Article #8

SPECIAL FEATURE Opioid abuse and misuse
SPECIAL FEATURE ar Layar
The opioid abuse and misuse epidemic: Implications
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for pharmacists in hospitals and health systems
Daniel J. Cobaugh, Carl Gainor, Cynthia L. Gaston, Tai C. Kwong,
Barbarajean Magnani, Mary Lynn McPherson, Jacob T. Painter, and Edward P. Krenzelok
M
isuse and abuse of prescription
opioids in the United States Purpose. The current epidemic of prescrip- screening and confirmatory tests. In re-
constitute a public health crisis tion opioid abuse and misuse in the United cent years, there has been an increase in
States is discussed, with an emphasis on federal enforcement actions against phar-
that has grown to epidemic propor-
the pharmacist’s role in ensuring safe and macies and prescription drug wholesalers
tions over the last decade. The Centers effective opioid use. involved in improper opioid distribution,
for Disease Control and Prevention Summary. U.S. sales of prescription opioids as well as increased reliance on state-level
(CDC) has identified prescription increased fourfold from 1999 to 2010, with prescription drug monitoring programs to
drug abuse and overdose as one of the an alarming rise in deaths and emergency track patterns of opioid use and improper
top five health threats for 2014.1 It is department visits associated with the use sales. Pharmacies are urged to implement or
imperative that pharmacists across of fentanyl, hydrocodone, oxycodone, and promote appropriate guidelines on opioid
other opioid medications. Signs and symp- therapy, including the use of pain manage-
the health system have a complete
toms of opioid toxicity may include altered ment agreement plans; policies to ensure
understanding of this epidemic. This mental status, hypoventilation, decreased adequate oversight of opioid prescribing,
article reviews the role of opioids in bowel motility, central nervous system and dispensing, and waste disposal; and educa-
pain management, the epidemiology respiratory depression, peripheral vaso- tional initiatives targeting patients as well as
of opioid misuse and abuse, the clini- dilation, pulmonary edema, hypotension, hospital and pharmacy staff.
cal toxicology of these medications, bradycardia, and seizures. In patients re- Conclusion. Pharmacists in hospitals and
and the role of laboratory analyses in ceiving long-term opioid therapy for chron- health systems can play a key role in recog-
ic pain, urine drug testing is an important nizing the various forms of opioid toxicity
monitoring opioid therapy, as well as
tool for monitoring and assessment of and in preventing inappropriate prescrib-
legal issues surrounding opioid dis- therapy; knowledge of opioid metabolic ing and diversion of opioids.
tribution and therapy, the use of pre- pathways and assay limitations is essential Am J Health-Syst Pharm. 2014; 71:1539-
scription drug monitoring programs for appropriate use and interpretation of 54
to combat opioid abuse and misuse,
and implications for medication-use
policy in hospitals and health systems.
seed, and the term opiates refers to to opioid receptors.2 Opioids have
Opioid use in pain management naturally occurring alkaloids (e.g., been used for thousands of years for
The term opium refers to a mix- morphine, codeine). The term opioid the treatment of moderate-to-severe
ture of alkaloids from the poppy refers to all compounds that bind acute and chronic pain. In 1806,
Daniel J. Cobaugh, Pharm.D., DABAT, FAACT, is Vice President, Pharm.D., BCPS, CPE, is Professor and Vice Chair, Department of
ASHP Research and Education Foundation, Bethesda, MD. Carl Pharmacy Practice and Science, University of Maryland School of
Gainor, J.D., Ph.D., is Clinical Assistant Professor of Pharmaceutical Pharmacy, Baltimore. Jacob T. Painter, Pharm.D., M.B.A., Ph.D.,
Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, is Assistant Professor of Pharmaceutical Evaluation and Policy,
PA. Cynthia L. Gaston, Pharm.D., BCPS, is Medication Use Policy University of Arkansas for Medical Sciences, Little Rock. Edward P.
Analyst, UW Health, Madison, WI. Tai C. Kwong, Ph.D., is Profes- Krenzelok, Pharm.D., FAACT, FEAPCCT, DABAT, is Professor
sor of Pathology and Laboratory Medicine, University of Rochester Emeritus, School of Pharmacy, University of Pittsburgh.
School of Medicine and Dentistry, and Director, Hematology and Address correspondence to Dr. Cobaugh (dcobaugh@ashp.org).
Chemistry Labs, Strong Memorial Hospital, University of Roches- The authors have declared no potential conflicts of interest.
ter Medical Center, Rochester, NY. Barbarajean Magnani, Ph.D.,
M.D., is Chair and Pathologist-in-Chief, Department of Pathology Copyright © 2014, American Society of Health-System Pharma-
and Laboratory Medicine, Tufts Medical Center, and Professor and cists, Inc. All rights reserved. 1079-2082/14/0902-1539.
Chair, Department of Anatomic and Clinical Pathology, Tufts Uni- DOI 10.2146/ajhp140157
versity School of Medicine, Boston, MA. Mary Lynn McPherson,
Am J Health-Syst Pharm—Vol 71 Sep 15, 2014 1539

Sertürner isolated morphine from postoperative pain is the use of pre- When opioids are part of the
opium; beginning in the 1850s, in- emptive analgesics. However, there is acute pain management regimen,
jectable morphine was used to treat limited evidence that demonstrates they may be administered by the
both acute and chronic pain. major clinical benefits (e.g., consistent oral, parenteral, and neuraxial routes.
Opioids provide their pharmaco- immediate postoperative pain relief, Research dating back almost 50 years
logic effects by binding to opioid re- reduced need for supplemental anal- demonstrated that small i.v. doses
ceptors located both within and out- gesia) after the use of preemptive an- of morphine administered on an
side of the central nervous system.2 algesics.8-12 Despite these findings, it is as-needed basis for acute pain are

Depending on which receptors they clear that optimal postoperative pain superior to scheduled dosing.17,18 The
bind to and their level of intrinsic management begins preoperatively, use of patient-controlled analgesia is
activity, opioids are classified as full continues through the perioperative a standard intervention used in con-
or partial agonists, mixed agonist– period, and is sustained through the temporary pain management for the
antagonists, or opioid antagonists. postoperative period as indicated treatment of acute pain. Increasingly,
The primary opioid receptor is the clinically. One useful strategy is the neuraxial opioid administration is
m receptor. The m receptor is re- use of a multimodal approach.13,14 part of an effective multimodal acute
sponsible for supraspinal analgesia, Opioids are used to treat acute pain management plan.19
respiratory depression, euphoria, pain when the pain cannot be man- When determining the dose of an
sedation, decreased gastrointestinal aged with nonopioid therapy alone. opioid for acute pain, it is critically
motility, pruritus, anorexia, seda- For example, the acute pain after a important for clinicians to take into
tion, and physical dependence. The dental procedure may be primarily account whether the patient is opioid
k receptor, another opioid receptor, controlled with the use of nonopioids naive or opioid tolerant. Opioid-
is responsible for spinal analgesia, such as an NSAID, possibly supple- tolerant patients are those who have
dyspnea, opioid dependence, seda- mented with an oral opioid as need- been taking regularly scheduled pre-
tion, respiratory depression, and dys- ed. Alternatively, a patient who has scribed opioids or have a history of
phoria. The s receptor is responsible had major surgery will likely require substance abuse related to illicit use
for dysphoria, psychotomimetic ef- parenteral opioid therapy for several of prescription opioids, illicit drug
fects, and stress-induced depression. days, potentially supplemented with use, or participation in an opioid
The role of the d-opioid receptor has nonopioid analgesics or coanalgesics. maintenance program. To avoid
not been well studied.2 While morphine, hydromorphone, underdosing the patient with acute
Opioids are used routinely to treat and fentanyl are the most frequently pain and possibly precipitating opi-
both acute and chronic cancer pain used parenteral opioids for acute oid withdrawal, this opioid tolerance
and noncancer pain. Numerous clini- pain, the selection of a specific opi- must be taken into consideration.
cal guidelines have been published oid for a given patient must be indi- One possible strategy is to continue
over the past 20 years to guide prac- vidualized. It is imperative that the a previously used opioid while treat-
titioners in the appropriate use of clinician obtain a pain medication ing the acute pain separately; another
opioids to treat moderate-to-severe history that captures previous opioid involves calculating a larger opioid
pain.3-7 The management of acute therapy and adverse reactions. For dose to treat the acute pain that in-
and chronic pain is generally best example, a patient may report that corporates an equianalgesic dose of
accomplished through a multimodal morphine causes significant itching the previous opioid.20,21
approach that includes nonpharma- whereas hydromorphone does not. Another important skill for prac-
cologic interventions, as well as nono- Genetic polymorphisms may explain titioners is the ability to safely and
pioid analgesics (e.g., acetaminophen, the interpatient variability often seen accurately calculate equianalgesic
nonsteroidal antiinflammatory drugs with opioid dosing. In 2013 the Food opioid doses when converting a pa-
[NSAIDs]), opioids, and coanalgesics and Drug Administration (FDA) tient from one opioid to another or
(e.g., anticonvulsants, antidepres- added a boxed warning to the drug from one route of administration or
sants, skeletal muscle relaxants, topi- label of codeine-containing products dosage formulation to another.22 A
cal or oral anesthetics).6 Appendix A regarding overdose deaths experi- commonly seen error occurs when
lists the American Pain Society rec- enced by children after tonsillectomy postoperative patients are switched
ommendations for considerations or adenoidectomy.15,16 Children from from an effective dosage of paren-
when selecting analgesics to treat certain ethnic groups are ultrarapid teral hydromorphone (e.g., 1 mg i.v.
acute or chronic pain. metabolizers of codeine, which can every four hours) to a nonequivalent
lead to higher-than-expected serum and ineffective oral opioid (e.g., oral
Opioid therapy for acute pain concentrations of morphine and a oxycodone 5 mg every four hours).
One potential strategy to reduce risk of death. This could result in pain relief failure
1540 Am J Health-Syst Pharm—Vol 71 Sep 15, 2014

as well as a loss of trust in the health Role of the urine drug test threne ring, such as hydromorphone,
care team by the patient and assump- Published practice guidelines for hydrocodone, dihydrocodeine, and
tions by providers that the patient opioid therapy for noncancer pain oxycodone, with varying sensitivities;
is exhibiting drug-seeking behavior from governmental agencies and these opioids, when present singly or
when the patient is actually dem- professional organizations (Appen- in combination, can also produce a
onstrating appropriate pain relief– dix B) recommend using urine drug positive immunoassay result. Thus,
seeking behavior. testing as part of the initial patient an immunoassay cannot be used to
evaluation, the treatment plan agree- monitor a patient using a prescribed

Opioids to treat chronic pain ment, and monitoring and assess- opioid for possible abuse of another
Chronic pain management strate- ment of therapy.26,27 The urine drug (i.e., nonprescribed) opioid.
gies are often viewed differently by test supplements tools such as patient Immunoreactivity assays for a
practitioners depending on whether self-reporting and behavioral moni- drug determine the assay sensitiv-
it is chronic cancer pain or noncan- toring, identifies noncompliance ity for that drug.28 For example, the
cer pain, although the same analge- with the prescribed medications, opiates assay is less reactive to hy-
sics are used to treat both. Both non- and detects the use of alcohol, undis- dromorphone than to morphine and
pharmacologic and pharmacologic closed medications, and illicit drugs. thus requires that a comparatively
strategies are used to treat chronic The advantage of urine drug tests higher hydromorphone concentra-
cancer pain and noncancer pain in a is that there are well-established tion be present for a positive result.
multimodal strategy. The prevalence analytical methods and extensive Therefore, a patient may test nega-
of pain in cancer patients and persis- experience in result interpretation28; tive for the prescribed opioid due to
tent pain in cancer survivors is high, the disadvantages include specimen lower assay sensitivity, especially if
and opioids are frequently part of the collection and the potential for tam- the drug is taken in low doses, which
treatment strategy. Researchers who pering and adulteration. Oral fluid can result in urine drug concentra-
conducted a recent systematic review testing, or saliva testing, is gaining in tions that fall below the assay cutoff;
of observational studies on the effec- popularity and has an advantage over this is a “clinical” false-negative result
tiveness of opioid therapy for cancer urinalysis in that it entails a simple and does not necessarily indicate
pain assigned a strong recommenda- and noninvasive specimen collection nonadherence.30,31 In this case, an
tion to the use of these agents to treat process. Oral fluid testing, however, alternative (and more sensitive and
cancer-related pain.23 faces technical challenges with regard specific) assay should be able to de-
The use of opioids in the manage- to both screening and confirmation tect the specific opioid. For example,
ment of acute pain and chronic cancer methodologies.29 oxycodone is poorly detected by the
pain is more widely accepted than The urine drug test menu, wheth- opiates assay, and the nonopiate opi-
their use in treating chronic noncan- er performed inhouse or by a refer- oids buprenorphine, fentanyl, and
cer pain. There are many reasons to ence laboratory, should test for com- methadone are not detected by the
explain this finding. The available monly prescribed opioids and the opiates assay at all. Detection of these
evidence that opioids conclusively re- typical illicit drug groups (Table 1). drugs requires analyte-specific (i.e.,
duce pain severity and increase func- The urine drug test is performed in drug-specific) immunoassays.
tion (e.g., activities of daily living) in most clinical settings by immuno- Most clinical laboratories perform
patients with chronic noncancer pain assays, which, if positive, may lead to confirmation testing using mass spec-
is not convincing. A review by Trescot confirmation testing. trometry (MS) assays such as liquid
and colleagues24 concluded that there Proper utilization of immunoassay- chromatography–mass spectrometry
was weak evidence of the long-term based urine drug testing and correct (LC/MS). The MS assays offer specific
(i.e., six months or longer) effective- interpretation of results must take identification of drugs and metabo-
ness of morphine and transdermal into consideration the limitations of lites and quantitative measurement
fentanyl in reducing pain and improv- immunoassays. at low concentrations, thus allowing
ing function. This review found no Most immunoassays, such as interpretation of cases involving the
evidence of effectiveness of other opi- those for the amphetamines, ben- presence of minor opioid metabolites
oids. Long-term opioid therapy may zodiazepines, and opioids, are class or pharmaceutical impurities.30 MS,
be associated with tolerance, opioid- assays; they detect not one target however, is costly and technologically
induced hyperalgesia, physical and drug but a family of related com- challenging, and its deployment is
psychological dependence, persistent pounds.28,30 For example, the opiates limited to large laboratories.
adverse effects, a lower quality of life, immunoassays detect morphine (the Correct interpretation of urine
higher rates of depression, and in- target analyte) and codeine and also drug test results requires knowledge
creased healthcare utilization.25 the related opioids with a phenan- of the limitations of the assay meth-

odology. Moreover, there should not mentioned previously, other pos- short-gut syndrome), concurrent
be unrealistic expectations of what sible explanations include dilu- medications, or diet.32
information can be obtained from tion or substitution of the urine An unexpected positive result sug-
the urine drug test. For example, the sample; genetic polymorphism in gests the patient may have taken un-
urine drug concentration cannot be enzymes and transporters involved disclosed medications or illicit drugs.
extrapolated reliably to gauge the in opioid metabolism and trans- Other explanations, however, must
serum drug concentration, nor can port (e.g., cytochrome P-450 en- also be considered. For example, the
it be used to infer patient adherence zymes, uridyl glucuronide trans- unexpected opioid may be present as

with the prescribed dosage regimen. ferase, P-glycoprotein), which can a minor metabolite of the prescribed
When interpreting an unex- result in lower drug concentrations; opioid and not as a result of abuse of
pected negative urine drug test, and altered pharmacokinetics due to the unexpected (nonprescribed) opi-
nonadherence may not be the only disorders involving reduced gastro- oid. For example, hydromorphone is
explanation. Besides the reasons intestinal absorption (e.g., diarrhea, a prescription opioid but also a minor
Table 1.
Recommended Urine Drug Test Menu for Patients Receiving Opioids for Noncancer Paina
Immunoassays
Drug/Class b
Target Analyte(s)b Cutoff Values (ng/mL)b Typical Confirmation Assay Targetsb
Amphetamines d-Methamphetamine 500, 1000 Amphetamines
Methamphetamine
Methylenedioxymethamphetamine
(MDMA)
Methylenedioxyamphetamine (MDA)
Barbiturates Secobarbital 200, 300 Amobarbital
Butalbital
Pentobarbital
Phenobarbital
Secobarbital
Benzodiazepines Nordiazepam 200, 300 Diazepam
Nordiazepam
Oxazepam
Temazepam
Clonazepam, 7-aminoclonazepam
Alprazolam, a-hydroxyalprazolam
Flunitrazepam, 7-aminoflunitrazepam
Lorazepam
Buprenorphine Buprenorphine 5 Buprenorphine, norbuprenorphine
Norbuprenorphine 10 Buprenorphine, norbuprenorphine
Cocaine Benzoylecgonine 150, 300 Benzoylecgonine, cocaine, cocaethylene
Fentanyl Fentanyl 2 Fentanyl, norfentanyl
Marijuana ∆9-Tetrahydrocannabinolcarboxylic 20, 50 ∆9-Tetrahydrocannabinolcarboxylic acid
acid
Methadone Methadone 300 Methadone, methadone metabolitec
Methadone metabolitec 300 Methadone, methadone metabolitec
Opiates Morphine 300, 2000 Morphine
Codeine
Oxycodone
Oxymorphone
Hydrocodone
Hydromorphone
Oxycodone Oxycodone 100 Oxycodone, noroxycodone, oxymorphone
Reproduced, with permission, from reference 31.
a
Consult laboratory for specifics of assays in use.

b
2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP).
c

metabolite of morphine33 (Figure 1). category, opioid-containing analgesics 10,000 in Florida, with the highest
Knowing the metabolic pathway and were the most frequently implicated sales rates reported in the Southeast
the relative concentrations of both medication class, accounting for an and the Northwest.
morphine and hydromorphone may estimated 1,167 (24.8%) of the evalu- In a review of 295 unintentional
help to distinguish between the two ated cases.37 Sales of prescription opi- pharmaceutical overdose deaths in
scenarios.33 oids in 2010 were four times those in West Virginia, opioids were impli-
An alternative explanation for an 1999. Overdose deaths involving opi- cated in 93% of cases.40 However,
unexpected positive urine test result oid medications now exceed deaths 44% of the decedents had not been

is that high-sensitivity MS assays can involving heroin and cocaine com- prescribed an opioid. Ninety per-
detect opioids at very low concentra- bined. In 2010 alone, 16,500 people cent of the decedents were men
tions, and some opioids are impuri- died from analgesic-related overdoses, ranging in age from 18 to 70 years,
ties created during pharmaceutical the majority of which involved opi- with a mean age of 39 years. Sixty-
manufacturing processes; specifi- oids.38 Deaths from opioid analgesics three percent of the deaths were
cally, hydrocodone and codeine are have been reported across the United associated with pharmaceutical di-
impurities in pharmaceutical prepa- States, in all age groups, and spe- version, and 21% involved evidence
rations of oxycodone and morphine, cific opioids such as hydrocodone, of doctor shopping. The 35- to
respectively. 34,35 A very low ratio methadone, morphine, and oxyco- 44-years age range was associated
(<1%) of the unexpected opioid done have been implicated. In 2008, with a notably higher rate of doctor
(e.g., hydrocodone) to the prescribed overdose death rates ranged from 5.5 shopping. Substance abuse indica-
opiate (e.g., oxycodone) suggests that per 100,000 population in Nebraska tors were identified in 95% of the
the unexpected opioid is present as a to 27.0 per 100,000 in New Mexico.39 decedents, and having prescriptions
manufacturing impurity.34 The prevalence of nonmedical use of for five or more controlled sub-
The urine drug test is a useful opioids in 2008–09 ranged from 3.6% stances was more common in women
laboratory test for the manage- in Nebraska to 8.1% in Oklahoma. (30.9%) than in men (16.7%).40
ment of patients on chronic opioid Rates of prescription opioid sales in DAWN also collects important
therapy. Consultation with a clinical 2008 ranged from 3.7 kg per 10,000 data that provide insights into recent
laboratory professional can help to population in Illinois to 12.6 kg per national trends in drug-related mor-
maximize the clinical efficacy of the
urine drug test.
Figure 1. Pathways of opiate metabolism. 6-AM = 6-acetylmorphine. Modified from
Epidemiology of opioid misuse
reference 30.
and abuse
Reports from CDC, the Drug Abuse
Warning Network (DAWN), and the Heroin
National Poison Data System have
demonstrated an alarming increase in Oxymorphine Oxycodone
6-AM
opioid misuse and abuse over the last
two decades.1,36-41 Poisoning deaths in
the United States nearly doubled from
Poppy Morphine Codeine
1999 to 2006, from 20,000 to 37,000. seeds
This was due largely to deaths from
prescription opioid analgesics, with
methadone, oxycodone, and hydro-
codone most frequently implicated. Hydromorphone Hydrocodone
This increase in deaths coincided with
a nearly fourfold increase in the use
of prescription opioids nationally.36
A review of data on individuals with
adverse drug events who were treated Dihydrocodeine
in emergency departments from
January 1, 2004, through December
31, 2005, found that central nervous
Metabolite as well Major Minor Manufacturing
system agents constituted the most as prescribed medication pathway pathway impurity
frequently implicated therapeutic
category (21.4% of cases); within that

bidity and mortality. A 2010 report of vomiting and pulmonary aspira- hours and even longer if the use of
from DAWN on emergency depart- tion that can complicate respiratory naloxone was necessary to reverse
ment visits for the misuse and abuse depression.45 Respiratory depression, the associated central nervous system
of all drugs estimated an increase modulated by the effects of opioids and respiratory depression.50 The
from 1.6 million cases in 2004 to 2 on medullary chemoreceptors’ ability high affinity of buprenorphine for
million cases in 2008.41 The number to detect hypercapnia, and the conse- the m receptor may necessitate doses
of visits related to opioid analgesics quential reduced respiratory rate are of naloxone that exceed customary
increased by 111% (from 144,600 diagnostic of opioid toxicity; a re- doses in both children and adults

to 305,900 visits) in the same time spiratory rate of less than 12 breaths or the use of a naloxone infusion.52
period. Visit rates increased across per minute is characteristic.46 Each Buprenorphine has minimal bio-
the five years for fentanyl, hydroco- opioid has unique pharmacokinetic availability, and since most pediatric
done, hydromorphone, methadone, and pharmacodynamic properties exposures involve the sublingual
morphine, and oxycodone; for oxy- that determine the extent and dura- route, the use of activated charcoal is
codone, estimated annual emergency tion of toxicity and affect treatment unnecessary unless there are coinges-
department visits increased from decisions, and these differences must tants that dictate its use.
41,700 to 105,200.38 be considered when evaluating the Fentanyl. Fentanyl is a pure syn-
In Florida, from 2003 through patient with opioid toxicity. While thetic opioid agonist of high potency
2009, the death rate due to prescrip- not yet applicable clinically, human (80–100 times that of morphine)
tion drugs increased by 84.2%, from genomics is linked to the magnitude with a short duration of action.53 It
7.3 to 13.4 per 100,000 people. 41 of toxicity for some drugs, and, as is a m-opioid receptor agonist indi-
The greatest increases in rates were mentioned previously, at least one cated for the treatment of chronic
observed with oxycodone (264.6%), opioid receptor polymorphism has pain, with delivery achieved via
alprazolam (233.8%), and metha- been identified and may have diag- transdermal patches, nasal spray, and
done (79.2%). Figure 2 compares nostic and treatment implications in transmucosal products. Intravenous
Florida overdose trends for opioids the future.47 fentanyl is used in the periopera-
as a group and for hydrocodone, tive setting, postoperatively for pain
methadone, morphine, and oxyco- Characteristics of selected opioids management, and as a sedative in
done specifically. Buprenorphine. Buprenorphine the emergency department and criti-
is a potent semisynthetic opioid cal care settings, and it is associated
Clinical toxicology with partial agonist activity at the with notable morbidity and mortal-
While all opioids have some de- m receptor. Its primary indication is ity when abused or when prescribed
gree of affinity for the m-, d-, and treatment of opioid addiction since inappropriately to opioid-naive indi-
k-opioid receptors, the m-opioid re- it has an extraordinarily high affin- viduals. Fentanyl patch ingestion for
ceptor is responsible for the majority ity for the m receptor and the ability abuse purposes is common; unused
of the adverse effects associated with to prevent binding of other opioids. or spent patches contain fentanyl in
opioid misuse, abuse, and overdose.43 Buprenorphine formulations for a matrix or reservoir that becomes
The classical elements of the opioid opioid maintenance therapy are sub- bioavailable when ingested.54-58 Ad-
toxidrome include altered mental lingual tablets and a sublingual film ditionally, the inappropriate use of
status, hypoventilation, decreased that are coformulated with naloxone, fentanyl patches on compromised
bowel motility, and miosis. Contrary which serves as a deterrent to the skin (e.g., sunburned skin) or with
to conventional wisdom, miosis is i.v. abuse of buprenorphine. Unlike external heat sources such as heating
not a universal finding in opioid- methadone, whose use requires the pads and blankets, saunas, and hot
toxic patients and neither its pres- individual to obtain a daily dose at tubs increases transdermal absorp-
ence nor absence is pathognomonic a methadone clinic, buprenorphine tion and may result in fentanyl toxic-
of opioid toxicity or the lack thereof. is dispensed through licensed office- ity.59 Fentanyl toxicity is character-
For example, hypoxic patients and based practices, and multiple doses ized by the classical opioid toxidrome
those who coingest anticholinergic can be dispensed.48,49 Consequently, along with sustained central nervous
agents may exhibit mydriasis. Other unintentional exposures to bu- system and respiratory depression.
findings may include peripheral va- prenorphine are now commonplace Unlike the parenteral therapeutic use
sodilation, pulmonary edema, hypo- in the pediatric population and of fentanyl, the ingestion of patches
tension, bradycardia, chest wall rigid- may be associated with significant is associated with an extremely long
ity, and myoclonus (with fentanyl) morbidity.48-51 Due to the long half- duration of action that may neces-
and seizures (with meperidine).42-44 life of buprenorphine, children who sitate the prolonged use of naloxone.
Opioids induce a delay in gastric may have been exposed to a single Hydrocodone. The fixed com-
emptying and may increase the risk dose should be hospitalized for 24 bination of hydrocodone and acet-

aminophen is the most commonly concentrations should be obtained. mately 24 hours (range, 8–59 hours)
prescribed generic medication in the Hydrocodone is also available with makes it suitable for once-daily dos-
United States.60 Given the prominent ibuprofen as a combination product. ing and ideal for the prevention of
presence of hydrocodone-containing The treatment of an overdose may opioid withdrawal65; that character-
products in U.S. homes, children are include the use of activated charcoal istic is also one of its major toxico-
at a pronounced risk of being ex- to prevent drug absorption, nalox- logical drawbacks, since methadone
posed to hydrocodone. Hydrocodone one to reverse the effects of hydro- toxicity, especially a decreased level
has considerable abuse potential codone, and acetylcysteine to treat of consciousness and respiratory

and is associated with substantial acetaminophen toxicity. If the pa- depression, may be prolonged con-
morbidity and mortality.61 As with tient develops salicylate toxicity from siderably. Therefore, a naloxone
other opioids, hydrocodone has a combination hydrocodone–aspirin infusion is often necessary to prevent
considerable affinity for m receptors product, appropriate supportive the recurrence of respiratory depres-
and its toxic effects are consistent care (e.g., airway protection and sion.66 Opioid-addicted individuals
with the classical opioid toxidrome. ventilatory support, sodium bicar- who rely on or abuse methadone
Hydrocodone has been approved bonate to reverse acidemia, seda- often use multiple pharmaceuticals
for manufacture in a single-entity tives, anticonvulsants) and interven- that produce synergistic toxicity and
extended-release form as a Schedule tions (e.g., hemodialysis) must be increased morbidity and mortal-
II product, but currently it is always initiated to prevent possibly life- ity.67-69 This is especially true when
combined with acetaminophen as an threatening salicylate toxicity. methadone users take benzodiaz-
oral analgesic product.62 Therefore, Methadone. The use of metha- epines concurrently.68-70 Methadone,
overdoses of hydrocodone-containing done, a synthetic m agonist, has like all opioids, may cause airway
analgesics are also complicated by evolved beyond its traditional role in musculature relaxation and resultant
the presence of acetaminophen and helping to prevent opioid withdrawal airway obstruction and sleep apnea.
are one of the leading causes of in patients enrolled in methadone Benzodiazepines contribute to death
acetaminophen-related fatalities due maintenance programs. Methadone by exacerbating the adverse effects of
to hepatic necrosis.63,64 Consequently, is now also used in the management methadone. Researchers who evalu-
when an exposure to a hydrocodone- of severe pain in patients with cancer ated 1193 opioid overdoses that oc-
containing product is suspected, or non-cancer-related chronic pain. curred in one Australian state over a
serum acetaminophen and salicylate Methadone’s long half-life of approxi- 10-year period reported that nearly
Figure 2. Opioid overdose deaths in Florida in 2003–09, with death rates shown for opioids as a class and for specific opioid medications.41
14
12
Deaths per 100,000 Population
10
All opioids
6
Hydrocodone
Methadone
4
Morphine
2 Oxycodone
0
2003 2004 2005 2006 2007 2008 2009
Year

63.7% of methadone-related fa- central nervous system or respiratory administration, and this intervention
talities (n = 193) were complicated by depression, naloxone will reverse the has been implemented in many cit-
the concurrent presence (and likely adverse effects of opioids. There- ies worldwide.81-84 Additionally, in
the abuse) of benzodiazepines.68 An- fore, intubation is unnecessary in early 2014 FDA approved a naloxone
other often overlooked adverse event most patients experiencing opioid delivery system that enables subcu-
that is associated with both metha- intoxication. Naloxone is gener- taneous or intramuscular naloxone
done maintenance use and overdose ally administered intravenously. administration by individuals who
is Q-T interval prolongation, which Opioid-dependent individuals who are not health professionals.86 The

increases the risk of developing abuse substances intravenously may apparatus is technically similar to
ventricular dysrhythmias, including have inadequate vascular access; the automatic defibrillators that are
torsades de pointes.70-73 naloxone is effective via any paren- located in public venues. When ac-
Oxycodone. Oxycodone is a po- teral route (intramuscular, subcu- tivated, it provides the person who
tent semisynthetic opioid and, like taneous, or sublingual), through an is administering the naloxone with
other potent opioids, has a high af- endotracheal tube, intranasally, or by verbal instructions on the use of the
finity for the m receptors. It has been nebulization.42,80-84 drug. The device delivers 0.4 mg of
used commonly in combination with While naloxone can rapidly re- naloxone per dose.
both aspirin and acetaminophen. verse the symptoms of opioid toxic- Opioids may be taken by any
However, when oxycodone was in- ity, its administration can precipitate route (e.g., orally, intravenously, via
troduced in 1995 as a single-entity acute opioid withdrawal. Opioid nasal insufflation); therefore, gas-
sustained-release preparation, its use withdrawal is unlikely to be life- trointestinal decontamination may
became widespread and its abuse threatening. However, it is extremely not be indicated or effective. If the
became epidemic.74 Abusers ingested, uncomfortable for the patient, who opioid was ingested, the only gastro-
injected, and nasally insufflated the may become agitated and combat- intestinal decontamination that may
product, since crushing and snorting ive. In the emergency department be effective is the administration of
the drug resulted in its rapid release setting, naloxone should be admin- an aqueous slurry of activated char-
and high blood concentrations. The istered intravenously at the smallest coal within two hours of the inges-
sustained-release product has been effective dose and then adjusted tion87; gastric lavage, emesis, and ca-
reformulated to reduce the abuse accordingly to reverse respiratory thartics have no role in these cases.
potential.75 Similar to methadone, depression. The initial adult i.v. dose The clinician must recognize that
oxycodone is often abused concur- is 0.04 mg and can be followed (if coingestants (e.g., acetaminophen)
rently with benzodiazepines such as necessary) by progressively larger or illicit drugs (e.g., cocaine) may
alprazolam and other psychoactive doses every 2–3 minutes until opioid have been used and that the patient
drugs that enhance toxicity.76,77 Espe- toxicity is reversed42,85; some clini- may require additional treatment
cially in overdose, oxycodone is asso- cians advocate adjusting the dose by to prevent or reverse the effects of
ciated with an increased risk of Q-T 0.04-mg increments to prevent with- these agents.
interval prolongation.78,79 drawal.85 The half-life of naloxone is With some overdoses, such as those
approximately 30 minutes, whereas involving acetaminophen, laboratory
Diagnosis and treatment the half-life of most opioids exceeds testing is diagnostic and determines
Respiratory depression is the that notably, necessitating the con- the appropriate therapeutic interven-
result of opioid toxicity, and sup- tinued administration of naloxone tions (e.g., acetylcysteine administra-
portive care to restore ventilation to prevent recurrent respiratory de- tion). However, laboratory testing has
and oxygenation is the cornerstone pression; this is often accomplished limited value in the treatment of the
of patient management. The conven- through the use of a naloxone infu- patient with opioid toxicity.88 Most
tional management of respiratory sion. Patients who receive naloxone initial laboratory toxicology screens
depression in most poisoned patients must not be discharged until several focus on analyzing a urine speci-
is to perform endotracheal intuba- hours have passed since the last nal- men, which provides only qualitative
tion and provide ventilatory support. oxone dose in order to ensure that evidence of exposure to opioids with a
In contrast, respiratory depression opioid toxicity is no longer a risk. phenanthrene ring (e.g., morphine).
in the patient with opioid toxicity In the prehospital setting, it may The semisynthetic (e.g., hydrocodo-
can be treated with the competitive be difficult for emergency medi- ne) and synthetic (e.g., fentanyl) opi-
m-opioid receptor antagonist nalox- cal providers and companions of oids may be detected only at higher
one.42 Unless the patient has a trau- opioid users to administer naloxone concentrations (as with hydrocodone)
matic brain injury, has prolonged parenterally. The administration of or not at all (as with fentanyl) with the
hypoxia, or has used an additional intranasal naloxone has been deter- conventional assays that are utilized
substance or substances that produce mined to be as effective as parenteral by most hospitals.88 In a patient with

respiratory depression, waiting for the chain pharmacies in central Florida, Numerous health systems operate
results of a laboratory test delays the alleging that the pharmacies had im- outpatient and retail pharmacies,
use of appropriate therapy. The pa- properly sold massive quantities of and hospitals have risks associated
tient history and the clinical presen- oxycodone. Although the parent cor- with employee theft, loss or destruc-
tation are the best indicators that the poration argued that the pharmacies tion of controlled substances, record-
patient is experiencing opioid toxicity had adopted new policies to verify the keeping issues, and documentation
and requires treatment. legitimacy of prescriptions for such of a legitimate medical need for the
drugs, DEA revoked the registrations use of opioids.

Legal implications in October 2012. The diversion of opioids and
As a result of the increases in 3. A national long-term care pharmacy other controlled substances from
opioid-related deaths, over the last agreed to pay $50 million to resolve hospital pharmacies may result from
two years the Drug Enforcement claims that its facilities dispensed con- improper actions by employees.89
Administration (DEA) has become trolled substances improperly. Two Hospitals, like many other employ-
much more aggressive in its enforce- of the allegations against the long- ers, are subject to the risk that some
ment of the Controlled Substances term care pharmacy were that some employees will steal merchandise. In
Act (CSA) with respect to prescrip- prescriptions did not contain all the addition, hospital pharmacies are at
tion drug wholesalers, physicians, items required by CSA regulations (21 risk for diversion related to the use
pharmacists, and pharmacies that C.F.R. 1306.14 and 1306.24) and that of prefilled syringes or single-use
distribute, prescribe, and dispense the pharmacy had not properly docu- vials of controlled substances when
controlled substances. Historically, mented partially filled prescriptions. the prescriber orders a dose that is
DEA focused its enforcement ac- The DEA administrator was quoted less than the total contents of the
tions on independent community as saying, “This case highlights the syringe or vial. If the syringe or vial
pharmacies more than retail chain responsibilities of pharmacists, doc- contains 100 mg of an opioid but the
or hospital pharmacies, but in 2012 tors and others when prescribing and prescribed dose is 75 mg, the disposal
that focus expanded to include legal dispensing controlled substances.” of the remaining 25 mg can become a
actions against large chain pharma- 4. The attorney general of West Virginia diversion risk. As an example, a nurse
cies, long-term care pharmacies, and filed legal actions against over a dozen could carry an empty sterile vial in
prescription drug wholesalers. drug wholesalers, alleging that the a pocket and, instead of destroying
A brief review of some of the pros- distributors failed to properly assure the excess drug, inject it into the vial;
ecutions undertaken by DEA and a that orders for controlled substances this pattern could be repeated several
state government in 2012 and 2013, were for legitimate quantities, thereby times throughout the shift, and by
as well as the resulting court actions contributing to the drug abuse prob- the time the nurse left the hospital
(summarized in news releases avail- lems in West Virginia. at the end of the day, he could have
able from the U.S. Department of 5. DEA took separate actions against diverted a substantial quantity of
Justice website [www.justice.gov/dea/ at least six Florida chain pharmacies a controlled substance that was
pr/news.shtml]), is illustrative of the and issued an immediate suspension extremely difficult to trace. In this
current practice environment: of registration against the chain’s case, the hospital could not identify
wholesale distribution center. The or demonstrate a shortage from the
1. DEA issued an immediate suspension agency alleged that the pharmacies patient records. A director of phar-
order on a wholesaler’s distribution did not keep adequate records and macy must be vigilant to these risks
facility. DEA alleged that the whole- filled prescriptions that were not is- and establish and consistently apply
saler endangered the public health sued for a legitimate medical use. policies and procedures that will
by selling excessive quantities of These cases and others pending in minimize the risk of employee theft
oxycodone to certain pharmacies in additional states were resolved when or diversion of controlled substances.
Florida. This was one of the first times the pharmacy chain agreed to pay The final area for legal consider-
DEA argued that a drug wholesaler $80 million—the largest settlement in ation is the actual use of controlled
had a responsibility for the actions of DEA history—and to the suspension substances in the health-system
its customers. This action was settled of dispensing privileges in some stores environment for inpatients and
with the wholesaler agreeing to not until 2015. outpatients. Health-system phar-
sell any controlled substances from its macists must be familiar with DEA
Florida facility until May 2014, estab- Health-system pharmacists are regulations controlling the use of
lish a customer monitoring program, subject to the same level of DEA opioids in the inpatient setting.
and report suspicious orders to DEA. scrutiny as retail pharmacists and Hospitals have the same legal duty
2. DEA suspended the controlled sub- have similar responsibilities in re- as retail pharmacies to ensure that
stance registrations of two retail lation to controlled substances. controlled substances are ordered for

a legitimate medical purpose. The therapy to a patient as an inciden- at risk for addiction to a controlled
definition of legitimacy is subject to tal adjunct to medical or surgical substance, and (4) provide informa-
change, however, as evidenced by the treatment of conditions other than tion to researchers and public health
September 2013 change in the FDA addiction, thereby allowing a hos- officials for identification of drug-
labeling standards for long-acting pitalized addicted person to avoid use trends and public health needs.92
and extended-release opioid analge- the risk of withdrawal while being Because PDMP laws flow from
sics.90 The new labeling indicates that treated for some other condition. It state legislatures and the rules and
these drugs should only be used for is even possible to withdraw the pa- regulations are determined by the

pain severe enough to require daily, tient from the opioid addiction if the executive body identified in each
around-the-clock, long-term opioid withdrawal is accomplished during state’s statutes, each state has deter-
treatment and for which alternative legitimate treatment for some other mined its own laws, regulations, rules
options are inadequate. medical or surgical condition. The for implementation, and program
This issue of appropriate opioid other important exception found in structure. There is state-to-state
therapy may appear to be less of a section 1306.07(c) is that hospital variation in terms of which agency
problem in the hospital environment staff may administer or dispense houses the program (e.g., depart-
than in the retail sector, but health- opioids to an addicted patient with ment of public health, office of at-
system pharmacists must remain intractable pain for whom no relief torney general, board of pharmacy),
vigilant for questionable orders or or cure is possible or none has been which controlled substances are
prescriptions. As individuals who found after reasonable efforts. As monitored (e.g., Schedule II only,
abuse drugs find it more difficult to an example, this provision protects Schedules II–V, other drugs), how
obtain opioids from retail pharma- health-system pharmacists treating often pharmacy reporting is required
cies, they may turn to emergency a patient with cancer (as either an (e.g., weekly, biweekly, monthly),
departments and outpatient phar- inpatient or an outpatient) who has and who can query the database
macies to obtain these medications. become addicted to opioids. (e.g., prescribers, pharmacists, law
Further, health-system pharmacists enforcement).93 Another key factor
must also remember that all orders, Prescription drug monitoring differing among states is whether
prescriptions, and prescription labels programs the system is proactive or reactive.
must be complete and accurate, as Prescription drug monitoring In proactive systems, information is
mandated by DEA regulations. Poli- programs (PDMPs) are electronic delivered to prescribers or dispensers
cies should be in place to ensure that databases created and overseen at the when certain prescribing or dispens-
these record-keeping requirements state level to collect data on opioids ing thresholds are met by a patient
are met. and other controlled substances as under their care. Reactive systems
In addition to ensuring that well as noncontrolled drugs with query available information, but the
opioids are being ordered for a le- potential for abuse. PDMPs are system is utilized only at the discre-
gitimate medical purpose and that currently active in 47 states.91 New tion of the prescriber or dispenser.93
proper record-keeping and labeling Hampshire and Maryland are in the Finally, states differ in requirements
procedures are followed, health- process of implementing systems, for prescribers or pharmacists to
system pharmacists must understand and the District of Columbia has utilize the PDMP. Currently, 16 states
the restrictions on using opioids pending legislation. Missouri is the require mandatory PDMP use when
for maintenance or detoxification only state without a PDMP and no various conditions are met before
of patients who are drug addicted. pending legislation. The goals of certain controlled substances can be
The basic rule is that only an opi- individual PDMPs vary from state to prescribed.93
oid treatment program registered state, but in general these programs The effectiveness of PDMPs in
with DEA is permitted to use an are designed to (1) monitor prescrib- accomplishing the goals listed above
opioid drug to maintain or detoxify ing and dispensing to individual pa- has not been investigated thoroughly.
an opioid-addicted individual; the tients, thereby providing treatment Research that has been conducted
one exception is if a buprenorphine history information to the health in this field has generally examined
product is ordered by a specially professionals responsible for a pa- either the effect programs have on
certified prescriber. However, there tient’s care, (2) provide information opioid-related outcomes (e.g., hos-
is a critical exception in the DEA to parties, including law enforce- pital admissions, mortality) or the
regulations pertaining to hospital- ment, for the identification and de- ability of the program to influence
ized patients: Provisions of 21 C.F.R., terrence of prescription drug abuse behaviors associated with abuse and
section 1306.07(c), stipulate that the and diversion, (3) provide informa- misuse of opioids.
hospital staff is permitted to provide tion to practitioners and third parties There are conflicting findings
opioid maintenance or detoxification for the identification of individuals regarding the ability of PDMPs to

reduce mortality related to opioid tions into possible doctor shopping rant behavior along with appropriate
abuse. A 2011 study of opioid over- from 156 to 16 days.101 documentation. Operational policies
dose deaths in 19 states found that CDC and the Office of National outline procedures to ensure proper
PDMP status was not associated with Drug Control Policy have identified control and accountability and pre-
decreased drug overdose or opioid- PDMPs as important strategies in vent diversion.
related mortality.94 However, new the response to the opioid abuse and Consistent practice for appropriate
data from the RADARS (Researched misuse epidemic.103 The continued screening, assessment, and prescrib-
Abuse, Diversion and Addiction- expansion of PDMPs to cover all 50 ing for pain can be directed through

Related Surveillance) System’s Poison states and the District of Columbia computerized prescriber order entry
Center Program and Opioid Treat- is a good first step in implement- (CPOE), clinical decision support
ment Program surveillance databases ing this strategy; however, looking (CDS), pharmacy and therapeutics
show an association between the beyond this, the National Alliance committee–approved guidelines,
presence of a PDMP and a decrease for Model State Drug Laws and the and formulary restrictions. Printed
in the number of poison center inter- National Safety Council have recom- or computerized order sets should
ventions as well as a decrease in ad- mended PDMP best practices for include best practices and standard-
missions for opioid overdose.95 One states to consider.104 Interstate data ize prescribing of appropriate doses,
weakness in this area of research thus sharing, the expansion of authorized patient-controlled analgesia, epidural
far has been the treatment of PDMP users (including allowing delegate opioid infusions, procedure-specific
presence as a dichotomous variable. access), and the determination of dosing protocols, and monitoring.
Because of the varying structures of compulsory-use requirements by Discharge and ambulatory care order
these programs, their effectiveness is professional licensing boards are key sets or protocols can be utilized to
likely to vary from state to state; this components of these recommenda- ensure consistent discharge analgesia
is especially true when comparing tions.104 As the expansion of PDMPs regimens and minimize the amount
reactive and proactive programs. across the nation continues, utiliza- of opioid dispensed after routine
While the effectiveness of tion of the growing body of evidence outpatient procedures or minor
PDMPs at reducing poor outcomes relating to these programs to identify surgeries. If the prescriber concludes
associated with opioids has not and implement program improve- that opioids are required, a standard
been shown definitively, the ability ments will be important. Implement- minimal number of doses for each
of these programs to influence the ing evidence-based policy changes procedure can be designated (e.g.,
behavior of prescribers, pharmacists, to increase PDMP effectiveness at 5–10 doses) instead of an ample
and patients is well established. Stud- achieving the various program goals supply to cover any and all pain. By
ies using survey methods have shown described above will ensure greater minimizing the amounts of opioids
that providers who utilize PDMP utility for all stakeholders in the that are prescribed routinely but are
reports are likely to change their future. not used by patients, the amounts of
prescribing practices in response to opioids available in the community
the new information. These studies Implications for medication-use for misuse and abuse can be reduced.
have taken place in a variety of set- policy in health systems Prescribers can receive additional
tings (e.g., primary care,96 emergency Opioids are included on the Insti- direction through best-practice alerts
department,97 substance abuse treat- tute for Safe Medication Practices list or red flags built into CPOE and CDS
ment programs98) and in several dis- of high-alert medications (i.e., agents systems regarding dose limits and
tinct geographic locations.99-101 While associated with a high risk of patient the risks of respiratory depression
studies of pharmacists are more lim- harm when used inappropriately) or misuse. Safe prescribing through
ited, pharmacists’ attitudes toward and require heightened oversight in formulary restrictions and guidelines
PDMPs have been positive, with their hospitals and health systems.105 Insti- further minimizes risk and liability
primary use of the programs being tutional policies, beyond federal and from high-harm opioids such as me-
to help reduce doctor shopping.102 state legal requirements, further di- peridine and codeine. Due to the risk
One of the most straightforward uses rect appropriate use and monitoring of neurotoxicity, meperidine is not
of PDMPs is altering this aberrant of opioids and promote standardized recommended for pain treatment
patient behavior by providing a co- practices to prevent and identify and should be removed from the
ordinated and convenient source of diversion. Clinical policies can ad- formulary or restricted to treatment
controlled substance use information dress appropriate treatment of severe of rigors.106,107 Codeine use should
to prescribers, pharmacists, and law pain with opioid medications, which also be limited due to the drug’s
enforcement. One study showed that requires ongoing assessment and re- unpredictable analgesia arising from
PDMP implementation reduced the assessment of analgesia, activities of a genetic polymorphism and a re-
time necessary to conduct investiga- daily living, adverse effects, and aber- cent FDA boxed warning on its use

in children after tonsillectomy or the placement of limits on a patient’s ing of inappropriate prescriptions
adenoidectomy.108,109 opioid supply, more frequent clinic by identifying prescribers writing
Some emergency departments appointments and urine drug screen- for larger quantities of high-risk
restrict the prescribing of opioids by ing, selection of therapy with a lower medications more frequently than
limiting quantities to a small amount street value, or referral to a substance others within the same specialty
for the short-term treatment of acute abuse specialist. In addition to these and geographic area.118 Pharmacists
pain and restricting treatment of measures, some facilities require more from these facilities stopped filling
patients with chronic pain.110,111 In frequent monitoring and documenta- prescriptions if the prescribers were

some emergency departments, pa- tion of therapeutic benefit for patients unable or unwilling to justify their
tients with chronic pain are treated receiving opioid doses over a target practice of prescribing high volumes
with nonopioid analgesics and then threshold (e.g., greater than 120 mg of of high-risk medications. As dis-
referred for follow-up care. In con- oral morphine equivalents per day) to cussed above, the absence of these
junction with these policies, emer- identify potentially inappropriate use types of measures can place health-
gency physicians do not replace lost and minimize harmful consequences system pharmacies and pharmacists
or stolen opioids, and signage in the associated with high opioid doses.116 in legal jeopardy.
emergency department delineates The pharmacist’s role in opioid Education of healthcare staff, as
the policy clearly. These policies and therapy and developing guidelines, well as patients, on appropriate treat-
practices are most effective if coordi- policies, and patient education to ment of pain, including nondrug
nated within a geographic area. promote safe practices is paramount and nonopioid therapy, and the risk
Management of opioid-dependent in both the inpatient and ambulatory of opioid diversion is recommend-
chronic pain can be challenging due care settings.117 In addition to their ed to minimize opioid abuse.116,117
to common comorbidities of depres- important legal responsibilities to Pharmacists can be instrumental in
sion, anxiety, and addiction.112,113 De- ensure appropriate prescribing and developing educational content for
velopment of institutional guidelines dispensing, ambulatory care phar- their institution, patients, and the
or protocols can provide a consistent macists should further define orga- public. Medication counseling dur-
and safe method of initiating and nizational practices for consistent ing dispensing provides the perfect
monitoring therapy for these pa- dispensing of opioids. For example, opportunity to counsel patients to
tients.114,115 Along with a thorough pharmacies could require a check of lock up opioids, never share medica-
history and physical examination, the state PDMP prior to the dispens- tions with others, and appropriately
chronic pain management plans ing of opioids to new or unfamiliar dispose of unused medications.
should include universal screening patients, especially those residing a Prevention of opioid diversion
for illicit drug use and addictive long distance from the pharmacy, within the healthcare system occurs
disorders prior to initiation of treat- along with a government-issued through implementation of com-
ment. One exception is the patient identification for picking up opi- prehensive policies accounting for
with limited life expectancy. Screen- oid prescriptions. Other standards opioids from the point of ordering to
ing may include the urine drug might include criteria for contacting administration to the patient.119
screen, review of public records for prescribers and law enforcement of- The numbers of personnel re-
prior convictions, and evaluation of ficials regarding potentially forged sponsible for ordering, receiving, and
state PDMPs. Similarly, as discussed or altered prescriptions, frequent taking inventory of controlled sub-
in Appendix B, a pain management requests for early prescription refills, stances should be limited, and those
agreement plan (PMAP), or “opioid and unusual patient behavior. A responsibilities should be rotated.
contract,” should be constructed standard documentation process for Preemployment criminal background
for most patients. The intent of the the steps required for prescription checks and urine drug screening
PMAP is to provide full disclosure of validation should be implemented should be considered for employees
the risks and benefits of opioid ther- as well. Despite their best efforts to with these direct responsibilities.
apy and institutional policies with identify inappropriate prescriptions, Technology and automated dispens-
regard to ongoing regular pain as- pharmacists may face the challenge ing devices further facilitate tracking
sessment, random urine drug screen- of opioid prescriptions written by and documentation of opioids and
ing, and the use of a single opioid valid prescribers for large quanti- generate utilization reports. One vul-
prescriber group and pharmacy. In ties of opioids with questionable nerable step in the process is opioid
addition, the PMAP addresses conse- indications (sometimes referred to waste disposal.120 A “second-witness”
quences of missed appointments, ab- as “pill-mill” operations) but with policy (i.e., a requirement that not
errancies in urine drug tests, and ille- insufficient information to validate a just one but two coworkers be present
gal actions related to substance abuse. patient–prescriber relationship. One during the disposal of drug waste),
Violation of a PMAP may require pharmacy chain limited the dispens- with appropriate documentation,

should be required for all instances of cies that aim at reducing the misuse 8. Bromley L. Pre-emptive analgesia and
protective premedication. What is the
waste disposal at the point of patient and abuse of opioids, it is impera- difference? Biomed Pharmacother. 2006;
care as well as in the pharmacy. Also, tive that health-system pharmacists 60:336-40.
pharmacy policy must reinforce ac- understand the appropriate role of 9. Dahl JB, Møiniche S. Pre-emptive anal-
gesia. Br Med Bull. 2004; 71:13-27.
tual witnessing, as opposed to “virtual opioids in the treatment of pain, the 10. Grape S, Tramer MR. Do we need pre-
witnessing,” which occurs when a co- epidemiology of the opioid abuse emptive analgesia for the treatment of
worker attests to but does not actually epidemic and the clinical toxicology postoperative pain? Best Pract Res Clin
Anaesthesiol. 2007; 21:51-63.
visualize the disposal of waste. Rec- of these agents, legal implications for

11. Kelly DJ, Ahmad M, Brull SJ. Preemptive
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12. Møiniche S, Kehlet J, Dahl JB. A qualita-
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oid use should be conducted to help propriate prescribing and diversion drug safety communication: safety
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deadiversion.usdoj.gov/pubs/manuals/ goal is achieved. It is critically important that should be knowledgeable of opioid-related ad-
pharm2/ (accessed 2013 Oct 26). practitioners set realistic therapeutic goals in verse effects and prevent, identify, and manage
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Diversion of drugs within health care not only a reduction in pain severity but demon- Use of psychotherapeutic cointerventions.
facilities, a multiple-victim crime: pat- strated improvement in functioning. Selection Psychotherapeutic interventions, functional
terns of diversion, scope, consequences, of a specific opioid to treat chronic noncancer restoration, interdisciplinary therapy, and nono-
detection, and prevention. Mayo Clin pain is also a patient-specific decision based on pioid therapies should routinely be integrated
Proc. 2012; 87:674-82. into the patient’s plan of care.
patient- and drug-related variables. Patient-
Appendix A—Key considerations in related variables include considerations such as Driving and work safety. Patients should be
analgesic selection6 renal and hepatic functions, body habitus (for counseled about the risks of driving and work
transdermal opioids), ability to swallow tablets safety while taking opioids and counseled about
• Cause of the patient’s pain
or capsules, history of responsiveness to opioids avoiding unsafe behaviors.
• Patient’s age and general health, and the pres-
in the past (positive and negative), and history of Identifying a medical home and when to
ence of comorbidities
opioid allergy or intolerance, among others. The obtain consultation. If the patient’s primary care
• Potential for adverse outcomes associated
six opioids recommended for the management provider is not prescribing the chronic opioid
with medication-related adverse effects
of chronic severe pain in the elderly by an inter- therapy, there should be close communication
• Potential drug interactions
national expert panel are buprenorphine, fen- between this provider and other prescribers.
• Comorbidities that may be relieved by the
tanyl, hydromorphone, methadone, morphine, Patients with chronic pain often benefit from
nonanalgesic effects of the medications (e.g.,
and oxycodone. interdisciplinary pain management.
sleep disturbances, depression, anxiety)
Methadone. Methadone is an opioid with Breakthrough pain. Patients with persistent
• Comorbidities that may be exacerbated by
complicated and variable pharmacokinetic and pain that requires around-the-clock opioid ther-
the nonanalgesic effects of the medications
pharmacodynamic parameters. Clinicians who apy should be evaluated for a trial of “as-needed”
(e.g., hypertension, gastrointestinal ulcer-
choose to use methadone for chronic opioid opioid therapy after considering the risks and
ation, renal impairment, sleep apnea, cogni-
therapy must become expert in the use of this benefits of such an intervention.
tive impairment)
agent. This includes a keen understanding of Opioids in pregnancy. Women of childbear-
• Costs of therapy
whether or not a patient is an appropriate can- ing age should be counseled about the risks
• Potential risks for medication abuse
didate for methadone after performing a careful and benefits of chronic opioid therapy during
• Risks of intentional or unintentional overdose
risk assessment, including a cardiac assessment; pregnancy and after delivery. The use of opioids
Appendix B—Summary of American dosing strategies for both opioid-naive and during pregnancy is not encouraged, and risks
opioid-tolerant patients; and how to monitor a to the patient and newborn must be considered
Pain Society–American Academy of
patient receiving methadone. Methadone has a and dealt with.
Pain Medicine recommendations on very long and variable half-life; therefore, start- Opioid policies. Practitioners need to be
use of chronic opioid therapy in chronic ing doses should be conservative, patients should aware of state and federal laws and guidelines as
noncancer pain7 be monitored closely, and doses should not be they pertain to chronic opioid therapy. Opioids
Patient selection and risk stratification. Be- adjusted before four to seven days. are an effective tool in the management of acute
fore beginning opioid therapy, clinicians should Monitoring. Patients receiving chronic and chronic pain, but as with all pharmacothera-
conduct a history and a physical examination opioid therapy must be regularly monitored to peutic interventions, risks and benefits must be
and collect other information as appropri- ensure progress is being made toward achieving assessed before and during therapy to ensure safe
ate, including a risk assessment for opioid use. therapeutic goals, adherence to the prescribed and effective outcomes for patients.

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SPECIAL FEATURE Opioid abuse and misuse

SPECIAL FEATURE ar Layar

The opioid abuse and misuse epidemic: Implications

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