CE UPDATEDRUGS OF ABUSE I

Robert H. Williams, PhD, DABCC, MT(ASCP)

Timothy Erickson, MD

Emergency Diagnosis
of Opioid Intoxication
ABSTRACT Opioids are widely used for analgesic purposes.
If taken as prescribed, they are safe and effective. Overdosing,
however, can cause coma and life-threatening respiratory
depression. In the acute care setting, physicians often base
treatment on the presence of classic opioid syndrome
characteristicsmental status depression, hypoventilation,
miosis (pinpoint pupils), and reduced bowel motility. Rather
than identify and quantify the specific agent, laboratories
should confirm opioid intoxication qualitatively with a urine
drug screen. With this information, physicians may expedite
treatment with opioid antagonists (naloxone), which help
patients to resume spontaneous respiration. Because the drug
level does not always correlate with the severity of illness,
quantitative drug levels are rarely needed. Hypoglycemia,
hypoxia, and hypothermia are also seen with opioid overdose.

Suspecting opioid overdose, the physician

ordered tests (Table 1) and intravenously administered a bolus dose of 0.4 mg of naloxone and 50%
dextrose. Although the patient began to arouse
from coma within a few seconds, he quickly
relapsed into respiratory depression. The physician gave a higher (2 mg) bolus dose of naloxone.
The patient responded within 1 to 2 minutes and
became fully alert and oriented, and his pupils
became dilated. He was also diaphoretic and
appeared agitated. Lung examination showed
bilateral rales auscultated at the bases. A chest
radiograph revealed diffuse patchy infiltrates. The
classic symptoms of opioid overdose coupled with
the opioid-positive urine drug screen test result
confirmed the diagnosis of opioid intoxication.
The patient was given 50% dextrose for his
hypoglycemia. Because he had a history of drug
This is the first article in a 3-part continuing education series on drugs of abuse. On
abuse, the patient was kept an additional 8 hours
completion of this article the reader will be able to correlate clinical findings with
for observation and psychiatric evaluation for
laboratory data to assist the clinician in diagnosis and describe therapeutic
drug-abuse detoxification. Although admitting to
interventions for managing patients with opioid poisoning.
frequent heroin abuse, the patient denied suicidal
attempts and claimed he just had a bad cut
From the University
Case Presentation
tonight. He remained in the emergency departof Illinois at Chicago
ment for several hours, became more uncooperaA
25-year-old
man
with
a
history
of
drug
abuse
Medical Center,
was unresponsive to treatment by paramedics at tive, and demanded to be discharged.
Departments of
Pathology (Dr
an inner-city nightclub. On arrival to the emerWilliams) and
gency department, the patient was hypoventilat- History of Opioids
Emergency Medicine
ing, cyanotic with small pupils, and responding The medicinal value of opiates has been known
(Dr Erickson),
only to deep painful stimuli. The patients skin was for more than 2,000 years.1 The naturally occurChicago, IL.
cool and dry. Needle tracks were observed along ring alkaloid analgesics come from the poppy
Reprint requests to
the upper extremities. His pulse was 56 beats per plant, Papaver somniferum. The milky exudate
Dr Williams,
minute; respiration rate, 6 per minute; blood pres- from unripe seeds of this plant contains several
University of Illinois
at Chicago Medical
sure, 95/60 mm Hg, and temperature, 35.4C pharmacologically active compounds such as
Center, Department
(95.8F). The patients abdomen was soft and had
of Pathology,
hypoactive bowel sounds. An electrocardiogram
Division of Clinical
revealed a sinus bradycardia.
Pathology (M/C 750),
840 S Wood St, 201G
CSB, Chicago, IL
60612; e-mail:
rwilliam@uic.edu

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Table 1. Laboratory Test Results for Patient Suspected of Opioid Intoxication

Test

Result

Reference Range

Arterial blood gas levels: room air/40% oxygen

pH

7.20/7.39

7.35-7.45

pCO2, mm Hg

60/37

35-45

pO2, mm Hg

50/135

90-95*

18/22

24-28

Sodium, mEq/L (mmol/L)

145 (145)

136-145 (136-145)

Potassium, mEq/L (mmol/L)

3.2 (3.2)

3.5-5.0 (3.5-5.0)

Chloride, mEq/L (mmol/L)

109 (109)

99-109 (99-109)

Bicarbonate, mEq/L (mmol/L)

18 (18)

22-28 (22-28)

Urea nitrogen, mmol/L (mg/dL)

29 (10.4)

10-20 (3.6-7.1)

Creatinine, mmol/L (mg/dL)

1.2 (106)

0.6-1.2 (53-106)

Before 50% dextrose

55 (3.1)

70-105 (3.95.8)

After 50% dextrose

125 (6.9)

70-105 (3.95.8)

3.9 (3.9)

4.7-6.1 (4.7-6.1)

9,500 (9.5)

4,800-10,800 (4.8-10.8)

Hemoglobin level, g/dL (g/L)

12.0 (120)

14.0-18.0 (140-180)

Hematocrit, % (proportion of 1.0)

37 (0.37)

42-52 (0.42-0.52)

120 (120)

150-400 (150-400)

70 (15.2)

<5 (<1.1)

Amphetamines

None detected

None detected

Cannabinoids

None detected

None detected

Cocaine metabolite

None detected

None detected

Barbiturates

None detected

None detected

Opiates

Positive

None detected

Phencyclidine

None detected

None detected

Bicarbonate, mmol/L
Serum constituent levels
Electrolytes

Glucose, mmol/L (mg/dL)

RBC count, 3 106/mL (3 1012/L)

WBC count, /mL (3

Platelet count, 3

109/L)

103/mL

(3

109/L)

Blood ethanol level, mg/dL (mmol/L)

Scientific Communications

CBC

Section

Drugs in urine

*Room air.

morphine and codeine (methylmorphine). The

dried extract is opium. Although morphine
(named after Morpheus, the god of dreams) is the
principal alkaloid of opium, opioid refers to the
naturally occurring compounds, semisynthetic
alkaloids prepared from the extract, and synthetic
surrogates with morphine-like pharmacologic
effects (rather than morphine-like structures).2

In 1874, heroin (diacetylmorphine) appeared

as the first semisynthetic derivative made from
morphine. It became available as a pharmaceutical
preparation in 1898. Although therapeutic use of
heroin is illegal in the United States, it rose to epidemic proportions by the 1970s (Fig 1). In
response to increasing concerns about opioid
addiction and toxicity, Congress made the nonmedicinal use of opioids illegal by passing the
Harrison Narcotic Act in 1914. Today, with lower

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prices and higher purity, heroin is a prevalent street

drug.3 Users claim that it gives an enhanced
euphoric effect. Because intravenous injections have
led to complications such as endocarditis and AIDS,
abusers have sought other, less risky modes
(intranasal, smoking) of administration. Although
traditionally smuggled from Southeast Asia,
Afghanistan, and Nigeria, most heroin in the United
States comes from South America and Mexico.
Opioid Metabolism and Pharmacology

Fig 1. Needle tracks are evident on the arm of a man who was found dead due
to an apparent heroin overdose.

Table 2. Opioid Receptors and Their Clinical Effects

Receptor
Mu

Clinical Manifestations
Analgesia
Spinal (mu2)
Supraspinal, brain (mu1)
Central depression
Bradycardia
Hypothermia
Reduced gastrointestinal tract motility
Respiratory depression
Miosis (ie, pupil contraction)
Physical dependence
Pruritis (ie, itching)

Kappa

Miosis
Sedation
Spinal analgesia

Delta

Delusions
Dysphoria (ie, restlessness or malaise)
Hallucinations
Psychomotor change

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Most opioids are readily absorbed after injection.

Absorption is also high from the gastrointestinal
tract, although bioavailability and pharmacologic
effects vary with rates of first-pass metabolism.
Protein binding of opioids in plasma varies considerably, and tissue localization depends on lipid
solubility and tissue perfusion. Metabolism takes
place primarily in the liver. Because some opioids
undergo significant first-pass metabolism, giving
the drug orally may reduce its efficacy. Metabolites
are excreted primarily in the urine, and small
amounts combine with glucuronide for removal
in the feces. The metabolic pathways for natural
and synthetic opioids are shown in Figure 2.
The pharmacologic effects of opioids are
attributed to their binding to specific receptors in
the central nervous system. At least 3 major opioid
receptor subtypes exist: mu, kappa, and delta.4
Interactions of opioids with these receptors are
associated with the clinical manifestations in Table
2. Opioids modulate cerebral cortical pain perception at supraspinal (brain), spinal, and peripheral
levels. The mu receptors mediate most analgesic
effects of morphine and related compounds
within the brain (supraspinal analgesia).5
Although interaction with kappa receptors produces analgesia in the spinal cord, psychomimetic
effects (dysphoria) via kappa receptor interaction
in the brain may also occur, thus limiting the clinical use of opioids.
The sigma receptor was once considered an
opioid subtype.6 Because the opioid antagonist,
naloxone, has no effect, the sigma receptor is no
longer grouped with opioid receptors.7 The receptor does, however, have a role in opioid pharmacology because several key opioids, such as
dextromethorphan and pentazocine, are sigmareceptor agonists.

Clinical Effects of Opioids

Opioids find use in many situations, including

surgical and medical emergencies. They are used
for anesthesia, sedation, and postoperative analgesia and to treat trauma and burns, pain in orthopedic and terminal illness, cough, and diarrhea.
The major effects of opioids are on the central
nervous system. Opioids provide analgesia without
sedation, euphoria, or loss of consciousness. They
also affect the pulmonary, cardiovascular, and gastrointestinal systems by causing respiratory
depression, bradycardia, nausea, vomiting, and

other classic symptoms associated with intoxication or withdrawal (Table 3).

Diagnosis of Opioid Intoxication

Although most clinical findings are nonspecific, a

constellation of classic signsmental depression,
hypoventilation, miosis, and sometimes reduced
bowel motilitycalled the opioid toxidrome
often develops in patients with opioid intoxication. Differentiating acute opioid intoxication
from other conditions with similar clinical presentation can be challenging. Besides the opioid syndrome, the readily treatable hypoglycemia,
hypoxia, and hypothermia are often seen with opioid poisoning; these symptoms, however, can also
occur with phencyclidine, phenothiazine, sedative-hypnotic (benzodiazepines), and clonidine
poisoning. Although clinicians can often rule out
some drugs on the basis of other signs and symptomsnystagmus (phencyclidine), electrocardiographic changes (phenothiazine), normal vital
signs and coma (benzodiazepines)others such
as clonidine are not so easily eliminated. Thus, a
simple opioid-positive drug screen test result from
the laboratory is most helpful.

Codeine*

Scientific Communications

Opioids are classified according to their mode

of action as full agonists, mixed agonists-antagonists, and full antagonists. Full agonists have an
affinity for a specific type of opioid receptor.
Mixed agonist-antagonists have an agonistic effect
with one class of receptor and an antagonistic
effect with another. Full antagonists, via increased
affinity or competitive binding, can prevent opioid binding or displace an opioid from its receptor. Full antagonists have a reduced analgesic
effect. Naloxone is a potent antagonist with no
analgesic effects.

Heroin

Hydrolysis
N-Demethylation

6-Monoacetylmorphine*

Section

Norcodeine*
Hydrolysis

O-Demethylation

Morphine*
N-Demethylation

Normorphine*

Fig 2. Schematic representation of metabolic profile of morphine, codeine, and heroin. *Indicates compounds
conjugated with glucuronic acid and sulfate. From El Sohly MA, Jones AB. Origin of morphine and codeine in
biological fluids. In: Liu RH, Goldberger BA, eds. Handbook of Workplace Drug Testing. Washington, DC: AACC
Press; 1995:230. Used with permission.

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Table 3. Clinical Findings in Opioid Intoxication and Withdrawal

Intoxication

be small (0.1 mg), then increased to 0.4, 2.0, and

10 mg.8 Emesis often accompanies acute withdrawal as well. If the patient does not immediately
regain consciousness, additional complications
such as head trauma or intoxication with ethanol
or sedative-hypnotic agents may be present. If
naloxone produces no response at all, the patient
may require intubation and a computed tomography scan of the head to rule out cerebral bleeding
or head trauma.

Bradycardia
Coma
Decreased gastrointestinal tract motility
Depressed mental status
Depressed respiratory drive
Hypotension
Hypothermia
Miosis (ie, pupil contraction)

Opioids Requiring
Special Consideration
Heroin

Needle track marks on skin

Withdrawal
Agitation
Diarrhea
Diaphoresis (ie, heavy perspiration)
Hypertension
Muscle cramps
Mydriasis (ie, pupil dilation)
Piloerection (ie, hair erection)
Tachycardia
Tachypnea (ie, rapid shallow breathing)
Vomiting
Yawning

Patient Management

The common methods to treat opioid intoxication

are shown in Table 4. Other than treating the
hypoglycemia, the first step is to reverse the central depression caused by the opioid. Naloxone, an
opioid antagonist with a 20- to 30-minute half-life
is usually used for this purpose. In most nonopioid-dependent patients with acute opioid overdose, small doses (0.1 to 0.4 mg) generally reverse
the effects of intoxication. Although naloxone is
safe even at high doses (10 mg), giving 0.4-mg
doses to opioid-dependent patients often results
in acute withdrawal, leading to significant stress
for both patient and healthcare personnel (see
Table 4). The initial doses for these patients should

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As the most widely abused opioid, heroin is synthesized by acetylating morphine, which increases
the analgesic potency 2- to 3-fold. Heroin is often
mixed (cut) with common diluents such as sugar,
baking soda, flour, and talc. In the United States,
street purity ranges from 10% to 80%, depending on geographic location. Peak plasma concentrations occur within a few minutes of drug
administration. With a half-life of a few minutes,
heroin is rarely detected in body fluids. The drug
undergoes rapid deacetylation to 6-acetylmorphine (6-AM), a metabolite with 4 times the
potency of morphine. Because heroin has no
affinity for opioid receptors in the brain, its analgesic properties are due to the combined effects of
6-AM and its morphine metabolite. Death due to
heroin administration is generally the result of
profound respiratory depression.
The illicit transport of heroin between countries is a socioeconomic problem. Couriers of
heroin (or cocaine), called mules or body
packers, ingest numerous multiply wrapped
packages of concentrated drug, to have them later
removed cathartically (Fig 3). Often asymptomatic, the drug transporters risk delayed or prolonged toxic effects if the packets rupture before
they are removed. With the aid of abdominal
radiography, emergency department physicians
can confirm gastrointestinal smuggling,9 though
the radiographs do not reveal the packet contents.
If the courier presents with symptoms suggestive
of packet rupture, physicians treat according to
history and lab results. Heroin cases require continuous naloxone infusion, whereas cocaine cases
need surgery.10

Table 4. Treatment of Opioid Intoxication

If hypoglycemic, administer oxygen, 50% dextrose.

If comatose with suspected drug overdose, give direct opioid antagonist (naloxone): Initial dose 2-mg by
intravenous push (restrain patient before administration because naloxone precipitates withdrawal); up to
10-mg dose with longer-acting opioids and higher grades of heroin; drip if repeated boluses required.

If naloxone ineffective and patient remains comatose, consider other causes and be prepared to intubate and
ventilate patient.

If patient in withdrawal, give supportive care, intravenous fluids for hydration; consider giving clonidine or
methadone or refer patient to substance abuse detoxification center.

Fentanyl

Propoxyphene

Fentanyl (Sublimaze), a short-acting, opioid agonist with 50 to 100 times the potency of morphine,
is used widely in clinical medicine. Fentanyl and
its illicit analogues (3-methyl fentanyl) are prevalent drugs of abuse in some regions of the United
States.11 Although they supposedly receive a more
intense rush with heroin, long-term heroin users
generally cannot distinguish fentanyl from
heroin.12 Epidemics of heroin-related deaths have
been associated with heroin tainted with fentanyl
analogue. One of the first occurred in Orange
County, CA. The epidemic involved the fentanyl
analogue, alpha-methylfentanyl, or China
White. Since then, similar epidemics have
occurred in Pittsburgh (1998), Philadelphia
(1992), and, most recently, in New York.13 Typically, patients are comatose and apneic, and blood
or urine analyses reveal no opioids.14 Owing to
their high potency (up to 6,000 times greater than
morphine), high doses of naloxone may be needed
to counteract the effects of alpha-methylfentanyl.

Like its structural analogue, propoxyphene binds

to mu receptors to produce the clinical findings
seen with opioid use. Propoxyphene and its active
metabolite, norpropoxyphene, produce lifethreatening respiratory arrest in an overdose situation. These compounds may also (1) produce
cardiac toxic effects by blocking the fast sodium
channels of the myocardium, and (2) precipitate
seizures resulting from central nervous system
toxic effects. When patients take an overdose of
propoxyphene formulated with either acetaminophen (Darvocet-N) or salicylate, they
become poisoned with the nonopioid analgesiaenhancing medications as well. In these cases,
quantitative measurements of acetaminophen or
salicylates are indicated.
Fig 3. Abdominal
radiograph shows
numerous drug
packets swallowed
by a courier, or
body packer. The
contents of the
packets were later
determined to be
heroin.

Codeine

Section

A semisynthetic agent produced by the methylation of morphine, codeine has low-to-moderate

analgesic properties. Even at low doses, the drug
effectively suppresses cough.15 Codeine is often
formulated with nonopioid analgesics such as
aspirin or acetaminophen. Between 10% and 20%
is excreted unchanged, and 10% is metabolized to
morphine (which accounts for most of its analgesic effects). Codeine conjugates are excreted
before morphine conjugates. After 3 days of use,
codeine metabolites resemble those associated
with morphine or heroin use. The appearance of
norcodeine in urine, however, indicates codeine
use because heroin and morphine are not metabolized to norcodeine.

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Like codeine, the opioid dextromethorphan is a

cough suppressant. It is unlikely, however, that
dextromethorphan exerts this effect through an
opioid receptor. Unlike its potent optical isomer
(levorphanol), dextromethorphan has no analgesic properties, although at high doses, it binds
opioid receptors to produce miosis and depress
the central nervous system. Dextrorphan, the
metabolite of dextromethorphan, reacts with the
sigma receptor to produce a psychosis similar to that
obtained with phencyclidine.16 In addition, urine
from long-term dextromethorphan users or overdose patients produces false-positive immunoassay
results for the structurally similar phencyclidine.

property, however, enhances its antidiarrheal

effects resulting from its interaction with the gastrointestinal mu receptor. Diphenoxylate is combined with a small dose of atropine to augment
these antidiarrheal properties.
When ingested by children, adult formulations containing diphenoxylate induce toxic
effects. The onset is often delayed, most likely
due to the production of the more potent liver
metabolite, difenoxin, which has a longer serum
half-life than diphenoxylate.20
Loperamide (Imodium) is another insoluble
meperidine analogue used to treat diarrhea. The
few cases of adverse outcomes suggest that this
drug is safer to use than diphenoxylate.

Pentazocine

Methadone

In the past, patients abusing pentazocine (Talwin)

administered it with a blue capsule of tripelennamine. Consequently, abusers referred to the combination as Ts and blues.17 Pentazocine, despite its
agonist-antagonist effects, remains widely abused
when combined with methylphenidate.

A mu agonist taken orally, methadone is a wellknown maintenance drug for heroin addicts. As a
legal drug, the long-acting opioid replaces the
illicit heroin. Patients are given high therapeutic
doses to prevent their surreptitious use of illicit
drugs,21 resulting in methadone overdose. When
this occurs, symptoms similar to those of morphine overdose appear, but for longer periods (up
to 24 hours). Unlike patients with uncomplicated
heroin overdose (who are treated and discharged
if asymptomatic for awhile22), methadone-overdose patients must be hospitalized to treat the
prolonged toxic effects and to guard against their
recurrence. In countries such as England, accidental ingestion of methadone by children is increasing and often ends in death.23

Dextromethorphan

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Meperidine

Meperidine is not a prevalent illicit drug, although

it is often used to treat acute or chronic pain. Longterm users, especially those with renal insufficiency, are at risk for toxic effects caused by the
active hepatic metabolite normeperidine.18 This
metabolite is eliminated by the kidney and induces
tremor, myoclonus, or seizures. Interacting primarily
with opioid receptors, meperidine can also exert
effects with other receptor classes. Most notable are
its serotonin effects, particularly in patients receiving monoamine oxidase inhibitors. The excessive
meperidine-induced release of presynaptic serotonin may produce the serotonin syndrome
characterized by muscle rigidity, hyperthermia,
altered mental status, and death.19
Diphenoxylate and Loperamide

Although structurally related to meperidine,

diphenoxylate is insoluble, which limits its
absorption from the gastrointestinal tract. This

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Laboratory Diagnosis
of Opioid Poisoning

Besides ordering radiographic images for cerebral

bleeding or electrocardiograms to monitor bradycardia, clinicians treating patients suspected of
opioid overdose order arterial blood gases, electrolytes, glucose, renal function tests, and toxicology tests to confirm the presence of opioids or

The federal government made these changes

for 2 reasons: (1) to detect morphine and codeine
and (2) to confirm illicit heroin use. Thus testing
for the heroin metabolite 6-AM became mandatory with the confirmation cutoff level set at 10
ng/mL.26 The presence of the 6-AM is important
because human beings cannot acetylate morphine
to make monoacetylmorphine, but they can
deacetylate heroin (diacetylmorphine) to form 6AM. For this reason, the presence of 6-AM is
unequivocal evidence of heroin use. One drawback with 6-AM is its short urinary half-life,
which limits detection time to approximately 2 to
8 hours.
Conclusion

Scientific Communications

Patients brought to the emergency department

with opioid intoxication receive rapid clinical diagnosis and treatment owing to the uniqueness of the
opioid toxidrome. Although urine drug screen tests
do not identify specific opioids, they confirm their
presence, which aids the clinician in prescribing
treatment. However, a urine drug screen test negative for opioids does not rule out the presence of
opioids such as fentanyl, which is effective at low
concentrations in biologic fluids and often nondetectable by most routine screening techniques.l
References

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L A B O R ATO RY M E D I C I N E

1. Mann J. Murder, Magic and Medicine. Oxford, England:

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Section

compounds that may give rise to similar symptoms. Most opiate immunoassays are not specific
owing to cross-reactivity with structurally related
compounds. Overall specificity of immunoassays
depends on the antibody characteristics and
whether the assay is homogeneous or heterogeneous. Although qualitative urine drug screen tests
are helpful, opioid-negative results do not rule out
the presence of opioids. The interpretation of qualitative urine drug screening tests is often based on
cutoff values, below which the result is considered
negative for the drug in question. Because an opioid may not react significantly with the assay antibody, or, like the potent opioid fentanyl, it may
exist at undetectable low levels in the blood, clinicians should not assume that this negative result
rules out the presence of the drug. This is not necessarily an issue in workplace testing; although in
the emergency setting, the presence of any drug
may help to explain a patients toxic symptoms.
Fortunately, drug intoxication levels in emergency
situations are much higher than the cutoff values
used by most laboratories.
In the workplace, the selection and application
of cutoff values is different because many factors
other than drug abuse have caused false-positive
results. For example, ingestion of moderate-tolarge amounts of poppy seeds on bagels produced
false-positive result for opioids, especially when
the test was done 2 hours after ingestion.24,25
These seeds, which contain codeine and morphine, are often used for culinary purposes and
come from poppy plants similar to P somniferum.
Another cause of false-positive opioid results was
the use of prescribed medications containing
morphine or codeine. For these reasons the US
Department of Health and Human Services, in
federally regulated drug testing programs, raised
the opioid cutoff value from 300 to 2,000 ng/mL
for immunoassay tests. For gas chromatographymass spectrometry confirmation of codeine
and morphine, the department raised the cutoff
value to the same levels.26

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9. Hierholzer J, Cordes M, Tantow H, et al. Drug smuggling

by ingested cocaine filled packages: conventional x-ray and
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implication of fentanyl use based on reports from self-identified users. J Psychoactive Drugs. 1983;15:293-301.
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15. Reisine T, Pasternak G. Opioid analgesics and antagonists.
In: Hardman JG, Limbird LE, Molinoff PB, et al, eds. Goodman
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16. Szekely JI, Sharpe LG, Jaffe JH. Induction of phencyclidine-like behavior in rats by dextrophan but not dextromethorphan. Pharmacol Biochem Behav. 1991;40:381-384.
17. DeBard ML, Jagger JA. Ts and Bs: midwestern heroin
substitute. Clin Toxicol. 1981;18:1117-1123.
18. Kaiko RF, Foley KM, Grabinski PY, et al. Central nervous
system excitatory effects of meperidine in cancer patients. Ann
Neurol. 1983;13:180-185.

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19. Browne B, Linter S. Monoamine oxidase inhibitors and

narcotic analgesics: a critical review of the implications for
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