±0.84) x 10-7M
Drug alone
-8
-7
84.04 (±2.29)%
After naltrexone, 10 M
5.24 (±0.99) x 10 M
82.10 (±4.75)%
After UM 979, 10-8M
4.67 (±1.20) x 10-7M
70.28 (±4.88)%
SUMMARY:
This compound is not a typical opioid:
It so alters the behavior of the monkeys (motor
incoordination, apparent confusion and marked
alteration in the animals' response to their
environment) that abstinence signs cannot be
graded accurately
The drug is self-administered by monkeys
It cospetes for etorphine binding sites with a morphine-like sodium ratio but a very low potency
In the mouse vas deferens preparation, it depresses
the electrically driven twitch, but it is far
less potent and somewhat less effective than
morphine and its actions are not blocked by naltrexone or UM 979
In the guinea-pig ileum preparation, the drug has a
biphasic action: in low doses it depresses the
electrically induced twitch somewhat, but at
higher doses it enhances the twitch without altering the resting tension of the preparation
In the muse hot-plate test, UM 1177 is a moderately
potent analgesic
363
314-300 0 -80 - 25
UM 1176 NIH 9562
MOUSE ANALGESIA, ED50 (mg/kg)
Hot Plate:
1.3 (1.0-1.7)
Nilsen:
(-)-7,l2
alpha-Dimethyl-9-hydroxy-4-methyl-C-homobenzomorphan
PHYSICAL DEPENDENCE EVALUATION IN RHESUS MONKEYS
Apparently this drug does not suppress or precipitate morphine
abstinence signs. It so alters the behavior of the monkeys, with
prominent confusion and ataxia, that it is not possible to grade
the abstinenoe signs accurately. Doses tested: SDS, 0.7-5.6;
normals, 5.6 mg/kg. Vehicle: water.
SELF-ADMINISTRATION BY MONKEYS
UM 1176 was self-injected by two of three monkeys at rates
comparable to those of codeine;
it was comparable to codeine in
potency. Higher doses were not evaluated due to solubility
problems.
364
UM 1176 NIH 9562 (continued)
DISPLACEMENT OF STEREOSPECIFIC
EC50 (nM)
3
H-ETORPHINE BINDING
+Na
-Na
453.1
245.5
+Na/-Na
1.85
DEPRESSION OF TWITCH IN ELECTRICALLY DRIVEN GUINEA-PIG ILEUM
Maximum
Depression
EC50
1.86 (±0.22) x 10-7M
Drug alone
-7
29.13 (±3.17)%
After naltrexone, 10 M
(No response to any dose of UM 1176)
After UM 979, 10-7M
(No response to any dose of UM 1176)
DEPRESSION OF TWITCH IN ELECTRICALLY DRIVEN MOUSE VAS DEFERENS
Maximum
Depression
EC50
Drug alone
-8
After naltrexone, 10 M
-8
After UM 979, 10 M
7.97 (±0.74) x 10-7M
81.97 (±2.91)%
1.72 (±0.34) x 10-6M
78.02 (±4.93)%
-6
3.22 (±1.38) x 10 M
68.55 (±3.37)%
SUMMARY:
This compound is not a typical opioid:
Apparently it does not affect the signs of morphine
abstinence, but it causes so much atypical bahavior (motor incoordination, apprehension, apparent
confusion) that it is not possible to grade abstinence signs accurately
It competes for etorphine binding sites with a morphine-like sodium ratio and low potency
In depressing the
preparation, it
less effective
not blocked by
twitch in the muse vas deferens
is far less potent and some what
than morphine and its actions are
naltrexone or UM 979
In the guinea-pig ileum preparation, the drug has a
biphasic action: in low doses it depresses the
electrically induced twitch somewhat, but at higher
doses it enhances the twitch without altering the
resting tension
The drug is self-administered by monkeys
It is a moderately potent analgesic in the mouse hotplate test
UM 1176 differs structurally from UM 1177 in that the
methyl group in the 12-position is alpha instead
of beta in configuration, and is the 1 isomer.
365
UM 1170 NIH 9541 MCV 4146
MOUSE ANAGESIA, ED50 (mg/kg)
Hot Plate:
21.8 (14.6-32.7)
Nilsen:
4 beta-(m-Methoxyphenyl)-1,3-dimzthyl-4 alpha-pipzridinol
propionate hydrochloride
PHYSICAL DEPENDENCE EVALUATION IN RHESUS MONKEYS
This is an opioid agonist, less potent than morphine and
somewhat shorter acting. Doses tested: SDS, 5.0-20.0 mg/kg.
Vehicle: water.
SELF-ADMINISTRATION
BY
MONKEYS
UM 1170 was self-injected at rates comparable to codeine in
one of three monkeys at the highest dose. Higher doses of the
drug were not evaluated due to inadequate drug supply.
366
UM 1170 NIH 9541 MCV 4146 (continued)
DISPLACEMENT OF STEREOSPECIFIC
EC50 (nM)
3
H-ETORPHINE BINDING
+Na
-Na
>2000
>2000
+Na/-Na
DEPRESSION OF TWITCH IN ELECTRICALLY DRIVEN GUINEA-PIG ILEUM
Maximun
Depression
EC50
3.08 (±1.72) x 10-4M
Drug alone
-7
4
90.90 (±4.60)%
After naltrexone, 10 M
1.89 (±0.51) x 10- M
91.63 (±5.01)%
After UM 979, 10-7M
3.70 (±0.16) x 10-4M
88.89 (±11.1)%
DEPRESSION OF TWITCH IN ELECTRICALLY DRIVEN MOUSE VAS DEFERENS
EC50
Maximum
Depression
7.78 (+4.06) x 10-8M
38.61 (±2.63)%
After naltrexone, 10 M
1.54 (±0.55) x 10-8M
25.05 (±1.49)%
After UM 979, 10-8M
5.94 (±1.93) x 10-8M
35.54 (±3.52)%
Drug alone
-8
SUMMARY:
This drug seems to be an opioid of low potency:
To suppress the signs of morphine abstinence, a dose
of 20 mg/kg is required
Data are insufficient to determine whether or not
doses above 1 mg/kg are self-administered; lower
doses are not
If it competes for etorphine binding sites, the EC50
is greater than 2000 nM
In the mouse hot-plate test, it has analgetic activity but the ED50 is 21.8 mg/kg
It depresses the electrically induced twitch in the
guinea-pig ileum preparation but only at the
enormous concentration of 10-4 M, and this action
is not antagonized by naltrexone or UM 979
Only on the mouse vas deferens preparation does this drug
have a potency approaching that of morphine, and the
effect on this tissue is not blocked by naltrexone
or UM 979.
367
UM 1168 NIH 9539
MOUSE ANALGESIA, ED50 (mg/kg)
Hot Plate:
0.32 (0.25-0.42)
Nilsen:
17-Cyclopropylmethyl-3-hydroxy-6-oxamorphinan
tartrate
PHYSICAL DEPENDENCE EVALUATION IN RHESUS MONKEYS
This drug is an opioid antagonist, approximately equal in
potency to, but longer lasting than, naloxone. Doses tested:
SDS, 0.2; NW, 0.05-0.4 mg/kg. Vehicle: water.
SELF-ADMINISTRATION BY MONKEYS
UM 1168, at none of the doses tested, maintained selfinjection at rates above those seen with saline.
368
UM 1168 NIH 9539 (continued)
DISPLACEMENT- OF STEREOSPECIFIC
3
H-ETORPHINE BINDING
+Na
1.03
EC50 (nM)
-Na
+Na/-Na
0.972
1.06
DEPRESSION OF TWITCH IN ELECTRICALLY DRIVEN GUINEA-PIG ILEUM
Maximum
Depression
EC50
4.83 (±2.28) x 10-9M
Drug alone
-9
-8
19.29 (±5.38)%
After naltrexone, 10 M
3.47 (±1.08) x 10 M
52.91 (±6.28)%
After UM 979, 10-7M
9.20 (±2.18) x 10-9M
45.28 (±4.27)%
DEPRESSION OF TWITCH IN ELECTRICALLY DRIVEN MOUSE VAS DEFERENS
EC 5 0
Maximum
Depression
6.28 (±1.29) x 10-9M
88.38 (±1.97)%
After naltrexone, 10 M
8.27 (±1.68) x 10-9M
91.36 (±1.62)%
After UM 979, 10-8M
6.53 (±1.19) x 10-9M
91.06 (±1.68)%
Drug alone
-8
SUMMARY
This compound behaves like many other opioid antagonists in
that:
It precipitates the abstinence syndrome in the morphine-dependent monkey
Naltrexone and UM 979 do not greatly antagonize its
twitch-depressant actions in the guinea-pig ileum
and mouse vas deferens preparations
It is not self-administered by monkeys
It has a high affinity and an intermediate sodiumresponse ratio in competing with etorphine for
binding sites
Nevertheless:
Unlike naloxone and naltrexone, it is a potent
analgesic in the mouse hot-plate test
369
UM 1158 NIH 9512 MCV 4144 Baclofen
MOUSE ANALGESIA, ED50 (mg/kg)
Hot Plati:
2.1 (1.5-2.7)
Six out of seven were
Nilsen:
affected at 40 mg/kg, a toxic
dose
beta-Aminomethyl- p-chlorohydrocinnamic
acid
PHYSICAL DEPENDENCE EVALUTION IN RHESUS MONKEYS
This compound causes an atypical CNS depression with bizarre
uncoordinated behavior and a catatonic appearance. These effects
were not reversed by the administration of nalorphine or of naloxone. Doses tested: SDS, 1.0-8.0; NW, 1.0; normals, 8.0 mg/kg.
Vehicle:
dilute hydrochloric acid.
SELF-ADMINISTRATION BY MONKEYS
UM ll58 maintained response rates above saline but well below
codeine in two of the three monkeys tested, and in only one of
these two monkeys, and only at one dose, did the rate exceed one
response per second. This is the first compound to be tested as
an unknown after it had been studied as a known drug (see 1978
Annual Report, p. 658). Results of the two studies are comparable.
370
UM 1158 NIH 9512 MCV 4144 Baclofen (continued)
DISPLACEMENT OF STEREOSPECIFIC
3
H-ETORPHINE BINDING
-Na
+Na
EC50 (nM)
+Na/-Na
>2000
>2000
DEPRESSION OF TWITCH IN ELECTRICALLY DRIVEN GUINEA-PIG ILEUM
EC50
Maximum
Depression
4.47 (±1.26) x 10-7M
Drug alone
-7
After naltrexone, 10 M
-7
After UM 979, 10 M
38.77 (±4.03)%
-5
28.94 (±10.9)%
-6
43.78 (±6.72)%
2.10 (±1.09) x 10 M
1.38 (±0.43) x 10 M
DEPRESSION OF TWITCH IN ELECTRICALLY DRIVE MOUSE VAS DEFERENS
Maximum
Depression
EC50
3.37 (±1.98) x 10-7M
Drug alone
-8
7
69.02 (±2.14)%
After naltrexone, 10 M
5.34 (±2.25) x 10- M
61.83 (±4.74)%
After UM 979, 10-8M
7.34 (±6.59) x 10-6M
58.78 (±8.78)%
SUMMARY
This compound is neither an opioid agonist nor an opioid antagonist:
It neither suppresses nor precipitates morphine abstinence signs in the monkey
Its direct effects in the monkey are not reversed by
nalorphine or naloxone
It does not compete effectively for etorphine binding sites
Nevertheless
:
UM 1158 is a potent analgesic in the mouse hot-plate
test
It causes atypical behavior in monkeys (incoordination,
catatonia, apparent disorientation)
Generally, it is not self-administered by monkeys
Interestingly:
On the guinea-pig ileum preparation, the EC50 of this
drug was increased 50-fold by naltrexone, while on
the mouse vas deferens the EC50 was increased
20 times by UM 979
371
UM 1150 NIH 9466 MCV 4130
MOUSE ANALGESIA, ED50 (mg/kg)
Hot Plate:
17.2 (13.3-22.2)
(Poor dose-response at
higher dose levels)
(-)-17-(Cyclopropylmethyl)-3-hydroxymorphinan-6-one
sulfonate
methane-
PHYSICAL DEPENDENCE EVALUATION IN RHESUS MONKEYS
This drug is a potent antagonist which precipitates longlasting abstinence signs in the dependent monkey. In normal
animals it produced CNS depression which is antagonized by
naloxone but potentiated by nalorphine.
Doses tested: SDS,
0.5; NW, 0.0625-0.5; normals, 0.5 mg/kg. Vehicle: water.
SELF-ADMINISTRATION BY MONKEYS
As shown above, none of the doses of UM ll50 maintained
response rates above those of saline.
372
UM 1150 NIH 9466 MCV 4130 (continued)
DISPLACEMENT OF STEREOSPECIFIC
EC50 (nM)
3
H-ETORPHINE BINDING
+Na
-Na
+Na/-Na
0.475
0.945
0.50
DEPRESSION OF TWITCH IN ELECTRICALLY DRIVEN GUINEA-PIG ILEUM
Maximum
Depression
EC50
3.54 (±0.56) x 10-9M
Drug alone
-7
After naltrexone, 10 M
-7
After UM 979, 10 M
-9
72.24 (±2.84)%
5.69 (±1.25) x 10 M
73.96 (±1.18)%
3.39 (±0.26) x 10-9M
69.11 (±4.38)%
DEPRESSION OF TWITCH IN ELECTRICALLY DRIVEN MOUSE VAS DEFERENCES
Maximun
Depression
EC50
Drug alone
2.04 (±0.60) x 10-9M
28.11 (±2.51)%
After naltrexone, 10-8M
1.19 (±0.40) x 10-8M
40.63 (±3.67)%
-8
After UM 979, 10 M
-9
5.35 (±1.68) x 10 M
32.53 (±7.28)%
SUMMARY
This compound is similar nalorphine in many respects:
It precipitates the signs of abstinence in morphinedependent monkeys
It is not self-administered by monkeys
It has a high affinity and a low sodium-response
ratio in competing with etorphine for binding
sites
It has analgetic activity in the mouse hot-plate test
In normal monkeys it produces CNS depression which is
antagonized by naloxone
On the mouse vas deferens preparation, the EC50 is
increased significantly by naltrexone
This compound is remarkable for its long duration of action in
the monkey (40 hours) and for its high affinity for
the etorphine binding site (EC50 of 0.475 in the
presence of sodium)
373
UM 1147
NIH 9356
MOUSE ANALGESIA, ED50 (mg/kg)
Hot Plate: 4.0 (2.4-6.7)
Nilsen: six out of eight affected at 20 mg/kg (toxic);
Nero out of eight at 10 mg/kg
cis-3-Carbethoxy-4-hydroxy-l-methylpiperidine
benzoate) hydrochloride
4-(3,4-dimthoxy-
PHYSICAL DEPENDENCE EVALUATION IN RHESUS MONKEYS
This opioid antagonist is less potent but longer acting than
Higher doses cause convulsions.
naloqhine.
In non-dependent
monkeys it causes mild CNS depression which is antagonized by
nalorphine and by naloxone. Doses tested: SDS, 2.0-4.0; NW,
2.0-8.0; nomals, 4.0 mg/kg. Vehicle: water.
SELF-ADMINISTRATION BY MONKEYS
None of the tested doses of UM 1147 maintained rates of
responding above those of saline.
374
UM 1147 NIH 9356 (continued)
DISPLACEMENT OF STEREOSPECIFIC
EC50 (nM)
3
H-ETORPHINE BINDING
+Na
-Na
>2000
>2000
+Na/-Na
DEPRESSION OF TWITCH IN ELECTRICALLY DRIVEN GUINEA-PIG ILEUM
Only concentrations of 10-8 and 3 x 10-8M of UM 1147 depressed
the twitch, and then only to the extent of 18 per cent. At concentrations between 10-7 and 3 x 10-5M, the drug caused contraction
(baseline shift), with an EC50 of 1.15 (±0.45) x 10-5M. The maximun contraction was 74.40 (±6.16)% of that produced by a maximally
effective concentration of carbachol (10-5M). In the presence of
UM 1147 (10-7M), the EC50 for morphine to depress the twitch was
5.86 (±1.93) x 10-8M; for morphine alone, the EC50 in this preparation was 3.41 (+1.03) x 10-8M.
DEPPRESSION OF TWITCH IN ELECTRICALLY DRIVEN MOUSE VAS DEFERENS
Maximum
Depression
EC50
4.12 (±0.76) x 10-9M
Drug alone
-8
After naltrexone, 10 M
-8
After UM 979, 10 M
88.64 (±2.71)%
-9
86.15 (±4.88)%
-9
90.56 (±3.211%
8.68 (±2.88) x 10 M
4.18 (±0.20) x 10 M
SUMMARY
In some ways, UM ll47 seems to belong to the opioid family of
drugs and in some ways it does not. For instance:
In non-withdrawn, morphine-dependent monkeys, it precipitates what appears to be atypical abstinence
syndrome, and it intensifies the abstinence signs
in withdrawing, dependent monkeys
In normal-monkeys it produces CNS depression which is
antagonized by nalorphine and naloxone.
On the other hand:
UM 1147 does not compete effectively for the etorphine
binding site
On the guinea-pig ileum, a large dose (10-7M) failed
to antagonize the actions of morphine
Miscellaneously:
UM 1147 is not self-administered by rhesus monkeys
It is a moderately potent analgesic in the mouse hotplate test
In the guinea-pig ileum preparation, it causes a contraction, similar to that seen with the "abstinence-producing compounds", UM 1037 and UM 1046
375
UM 1130A NIH 9364A
MOUSE ANALGESIA, ED 50 (mg/kg)
Hot Plate:
Nilsen:
0.04 (0.03-0.05)
0.01 (0.008-0.017)
(-)-2-(2-Cyanoethyl)-5,9 alpha-dimthyl-2'-hydroxy-6,7benzomorphan hydrobramide
PHYSICAL DEPENDENCE EVALUATION IN RHESUS MONKEYS
This unusual compound precipitates abstinence signs in the nomwithdrawn, morphine-dependent animal but does not make abstinence
more severe in the with drawn monkeys.
In the latter animals, it
causes ataxia, tremors and stupor. Doses tested: SDS, 0.162.56; NW, 0-32-1.28 mg/kg. Vehicle: water.
SELF-ADMINISTRATION BY MONKEYS
UM 1130A maintained self-injection responding in only one
of three monkeys tested with the compound. At no dose did
the drug maintain response rates comparable to those with
codeine.
376
UM 1130A NM 9364A (continued)
DISPLACEMENT OF STEREOSPECIFIC
EC50 (nM)
3
H-ETORPHINE BINDING
+Na
-Na
34.8
22.7
+Na/-Na
1.53
DEPRESSION OF TWITCH IN ELECRICALLY DRIVEN GUINEA-PIG ILEUM
Maximum
Depression
EC50
Drug alone
8.55 (+1.06) x 10-9M
42.28 (±7.41)%
After naltrexone, 10-7M
7.45 (±1.57) x 10-8M
54.02 (±8.75)%
-7
-7
1.07 (±0.03) x 10 M
After UM 979, 10 M
46.91 (±6.55)
DEPRESSION OF TWITCH IN ELECTRICALLY DRIVEN MOUSE VAS DEFERENS
Maximum
Depression
EC50
5.47 (±0.82) x 10-8M
Drug alone
-8
After naltrexone, 10 M
-8
After UM 979, 10 M
100.0 (±0.00)%
-7
96.60 (±1.70)%
-8
100.0 (±0.00)%
1.41 (±0.42) x 10 M
5.50 (±1.45) x 10 M
SUMMARY
Opioid agonist activity is suggested by several observations:
UM 1130A is a potent analgesic in the muse hot-plate
test
Naltrexone antagonizes its depressant effect upon
the guinea-pig ileum and mouse vas deferens preparations, and UM 979 antagonizes its effects on
the guinea pig ileum
It competes for etorphine binding sites with moderately high affinity and sodium ratio
In the monkey it causes mydriasis, ataxia and stupor
However:
It does not suppress the signs of morphine abstinence
in the monkey; in fact, it precipitates abstinence signs in dependent animals
It has little if any tendency for self-administration
377
UM 1179 NIH 9565
MOUSE ANALGESIA, ED50 (mg/kg)
Hot Plate:
0.57 (0.42-0.78)
Nilsen:
(-)-7,12
beta-Dimethyl-9-hydroxy-4-methyl-C-hamobenzomorphan
PHYSICAL DEPENDENCE EVALUATION IN RHESUS MONKEYS
This drug causes such marked motor incoordination and apparent
confusion that the signs of morphine abstinence cannot be evaluated. There is no evidence that it suppresses abstinence, although one cannot be sure. Doses tested: SDS, 0.3-2.4; normals,
2.4 mg/kg. Vehicle: 2/3 ethanol; 1/3 Emulphor EL 620.
SELF-ADMINISTRATION BY MONKEYS
UM 1179 maintained rates of responding comparable to codeine
in two of the three monkeys; the third monkey showed maximal
rates of responding that were slightly below those of codeine.
These lower rates obtained at a lower dose.
378
M 1175 NIH 9561
MOUSE ANALGESIA,
Hot Plate:
ED50
(mg/kg)
8.2 (5.4-12.4)
Nilsen:
(+)-7,12
alpha-Dimethyl-9-hydroxy-4-methyl-C-homobenzomorphan
PHYSICAL DEPENDENCE EVALUATION IN RHESUS MONKEYS
This drug causes marked alteration in the behavior of the monkeys. in that they show marked muscle incoordination, fail to behave normally to handling and appear to be confused. The drug
neither suppresses nor precipitates the abstinence syndrome in
these morphine-dependent monkeys. Doses tested: SDS, 0.5-4.0
mg/kg. Vehicle: water.
SELF-ADMINISTRATION
BY
MONKEYS
Self-injection rates of responding in one of three monkeys
(1146) were higher for the vehicle (Emulphor plus ethanol) than
for saline. When this is taken into account, UM 1176 maintained
self-injection behavior at no dose comparable to codeine. The
single dose of 4.1 x 10-8 M/kg/injection may have maintained
minimal self-injection responding.
379
314-300 0 -80 - 26
UM 113lB NIH 9365B
MOUSE ANALGESIA, ED50 (mg/kg)
Hot Plate: No dose-response
(One out of ten affected at
100 mg/kg)
Nilsen:
(+)-2-(2-Cyanoethyl)-5,9
alpha-dinethyl-2'-hydroxy-6,7benzomorphan hydrobromide
PHYSICAL
DEPENDENCE EVALUATION IN RHESUS MONKEYS
In the doses tested, the drug had only minimal CNS depressant
effects. The supply of drug is depleted, so higher doses could
not be tested. Doses tested: SDS, 1.5-12.0 mg/kg.
SELF-ADMINISTRATION BY MONKEYS
UM 1131B maintained self-injection rates slightly above these
for saline at one dose in two of the three monkeys exposed to it.
380
UM 998 NIH 8877
MOUSE ANALGESIA, ED50 (mg/kg)
Hot Plate:
Nilsen:
3.4
(+)-l-m-Hydroxyphenyl-6,7-dimethyl-6-azabicyclo
hydrobromide
8.0 (6.2-10.2)
(2.1-5.6)
[3,2,1]
octane
PHYSICAL DEPENDENCE EVALUATION IN RHESUS MONKEYS
This drug is a morphine antagonist, significantly less potent
than nalorphine. Cases tested: SDS, 1.0; NW, 1.0-8.0 mg/kg.
Vehicle: water. Previously described in the 1975 ANNUAL REPORT.
SELF-ADMINISTRATION BY MONKEYS
At no tested dose was UM 998 self-injected at rates exceeding
those for saline.
381
UM 979 NIH 8859 Mr-1452-MS
MOUSE ANALGESIA, ED50, (mg/kg)
Inactive to 100
Hot Plate:
mg/kg, a toxic dose.
(-)-5,9
alpha-Dimethyl-2-(3-furylmethyl)-2'-hydroxy-6,7benzomorphan methanesulfonate
PHYSICAL DEPENDENCE EVALUATION IN RHESUS MONKEYS
This is a potent narcotic antagonist with a very steep doseresponse curve. Doses tested: SDS, 0.1; NW, 0.025-0.10 mg/kg.
Previously described in the 1974 ANNUAL, REPORT.
Vehicle: water.
SELF-ADMINISTRATION BY MONKEYS
UM 979 does not maintain responding at rates greater than
saline in any dose tested.
382
UM 921 NIH 8747
MOUSE ANALGESIA, ED50 (mg/kg)
Hot Plate:
Nilsen:
(-)-N-Cyclopropylmethyl-2-hydroxymorphinan
4.4 (3.4-5.8)
1.2 (0.83-1.64)
hydrochloride
PHYSICAL DEPENDENCE EVALUATION IN RHESUS MONKEYS
This drug is a long-acting morphine antagonist which shows
more depression and ataxia than does nalorphine. Doses tested:
SDS, 4.0; NW, 2.0-16.0 mg/kg. Vehicle: water. Previously
described in the 1974 ANNUAL REPORT.
SELF-ADMINISTRATION BY MONKEYS
Only one dose in one monkey produced responding at a rate
greater than saline.
383
UM 729 NIH 8310 and NIH 8377
MOUSE ANALGESIA
Hot Plate:
mg/kg.
ED50 (mg/kg)
Inactive to 100
Nilsen:
3-Allyl-7-methoxy-1,2,4,5-tetrahydro-3-(3 H )-benzazepine
hydrochloride
PHYSICAL DEPENDENCE EVALUATION IN RHESUS MONKEYS
The sedative effects of the drug were reproduced in non-dependent monkeys. Nalorphine (2.0 mg/kg) enhanced these depressant
effects, and very high doses of naloxone (8.0 mg/kg) produced
only slight antagonism - probably through non-specific mechanisms.
Dose tested: SDS, 5.0 mg/kg. Vehicle: water.
SELF-ADMINISTRATION
BY MONKEYS
At the doses evaluated, UM 729 was not self-injected at rates
above those of saline.
384
Doses
Tested
(mg/kg)
Compounds
At 3 mg/kg the drug neither
suppressed nor precipitated
the signs of morphine abstinence. At 6 mg/kg it caused
convulsions, and therefore
it was not studied at higher
doses.
SDS
3.0
6.0
NW
3.0
UM 1181 NIH 9559
Effects
MOUSE ANALGESIA, ED50 (mg/kg)
Hot Plate:
1-Methyl-4-piperidinol 2,4-dinethyl5-acetylpyrrole-3-carboxylate
hydrochloride
DISPLACEMENT OF STEREOSPECIFIC
-Na
EC50 (nM)
3
Vehicle:
13.2
(10.6-16.4)
water
H-ETORPHINE BINDING
+Na/-Na
+Na
397,000
l29,000
SDS
5.0
10.0
NW
10.0
UM 1180 NIH 9584
Nilsen:
5.0 (4.4-5.8)
3.07
At 10 mg/kg the drug neither
suppressed nor precipitated
the signs of morphine abstinence. The supply of drug is
depleted so higher doses
could not be tested.
MOUSE ANALGESIA, ED50 (mg/kg)
Hot Plate: No dose-response.
Only one out of ten was
affected at 100 mg/kg.
N-2-Hydroxyethylnorketobemidone
hydrobromide
DISPLACEMENT OF STEREOSPECIFIC
-Na
EC50 (nM)
Vehicle:
3
water
H-ETORPHINE BINDING
+Na/-Na
+Na
6550
3304
385
1.98
Doses
Tested
(mg/kg)
Compounds
UM 1198 NIH 9650
SDS
5.0
NW
2.5
5.0
Effects
A narcotic antagonist, less
potent than nalorphine. The
supply of the drug is depleted.
Mouse ED50:
3.2 (2.3-4.4)
N-4-Methylpentylnorketobemidone
hydrobromide
Vehicle:
water
SDS
5.0
NW
5.0
10.0
A narcotic antagonist, less
potent than nalorphine. Drug
supply depleted.
Mouse
ED50: Poor dose-response. Eight out of ten
affected at 80 mg/kg; two
out of ten at 50 mg/kg.
N-2-Methylpentylnor ketobemidone
hydrobromide
Vehicle:
water
UM 1191 NIH 9636
SDS
4.0
NW
4.0
8.0
It appears to be a
cotic antagonist.
doses could not be
because the supply
is exhausted.
Mouse ED50:
weak narHigher
tested
of drug
8.3 (6.3-11.0)
N-3-Methylbutylnorketobemidone
hydrobromide
Vehicle: water; drug precipitates in bottle as solution
386
cools
Doses
Tested
(mg/kg)
Compounds
SDS
2.5
5.0
NW
5.0
10.0
Effects
It neither suppresses nor
precipitates the signs of
morphine abstinence, but at
the dose of 10 mg/kg it
caused the monkeys to appear
pre-convulsive, and so higher
doses were not to tested.
Mouse ED50:
Nilsen:
4.6 (3.3-6.4)
6.0 (4.5-7.9)
1,4-Dimethyl-4-piperidinol-4-(2,4,5-trimathylpyrrole3-carboxylate) hydrochloride
Vehicle: water
UM 1188 NIH 9626
SDS
4.0
8.0
NW
8.0
At 8 mg/kg, the drug caused
very slight abstinence signs
in non-withdrawn monkeys.
Since the supply was depleted, higher doses could not
be tested.
Mouse ED50:
7.3 (5.2-10.2)
Nilsen: (oral) 14.1 (10.2-19.5)
N-(3-Ketolpentyl)norketobemidone
hydrobromide
Vehicle:
water
UM 1182 NIH 9451
SDS
1.6
3.2
6.4
At 6.4 mg/kg, the drug seemed
to slow the progression of
abstinence signs without
actually reversing the proAt that dose, the drug
cess.
seemed to be preconvulsive,
and so higher doses were not
tested. Drug depleted.
Mouse ED50:
Nilsen:
1,4-Dimathyl-4-piperidinol 4-(3,4dimthoxybenzoate) hydrochloride
Vehicle:
water
387
3.2 (2.1-4.8)
6.0 (4.5-7.9)
Compounds
DOSES
Tested
(mg/kg)
Effects
UM 1179 NIH 9565
SDS
0.3
0.6
1.2
2.4
Normals
2.4
This drug causes such marked
motor incoordination and apparent confusion that signs.
of morphine abstinence cannot
be evaluated. There is no
evidence that it suppresses
abstinence, though one cannot
be sure
Mouse ED50:
0.57 (0.42-0-78)
(-)-7,12
beta-Dinethyl-9-hydroxy-4-methylC-homobenzomorphan
Vehicle:
2/3 ethanol;
1/3 Emulphor EL 620
UM 1178 NIH 9564
SDS
10.0
It causes CNS depression
without suppressing the
signs of morphine abstinence. Drug supply depleted.
Mouse ED50:
17.9 (12.3-26.0)
(+)-7,12
beta-Dimethyl-9-hydroxy-l-methylC-homobenzomorphan
Vehicle:
2/3 ethanol;
UM 1174 NIH 9560
1/3 Emulphor EL 620
SDS
1.0
2.0
4.0
Normals
4.0
This drug causes CNS depression with stupor, confusion
and mortor incoordination but
no clear effect upon the progression of morphine abstinence signs. Nalorphine and
naloxone had little effect
upon its actions.
Mouse ED50: 1.5 (1-1-2.0)
dl-9-Hydroxy-7,12 alpha-dimethyl-4-methylC-homobenzomorphan
Vehicle:
water
388
Compounds
Doses
Tested
(mg/kg)
Effects
UM 1159 NIH 9513
SDS
0.2
0.4
NW
0.4
Normals
0.4
It neither precipitates nor
suppresses morphine abstinence signs, but produces a
highly atypical form of CNS
depression, including dysphoria, confusion and cataThese effects were
tonia.
not reversed by nalorphine
or naloxone.
Mouse ED50:
0.32 (0.24-0.44)
dl-trans -5,6,6a beta,7,8,9,10,10a alpha-octahydro-l-acetoxy9 beta-hydroxy-6 beta-methyl-3-(5-phenyl-2-pentyloxy)phenanthridine hydrochloride
Vehicle:
2/3 ethanol;
1/3 Emulphor EL 620
UM 1155 NIH 9506 MCV 4140
SDS
1.0
NW
0.06
0.12
0.25
0.5
1.0
A potent, long-lasting opioid antagonist
Mouse Ed50: Inactive.
related jumpiness.
Nilsen:
Inactive.
at 100 mg/kg
Dose-
Toxic
2-Allyl-3a- m-hydroxyphenol-2,3,3a,4,7,7a-hexahydrocis-isoindole
Vehicle:
2/3 dilute hydrochloric acid
1/3 propylene glycol:
UM 1153 NIH 9390
SDS
5.0
NW
5.0
The dose of 5.0 mg/kg of
this drugneither suppressed
nor precipitated the signs
of morphine abstinence. Because of the small quantity
of drug available, other
doses were not tested.
Mouse ED50:
9.1 (5.2-15.9)
trans -3-(N-Cyclopropylmethyl-N-methylamino-l-phenyl1,2,3,4-tetrahydronaphthalene hydrochloride
Vehicle:
water
389
Doses
Tested
(mg/kg)
Compounds
UM
1152
NIH
9468
MCV
4131
SDS
3.0
6.0
NW
3.0
Effects
It neither suppresses nor
precipitates abstinence
sings at 3 mg/kg. At 6.0
mg/kg, it produced convulsions in one of two monkeys
Mouse ED50:
5.5 (3.8-7.8)
4-(Methyl- n-butylamino)-4-( m-hydroxyphenyl)-cyclohexanaone
ethylene ketal hydrochloride
Vehicle:
water
UM 1139 NIH 9380 MCV 4112
SDS
3.0
6.0
12.0
This relatively insoluble
compound was administered
in 100 percent propylene
In the doses tested
glycol.
it neither precipitated nor
suppressed abstinence signs,
though it caused mild CNS
depression with decreased
skeletal muscle tone. Drug
supply depleted.
Mouse ED50:
6.0 (4.4-8.3)
1,3-Dimethyl-4-phenyl-4-piperidylmethyl carbonatate
Vehicle:
100 per cent propylene glyool
UM 1133A NIH 9369A
SDS
1.0
2.0
NW
1.0
2.0
The drug precipitates abstinence signs in the non-withdrawn, morphine-dependent
monkeys, but it does not
intensify the withdrawal
signs in monkeys which are
already spontaneously withIt causes signs of
drawing.
CNS depression, including
ataxia and stupor.
Mouse ED50:
Nilsen:
0.9 (0-7-1.2)
0.6 (0.4-0.8)
dl-2-(3-Cyanopropyl)-5,9
alpha-dimethyl-2'-hydroxy-6,7benzotorphan hydrobromide
390
Compounds
Doses
Tested
(mg/kg)
UM 891 NIH 8687
SDS
0.003
0.006
0.012
0.025
0.05
Effects
The drug suppresses abstinenloe signs and causes marked CNS depression
Mouse ED50:
2-(2-(4-Phenyl-4-propionoxypiperidino)ethylamino)
Vehicle:
0.05 (0.04-0.06)
benzamide
water
UM 889 NIH 8684
SDS
0.1
NW
0.1
0.2
0.4
0.8
1.6
This drug is a nalorphinelike antagonist, 1/3 as potent. The abstinence syndrome precipitated by this
drug differed from that precipitated by nalorphine in
that retching and vomiting
were minimal with UM 889
Mouse ED50:
0.16 (0.13-0.21)
(-)-m-(l-Cyclopropylmethyl-3-ethyl-hexahydro-l H -azepin-3-yl)
phenol fumarate
Vehicle:
water
UM 884, UM 899, UM 1095
Loperamide
NIH 8635, NIH 8714, NIH 9230 MCV 4073
SDS
2.0
4.0
8.0
16.0
At 2.0 mg/kg the drug caused
partial, long-lasting suppression of abstinence, whether the drug was dissolved
in water, 33% propylene glycol or 100% DMSO. At 4.0
and 8.0 in 33% PG, it produced complete, long-lasting
suppression of abstinence.
Mouse ED50:
2.6 (2.1-3.2)
4-(p-Chlorophenyl)-4-hydroxy-N,N-dimathyl-alpha,alpha-diphenyl1-piperidinebutyramide
hydrochloride
Vehicle:
water, 33% propylene glycol or 100% dimethylsulfoxide
391
Doses
Tested
(mg/kg)
Compounds
UM 866, UM 900
Effects
NIH 8636, NIH 8715
SDS
2.0
4.0
8.0
When given in 50% propylene
glycol, it caused long-lasting suppression of abstinence signs and CNS depression.
When given in DMSO, it had
no apparent effect other than
causing abscesses.
Mouse ED50:
2.9 (2.4-3.5)
4-(4-Chloro-alpha, alpha, alpha-trifluoro-m -tolyl)-4-hydroxy-N,Ndimathyl-alpha, alpha-diphenyl-1-piperidinebutyramide HCl
Vehicle:
50 per cent propylene glycol or 100 per cent DMSO
UM 762 NIH 8444
SDS
1.0
2.0
4.0
8.0
16.0
NW
16.0
At a dose of 16 mg/kg, it
seemed to intensify the signs
of abstinence, but this dose
in 2 non-withdrawn monkeys
did not precipitate abstinence.
Mouse ED50:
2.2 (1.8-2.7)
4-Amino-3,5-dibromo-alpha-((dimathylamino)methyl)benzyl
hydrochloride
Vehicle:
alcohol
water
UM 720 NIH 8366
SDS
4.0
8.0
16.0
It neither suppresses nor
precipitates abstinence
signs, but at the highest
dose caused CNS stimulation.
Animals appeared pre-convulsive.
Mouse
ED50:
9.8
(8.0-12.1)
3-(p-Aminophenethyl)-7-methoxy-l,2,4,5-tetrahydro-3-(3H)benzazepine dihydrochloride
Vehicle:
water
392
Compounds
Doses
Tested
(mg/kg)
UM 706 NIH 8400
SDS
2.0
4.0
8.0
16.0
32.0
Effects
Nearly complete suppression
of abstinence signs at 32.0
mg/kg, a dose which caused
severe tremors and marked
apprehension
Mouse ED50:
11.5 (9.3-14.3)
2-Cyclopropylcarbonyloxy-4-dimthylamino-3-methyl-1,2diphenylbutane
Vehicle:
water
UM 635 NIH 8251
SDS
1.0
32.0
NW
0.5
1.0
2.0
4.0
8.0
16.0
32.0
This drug is a weak nalorphine-like antagonist. Its
dose-response curve is flat
and has a low maximum. The
drug also has sedative proparties.
Mouse ED50:
1.9
(1.7-2.1)
N-Isopropyl-N-methyl-3-formamido-1-pyrazole carboxamide
Vehicle:
water
UM 625 NIH 8242
SDS
2.0
4.0
8.0
16.0
It suppresses the signs of
morphine abstinence. At
the highest dose it caused
coma and a slight convulsion.
Mouse ED50:
Inactive. Only
two of ten affected at 100
mg/kg
l-(beta-Carbethoxyethy1)-4-carbethoxy-4-phenylpiperidine
hydrochloride
Vehicle:
water
393
Doses
Tested
(mg/kg)
Compounds
UM 623, UM 668
NIH 8240, NIH 8299
SDS
0.5
1.0
2.0
4.0
8.0
NW
2.0
4.0
8.0
Effects
GPA 1657
A nalorphine-like antagonist,
approximately 20 times less
potent. A Primary Addiction
study of this compounds was
included in the ANNUAL REPORT of 1967.
Mouse ED50: 0.18 (0.15-0.20)
(-)-2'-Hydroxy-2,9 beta-dimethyl-5-phenyl-6,7-benzomorphan
hydrochloride
Vehicle:
propylene glycol plus water
UM 610 NIH 8225
SDS
1.0
2.0
4.0
8.0
16.0
32.0
64.0
This drug does not suppress
the signs of morphine abstinence, but in a Primary Addiction study (see ANNUAL
REPORT of 1963) it was found
to produce mild abstinence
signs of its own - mostly
hyperirritability and tenderness, with few if any GI
signs.
Mouse ED50:
Oral:
2-(4-Ethoxybenzoyl)-5-methyl-3benzofuran hydrochloride
Vehicle:
47.7 (42.9-53.0)
(2-pyrrolidinoethoxy)-
water
UM 604 NIH 8216
SDS
1.0
2.0
4.0
8.0
16.0
NW
16.0
32.0
This drug is a weak nalorphinelike antagonist, with CNS
stimulant properties and a
low margin of safety
Mouse ED50: 6.1 (5.3-7.1)
Nilsen:
2-Methyl-5-phenyl-6,7-benzomorphan hydrobromide
Vehicle:
2.3 (2.0-2.6)
water
394
5.4 (3.7-7.9)
Doses
Tested
(mg/kg)
Compounds
UM 461 NIH 8034
SDS
0.4
0.8
1.6
Effects
A dose of 1.6 mg/kg of this
drug is required to produce
complete suppression of all
morphine abstinence signs.
It produces more sedation
than would an equivalent
dose of morphine.
Mouse ED50:
Oral :
2.0 (1.7-2.3)
19.1 (15.8-23-0)
1-(2-(1,4-Benzodioxanyl)-methyl)-4-(2-oxo-1-benzimidazolinylpiperidine
Vehicle:
water
UM 485 NIH 8062
SDS
0.003
0.01
0.015
0.03
0.06
0.125
0.25
2.0
In a dose of 0.03 mg/kg it
produces complete suppression of morphine abstinence
plus intermediate level
CNS depression
Mouse ED50:
Oral:
0.032 (0.0280.037)
0.46 (0.40-0.53)
2-Acetyl-1,2,3,4-tetrahydroisoquinoline-4-spiro-4'-(l'-(3-cyano3,3-diphenylpropyl)) piperidine hydrochloride
Vehicle:
propylene glycol
UM 149 NIH 7413
SDS
5.0
10.0
20.0
The tested doses failed to
to suppress the signs of
morphine abstinence.
Mouse ED50: Inactive. Only
one out of ten affected
at 250 mg/kg
4-Carbethoxy-1-methyl-4-phenylpiperidine N-oxide hydrobromide
Vehicle:
water
395
314-300 0 -80 - 27
PRIMARY ADDICTION STUDY
UM 884 (NIH 8635); UM 899 (NIH 8714); UM 1095 (NIH 9230); Loperamide
4-(p-chlorophenyl)-4-hydroxy-N,N-dimethyl-alpha,alphadiphenyl-1-piperidine butyramide hydrochloride
Previous studies in this laboratory. Under three different code
numbers, this compound has been submitted for single-dosesuppression studies:
As UM 899 (NIH 8714), the material was dissolved in 100 per
cent dimethylsulfoxide. In this solvent, a dose of 4.0
mg/kg caused no apparent effect, while a dose of 16 mg/kg
produced a very slight amelioration of opioid abstinence
signs, but caused abscesses at the injection sites. Therefore, the study of UM 899 was discontinued.
As UM 884 (NIH 8635), this drug was dissolved in 30 per cent
propylene glycol. At 2.0 mg/kg, it produced partial suppression of morphine abstinence signs; at 4.0 mg/kg, the
suppression was almost complete; at 8.0, the drug caused
complete suppression of abstinence and also produced sedation. The effects were slow in onset (peaking in 3 to 4
hours) and the abstinence suppression was of long duration
(12 hours at 8.0 mg/kg).
Oral administration of 8.0 mg/kg of this drug produced
complete suppression of abstinence signs, and this effect
was still apparent 12-14 hours after drug administration.
Nomally, single dose suppression tests are performed blindly,
with the compound identified only by code number. When
this drug was re-investigated as UM 1095 (NIH 9230), its
identity and structure were known to the investigators.
At a dose of 2.0 mg/kg, it was given to different animals
in water solution, in 30 per cent propylene glycol and in
100 per cent DMSO. The results with these three solvents
were similar, with the drug showing marked, long-lasting,
abstinence-relieving properties.
Dosage schedule. During this Primary Addiction Study, the dose of
loperamide was changed several times, in an attempt to maintain
drug effects between injections but still not produce dangerous
levels of CNS depression. The doses which were used were:
Day 1
Days 2-6
Days 7-9
Days 10-15
-
2.0
0.5
1.0
2.0
396
mg/kg,
mg/kg,
mg/kg,
mg/kg,
every
every
every
every
6
6
6
6
hours
hours
hours
hours
Days 16-20
Days 21-29
Days 30-34
Day 35
-
1.0 mg/kg, every 6 hours
2.0 mg/kg, every 8 hours
2.0 mg/kg, every 6 hours
abrupt withdrawal
Animals. This study was started with monkeys numbered 820, 821
and 822. Within 24 hours, monkey #822 had died of acute, druginduced respiratory depression. That animal was replaced by
monkey #824 for the remainder of the study.
Acute effects. Loperamide caused morphine-like CNS depression,
with the monkeys staring into space and showing body sag, muscle
weakness, occasional scratching and slight pupil dilatation. At
the initial dose of 2.0 mg/kg every 6 hours, there was an apparent
cumulation of the drug, because all three animals developed respiratory depression. One animal died, as noted above, and the other
two were given naloxone, 2.0 mg/kg, which reversed the effects of
loperamide.
The doses of 0.5 and 1.0 mg/kg produced milder CNS depression, and
it appeared that tolerance developed to these doses upon repeated
administration, such that after several days of drug administration
the drug effects did not last through the six-hour interinjection
interval. On the other hand, at a time when tolerance had developed to the lower doses, the administration of 2.0 mg/kg every six
hours produced progressively more severe muscle weakness and
ataxia--suggesting again that cumulation was occurring at this
dose. On the other hand, the every-eight-hour administration of
2.0 mg/kg did not sustain a drug effect throughout the interinjection interval. Thus, no truly satisfactory injection schedule was
achieved in this study.
Physical dependence. A naloxone challenge was perfomed on the
14th day of the study, at a time when the monkeys had been receiving loperamide at the highest dose (2.0 mg/kg every 6 hours) for
several days. The precipitated abstinence syndrome was very severe
Signs ap— in the range between 6 and 7 on the Seevers scale.
peared within two minutes of naloxone administration. All three
monkeys screamed constantly, showed severe autonomic signs and
Though the abstinence
were so sick that they could not move.
signs decreased in intensity with the passage of time, they were
still apparent to a certain extent for six hours, until the monkeys received a dose of loperamide.
On the 16th day, nalorphine was used to precipitate abstinence
signs, which were less severe and somewhat different in character
from those seen two days earlier with naloxone. After nalorphine,
the monkeys showed marked irritability when handled, and this
irritability was of a general nature, rather than localized to the
abdominal area. The animals were irritable towards each other,
though there were periods during which they became calm, sitting
quietly, ignoring one another and staring into space. The severity of the nalorphine-precipitated abstinence was graded as
slightly greater than 4 on the Seevers scale.
397
Abrupt withdrawal of lopermide occurred on the 35th day of the
A typical opioid withdrawal syndrome developed slowly in
study.
For the first 24 hours, there were
each of the three animals.
essentially no signs. Between 60 and 90 hours after the last
dose of loperamide, the abstinence syndrome reached a level of
approximately 4 on the Seevers scale; by 120 hours, the signs
had become minimal; after 160 hours, the signs were completely
gone.
Summary. Loperamide is a relatively insoluble drug with longlasting opioid properties. Acute administration produces morphine-like CNS depression which is antagonized by naloxone. It
relieves the abstinence syndrome in morphine-dependent monkeys.
Onchronic administration, there appears to be both cumulation
and tolerance development. Physical dependence develops, such
that opioid abstinence signs appear gradually when loperamide
administration is discontinued abruptly or develop acutely when
the animals are challenged with nalorphine or naloxone.
ACKNOWLEDGMENT.
The authors wish to acknowledge the excellent
technical assistance of Fred M. Adams, James Goodrich, Gail
Renard, Douglas Solecki, George Christmas, Michael Jewett and
Patricia J. Dahlstrom.
This work was supported by Grant DA 00254-07 from the National
Institute on Drug Abuse and by The Committee on Problems of Drug
Dependence, Inc.
AUTHORS:
Henry H. Swain, M.D.
James H. Woods, Ph.D.
Fedor Medzihradsky, Ph.D.
Charles B. Smith, M.D., Ph.D.
Clifton L. Fly
Department of Pharmacology
M6322 Medical Science Building I
The University of Michigan
Ann Arbor, MI 48109
398
Papers Read by Title
But Not Presented
at the 41st Annual
CPDD Meeting
Effects of Alcohol Abuse on
Progression of Liver Disease in
Methadone-Maintained Patients
Beverley, C. L.; Kreek, M. J.; Wells, A. O.; Curtis, J. L.
To determine whether chronic abuse of alcohol produced rapid
deterioration of liver function in methadone-maintained patients,
a 2-year prospective study was conducted in a single methadone
maintenance treatment clinic in New York City (1-8). Sixty-eight,
or 31 percent of patients enrolled in treatment were identified
as chronic alcohol abusers at the beginning of the prospective
study period.
At the end of the 2-year period, 28 (41 percent) of patients
initially identified as alcohol abusers remained in methadone
maintenance treatment; 55 percent of the remaining non-alcoholabusing clinic population remained in treatment at the end of the
2-year period.
At least 54 percent of alcohol-abusing patients remaining in
methadone maintenance treatment during the study period showed
improvement or no change in liver function tests (SGOT, bilirubin,
alkaline phosphatase). Analysis of similar data available on
these 28 patients for up to 4 years preceding the study showed
that liver function had either improved or not changed in 61 percent over a 2 to 6-year period. Data were available for 3 years
or longer for 72 percent of these patients.
At the end of the prospective period, 40 patients (59 percent)
initially identified as alcohol abusers had terminated treatment.
Comparable liver function test data are available for only 2 of
these patients during the prospective study period. However,
during the combined 2-to 6-year period, data were available for
19 patients (48 percent). Improvement or no change in liver
function was observed in only 20% of these patients. There were
no deaths due to liver disease in the alcohol-abusing patients.
Liver function tests of 28 randomly selected non-alcohol-abusing
methadone-maintained patients enrolled in the clinic throughout
the prospective study period were evaluated retrospectively.
Comparable test data were available for 17 patients (61 percent)
399
during the study period. Improvement or no change in liver test
values was observed in 54 percent of these patients during 2
years, and 75 percent in the combined 2 to 6-year period.
These data show that there was no rapid deterioration in liver
function, as evidenced by laboratory tests, in alcohol-abusing
methadone-maintained patients remaining in treatment. Since 41
percent of-the alcohol-abusing patients remained in methadone
treatment for at least 2 years and, of these, 72 percent had been
followed for longer than 3 years, the commonly held opinion that
methadone maintenance treatment for the alcoholic heroin addict
or former addict is ineffective and possibly hopeless may no
longer be valid (9,10).
REFERENCES
1.
Stimmel, B., Vernace, S., and Tobias, H. Hepatic dysfunction
in heroin addicts: The role of the needle. J. Amer. Med. Assn.,
222:811-812, 1972.
2.
Kreek, M.J., Dodes, L., Kane, S. et al. Long-term methadone
maintenance therapy: effects on liver function. Ann. Intern.
Med., 77:598-602, 1972.
3.
Scott, N.R., Winslow, W.W., and Gorman, D.G. Epidemiology of
alcoholism in a methadone maintenance program. Proceedings of
the Fifth National Conference on Methadone Treatment, I:284287, 1973.
4.
Bihari, B. Alcoholism in M.M.T.P. patients: etiological
factors and treatment approaches. Proceedings of the Fifth
National Conference on Methadone Treatment, I:288-295, 1973.
5.
Stimmel, B., Cohen, M., and Hanbury, R. Alcoholism and polydrug abuse in persons on methadone maintenance. Ann. N.Y.
Acad. Sci., 311:99-109, 1978.
6.
Kreek, M.J. Medical complications in methadone patients.
Ann. N.Y. Acad. Sci., 311:110-134, 1978.
7.
Freedman, Z.L. Methadone and alcohol. Ann. N.Y. Acad. Sci.,
273:624-628, 1976.
8.
Siassi, I., and Alston, D.C. Methadone maintenance and the
problem with alcohol. Amer. J. Drug & Alcohol Abuse, 3:267277, 1976.
9.
Dole, V.P., and Joseph, H. Long-term outcome of patients
treated with methadone maintenance. Ann. N.Y. Acad. Sci.
311:181-189, 1978.
10.
Gordis, E., and Sereny, G. Effect of prior narcotic addiction
on response to treatment of alcoholism. Alcoholism: Clinical
and Experimental Research (in press 1979).
400
ACKNOWLEDGEMENTS
This study was supported in part by Grant DA-01138 from the
National Institute on Drug Abuse and in part by a Research
Scientist Award to Dr. Kreek (DA-00049) from HEW-ADAMHA-NIDA.
AUTHORS
Cordia L. Beverley, M.D.
The Rockefeller University
1230 York Avenue
New York, New York 10021
Mary Jeanne Kreek, M.D.
The Rockefeller University
1230 York Avenue
New York, New York 10021
Aaron O. Wells, M.D.
New York Hospital-Cornell Medical Center
525 East 68th Street
New York, New York 10021
James L. Curtis, M.D.
Cornell University Medical College
1300 York Avenue
New York, New York 10021
401
Modification of Treatment
Compliance as a Function of
Contingent Payment
Manipulations
Grabowski, J.; O’Brien, C. P.; Greenstein, R.; Long, M.;
Steinberg-Donato, S.; Ternes, J.
A problem common to treatment regimens is that of establishing
compliance (Swinyard, 1975). However, as Zifferblatt (1975) has
noted, noncompliance should be amenable to change using behavior
modification techniques. Stitzer and Bigelow (in press) and
others (Stitzer, Bigelow, and Liebson, in press; Liebson,
Tomassello and Bigelow, 1978) have suggested specific behaviorally based procedures which may enhance compliance in drug
treatment programs.
The degree of compliance which can be inherently generated by
a specific treatment form is illustrated by pharmacological agents
used as adjuncts in treatment of opiate use. Methadone is itself
a positive reinforcer and this in combination with existence of
physical dependence contributes to continuing attendance at a
clinic where other treatment can be provided. LAAM is only mildly
reinforcing but produces physical dependence and thus continued
access to other treatment options is probable. Naltrexone, an
opiate antagonist, does not generate physical dependence, has no
immediate positive reinforcing properties and thus, like many
other treatment forms, has no inherent characteristics increasing
the probability of regular "treatment-seeking behavior."
A patient expressing a "strong" desire to remain opiate free and
taking naltrexone is not provided with a built in mechanism in
the pharmacological treatment to engage in persistent "treatmentseeking behavior." Therefore treatment visits may be irregular
or terminate early in the opiate free period. Abbreviated
duration may be disadvantageous since it has been reported that
successful outcome is correlated with duration of naltrexone
treatment (Resnik and Schuyten-Resnik, 1976) and irregularity of
naltrexone ingestion precludes effective opiate blockade and thus
the possibility of reinitiation of opiate use emerges.
Meyer et al.(1976) noted that the behaviorally based procedure
of making small daily payments increased likelihood of clinic
attendance by patients taking naltrexone. Curran, Doyle and
402
Savage (1977) implemented an equivalent reinforcement schedule
procedure with less clear benefit. Since combinations of response
and temporal requirements constituting reinforcement schedules
have been demonstrated to be powerful determinants of rate and
pattern of behavior it might be expected that effective alternatives to the simple 1:1 payment procedure may further enhance
compliance.
The purpose of the present study was to examine the
effects of payment and scheduling on compliance with a naltrexone
treatment regimen.
METHOD
Subjects: Nine individuals (age range 24-30) with a past history
of opiate use who were being treated with naltrexone served as
subjects. Naltrexone was one treatment choice available to patients
and thus involve self-selection.
Setting: The treatment setting was the University of Pennsylvania/
Philadelphia Veterans Administration Hospital Drug Dependence
Treatment Center. Diverse services are provided by a variety of
professional staff members.
Procedure : Individuals who decided in favor of treatment with
naltrexone were given the opportunity for involvement in the
study.
Each patient was asked to read an "Information and Consent"
form which included multiple choice questions requiring correct
responses (Grabowski, O'Brien, and Mintz, 1979). The patients'
questions were then answered and they were asked to sign the form
if they were interested in participating.
Opiate detoxification and initiation of preliminary low doses of
naltrexone were accomplished on an inpatient basis followed by
initiation of a thrice weekly regimen on an outpatient basis.
Patients entering the payment study were assigned to schedule
groups sequentially, including: Continuous Reinforcement (CRF;
for which payment occurred on each visit), a Fixed Interval
(FI; payment once each week), Fixed Ratio (FR; payment every third
visit) or a Variable Ratio (VR; payment mean every third visit)
Patients received $3.35 each day for the first three
schedule.
visits. In subsequent weeks the several reinforcement schedules
were initiated. The CRF and VR reinforcement schedules were
deleted as maintenance schedules later in the study. After eight
weeks on the initial schedule, conditions were reversed. Subjects
on response-based schedules (CRF, FR, VR) were switched to the
time-based (FI) schedule and those receiving payment under timebased (PI) contingencies were switched to the response-based (FR)
procedure.
After four weeks the conditions were again reversed
and thus the original schedules were reinstated.
The total possible payment per month ($40.20) was the same under
all schedules: CRF payments were $3.35 each, while FR, VR and FI
payments were $10.05. Payments were dispensed by a person not
involved in treating naltrexone patients.
403
RESULTS
In general, providing payment appears to increase the duration
of treatment with naltrexone. Prior to introduction of the
payment schedules retention through the first month of treatment
was 60% (74 of 125) of all patients completing the naltrexone
induction sequence. For payment schedule patients, 89% (8 of 9)
remained in treatment for at least one month. The percentage
of patients departing from treatment during the first four months
continued to increase more rapidly for those not receiving
payment (Figure 1).
Figure 1: Percentage of naltrexone regimen patients
remaining in treatment over successive four-week periods.
Patients (N=9) in the study received payment contingent
Previously patients
on attendance/ingestion
(N-126) had received payment for other procedures and
it was not contingent on adherence to the nultrexone
1
regimen
© 1979, Marcel Dekker, Inc.
The pattern of attendance suggests differences were due in part
to the prevailing maintenance payment schedule. Patients attended
the clinic and ingested naltrexone on 88.0% (140 of 159) of the
scheduled visits when payment was response-based; that is when
payment was directly contingent on number of doses ingested as in
the CRF, FR, and VR schedules. However, when payment was timebased, (FI), and "missed doses" did not necessarily delay payment,
patients attended the clinic and ingested naltrexone on 72.8%
(107/147) of the scheduled visits. The differences between
cumulative attendance/naltrexone ingestion data for response and
time-based schedules are statistically significant (P< .001).
404
When patients attended under the time-based schedule, payments
were made on Friday or on the first visit thereafter. All Friday
(payment day) appointments for naltrexone ingestion were kept
when the prevailing schedule was time-based. Therefore, the
cumulative percentage of "missed doses" (27.2%) under the timebased schedule occurred on Monday or Wednesday, i.e., the days
on which no payment was scheduled. When payment was contingent
on the number of naltrexone doses ingested, no pattern of "missed
doses" was evident. That changes in the pattern of attendance
generally covaried with systematic schedule reversals indicates
that control was generated by the maintenance schedule (b,c,d,
Figure 2). However, some patients ingested naltrexone consistently,
Figure 2: Data for 4 patients illustrating patterns of
attendance as a function of the maintenance reinforcement
schedule. In b, c and d, clinic attendance/neltrexone
ingestion covaried with schedule changes.
Data in a is for
patient whose consistent attendance continued during the FI
schedule which "permitted" missed visits. (a) CRF, continuous
reinforcement; (b) FR, fixed ratio; (c) VR, variable ratio;
(d) FI, fixed interval. © 1979, Marcel Dekker, Inc.1
405
regardless of the reinforcement schedule (a, Figure 2) which indicates, as might be expected, that payment was only one of
several determinants of the behavior.
DISCUSSION
This preliminary study permitted evaluation of several factors
modulating compliance to a naltrexone treatment regimen. The
results support those of Meyer et al. (1976) which indicated that
monetary reinforcement may increase naltrexone treatment duration.
In addition the results suggest that use of specific schedules
of reinforcement may reduce inconsistent attendance/naltrexone
ingestion patterns, thereby reducing the problem of inadequate
opiate blockade.
Response-based schedules (CRF, FR, VR) generated a more regular
attendance pattern than time-based (FI) schedules, which was
desirable.
The VR schedule produced the most consistent behavior,
but the irregularity of payments was a source of continual complaints. As a result, VR payments were not viewed as acceptable,
based on therapeutic considerations. Although the CRF schedule
was both effective and considered acceptable by patients, it was
cumbersome to administer in the prevailing system and was
subsequently omitted.
Clearly this problem might not arise in
other clinics, and it is not necessarily a reason to exclude the
schedule. However, use of the CRF schedule was continued during
the first week of treatment in order to establish the procedure's
"credibility" with the patients.
In general, observations indicate that the FR schedule was optimal
for several reasons: It provided predictable reinforcement for
naltrexone ingestion; the explicit consequence for missed doses
was delay of payment; and finally patients perceived the schedule
as fair and the most desirable of those available, since it
provided consistent meaningful payment each week.
A question of some concern was whether the monetary payments
available to patients were adequate reinforcers. The total amount
of $40.20 each month appeared sufficient to significantly increase
the duration of treatment. Larger weekly payments or additional
monthly "bonuses" for regular attendance would probably be even
more effective. Subsequent experience with several patients
having substantial incomes produced mixed results with one insisting on payment and others ignoring it.
Finally, it has been suggested that when a patient misses a
naltrexone dose, he is making an explicit behavioral statement
of intent to use opiates. It has also been suggested that the
patient is "testing his will power." Although fairly simplistic,
both patterns of behavioral statement should be considered. An
alternative view is that a primary determinant of missed doses
is absence of both positive reinforcing consequences and the
negative reinforcers associated with physical dependence. From
this perspective it is essential to differentiate short-term
406
behavioral variability and long-term goals. The patient with a
history of opiate use enters naltrexone treatment with a long-term
goal established and has overcome several obstacles to do so.
It seems unreasonable to suggest that by missing a dose of naltrexone he is abrogating long-term goals.
Naltrexone treatment is a possible means for individuals to achieve
the goal of opiate independence. However because naltrexone
ingestion is not intrinsically reinforcing, patients may miss
doses.
Such omissions will weaken the antagonist-generated blockade, and in combination with availability of opiates this may
result in relapse for the former user. Since therapeutic techniques do exist to increase compliance it seems reasonable to
make use of them. That providing extrinsic reinforcers does not
have the elegance of the elusive concepts of "will power" or
"good motivation" should not serve as a deterrent to their use.
REFERENCES
Curran, F., Doyle, P.A., and Savage, C. Maximizing narcotic
antagonist (naltrexone) treatment through use of behavioral
Presented at the National Drug Abuse Conference,
reinforcement.
San Francisco, May 1977.
Grabowski, J., O'Brien, C.P., Greenstein, R., Long, M., SteinbergDonato, S., and Ternes, J. Effects of contingent payment on compliance with a naltrexone regimen. The American Journal of Drug
and Alcohol Abuse, 6(3), 1979. Marcel Dekker, Inc., N.Y.
Grabowski, J., O'Brien, C.P., and Mintz, J. Increasing the
likelihood that consent is informed. Journal of Applied Behavior
Analysis, (in press), 1979.
Liebson I.A., Tommasello, A., and Bigelow, G. A behavioral
treatment of alcoholic methadone patients. Annals Of Internal
Medicine, 89, 1978, 342-344.
Meyer, H., Randall, M. Barrington, B.A., Mirin, S., and
Greenberg, I. Limitations of an extinction approach to narcotic
antagonist treatment. In D. Julius and P. Renault (eds.),
Narcotic Antagonists: Naltrexone. National Institute on Drug
Abuse Research Monograph 9. DHEW Pub. NO. (ADM)76-387.
Washington, D.C.: Supt. of Docs., U.S. Govt. Print. Off., 1976.
Resnik, R., and Schuyten-Resnik, E. A point of view concerning
treatment approaches with narcotic antagonists. In D. Julius and
P. Renault (eds.), Narcotic Antagonists: Naltrexone. National
Institute on Drug Abuse Research Monograph 9. DHEW Pub. No.
Washington, D.C., Supt. of Docs., U.S. Govt. Print.
(ADM)76-387.
Off., 1976.
Stitzer, M., and Bigelow, G. Contingency management in a
methadone maintenance program: Availability of reinforcers.
International Journal Of The Addictions, (in press).
407
Stitzer, M., Bigelow, G., and Liebson, I. Supplementary methadone
self-administration among methadone maintenance clients. Submitted
to Addictive Behaviors.
Swinyard, E.A. Principles of prescription order writing and patient
compliance instruction. In L.S. Goodman and A. Gilman (eds.), The
Pharmacological Basis of Therapeutics. New York
Zifferblatt, S. Increased patient compliance through the applied
analysis of behavior. Preventive Medicine, 1975, 4, 173-182.
ACKNOWLEDGMENT
Supported in part by grant DA 001218, National Institute on Drug
Abuse.
AUTHORS
J.
C.
R.
M.
S.
J.
Grabowski, Ph.D.
P. O'Brien, M.D., Ph.D.
Greenstein, M.D.
Long, B.S., R.N.
Steinberg-Donato, B.A.
Ternes, Ph.D.
Department of Psychiatry
University of Pennsylvania
Drug Dependence Treatment/Research Center
Philadelphia Veterans Administration Hospital
Philadelphia, Pennsylvania 19104
FOOTNOTE
1. Figure 1 and figure 2 and a modified version of this text originally appeared in Grabowski, J.; O'Brien, C.P.; Greenstein, R.;
Long, M.; Steinberg-Donate, S.; and Terries, J.; Effects of contingent payment on compliance with a naltrexone regimen; The American
Journal of Drug and Alcohol Abuse; Vol. 6, No. 3; copyright
1979; Marcel Dekker, Inc; New York, New York. They are used with
permission of Marcel Dekker, Inc., and may not be further reproduced without their specific permission.
408
The Effect of I-Alpha Acetyl
Methadol in Morphine-Dependent
Rats
Riley, A. L.; Etherton, D. S.; Shapiro, R. M.
L-alpha acetyl methadol (LAAM) has recently been introduced as
one alternative to methadone in the maintenance therapy for
narcotic addiction (Blaine 1978; Blaise and Renault, 1976).
Before it can be considered a viable alternative, however,
several issues must be assessed. First, it must be detemined
if LAAM can adequately substitute for morphine in narcoticdependent subjects, and as such, prevent the occurrence of withdrawal. Secondly, it must be determined if subjects maintained
on LAAM following morphine withdrawal become dependent on this
substitute.
Several reports using rats as subjects have demonstrated that
LAAM given continuously via intraperitoneal or intravenous
infusion can partially substitute for morphine in morphinedependent subjects (Patrick, Dewey, and Harris, 1976; Young,
Steinfels, and Khazan, 1978). Under both administration techniques, dependence to LAAM was reported. Clinical research has
basically extended these findings to humans , i.e., substitution
with dependence (see Blaine, 1978).
The present experiments examined the substitution potential
and dependence liability when LAAM is administered intermittently
via daily intraperitoneal injection.
EXPERIMENT
1
Procedure
The subjects were 24 experimentally naive, female rats of LongEvans descent, approximately 90 days of age. Each subject was
maintained in an individual wire mesh cage and given ad libitum
access to food and water throughout the experiment. All subjects
were maintained on a 12-hr light/l2-hr dark cycle for the duration of the study. Ambient temperature was maintained at
72° ± 2° F. Body eights were monitored daily, 15 min prior to
drug or control injection.
409
314-300 0 -80 - 28
Phase I: Morphine maintenance. Following a week of daily
injections of distilled water, subjectswere randomly assigned
to four groups (n=6 for each group). Groups MS and ML were
given daily intraperitoneal (IP) injections of morphine sulfate
(80 mg/kg) for 2l consecutive days. Groups SS and SL were given
volumetrically equivalent, daily IP injections of distilled
water for 21 consecutive days.
Phase II: LAAM substitution. On the day following the last
morphine or control injection (Day 29), Groups ML and SL were
injected IP with LAAM (8 mg/kg) and Groups MS and SS were injected with distilled water. These injections were given daily
for 14 consecutive days.
Phase III: LAAM withdrawal. On the day following the last LAAM
or control injection (Day 44), all subjects were injected IP
with distilled water. These water injections were given for
seven consecutive days.
Results
The substitution by and withdrawal from LAAM are indexed by the
maintenance and loss, respectively, of body weight from baseline.
While there were no differences in body weights among groups
during the initial seven days of water injections (Days 1-7), a
significant difference emerged among groups when differential
treatments were administered. Groups MS and ML, subjects
receiving morphine during Phase I, significantly decreased in
body weight in relation to the water-injected groups. With
repeated injections of morphine, Groups MS and ML showed partial
recovery to baseline, suggesting that tolerance to the effects of
morphine had occurred during this maintenance phase.
Figure 1
410
Figure 1 presents the percent shift in body weight from baseline
(B) for each group during Phase II, LAAM substitution. On the
first day of Phase II (Day 29) when water was given in place
of morphine to morphine-dependent rats (Group MS), there was a
decrease in body weight (2-3 percent) 24 hr following the water
injection, suggesting spontaneous withdrawal from morphine.
With repeated water injections, body weights for Group MS gradually recovered, approximating a normal rate of weight increase
after five days of morphine withdrawal. on Day 29, when LAAM
replaced morphine in morphine-dependent rats (Group ML), morphine
withdrawal was not evident, i.e., LAAM prevented the weight loss
seen in Group MS. Instead of a body weight decrease, Group ML
significantly increased in body weight. That subjects given
LAAM without a prior history of morphine (Group SL) decreased in
body weight following the LAAM injection suggests that crosstolerance developed between morphine and LAAM in Group ML. With
repeated LAAM injections, Group ML gradually decreased in body
weight below the pre-LAAM baseline, recovering to baseline after
11 daily injections. Group SL further decreased in body weight
with repeated injections. After 11 daily injections, these
subjects gradually increased in weight, although never recovering
to their pre-LAAM baseline. Group SS, subjects maintained on
water througout the first 43 days, showed normal body weight
increases over repeated water injections.
Figure 2
Figure 2 presents the percent shift in body weight from baseline
(B) for each group during Phase III, LAAM withdrawal. On the
first day of LAAM withdrawal (Phase III), when all subjects were
injected with distilled water, significant differences emerged
among groups. Both Groups ML and SL, subjects previously maintained on LAAM, showed a significant reduction in body weight
(5 percent) 24 hr following the water injection. While at 24 hr
withdrawal from LAAM (5 percent baseline shift) is more severe
411
than withdrawal from morphine (2-3 percent, see figure 1), weight
losses following shorter intervals, e.g., 6 hr after either morphine or LAAM withdrawal, are more severe for morphine
(14 percent) than LAAM (3 percent). Groups SS and MS showed no
significant change in body weight in response to water injection.
With repeated injections of water, both Groups ML and SL gradually increased in body weights, recovering to baseline within 4-5
days following LAAM withdrawal. Group SS and MS gradually increased body weights over repeated water injections.
Discussion
While LAAM was effective in preventing withdrawal from morphine,
the substitutionwas incomplete, i.e., there was an increase in
body weight followed by a gradual decline below baseline weight
with repeated LAAM injections. This initial increase and subsequent decrease could reflect the hyperphagic (Riley, Schoonover,
and Shapiro, 1978) and debilitating (see Group SL) effects,
respectively, of this relatively high dose of LAAM. The dependence to LAAM may also be a function of the dose of LAAM. At
this dose, the substitution potential. of LAAM is partially offset
both by the incomplete substitution and rapid dependence
liability. To determine if these effects are characteristic of
LAAM in general, Experiment 2 examined the substitution potential
of LAAM across a range of doses.
EXPERIMENT 2
Procedure
In all unspecified details, Experiment 2 is similar to Experiment 1. Following adaptation to water injections, all subjects
were maintained on morphine for 14 consecutive days. At this
point different groups of subjects (n=6 for each group) were
injected with 1, 3, 4, or 6 mg/kg of LAAM. These injections
were given daily for seven consecutive days. Following the
seven days of LAAM substitution, all subjects were injected with
distilled water to assess spontaneous witdrawal from LAAM.
Results
As in Experiment 1, when LAAM substituted for morphine in
morphine-dependent subjects, there was no immediate evidence of
withdrawal from morphine. Similar to Experimental, at doses of
3, 4, and 6 mg/kg, there was a significant increase in body
weight followed by a gradual decrease below baseline weight with
repeated injections of LAAM. Figure 3 presents the percent
shift in body weight from baseline (B) for each group during
this phase of LAAM substitution for morphine. The data for
Group ML (8 mg/kg) from Experiment 1 is included in figure 3
for comparison. As figure 3 presents, this initial increase and
subsequent decrease was not evident for subjects receiving the
lowest dose of LAAM, 1 mg/kg. Subjects in this group maintained
412
normal growth over this seven day period.
Figure 3
When water replaced LAAM during withdrawal, all groups decreased
in body weight, suggesting dependence to LAAM. This decrease,
however, was significantly less at the 1 mg/kg dose (2 percent
shift from baseline) than at the higher doses (5 percent shift).
Discussion
It is clear from the data that LAAM substitute for morphine
in morphine-dependent rats. Only at 1 mg/kg, however, was this
substitution complete, i.e., there was no initial increase and
subsequent decrease characteristic of the higher doses. That
the substitution is complete at this dose of LAAM suggests that
the incomplete substitution seen in the other groups may result
from the hyperphagic and debilitating effects of the higher doses
of LAAM.
While 1 mg/kg LAAM has effective as a substitute, similar to the
higher doses, dependence did occur at this dose. Although withdrawal from this dose was less severe than that at the intermediate and high doses, the dependence liability of LAAM in
It is
general my in part offset its substitution potential.
possible, however, that with even smaller doses of LAAM substitution would be complete without dependence.
The present experiments, and those of Patrick, Dewey, and Harris
(1976) and Young, Steinfels, and Khazan (1978), suggest that
LAAM my be effective in the drug maintenance therapy of narcotic
Such conclusions, however, should be cautiously made
addiction.
until such demonstrations of substitution efficacy more closely
parallel clinical parameters, e.g., the spaced administration of
LAAM for both morphine and methadone.
413
REFERENCES
Blaine, J. Early clinical studies of levo-alpha acetyl methadol
(LAAM): An opiate for use in the medical treatment of chronic
heroin dependence. In: Petersen, R., ed. The International
Challenge of Drug Abuse. National Institute of Drug Abuse Research Monograph 19. DHEW Pub. No. (ADM) 78-654. Washington,
D.C.: superintendent of Documents, U.S. Government Printing
Office, 1978. pp. 249-259.
Blaine, J., and Renault, P., eds. Rx: 3x/week LAAM Alternative
to Methadone. National Institute of Drug Abuse Research Monograph 8. DHEW Pub. No. (ADM) 76-347. Washington, D.C.: Superintendent of Documents, U.S. Government Printing Office, 1976.
127 pp.
Patrick, G., Dewey, W., and Harris, L. Chronic infusion of
narcotics in rats: Pharmacodynamics of morphine and assessment
of dependence liability of other analgesics. Comm Prob Drug
Dep, 38: 52-62, 1976.
Riley, A., Schoonover, F., and Shapiro, R. A comparison of 1alpha acetyl methadol and methadone: Weight loss in response to
non-precipitated and naloxone-precipitated withdrawal. Unpublished manuscript, 1979.
Young, G., Steinfels, G., and Khazan, N. Transitional patterns
of self-administration following substitution of methadone or
1-alpha-acetyl methadol (LAAM) for morphine in dependent rats.
Drug Alc Dependence, 3: 273-279, 1978.
AUTHORS
Anthony L. Riley, Ph.D., Deborah S. Etherton, and Robert M. Shapiro.
Department of Psychology, The American University, Washington,
D.C., 20016.
414
Outcome for Structural Family Therapy With
Drug Addicts
Stanton, M. D.; Todd, T. C.; Steier, F.
This paper presents some treatment followup results from a research
program evaluating the efficacy of brief family therapy with heroin
addicts. Preliminary data with a smaller group of subjects (Stanton
& Todd, 1976) indicated that this treatment approach showed promise
for reducing addiction. The present study extends the findings to
a six-month posttreatment period.
BACKGROUND
Reviews of the literature (Harbin & Maziar, 1975; Seldin, 1972;
Stanton, 1978, 1979). indicate that there is a fairly large and
growing body of literature on the nature and importance of family
factors in heroin addiction. The consensus of these reviewers is
that drug addiction is a symptom maintained to serve family functions. Frequently it fits into a repetitive pattern such that
when the addict starts to abstain or "clean up" family turmoil
ensues and his parents' marital problems become exacerbated; when
he gets "dirty" again the family stabilizes and reunites in relation to him and his problem (Alexander & Dibb, 1975; Harbin &
Maziar, 1975; Schwartzman, 1975; Stanton, 1978, 1979, Stanton, et
al, 1978). This pattern resembles that noted by Haley (1973, 1976)
and others for schizophrenics, in which improvement in the identified patient results in increased difficulty between his parents.
In another parallel to schizophrenics, the most common family relationship structure reported for male addicts is one in which the
mother is dominant and overprotective, while the (often alcoholic)
father is detached, uninvolved, or absent. Of particular note is
the frequency of contact between adult addicts and their mothers.
This was first reported by Vaillant (1966) who found that 72 percent of his addicts still lived with their mothers at age 22.
When those whose mothers died prior to the addicts' 16th birthday
were deducted, the percentage rose to 90 percent. A 1972 survey
of our own taken among 85 addicts at the Philadelphia VA found that
of those with living parents, 82 percent saw their mothers and 58
percent saw their fathers at least weekly; 66 percent saw their
mothers daily. The figures become even more impressive when one
realizes that the average age of these men was 28 and all had been
415
in the military for at least several months.
While therapy has gone on at a number of centers and is gaining more
visibility and momentum, it has generally not been accompanied by
evaluative efforts. In their comprehensive review of the outcome
research on marital and family therapy Gurman and Kniskern (1978)
located over 200 studies and only two (including our own; Stanton
& Todd, 1976) dealt with drug addicts or abusers. This is unfortunate, as the approach has shown enough promise with other types
of disorders for Gurman and Kniskern to note that in every study
in which it has been compared with other kinds of treatment it has
emerged with equal or, in two-thirds of the studies, superior results. These authors also note that the most impressive findings
have been obtained with "structural" family therapy (Minuchin,
1974; Rosman, et al., 1976), which is the kind being investigated
in the present project.
The structural approach to family treatment has its underpinnings
in the work of Minuchin (1974) and Haley (1976), and is an active
technique in which the therapist attempts to bring about change in
family interactions within the actual session. Specific tasks and
concrete behavioral indicators are used.
It is goal-oriented and
symptom-focused and has been shown to be effective with different
types of problems and different types of therapists.
It is our thesis that family patterns and family development are
crucial in understanding and coping with this phenomenon. In examining current family process we are also assuming that present
day events help to maintain the addiction of one or more members.
We have undertaken a program designed to induce subjects to participate in an experience which strikes directly at family involvement
and its current contribution to drug abuse in one or more of its
members.
Such a plan permits clarification of issues and resolution
of problems and family patterns which, left alone, would perpetuate
themselves.
A further advantage of our family therapy approach is
therapeutic contact with other family members who either are high
risks themselves for the development of drug dependence and/or other
symptomatology, or who tend to engender such patterns in other family
members, particularly their offspring.
METHOD
Subjects
The sample consisted of 95 male addicts under age 36 (mean=26) plus
their families of origin. All were enrolled in the Drug Dependence
Treatment Center (DDTC) program of the Philadelphia VA Hospital.
Half of the group was black and half white. They lived within one
hour's drive from the research site. The index subjects had had
military experience; thirty-five percent had been to Vietnam, 23
percent were married, and 54 percent lived with a parent. To be
selected the index subjects must have been in contact with one of
their parents or parent substitutes (e.g. stepmother, mother's boyfriend) at least weekly and the other at least monthly; these
416
"parents" had to be living together. Those who had previously been
treated in family therapy were excluded. The addicts could not have
had a history of psychosis, nor could they have had a VA medical
disability of 30 percent or more.
In addition, the drug-patient
subjects had to have been (a) addicted to opiates for at least two
years, (b) on methadone (at least initially), and (c) not have a
sibling enrolled in the VA drug program.
VA Treatment Program and Intake Procedures
Family treatment was adjunct to the overall VA DDTC treatment program in which the patients were enrolled. For a given patient,
the program included individual counseling, methadone, at least
weekly urinalysis and detoxification. These VA patients were on
some level of methadone maintenance, although abstinence from methadone was a desired goal of DDTC treatment.
All veterans who appeared for treatment at the DDTC were administered
an intake interview to determine their eligibility for this project.
They were seen by an intake counselor and psychiatrist. Approximately one-fourth were eligible for our study. The major reasons
for exclusion were age, deceased parent, infrequent parent contact
or nonaddiction to heroin. If judged eligible they were asked for
additional information about their drug use, job history, family
demographics, etc. Our project was then contacted to see if any
treatment openings existed.
If not, nothing was said to these
patients about family treatment and they became part of our "nonfamily treatment" group.
If an opening did exist they were assigned
randomly to the available therapists.
It was the therapist's job to explain to the patient that family
treatment would be part of his program. The patient had the option
of refusing after the therapist had tried to enlist him. The therapist had two responsibilities at this point: one was to oversee the
patient's drug treatment plan such as adjusting methadone dosage,
etc., and the other was to get the family in. His goal was to have
both parents and any siblings over age 12 living nearby come in with
the patient for a family evaluation session (FES). The therapist
did not know to which treatment conditions the family would be
assigned. Families were randomly assigned to the three family
treatment conditions - paid family therapy, unpaid family therapy,
or family movie treatment. Treatment proceeded from that point.
Treatment Groups
Four treatment groups were involved, three of which included the
families of the addicts during treatment. The fourth included family
members only for the followup interviews. The treatment period
(intake to termination) for family groups averaged 4 1/2 to 5
months in length.
Nine therapists were involved and they had at least two years experience, got weekly supervision and also served as drug counselors.
In 86 percent of the cases they were matched by race with the
417
patients (black patient, black therapist, etc.).
1. Paid family therapy (N=18). At the end of the FES a contract was
made with the family to attend 10 family therapy sessions. The
usual rationale given was that the family is important for helping
the addict get off and stay off of drugs. Sessions usually included
In some cases therapy extended beyond
most or all of the family.
10 sessions, particularly if a crisis occurred near termination.
This therapy mode also included reimbursement to counteract the low
motivation for treatment which these families have historically
shown. In brief, every family member over age 12 received $5 at
each session he attended. He also got a chance to increase his
payment, however, if the addict member had been "clean" that week,
by means of a drawing following each session. For every family member present $5 was added to the sum to be drawn for, so that the
total was as high as, say $30 if six members attended. If it was
a "dirty" week the sum was held until the next week and the combined total for both weeks was drawn for at that time. Neither the
standard payment nor drawing were provided for more than ten sessions. It also mobilized all family members to Put pressure on each
other to attend and on the addict to attend and abstain from drug
use. Further, the use of clean urines as a contingency for reimbursement served as a check against the misuse of payment sums by
the addict.
2. Unpaid family therapy (N=19). Procedures for this group were
identical to those for the paid group except that no money (aside
from the evaluation sessions) was provided to the family. This
group allows determination of whether reimbursement is important in
(a) getting people into treatment, (b) keeping then in, and (c)
Producing improvement.
3. Family movie treatment (N=15). This program required the family
to come in once a week for 10 weeks to view 10 anthropology movies
about People in various foreign cultures. The rationale was that
"we find that families which at times have difficulties can be helped
by seeing how people in other cultures and societies live and work
together, i.e., it gives then a perspective." Movies were selected
because, in contrast to family therapy, they did not Permit much
interaction among family members during their time at the research
site. A research associate administered the movies and instead of
having a family therapist the addicts in this group became patients
of the VA DDTC Senior Drug Counselor. These families were paid and
got urinalysis reports in the same manner as the paid family therapy
group. Thus the movie program served as a control for the effects
of reimbursement and the effect on the family of meeting every week
for an hour. The latter should not be underemphasized, for most of
these families rarely got together for family activities.
4. Nonfamily (methadone only) treatment (N=43). These were addicts
at the DDTC who met all of our criteria for inclusion in the study
but were not selected for one of the family treatment groups. Instead they underwent the usual DDTC treatment procedures and entered
418
the methadone, individual counseling and other programs; they were
assigned a drug counselor. However, to be included in our study
they had to remain in the methadone program for at least one month.
In comparison with family treatment patients, this group provides us
with a baseline estimate as to the treatment outcomes which can be
expected with similar subjects in an ongoing multi-modal methadone
program.
Followups
Followup interviews were obtained on patients in all four groups by
two interviewers who had no involvement in the treatment. Sane interviews were held in the clinic, while others included home visits.
Race of interviewer and family were matched.
The period assessed stretched from the end of family treatment (approximately 18 weeks from intake date) to a point six months posttreatment. For the non family group a parallel timespan was assessed.
Followup data usually included interviews with the addicts, and at
least one or both parents, often supplemented by interviews with
spouses, siblings, relatives, parole officer and drug counselor or
All interviews with addicts were accompanied by urine
therapist.
samples taken and observed at the time. The 40 and 90 minute structured interview covered drug and alcohol use by addict and other
members, employment or school progress of addict, living arrangements, family contacts of addict, medical problems;, legal problems,
and any other changes during the past six months.
The generic outcome measure employed is the percentage of days that
a patient did not use a particular drug (or drugs) over the sixmonth period. Estimates were derived from the following sources:
addict self-reports, family member or spouse reports, drug counselor and therapist reports, DDTC records/charts and urinalysis
results. Employment and enrollment in school were also assessed.
The eight dependent or outcome variables measured were:
1. Percent days free of:
a. Heroin, opiates and illegal methadone e. All illegal drugs
f. Alcohol
b. Legal methadone
g. All illegal drugs and
c. All legal and illegal opiates
alcohol
d. All nonopiate illegal drugs
2. Percent "working" days spent working or in school.
The eight outcome variables, compared across all four groups, are
presented in Table 1. Oneway analyses of variance were performed
for all of them. Paid family therapy emerged as the most effective
treatment across all drug variables. No difference emerged on the
"working/school days" variable.
DISCUSSION
The efficacy of brief, paid family therapy for reducing opiate we
Seems to be established. Unpaid family therapy also appeared
419
ANALYSIS OF VARIANCE OF OUTCOME OVER SIX MONTHS POST TREATMENT
Non-Family Family Treatment(N=52) Level
Treatment
of
Unpaid Paid
Dependent Variable
(methadone) Movie Family Family SignifiN=43
N=19
N=15
N=18
cance
Mean % days free of
heroin, opiates &
82.6% 83.0%
all illegal methadone
54.1%
85.5%
p<.05*
Mean % days free of
NS
41.8
27.1
legal methadone
45.0
61.9
Mean % days free of
all legal & illegal
23.5
21.9
opiates
37.4
55.7
p<.05
Mean % days free of
all non-opiate
55.7
44.1
63.6
78.8
illegal drugs #
p<.01
Mean % days free of
25.1
all illegal drugs
4 5 . 7 50.5
67.1
p<.001
Mean % days free of
##
42.2
56.8
alcohol
65.6
67.4
p<.10
Mean % days free of
all illegal drugs
25.0 27.2
10.1
& alcohol
43.1
p<.05**
Mean % "Working"
days spent working
38.3
57.8
48.5
46.4
or in school#
NS
# Due to missing data, the N's for Non-family treatment for these
variables were 39.
## Due to missing data, the N for Non-family treatment for this
variable was 38.
* For analysis, a logarithmic transformation was applied due to
heterogeneity of variance: x1 = log [(181-x) +1]..
** For analysis , a logarithmic transformation was applied due to
heterogeneity of variance: x1 = log (x+1).
slightly more effective than movie treatment and nonfamily (methadone) treatment.
Reimbursement may have affected outcome, but its major impact was
on attendance: the average number of sessions for paid family therapy was 9.3, for (paid) movie, 8.8, and for unpaid family therapy,
6.2 (p< .005). Payment seemed instrumental in getting families to
participate.
Of course it also mobilized them to focus on and
support the addict's abstinence, since the family lost money if he
was "dirty" and stood to gain if he was "clean."
One area for further study pertains to patients who refused to become involved in family treatment. This happened in 27 cases, 29
percent of those approached. We made comparisons across 18 demographic variables (age, level of addiction, employment, SES, etc.)
between these refusers and the cases which became engaged. They
differed significantly on two of these - a higher percentage of refusers were black and more of them were enrolled in school or training programs. We plan to obtain followup data on refusers to deter420
mine whether their outcomes were better or worse than engagers.
In sum, brief structural family therapy shows considerable promise
as a way of conceptualizing treatment strategy and bringing about
change in this patient group.
It is rare that any kind of treatment
can show the kind of improvement demonstrated here with any subset
of heroin addicts. Whether the effects hold for a period longer
than six months is a question left to longterm followup investigations which we are presently conducting.
REFERENCES
Alexander, B.K. and Dibb, G.S. Opiate addicts and their parents.
Fam Process, 14:499-514, 1975.
Blum, R.H. and Associates. Horatio Alger's Children, San Francisco:
Jossey-Bass, 1972.
Gurman, A.S. and Kniskerm, D.P. Research on marital and family
therapy: Progress, perspective and prospect. In: S.L. Garfield and
A.E. Bergin, eds. Handbook of Psychotherapy and Behavior Change: An
Empirical Analysis (second edition). New York: Wiley, 1978.
Haley, J. Uncommon Therapy, New York: Norton, 1973.
Haley, J. Problem-solving Therapy. San Francisco: Jossey-Bass, 1976.
Harbin, H.T. and Maziar, H.M. The families of drug abusers: A literature review. Fam Process, 14:441-431, 1975.
Minuchin, S. Families and Family Therapy. Cambridge, Mass.:Harvard,
1974.
Rosman, B.L., Minuchin, S., Liebman, R. and Baker, L. Input and outcome of family therapy in anorexia nervosa. In: J.L. Claghore, ed.
Successful Psychotherapy. New York: Brunner-Mazel, 1976.
Schwartzman, J. The addict, abstinence and the family. Amer J Psychiat
132:154-157, 1975.
Seldin, N.E. The family of the addict: A review of the literature.
Int J Addic, 7:97-107, 1972.
Stanton, M.D. Family treatment of drug problems: A review. In: R.
Dupont, A. Goldstein and J. O'Donnell, Eds., Handbook on Drug Abuse.
Washington. D.C.: U.S. Government Printing Office.
Stanton, M.D. Drugs and the family. Marriage and Family Rev 2(l):
1-15, 1979.
Stanton, M.D. and Todd, T.C. Structural family therapy with heroin
addicts: Some outcome data. presented at the Society for Psychotherapy Research, San Diego, 1976.
Stanton, M.D., Todd, T.C., Heard, D.B., Kirschner, S., Kleiman, J.I.,
Mowatt, D.T., Riley, P., Scott, S.M. and Van Deusen, J.M., 1978.
Heroin addiction as a family phenomenon: A new conceptual model.
Am J Drug Alcohol Abuse, 5:125-150.
Vaillant, G.F. A twelve-year follow-up of New York narcotic addicts:
III. Some social and psychiatric characteristics. Arch Gen Psychiatry,
15:599-609, 1966.
AUTHORS
M. Duncan Stanton, Ph.D., Philadelphia Child Guidance Clinic/ University of Pennsylvania/ Drug Dependence Treatment Center, Philadelphia
VA Hospital; Thomas C. Todd, Ph.D., Harlem Valley Psychiatric Center,
Wingdale, N.Y.; Frederick Steier, M.S., Philadelphia Child Guidance
Clinic, Philadelphia, PA 19104
421
General Cardiovascular
Pharmacology of I- Acetylmethadol (LAAM)
Stickney, J. L.; Eikenburg, D. C.; Keedy, J. D.
INTRODUCTION
LAAM, L- -acetylmethadol, is an orally effective narcotic agonist
with a duration of action that ranges from 48 to 72 hours (Fraser
and Isbell, 1951, 1952). Jaffe and his coworkers were among the
first to recognize the possible usefulness of LAAM in the medical
treatment of persons physically dependent on heroin or related
drugs (Jaffe et al., 1970; Jaffe and Senay, 1971). LAAM is now
in the final stages of Phase III clinical testing (Whysner, 1976).
Initial cardiac studies showed that the drug, as well as its major
metabolites (N-LAAM, l- -acetylnormethadol and DN-LAAM, l- -acetyldinomethadol; Billings et al., 1974) possess chronotropic
(Stickney, 1977a) and inotropic (Stickney, 1977b) activity in isolated guinea pig atria. Subsequent studies have been concerned
with the identification of mechanisms underlying these effects
(Stickney, 1978a,b). Additional work has shown that the responses
occur not only in cardiac tissues isolated from other species
(Stickney and Keedy, 1978), but in vivo as well. We have observed
cardiovascular responses to LAAM and congeners in anesthetized
dogs and cats (Sikenburg and Stickney, 1978). Cardiac responses
to LAAM have also been identified in unanesthetized dogs (Waters
et al., 1978) and unanesthetized rhesus monkeys (Masten et al.,
1978).
METHODS AND MATERIALS
Experiments on Isolated Tissue
The cardiac effects of LAAM and congeners were studied on tissues
isolated from four species: guinea pig, rat, rabbit, and cat.
The methods have been described in detail elsewhere (Stickney,
1977a,b).
Experiments In Vivo
Mongrel dogs or cats were anesthetized with pentobarbital sodium
422
administered intravenously (dogs, 30 mg/kg; cats, 35 mg/kg) and
artificially respired with room air via a tracheal cannula. A
femoral artery was cannulated and arterial blood pressure (BP)
monitored via a Statham pressure transducer. The Lead II electrocardiogram (ECG) also was recorded. Heart rate (HR) was monitored
using a tachograph.
Either analysis of variance or Student's t-test was used to
determine significant differences between-groups. The level of
significance chosen was p <.05.
L- -Acetylmethadol, l- -acetylnormethadol and l- -acetyldinormethadol (all HCl salts) were supplied by the National Institute
for Drug Abuse (NIDA) from Research Triangle Park, North Carolina.
RESULTS
Experiments on Isolated Tissues
The inotropic and chronotropic effects of LAAM are summarized in
Tables 1 and 2, respectively.
Experiments In Vivo
The intravenous administration of LAAM to anesthetized dogs significantly decreased HR, CF, and BP. The data are summarized in
Table 3. N-LAAM and DN-LAAM effected similar responses. N-LAAM
was more potent than LAAM and DN-LAAM.
Three parameters were monitored during a one minute occlusion of
the common carotid arteries bilaterally: mean arterial blood
pressure, heart rate, and myocardial contractile force. The
three narcotic agonists significantly decreased the responses of
all parameters. N-LAAM was most potent.
Table 4 shows that LAAM produced a significant dose-dependent
decrease in HR and mean BP in cats. Myocardial contractile force
was not monitored.
DISCUSSION
There are brief statements in both the clinical (Ling et al.,
1976) and animal (Archer, 1976; Wolves and Archer, 1976) literature
which suggest that LAAM may have cardiovascular effects. However,
it appears as though these effects had not been studied in a
systemtic manner until the experiments in this laboratory were
undertaken.
The data collated in this paper suggest that an investigation of
the cardiovascular effects of LAAM in man is warranted. LAAM
produced significant cardiac or cardiovascular responses in all
four species examined.
Chronotropic activity was studied in right atria from three spe-
423
TABLE 1
Effecta of 1-
-Acetylmethadol on Contractile Force of Cardiac Tissue From Four Species
1 x 10-8b
Ratc
0
Guinea pigc
Rabbit C
-0.24±0.9
Cat d.
a
8.08±1.1
0.80±1.l
1 x 10-7
1 x 10-6
5 x 10-6
1 x 10-5
5 x 10-5
0.03±1.9
1.00±1.8
5.5±1.6
8.9±2.0
8.5±2.8
-14.6±5.1
10.6±3.7
16.13±4.9
19.3±3.1
3.95±6.3
-20.48±2.7
1.26±1.4
6.08±0.8
11.96±1.8
-10.74±2.1
-52.50±9.3
-1.93±3.7
-9.63±5.3
-17.87±7.1
-41.30±7.8
-61.23±8.0
11.88±2.5
0
-1.68±4.8
Percent change from control height of contraction ± SEM;
left atria; dright papillary muscles.
C
b
molar concentration of 1-
1 x 10-4
-acetylmethadol;
TABLE 2
Effect
a
of 1-
-Acetylmethadol on the Spontaneous Rate of Beating of Right Atria From Three Species
1 x 10-8b
Rat
Rabbit
Guinea Pig
a
-0.82±0.5
0
-1.47±0.7
1 x 10-7
1 x 10-6
5 x 10-6
1 x 10-5
5 x 10-5
1 x 10-4
-0.83±0.5
-1.65±0.8
-0.85±1.0
0.27±1.6
-2.32±3.1
-11.22±4.4
-0.86±0.9
-9.02±0.2
-13.52±2.1
-20.12±4.9
-32.80±6.7
-6.03±1.42
-7.85±3.2
-22.7±7.9
-39.6±10.1
-71.3±10.6
0
-1.74±1.2
Percent change from control rate of beating ± SEM
b
Molar concentration of l-
-acetylmethadol.
TABLE 3
Effect of l-
Control
0.027 a
HR b
171.4 ± 7.1
170.8 ± 8.5
164.4 ± 8.2
121.6 ± 12.4
MAP c
132.2 ± 2.9
138.4 ± 10.0
125.0 ± 4.0
108.0 ± 4.3
103.2 ± 4.2
94.6 ± 6.1
64.5 ± 8.9
53.2 ± 8.2
49.5 ± 7.3
47.8 ± 7.6
CF d
a
-Acetylmethadol on Mean Arterial Pressure (MAP), Heart Rate (HR) and Myocardial
Contractile Force (CF) in the Dog
70.0 ± 9.6
Dose of 1-
0.27
66.2 ± 8.3
b
-acetylmethadol in mg/kg;
1.37
c
beats per min. ± SEM;
2.73
96.0 ± 10.2
mm Hg ± SEM;
d
5.46
93.4 ± 9.5
grams of tension ± SEM
TABLE 4
Effect of l-
a
-Acetylmethadol on Mean Arterial Pressure (MAP) and Heart Rate (HR) in The Cat
Control
0.027 a
HR b
193.0 ± 9.4
192.0 ± 8.8
MAP c
114.0 ± 5.6
116.8 ± 6.3
dose of 1-
-acetylmethadol in mg/kg;
0.27
b
1.37
2.73
5.46
192.0 ± 11.9
166.0 ± 6.6
128.0 ± 6.6
113.0 ± 5.4
115.6 ± 6.1
105.4 ± 5.0
89.8 ± 4.3
79.0 ± 5.1
beats per min. ± SEM;
c
mm Hg ± SEM.
cies. LAAM and congeners decreased the spontaneous rate of beating in all preparations. The results suggest that a general
negative chronotropic action is an inherent property of the drug.
Experiments carried out on anesthetized cats and dogs support
this hypothesis. The narcotic agonists produced a dose-dependent
decrease in heart rate in vivo The in vivo studies have been
extended and it appears that there are at least two mechanisms
for the negative chronotropic response. One mechanism seems to
be direct and similar to that found in the isolated preparations;
the other appears to involve an interaction with the sympathetic
nervous system (Eikenburg and Stickney, 1978).
A negative inotropic response was observed in isolated tissue
preparations of four species. The mechanism by which LAAM produces
the negative inotropic response has not been identified. An
may play a role in the
alteration in the disposition of Ca++
response (Stickney, 1978b). A negative inotropic response also
was effected in the anesthetized dog.
LAAM was found not only to produce a significant depressor response
in anesthetized dogs, but the drug also attenuated the pressor
response to a one minute occlusion of the common carotid arteries
bilaterally.
These findings suggest that the drug has the potential
for interfering with reflexes which normally act to maintain
cardiovascular homostasis.
The data obtained in these series of experiments indicate that
cardiovascular effects of LAAM would be of toxicological rather
than therapeutic significance because the concentrations of LAAM
required to produce the effects are higher than those reported
under conditions where drug administration to humans has been
monitored carefully (Kaiko and Inturrisi, 1975; Lau and Henderson,
1975). however, such concentrations might be found under certain
conditions:
in persons who receive standard dose regimen but who
metabolize the drug more slowly (Billings et al., 1974); in persons who accidentally or intentionally ingest excessive amounts
of the drug. Finally, one cannot exclude the possibility that
persons with chronic heart failure or other types of cardiovascular
pathophysiology, and persons taking other medications which
depress the heart might be sensitive to the cardiovascular effects
of LAAM and congeners. In this regard, it is noteworthy that NLAAM appears to be a more potent cardiovascular depressant than
LAAM; the former has a longer biological half-life than the
latter.
In summary, studies carried out in this laboratory and other laboratories (Lee and Berkowitz, 1977; Masten et al., 1978; and
Waters et al., 1978) have yielded results which suggest that the
cardiovascular effects of LAAM in man should be studied.
ACKNOWLEDGEMENTS
This work was supported by USPHS grants DA 00962 and GM 07392.
426
REFERENCES
Archer, S. Pharmacology of LAAM. In: Rx:3x/Week LAAM: Alternative
to Methadone, Blaine, J.D., and Renault, P.F., eds. National Institute on Drug Abuse Research Monograph 8. DHEW Pub. No. (ADM)76-347.
Washington, D.C.: Supt. of Docs., U.S. Govt. Print. Off., 1976.
pp. 15-28.
Billings, R.E., McMahon, R.E. and Blake, D.A. 1-Acetylmethadol
(LAAM) treatment of opiate dependence: Plasma and urine levels
of two phamacologically active metabolites. Life Sci, 14:14371446, 1974.
Eikenburg, D.C. and Stickney, J.L. Cardiovascular responses to
l- -acetylmethadol (LAAM) in anesthetized dogs. Pharmacologist,
20:269, 1978.
Fraser, H.F. and Isbell, H. Addiction potentialities of isomers
of
6-dimethylamino-4-4-diphenyl-3-acetoxy-heptane
(acetylmethadol).
J Pharmacol Exp Ther, 101:12, 1951.
Fraser, H.F. and Isbell, H. Actions and addition liabilities of
alpha-acetylmthadols in man. J Phamacol Exp Ther, 105:458-465,
1952.
Jaffe, J., Schuster, C., Smith, B. and Blachley, P. Comparison of
acetylmethadol and methadone in the treatment of long term heroin
users. J Amer Med Assoc, 211:1834-1836, 1970.
Jaffe, J. and Senay, E. Methadone and l-methadylacetate: Use in
management of narcotic addicts. J Amer Med Assoc, 216:1303-1305,
1971.
Kaiko, R.F. and Inturrisi, C.E. Disposition of acetylmethadol in
relation to pharmacological action. Clin Pharmacol Ther, 18:96103, 1975.
Lau, H.M. and Henderson, G. Plasm levels of l- -acetylmethadol
(LAAM) and metabolites following acute and chronic oral administration in man. Proc West Pharmacol Soc, 18:270-274, 1975.
Lee, C. and Berkmitz, B.A. Calcium antagonist activity of methadone, l-acetylmethadol and l-pentazocine in the rat aortic strip.
J Pharmacol Exp Ther, 202:646-653, 1977.
Ling, W., Charuvastra, C., Kaim, S. and Klett, C. Methadyl acetate
and methadone as maintenance treatments for heroin addicts. Arch
Gen Psychiatry, 33:709-720, 1976.
Masten, L.W., Bedford, J.A., Guinn, M.M. and Wilson, M.C. Clinical
experiences with repeated oral administration of 1-alpha-acetylmethadol (LAAM) in the rhesus monkey. Drug Chem Toxicol, 1:173190, 1978.
Stickney, J.L. Cardiac effects of l- -acetylmethadol. I. Chronotropic effects in vitro. Toxicol Appl Pharmacol, 40:23-32, 1977a.
427
Stickney, J.L. Inotropic effects of 1- -acetylmethadol (LAAM).
Europ J Pharmacol, 43:289-292, 1977b.
Stickney, J.L. Effect of autonomic blocking agents on chronotropic
actions of 1- -acetylmethadol. Arch Int Pharmacodynamics, 231:7080, 1978a.
Stickney, J.L. Cardiac effects of 1- -acetylmethadol. IV. Mechanisms of inotropic effects. Toxicol Appl Pharmacol, 44:471-479,
1978b.
Stickney, J.L. and Keedy, J.D. Cardiac effects of 1- -acetylmethadol (LAAM) in vitro: Comparative phamacology. Pharmacologist, 20:269, 1978.
Waters, I.W., Catravas, J.D., Guinn, M.M. and Davis, W.M. Effects
of 1- -acetylmethadol (LAAM) on various physiological parameters
in the conscious dog. Arch Int Pharmacodynamics, 231:157-167, 1978.
Whysner, J.A. Phase III clinical study of levo-alpha-acetylmethadol.
In: Rx:3x/Week LAAM: Alternative to Methadone, Blaine, J.D., and
Renault, P.F., eds. National Institute on Drug Abuse Research Monograph 8. DHEW Pub. No. (ADM)76-347. Washington, D.C.: Supt. of
Docs., U.S. Govt. Print. Off., 1976. pp. 109-111.
Wolven, A., and Archer, S. Toxicology of LAAM. In. Rx:3x/Week
LAAM: Alternative to Methadone, Blaine, J.D., and Renault, P.F., eds.
National Institute on Drug Abuse Research Monograph 8. DREW Pub. No.
(ADM)76-347. Washington, D.C.: Supt. of Docs., U.S. Govt. Print.
Off., 1976. pp. 29-38.
AUTHORS
J. L. Stickney, Ph.D., Associate Professor; D.C. Eikenburg, B.S.,
Predoctoral Fellow; and J.D. Keedy, M.S., Laboratory Research
Technician, all of the Department of Phannacology and Toxicology,
Michigan State University, East. Lansing, Michigan 48824
428
On the Relative Efficacy of LAAM
and Methadone
Whysner, J. A.; Thomas, D. B.; Ling, W.; Charuvastra, C.
INTRODUCTION
Prior to the VA-SAODAP Cooperative study, several clinical investigations had demonstrated that LAAM could be a safe and effective alternative to methadone for the maintenance of opiate
addicts. Additionally, LAAM was a longer-acting drug, and so
offered several advantages inherent in three-times-per week dosing: (1) lowered clinic costs, (2) an end to the problem of
diversion, with its associated mortality, which resulted from
methadone take-home doses, and (3) a less specific advantage,
an opportunity to reorient patients from daily hassles and anxieties over drugs and dosages, to more socially acceptable concerns and pursuits.
The VA-SAODAP study, then, was designed to compare LAAM and
methadone in a fully randomized double-blind fashion. The sample
population was comprised of 430 street addicts from 12 VA hospitals. The duration of study treatment was 40 weeks. Intake
began April 1973, and the last patient completed the study on
March 31, 1975.
The study design specifically addressed two issues:
(1) the relative safety and efficacy of LAAM, as compared with methadone,
and (2) the safety and efficacy of two dose levels of methadone.
Some investigators, such as Dole and Nyswander (1) had argued for
relatively high doses of methadone (100 mg), whereas others, such
as Goldstein (2) had determined that 50 mg was just as potent in
providing an effective "blockade" against the effect of heroin.
This paper reports on the efficacy of three treatment regimens,
LAAM, 80 mg TIW, and methadone, 50 or 100 mg daily, as assessed
by random screens for urine opiates and symptoms and signs of
chronic abstinence, in addition to several contingent variables,
such as amount of criminal involvement.
The safety data for LAAM and for methadone have already been an429
alyzed in detail in previous publications (3) and will not be
discussed here.
METHOD
Patients--Each of 12 VA hospital clinics contributed patients to
the cooperative study; all clinics followed a common protocol.
Patients were eligible for participation if they (l) net all the
FDA criteria for admission to maintenance programs, (2) were men,
aged 18-60, and (3) were not currently enrolled in another methadone program. Incapacitating or life-threatening conditions,
disease requiring regular, repeated medication, psychotic states,
epilepsy, and current severe alcoholism were also criteria for
exclusion.
Drug treatment--Patients were randomly assigned, double-blind to
one of three treatment groups, according to a schedule supplied
centrally:
1. Methadone, stabilized at 50 mg daily
2. Methadone, stabilized at 100 mg daily
3. LAAM, stabilized at 80 mg TIW
For each patient, a series of individual-dose bottles, nukered
from 1 to 280, was supplied. In all three groups, the initial
dose was 30 mg; this was incremented by 10 mg each succeeding
Monday, until the patient had achieved his stipulated target
dose. The sequence of these increments was controlled by bottle
number. The first 8 weeks of the study was considered as an induction period.
The two methadone groups were given active medication daily, but
the LAAM group received active medication on Monday, Wednesday,
and Friday only; placebo (dextromethorphan plus quinine) was given
on the other 4 days.
Measures of efficacy--While the ultimate aim of any maintenance
treatment is amelioration in the actual day-to-day lives of addicts, the primary pharmacological goal of-any maintenance therapy must be the blockade of craving for illicit opiates. Therefore, in this study, the most direct, and objective, measure of
treatment efficacy was ccnsidered to be amount of decrease
(or cessation) in the use of the primary drug of dependence.
The presence (or absence) of abstinence signs and symptoms, as
noted on the Symptoms-Sign Checklist (a prepared form comprised
of 31 symptom-signs; complaints were elicited by general guestioning), was also considered a direct measure of drug treatment
efficacy.
Indicators for this criterion included monthly vital
sign readings (pulse, blood pressure, temperature: objective
indicators), plus routine self-reports of symptom-signs and any
information gained from drug-related early terminations from
treatment (subjective indicators).
Patients also made periodic reports on their own opiate use, and,
430
at the end of the study or early termination, evaluated their
treatment outcome, in terms of factors like criminal activity.
Staff, as wall, assessed the amount of illicit drug use by patients, and noted the degree of change in socioeconomic adjustment and social relationships.
Methods for testing urines--At the clinics, urine spectiware
collected once per week on a random, unannounced basis, under
direct observation prevent substitution. Urine specimens
were then screened for morphine by the Enzyne Multiplied Immunoassay technique (EMIT) and thin-layer chromatography (TLC). If
both results were positive, the test was considered "confirmed";
if the EMIT was positive and the TLC was negative, the sample
was hydrolyzed, and TLC was run again.
If the second TLC procedure gave positive findings, the sample was considered positive.
RESULTS
Illicit opiate use--As shown in Table 1, patient urine data were
categorized according to two criteria, "cohort" and "period".
Two cohorts of patients ware designated: those who had completed
a minimum of 24 weeks in the study, and those who finishedthe
scheduled 40 weeks.
"Period" indicates which portion of the study
is being considered: the first 8 Weeks, or induction period, the
entire study (0-40 weeks), including the induction period (irrespective of when individual patients terminated), or the study
period between the end of the induction period and termination
from the study (9-40 weeks). In terms of trends and patterns
of illicit opiate use, this last period was considered the most
significant.
If all clients with 4 or more urines collected are considered,
the M-50 group shows a higher proportion of illicit opiate use
than either the M-100 or the L-80 group. For the 24-week cohort,
no differences were seen among groups during the induction period. But when the two later periods (9-40 and 0-40 weeks) are
considered, significant differences energe among the three treatment groups in terms of proportions of dirty urines. Now M-50
shows the highest proportion, followed by M-100; LAAM patients
had the lowest proportion of illicit opiate use. Considering the
40-week cohort, the study completers, M-50 patients again show
higher proportions of dirty urines, after the first 8 weeks of
the study.
Thus, the trend that emerges from a consideration of these individual items shows an initial decline in dirty urines mg
all groups, but a gradual increase among the M-50 group, as the
study proceeds. The M-100 group remains at a somewhat lower
level, while the L-80 group shows a gradual decline across the
Study (this lower frequency of dirty urines among LAAM patients,
after the first 8 weeks, was statistically significant). As
demonstrated by the cohort analysis, these group differences resulted fromchanges in the behavior of individuals, rather than
from differences in illicit drug use by those who terminated
431
within the drug groups.
The evaluation of patients' illicit drug abuse by clinic staff,
as well as patients' self-reports on illicit opiate use, generally support these findings. The data indicate that the M-50
group has significantly higher levels of involvement with illicit opiate use.
An alternative approach to analysis of urine data, the Urine Index, was detailed in a previous publication (3).
Abstinence syndrome--The M-50 group showed slight, but persistent, indication of abstinence, as evidenced by elevated blood
pressure and temperature. For diastolic blood pressure change
scores (comparing M-50 with M-100 and L-80) ware statistically
significant at weeks 12 and 28; systolic blood pressure change
scores were significant at week 12. Considering change scores
for temperature, M-50 was significantly different from M-100 and
L-80 at weeks 4, 16, and 28. No evidence of abstinence was
noted in either the M-100 or L-80 groups. Further, there was a
slight excess of M-50 patients with multiple complaints related
to underdosing.
Social adjustment--M-50 patients also did poorly in areas less
directly related to the pharmacologic effects of the drug: they
had significantly more criminal involvement (by self-report),
higher proportions of arrests , and were more likely to spend time
in jail.
DISCUSSION
In this study, LAAM patients not only showed lower levels of
opiate use, but also a pattern of progressive improvement (after
the initial 8-week stabilization period): a gradual decline in
the proportion of dirty urines was observed over the course of
the study. M-100 patients did less well, but, in general, tended
to show decreases in illicit opiate usage over time that ware
similar to those in the L-80 group.
More striking-were the results from the M-50 group: by every
method of analysis. used, this group showed both an excess of patients with high frequencies of dirty urines and a trend, over
time, toward increases in numbers of positive urines.
A surprising finding in this study was a slight but statistically
significant elevation in blood pressure and temperature. These
measurements were taken at the time of dosing and appear to represent abstinence associated with the daily minimum in plasma
concentration. The findings would suggest that M-50 are more
likely to feel abstinence 24 hours after their last dose than do
M-100 at 24 hours or L-80 patients at 48-72 hours.
Such findings suggest that the M-50 group experienced chronic
432
underdosing, during the study, and so attempted to compensate
for such underdosing by reverting to their usual practice of
using street heroin. The results from urine screens indicating
underdosing (among M-50 patients) were corroborated by several
other findings: the indications of abstinence and the poor outcomes on indices of social adjustsment, as exemplified by the high
proportion of arrests among this group.
The results of this large scale study, then, have established LAAM
as a maintenance agent that demonstrates some superiority to
methadone, in terms of ability to decrease the use of illicit
opiates. Further, the conclusion of Garbutt and Goldstein that
50 mg of methadone is equally as effective for maintenance of addicts as higher doses, has been seriously challenged: patients
given 50 mg of methadone daily showed consistently poorer outcomes, in several measures of efficacy, than either M-100 or L80 subjects.
Some clinicians have felt that patients could be stabilized on
any pre-established level of methadone, since they have presumed
that the body is able to adjust its opiate needs to the level of
maintenance agent prescribed. Our results suggest that such inflexibility may be unwise: individual patients should probably
have methadone doses carefully tailored to meet individual needs.
REFERENCES
Dole, V.P., and Nyswander, M.A. A medical treatment for D-acetylmorphine (heroin) addiction. JAMA, 193: 646-650, 1965.
Garbutt, G.D., and Goldstein, A. Blind comparison of three
methadone dosages in 180 patients. Proc Fourth National Conf
on Methadone Treatment. National Asssociation for Prevention
of Addiction to Narcotics. New York, 1972. pp. 411-414.
Ling, W., et al. Methadyl acetate and methadone as maintenance
treatments forheroin addicts: A Veterans Administration cooperative study. Arch Gen Psych, 33: 709-720, 1976.
AUTHORS
John A. Whysner
David B. Thomas
Medical Research Applications, Inc.
McLean, Virginia 22101
Walter Ling
Drug Dependence Treatment Program
Veterans Administration Hospital
Sepulveda, California 91343
Charles Charuvastra
Drug Dependence Treatment Program
Veterans Administration Hospital
Brentwood, Los Angeles, California 90073
433
TABLE l
ANALYSIS OF VARIANCE OF ILLICIT MORPHINE IN URINES WITH MEAN DEVIATIONS FOR SELECTED COHORTS AND
TIME PERIODS
Cohort
Period
M-50
Mean
Deviations
M-100
All a
Subjects
40 weeks
0.06
24 weekb
1st 8 wks
24 Week
Other
Significant
Differences
L-80
P-Value
-0.03
-0.03
0.02*
0.00
0.01
-0.01
0.90
9-40 wks
0.08
-0.02
-0.08
0.00*
f
24 Week
40 wks
0.06
-0.01
-0.06
0.01*
f
40 Weekc
1st 8 wks
-0.02
0.02
-0.01
0.79
40 week
9-40 wks
0.06
-0.01
-0.06
0.03*
40 week
40 wks
0.05
-0.01
-0.05
0.12
8 Weekd
1st 8 wks
0.02
-0.01
-0.01
0.75
e
f
*Categories in this column indicate significant (p <.05) differences between study medication
groups as determined by the Parametric Test.
a
All subjects who had at least 4 urines collected during the study are included in this analysis.
All subjects who attended at least 24 weeks of the study are included in this analysis.
c
All subjects who attended the entire 40 weeks of the study are included in this analysis.
d
All subjects who attended at least the first 8 weeks of the study and had at least 4 urines collected are included in this analysis.
e
Meth-50 significantly (p<.05) different from Meth-100 and LAAM-80.
f
Meth-50, Meth-100, and LAAM-80 significantly different from each other.
b
Lack of Toxicity of High Dose
Propoxyphene Napsylate When
Used for Maintenance Treatment of
Addiction
Woody, G. E.; Tennant, F. S.; McLellan, A. T.;
O’Brien, C. P.; Mintz, J.
Within the last six years clinical reports have suggested that
propoxyphene can be used for detoxification and maintenance treatment of narcotic addicts (Tennant, 1974, 1975; Inaba, Gay, Whitehead, 1974). Propoxyphene is chemically similar to methadone
and has weak narcotic agonist properties (Jasinski, Pevnick,
Clark, 1977). Probably only addicts with low levels of physical
dependence can be treated comfortably with propoxyphene as the
doses necessary to suppress abstinence symptoms, even in this
selected group, are high (800-1400 mg/day of napsylate salt;
500-900 mg/day of the hydrochloride). At these doses, side effects
often occur (Tennant, 1973; Mattson, Weisman, Levy, 1969). Typically, they reflect central nervous system irritability or
depression and include nausea, dysphoria, dizziness, drowsiness,
tremulousness, anxiety and seizures. They can be minimized by
giving propoxyphene in divided doses rather than in one single
dose (Tennant, 1973).
A recently completed double blind study has shown that low dose
(maximum 36 mg/day) methadone maintenance is superior to high
dose (maximum 1200 mg/day propoxyphene napsylate for maintenance
treatment (Woody, Mintz, Tennant, this volume). Another double
blind study has shown that methadone (initial dosage of 24 mg/day)
suppressed abstinence symptoms better than propoxyphene napsylate
(800 mg/day) in a heroin detoxification program (Tennant, Russell,
Casas, 1975). These findings are consistent with the early work
of Fraser and Isbell (1960) and the more recent findings of
Jasinski et al. (1977).
Though propoxyphene appears to be generally less effective than
methadone in narcotic detoxification and maintenance, there may
be some cases where propoxyphene may be preferable. Propoxyphene
is less euphorogenic, less physically addicting, and is therefore
less liable to be abused than methadone and other narcotics. It
may appeal to individuals who have low levels of physical dependence and who need medication but wish to avoid stronger opiates;
and it is stocked and easily available in most pharmacies.
435
However, propoxyphene is not approved by the Food and Drug Administration for use in the treatment of addiction. One reason for
this lack of approval is that there are little data on possible
toxic effects from the chronic use of high doses in humans. Kiplinger et al (1971) studied humans dosed with the hydrochloride
(260 mg/day, n = 24) and napsylate (400 mg/day, n = 25) salts.
These doses, which are within the usual analgesic range, were
continued for six months and no changes in urine, blood, physical
exams or electrocardiograms were found. Emerson et al. (1971)
found weight loss and increases in alkaline phosphatase in dogs
who were given three times the normal human dose of both the
napsylate and hydrochloride salts, over a period of 90 days.
Higher doses produced liver enlargement and fatty changes. They
also found that rats given 40 to 100 times the human dose over
90 - 180 days developed enlarged and fatty livers.
This paper presents toxicologic data from two studies, one done
in Philadelphia and one in Los Angeles, in which high doses of
propoxyphene napsylate were compared with low doses of methadone
for maintenance treatment of narcotic addicts. Protocols were
almost identical in each study and the clinical results, mentioned
earlier, are detailed in a separate paper (Woody, Mintz, Tennant,
this volume).
In this study, addicts applying for maintenance treatment were
randomly assigned to one of two groups: one received low dose
methadone, the other high dose propoxyphene napsylate. Only
patients who were non psychotic, who had no serious physical
illnesses and who were judged (by history and physical exam) to
have a low level of physical dependence were approached about
participating in this study. Patients received medicines daily,
seven days per week, for a maximum of 6 months. Details of the
dispensing procedure have been outlined in another paper (Woody,
Mintz, Tennant, this volume). After informed consent was obtained,
patients were started on 12 to 24 mg of methadone per day or 400
to 800 mg of propoxyphene napsylate per day. They were observed
closely during the next one to two weeks with an eye to dosage
adjustment and side effects. Dose was gradually increased over
two weeks to an average level of 32 mg/day of methadone or 500 mg
twice daily of proxyphene napsylate. One hundred forty-seven
subjects were treated in Philadelphia (Propoxyphene 79, Methadone
68) and 80 in Los Angeles (Propoxyphene 46, Methadone 34). A
physical exam with CBC, SMA 6/12, and urinalysis was done at
intake, at two weeks, four weeks and each month thereafter until
termination.
A chest x-ray and an EEG were done at intake and
at six months, or termination. Patients who stayed on the study
for the entire six months were usually switched to low dose methadone treatment, although a few detoxified.
RESULTS
Two types of analyses were performed on the monthly toxicologic
data for subjects in the propoxyphene study groups. In the first
436
analysis the absolute values of the test results were examined at
each monthly interval using a repeated measures analysis of
variance design. This type of analysis was selected under the
assumption that the accumulated effects of the medication might
produce progressive changes in the test results over the monthly
examination points. In the Philadelphia group, 79 patients began
propoxyphene treatment; of those, 57 dropped out prior to one
month and were not considered in the analyses. Three separate
analyses were computed for those remaining subjects who received
two months of treatment (n=22), those who received four months of
treatment (n = 17), and those who completed six months of treatment
(n = 14). Results of each of these analyses indicated no significant changes in the absolute values of the laboratory results in
27 of the 28 tests. Subjects who had completed six months of
propoxyphene treatment showed a significant reduction in total
bilirubin (p<.05) from a mean of .87 baseline, to a mean of .50
at the six month interval. This constituted a change from an
abnormally high value to a level within normal limits.
In the Los Angeles group 46 patients were placed on propoxyphene,
and 36 remained in treatment for a month. Analyses of the toxicologic data on these 36 subjects produced results which were
comparable to the Philadelphia findings. That is, none of the
tests analyzed showed evidence of a significant change over the
course of the study.
While these analyses demonstrated no significant changes in the
mean values of the laboratory tests, it was possible that there
were changes in the incidence of abnormal values in these tests
over the course of the study. To test this possibility the
Philadelphia subjects were again divided into the three length of
treatment groups, and chi square analyses were computed on each
laboratory test using frequency of abnormal values as the measure.
Again, twenty-six of the laboratory tests demonstrated no significant changes in the frequency of abnormal values over the
course of the study. However, SGOT and total bilirubin analyses
were both found to show significant decreases (p<.05) in the
frequency of abnormal values for those subjects who completed
six months of the study.
Analysis of the EKG data on the propoxyphene subjects from Philadelphia demonstrated that virtually all patients had values within
normal limits. While two of the subjects had slightly abnormal
results at baseline, each became normal during the study. EKGs
were examined carefully by a cardiologist for signs of the development of conduction disturbances and none were found. EEGs showed
signs of medication effects, similar to those seen with sedatives
and minor tranquilizers. No seizure activity was noted at any
time either clinically or on EEG. The physical complaints reported
by the propoxyphene subjects during the study were generally typical
of the assorted illnesses commonly seen in patients on a maintenance
program. Nineteen of the propoxyphene subjects reported abnormal
physical symptoms at some time during the study. The most common
437
abnormality reported was respiratory infection which occurred in
four patients. In addition, a small percentage of these subjects
reported increased anxiety, restlessness, and confusion which
stopped when propoxyphene was discontinued.
To summarize, analyses of the toxicologic data and reports of
physical complaints for those subjects maintained on high doses of
propoxyphene showed no general evidence of systematic change in
the absolute values of the tests or in the frequency of abnormal
results over the course of the study. Two specific tests of liver
function did show evidence of change, in the direction of normalization, for those subjects who completed six months of medication.
It should be noted that these results were paralleled by the data
for the methadone group who similarly showed no general evidence
of change in toxicological tests, nor in reports of physical
complaints over the course of the study.
Two rather serious incidents did develop during the course of
propoxyphene treatment and require comment.
One propoxyphene patient, a 52-year-old male with mild diabetes,
developed a transient cerebral ischemic attack. This required
hospitalization and resolved within 24 hours. Over the next two
years, no subsequent episodes occurred. A second patient became
obtunded apparently as a result of propoxyphene and sedative drugs.
He was receiving 300 mg propoxyphene twice daily and the incident
occurred on the third treatment day. He was known to abuse alcohol,
sedatives and benzodiazepines along with narcotics. When interviewed
in a local hospital several days after the incident, he claimed to
have taken two 30 mg flurazepam capsules and five "pills" of unknown
content, in addition to the study medication. He may have taken more
medication with the propoxyphene, but no additional history or toxicologic data were available.
DISCUSSION
One hundred twenty-seven patients received at least one dose of
propoxyphene and the average daily dose used by patients who
continued on this study was within the lower limits reported to be
fatal in nontolerant humans who take this drug rapidly and at one
time (Hudson, Barringer, McBay, 1977; Rejent, Michalek, Lehotay,
1977). Other than the single patient who became obtunded while
taking unknown drugs and benzodiazepines with propoxyphene, we did
not see any cases resembling the propoxyphene overdoses reported
by others (McBay, Hudson, 1975; Sturner, Garriott, 1973; Carson,
Carson, 1977). We think this reflects an absence of CNS depression
by propoxyphene in this population, probably due to tolerance for
narcotic agonist effects. Of course, this tolerance is absent in
nonaddicts who take propoxyphene impulsively and often with suicidal
intent (Hudson, Barringer, McBay, 1977).
The only consistent toxic effect observed was a syndrome which could
be characterized as central nervous system "irritability." It
usually consisted of increased anxiety, restlessness, or confusion,
438
which stopped when the drug was discontinued or when the dose was
lowered. We noted these symptoms in 12% of patients who took
propoxyphene for more than one month.
In conclusion, this study does not show clear evidence of serious
toxicity when propoxyphene napsylate is used for maintenance treatment of addiction in divided doses, starting with a maximum of
400 mg twice daily and increasing by as much as 200 mg/day to a
maximum of 600 mg twice daily. Propoxyphene does not appear to
work as well as methadone for maintenance or detoxification (Woody,
Mintz, Tennant, this volume), but clearly it works with some addict
patients.
ACKNOWLEDGEMENTS
We express our appreciation to Sue Malenbaum, Shelly Steinberg,
and Beverly Pomerantz, whose work on this project contributed to
the findings reported here.
REFERENCES
Carson, D.J.L., Carson, E.D. Fatal Dextropoxyphene Poisoning in
Northern Ireland. Lancet, April 23, 1977, p 894-897.
Emmerson, J.L., Gibson, W.R., Harris, P.N., et al. Short term
Toxicity of Propoxyphene Salts in Rats and Dogs. Tox Appl Pharm
19(3): 452-470, 1971.
Fraser, H.F., Isbell, H. Pharmacology and Addiction Liability of
dl-and d-propoxyphene. Bull Narc 12:9-14, 1960.
Hudson, P., Barringer, M., McBay, A.J. Fatal Poisoning with Propoxyphene: Report from 100 Consecutive Cases. Southern Med Journal
70(8): 938-942, 1977.
Inaba, D.S., Gay, G.R., Whitehead, C.A. and Newmeyer, J.A. The
Use of Propoxyphene Napsylate in the Treatment of Heroin and
Methadone Addiction. The Western Journal of Medicine, Vol. 121(2),
August 1974, p. 106-111.
Jasinski, D.R., Pevnick, J.S., Clark, S.C. and Griffith, J. D.
Therapeutic Usefulness of Propoxyphene Napsylate in Narcotic
Addiction. Arch Gen Psych 34:227-233, 1977.
Kiplinger, G.F., Gruber, C.M., Pierce, E.C. A Comparative Study
of the Effects of Chronic Administration of Propoxyphene Salts to
Normal Volunteers. Tox Appl Pharm 19(3): 528-536, 1971.
Mattson, R.H., Weisman, G.K. and Levy, L. L. Dependence and
Central Nervous System Toxicity Associated with the Use of Propoxyphene Hydrochloride. Transactions of the American Neurol
ASSOC, Vol 94, 1969, p 229-301.
439
McBay, A.J., Hudson, P. Propoxyphene Overdose Deaths. JAMA 233
(12): 1257, 1975.
Rejent, T.A., Michalek, R.W. and Lehotay, J.M. Propoxyphene
Associated Deaths: Methods, Post Mortem Levels in Blood and
Liver. Clin Toxic 11(1): 43-51, 1977.
Sturner, W.Q., Garriott, J.C. Deaths Involving Propoxyphene.
JAMA 223(10): 1125-1130, 1973.
Tennant, F.S. Propoxyphene Napsylate for Heroin Addiction. JAMA,
Vol 226(8), November 19, 1973, p 1012.
Tennant, F.S. Propoxyphene Napsylate (Darvon-N) Treatment of
Heroin Addicts. J of the National Med ASSOC, January 1974, p 2324.
Tennant, F.S., Russell, B.A., Shannon, J.A. and Casas, S.K. Outpatient Withdrawal from Methadone Maintenance with Propoxyphene
Napsylate (Darvon-N). J of Psychedelic Drugs, Vol 7(3), July September 1975, p 269-271:
Tennant, F.S. Russell, B.A., Casas, S.K. and Bleich, R.N. Heroin
Detoxification - A Comparison of Propoxyphene and Methadone. JAMA,
Vol 232(10), 1975, p 1019-1022.
Woody, G.E., Mintz, J., Tennant, F.S., McLellan, A.T., O'Brien,
C.P. Usefulness of Propoxyphene Napsylate for Maintenance Treatment of Narcotic Addiction. Submitted for publication (1979).
AUTHORS:
George E. Woody, M.D.; Forest S. Tennant, M.D.; A. Thomas McLellan,
Ph.D.; Charles P. O'Brien, M.D., Ph.D.; Jim Mintz, Ph.D.
From: Department of Psychiatry, University of Pennsylvania, Drug
Dependence Treatment and Research Center, Philadelphia, Pa.,
Veterans Administration Medical Center, Philadelphia, Pa., and
Division of Epidemiology, UCLA School of Public Health, LOS
Angeles, Calif.
440
SUBJECT INDEX
Abstinence
See Withdrawal
(-)-l- -Acetyl-N,N-dinormethadol
binding to blood constituents, 54-60
cardiovascular pharmacology, 422-428
self-administration and REM sleep EEG, 114-120
l-
-Acetylmethadol
binding to blood constituents, 54-60
cardiovascular effects, in vivo and isolated organs, 422-428
effects in morphine-dependent rats, 409-414
effects of chronic treatment on phencyclidine response in
rats, 212-218
phase III clinical evaluation: comparative epidemiology of
mortality in LAAM and methadone, 289-295
relative efficacy in opiate maintenance program; comparison
with methadone, 429-434
self-administration and REM sleep EEG, 114-120
(-)-1- -Acetyl-N-normethadol
binding to blood constituents, 54-60
cardiovascular pharmacology, 422-428
self-administration and REM sleep EEG, 114-120
2-Acetyl-1,2,3,4-tetrahydroisoquinoline-4-spiro-4'-[1'-(3-cyano3,3-diphenylpropyl)] piperidine hydrochloride
mouse analgesia, 395
physical dependence, monkeys, 395
Addiction
closing the Bakersfield Methadone Clinic, 136-141
conditioned heroin responses; readdiction liability, 268-274
drug addiction in Baltimore from 1950-1977, an overview,
184-190
impact of heroin upon criminality, 163-169
maintenance treatment of narcotic addiction; usefulness of
propoxyphene napsylate, 240-246
Addiction severity index
evaluation and classification of substance abuse, 142-148
Addicts
drug abusers, pathological feelings, 170-176
drug addiction in Baltimore from 1950-1977, an overview,
184-190
outcome for structural family therapy with heroin addicts,
415-421
unreinforced self injections: effects on rituals and outcome
in heroin addicts, 275-281
D-Ala2-D-leu5-enkephalin
binding to the opiate receptor, 48-49
441
Alcohol
development of psychiatric disorders in abusers, 149-155
drug abusers, pathological feelings, 170-176
effects of abuse on progression of liver disease in
methadone-maintained patients, 399-401
ethnoeconomic approach to the relationship between crime
and drug abuse, 156-162
Alcoholics
evaluation by the addiction severity index, 142-148
8
-Alkyl-N-cycloalkyl-dihydrocodeinones
synthesis, analgesic activity and narcotic antagonism, 93-98
8
-Alkyl-N-cycloalkyl-dihydromorphinones
synthesis, analgesic activity and narcotic antagonism, 93-98
8-Alkyldihydrocodeinones
synthesis, analgesic activity and narcotic antagonism, 93-98
2-Allyl-3a- m-hydroxyphenyl-2,3,3a,4,7,7a-hexahydro-c i s-iosindole
dependence studies, in monkeys, 338
mouse analgesia, 389
physical dependence, monkeys, 389
3-Allyl-7-methoxy-l,2,4,5-tetrahydro-3-(3 H )-benzazepine hydrochloride
mouse analgesia, 384
physical dependence, monkeys, 384
self-administration, monkeys, 384
N-Allylnormetazocine
effects on flurothyl seizure thresholds in rats, 199
4-Amino-3,5-dibromo-alpha-[(dimethylamino) methyl] benzyl alcohol
hydrochloride
mouse analgesia, 392
physical dependence, monkeys,-392
beta-Aminomethyl- p-chlorohydrocinnamic acid
guinea-pig ileum, 359-371
mouse analgesia, 370
mouse vas deferens, 359-371
physical dependence, monkeys, 340-370
self-administration, monkeys, 370
stereospecific binding, 371
3-(p-Aminophenethyl)-7-methoxy-1,2,4,5-tetrahydro-3-(3 H )-benzazepine
dihydrochloride
mouse analgesia, 392
physical dependence, monkeys, 392
(-)- -Amino-propiophenone
See Cathinone
442
Amphetamines
behavioral effects in monkeys and rats; comparison with
cathinone, 324-325
comparison with (-) cathinone and (+) cathine; in vivo
and isolated organs, 322-323
development of psychiatric disorders in abusers, 149-155
drug addiction in Baltimore from 1950-1977, an overview,
184-190
drug schedule, 14, 17-28
medical withdrawal; outpatient treatment, 178
outpatient treatment and outcome of prescription drug abuse,
177-183
d-Amphetamine
drug discrimination by monkeys and pigeons, 128-134
Analgesia
morphine tolerance to, 36-47
Analgesics
clinical analgesic assay of oral zomepirac and intramuscular
morphine, 261-267
i.m. heroin and morphine in cancer patients with postoperative
pain, 254-260
Apomorphine
drug discrimination by monkeys and pigeons, 128-134
drug schedule, 14
0-Arylmorphinans
analgesic activities, 80
Atropine
paradoxical effects in opiate dependence and tolerance, 220
Baclofen
See
-(Aminomethyl)- p-chlorohydrocinnamic acid
Bakersfield Methadone Clinic
effects of closing, 136-141
Barbiturates
development of psychiatric disorders in abusers, 149-155
drug addiction in Baltimore from 1950-1977,
184-190
drug schedule, 14, 17-28
outpatient treatment and outcome of prescription drug
abuse, 177-183
Bemegride
drug discrimination by monkeys and pigeons, 128-134
443
Benzodiazepines
development of psychiatric disorders in abusers, 149-155
drug schedule, 14
1-(2-(1,4-Benzodioxanyl)-methyl)-4-(2-oxo- 1 -benzimidazolinyl)piperidine
mouse analgesia, 395
physical dependence, monkeys, 395
Binding sites
See Opiate receptors
Body temperature
tolerance to the effect of morphine on, 36-47
Buprenorphine
effect on flurothyl seizure thresholds in rats, 198-204
guinea-pig ileum and mouse vas deferens, 359
Butabarbital
drug schedule, 14
Butisol
See Butabarbital
Butorphanol
guinea-pig ileum and mouse vas deferens, 359
N-n-Butylnormeperidine hydrochloride
dependence studies, in monkeys, 344
N-sec-Butylnormeperidine hydrochloride
dependence studies, in monkeys, 345
Calcium
opiate analgesia, tolerance and physical dependence, 7-9
1-(beta-Carbethoxyethy1)-4-carbethoxy-4-phenylpiperidine hydrochloride
mouse analgesia, 393
physical dependence, monkeys, 393
cis-3-Carbethoxy-4-hydroxy-1-methylpiperidine-4-(3,4-dimethoxybenzoate) hydrochloride
guinea-pig ileum, 375
mouse analgesia, 374
mouse vas deferens, 375
physical dependence, monkeys, 374
self-administration, monkeys, 374
stereospecific binding, 375
4-Carbethoxy-1-methyl-4-phenylpiperidine N-oxide hydrobromide
mouse analgesia, 395
physical dependence, monkeys, 395
444
Cathedulines
khat polyester-type alkaloids, 318
Cathine
a khat active ingredient, 316,318,320
pharmacological effects of (+) cathine vs (-) cathinone and
amphetamine; in vivo and isolated organs, 322-323
Cathinone
a khat constituent;
identification and synthesis, 318-320
behavioral studies in monkeys and rats, 324-327
cardiovascular effects in rats and isolated atria of guineapig, 326
central effects of (-) cathinone comparison with (+) cathine
and amphetamine, 322-323
neurochemical mechanism, a preliminary study in mice and rats,
328-329
Chloral hydrate
drug schedule, 14, 17-28
4-(p-Chlorophenyl)-4-hydroxy-N,N-dimethyl- alpha,alpha-diphenyl-lpiperidinebutyramide
hydrochloride
mouse analgesia, 391
physical dependence, monkeys, 333,391
physical dependence, monkeys, 396-398
2-(0-Chlorophenyl)-2-(methylamino)-cyclohexanone
chronic spinal dog, self-administration, rotarod, acute
toxicity, discriminative stimulus properties, 61-69
4-(4-Chloro- alpha,alpha ,alpha -trifluoro-m-tolyl)-4-hydroxy-N,Ndimethyl- alpha,alpha-diphenyl-1-piperidinebutyramide HCl
mouse analgesia, 392 physical dependence, monkeys, 392
Chlorpromazine
hot plate and Nilsen tests in mice, 332
Clonidine
detoxification; protocol for rapid opiate withdrawal,
226-232
nonopiate treatment for opiate withdrawal, 233-239
See also
-2(2,6-Dichloroanilino)-2-imidazoline
hydrochloride
Cocaine
development of psychiatric disorders in abusers, 149-155
drug addiction in Baltimore from 1950-1977, an overview,
184-190
drug schedule, 14
Codeine
drug addiction in Baltimore from 1950-1977, an overview,
184-190
445
Codeine
drug discrimination by monkeys and pigeons, 128-134
drug schedule, 14
hot plate and Nilsen tests in mice, 332
liquid codeine, drug addiction in Baltimore from 1950-1977,
an overview, 184-190
mouse analgesia, 360
outpatient treatment and outcome of prescription drug abuse,
177-183
stereospecific binding, 358
Compliance
in drug treatment programs as a function of payment manipulations, 402-408
Controlled substances
effects of scheduling on economics of drug development, 17-28
prescription of, 11-16
Crime
effects of closing the Bakersfield Methadone Clinic, 136-141
impact of heroin addiction, 163-169
relationship to drug use, 156-162
Cross tolerance
between morphine and levorphanol, 43-44
(-)-2-(2-Cyanoethyl)-5,9 alpha -dimethyl-2'-hydroxy-6,7-benzomorphan
hvdrobromide
guinea-pig ileum, 377
mouse analgesia, 376
mouse vas deferens, 377
physical dependence, monkeys, 376
self-administration, monkeys, 376
stereospecific binding, 377
(+)-2-(2-Cyanoethyl)-5,9 alpha -dimethyl-2'-hydroxy-6,7-benzomorphan
hydrobromide
mouse analgesia, 380
physical dependence, monkeys, 380
self-administration, monkeys, 380
dl-2-(3-Cyanopropyl)-5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphan
hydrobromide
mouse analgesia, 390
physical dependence, monkeys, 390
2-(2-Cyanoethyl)-9- alpha-ethyl-2'-hydroxy-5-methyl)-6,7-benzomorphan
dependence studies, in monkeys, 338
-(-)-N-(2-Cyanoethyl)-3-hydroxymorphinan
dependence studies, in monkeys, 335
Cyclazocine
analgesic tests in mice, 331,332,361
446
Cyclazocine
drug discrimination by monkeys and pigeons, 128-134
effect on flurothyl seizure thresholds in rats, 198-204
stereospecific binding, 358
N-Cyclobutylmethyl-3-hydroxy-8-beta-methyl-6-oxomorphinan
dependence studies in monkeys, 339
tartrate
2-Cyclopropylcarbonyloxy-4-dimethylamino-3-methyl-1,2-diphenylbutane
mouse analgesia, 393
physical dependence, monkeys, 393
17-Cyclopropylmethyl-8
-ethyl-7,8-dihydronorcodeinone
narcotic agonist-antagonist analgesic and physical dependence
studies, 99-105
(-)-m-(1-Cyclopropylmethyl-3-ethylhexahydro-1 H azepin-3-yl)phenol
fumarate
mouse analgesia, 391
physical dependence, monkeys, 391
N-Cyclopropylmethyl-8-beta-ethylnordihydrocodeinone hydrochloride
dependence studies, in monkeys, 339
3-Cyclopropylmethyl-1,2,3,4,5,6-hexahydro-8-hydroxy-6-methyl-3benzazocine
drug discrimination, 128-134
(-)-N-Cyclopropylmethyl-2-hydroxymorphinan
mouse analgesia, 383
physical dependence, monkeys, 383
self-administration, monkeys, 383
hydrochloride
(-)-17-(Cyclopropylmethyl)-3-hydroxymorphinan-6-one
sulfonate
guinea-pig ileum, 359-373
mouse analgesia, 372
mouse vas deferens, 359-373
physical dependence, monkey, 336,372
self-administration, monkeys, 372
stereospecific binding, 373
methane-
17-Cyclopropylmethyl-3-hydroxy-6-oxamorphinan tartrate
guinea-pig ileum, 369
mouse analgesia, 368
mouse vas deferens, 369
physical dependence, monkeys, 368
self-administration, monkeys, 368
stereospecific binding, 369
trans -3-(N-Cyclopropylmethyl-N-methylamino)-l-phenyl-1,2,3,4tetrahydronaphthalene
hydrochloride
mouse analgesia, 389
physical dependence, monkeys, 389
447
Cyclorphan
drug discrimination by monkeys and pigeons, 128-134
effect on flurothyl seizure thresholds in rats, 198-204
Darvon
See
Propoxyphene
Demerol
drug addiction in Baltimore from 1950-1977, an overview,
184-190
See also, Meperidine
3-Deoxydihydromorphinone
hydrochloride
dependence studies, in monkeys, 345
Dependence studies
influence of the mode of morphine administration on, 36-47
new compounds in the Rhesus monkey, 330-350
Detoxification
clonidine hydrochloride; non-opiate treatment for opiate
withdrawal, 226-232
opiate detoxification:
treatment compliance and payment
manipulations, 402-408
outpatient treatment and outcome of prescription drug abuse,
177-183
Dextrorphan
drug discrimination by monkeys and pigeons, 128-134
stereospecific binding, 358
Diacetylmorphine
See Heroin
Diazepam
outpatient treatment and outcome of prescription drug abuse,
177-183
2-(2,6-Dichloroanilino)-2-imidazoline hydrochloride
dependence studies, in monkeys, 342
7,8-Didehydro-4,5- alpha-epoxy-17-methylmorphinan-3,6- alpha -diol
diacetate ester
See Heroin
3,6-Dideoxydihydromorphine hydrochloride
dependence studies, in monkeys, 346
1-Diethylaminocyclohexane-carbonitrile
chronic spinal dog, self-administration, rotarod, acute toxicity,
discriminative stimulus properties, 61-69
2,9-alpha-Diethyl-2'-hydroxy-5-methyl-6,7-benzomorphan
dependence studies, in monkeys, 336
448
N,N-Diethyl-1-phenylcyclohexylamine
chronic spinal dog, self-administration, rotarod, acute toxicity,
discriminative stimulus properties, 61-69
Diethylproprion
drug schedule, 14
Dihydromorphine
binding to the opiate receptor, 48-49
Dihydromorphinone
drug schedule, 14
hot plate and Nilsen tests in mice, 332,360
Dilaudid
drug addiction in Baltimore from 1950-1977, an overview, 184-190
See also Hydromorphone
(-)-5,9 alpha -Dimethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphan
methanesulfonate
drug discrimination, 128-134
mouse analgesia, 382
physical dependence, monkeys, 382
self-administration, monkeys, 382
(-)-7,12 alpha-Dimethyl-9-hydroxy-4-methyl-C-homobenzomorphan
guinea-pig ileum, 365
mouse analgesia, 364
mouse vas deferens, 365
physical dependence, monkeys, 364
self-administration, monkeys, 364
stereospecific binding, 365
(-)-7,12 beta-Dimethyl-9-hydroxy-4-methyl-C-homobenzomorphan
mouse analgesia, 388
physical dependence, monkeys, 378,388
self-administration, monkeys, 378
(+)-7,12 alpha-Dimethyl-9-hydroxy-4-methyl-C-homobenzomorphan
mouse analgesia, 379
physical dependence, monkeys, 379
self-administration, monkeys, 379
(+)-7,12 beta-Dimethyl-9-hydroxy-4-methyl-C-homobenzomorphan
mouse analgesia, 388
physical dependence, monkeys, 388
dl-7,12 beta-Dimethyl-9-hydroxy-4-methyl-C-homobenzomorphan
guinea-pig ileum, 363
mouse analgesia, 362
mouse vas deferens, 363
physical dependence, monkeys, 362
self-administration, monkeys, 362
stereospecific binding, 363
449
[(+)-1R/S,5R/S,9R/S,2"R/S]-5,9-dimethyl-2'-hydroxy-2-tetrahydrofurfuryl-6,7-benzomorphan
drug discrimination, 128-134
1,3-Dimethyl-4-phenyl-4-piperidylethyl
carbonate
dependence studies, in monkeys, 335
1,3-Dimethyl-4-phenyl-4-piperidylmethyl
mouse analgesia, 390
physical dependence, monkeys, 390
carbonate
1,4-Dimethyl-4-piperidinol-4-(3,4-dimethoxybenzoate)
mouse analgesia, 387
physical dependence, monkeys, 387
hydrochloride
1,4-Dimethyl-4-piperidinol-4-(2,4,5-trimethylpyrrole-3-carboxylate)
hydrochloride
mouse analgesia, 387
physical dependence, monkeys, 387
dinor -LAAM
See (-)-1-
-Acetyl-N,N-dinormethadol
Diphenoxylate hydrochloride
use in detoxification and medical withdrawal; outpatient
treatment, 178
Dolophine
drug addiction in Baltimore from 1950-1977, an overview, 184-190
See also Methadone
Doriden
See
Glutethimide
Drug abuse
alcohol abuse and progression of liver disease in methadonemaintained patients, 399-401
medical withdrawal and medical maintenance, 177-183
outpatient treatment and outcome of prescription drug abuse,
177-183
Drug dependence
biological testing program, 351-355
dependence within the opiate-sensitive neurone, 219-225
intravenous phencyclidine self-administration in monkeys, 205-211
programme of WHO, 70-73
See also Dependence
Drug
development
effect of scheduling, 17-28
Drug
discrimination
narcotics in monkeys and pigeons, 128-134
450
Drug responses
conditioned drug responses to naturalistic stimuli, 282-288
Drug use
relationship to crime, 156-162
Drug users
development of psychiatric disorders, 149-155
evaluation by the addiction severity index, 142-148
"Drugstore dope"
drug addiction in Baltimore from 1950-1977, an overview,
184-190
Economic behavior
relationship between crime and drug use, 156-162
EEG
REM sleep and opioid self-administration, 114-120
Enkephalins
biosynthesis in the myenteric plexus of the guinea-pig ileum,
48-53
interaction with the opiate receptor, 48-53
Ethchlorvynol
drug schedule, 14
Ethinamate
drug schedule, 14
2-(4-Ethoxybenzoyl)-5-methyl-3-(2-pyrrolidinoethoxy)-benzofuran
hydrochloride
mouse analgesia, 394
physical dependence, monkeys, 394
8 -Ethyl-dihydrocodeinones
analgesic and narcotic antagonist activities, 101
8 -Ethyl-dihydromorphinones
analgesic and narcotic antagonist activities, 101
9 -Ethyl-2-hexyl-2'-hydroxy-5-methyl-6,7-benzomorphan
dependence studies, in monkeys, 334
Ethylketazocine
drug discrimination by monkeys and pigeons, 128-134
guinea-pig ileum and mouse vas deferens, 359
Ethylketocyclazocine
effect on flurothyl seizure thresholds in rats, 198-204
N-Ethyl-1-phenylcyclohexylamine
chronic spinal dog, self-administration, rotarod, acute toxicity,
discriminative stimulus properties, 61-69
451
Etorphine
binding to the opiate receptor, 48-49
drug discrimination by monkeys and pigeons, 128-134
effect on flurothyl seizure threshold in rats, 198-204
FDA
impact of regulations on development of psychoactive drugs,
29-35
Fenfluramine
drug schedule, 14
FK 33824
drug discrimination, 128-134
Flurothyl
effects of opioids on flurothyl seizure thresholds in rats,
198-204
Glutethimide
drug schedule, 14
GPA 1657
See (-)-2'-Hydroxy-2,9 beta-dimethyl-5-phenyl-6,7-benzomorphan
hydrochloride
Hashish
histopathologic and clinical abnormalities of the respiratory
system in chronic hashish smokers, 309-315
Hatch-Metcalf Act
impact on development of psychoactive drugs, 29
Heroin
analgesic potency in cancer patients, 254-260
development of psychiatric disorders in abusers, 149-155
drug addiction in Baltimore from 1950-1977, an overview,
184-190
effects on pituitary-gonadal hormones in man, 302-308
ethnoeconomic approach to the relationship between crime and
drug use, 156-162
impact of addiction upon criminality, 163-169
outcome for structural family therapy with heroin addicts,
415-421
readdiction liability test-conditioned responses, 268-274
smoking, 4-5
unreinforced injections: effects on rituals and outcome in
heroin addicts, 275-281
1-[(2-alpha, 6 alpha, 11 S)-(±)-1-(1,2,3,4,5,6-Hexahydro-8-hydroxy3,6,11-trimethyl-2,6-methanol-3-benzazocin-11-yl)]-6-methyl-3heptanone methanesulfonate
dependence studies, in monkeys, 348
452
l-[(2-alpha,6- a l p h a ,
11S)-(±)-1-(1,2,3,4,5,6-Hexahydro-8-hydroxy-3,
6,11-trimethyl-2,6-methanol-3-benzazocin-11-yl)]-3-octanone
methanesulfonate
dependence studies, in monkeys, 348
Hormones
heroin and naltrexone effects on pituitary-gonadal hormones in
man, 302-308
Hydromorphone
unreinforced self-injections: effects on rituals and outcome in
heroin addicts, 275-281
(+)-9-Hydroxy-4,7-dimethyl-C-homobenzomorphan
dependence studies, in monkeys, 347
hydrobromide
(-)-9-Hydroxy-4,7-dimethyl-C-homobenzomorphan
dependence studies, in monkeys, 347
hydrobromide
(+)-9-Hydroxy-4,7-dimethyl-C-homobenzomorphan
dependence studies, in monkeys, 346
hydrobromide
dl-9-Hydroxy-7,12 alpha -dimethyl-4-methyl-C-homobenzomorphan
mouse analgesia, 388
physical dependence, monkeys, 388
(-)-2'-Hydroxy-2,9 beta-dimethyl-5-phenyl-6,7-benzomorphan hydrochloride
mouse analgesia, 394
physical dependence, monkeys, 394
N-2-Hydroxyethylnorketobemidone
hydrobromide
mouse analgesia, 385
physical dependence, monkeys, 385
stereospecific binding, 385
2-Hydroxy-3-methoxy-6
-naltrexol
plasma levels in schizophrenic patients after large oral doses
of naltrexone, 296-301
5-(3-Hydroxyphenyl)-3-azabicyclo (3.3.1 ) nonane hydrobromide
dependence studies, in monkeys, 333
(±)-1-m -Hydroxyphenyl-6,7-dimethyl-6-azabicyclo[3.2.l]octane
bromide
mouse analgesia, 381
physical dependence, monkeys, 381
self-administration, monkeys, 381
hydro-
10-m-Hydroxyphenyl-2-phenethyl- cis-decahydroisoquinoline
dependence studies, in monkeys, 342
Hydroxyzine pamoate
use in detoxification and medical withdrawal: outpatient treatment, 177-183
453
314-300 0 -80 - 31
Hyperthermia
See Body temperature
Hypothermia
See Body temperature
Indoklon
See Flurothyl
International Narcotics Control Board
control of dependence-producing drugs, 74-76
N-Isopropyl-N-methyl-3-formamido-1-pyrazole
mouse analgesia, 393
physical dependence, monkeys, 393
carboxamide
Ketazocine
drug discrimination by monkeys and pigeons, 128-134
effect on flurothyl seizure thresholds in rats, 198-204
N-(3-Ketopentyl)norketobemidone hydrobromide
mouse analgesia, 387
physical dependence, monkeys, 387
Khat
assessment of public health and social problems, 316-317
clinical effects, 319
research on the chemical composition, 320-321
the problem today, 318-319
LAAM
See 1- -Acetylmethadol
Learning
in rats perinatally exposed to methadone, 121-127
Lefetamine
cross self-administration with loperamide, 111
drug schedule, 70
Levallorphan
stereospecific binding, 358
Levorphanol
cross-tolerance to the hyperthermic effect of morphine, 43
effect on flurothyl seizure thresholds in rats, 198-204
mouse analgesia, 332-360
stereospecific binding, 358
Loperamide
dependence potential in monkeys; 106-113
See also 4-(p-Chlorophenyl-4-hydroxy-N,N-dimethyl- alpha,alphadiphenyl-1-piperidine butyramide hydrochloride
454
LSD
drug schedule, 17-28
Luteinizing hormone
heroin and naltrexone effects on secretion: tolerance and
supersensitivity, 302-308
Maintenance
effects of closing the Bakersfield Methadone Clinic, 136-141
medical maintenance with drug of abuse, 177-183
Marijuana
drug schedule, 17-28
pulmonary effects, in man, 309-315
MCN-2783-21-98
See Zomepirac
MCV 4073
See 4-(p-Chlorophenyl)-4-hydroxy-N,N-dimethyl- alpha,alphadiphenyl-1-piperidinebutyramide
hydrochloride
MCV 4075
See 5-(3-Hydroxphenyl)-3-azabicyclo (3.3.1) nonane hydrobromide
MCV 4084
See 9
-Ethyl-2-hexyl-2'-hydroxy-5-methyl-6,7-benzomorphan
MCV 4106
See 8
-Methyldihydrocodeinone
hydrochloride
MCV 4107
See
-(-)-N-(2-Cyanoethyl)-3-hydroxymorphinan
MCV 4112
See
1,3-Dimethyl-4-phenyl-4-piperidylmethyl
MCV 4120
See
1,3-Dimethyl-4-phenyl-4-piperidylethyl
carbonate
carbonate
MCV 4121
See 2,9-alpha-Diethyl-2'-hydroxy-5-methyl-6,7-benzomorphan
MCV 4130
See
(-)-17-(Cyclopropylmethyl)-3-hydroxymorphinan-6-one
methanesulfonate
MCV 4131
See 4-(Methyl- n-butylamino)-4-( n-hydroxyphenyl)-cyclohexanone
ethylene ketal hydrochloride
MCV 4133
See (±)-trans-N-Methyl-N-2-pyrrolidinylcyclohexyl-2-(3,4dichlorphenyl) acetamide HCl
455
MCV 4137
See 2-(2-Cyanoethyl)-9-alpha-ethyl-2'-hydroxy-5-methyl-6,7benzomorphan
MCV 4140
See 2-Allyl-3a-m-hydroxyphenol-2,3,3a,4,7,7a-hexahydrocis-isoindole
MCV 4142
See
N-Cyclopropylmethyl-8-beta-ethyl nordihydrocodeinone
hydrochloride
MCV 4143
See N-Cyclobutylmethyl-3-hydroxy-8-beta-methyl-6-oxomorphinan
tartrate
MCV 4144
See beta-Aminomethyl- p-chlorohydrocinnamic acid
MCV 4146
See 4 beta-(m-Methoxyphenyl)-1,3-dimethyl-4
propionate hydrochloride
alpha-piperidinol
MCV 4147
See 1-(4-Methylphenyl)-3-azabicyclo-[3.1.0] hexane hydrochloride
MCV 4152
See
(+)-Naloxone
hydrochloride
MCV 4154
See 10- m -Hydroxyphenyl-2-phenethyl- cis-decahydroisoquinoline
MCV 4155
See 2-(2,6-Dichloroanilino)-2-imidazoline hydrochloride
MCV 4158
See 1-(1-Phenylcyclohexyl)piperidine hydrochloride
MCV 4161
See (-)-trans-5,6,6a beta-7,8,9,10,10a alpha-Octahydro-1-acetoxy6-beta-methyl-3-(5-phenyl-2-pentyloxy)-phenanthridine
hydrochloride
MCV 4163
See N-n-Butylnormeperidine
hydrochloride
MCV 4164
See N-sec-Butylnormeperidine hydrochloride
MCV 4165
See
3-Deoxydihydromorphinone
hydrochloride
MCV 4166
See 3,6-dideoxydihydromorphine hydrochloride
456
MCV 4167
See (+)-9-Hydroxy-4,7-dimethyl-C-homobenzomorphan
hydrobromide
MCV 4168
See
(+)-9-Hydroxy-4,7-dimethyl-C-homobenzomorphan
hydrobromide
MCV 4160
See
(-)-9-Hydroxy-4,7-dimethyl-C-homobenzomorphan
hydrobromide
MCV 4175
See 1-[(2-alpha, 6-alpha, 11 S)-(±)-1-(1,2,3,4,5,6-Hexahydro8-hydroxy-3,6,11-trimethyl-2,6-methano1-3-benzazocin-11yl)]-3-octanone methanesulfonate
MCV 4176
See l-[(2-alpha ,6 alpha, 11 S)-(±)-1-(1,2,3,4,5,6-Hexahydro8-hydroxy-3,6,11-trimethyl-2,6-methanol-3-benzazocin11-yl)]-6-methyl-3-heptanone methanesulfonate
MCV 4183
See 2-(2,6-Dichloroanilino)-2-imidazoline hydrochloride
MCV 4184
See Yohimbine hydrochloride
Mecloqualone
drug schedule, 71
Meperidine
drug discrimination, 128-134
drug schedule, 14-15
effect on flurothyl seizure thresholds in rats, 198-204
guinea-pig ileum and mouse vas deferens, 359
mouse analgesia, 332, 360
Meprobamate
drug schedule, 14, 17-28
(-)-Metazocine
mouse analgesia, 332, 360
Methadone
alcohol abuse and liver disease in methadone-maintained patients,
399-401
comparative epidemiology of mortality in LAAM and methadone,
289-295
development of psychiatric disorders in abusers, 149-155
drug addiction in Baltimore from 1950-1977, an overview, 184-190
drug schedule, 14-15
effects of chronic treatment on phencyclidine response in
rats, 212-218
effects of closing the Bakersfield Clinic, 136-141
effect on flurothyl seizure thresholds in rats, 198-204
maintenance treatment of narcotic addiction; comparison
with methadone, 240-246
457
Methadone
perinatal exposure in rats; motor activity and learning
ability, 121-127
relative efficacy in opiate maintenance program; comparison
with LAAM, 429-434
self-administration and REM sleep EEG, 114-120
Methamphetamine
drug schedule, 17-28
Methaqualone
drug schedule, 14
4-beta(m-Methoxyphenyl)-1,3-dimethyl-4 alpha-piperidinol propionate
hydrochloride
guinea-pig ileum, 367
mouse analgesia, 366
mouse vas deferens, 367
physical dependence, monkeys, 340,366
self-administration, monkeys, 366
stereospecific binding, 367
1-Methylaminocyclohexane-carbonitrile
chronic spinal dog, self-administration, rotarod, acute
toxicity, discriminative stimulus properties, 61-69
4-(Methyl- n-Butylamino)-4-( m-hydroxyphenyl)cyclohexanone
ketal hydrochloride
mouse analgesia, 390
physical dependence, monkeys, 337-390
ethylene
N-3-Methylbutylnorketobemidone hydrobromide
mouse analgesia, 386
physical dependence, monkeys, 386
8 -Methyldihydrocodeinone hydrochloride
dependence studies, in monkeys, 334
N-2-Methylpentylnorketobemidone hydrobromide
mouse analgesia, 386
physical dependence, monkeys, 386
N-4-Methylpentylnorketobemidone hydrobromide
mouse analgesia, 386
physical dependence, monkeys, 386
Methylphenidate
development of psychiatric disorders in abusers, 149-155
drug schedule, 14, 17-28
medical withdrawal; outpatient treatment, 178
1-(4-Methylphenyl)-3-azabicyclo-[3.1.0] hexane
dependence studies, in monkeys, 341
458
hydrochloride
2-Methyl-5-phenyl-6,7-benzomorphan hydrobromide
mouse analgesia, 394
physical dependence, monkeys, 394
N-Methyl-1-phenylcyclohexylamine
chronic spinal dog, self-administration, rotarod, acute toxicity,
discriminative stimulus properties, 61-69
l-Methyl-4-piperidinol-2,4-dimethyl-5-acetylpyrrole-3-carboxylate
hydrochloride
mouse analgesia, 385
physical dependence, monkeys, 385
stereospecific binding, 385
Methylprylon
drug schedule, 14
(+)-trans-N-Methyl-N-2-pyrrolidinylcyclohexyl-2-(3,4-dichlorophenyl) acetamide HCl
dependence studies, in monkeys, 337
Morphine
analgesic potency in cancer patients, 254-260
analgesic tests in mice, 331
clinical analgesic assay of i.m. morphine vs oral zomepirac
conjugation, 3
N-dimethylation, 2-3
drug addiction in Baltimore from 1950-1977, an overview,
184-190
drug discrimination, 128-134
drug schedule, 14
effects of chronic treatment on phencyclidine response in rats,
212-218
effects on fetal rats in utero, 191-197
effect on flurothyl seizure thresholds in rats, 198-204
guinea-pig ileum and mouse vas deferens, 359
hot plate and Nilsen tests in mice, 332
influence of mode of administration on tolerance and dependence, 36-47
mouse analgesia, 360
pellet implantation technique, 5
self-administration and REM sleep EEG, 114-120
stereospecific binding, 358
Morphine pellets
nylon-enshrouded,
36-47
1-Morpholinocyclohexane-carbonitrile
chronic spinal dog, self-administration, rotarod, acute
toxicity, discriminative stimulus properties, 61-69
Motor activity
in rats perinatally exposed to methadone, 121-127
459
Moxazocine
effect on flurothyl seizure thresholds in rats, 198-204
Mr-1452-MS
See (-)-5,9 alpha-Dimethyl-2-(3-furylmethyl)-2'-hydroxy6,7-benzomorphan
methanesulfonate
Nalbuphine
effect on flurothyl seizure thresholds in rats, 198-204
Nalorphine
analgesic tests in mice, 331
drug discrimination, 128-134
drug schedule, 17-28
effect on flurothyl seizure thresholds in rats, 198-204
mouse analgesia, 332, 361
stereospecific binding, 358
Naloxone
agonist-antagonist tests in mice, 331
effects of fetal rats in utero, 191-197
effect on flurothyl seizure thresholds in rats, 198-204
drug discrimination, 128-134
mouse analgesia, 361
sterospecific binding, 358
(+)-Naloxone hydrochloride
dependence studies, in monkeys, 341
6 -Naltrexol
plasma levels in schizophrenic patients after large oral
doses of naltrexone, 296-301
Naltrexone
agonist-antagonist tests in mice, 331
drug discrimination, 128-134
effects on pituitary-gonadal hormones in man, 302-308
mouse analgesia, 361
opiate detoxification program; treatment compliance as a
function of payments, 402-408
plasma levels of naltrexone and its metabolites in schizophrenic
patients after large oral doses, 296-301
stereospecific binding, 358
Nantradol
stereospecific and analgesic activity, 84-92
Narcotics
drug addiction in Baltimore from 1950-1977, an overview, 184-190
drug schedule, 14, 17
maintenance treatment of narcotic addiction; usefulness of
proproxyphene napsylate, 240-246
management of neonatal narcotic abstinence: phenobarbital
loading dose method, 247-253
See also individual agents
460
Narcotic antagonists
plasma levels of naltrexone in schizophrenic patients,
296-301
See also individual agents
Narcotic receptors
dependence within the opiate-sensitive neurone, 219-225
effects of mu narcotic receptor agonists on flurothyl
seizure thresholds in rats, 198-204
effects of sigma narcotic receptor agonists on flurothyl
seizure thresholds in rats, 198-204
Nathan B. Eddy Award
"Hooked for Thirty Years: Tales of an Investigator",
E. Leong Way, 1-10
Neonatal
management of neonatal narcotic abstinence; phenobarbital loading
dose method, 247-253
Nicocodeine
See 6-Nicotinoylcodeine
6-Nicotinoylcodeine
drug schedule, 70
NIH 7413
See
NIH 8034
See
NIH 8062
See
4-Carbethoxy-1-methyl-4-phenylpiperidine
bromide
N-oxide
hydro-
1-[2-(1,4-Benzodioxanyl)-methyl]-4-(2-oxo-l-benzimidazo1inyl)piperidine
2-Acetyl-1,2,3,4-tetrahydroisoquinoline-4-spiro-4'-[1'(3-cyano-3,3-diphenylpropyl)] piperidine hydrochloride
NIH 8216
See 2-Methyl-5-phenyl-6,7-benzomorphan hydrobromide
NIH 8225
See
2-(4-Ethoxybenzoyl)-5-methyl-3-(2-pyrrolidinoethoxy)benzofuran hydrochloride
NIH 8240
See (-)-2'-Hydroxy-2,9 beta-dimethyl-5-phenyl-6,7-benzomorphan
hydrochloride
NIH 8242
See 1-(beta -Carbethoxyethyl)-4-carbethoxy-4-phenylpiperidine
hydrochloride
NIH 8251
See
N-Isopropyl-N-methyl-3-formamido-l-pyrazole
461
carboxamide
NIH 8299
See (-)-2'-Hydroxy-2,9 beta-dimethyl-S-phenyl-6,7-benzomorphan
hydrochloride
NIH 8310
See
3-Allyl-7-methoxy-1,2,4,5-tetrahydro-3-(3 H )-benzazepine
hydrochloride
NIH 8366
See 3-(p-Aminophenethyl)-7-methoxy-1,2,4,5-tetrahydro-3(3H )-benzazepine dihydrochloride
NIH 8377
See 3-Allyl-7-methoxy-1,2,4,5-tetrahydro-3-(3 H)-benzazepine
hydrochloride
NIH 8400
See 2-Cyclopropylcarbonyloxy-4-dimethylamino-3-methyl-1,2diphenylbutane
NIH 8444
See 4-Amino 3,5-dibromo-alpha-((dimethylamino)
alcohol hydrochloride
NIH 8635
See
methy)
benzyl
4(p-Chlorophenyl)-4-hydroxy-N,N-dimethyl-alpha ,alpha-diphenyl
-1-piperidine butyramide hydrochloride
NIH 8636
See 4-(4-Chloro-alpha,alpha-alpha-trifluoro-m-tolyl)-4-hydroxyN,N-dimethyl-alpha,alpha,-diphenyl- 1 -piperidinebutyramide
HCl
NIH 8684
See (-)-m-(l-Cyclopropylmethyl-3-ethyl-hexahydro-lH-azepin-3yl) phenolfumarate
NIH 8687
See
NIH 8714
See
2-(2-(4-Phenyl-4-propionoxypiperidino)
benzamide
ethylamino)
4(p-Chlorophenyl)-4-hydroxy-N,N-dimethyl-alpha,alpha -diphenyl1-piperidine butyramide hydrochloride
NIH 8715
See 4-(4-Chloro-alpha,alpha,alpha-trifluro-m-tolyl)-4-hydroxyN,N-dimethyl-alpha,alpha-diphenyl-1-piperidinebutyramide
HCl
NIH 8747
See (-)-N-Cyclopropylmethyl-2-hydroxymorphinan
hydrochloride
NIH 8859
See (-)-5,9 alpha-Dimethyl-2-(3-furylmethyl )-2'-hydroxy-6,7benzomorphan methanesulfonate
462
NIH 8877
See
(+)-1-m-Hydroxyphenyl-6,7-dimethyl-6-azabicyclo[3,2,l]octane
hydrobromide
NIH 9230
See 4-(p-Chlorophenyl)-4-hydroxy-N,N-dimethyl- alpha,alphadiphenyl- 1-piperidine butyramide hydrochloride
NIH 9234
See 5-(3-Hydroxyphenyl)-3-azabicyclo (3.3.1) nonane hydrobromide
NIH 9258
See 2,9-alpha -diethyl-2'-hydroxy-5-methyl-6,7-benzomorphan
NIH 9261
See 9 -Ethyl-2-hexyl-2'-hydroxy-5-methyl-6,7-benzomorphan
NIH 9264
See
1,3-Dimethyl-4-phenyl-4-piperidylethyl
NIH 9352
See 8 -Methyldihydrocodeinone
NIH 9354
See
carbonate
hydrochloride
-(-)-N-(2-Cyanoethyl)-3-hydroxymorphinan
NIH 9356
See cis-3-Carbethoxy-4-hydroxy-1-methylpiperidine
dimethoxy-benzoate) hydrochloride
4-(3,4-
NIH 9364 A
See (-)-2-(2-Cyanoethyl)-5,9 alpha -dimethyl-2'-hydroxy6,7-benzomorphan hydrobromide
NIH 9365 B
See (+)-2-(2-Cyanoethyl)-5,9 alpha-dimethyl-2'-hydroxy6,7-benzomorphan hydrobromide
NIH 9369 A
dl-2-(3-Cyanopropyl)-5,9 alpha-dimethyl-2'-hydroxy, 6,7benzomorphan hydrobromide
NIH 9380
See 1,3-Dimethyl-4-phenyl-4-piperidylmethyl carbonate
NIH 9390
See trans-3-N-Cyclopropylmethyl-N-methylamino-1-phenyl1,2,3,4-tetrahydronaphthalene
hydrochloride
NIH 9451
See
1,4-Dimethyl-4-piperidinol
hydrochloride
463
4-(3,4-dimethoxybenzoate)
NIH 9463
See
NIH 9466
See
1,4-Dimethyl-4-piperidinol-4-(2,4,5-trimethylpyrrole-3carboxylate) hydrochloride
(-)-17-(Cyclopropylmethyl)-3-hydroxymorphinan-6-one
sulfonate
methane
NIH 9468
See 4-(Methyl-n-butylamino)-4-(m-hydroxyphenyl)-cyclohexanone
ethylene ketal hydrochloride
NIH 9470
See (+)-trans-N-Methyl-N-(2-pyrrolidinyl) cyclohexyl-2-(3,4dichlorophenyl) acetamide HCl
NIH 9484
See 2-(2-Cyanoethyl)-9- alpha-ethyl-2'-hydroxy-5-methyl-6,7-benzomorphan
NIH 9506
See 2-Allyl-3a-m-hydroxyphenyl-2,3,3a,6,7,7a-hexahydro-cisisoindole
NIH 9508
See
N-Cyclopropylmethyl-8-beta-ethyl nordihydrocodeinone hydrochloride
NIH 9509
See N-Cyclobutylmethyl-3-Hydroxy-8-beta-methyl-6-oxomorphinan
tartrate
NIH 9512
See
-(Aminomethyl)-p-chlorohydrocinnamic
acid
NIH 9513
See dl-trans-5,6,6a beta, 7,8,9,10,10a alpha-Octahydro-l-acetoxy9 beta-hydroxy-6 beta-methyl-3-(5-phenyl-2-pentyloxy)phenanthridine hydrochloride
NIH 9539
See 17-Cyclopropylmethyl-3-hydroxy-6-oxamorphinan tartrate
NIH 9541
See 4 beta-(m-Methoxyphenyl)-1,3-dimethy l-4-alpha-piperidinol
propionate hydrochloride
NIH 9542
See
1-(4-Methylphenyl)-3-azabicyclo-[3.1 .O] hexane hydrochloride
NIH 9548
See (+)-Naloxone hydrochloride
NIH 9549
See
2-(2,6-Dichloro-anilineo)-2-imidazoline
464
hydrochloride
NIH 9551
See lO-m -Hydroxyphenyl-2-phenethyl- cis-decahydroisoquinoline
NIH 9559
See 1-Methyl-4-piperidinol-2,4-dimethyl-5-acetylpyrrole-3carboxylate hydrochloride
NIH 9560
See
dl-9-Hydroxy-7,12 alpha -dimethyl-4-methyl-C-homobenzomorphan
NIH 9561
See (+)-7,12 alpha-Dimethyl-9-hydroxy-4-methyl-C-homobenzomorphan
NIH 9562
See (-)-7,12 alpha-Dimethyl-9-hydroxy-4-methyl-C-homobenzomorphan
NIH 9563
See
dl-7,12
beta-Dimethyl-9-hydroxy-4-methyl-C-homobenzomorphan
NIH 9564
See (+)-7,12 beta-Dimethyl-9-hydroxy-4-methyl-C-homobenzomorphan
NIH 9565
See (-)-7,12 beta-Dimethyl-9-hydroxy-4-methyl-C-homobenzomorphan
NIH 9571
See
2-(2,6-Dichloroanilino)-2-imidazoline
NIH 9579
See
3-Deoxydihydromorphinone
NIH 9580
See
1-(1-Phenylcyclohexyl)
NIH 9584
See
N-2-Hydroxyethylnorketobemidone
hydrochloride
hydrochloride
piperidine
hydrochloride
hydrobromide
NIH 9596
See (-)-trans-5,6,6a, beta-7,8,9,10,10a alpha-octahydro-1acetoxy-6- beta -methyl-3-(5-phenyl-2-pentyloxy)phenanthridine hydrochloride
NIH 9599
See N-n-Butylnormeperidine
NIH 9600
See N-sec-Butylnormeperidine
hydrochloride
hydrochloride
NIH 9607
See 3,6-Dideoxydihydromorphine hydrochloride
NIH 9612
See
(±)-9-Hydroxy-4,7-dimethyl-C-homobenzomorphan
465
hydrobromide
NIH 9613
See (+)-9-Hydroxy-4,7-dimethyl-C-homobenzomorphan
NIH 9614
See (-)-9-Hydroxy-4,7-dimethyl-C-homobenzomorphan
hydrobromide
hydrobromide
NIH 9624
See 1-[(2-alpha,6-alpha ,llS)-(+)-1-(1,2,3,4,5,6,-hexahydro-8hydroxy-3,6,11-trimethyl-2,6-methanol-3-benzazocin-11-yl)]3-octanone methanesulfonate
NIH 9625
See
1-[(2-alpha , 6 alpha, llS)-(±)-1-(1,2,3,4,5,6-hexahydro-8hydroxy-3,6,11-trimethyl-2,6-methanol-3-benzazocin-11-yl)]6-methyl-3-heptanone
methanesulfonate
NIH 9626
See N-(3-Ketopentyl)norketobemidone
hydrobromide
NIH 9636
See N-3-Methylbutylnorketobemidone hydrobromide
NIH 9649
See N-2-Methylpentylnorketobemidone hydrobromide
NIH 9650
See N-4-Methylpentylnorketobemidone hydrobromide
NIH 9689
See Yohimbine hydrochloride
NLAAM
See (-)
NNLAAM
See (-)
Noludar
See
-Acetyl-N-normethadol
-Acetyl-N,N-dinormethadol
Methylprylon
Norcyclazocine
effect on flurothyl seizure thresholds in rats, 198-204
nor-LAAM
See (-)- -Acetyl-N-normethadol
Normeperidine
effect on flurothyl seizure thresholds in rats, 198-204
Normorphine
effect on flurothyl seizure thresholds in rats, 198-204
Norpseudoephedrine
See Cathine
466
(-)-trans-5,6,6a beta, 7,8,9,10,10a alpha-Octahydro-1-acetoxy-6- betamethyl-3-(5-phenyl-2-pentyloxy)-phenanthridine
hydrochloride
dependence studies, in monkeys, 344
dl-trans-5,6,6a beta, 7,8,9,10,10a alpha-Octahydro-1-acetoxy-9 betahydroxy-6 beta-methyl-3-(5-phenyl-2-pentyloxy)-phenanthridine hydrochloride
mouse analgesia, 389
physical dependence, monkeys, 389
Opiates
Clonidine:
non-opiate treatment for opiate withdrawal, 226-232,
233-239
drug abusers, pathological feelings, 170-176
drug schedule, 14, 17-28
effects on fetal rats in utero; a quantitative method, 191-197
self-administration and REM sleep EEG, 114-120
Opiate receptors
enkephalin interaction, 48-53
See also narcotic receptors
Opioids
effects on flurothyl seizure thresholds in rats, 198-204
Opium
drug schedule, 14
Outpatient treatment
prescription drug abuse;
tenance, 177-183
medical withdrawal and medical main-
Oxycodone
drug schedule, 14
outpatient treatment and outcome of prescription drug abuse,
177-183
Pantopon
drug addiction in Baltimore from 1950-1977, an overview, 184-190
drug schedule, 14-15
Paraldehyde
drug schedule, 14
Paregoric
drug schedule, 15, 17-28
PCP
See
L-(1-Phencyclohexyl)piperidine
Pemoline
drug schedule, 14
Pentazocine
analgesic tests in mice, 331,332,361
467
Pentazocine
drug discrimination by monkeys and pigeons, 128-134
drug schedule, 15
effect on flurothyl seizure thresholds in rats, 198-204
guinea-pig ileum and mouse vas deferens, 359
outpatient treatment and outcome of prescription drug abuse,
177-183
d-Pentazocine
stereospecific binding, 358
1-Pentazocine
stereospecific binding, 358
Pentobarbital
drug discrimination, 128-134
Percodan
See Oxycodone
Phenazocine
effect on flurothyl seizure thresholds in rats, 198-204
Phencyclidine
development of psychiatric disorders in abusers, 149-155
drug schedule, 14, 71
effects of chronic treatment with morphine, methadone, and LAAM
on the response, in rats, 212-218
self-administration leading to physical dependence, in monkeys,
205-211
See also 1-(1-Phencyclohexyl) piperidine
Phenmetrazine
drug schedule, 14, 17-28
Phenobarbital
drug schedule, 70,14
loading dose method;
247-253
management of neonatal narcotic abstinence,
Phenoxybenzamine
protection of opiate binding sites, 49
(-)-3-Phenoxy-N-methylmorphinan
analgesic activity, 77-83
opiate receptor binding, 81
1-(1-Phenylcyclohexyl)-4-hydroxypiperidine
chronic spinal dog, self-administration, rotarod, acute toxicity,
discriminative stimulus properties, 61-69
1-(1-Phenylcyclohexyl)
morpholine
chronic spinal dog, self-administration, rotarod, acute toxicity,
discriminative stimulus properties, 61-69
1-(1-Phenylcylohexyl) piperidine
chronic spinal dog, self-administration, rotarod, acute toxicity,
discriminative stimulus properties, 61-69
468
1-(1-Phenylcyclohexyl) piperidine hydrochloride
dependence studies, in monkeys, 343
1-(1-Phenylcyclohexyl)
pyrrolidine
chronic spinal dog, self-administration, rotarod, acute toxicity,
discriminative stimulus properties, 61-69
4-Phenyl-4-piperidinocyclohexanol
chronic spinal dog, self-administration, rotarod, acute toxicity,
discriminative stimulus properties, 61-69
2-(2-(4-Phenyl-4-propionoxypiperidino) ethylamino)
mouse analgesia, 391
physical dependence, monkeys, 391
benzamide
1-Piperidinocyclohexane-carbonitrile
chronic spinal dog, self-administration, rotarod, acute toxicity,
discriminative stimulus properties, 61-69
Placidyl
See Ethchlorvynol
Pondimen
See
Fenfluramine
Propoxyphene
drug schedule, 15, 71
Propoxyphene hydrochloride
outpatient treatment and outcome of prescription drug abuse,
177-183
Propoxyphene napsylate
lack of toxicity when used for maintenance treatment of addiction, 435-440
maintenance treatment of narcotic addiction, comparison with
methadone, 240-246
use in detoxification and medical withdrawal: outpatient treatment, 178
usefulness in maintenance treatment-of narcotic addiction, 240-246
1-Propylaminocyclohexane-carbonitrile
chronic spinal dog, self-administration, rotarod, acute toxicity,
discriminative stimulus properties, 61-69
N-Propyl-1-phenyl-cyclohexylamine
chronic spinal dog, self-administration, rotarod, acute toxicity,
discriminative stimulus properties, 61-69
Psychiatric disorders
development in drug users, 149-155
Psychoactive drugs
impact of regulations on their development, 29-35
469
314-300 0 -80 - 32
1-Pyrrolidinocyclohexane-carbonitrile
chronic spinal dog, self-administration, rotarod, acute toxicity,
discriminative stimulus properties, 61-69
Quaalude
See Methaqualone
Receptor
opiate, 9
Regulations
impact on development of psychoactive drugs, 29-35
REM sleep
EEG and opioid self-administration, 114-120
Scheduling
effect on economics of drug development, 17-28
Schizophrenia
naltrexone and its metabolites levels in patient plasma after
large oral doses, 296-301
Sedative-Hypnotics
drug abusers, pathological feelings, 170-176
Self-administration
opiates and REM sleep EEG, 114-120
SKF 10,047
drug discrimination by monkeys and pigeons, 128-134
See also N-allylnormetazocine
Sodium 5-(p-chlorobenzoyl)-1.4
dihydrate
See Zomepirac
dimethyl-1H-pyrrole-2-acetate
Substance abuse
addiction severity index, 142-148
Sufentanil
drug schedule, 71
Supersensitivity
effects of heroin and naltrexone on pituitary-gonadal hormones,
302-308
Talwin
See Pentazocine
Temperature
See Body temperature
Tenuate
See
Diethylpropion
470
Testosterone
heroin and naltrexone effects on secretion: tolerance and supersensitivity, 302-308
Tetrahydrocannabinol
drug schedule, 18-19
1-[1-(2-Thienyl) cyclohexyl] morpholine
chronic spinal dog, self-administration, rotarod, acute toxicity,
discriminative stimulus properties, 61-69
1-[1-(2-Thienyl) cyclohexyl] piperidine
chronic spinal dog, self-administration, rotarod, acute toxicity,
discriminative stimulus properties, 61-69
Thyrotropin releasing hormone
drug discrimination, 128-134
Tilidine
drug schedule, 71
Tolerance
cross tolerance between cathinone and amphetamines; behavioral
studies in monkeys and rats, 322-323
effects of heroin and naltrexone on pituitary-gonadal hormones,
302-308
influence of the mode of morphine administration on, 36-47
TR-5109
See
17-Cyclopropylmethyl-8
-ethyl-7,8-dihydronorcodeinone
TRH
See Thyrotropin releasing hormone
Try-D-Ala-Gly-MePhe-Met(o)-al
See FK 33824
UM 149
See 4-Carbethoxy-1-methyl-4-phenylpiperidine
N-oxide
hydrobromide
UM 461
See 1-(2-(1,4-Benzodioxanyl)-methyl)-4-(2-oxo-1-benzimidazolinylpiperidine
UM 485
See 2-Acetyl-1,2,3,4-tetrahydroisoquinoline-4-spiro-4'-(1'(3 cyano-3,3-diphenylpropyl)) piperidine hydrochloride
UM 604
See 2-Methyl-5-phenyl-6,7-benzomorphan hydrobromide
UM 610
See 2-(4-Ethoxybenzoyl)-5-methyl-3-(2-pyrrolidinoethoxy)benzofuran hydrochloride
471
UM 623
See
UM 625
See
UM 635
See
(-)-2'-Hydroxy-2,9
hydrochloride
beta-dimethyl-5-phenyl-6,7-benzomorphan
1-( beta -Carbethoxyethyl)-4-carbethoxy-4-phenylpiperidine
hydrochloride
N-Isopropyl-N-methyl-3-formamido-1-pyrazole
carboxamide
UM 668
See (-)-2'-Hydroxy-2,9 beta -dimethyl-5-phenyl-6,7-benzomorphan
hydrochloride
UM 706
See 2-Cyclopropylcarbonyloxy-4-dimethylamino-3-methyl-1,2diphenyl-butane
UM 720
See 3-(p-Aminophenethyl)-7-methoxy-1,2,4,5-tetrahydro-3-(3
benzazepine dihydrochloride
UM 729
See
H)-
3-Allyl-7-methoxy-l,2,4,5-tetrahydro-3-(3H)-benzazepine
hydrochloride
UM 762
See 4-Amino 3,5-dibromo-alpha-[(dimethylamino)methyl]benzyl
alcohol hydrochloride
UM 866
See 4-(4-Chloro-alpha,alpha,alpha-trifluoro-m-tolyl)-4-hydroxyN,N-dimethyl- alpha ,alpha-dlphenyl-1-piperidinebutyramide
UM 884
See 4-(p-Chloro-phenyl)-4-hydroxy-N,N-dimethyl- alpha,alphadiphenyl-1-piperidinebutyramide hydrochloride
UM 889
See
UM 891
See
(-)- m -(1-Cyclopropylmethyl-3-ethyl-hexahydro-1H-azepin-3-yl)
phenolfumarate
2-[2-(4-Phenyl-4-propionoxypiperidino)ethylamino]benzamide
UM 899
See 4-(p-Chlorophenyl)-4-hydroxy-N,N-dimethyl- alpha,alpha-diphenyl
1-piperidinebutyramide hydrochloride
UM 900
See 4-(4-Chloro-alpha,alpha,alpha-trifluoro-m-tolyl)-4-hydroxyN,N-dimethyl-alpha,alpha-diphenyl-1-piperidinebutyramide
HCl
472
UM 909
drug discrimination by monkeys and pigeons, 128-134
guinea-pig ileum and mouse vas deferens, 359
UM 911
guinea-pig ileum and mouse vas deferens, 359
UM 921
See (-)-N-Cyclopropylmethyl-2-hydroxymorphinan hydrochloride
UM 979
See (-)-5,9 alpha-Dimethyl-2-(3-furylmethyl)-2'-hydroxy-6,7benzomorphan methanesulfonate
UM 998
See (±)-1-m-Hydroxyphenyl-6,7-dimethyl-6-azabicyclo
octane hydrobromide
UM 1046
See
[3,2,1]
3-Cyclopropylmethyl-1,2,3,4,5,6-hexahydro-8-hydroxy-6-methyl3-benzazocine
UM 1070
guinea-pig ileum and mouse vas deferens, 359
UM 1072
See ((+)-(1R/S, 5R/S, 9R/S,2" R/S)-5,9-dimethyl-2'-hydroxy-2tetrahydrofurfuryl-6,7-benzomorphan
UM 1095
See
4(p-Chlorophenyl)-4-hydroxy-N,N-dimethyl- alpha,alphadiphenyl-1-piperidine butyramide hydrochloride
UM 1130 A
See (-)-2-(2-Cyanoethyl)-5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphan hydrobromide
UM 1131 B
See (+)-2-(2-Cyanoethyl)-5,9
morphan hydrobromide
alpha-dimethyl-2'-hydroxy-6,7-benzo-
UM 1133 A
dl-2-(3-Cyanopropyl)-5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphan hydrobromide
UM 1 139
See
UM 1 147
See
1,3-Dimethyl-4-phenyl-4-piperidylmethyl
carbonate
cis-3-Carbethoxy-4-hydroxy-1-methylpiperidine
dimethoxy-benzoate)
hydrochloride
473
4-(3,4-
UM 1150
See
(-)-17-(Cyclopropylmethyl)-3-hydroxymorphinan-6-one
sulfonate
methane-
UM 1152
See 4-(Methyl-n-butylamino)-4-(m-hydroxyphenyl)-cyclohexanone
ethylene ketal hydrochloride
UM 1153
See trans -3-(N-Cyclopropylmethyl-N-methylamino-l-phenyl-1,2,3,4tetrahydronaphthalene hydrochloride
UM 1155
See 2-Allyl-3a-m-hydroxyphenol-2,3,3a,4,7,7a-hexahydro-cisisoindole
UM 1158
See beta-Aminomethyl-p-chlorohydrocinnamic acid
UM 1159
See dl- trans-5,6,6a beta, 7,8,9,10,10a alpha-Octahydro-l-acetoxy9 beta-hydroxy-6 beta-methyl-3-(5-phenyl-2-pentyloxy)phenanthridine
hydrochloride
UM 1167
guinea-pig ileum and mouse vas deferens, 359
UM 1168
See 17-Cyclopropylmethyl-3-hydroxy-6-oxamorphinan tartrate
UM 1169
guinea-pig ileum and mouse vas deferens, 359
UM 1170
See 4 beta-(m-Methoxyphenyl)-1,3-dimethyl-4
propionate hydrochloride
alpha-piperidinol
UM 1174
See dl-9-Hydroxy-7, 12 alpha-dimethyl-4-methyl-C-homobenzomorphan
UM 1175
See (+)-7,12 alpha-Dimethyl-9-hydroxy-4-methyl-C-homobenzomorphan
UM 1176
See (-)-7,12 alpha-Dimethyl-9-hydroxy-4-methyl-C-homobenzomorphan
UM 1177
See
dl-7,12
beta-Dimethyl-9-hydroxy-4-methyl-C-homobenzomorphan
UM 1178
See (+)-7,12 beta-Dimethyl-9-hydroxy-4-methyl-C-homobenzomorphan
UM 1179
See (-)-7,12 beta-Dimethyl-9-hydroxy-4-methyl-C-homobenzomorphan
474
UM 1180
See
UM 1181
See
UM 1182
See
UM 1188
See
UM 1189
See
UM 1191
See
N-2-Hydroxyethylnorketobemidone
hydrobromide
1-Methyl-4-piperidinol-2,4-dimethyl-5-acetylpyrrole-3-carboxylate hydrochloride
1,4-Dimethyl-4-piperidinol-4-(3,4-dimethoxybenzoate)
chloride
N-(-Ketopentyl)norketobemidone
hydro-
hydrobromide
1,4-Dimethyl-4-piperidinol-4-(2,4,5-trimethylpyrrole-3carboxylate) hydrochloride
N-3-Methylbutylnorketobemidone
hydrobromide
UM 1195
guinea-pig ileum and mouse vas deferens, 359
UM 1197
See
N-2-Methylpentylnorketobemidone
hydrobromide
UM 1198
See
N-4-Methylpentylnorketobemidone
hydrobromide
United Nations Narcotics Laboratory
study of the chemical composition of khat, 316-317, 320-321
Valium
drug addiction in Baltimore from 1950-1977, an overview, 184-190
Valmid
See Ethinamate
Withdrawal
clonidine hydrochloride: a non-opiate treatment of opiate withdrawal, 233-239
management of neonatal narcotic abstinence; phenobarbital
loading dose method, 247-253
medical withdrawal outpatient treatment and outcome of prescription drug abuse, 177-183
protocol for rapid opiate withdrawal; clonidine detoxificatrion,
226-232
World Health Organization
assessment of public health and social problems associated with
khat chewing, 316-317
drug dependence programme, 70-73
475
Yohimbine Hydrochloride
dependence studies, in monkeys, 349
Zomepirac
clinical analgesic assay of oral zomepirac vs i.m. morphine,
261-267
476
AUTHOR INDEX
Aceto, M. D., 330
Etherton, D. S., 409
Adler, M. W., 198
Finnegan, L. P., 247
Anglin, M. D., 135
Fly, C. L., 356
Balster, R. L., 205
Friedman, E. G., 163
Ball, J. C., 163
Geller, E. B., 198
Baruth, H., 77
Gillan, M. G. C., 48
Belmore, S., 170
Gold, M. S., 226
Beverley, C. L., 399
Goldstein, P. J., 156
Braenden, O. J., 320
Gorodetzky, C. W., 61
Campbell, 0. L., 328
Grabowski, J., 275, 282, 402
Castro, A., 99
Greenstein, R., 275, 402
Cavallito, C. J., 17
Grell, R., 36
Charuvastra, C., 429
Halbach, H., 318
Coale, E. H., Jr., 128
Harris, L. S., 54, 328, 330
Cochin, J., 36
Heidrich, G., III, 254, 261
Cohen, S., 11
Hein, D. W., 128
Collier, H. O. J., 219
Herling, S., 128
Cone, E. J., 61
Hopkins, L. E., 247
Corbett, A. D., 48
Houde, R. W., 254, 261
Cowan, A., 198
Howd, R. A., 212
Cowan, J. D., 170
Howes, J. F., 99
Curtis, J. L., 399
Jacobson, A. E., 351
Dewey, W. L., 328, 330
Jarvik, M. E., 268
Eikenburg, D. C., 422
Jasinski, D. R., 61
Ellingboe, J., 302
Johanson, C. E., 324
477
AUTHOR INDEX
Johnson, M. R., 84
McLellan, A. T., 142, 149, 240,
275, 435
Jordan-Hayes, J., 282
Martin, B. R., 54
Kaiko, R. F., 254, 261
May, E. L., 330
Kay, D. C., 170
Medzihradsky, F., 356
Kaymakcalan, S., 74
Mello, N. K., 302
Keedy, J. D., 422
Mendelson, J. H., 302
Khan, I., 70, 316
Miller, J. M., 36
Khazan, N., 114
Milne, G. M., 84
Kirby, M. L., 191
Mintz, J., 240, 435
Kleber, H. D., 226
Mitros, T. F., 247
Knoll, J., 322
Miyasato, K., 106
Koe, B. K., 84
Mohacsi, E., 77
Kosterlitz, H. W., 48
Moreno, F., 99
Kotick, M. P., 93
Mule, S. J., 296
Kreek, M. J., 399
Kuehnle, J., 302
Neidert, G. L., 170
Newmann, M. C., 289
Lasagna, L., 29
Nurco, D. N., 163, 184
Leimgruber, W., 77
Leland, D. L., 93
O'Brien, C. P., 142, 149, 240,
275, 282, 402, 435
Ling, W., 429
Osgood, P. F., 99
Long, M., 402
Paterson, S. J., 48
Luborsky, L., 142
Polazzi, J. O., 93
McGlothlin, W. H., 135
Pottash, A. L. C., 226
McKnight, A. T., 48
Poulsen, J. L., 36
McLaughlin, P. J., 121
478
AUTHOR INDEX
Pryor, G. T., 212
Sweeney, D. R., 226
Su, T. P., 61
Razdan, R. K., 99
Rawson, R. A., 233
Tennant, F. S., Jr., 177, 240,
309, 435
Resnick, R. B., 233
Ternes, J. W., 275, 282, 402
Riley, A. L., 409
Thomas, D. B., 289, 429
Risner, M. E., 61
Todd, T. C., 415
Robson, L. E., 48
Toro-Goyco, E., 54
Rogers, A., 254, 261
Rosecrans, J. A., 328
Valentino, R. J., 128
Rosen, L., 163
Vaupel, D. B., 61
ROSOW, C. E., 36
Verebey, K., 296
Ross, F. E., 170
Villarreal, J., 99
Sato, J., 106
Wallenstein, S. L., 254, 261
Schuster, C. R., 324
Washton, A. M., 233
Schut, R. N., 93
Way, E. L., 1
Shannon, H. E., 61
Wegner, N., 184
Shapiro, R. M., 409
Wellerstein, H., 282
Sideroff, S. I., 268
Wells, A. O., 399
Smith, C. B., 356
Whysner, J. A., 289, 429
Sosa, R. P., 48
Woods, J. H., 128, 356
Stanton, M. D., 415
Woody, G. E., 142, 149, 240, 435
Steier, F., 415
Woolverton, W. L., 205
Steinberg-Donato, S., 402
Yanagita, T., 106, 326
Steinfels, G. F., 114
Young, G. A., 114
Stickney, J. L., 422
Swain, H. H., 356
Zagon, I. S., 121
479
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FINDINGS OF DRUG ABUSE RESEARCH. An annotated bibliography of
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