CHAPTER 53

Management of Opioid Intoxication and

Withdrawal
Jeanette M. Tetrault and Patrick G. O’Connor
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 CHAPTER OUTLINE
Introduction
Opioid Intoxication and Overdose
Opioid Withdrawal
Conclusions

INTRODUCTION
Opioids include substances that are derived directly from the opium poppy (such as morphine
and codeine), the semisynthetic opioids (such as heroin), and the purely synthetic opioids
(such as methadone and fentanyl).
These compounds share several pharmacological effects, including sedation, respiratory
depression, and analgesia, and common clinical features of intoxication and withdrawal. This
chapter reviews the clinical features of opioid intoxication and withdrawal.
Although all drugs in the class are associated with clinical withdrawal syndromes, those
most commonly encountered in clinical practice include heroin, methadone, morphine,
oxycodone, codeine, hydrocodone, and meperidine (1).

OPIOID INTOXICATION AND OVERDOSE

Clinical Picture
The prevalence of opioid use in the United States continues to increase. According to the
results of the National Survey on Drug Use and Health, among individuals 12 years of age or
older, self-reported lifetime heroin use has increased from 1.2% in 2000 to 1.9% in 2015 (1).
Similarly, there has been an increase in the lifetime nonmedical use of prescription opioids
among individuals 12 years of age and older from 8.6% in 2000 to 13.6% in 2014. After
2014, there was a change in methodology of the National Survey of Drug Use making it
challenging to make comparisons for certain questions (1,2). Opioid intoxication and
overdose may present in a variety of settings. Although mild-to-moderate intoxication,
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characterized by euphoria or sedation, usually is not life threatening, severe intoxication or

overdose is a medical emergency that causes many preventable deaths and thus requires
immediate attention (3). Opioid overdose is characterized by the classic signs of depressed
mental status, decreased respiratory rate, decreased bowel sounds, and miotic pupils. In a
retrospective analysis of consecutive cases of presumed opioid overdose in patients initially
managed by emergency medical services personnel in an urban setting, 16% were either dead
or in full cardiopulmonary arrest at the time of the initial emergency medical service
evaluation (4). As the prevalence of opioid use has increased in the United States, the
incidence of opioid overdose has increased as well. Among almost 48,000 substance related

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 overdose deaths that occurred in the United States in 2014, 61% were due to opioids and
opioid death rates increased by 15.6% from 2014 to 2015 (5). Additionally, for patients
prescribed opioids for chronic, noncancer pain, overdose risk increases in a dose-dependent
fashion. Of 9,940 patients receiving prescription opioids in a managed care organization from
1997 to 2005, 51 overdoses were noted, 6 of which were fatal. Compared to patients
receiving 1 to 20 mg/d of morphine equivalents, those receiving 50 to 99 mg/d had a 3.7-fold
increased risk of overdose, and those receiving 100 or more mg per day had an 8.9-fold
increase in overdose risk (6). Accidental overdose may occur in a variety of settings. Of
increasing concern are accidental overdoses occurring in several US cities where heroin or
other substances are mixed with more potent opioids (eg, fentanyl) (7–10). Despite these
increases, opioid overdose can be treated successfully, if patients present in a timely manner
and general principles of overdose management (as well as specific therapies for opioid
overdose) are employed. In a retrospective analysis in Finland, the survival-to-hospital
discharge rate of cardiopulmonary arrest after heroin overdose (16%) was found to be similar
to that of other poisonings (11%) (11).
Nonfatal opioid overdose is an additional cause of significant morbidity, and the true
prevalence may not be well understood because many nonfatal overdoses are not brought to
medical attention (12). The prevalence of nonfatal overdose ranged from 10% to 69% as
reported in recent literature (12). The factors associated with nonfatal opioid overdose
include injection as the route of administration, sporadic heroin use, needing help with
injection, prior overdose, and multiple drug use.
The pharmacological actions responsible for opioid intoxication and overdose involve
central nervous system (CNS) mu, kappa, and delta opioid receptors (13,14) that also interact
with endogenous substances, including the endorphins (15). Of primary concern in the
management of overdose are interactions with mu receptors, which can lead to sedation and
respiratory depression. The mechanism of respiratory depression with opioids presumably is
direct suppression of respiratory centers in the brain stem and medulla (14).
The level of tolerance to opioids can have a significant effect on an individual’s risk of
opioid overdose. In addition, tolerance to respiratory depression may be slower than
tolerance to euphoric effects, thus explaining why overdose occurs so often, even among
“experienced” opioid users (16,17). Patients who have undergone medically supervised
withdrawal or those who have experienced intentional or unintentional abstinence from
opioids for any reason (eg, incarceration) may be particularly susceptible to death from
heroin overdose (18–20). Nonfatal overdose is also common among patients undergoing
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medically supervised withdrawal—occurring in 27% of a cohort of 201 patients with opioid

use disorder patients followed for 2 years after withdrawal. Among this group, prior overdose
attempts and depressive symptoms were risk factors for nonfatal overdose (21). Although
injecting opioids may be the route of administration associated with the highest risk of
overdose, increasingly popular noninjection routes are associated with significant risk as well
(22). Additionally, case reports of fatal opioid overdose among opioid-naive patients who use
cocaine have been published whereby these patients have unknowingly used pure fentanyl
instead of cocaine (7). Persons who administer opioids of potency that they are

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 unaccustomed to may experience opioid overdose. Finally, patients who administer opioids in
addition to other substances known to exacerbate the opioid effect (eg, benzodiazepines,
sedatives) may be more prone to overdose.

Diagnosis
As with most clinical challenges, evaluation of opioid intoxication begins with the collection
of patient data through a detailed history and physical examination (Table 53-1). An
important issue in the patient with moderate to severe respiratory depression is the immediate
institution of pharmacological and supportive therapies to ameliorate morbidity and prevent
mortality.

TABLE 53-1 Diagnosis of Opioid Overdose

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ause multiple sources of information (family, hospital recrods,etc) to obtain complete history.

When available, historical information can be obtained concerning opioid use (including the
specific drug, amount, and time of last use) either directly from the patient or from friends
and family members; this information can supplement available hospital records. In addition
to opioids, it is important to ask about use of other drugs or alcohol because of the likelihood
use of more than one drug (23–25). Identification of multiple drug use has important

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 implications for patient management; for example, identification of the frequent co-
occurrence of opioid and benzodiazepine overdose may indicate the need for additional
therapy directed at reversing the benzodiazepine component of the overdose with flumazenil
(26,27). This also is true in cases of suspected opioid overdose in children who are at high
risk of co-occurring opioid and benzodiazepine toxicity and who thus may require
management of both on presentation for medical care (28). Multiple drug overdose often
accounts for significant morbidity and mortality. More than half of all drug overdose deaths
result from multiple drug overdose with opioids, alcohol, and cocaine (29,30).
Physical examination of the opioid-intoxicated patient may find CNS and respiratory
depression, as well as miosis and direct evidence of drug use, such as needle tracks or soft
tissue infection. The heroin overdose syndrome, described as a triad of altered mental status,
depressed respiration, and miotic pupils, has a sensitivity of 92% and a specificity of 76% for
the diagnosis of heroin overdose (3). Additional evidence supports the use of clinical
characteristics in the diagnosis of heroin overdose. In a study of 730 patients in Los Angeles
receiving naloxone for suspected heroin overdose, the presence of one of the three clinical signs
—respirations <12 per minute, presence of pinpoint pupils, and circumstantial evidence of
opioid use—had a sensitivity of 92% and a specificity of 76%, whereas the sensitivity of
naloxone response was 88%, and specificity was 86% (31). The laboratory can also provide
important supportive information in the evaluation of opioid intoxication, including urine
toxicology testing for naturally occurring and synthetic opioids. Be aware that often drug
testing for “opiates” is limited to derivatives of the opium poppy and may not include the
wider array of “opioids” (semisynthetic and synthetic opioids).
It is important to consider the differential diagnosis in patients presenting with symptoms
of opioid intoxication. Other possibilities of depressed mental status include hypoglycemia,
acidemia or other fluid and electrolyte disorders, or complications from end-stage liver
disease. Additionally, acute mental status changes from HIV-related opportunistic infections
may mimic those of opioid intoxication (32). Although, overall, HIV incidence is decreasing,
outbreaks among people who inject drugs are of concern (33). Finally, intoxication from
other substances should be considered. Therefore, toxicology testing should be performed
immediately in emergency settings. Urine toxicology is preferred, because urine contains
higher concentrations of drugs and their metabolites than serum. Results usually are
qualitative, indicating only the presence or absence of specific substances. Even when the
results of toxicological screening are not available until after acute management has been
initiated, drug testing may support the diagnosis of drug intoxication and also may reveal the
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presence of other drugs not suspected on initial evaluation. Benzodiazepine misuse is

common among patients with opioid misuse and opioid use disorder, and some
benzodiazepines (such as clonazepam) may not be readily detectable by standard urine
toxicology testing. Alternative approaches involving the examination of serum may be useful
in documenting benzodiazepine use (34).
Kellermann et al. (35) examined the effects of drug testing on suspected overdose in a
study of 405 adult patients who presented to an emergency department. Although initial
clinical management did not change significantly on the basis of the toxicology results,

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 implications for treatment beyond the acute event were noted. Poor follow-up of drug testing
also was demonstrated in a study of alcohol intoxication in patients injured in motor vehicle
crashes. In that study, none of 47 patients who had alcohol levels between 200 and 500
mg/dL were referred for a follow-up visit to address their alcohol use (36). Thus, toxicology
testing is useful not only for acute management but also for planning care after discharge
from the acute setting (37). Referral to alcohol and drug treatment programs from the
emergency department may be an effective mechanism to link patients with opioid use
disorder, who otherwise may not interface with the medical system, with available treatment
programs (38). Although the emergency department presents a unique opportunity to screen
patients for substance use and link them to appropriate care, engagement in care often proves
challenging (39). Therefore, unique models of emergency department initiation of opioid
agonist treatment with direct linkage to care should be developed, tried, and studied as they
hold significant promise (40).
Opioid use and overdose also may be complicated by the effects of substances employed
to “cut” drugs purchased on the street. Along with inert substances present to add bulk, active
substances—including dextromethorphan, lidocaine, and scopolamine—may be present.
Additionally, unusual complications may present as a result of contamination of illicit
substances. For instance, recent case reports of patients presenting with cutaneous necrosis,
purpura, and neutropenia have been linked to levamisole (an antihelminthic,
immunomodulatory, and antineoplastic medication)-contaminated cocaine (41).
Although the classic “triad” of respiratory depression, coma, and pinpoint pupils usually
alerts clinicians to the possibility of opioid overdose, atypical presentations may cause some
initial confusion. In a study of 43 hospitalized patients who received naloxone for a clinically
suspected opioid overdose, only two patients had the classic triad, suggesting that a high
index of suspicion should be maintained in patients who may have atypical presentations
(42).

Management
In a case of suspected severe opioid intoxication, resulting in overdose, general supportive
management must be instituted simultaneously with the specific antidote, naloxone (Table
53-2) (3). Opioid overdose is characterized by the classic signs of depressed mental status,
decreased respiratory rate, decreased bowel sounds, and miotic pupils. Individuals who
present with signs and symptoms of mild-to-moderate opioid intoxication without overdose
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can be monitored and treated supportively without naloxone administration. Adult basic life
support and adult advanced cardiac life support need to be available (43,44). The clinician
needs to assure that an adequate airway is established and that respiratory and cardiac
function are appropriately assessed and managed. Adequate intravenous access is essential so
that fluids and pharmacological agents can be administered as needed. Finally, frequent
monitoring of vital signs and cardiorespiratory status is required until it is clearly established
that the opioid and any other intoxicating substances have been cleared from the patient’s
system. Additionally, the clinician must consider the half-life of the ingested substance as

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 multiple doses of naloxone or an intravenous naloxone drip may need to be instituted in the
case of ingesting of a long-acting opioid.

TABLE 53-2 Management of Opioid Overdose

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In the course of managing patients with suspected opioid overdose, clinicians need to be
aware of the co-occurrence of acute medical conditions and the exacerbation of chronic
medical conditions often seen in this population (32,45). For example, prolonged hypoxia in
overdose survivors can result in rhabdomyolysis and myocardial infarction (46). Other

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 issues, such as acute infections, trauma, and chronic liver disease (including chronic hepatitis
C virus [HCV] infection), may have major implications for management of the overdose
patient (45).

Pharmacological Therapies
When a patient presents to an emergency department with miosis and respiratory depression,
pharmacological therapy for opioid overdose should be instituted immediately (3). Naloxone
hydrochloride, a pure opioid antagonist, can effectively reverse the CNS effects of opioid
intoxication and overdose. An initial intravenous dose of 0.4 to 0.8 mg will quickly reverse
neurological and cardiorespiratory depression. The onset of action of intravenously
administered naloxone, as manifested by antagonism of opioid overdose, is ~2 minutes.
Although intravenous naloxone should work more rapidly than subcutaneous naloxone, one
study demonstrated that the subcutaneous route may be just as effective for managing
patients before they arrive in the emergency department; additionally, the slower absorption
time of the subcutaneous route may be compensated for by the delay in establishing adequate
intravenous access (47). Intranasal naloxone, dosed at 2 mg, can be used effectively to
reverse opioid overdose in both the prehospital and hospital settings (48,49).
Overdose with opioids that are more potent (such as fentanyl) or longer acting (such as
methadone) may require higher doses of naloxone given over longer periods of time, as by
ongoing naloxone infusion (50). In patients who do not respond to multiple doses of
naloxone, alternative causes of the failure to respond must be considered, including overdose
with substances other than opioids. Of increasing concern are more potent opioids and opioid
combinations, which may be less responsive to naloxone. These include carfentanil and U-
47700 (“gray death,” which includes a dangerous combination of fentanyl, carfentanil, and
heroin) (51,52). Along with the need to monitor patients for continued naloxone
requirements, another important consideration to anticipate in administering naloxone is the
possibility of initiating a significant withdrawal syndrome.

Follow-Up Care
Pharmacological management of acute opioid overdose may be the first step in engaging
patients with opioid use disorders into medical care and addiction treatment once the
overdose event has resolved. In one study of 924 injection drug users in Baltimore, MD, 368
(40%) reported ever having an overdose. Twenty-six percent of the patients with an overdose
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sought drug treatment within 30 days after the event; the most common reason for seeking
treatment was noted to be speaking with someone about treatment options at the time of the
overdose. Multiple “missed opportunities” were noted: 87% of overdose patients treated by
emergency medical services, 74% of overdose patients treated in the emergency room, and
57% of overdose patients hospitalized denied receiving drug treatment information from the
medical staff (53). Despite these and similar findings, clinicians who manage overdose
patients should establish the need for ongoing addiction treatment as the major goal of patient
management while caring for overdose-related complications.

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 For medical personnel, two common questions that arise when patients with opioid
overdose are seen in the emergency department are which patients can be discharged and
when they can be discharged. Clearly, patients with major acute medical or psychiatric
comorbidities, including suicidal ideation, should be hospitalized for further treatment. In the
absence of these issues, resolution of the symptoms of intoxication and establishment of
follow-up referrals for addiction, medical, and psychiatric care are necessary before a patient
can be discharged safely. In a study of 573 emergency department patients, a group of
investigators developed a clinical prediction rule to identify patients with opioid overdose
who could be safely discharged 1 hour after naloxone administration. The authors reported
that patients who can be safely discharged are those who can mobilize as usual, have oxygen
saturation on room air of >92%, have a respiratory rate >10 breaths/min and <20
breaths/min, have a temperature of >35.0°C and <37.5°C, have a heart rate >50 beats/min
and <100 beats/min, and have a Glasgow Coma Scale score of 15. Such patients are at lower
risk of adverse events (54). Models of emergency care that allow for initiation of
pharmacotherapy in the emergency department are more effective at engaging patients in
addiction treatment than brief intervention and referral. In a randomized clinical trial of
emergency department–initiated buprenorphine by D’Onofrio et al., 78% of patients with
opioid use disorder who presented to an urban ED and were started on buprenorphine were
engaged in addiction treatment 30 days after the ED visit, compared with 37% in the referral
group and 45% in the brief intervention group (40).
Recent evidence suggests that naloxone also may have a role in the prevention and
treatment of opioid overdose when used in the community by people who use drugs
themselves. This concept is based on the fact that most people who use illicit opiates have
witnessed overdoses and many have witnessed overdose-related deaths (55). Models of
community-based naloxone for overdose prevention have shown improvement in patient and
bystander recognition of overdose and use of naloxone (55,56). More importantly, overdose
education and naloxone distribution reduces death from heroin overdose (54,57).
Other public health approaches aimed at reducing opioid overdose and overdose
mortality have shown promise in the literature. These include community-based supervised
injecting facilities (58–60) and use of diacetylmorphine (ie, heroin) to treat heroin use
disorder in countries where this therapy is available (61,62).

OPIOID WITHDRAWAL
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The opioid abstinence syndrome is characterized by two phases (63). In the initial phase,
patients with chronic opioid exposure experience acute withdrawal. This is followed by the
more chronic signs of a protracted abstinence syndrome. Current pharmacotherapeutic
strategies are based on this duality.

Acute Withdrawal
In the initial opioid withdrawal phase, the patient typically experiences a range of symptoms,

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 for varying lengths of time (depending on the half-life of the opioid). Such symptoms include
gastrointestinal distress (such as diarrhea and vomiting), thermoregulation disturbances,
insomnia, muscle and joint pain, and marked anxiety and dysphoria. Although these
symptoms generally (unless there is acute medical comorbidity) include no life-threatening
complications (unlike alcohol withdrawal syndrome), the acute withdrawal syndrome causes
marked discomfort, often prompting continuation of opioid use even in the absence of any
opioid-associated euphoria.

Chronic Physiological Dependence and Protracted

Abstinence
In patients with a chronic opioid use disorder presenting with acute withdrawal, medically
supervised withdrawal or induction onto opioid agonist therapy is the first step of treatment.
Himmelsbach (14,63), reporting on 21 prisoners addicted to morphine, observed that
“physical recovery requires not <6 months of total abstinence.” Factors he measured included
temperature, sleep, respiration, weight, basal metabolic rate, blood pressure, and hematocrit.
The times required for return to baseline ranged from 1 week to about 6 months. Martin and
Jasinski (64) reported in a subsequent study that this phase persisted for 6 months or more
after withdrawal and that it was associated with “altered physiological function.” They found
decreased blood pressure, decreased heart rate and body temperature, miosis, and a decreased
sensitivity of the respiratory center to carbon dioxide, beginning about 6 weeks after
withdrawal and persisting for 26 or more weeks. They also found increased sedimentation
rates (which persisted for months) and electroencephalogram changes.
Martin and Jasinski also postulated a relationship between the protracted abstinence
syndrome and relapse. Based on similar observations, Dole (65) concluded that “human
addicts almost always return to use narcotics” after withdrawal in the hospital . In his article,
he reviewed the relative importance of metabolic and conditioned factors in relapse and
concluded that the underlying drive is metabolic, arguing that “psychological factors are only
triggers for relapse.”
The concept of protracted abstinence has been controversial (66), but remains a useful
model for scientific hypothesis testing and development of new therapeutic approaches (67).
Accordingly, Dole recommended methadone maintenance treatment, even though “it does
establish physical dependence.” Because, as Dole pointed out, methadone continues physical
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dependence, protracted abstinence may continue to be a problem whenever withdrawal

management from opioids is undertaken. However, methadone treatment, when prescribed at
appropriate doses, provides a “narcotic blockade,” which blocks the euphoric effect of
exogenous opioids and stabilizes psychosocial functioning (68–71).
In addition to biological considerations, psychosocial concomitants of opioid use disorder
also necessitate longer, more specialized adjunct treatments for these additional problems.

Clinical Picture

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 Withdrawal from opioids results in a specific constellation of symptoms. Although some
opioid withdrawal symptoms overlap withdrawal from sedative–hypnotics, opioid
withdrawal generally is considered less likely to produce severe morbidity or mortality.
Clinical phenomena associated with opioid withdrawal include neurophysiological rebound
in the organ systems on which opioids have their primary actions (13). Thus, the generalized
CNS suppression that occurs with opioid use is replaced by CNS hyperactivity.
The severity of opioid withdrawal syndrome varies with the specific opioid used and the
dose and duration of drug use. In addition, route of administration appears to be important as
well. Data from one study suggests that injection drug use is associated with significantly
higher withdrawal symptom scores than was inhaled opioid use for comparable heroin doses
(72). The time to onset of opioid withdrawal symptoms depends on the half-life of the drug
being used. For example, withdrawal may begin 4 to 6 hours after the last use of heroin, but
up to 36 hours after the last use of methadone.
Neuropharmacological studies of opioid withdrawal have supported the clinical picture
of CNS noradrenergic hyperactivity (73). Therapies to alter the course of opioid withdrawal
(such as clonidine) are designed to decrease this hyperactivity, which occurs primarily at the
locus coeruleus (74,75). Evidence for the role of noradrenergic hyperactivity in opioid
withdrawal has been provided by studies showing elevated norepinephrine metabolite levels
(76).

Diagnosis
The opioid withdrawal syndrome involves a constellation of clinical manifestations. Several
clinical tools are available to measure the severity of opioid withdrawal. One such tool is the
Clinical Opiate Withdrawal Scale (COWS) (Table 53-3) (77). Other validated scales can also
be employed for assessment. These include the 10-item Short Opioid Withdrawal Scale,
which takes less than a minute to administer (78); the 16-item Subjective Opioid Withdrawal
Scale; and the 13-item Objective Opioid Withdrawal Scale (79). Early findings may include
abnormalities in vital signs, including tachycardia and hypertension. Bothersome CNS
system symptoms include restlessness, irritability, and insomnia. Opioid craving also occurs
in proportion to the severity of physiological withdrawal symptoms. Pupillary dilation can be
marked. A variety of cutaneous and mucocutaneous symptoms (including lacrimation,
rhinorrhea, and piloerection—also known as “gooseflesh”) can occur as well. Patients
frequently report yawning and sneezing. Gastrointestinal symptoms, which initially may be
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mild (anorexia), can progress in moderate to severe withdrawal to include nausea, vomiting,
and diarrhea. This combination of uncomfortable symptomatology and intense craving
frequently leads to return to drug use (66).

TABLE 53-3 Clinical Opiate Withdrawal Scale

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 Adapted from “Flowsheet for measuring symptoms during buprenorphine induction.” Available at www.naabt.org.
Accessed November 1, 2007.

As with the onset of the opioid withdrawal syndrome, the duration also varies with the half-
life of the drug used and the duration of drug use. For example, the meperidine abstinence
syndrome may peak within 8 to 12 hours and last only 4 to 5 days (13), whereas heroin
withdrawal symptoms generally peak within 36 to 72 hours and may last for 7 to 14 days
(65).
A protracted abstinence syndrome has been described, in which a variety of symptoms
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may last beyond the typical acute withdrawal period (80). Findings in prolonged and
protracted abstinence may include mild abnormalities in vital signs and continued craving
(81). Despite the extensive literature on protracted withdrawal, a universal definition and
diagnostic criteria are lacking, making diagnosis difficult in individual patients (66).

Management
As in the management of opioid intoxication and overdose, management of opioid

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 withdrawal syndrome involves a combination of general supportive measures and specific
pharmacological therapies. It is very important for the clinician to do a thorough evaluation
to rule out other medical conditions that may be complicating the opioid withdrawal
syndrome. The choice of pharmacotherapy used to treat withdrawal may be influenced by the
presence and severity of a patient’s underlying medical comorbidities (37).
In addition to assessment of general health, it is important to obtain objective information
to help guide the management of patients undergoing opioid withdrawal. Thus, a physical
examination should be performed to detect specific findings consistent with withdrawal to
establish the diagnosis.
General supportive measures for managing withdrawal include providing a safe
environment and adequate nutrition, as well as reassuring patients that their symptoms will
be taken seriously. Additionally, patients with underlying acute or chronic pain need
reassurance that their pain will be assessed and managed. The decision as to whether to
perform medically supervised withdrawal on an outpatient or inpatient basis depends on the
presence of comorbid medical and psychiatric problems, the availability of social supports
(such as family members to provide monitoring and transportation), and the presence of use
of multiple drugs. Access to methods of medically supervised withdrawal also may affect this
decision; for example, methadone withdrawal management has been restricted by federal
legislation to inpatient settings or specialized licensed outpatient drug treatment programs
(82); however, more recent federal initiatives allow some opioid-based treatments to be used
under less restricted circumstances (83,84).
In the course of managing the opioid withdrawal syndrome, clinicians also need to be
able to address medical conditions that commonly occur in people with opioid use disorder
(32,45). Issues such as acute bacterial infections, HIV, and HCV-related consequences may
complicate opioid withdrawal syndrome presentation and management. For instance, some
studies suggest diminished expression of endogenous interferon-α and enhanced HCV viral
replication in patients both using and withdrawing from opioids suggesting that opioid use
and withdrawal favor HCV persistence in hepatocytes (85), whereas other studies suggest
that intravenous drug use increases cytokine response in patients coinfected with HIV and
HCV (86). In addition to recognition and management of comorbid chronic viral infections,
clinicians also need to be aware of underlying acute and chronic pain as this can often
complicate opioid use, opioid craving, and opioid withdrawal. (See section 12 of this
textbook (87).)
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Pharmacological Therapies for Opioid Withdrawal

Several pharmacological therapies are available to treat symptoms of opioid withdrawal
syndrome. These therapies involve the use of opioid agonists (such as methadone), alpha-2
adrenergic agonists (such as clonidine), or an opioid partial agonist (buprenorphine or
buprenorphine/naloxone) (88).

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 Full Opioid Agonists
Slow Withdrawal from Methadone
It is important to distinguish between withdrawal from short-acting opioids such
as heroin (plasma half-life of morphine, the main metabolite: 3 to 4 hours)
and long-acting opioids such as methadone (plasma half-life: 13 to 47 hours).
For short-acting opioids, the natural course of the opioid withdrawal syndrome
generally is relatively brief, but more intense and associated with a higher degree
of discomfort than with equivalent doses of long-acting opioids. However, there
is considerable individual variation, so that strong early opioid withdrawal
symptoms from methadone are possible, as are delayed severe heroin withdrawal
symptoms.
One treatment strategy employing this general principle is to stabilize
patients with physiological dependence on heroin with methadone and then
gradually decrease the methadone dose over months rather than days. Initially,
methadone may be given in 5- to 10- mg increments, p.r.n., as the physical
signs of abstinence begin to appear, up to a total of 30 to 40 mg over the first
24 hours. In the ambulatory setting, this treatment strategy can only be employed
by facilities licensed to prescribe methadone for the treatment of opioid use
disorder (89). In the acute hospital setting, methadone can be used to treat opioid
withdrawal without federal restriction. Ideally, patients are then transitioned to
outpatient methadone treatment at discharge.
The protocol for slow withdrawal from methadone is similar to the strategy
used for withdrawal from methadone maintenance treatment. After a
stabilizing dose has been reached, methadone can be tapered by 20% a day for
inpatients, leading to a 1- to 2-week procedure. Alternatively, the dose is tapered
by 5% per day for outpatients, in a gradual cessation phase lasting as long as 6
months (90). Senay et al. (91) studied the effects of rapid (reductions of 10% of
initial dose per week) and gradual (3% per week) outpatient cessation under
double-blind conditions. They found that the 10% weekly decrements were
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associated with higher dropout rates, increased illicit opioid use, and elevated
levels of subjective distress. The authors recommended a dose-tapering rate of
about 3% per week from methadone maintenance. On such a regimen,
successful withdrawal can be achieved by as many as 80% of inpatients and
40% of outpatients, as measured by completion of withdrawal and a withdrawal-
free naloxone challenge test. The longer duration of the procedure and the greater
discomfort make outpatient withdrawal management with methadone especially
vulnerable to patient dropout and continuing illicit opioid use. One study showed
that even when coupled with enhanced psychosocial counseling, patients
enrolled in 6-month methadone withdrawal management programs demonstrated
greater illicit opioid use and greater drug-related HIV risk behaviors than
patients enrolled in methadone maintenance
(92); therefore, methadone withdrawal should only be employed in carefully
selected patients.