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DOI: 10.1176/appi.books.9781585623440.351256
Textbook of Substance Abuse Treatment >
Chapter 19. Detoxification of Opioids
DETOXIFICATION OF OPIOIDS: INTRODUCTION
Thirty-five years ago the senior author of this chapter wrote an article on the history of opioid
withdrawal approaches. The introduction remains true today.
The history of the treatment of narcotic withdrawal is a long and mainly dishonorable one. The trail is
strewn with cures enthusiastically received and then quietly dropped when they turned out to be
relatively ineffective or, even worse, productive of greater morbidity and mortality. Because of this
history, one must be especially careful in proposing new techniques that they meet the twin demands of
safety and efficacy. Any claims for a new method should be put forward with modesty and viewed with
skepticism until amply documented by careful experimental procedures. (Kleber and Riordan 1982, p.
30)
Opioid detoxification continues to be used for most heroin abusers as a pretreatment procedure
before residential therapeutic community treatment, outpatient drug-free treatments, and opioid
antagonist maintenance treatment. It is also used by some who do not seek long-term treatment
either because they expect that they can remain abstinent from opioids without additional help or
because they do not seriously intend to remain abstinent. Although therapeutic community and
antagonist maintenance treatments are effective for many patients, the prerequisite detoxification
and associated withdrawal discomfort can be a barrier to entering such treatment for many
patients.
Despite improvements over the past 30 years, most current approaches to detoxification continue
to be plagued by high dropout rates and high relapse rates. Because most opioid-dependent
individuals have unsuccessfully tried to stop on their own, they often fear the physical discomfort
of opioid withdrawal and delay or avoid seeking help for it. Others attempt detoxification with
medical assistance but frequently do not complete it because they are just trying to lower the cost
of their habit. Finally, even those who successfully complete detoxification have a high relapse
rate. These problems have given rise to techniques such as the “ultrarapid” or anesthesia-assisted
detoxification and antagonist induction procedures, which are offered at high cost without evidence
of improved patient outcomes, despite increased risk. Although many opioid-dependent patients
may do better on agonist maintenance (e.g., methadone, buprenorphine), for those who either do
not want such treatment or cannot do well on it, there remain drug-free or antagonist maintenance
approaches. For such individuals, detoxification is a necessary part of entering treatment, but it has
not yet achieved its full potential for the transition. The advent of buprenorphine and better
adrenergic agonists for opioid detoxification may improve this transition and enable more patients
both to enter such treatment and to achieve sustained abstinence from opioids.
DEPENDENCE, TOLERANCE, AND DETOXIFICATION
Physical dependence refers to the physiological state that follows chronic, regular use of a
substance. It is clinically evidenced by the emergence of a characteristic withdrawal syndrome (for
that drug or class of drugs) following a significant reduction in the amount of the drug regularly
ingested. The withdrawal syndrome can be understood to be the physiological manifestation of
nervous system changes that are unmasked when the drug is no longer present. Tolerance almost
always accompanies physical dependence.
Tolerance describes the phenomenon by which a drug’s effectiveness diminishes over time with
regular use of the drug. This is seen either when the effects of a fixed amount of drug lessen or
when an individual needs greater amounts of the drug to produce the same effects initiallyPrint: Chapter 19. Detoxification of Opioids http://www.psychiatryonline.com/popup.aspx?aID=351260&print=yes…
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produced by smaller amounts. Tolerance typically occurs by reduced end organ response to the
drug (pharmacodynamic tolerance) or by increased metabolism of the drug (pharmacokinetic
tolerance), although other physiological mechanisms may uncommonly play a role.
Addiction is a less precise term, sometimes used synonymously with the DSM-IV-TR (American
Psychiatric Association 2000) diagnosis of substance dependence and used to describe compulsive
use of a drug and overwhelming involvement with its procurement and use. Tolerance, physical
dependence, and withdrawal may be present in the absence of addiction or a DSM-IV-TR diagnosis
of dependence. Substance dependence was used instead of addiction to avoid the stigma associated
with the latter term, but this can be confusing because individuals receiving chronic opioid
analgesia may become “dependent” on the drug but not meet criteria for substance dependence.
DSM-V may remedy this by returning to the term addiction.
Detoxification refers to the process of taking an individual off of a drug on which he or she has
become physically dependent. The detoxification may be done abruptly or gradually (Kleber 1981).
A variety of medication options are available for use in opioid detoxification: 1) the drug on which
the individual is dependent, 2) other drugs that produce cross-tolerance, 3) medications to provide
symptomatic relief, and 4) drugs that affect the mechanisms by which withdrawal is expressed.
Settings for detoxification can include inpatient, residential, day, or outpatient programs.
Given the current armamentarium of medications, opioid detoxification can be accomplished safely,
relatively quickly, and with a minimum of discomfort. Unfortunately, the method chosen often
depends more on what is available than on what is ideal. This is a consequence of many factors:
physician or patient preference or bias, the availability of physicians trained in detoxification
methods, federal and state regulations, insurance or other funding mechanisms, and the methods
available in a given setting in a particular geographical area. Some clinicians prefer the term
withdrawal to detoxification because of the latter’s connotation of opioids as toxic.
GOALS OF DETOXIFICATION
The goals of the detoxification process are as follows:
- To rid the body of the acute physiological dependence associated with chronic daily opioid use
- To diminish, or ideally to eliminate, the pain and discomfort of opioid withdrawal
To provide a safe and humane treatment that assists the individual in remaining abstinent during the
acute phase of withdrawal
To provide an environment that increases the likelihood of continued treatment and to refer to such
treatment centers
To identify any medical problems and to treat them or make referrals for additional care following
detoxification
To begin educating the patient about issues related to health and relapse prevention and to begin
exploring issues related to family, vocational, and legal problems that may need referral
WHEN IS DETOXIFICATION SUCCESSFUL?
Because relatively few opioid-dependent individuals can sustain abstinence from opioids without
additional help immediately after detoxification, detoxification should be viewed as the first stage
of treatment. It is unrealistic to expect detoxification alone to produce the more ambitious goals of
long-term treatment, including improvements in employment, criminal behavior, interpersonal
relationships, and general physical and psychological well-being. Success is a function not only of
safety and comfort but also of treatment retention and participation in longer-term treatment. This
does not mean that detoxification is necessarily a failure if the person does not agree to long-term
treatment. Younger patients may see no need for longer-term treatment, but when they return a
second or third time, they are frequently more realistic and more willing to consider longer-term
treatment. Because of the relapsing nature of opioid dependence, formal detoxification may be
required many times over the course of the disorder.
SETTING CHOICEPrint: Chapter 19. Detoxification of Opioids http://www.psychiatryonline.com/popup.aspx?aID=351260&print=yes…
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Detoxification can take place in an outpatient, inpatient, or partial hospitalization setting.
Outpatient treatment is the least expensive setting and may enable the patient to continue working
or carrying on his or her life. It has the potential advantage of forcing a person to confront the
home environment, with its usual drug cues, and immediately find alternatives to use in response
to these cues. The disadvantages of outpatient detoxification include immediate access to drugs
when drug craving may be extremely high, more difficulty assessing and dealing with other medical
conditions, the possible need for detoxification to proceed more slowly, and its low success rate.
During inpatient detoxification, access to drugs or to craving-inducing stimuli can be minimized, the
patient can be observed more closely for medical problems or complications, and the withdrawal
can be more rapid. If the program is comprehensive, more attention can be focused on other
aspects of the patient’s life in the family, vocational, medical, and psychiatric arenas. The
disadvantages are primarily the cost and the disruption in the patient’s life caused by the need to
be away from work and home.
Partial hospitalization programs are considerably less expensive than inpatient programs, while
retaining some of the inpatient advantages; nevertheless, they are not widely available. The
clinician is usually forced to choose between inpatient and outpatient settings, and the choices are
often limited by factors such as insurance coverage and the availability of programs. As a result of
managed care restrictions, inpatient detoxification has become primarily for those patients who are
homeless, have serious medical or psychiatric problems, or have repeatedly failed outpatient
detoxification. Although inpatient detoxification has a much higher completion rate (up to 80%)
compared with outpatient programs (as low as 17%; Gossop et al. 1986), its long-term advantages
related to relapse are less definite. Some patients need inpatient detoxification to achieve initial
abstinence. Work is still needed in accurately identifying which patients require inpatient treatment
and which would do well with an outpatient approach.
HISTORICAL OVERVIEW
In the past century, many treatments have been introduced for relieving the symptoms of opioid
withdrawal. Many of these treatments have proven either more addicting than the drug being
withdrawn or more dangerous than untreated withdrawal. In a masterful review, Kolb and
Himmelsbach (1938) looked back on 40 years of mostly futile attempts to treat narcotic
withdrawal, including the use of autohemotherapy (injection of blood previously withdrawn from
the patient), water balance therapy, and numerous toxic chemicals, alone or in combination. Kleber
and Riordan (1982) reviewed the earlier work by these writers and updated it with the techniques
that had been used in the 40 years since that article was published. Since that 1982 review, the
most common approach—methadone substitution and gradual withdrawal—has declined in
popularity, and the newer approaches described in this chapter have gained favor but may yet be
discarded if they are found wanting.
CLINICAL CHARACTERISTICS OF THE OPIOID ( AGONIST) WITHDRAWAL
SYNDROME
Naturally occurring opiates such as opium, morphine, and codeine; derivatives such as heroin,
hydromorphone, and dihydrocodeine; and synthetics such as methadone, meperidine, and fentanyl
are capable of creating physical dependence and may require detoxification if they have been taken
in sufficient quantities over time. In general, clinically significant withdrawal syndromes do not
develop after less than 2 weeks of daily opiate use (Jaffe and Martin 1975), but individuals
previously dependent on opioids may redevelop physical dependence much more quickly.
Factors Influencing Symptom Severity
The nature and severity of withdrawal symptoms when opioid-type drugs are halted relate to a
variety of factors:
Specific drug used. Rapidly metabolized drugs such as heroin are generally associated with more
severe but shorter-lived withdrawal phenomena, whereas drugs that dissociate slowly from the opioid
receptor, such as buprenorphine, or that are slowly excreted from the body, such as methadone, havePrint: Chapter 19. Detoxification of Opioids http://www.psychiatryonline.com/popup.aspx?aID=351260&print=yes…
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a slower onset with a less intense but more protracted withdrawal syndrome. In general, the longer the
duration of drug action, the less intense but longer lasting the withdrawal symptoms.
Total daily amount used. In general, the more opioids ingested daily, the more severe the withdrawal
syndrome. However, some researchers have suggested that dosage does not correlate well with
severity of withdrawal symptoms (Gossop et al. 1987).
Duration and regularity of use. Although some withdrawal can be seen when a single dose of morphine
is followed a few hours later by a narcotic antagonist (Heishman et al. 1989), clinically significant
withdrawal usually requires daily use of an adequate amount of the opioid for at least 2–3 weeks (Jaffe
and Martin 1975). In contrast, duration of use much beyond 2–3 months does not appear to be
associated with any greater severity. A good rule of thumb regarding the regularity of use and its
association with symptom severity is that the more intermittent the drug use, the less severe the
withdrawal.
Psychological and individual factors. In general, the greater the patient’s expectation that his or her
suffering would be relieved by an available medication, the more severe the reported withdrawal
symptoms. Thus, if an individual expects little symptom relief, there seems to be a diminution in the
withdrawal intensity reported. Anticipatory anxiety appears to increase withdrawal severity (Phillips et
- 1986). The patient’s personality and state of mind can also influence withdrawal severity, as can his
or her general physical health and ability to handle stress. Finally, some individuals appear to be far
more sensitive to opioid withdrawal symptoms than others.
Signs and Symptoms of Opioid Withdrawal
The agonist withdrawal syndrome can be conceptualized as rebound hyperactivity in the
biological systems suppressed by the agonists. (For a more detailed description of the
neurochemical mechanisms involved, see Chapter 18 of this volume, “Neurobiology of Opioids.”)
Withdrawal phenomena are generally the opposite of the acute agonistic effects of the opioid (e.g.,
acute opioids cause constipation and pupillary constriction, whereas withdrawal is associated with
diarrhea and pupillary dilatation). The clinical characteristics of opioid withdrawal may be
described in several ways. Some authors separate objective signs from subjective symptoms,
whereas others separate signs and symptoms into grades on the basis of severity. No single
classification is totally satisfactory.
Subjective symptoms, even under controlled conditions, are often more distressing than objective
signs. It also has been shown that opioid-dependent patients may experience major withdrawal
symptoms with minimal or no objective signs to confirm this discomfort. Table 19–1 lists the most
common signs and symptoms, which are divided into two categories based on their approximate
order of appearance.
TABLE 19–1. Signs and symptoms of opioid withdrawal
Early to moderate Moderate to advanced
Anorexia
Anxiety
Craving
Dysphoria
Fatigue
Headache
Increased respiratory rate
Irritability
Lacrimation
Mydriasis (mild)
Perspiration
Piloerection (gooseflesh)
Restlessness
Rhinorrhea
Abdominal cramps
Broken sleep
Hot or cold flashes
Increased blood pressure
Increased pulse
Low-grade fever
Muscle and bone pain
Muscle spasm (hence the term kicking the habit)
Mydriasis (with dilated fixed pupils at the peak)
Nausea and vomitingPrint: Chapter 19. Detoxification of Opioids http://www.psychiatryonline.com/popup.aspx?aID=351260&print=yes…
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Early to moderate Moderate to advanced
Yawning
When a short-acting opioid such as heroin has been taken chronically, the onset of withdrawal
begins with anxiety and craving about 8–12 hours after the last dose (see Table 19–2). This
progresses to dysphoria, yawning, lacrimation, rhinorrhea, perspiration, restlessness, and broken
sleep. Later, there are waves of gooseflesh, hot and cold flashes, aching of bones and muscles,
nausea, vomiting, diarrhea, abdominal cramps, weight loss, and low-grade fever. An untreated
individual in opioid withdrawal may lie in a fetal position (to ease abdominal cramping) and request
blankets, even on warm days (because of the hot and cold flashes). The individual’s skin may be
exquisitely sensitive to the touch. The heroin withdrawal syndrome typically reaches its peak
between 36 and 72 hours after the last dose, and the acute symptoms subside substantially within
5 days. With methadone withdrawal, in contrast, the peak occurs between days 4 and 6, and
symptoms do not substantially subside for 14–21 days (Kleber 1996). With a more short-acting
opioid, such as meperidine, craving may be intense, but the autonomic signs, such as pupillary
dilatation, are not particularly prominent. Usually, little nausea, vomiting, or diarrhea occurs, but at
peak intensity, the muscle twitching, restlessness, and nervousness may be worse than during
morphine withdrawal (Jaffe and Martin 1975). Regardless of which opioid is used, the acute
symptoms are followed by a more protracted abstinence syndrome, with subtle disturbances of
mood and sleep that can persist for 6–8 months (Martin and Jasinski 1969). An addicted individual
may not feel normal for months after the last drug use. Fatigue, dysphoria, irritability, and
insomnia may all increase the likelihood of relapse. Protracted abstinence may involve both
conditioning and physiological factors (Satel et al. 1993).
TABLE 19–2. Duration of effects and first appearance of withdrawal
Drug Effects wear
off (hoursa )
Appearance of nonpurposive
withdrawal symptoms
(hours)
Peak withdrawal
effects (hours)
Majority of
symptoms over
Fentanylb
1
3–5c
8–12 4–5 days
Meperidine 2–3 4–6 8–12 4–5 days
Oxycodoned
3–6 8–12 36–72 Approximately
7–10 days
Hydromorphone 4–5 4–5 36–72 Approximately
7–10 days
Heroin
4 e
8–12 36–72 7–10 days
Morphine 4–5 8–12 36–72 7–10 days
Codeine 4 8–12 36–72 Approximately
7–10 days
Hydrocodone 4–8 8–12 36–72 Approximately
7–10 days
Methadone 8–12 36–72 96–144 14–21 days
aDuration may vary with chronic dosing.
b Intravenous formulation described.
cBecause of continued skin absorption after the patch is removed, withdrawal symptoms can take 16–24
hours to occur with use of transdermal fentanyl.
dThe long-acting oral form may last up to 12 hours unless crushed, at which time it reverts back to being
short-acting.
eUsually taken two to four times per day.
EVALUATION AND DIAGNOSISPrint: Chapter 19. Detoxification of Opioids http://www.psychiatryonline.com/popup.aspx?aID=351260&print=yes…
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When the clinician first sees a patient, the patient should be evaluated to determine whether
detoxification is needed. Once this is determined, a more complete assessment is necessary to
devise an individual treatment plan. Thus, information needs to be gathered on a wider range of
areas, including psychological, psychosocial, and physical status.
The Interview
While gathering information in the interview, especially the drug history, a nonjudgmental attitude
on the part of the interviewer is more likely to elicit accurate data. Disdainful behavior may
produce false information and even drive the patient away.
Drug history
A review of current and past drug and alcohol use and abuse is necessary for adequate patient
assessment. The following information should be obtained for each current substance or group of
substances, with special emphasis on substance use during the past week:
Name of drug used, length of time used, frequency of use
Date or time of last use
Route of administration
Amount
Cost
Purpose (e.g., to get high, to relieve depression or boredom, to sleep, for energy, to relieve side
effects of other drugs, to avoid withdrawal)
For drugs previously used: name, age at which drug use started, length of time used, adverse effects
Previous treatment experiences: where, what kind, outcome
Prescription drugs currently used: name, reason for use, amount, frequency, duration of use, and last
dose
Other medical history
The medical history includes serious illnesses, chronic diseases, accidents, and hospitalizations. In
addition to the usual medical history, special attention should be given to the possible medical
complications of drug abuse. The medical history also includes the existence of current symptoms
in the various body systems. It is important to look for illnesses that may complicate withdrawal
and those that previously may have been ignored or missed because of the patient’s chaotic
lifestyle.
Medical conditions that can complicate withdrawal include many cardiovascular diseases, diabetes
mellitus, and others. The physiological stress induced by withdrawal may make the management of
these diseases more difficult. Patients with a history of cardiovascular disease or at significant risk
should have withdrawal signs of tachycardia and hypertension closely monitored and managed.
Glycemic control in diabetic patients may be markedly affected by the decreased oral intake,
vomiting, and diarrhea seen during detoxification. A comprehensive medical history will assist in
determining the method and setting most appropriate for detoxification.
Social functioning
Information with regard to social functioning should be gathered on the following topics: 1) living
arrangements (e.g., alone, with family); 2) marital status; 3) sexual orientation and functioning; 4)
employment and/or educational status; 5) family members’ (e.g., parents, siblings, spouse, other
key members) occupations, education, psychological state, and history of drug or alcohol problems;
6) friends (in particular, are there non-drug-using ones?); 7) recreational and leisure-time
activities; and 8) current and past legal status. The Addiction Severity Index is a useful instrument
for gathering this information (McLellan et al. 1985).
The interviewer should try to get a feel for the emotional and factual aspects of the interview
topics. For example: What is the patient’s attitude toward his or her job, and what type of job is it?
What is the quality of the patient’s marital or family relationships? How does the patient cope withPrint: Chapter 19. Detoxification of Opioids http://www.psychiatryonline.com/popup.aspx?aID=351260&print=yes…
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spare time at nights and on weekends when relapse is most likely to occur? Such questions can
identify the patient’s social supports and aid in planning for postdetoxification treatment. Prior
attempts at withdrawal and factors associated with relapse should be especially explored.
Psychological status
When carried out by a nonpsychiatrist physician, psychological evaluation may single out patients
who need early psychiatric referral for possible psychosis, delirium, psychiatric syndromes
secondary to medical conditions, serious depression, suicide, or tendency for violence. The
psychiatrist, in addition to exploring factors that could complicate withdrawal, should evaluate for
the presence of less obvious comorbid psychiatric syndromes. When possible, the evaluator should
ascertain whether psychiatric conditions preceded or followed the drug abuse. Some patients take
drugs to self-medicate dysphoric states of loneliness, depression, or anxiety or to control
unacceptable, usually aggressive, impulses. Conversely, continued use of certain drugs may lead to
or exacerbate psychiatric states not previously evident. Opioids seem to have antipsychotic effects
in some patients, and withdrawal can lead to an exacerbation or sudden appearance of psychotic
symptoms.
As part of the psychological state evaluation, a mental status examination should be carried out
and include orientation for place, person, and date; presence or absence of hallucinations,
delusions, or suicidal ideation; memory; intelligence, mood, and affect; thought processes;
preoccupations and behavior during the interview; judgment; and insight.
Physical Examination
Although there is no special physical examination for opioid-dependent individuals, certain
conditions could be either direct or indirect sequelae of drug abuse. Although some of these
findings appear in nondependent individuals and some dependent individuals may have few or none
of them, their presence aids proper diagnosis.
Cutaneous signs
The following cutaneous signs may be directly or indirectly associated with drug abuse:
Needle puncture marks. Needle marks are usually found over veins, especially in the antecubital area,
back of the hands, and forearms, but can be found anywhere on the body where a vein is reachable,
including the neck, tongue, dorsal vein of the penis, and between the toes.
“Tracks.” Tracks, or track marks, are one of the most common and readily recognizable signs of chronic
injection drug abuse. They are usually hyperpigmented linear scars located along veins. They result
both from frequent unsterile injections and from the deposit of carbon following needle sterilization
performed with a match or other sooty heating procedure. Tracks tend to lighten over time but may
never totally disappear.
Tattoos. Addicted individuals may try to hide tracks with tattoos over the area.
Hand edema. When addicted individuals run out of antecubital and forearm veins, they often turn to
veins in the fingers and back of the hands, which can lead to hand edema. Such edema can persist for
months.
Thrombophlebitis. Thrombophlebitis (blockage or inflammation of veins) may be found on the limbs of
injection drug users because their injections are often unsterile and because irritation is produced by
adulterants.
Arm or leg edema. Edema of an extremity can be a sign of vein thrombosis. Intravenous drug use can
increase a person’s risk of thrombosis because of thrombophlebitis or the trauma inflicted on veins by
repeated injections.
Abscesses and ulcers. Abscesses and ulcers are particularly common among individuals who are
intravenous drug users, because of the irritating quality of many chemicals. When secondary to heroin
injection, they are more likely to be septic and in the vicinity of veins.
Ulceration or perforation of the nasal septum. Frequent snorting of heroin can lead to ulceration of the
septum, whereas similar chronic use of cocaine can cause septal perforation secondary to
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Cigarette burns or scars from old burns. Cigarette burns or scars can result from drug-induced
drowsiness. It has been estimated that more than 90% of drug- and alcohol-dependent individuals
smoke tobacco.
Piloerection. Piloerection, a sign of opioid withdrawal, is usually found on the arms and trunk due to
spasm of the muscles around the hair follicle. Truncal piloerection is unusual in the absence of opioid
withdrawal.
Cheilosis. Cheilosis (cracking of skin at the corners of the mouth) is especially seen in chronic
amphetamine-using individuals and in opioid-addicted individuals prior to or during detoxification.
Contact dermatitis. In solvent-abusing individuals, contact dermatitis is seen around the nose, mouth,
and hands and is sometimes called glue-sniffer’s rash. In other abusers, it may occur around areas of
injection secondary to use of chemicals to cleanse the skin.
Jaundice. Jaundice due to hepatitis is usually from use of unsterilized shared needles and syringes.
Hepatitis C infection among injection drug users in New York City has been reported to be between
80% and 90%.
Monilial infection. Monilial infection, typically oral thrush, is a common finding in individuals with AIDS.
Additional signs and symptoms
Fever. Although uncommon, a temperature of 100.4°F or greater can be seen during uncomplicated
withdrawal. However, substance abuse patients are at elevated risk for various other causes of fever,
including infectious diseases. Therefore, etiologies causing fever other than withdrawal should always
be considered.
Constipation. Constipation is a common side effect of opioid use, caused by the drugs’ effects on
receptors in the brain, spinal cord, and enteric nervous systems.
Bronchospasm. Bronchospasm can be induced directly from opioids’ effect on histamine release.
Seizure. Seizures are not part of the withdrawal syndrome but can develop from the accumulation of
tramadol or a proconvulsant metabolite of meperidine.
Laboratory tests
The following laboratory tests should usually be performed:
Urine screening for drugs, including barbiturates, opioids, amphetamines, cocaine, benzodiazepines,
phencyclidine, and marijuana. The prescription opioids oxycodone, hydrocodone, fentanyl, and
buprenorphine require special dipsticks to be detected.
Complete blood count and differential; leukocytosis is common, and white blood cell counts greater
than 14,000/mm3 are not unusual.
Urinalysis
Blood chemistry profile (e.g., sequential multiple analysis 20 with serum amylase and magnesium)
Syphilis serology
HIV test (permission from the patient is necessary in many states)
Hepatitis antigen and antibody test
Chest X ray
Electrocardiogram in patients older than age 40 years
Pregnancy test in women (hold chest X ray until test is complete)
Tuberculin skin test (purified protein derivative)
Any other necessary test suggested by the history or physical examination
OPIOID AGONIST SUBSTITUTION AND TAPER
Because of cross-tolerance and cross-dependence among all opioids, one could, in theory, use
almost any opioid to prevent withdrawal and gradually detoxify opioid-dependent individuals. Two
opioids, however, deserve special attention for this purpose: methadone and buprenorphine.
Methadone
Until the approval of buprenorphine in 2002 for opioid detoxification and maintenance, the most
common detoxification method was methadone substitution and taper, although the methodPrint: Chapter 19. Detoxification of Opioids http://www.psychiatryonline.com/popup.aspx?aID=351260&print=yes…
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declined in popularity even before buprenorphine became widely available. Methadone has several
advantages over most other agents for detoxification:
It is orally effective, which eliminates the need for continued injection drug use.
Longer-acting opioids produce withdrawal syndromes that are milder but longer lasting and need to be
given less often, thus producing smoother withdrawal. However, at lower dosages methadone may
need to be given two times a day or more.
It is safe, provided that appropriate care is taken with initial dosing.
In general, a more addictive drug should not be used to detoxify a patient from a less addictive
one. In practice, this means that although methadone can be used to withdraw patients from
narcotics such as heroin, morphine, hydromorphone, oxycodone, or meperidine, it should be
avoided for drugs such as propoxyphene or pentazocine, for which the withdrawal should be
handled by gradually decreasing the dosage of the agent itself or by an agent such as clonidine.
Buprenorphine, given sublingually, will probably become the opioid of choice for withdrawal from
most opioids.
U.S. Food and Drug Administration (FDA) guidelines for narcotic detoxification describe two types
of detoxification: short-term and long-term. Short-term detoxification is for a period not more than
30 days; long-term detoxification is for a period not more than 180 days. Short-term detoxification
is most likely to occur with individuals currently dependent on opioids other than methadone.
Long-term detoxification is used for individuals already taking methadone and wishing to stop it,
although in some programs, individuals are taken directly from heroin to long-term detoxification
with methadone over a 6-month period. Prolonged detoxification avoids some of the withdrawal
symptoms that occur in more rapid detoxification and provides a setting in which psychosocial
rehabilitation can take place. However, the long-term effectiveness of this option, as opposed to
shorter-term detoxification or methadone maintenance, has not been shown.
Initiation of detoxification
If the patient has been taking opioids for medical purposes, and the physician is reasonably sure
about the amount being ingested, Table 19–3 can be used to convert the narcotic dosage into a
methadone dosage. With illicit drug use, the picture is very different. Knowledge of the exact
dosage is usually not available. The amount of narcotics in illegal “bags” can vary from dealer to
dealer, city to city, and even day to day. The physician must thus guess at the initial methadone
dosage. Given that the purity of heroin on the street has ranged from 50% to 80% in recent years,
the choice of an initial dosage is very important. It needs to be high enough to suppress withdrawal
symptoms so that the patient does not leave the program but low enough so that if the patient’s
habit were lower than presumed, the dosage would not be health- or life-threatening. Because 40
mg of methadone can be a fatal dose in some nontolerant individuals, the initial dose should be less
than 40 mg. One common approach to ensuring safety is to start with an oral dose of 10–20 mg,
large enough to control many heroin habits yet small enough to be safe for virtually everyone. If a
patient cannot initially tolerate oral methadone, then 5–10 mg or 50% of the planned oral dose can
be given as an intramuscular injection. The patient should be kept under observation to assess the
effect of the initial methadone dose. If withdrawal symptoms are initially present, the dose should
suppress them within 30–60 minutes; if withdrawal symptoms persist an hour after dosing, an
additional 5–10 mg of methadone can be given. When withdrawal symptoms are not initially
present, the patient should be observed for drowsiness or depressed respiration an hour after
dosing. When 10–20 mg is given as the initial dose, a similar amount may be given 12 hours later if
necessary. This split-dosing approach is usually not practical in outpatient detoxification but can be
used in inpatient settings. Unless evidence of narcotic use in excess of 40 mg of methadone
equivalent per day is documented, the initial dose should not exceed 30 mg, and the total 24-hour
dose should not exceed 40 mg the first few days. A safe initial dose in a nontolerant individual can
become dangerous if continued beyond 1 or 2 days, because of rising blood levels of methadone. A
dangerous dose manifests itself in drowsiness and/or signs of motor impairment, as well as miosis,
nausea, and possible mild hypothermia.Print: Chapter 19. Detoxification of Opioids http://www.psychiatryonline.com/popup.aspx?aID=351260&print=yes…
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TABLE 19–3. Drug relationships for withdrawal
Methadone, 1 mg, is equivalent to
Codeine, 30 mg
Dromoran, 1 mg
Fentanyl, 0.01 mg
Heroin, 1–2 mg
Hydrocodone, 0.5 mg
Hydromorphone, 0.5 mg
Laudanum (opium tincture), 3 mL
Levorphanol, 0.5 mg
Meperidine, 20 mg
Morphine, 3–4 mg
Oxycodone, 1.5 mg
Paregoric, 7–8 mL
Some clinicians disagree as to whether to start the withdrawal regimen in the absence of
withdrawal signs and symptoms. It is sometimes difficult to know with certainty that an individual
is currently physically dependent unless the clinician has observed the signs and symptoms of
opioid withdrawal. The history of drug taking may be unreliable, as a result of overreporting drug
use to increase the dose of prescribed opioid or underreporting to conceal a habit (more common
among addicted health care professionals). The drug history may be misleading even when the
patient is trying to be honest, because of the variable nature of illicitly obtained drugs. Physical
signs such as tracks tell of past drug use, not necessarily current use. Fresh needle marks may
provide little information about the frequency, nature, and amount of what was injected. Urinalyses
positive for drugs suggest recent use but do not establish the need for detoxification. Heroin,
detected as morphine in the urine, can be found up to approximately 48 hours after the last use
among infrequent users.
Definitive evidence of physical dependence can be collected in two ways: 1) by waiting until the
patient develops withdrawal signs and symptoms or 2) by producing withdrawal through
administration of naloxone. Parenteral naloxone can distinguish opioid-dependent from
nondependent individuals through the severity of withdrawal related to the naloxone dose. A
common method is to inject 0.2 mg of naloxone subcutaneously, followed by 0.4 mg 30 minutes
later if the results from the smaller dose are inconclusive. Some physicians recommend an initial
dose of 0.6–0.8 mg to speed up the process and rule out false negative results. Because of the
possibility of fetal injury or induced miscarriage, the naloxone test should not be done if the patient
is pregnant.
Whether the program is inpatient or outpatient, the availability of trained medical personnel will
often determine how the program will establish the need for medical detoxification. If, as is
commonly the case, the program uses the combined evidence of the medical history, physical
examination, and urine toxicology screening, it should still be prepared to wait for withdrawal signs
or administer a naloxone challenge test in borderline or doubtful situations. Once the need for
medical detoxification has been established, decisions still have to be made regarding the setting,
the specific method of detoxification, and the need for concurrent treatment of comorbid physical
or emotional problems. When serious physical or emotional problems are present, it is not
uncommon to delay the opioid taper by temporarily maintaining the individual on methadone,
attending to the acute problem, and then beginning the methadone taper once some stability has
been achieved in the other areas.
Length of withdrawalPrint: Chapter 19. Detoxification of Opioids http://www.psychiatryonline.com/popup.aspx?aID=351260&print=yes…
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The total methadone dosage necessary to stabilize a patient for the first 24 hours should be
repeated on day 2, either in one dose for outpatients or in divided doses for inpatients. Dosage
adjustments can then be made if the patient is sedated or remains in some withdrawal. Revision to
a higher dosage should preferably be made on the basis of objective signs of opioid withdrawal
rather than on subjective complaints alone. This is not always easy because certain signs, including
pupillary dilatation, may be modified by the methadone, even when the patient is undermedicated.
After the patient is stabilized, the dosage can then be gradually reduced. Two common approaches
are either to decrease the methadone dosage by 5 mg/day until zero dosage is reached or to
decrease it by 10 mg/day until a dosage of 10 mg/day is reached and then decrease it more slowly
(e.g., by 2 mg/day). For individuals who have large initial habits, the first method may be better,
whereas in those with a starting dosage of less than 50 mg/day of methadone, the latter approach
leads to more rapid passing of the withdrawal syndrome without any significant increase in
withdrawal severity or dropout rate (Strang and Gossop 1990).
Inpatient methadone substitution and taper is usually accomplished in 5–7 days, whereas
outpatient detoxification is often extended to minimize withdrawal symptoms and to decrease the
likelihood of dropout and relapse. Some inpatient programs complete the process in as few as 4
days, whereas some outpatient programs last for months. Symptoms of insomnia, fatigue, and
irritability or anxiety may linger for weeks or months. The acute phase of opioid withdrawal may be
considered complete and the patient discharged from the detoxification program when no objective
signs of opioid withdrawal occur for 48 hours in the absence of any opioid.
Withdrawal from methadone maintenance
For a patient withdrawing from methadone maintenance, the detoxification approach used tends to
be a function of the reasons for terminating methadone maintenance treatment. Patients in good
standing who desire to become drug free should be tapered off methadone slowly over a 3- to
6-month period. The most difficult period for patients usually occurs at methadone dosages less
than 25 mg/day because at these lower dosages, withdrawal symptoms may emerge sooner than
24 hours after a dose. Split doses, typically given two times a day, may help counter this problem;
however, they are not always possible or practical. The dosage of methadone is usually reduced by
5–10 mg/week until it reaches 25 mg/day. At that point, a reduction of no more than 5 mg/week is
often recommended. If the patient needs to be withdrawn more rapidly because he or she is being
discharged in bad standing, must leave the geographical area, or may be going to prison, then
withdrawal usually takes place during a 10- to 30-day period. For example, the patient dosage may
be decreased by 10 mg/day until a total dosage of 40 mg/day is reached, and then it is decreased
by 5 mg/day until the dosage of 5 mg/day is reached, at which point that dosage is given for 2–3
days. If the patient is on an inpatient or residential unit, divided doses are helpful, especially when
the total dosage is less than 25 mg/day.
Other drugs and supportive measures
Even with gradual withdrawal, some withdrawal symptoms usually emerge, and certain mild
symptoms may persist for many days after treatment has been completed. There is no consensus
on the use of other drugs during these periods. Tranquilizers or bedtime sedation can help allay the
patient’s anxiety and minimize the craving for opioids, but nonopioid medications are, at best, only
partially effective in relieving the specific symptoms of opioid abstinence, with the exception of 2
adrenergic agonists (e.g., clonidine or lofexidine; see the section “Other Detoxification Agents and
Methods” later in this chapter). If insomnia and other withdrawal symptoms are unusually severe,
especially in older patients, an incremental increase in the next dose of methadone and, therefore,
a slower withdrawal schedule can provide relief.
Insomnia not only is one of the more debilitating withdrawal symptoms but also diminishes a
patient’s ability to cope with other withdrawal symptoms. Barbiturates should generally not be
used to treat insomnia because of their abuse liability and low therapeutic index. Sedating
medications, including flurazepam, clonazepam, oxazepam, zolpidem, diphenhydramine,Print: Chapter 19. Detoxification of Opioids http://www.psychiatryonline.com/popup.aspx?aID=351260&print=yes…
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hydroxyzine, and antidepressants such as trazodone have all been proposed for withdrawal-related
insomnia. Because many opioid-dependent individuals may also abuse benzodiazepines, the choice
of those agents needs to be made carefully. Generally, few or no problems result when
benzodiazepines are used for up to a week in inpatient detoxification settings. Outpatient
detoxification presents more problems because there is no control over benzodiazepine use,
misuse, or diversion.
Comfort medications used to treat ancillary withdrawal symptoms include nonsteroidal
anti-inflammatory drugs (e.g., 600–800 mg of ibuprofen every 6–8 hours or 30 mg of ketorolac
tromethamine intramuscularly every 6 hours for no more than 5 days) for muscle cramps or pain;
dicyclomine 10 mg every 6 hours for abdominal cramps; bismuth subsalicylate 30 cc after each
loose stool; prochlorperazine 10 mg intramuscularly three times a day or ondansetron 8 mg orally
every 8 hours for nausea and vomiting; and 2 adrenergic agents (e.g., clonidine, guanfacine,
lofexidine) for flu-like symptoms.
Psychosocial support can also play an important role. A warm, kind, and reassuring attitude from
the treatment staff is most helpful. Involvement of patients in their own detoxification schedule
helps with inpatient, but not outpatient, detoxification (Dawe et al. 1991). The fewer the struggles
over medication dosing, the better the alliance can be with the patient. Visitors, however, can be a
problem and should be limited to immediate family members (i.e., parents or spouse) who are
known not to abuse drugs. Even parents have been known to smuggle in drugs under the pressure
of a patient’s entreaties that the staff does not understand the patient’s distress. A watchful
presence is therefore necessary around all visitors. Such attempts at deception may be less likely
to occur if family meetings are held and parents and significant others are well informed about the
approach to detoxification.
Other potentially helpful measures include warm baths, exercise, and various diets. Except when
specific nutritional deficiencies are present, there is no evidence for benefits from any particular
dietary regimen. However, because opioid-dependent patients are often malnourished, general
vitamin and mineral supplements should be given.
Buprenorphine
Buprenorphine is a partial receptor agonist and receptor antagonist. Although initially marketed
in the United States as a parenteral analgesic (Buprenex), buprenorphine was approved by the FDA
in late 2002 in sublingual tablet formulations for both detoxification and maintenance treatment of
opioid dependence. Buprenorphine sublingual tablets are available with buprenorphine only
(Subutex) and in combination with naloxone (Suboxone) in a 4:1 ratio. The addition of naloxone is
intended to reduce the risk of buprenorphine abuse by injection. Naloxone is not readily
bioavailable with sublingual administration because the potency ratio of parenteral to sublingual
naloxone is 15:1. Therefore, the small quantities of naloxone absorbed by the sublingual route will
generally not precipitate withdrawal. If, however, the sublingual tablet is crushed and snorted or
dissolved and injected, it may precipitate withdrawal, especially among heroin users, and thus
significantly reduce the risk of buprenorphine diversion. It is not entirely clear what dose of
injected naloxone will precipitate withdrawal in individuals receiving buprenorphine maintenance
(Eissenberg et al. 1996; Jasinski et al. 1978; Kosten et al. 1990; Mendelson and Jones 2003)
because buprenorphine has a long receptor half-life and greater affinity for opioid receptors than
does naloxone.
Many of the advantages noted earlier for methadone in detoxification apply equally to
buprenorphine, which is also long-acting, safe, and effective by a nonparenteral route of
administration. Initiation of buprenorphine for detoxification differs from methadone initiation in
that buprenorphine may precipitate withdrawal symptoms if it is given too soon following use of an
opioid agonist. When using buprenorphine for detoxification, one waits until the patient shows
some withdrawal symptoms (e.g., Clinical Opiate Withdrawal Scale score of 12 or more), at which
point buprenorphine usually serves to relieve these symptoms and is less likely to precipitate
withdrawal. When some of the older literature on buprenorphine is considered, one must keep inPrint: Chapter 19. Detoxification of Opioids http://www.psychiatryonline.com/popup.aspx?aID=351260&print=yes…
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mind that until the mid-1990s, buprenorphine was usually administered in an aqueous alcohol
solution, which is approximately twice as bioavailable as the tablet formulations now available.
A typical approach to managing heroin detoxification is to administer buprenorphine 2–4 mg
sublingually after the emergence of mild to moderate withdrawal (usually at least 12 hours after
the last use of heroin). Another 2- to 4-mg dose of buprenorphine sublingually may be administered
approximately 1 hour later, depending on the patient’s comfort level. Usually, a total of 8 mg of
buprenorphine is sufficient on the first day of detoxification, but 12 mg may be necessary in
patients with larger habits. On subsequent days, doses of buprenorphine between 8 and 16 mg
sublingually are usually sufficient to relieve withdrawal symptoms. Data are insufficient to make
definitive recommendations about the optimal subsequent duration of buprenorphine treatment in
detoxification. Some studies have used high-dose buprenorphine for as little as 1 day (Hopper et al.
2005; Kutz and Reznik 2001), whereas others have tapered buprenorphine over 13 days (Amass et
- 2004; Ling et al. 2005). For most patients, however, a slow taper over a few days after reaching
adequate withdrawal relief remains a safe and well-tolerated detoxification strategy.
Buprenorphine in doses of 16 mg or less may not suppress all signs and symptoms of withdrawal;
muscle ache, restlessness, yawning, mydriasis, and tremor have been reported (Lintzeris et al.
2002). One study reported that approximately 80% of participants treated with buprenorphine
received at least one ancillary medication for withdrawal symptoms, most commonly insomnia,
anxiety, restlessness, and arthralgias (Ling et al. 2005). The latter three symptoms usually respond
readily to 2 adrenergic agonists (e.g., 0.1 mg of clonidine every 4–6 hours).
When buprenorphine is stopped abruptly, the exact duration of withdrawal is not well known and
may vary considerably from patient to patient. Various periods have been reported, ranging from
no signs of abstinence after receiving 8 mg for 10 days (Mello and Mendelson 1980), to mild
symptoms appearing after 2–3 days and peaking at approximately 2 weeks after the last dose
(Jasinski et al. 1978), to mild symptoms peaking at 3–5 days and going away after another 5 days
(Fudala et al. 1990). Individual differences may be quite important, because a recent study
suggested that about one-fifth of the patients receiving daily buprenorphine maintenance therapy
of 16 mg sublingually for 10 days experienced significant end-of-dose withdrawal symptoms
(Lopatko et al. 2003). However, some studies have suggested that opioid withdrawal symptoms in
less-than-daily buprenorphine maintenance regimens are minimal to very mild for up to 96 hours
(Gross et al. 2001; Petry et al. 1999).
As the dosage of buprenorphine is increased, a ceiling effect of about 32 mg of buprenorphine
(comparable with approximately 20–30 mg of parenteral morphine) is reached. Buprenorphine is
thus less likely to produce the severe respiratory depression found with full agonists.
Nevertheless, deaths have been attributed to respiratory depression in patients treated with
buprenorphine, but in most cases the respiratory depression was attributed to concomitant use or
abuse of benzodiazepines (Reynaud et al. 1998; Tracqui et al. 1998).
It is possible to use buprenorphine to help individuals detoxify from methadone maintenance,
either to achieve a drug-free state or to transition to buprenorphine maintenance. A handful of
laboratory studies have been done (Mendelson et al. 1997; Preston et al. 1988; Strain et al. 1992,
1995; Walsh et al. 1995) of the effects of buprenorphine in populations receiving methadone
maintenance treatment. The results from these studies have been mixed and conflicting, with some
suggesting that higher doses of methadone and higher doses of buprenorphine produce more
severe precipitated withdrawal when buprenorphine is given to methadone-maintained individuals
and others suggesting that higher doses of buprenorphine produce more agonist effect and make
the transition easier. The timing of buprenorphine administration relative to the last use of
methadone is another important variable. In general, however, as with detoxification from heroin,
the patient should be at least in mild withdrawal, suggesting a minimum of 36 hours after the last
full methadone dose. Also, most researchers suggest tapering the methadone dose down to 40 mg
or less prior to buprenorphine induction. Two studies that used this procedure tapered methadone
nearly to zero before buprenorphine induction (Janiri et al. 1994; Levin et al. 1997). One studyPrint: Chapter 19. Detoxification of Opioids http://www.psychiatryonline.com/popup.aspx?aID=351260&print=yes…
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transitioned 51 patients receiving long-term methadone maintenance therapy of 30 mg or less onto
buprenorphine, with subsequent reductions, and reported no precipitated withdrawal during
induction and found the process feasible, safe, and acceptable to both patients and clinical staff
(Breen et al. 2003).
The possibility of using buprenorphine in rapid antagonist induction also has been studied. A
12-week randomized study compared anesthesia-assisted versus buprenorphine- or
clonidine-assisted detoxification followed by antagonist induction (Collins et al. 2005). The
buprenorphine group received a single dose of 8 mg on day 0 and none on day 1, and naltrexone
was started on day 2 at 12.5 mg and titrated up to a dosage of 50 mg/day. The senior author has
since modified this method by giving the 1-month depot naltrexone (Vivitrol) on day 3 or 4 once
the 25-mg oral naltrexone dose has been reached (Comer et al. 2006). The anesthesia group was
induced onto naltrexone 50 mg/day while under general anesthesia. Both groups received adjuvant
medications. The clonidine group had withdrawal symptoms treated with clonidine and other
adjuvant medications and was induced onto naltrexone the following week. All three groups were
found to have comparable mean withdrawal. Additional findings from this study will be presented
later in this chapter (see “Rapid Antagonist Induction Under General Anesthesia”).
In another study, 23 patients receiving a dosage of 3–6 mg/day of buprenorphine solution (more
bioavailable than the tablets) for 1 month were abruptly given increasing dosages of naltrexone
over 4 days, starting 24 hours after the last buprenorphine dose (Kosten et al. 1991). Minimal
withdrawal occurred, and 20 of the patients took the initial 6-mg naltrexone dose. However, only 4
patients continued the naltrexone at 50 mg/day beyond the 2 weeks. More recently, patients were
given buprenorphine solution 3 mg/day sublingually for 3 days followed by 25 mg of naltrexone
plus clonidine on day 4 and 50 mg of naltrexone on day 5 (O’Connor et al. 1997). The individuals in
the buprenorphine group had milder withdrawal and were more likely to complete detoxification
(81%) than were those in the clonidine group (65%). The buprenorphine group had detoxification
completion rates comparable with the clonidine-naltrexone comparison group (also 81%), but no
difference in naltrexone retention was found at 8 days. A small study used a 7-day buprenorphine
stabilization prior to anesthesia-assisted naltrexone induction, with less postprocedure morbidity
than a historical control population inducted onto naltrexone under anesthesia without
buprenorphine stabilization (Bochud Tornay et al. 2003). It would appear that a rapid detoxification
method involving buprenorphine as a bridge to antagonist induction and maintenance may
ultimately be the least painful and the most successful. The high naltrexone dropout rate may be
improved by transitioning quickly, as noted earlier, to the injectable 1-month naltrexone depot.
(Note: as of this writing, use of this agent for treating opiate dependence is an off-label use,
because the injectable is approved only for alcoholism.)
A recent systematic review compared buprenorphine treatment of withdrawal with other
detoxification strategies (Gowing et al. 2006a). Relative to clonidine, buprenorphine was found to
be more effective in ameliorating the symptoms of withdrawal; patients stayed in treatment longer,
particularly in outpatient settings, and were more likely to complete withdrawal treatment. In
addition, no significant difference in the incidence of adverse effects was found between clonidine
and buprenorphine. Buprenorphine, when compared with methadone treatment of withdrawal,
revealed no significant difference in terms of completion of treatment or severity of withdrawal,
and withdrawal symptoms resolved more quickly.
Summary
Studies examining gradual methadone withdrawal suggest the following:
Inpatient withdrawal has a significantly higher retention rate (about 80%) than short-term outpatient
withdrawal (as low as 13%–17%).
Although little evidence indicates that this initial higher rate is associated with better-sustained
abstinence 4–6 months later, more research is necessary to determine which patients need inpatient
withdrawal.
The success rate for short-term outpatient withdrawal appears about the same as reported by addictedPrint: Chapter 19. Detoxification of Opioids http://www.psychiatryonline.com/popup.aspx?aID=351260&print=yes…
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individuals attempting self-withdrawal.
The success rate for outpatient withdrawal appears to be improved substantially (up to 62%) if longer
periods (e.g., 4–6 months) and higher dosages are used.
Attention to psychosocial factors during outpatient withdrawal is associated with better retention and
less use of heroin.
Regardless of duration or dosage, once methadone is stopped, a rebound in withdrawal symptoms
lasting somewhat longer than 1 month occurs; these symptoms are probably connected with the high
postwithdrawal relapse rate.
Studies of buprenorphine in opioid detoxification suggest the following:
Buprenorphine shares many of the advantages of methadone in opioid detoxification—it is safe,
long-acting, and available for sublingual administration, thus diminishing the potential for misuse and
abuse of the drug. It may also have less post-withdrawal relapse, but further study is required.
Detoxification from buprenorphine is less severe than heroin or methadone withdrawal, even with
abrupt cessation of buprenorphine, but there are conflicting reports as to the timing of peak withdrawal
intensity, ranging between several days and several weeks.
Buprenorphine may play important roles in two procedures related to detoxification: 1) the transition of
patients in methadone maintenance to buprenorphine maintenance and potentially to drug-free
treatments and 2) the rapid induction of naltrexone in heroin-dependent patients who desire antagonist
maintenance treatment. More research is needed in both of these areas.
OTHER DETOXIFICATION AGENTS AND METHODS
Clonidine
The 2 adrenergic agonist drug clonidine, marketed as an antihypertensive, has been used to
facilitate opioid withdrawal in both inpatient and outpatient settings (Charney et al. 1986; Gold et
- 1978; Kleber et al. 1985). Clonidine at dosages of 0.6–2.0 mg/day reduces many of the
autonomic components of the opioid withdrawal syndrome, although craving, lethargy, insomnia,
restlessness, and muscle aches are not well suppressed (Charney et al. 1981; Jasinski et al. 1985).
Clonidine is believed to exert its ameliorative actions by binding to 2 autoreceptors in the brain
(e.g., locus coeruleus) and spinal cord. Both opioids and clonidine can suppress the activity of the
locus coeruleus, which is hyperactive during opioid withdrawal.
Inpatients stabilized at 50 mg/day or less of methadone can be switched abruptly to clonidine.
Dosages reaching 2.5 mg/day during precipitated withdrawal and antagonist induction have been
used, with careful monitoring of heart rate and blood pressure to minimize the risk of significant
hypotension and/or syncope. Sedation and hypotension have been the major side effects. The high
clonidine dosages are possible because precipitated withdrawal is hypertensive.
Clonidine also has been used for outpatient detoxification from either heroin or methadone
maintenance. Patients receiving methadone maintenance therapy at 20 mg/day or less are about
as successful after abrupt substitution of clonidine as after reduction of methadone by 1 mg/day
(Kleber et al. 1985). With experienced personnel, addicted persons can be successfully withdrawn
by using clonidine in a primary care setting. O’Connor et al. (1997) found that 65% of such patients
completed detoxification and entered the next phase of treatment. Clonidine has not been given
official FDA approval for use in controlling withdrawal, but it has been used so widely now, both in
the United States and abroad, that it has become accepted as an alternative to gradual methadone
reduction.
Although the group that originated the techniques also conducted many of the clonidine studies, a
number of both open and controlled studies have been published since the mid-1980s (Cami et al.
1985; Gerra et al. 1995; Pini et al. 1991; San et al. 1990). Studies show that clonidine (and other 2
adrenergic agonists such as lofexidine and guanfacine) are about as effective as gradual
methadone withdrawal, with the following differences: 1) methadone detoxification has fewer
symptoms early in withdrawal and more at the end; 2) clonidine has the opposite profile: dropouts
are more likely to occur early with clonidine and later with methadone; 3) clonidine has more sidePrint: Chapter 19. Detoxification of Opioids http://www.psychiatryonline.com/popup.aspx?aID=351260&print=yes…
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effects, especially hypotension and sedation; and 4) clonidine is less likely to be associated with
post-withdrawal rebound. It also appears that clonidine is more effective if given in the context of
abrupt opioid withdrawal rather than as an adjunct during gradual methadone tapering (Ghodse et
- 1994). In a direct comparison of clonidine with buprenorphine for short-term heroin
detoxification, however, the group receiving buprenorphine fared better on measures of retention
in detoxification, heroin use, and withdrawal severity scores than did the clonidine group (Lintzeris
et al. 2002).
Techniques of clonidine-aided detoxification
On the day before the start of clonidine detoxification, the usual dosage of opioid is given. On day 1
of the detoxification, the opioid is stopped abruptly, and clonidine is given in divided doses as
shown in Table 19–4. Clonidine is to be used with caution in patients who have hypotension or who
are taking antihypertensive medications. Use of tricyclic antidepressants within 3 weeks precludes
use of clonidine because these agents render the 2 receptors hyposensitive to clonidine. Other
exclusions include pregnancy, history of psychosis, cardiac arrhythmias, and other medical
conditions in which use of clonidine might aggravate the associated medical problems. Because
clonidine can cause sedation, patients should be cautioned about driving and operating equipment.
TABLE 19–4. Clonidine-aided detoxification
Schedule for heroin, morphine, oxycodone, meperidine, and other short-acting opioids
Outpatient/Inpatient
Day 1: 0.1–0.2 mg orally every 4–6 hours up to 1 mg
Days 2–4: 0.2–0.4 mg orally every 4–6 hours up to 1.2 mg
Day 5 to completion: Reduce by 0.2 mg/day, given in two or three divided doses; the nighttime dose should
be reduced last; or reduce total dosage by one-half each day, not to exceed 0.4 mg/day reduction
Schedule for methadone-maintained patients (20–30 mg/day methadone)
Day 1: 0.3 mg Total daily dose, given in divided doses every 4–6 hours
Day 2: 0.4–0.6 mg Total daily dose, given in divided doses every 4–6 hours
Day 3: 0.5–0.8 mg Total daily dose, given in divided doses every 4–6 hours
Day 4: 0.5–1.2 mg Total daily dose, given in divided doses every 4–6 hours
Days 5–10: Maintain on day 4 dosage
Day 11 to completion: Reduce by 0.2 mg/day, given in two or three divided doses; the nighttime dose should
be reduced last; if the patient complains of side effects, the dosage can be reduced by one-half each day, not
to exceed 0.4 mg/day reduction
When clonidine is used on an outpatient basis, it is usually advisable not to give the patient more
than a 2-day supply at one time if the circumstances permit. The patient should not drive during
the first few days. The patient’s blood pressure should be checked at the next visit. If dizziness
occurs, the clinician should instruct the patient to cut back on the dosage, increase fluid intake,
and/or lie down.
Lower clonidine dosages are used on day 1 because opioid withdrawal is less severe at that point,
and the patient usually needs time to adjust to the sedative effects of clonidine. It is useful to give
0.1 mg of clonidine as the initial dose and observe the patient’s reaction and blood pressure over
the next hour or two. The total daily dose should be divided into three doses given at 4- to 6-hour
intervals. Unless the patient is either very thin or very obese, standard dosages are used rather
than basing the dosage on body weight. The dosages from days 2 to 10 usually do not exceed 17
g/kg/day (approximately 1.3 mg/day).
During withdrawal from long-acting opioids such as methadone, clonidine dosages can be increased
gradually over several days. In treating withdrawal from short-acting opioids, however, dosages ofPrint: Chapter 19. Detoxification of Opioids http://www.psychiatryonline.com/popup.aspx?aID=351260&print=yes…
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clonidine are increased (i.e., titrated to symptoms) as rapidly as side effects permit because
serious withdrawal symptoms appear earlier. However, the total duration of clonidine dosing is
shorter.
Antiwithdrawal effects usually begin within 30 minutes and peak at 2–3 hours following oral
administration of clonidine. For inpatients, blood pressure should be checked before each dose; if it
is 85/55 mm Hg or lower, subsequent doses should be withheld until the pressure stabilizes.
Dizziness between doses is best handled by monitoring blood pressure and having the patient lie
down and increase fluid intake. If the pressure is too low, the dosage should be reduced. Sedation
is commonly experienced, especially within the first few days, but usually remits by day 3 or 4. Dry
mouth and facial pain are less common.
Insomnia is not usually a problem until day 3 or 4 of methadone withdrawal but occurs by day 2 or
3 with short-acting opioids. Paradoxically, clonidine may worsen the insomnia associated with
detoxification even while causing sedation during the day. Other withdrawal symptoms not relieved
by clonidine are primarily muscle aches, nervousness, and irritability. Benzodiazepines may be used
for both the muscle aches and the insomnia, but they should be given with caution, particularly in
outpatients, because many substance-dependent individuals abuse this class of drugs.
Clonidine is known to have mild analgesic effects. Thus, in withdrawing medical opioid addicts,
analgesia may not be needed during the withdrawal period, even though the original painful
condition persists to some extent. Pain usually returns 24–48 hours after the last clonidine dose; if
naltrexone is to be used, pain needs to be treated with nonopioid analgesics.
Clonidine patches
In some settings, clonidine is administered via transdermal patches (Spencer and Gregory 1989).
The patch, available in three different doses, supplies clonidine for up to 7 days and is removed if
systolic blood pressure falls below 80 mm Hg or diastolic blood pressure falls below 50 mm Hg. The
patches are removed after the first week of treatment and replaced by half the dosage on another
area of the upper body, if needed. Oral clonidine needs to be given during the first 2 days because
the steady-state levels of the transdermal medication are not reached for 24–48 hours after
application of the patch. Transdermal clonidine offers several advantages over the oral form,
including supplying an even blood level of medication without peaks and troughs and preventing
the buildup of withdrawal symptoms during the night. However, symptoms of clonidine toxicity,
including hypotension, bradycardia, somnolence, miosis, decreased respiratory rate, and
hypothermia, have been reported after oral ingestion (Horowitz et al. 2005). Physicians should be
aware of the potential for accidental overdose, especially among children, and warn patients to
monitor access to the medication. A patch designed to deliver 0.2 mg/day of clonidine after 7 days
of use may still contain 1.0–3.7 mg of active drug (MacGregor et al. 1985).
In summary, clonidine appears to be a safe and effective alternative to the gradual reduction of
methadone for opioid detoxification. Its disadvantages include more side effects and less coverage
of the entire spectrum of withdrawal symptoms. Its advantages include much lower potential for
diversion, because it is not an opioid, and more important, avoidance of the long residual
withdrawal symptoms that persist for weeks after methadone withdrawal. The availability of
buprenorphine for office-based prescribing has decreased interest in use of clonidine for opioid
detoxification except as an adjuvant to the buprenorphine.
Lofexidine
Hypotensive effects may limit the optimal dosing of clonidine for opioid withdrawal because some
patients cannot safely receive the recommended doses of clonidine without experiencing significant
hypotension. The 2 adrenergic agonist lofexidine, an analogue of clonidine, may be as effective as
clonidine for opioid withdrawal while producing less hypotension and sedation (Carnwath and
Hardman 1998; Kahn et al. 1997). The drug has been approved in England for opioid withdrawal,
and it is estimated that more than 70,000 patients have received it to date. Lofexidine is being
studied for possible submission to the FDA for use in opioid withdrawal.Print: Chapter 19. Detoxification of Opioids http://www.psychiatryonline.com/popup.aspx?aID=351260&print=yes…
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Utility of 2 Adrenergic Agonists
A recent systematic review of 2 adrenergic agonists in opioid detoxification (Gowing et al. 2002)
reported that these drugs are associated with similar or slightly greater opioid withdrawal
symptoms than a methadone taper, although withdrawal signs and symptoms resolved sooner with
the 2 agonists. Completion of detoxification is also slightly higher with methadone, and there are
more adverse effects with clonidine or lofexidine. This meta-analysis also confirmed that lofexidine
produces less hypotension than clonidine but is otherwise similar. The utility of the 2 agonists
alone may not be as great as that of buprenorphine alone, but they will continue to be useful
adjuncts in heroin detoxification, especially for physicians who do not have the necessary waiver
for buprenorphine prescribing.
Clonidine-Naltrexone Detoxification and Antagonist Induction
Although clonidine can be an effective alternative to methadone for opioid withdrawal, it does not
shorten substantially the time required for withdrawal. Furthermore, the success rate in outpatient
withdrawal leaves much to be desired. To solve these two problems, researchers first combined
clonidine and naloxone and then subsequently clonidine and naltrexone to provide a safe, effective,
and more rapid withdrawal with quick induction of antagonist maintenance for patients detoxifying
from either heroin or methadone. The method (Riordan and Kleber 1980) combines naltrexone’s
rapid, precipitated displacement of opioids from endogenous opioid receptors and consequent
severe withdrawal symptoms with aggressive use of clonidine prior to and following naltrexone to
provide withdrawal symptom relief. For those symptoms not adequately controlled by clonidine,
other medications are used, such as clonazepam or oxazepam for muscle spasms and insomnia and
antiemetics for nausea and vomiting.
Vining et al. (1988) described the method in detail, and O’Connor et al. (1995) provided an update
aimed at primary care practitioners. Other authors (Gerra et al. 1995; Senft 1991) have also
successfully used this procedure. In the O’Connor study (N = 68), 94% of the patients were able to
complete detoxification successfully and move on to the next phase of treatment. After 1 month,
however, there was no difference in treatment retention between the clonidine-alone and the
clonidine-naltrexone groups. The biggest limitation of this method is the need to monitor patients
for at least 8 hours on day 1 because of the potential severity of withdrawal that typically occurs
after the first dose of naltrexone, including possible delirium, and because of the need for careful
blood pressure monitoring during the detoxification procedure. Thus, trained staff and appropriate
space are necessary for this procedure.
An even more rapid version of the clonidine-naltrexone method was developed for inpatient use
(Brewer et al. 1988). Use of higher dosages of naltrexone and clonidine on day 1 as well as heavy
doses of diazepam reduced the average detoxification time to approximately 2 days. It has been
hypothesized that because the dosage of clonidine needed decreases after the first day, even
though the dosage of naltrexone is increasing, naltrexone is rapidly normalizing the number and
sensitivity of opioid receptors and reversing the opioid-induced central noradrenergic
hypersensitivity (Kleber et al. 1987).
The clonidine-naltrexone detoxification and antagonist induction technique appears to be a safe,
effective, and economical alternative to either gradual methadone taper or clonidine detoxification.
Its advantages, in trained hands, include a dramatic reduction in the time necessary to complete
detoxification, high completion rates (e.g., 55%–95%), and the ability to move rapidly to the next
stage of rehabilitation with fewer lingering withdrawal symptoms. The shortened time frame also
has economic advantages independent of the detoxification setting. Its disadvantages include
generally poorer patient acceptance, compared with other techniques; the need for intensive
monitoring by experienced staff, especially during the first day of treatment; and the need for
sufficient space in outpatient settings to accommodate potentially very sick patients. More
intensive variations on this approach, which may shorten the duration of symptoms, tend to require
hospitalization and do not appear to offer any significant advantage. No significant evidencePrint: Chapter 19. Detoxification of Opioids http://www.psychiatryonline.com/popup.aspx?aID=351260&print=yes…
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indicates that the technique is associated with any longer abstinence or retention on naltrexone
(Gowing et al. 2006b).
Rapid Antagonist Induction Under General Anesthesia
The rate-limiting factor of the clonidine-naltrexone method is the ability to find medications that
adequately relieve the symptoms of the precipitated withdrawal in the conscious patient. The
approach to the clonidine-naltrexone procedure used initially by Brewer et al. (1988) represents
one of the earliest attempts to address this problem. The procedure was further shortened and
advanced by being carryed out under general anesthesia (Loimer et al. 1989) (an ironic throwback
to the hibernation therapy of 1941, in which the patient was kept asleep from 1 to 3 days). Since
that time, the technique has been modified and improved (for review, see Brewer 1997). The
current method commonly uses naltrexone, propofol anesthesia, the antiemetic ondansetron, the
antidiarrheal octreotide, and clonidine and benzodiazepines for other withdrawal symptoms. Heavy
sedation via midazolam has been used instead of anesthesia. Endotracheal intubation is usually
used with general anesthesia but not with heavy sedation. At times, the opioid antagonist
nalmefene or naloxone is used prior to or instead of naltrexone. Some clinicians do the procedure
on an inpatient basis, others on an outpatient basis; some encourage naltrexone maintenance
and/or therapy after detoxification, and others simply refer the patient to Narcotics Anonymous.
What tends to be common is high price, usually ranging from $3,000 or more for the outpatient
approach to more than $10,000 for the inpatient procedure. Claims of high rates of abstinence
months after detoxification have been made, but no objective verification exists, and the samples
are not representative of the heroin- or opioid-dependent population as a whole.
Although some clinicians argue that these techniques are a magic bullet, others see them as
exploitation of opioid-dependent individuals and the general public: use of a technique with
potential serious morbidity and mortality to achieve opioid detoxification when safer (essentially
no mortality) and less expensive methods may readily be used instead (Collins et al. 2005; Kleber
1998). Advocates of the anesthesia approach argue that it is acceptable to expose individuals to
significant risks, including mortality, given the potentially life-threatening consequences of their
underlying illness. The high levels of patient interest in these approaches reflect the nearly
universal desire for a pain-free detoxification procedure. Some practitioners of these approaches
suggest that their patients are “detoxified in a day.” However, research with these procedures
suggests that significant withdrawal symptoms persist for several days or even weeks after the
procedure (Collins et al. 2005; Scherbaum et al. 1998). Furthermore, intermediate- and long-term
outcome data are limited. In a review of nine published anesthesia studies, only two had outcome
data beyond 7 days (O’Connor and Kosten 1998). The authors deplored the lack of randomized
design or control groups, the short-term outcomes studied, and the inadequate assessment of risks.
In one randomized trial of anesthesia-assisted antagonist induction/detoxification, the anesthesia
technique offered no advantage in treatment outcomes at 3 months following detoxification
(McGregor et al. 2002). Another randomized trial (Collins et al. 2005) comparing
anesthesia-assisted antagonist induction with buprenorphine-mediated naltrexone induction and
clonidine-assisted antagonist induction found the anesthesia group to have comparable levels of
withdrawal symptoms with the buprenorphine and clonidine groups. In addition, no significant
differences in any of the three groups were found with respect to treatment retention or mean
opioid-positive urine specimens over the course of the 12-week study. Three serious adverse
events were reported in the general anesthesia group, whereas none were reported in either the
buprenorphine or clonidine groups. Another randomized study (De Jong et al. 2005) of 272
opioid-dependent patients compared rapid detoxification using clonidine with general anesthesia;
both groups were started on antagonist treatment on day 1. The study found no significant
difference in opioid abstinence rates at 1 month or in severity of withdrawal. The average 1-month
cost for the rapid detoxification with general anesthesia group was 76% higher than that for the
clonidine group. Although no adverse events were reported in the clonidine group, the general
anesthesia group had five adverse events requiring hospitalization.
The morbidity of the procedure continues to raise the level of concern about its ultimate utility,Print: Chapter 19. Detoxification of Opioids http://www.psychiatryonline.com/popup.aspx?aID=351260&print=yes…
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even if one were to accept that the procedure might offer a means to attract highly resistant
patients into treatment. Several studies suggest that the procedure produces profound increases in
plasma catecholamines (Kienbaum et al. 1998, 2000). A series of six cases of individuals
presenting to Philadelphia-area emergency departments cited complications of pulmonary edema,
prolonged withdrawal, drug toxicity, rupture of varices, aspiration pneumonia, and death (Hamilton
et al. 2002). In fact, at least seven deaths have occurred within 72 hours of the procedure (Gevirtz
2002). Obviously, more deaths could occur if the approach were extended to dual-dependent
patients or those with cardiac or liver disease. Studies to date suggest that the procedure will
ultimately have at best a limited place in the treatment armamentarium for opioid dependence.
Tramadol
Tramadol hydrochloride is a centrally acting analgesic with partial opiate activity and inhibition of
serotonin and norepinephrine reuptake (Hennies et al. 1988). Partial opiate activity is due to
low-affinity binding of the parent compound and higher-affinity binding of the O-demethylated
metabolite M1 to opioid receptors (Gillen et al. 2000). Tramadol has been associated with a
withdrawal syndrome characterized by signs and symptoms of anxiety, diarrhea, hallucinations,
nausea, pain, piloerection, rigors, sweating, and tremor. This withdrawal syndrome is thought to be
due to its activity at the opioid receptor.
Tramadol has been available in the United States for more than a decade and has low abuse
potential (Cicero et al. 1999; Epstein et al. 2006). Few studies have investigated it for any utility as
a potential detoxification agent. A retrospective chart review compared 59 patients detoxified with
tramadol with 85 patients detoxified with clonidine on rates of leaving treatment against medical
advice (Sobey et al. 2003). The study found that patients detoxified with tramadol had a 23%
greater risk of leaving against staff advice compared with patients detoxified with clonidine. A
retrospective cohort control study compared tramadol with buprenorphine for inpatient
detoxification in 64 heroin-dependent patients (Tamaskar et al. 2003). Length of stay and
maximum withdrawal symptoms, as assessed by the Clinical Institute Narcotic Assessment, were
similar for both groups. Although these initial studies provide some encouragement for future
research on tramadol’s utility as a detoxification agent, there remains a major limiting factor with
the medication. Tramadol has the potential to induce seizures at dosages above 400 mg/day,
thereby reducing its therapeutic range for detoxification. Both studies (Sobey et al. 2003; Tamaskar
et al. 2003) used a fixed-dose tramadol detoxification protocol in which patients received 600 mg
on day 1 and were tapered down thereafter. Available evidence to date suggests using
better-established treatments for opioid detoxification, such as methadone, buprenorphine, or
clonidine, as opposed to tramadol.
SPECIAL PROBLEMS
Seizures
Opioid withdrawal or intoxication usually does not lead to seizures; however, seizures may
occasionally occur with chronic use of meperidine or intoxication with propoxyphene or tramadol. A
seizure may signify undiagnosed sedative-hypnotic withdrawal, stimulant intoxication, another
medical condition (e.g., head injury or epilepsy), or a faked or hysterical seizure. Because most
addicted individuals are polydrug users, possible abuse of sedative-type drugs (including alcohol,
barbiturates, and benzodiazepines) must be considered when providing treatment. If a patient is
suspected of sedative-hypnotic dependence, a pentobarbital challenge will help clarify the picture
(Smith and Wesson 1970; Wikler 1968). The challenge involves administration of 200 mg of
pentobarbital orally. An hour later, a nontolerant individual administered this dose will either be
asleep or show coarse nystagmus, gross ataxia, a positive Romberg’s sign, and dysarthria. If these
signs are lacking, physical dependence on one or more sedative-hypnotic drugs should be
presumed and treated correspondingly.
Mixed Addictions
Sedative-hypnotic (e.g., alcohol, benzodiazepine, barbiturate) dependence can lead to seriousPrint: Chapter 19. Detoxification of Opioids http://www.psychiatryonline.com/popup.aspx?aID=351260&print=yes…
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hazards, including seizures, toxic psychosis, hyperthermia, and even death. Withdrawal from
stimulant-type drugs is much less of a physical hazard, although it can be associated with severe
depression and even suicide. If sedative-hypnotic dependence is present, it may be preferable to
maintain the patient on methadone or buprenorphine, withdraw the sedative gradually, and then
withdraw the methadone.
Vomiting
Although vomiting can be a symptom of withdrawal, it can occur with no relation to the degree of
physical abstinence and in spite of all kinds of support measures, including reintoxication with
opioids. It usually can be handled by intramuscular injections of a drug such as trimethobenzamide
or prochlorperazine. As noted earlier, ondansetron, available in both oral and parenteral forms, can
be very effective in alleviating severe nausea and vomiting. Patients sometimes vomit so that they
will receive repeat medication or intramuscular doses (especially when opioids may be given).
Observation of the patient for 15–30 minutes after an opioid medication dose usually eliminates
this behavior.
Intoxication
Dosing to opioid intoxication is not necessary to prevent withdrawal symptoms and can prolong and
complicate the detoxification. If intoxication occurs, the next opioid dose should be decreased
sufficiently to prevent it at the next medication administration. Smoking while intoxicated or
otherwise impaired from the withdrawal-suppressing medications being used should not be
permitted, for obvious safety reasons, and when patients are ambulatory, they should be assisted
so as to avoid injury.
Repetitive Withdrawal
Addicted individuals often have a characteristic withdrawal syndrome focused on a particular organ
system. For one patient, withdrawal may involve the gastrointestinal system, commonly with
significant abdominal cramping; for another, the musculoskeletal system, typically with aching in
the bones or muscles. A supportive, reassuring, but firm approach usually helps patients with these
symptoms. In the absence of psychosis, antipsychotic medications are rarely necessary.
Other Medical Conditions
Opioid withdrawal is usually not accompanied by high fever, although low-grade temperature
elevation can occur (rarely above 100.4°F or 38°C). Acute febrile illnesses may temporarily
increase the severity of withdrawal symptoms, thus necessitating more methadone or
buprenorphine. When serious medical or surgical problems are present, withdrawal should be
delayed or done very gradually to minimize the degree of stress. The patient should be brought to
the point of tolerance, kept there for several days, and then slowly withdrawn. With certain
illnesses (e.g., acute myocardial infarction, renal colic), the patient should be maintained on
methadone until stable enough to permit withdrawal. The patient also should be evaluated carefully
to determine whether longer-term agonist maintenance is preferable to detoxification. When
withdrawal does take place, giving methadone or buprenorphine three or four times per day
instead of two times can minimize discomfort and stress.
Pregnancy
When pregnancy is complicated by heroin addiction, the patient and her physician are forced to
choose from several relatively undesirable alternatives. The ideal outcome would be for the woman
to abstain totally from drugs, licit and illicit, during the entire pregnancy. Unfortunately, this
usually does not occur. On an outpatient drug-free regimen, many patients cycle in and out of
opioid use, subjecting the fetus to periods of intoxication and withdrawal and a risk of spontaneous
abortion, stillbirth, prematurity, and possible developmental anomalies. The drug effects can be
compounded by the patient’s lifestyle, such as poor prenatal care, inadequate diet, and drug
adulterants. Residential placement to ensure drug-free status is usually resisted, especially if otherPrint: Chapter 19. Detoxification of Opioids http://www.psychiatryonline.com/popup.aspx?aID=351260&print=yes…
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children are at home, or it may be difficult to find, even when desired. The optimal practical
approach to the opioid-dependent pregnant woman avoids the risks of miscarriage and premature
birth associated with detoxification, although some have suggested that carefully selected women
may be safely withdrawn from opioids (Dashe et al. 1998).
The FDA has not approved any agonist or antagonist maintenance therapies for use in the
management of opioid dependence during pregnancy. Antagonist (naltrexone) maintenance is
typically avoided because the prerequisite detoxification increases the risk of miscarriage and
premature birth and because compliance problems increase the likelihood of cycling between
dependence and withdrawal. Nevertheless, some authors have reported successful outcomes of
naltrexone maintenance with small numbers of pregnant women (Hulse et al. 2001). Methadone
maintenance has been used for many years and is generally accepted as the standard approach to
the pregnant patient (Jarvis and Schnoll 1994). Dosing can be problematic because the increased
metabolism of methadone during pregnancy can render the usual dosage inadequate and require an
increased dosage rather than a decreased one (Jarvis et al. 1999). This can often be handled by
split dosing during the day. The infant will be born physically dependent on methadone and will
need to be withdrawn, but if prenatal care is adequate, no known birth defects are associated with
prenatal methadone exposure. If withdrawal from methadone maintenance is necessary, it should
occur during the second trimester at a rate no greater than 5 mg/week. During the first trimester,
withdrawal may be especially deleterious to fetal development; during the third trimester,
withdrawal may trigger premature labor.
A relatively recent alternative for the pregnant heroin-dependent patient is maintenance on
buprenorphine. There is much less experience with buprenorphine than with methadone in
pregnancy, but there have been various reports of treatment success with pregnant heroin users,
with good fetal outcomes (Johnson et al. 2001; Schindler et al. 2003). One randomized,
double-blind study compared buprenorphine with methadone maintenance in 30 pregnant
opioid-dependent patients beginning at an estimated gestational age of 16 weeks (Jones et al.
2005). Peak neonatal abstinence syndrome total scores did not significantly differ between groups.
Studies to date suggest that buprenorphine is comparable with methadone on outcome measures
assessed by neonatal abstinence syndrome and maternal and neonatal safety (Fischer et al. 2006;
Jones et al. 2005; Lejeune et al. 2006; Schindler et al. 2003). However, more research is needed to
help establish the parameters of its use in pregnancy and to further define its effects on newborns
beyond the neonatal period.
EXPERIMENTAL MEDICATIONS
Some investigators have suggested the possibility of other detoxification agents, none of which has
been researched thoroughly enough to be recommended at this time but for which there may be
some efficacy in the future (Herman and O’Brien 1997). These agents include low-affinity,
noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists such as dextromethorphan and
memantine; serotonergic agents such as the serotonin type 1A partial receptor agonist buspirone;
and the neutral endopeptidase inhibitor acetorphan. The effect of buspirone on withdrawal
symptoms in heroin addicts was recently compared with placebo and a methadone taper
(Buydens-Branchey et al. 2005). All groups initially completed a 5-day maintenance course of
methadone, with a last dose of 30 mg. No significant differences in withdrawal severity were found
for up to 7 days after completion of the maintenance phase between the groups receiving a
methadone taper or 30 mg/day or 45 mg/day of buspirone. One imperfectly controlled study
suggested that massive doses of vitamin C (300 mg/kg), supplemented with vitamin E, reduced
opioid withdrawal symptoms in most patients studied (Evangelou et al. 2000). We expect that
advances in neuropharmacology and other areas of brain science will continue to provide promising
candidate medications for use in opioid detoxification.
ALTERNATIVE/COMPLEMENTARY MEDICINE
Despite considerable attention to alternative/complementary medicine approaches in other areas
of medicine, opioid detoxification has received little of this attention, outside of the focus givenPrint: Chapter 19. Detoxification of Opioids http://www.psychiatryonline.com/popup.aspx?aID=351260&print=yes…
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over the last 30 years to acupuncture (discussed in the next section). A recent controlled study of
the traditional Chinese medicine practice of qigong suggested that it produces better withdrawal
relief than lofexidine (Li et al. 2002). In addition, some plant preparations, such as the West
African hallucinogen ibogaine, have developed enthusiastic followings, but lack support in
controlled studies of safety and efficacy. It has been reported that at least eight people have died
following ingestion of ibogaine (Alper 2001; Kontrimaviciute et al. 2006; Maas et al. 2006).
18-Methoxycoronaridine, an ibogaine derivative, which may be safer than the original ibogaine
plant extract, is under study. The Chinese herbal compound WeiniCom compared favorably with
buprenorphine on measures of withdrawal severity and heroin craving (Hao and Zhao 2000). More
research is needed to assess what role, if any, complementary medicine may play in the future of
opioid detoxification.
ACUPUNCTURE
Although acupuncture has been used for thousands of years in Chinese medicine to relieve pain, its
use in the treatment of narcotic withdrawal is much more recent. Wen and Cheung (1973) reported
more or less favorable results in 40 patients who received acupuncture with electrical stimulation.
A review 5 years later (Whitehead 1978) concluded that because the studies used inadequate
controls, they did not prove that the procedure worked.
Acupuncture consists of the use of thin needles inserted subcutaneously at points on the body
believed to be related to the body functions that need to be stimulated. For detoxification, points on
the external ear are usually used. Electroacupuncture involves applying small amounts of electricity
to needles, which are inserted in those acupuncture points on the external ear believed to affect
opioid withdrawal. Evidence from animal studies indicates that electroacupuncture is mediated
through the endorphin system, and its effects can be blocked by the use of naloxone. A small
laboratory study with heroin-dependent volunteers suggested that auricular acupuncture effects
are mediated through the endogenous opioid system, and it noted that 20% of patients are
resistant to acupuncture effects (Timofeev 1999).
Some studies or reviews have asserted that acupuncture and its closely related variants, including
electroacupuncture, are effective, whereas others have asserted that they are not (Alling et al.
1990; Brewington et al. 1994; Jordan 2006; National Council Against Health Fraud 1991; Ter Riet et
- 1990; Ulett 1992). Most studies have been flawed by the lack of random assignment or the lack
of a placebo control. One recent sham-controlled study of electroacupuncture suggested that both
objective and subjective symptoms of opioid withdrawal were reduced with active treatment
compared with the inactive control (Zhang et al. 2000). Although some studies suggest that
acupuncture detoxification can be as effective as gradual methadone withdrawal in symptom
alleviation, retention, and relapse rates, better-controlled studies are needed to confirm this
conclusion. Studies of these approaches have several methodological problems, including high
dropout rates, inconsistent placement of electrodes, inconsistent electrical parameters, and
problems in blinding patients and staff.
In general, programs that use acupuncture and its related variants tend to be enthusiastic about
the results; published reviews tend to be more critical. Acupuncture may be useful for some
patients, but many questions remain about its use. The optimal technique for detoxification
remains to be clarified. It also remains to be determined how acupuncture compares with other
detoxification methods described earlier in this chapter, especially methadone, buprenorphine, and
clonidine detoxifications. For those who prefer not to use medications, clearly there is something
appealing about a nonpharmaceutical technique. Additional questions include the following: What
are the characteristics of individuals most likely to benefit from acupuncture during opioid
withdrawal? For example, Washburn et al. (1993) suggested that heroin users with smaller habits
stay in treatment longer than those with larger habits. What are the optimal circumstances and
complementary approaches to be used during the procedure? As Brumbaugh (1993, p. 36) noted,
“Acupuncture is not a panacea, and it loses much of its efficacy. . .when practiced in isolation from
the more traditional Western modalities of counseling, pharmaceutical therapies, 12-stepPrint: Chapter 19. Detoxification of Opioids http://www.psychiatryonline.com/popup.aspx?aID=351260&print=yes…
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programs, and urine testing. It is best seen as an adjunct or a complement to these other forms.”
Acupuncture will become an important and standard part of opioid detoxification treatments only
after well-controlled studies establish its utility and begin to answer some of these more specific
questions.
CONCLUSION
For most opioid-dependent individuals, detoxification is only the first step in the long process of
remaining abstinent from illicit drugs. Success is a function not only of how comfortable the
procedure can be made but also of how well patients can be retained in both detoxification and
longer-term treatment. Whatever method is chosen, appropriate psychosocial interventions and
education must be available to prepare the patient for this next step. More information is needed as
to the best combinations of withdrawal techniques and patient characteristics. The ideal
detoxification method would be relatively rapid, inexpensive, comfortable, safe, and available on an
outpatient basis; it would also increase the likelihood that patients seek longer-term help. Although
none of the techniques reviewed in this chapter meets this ideal, significant progress has been
made in improving the pharmacology of opioid withdrawal. The recent FDA approval of
buprenorphine for opioid detoxification and maintenance therapy should make opioid dependence
treatments much more widely available. The more urgent area for future research is in improving
treatment retention at all phases of opioid dependence treatment. Compared with 60 years ago, the
current detoxification methods are faster and more comfortable. In the future, there may be
pharmacological approaches that decrease relapse by restoring the disordered neurochemistry
associated with protracted withdrawal, cue-induced craving, and comorbid psychiatric illness.
KEY POINTS
Although detoxification allows patients to initially overcome their physical dependence, without follow-up
treatment it is unlikely to lead to long-term recovery.
Various medications are used for opioid detoxification, including full opioid agonists (e.g., methadone),
partial opioid agonists (e.g., buprenorphine), opioid antagonists (e.g., naltrexone), 2 adrenergic agonists
(e.g., clonidine), and adjuvant medications (e.g., clonazepam, ibuprofen, bismuth subsalicylate) for
symptomatic relief.
Since its introduction to the United States in 2002, buprenorphine has been effectively used for
detoxification and maintenance because it is long-acting, can suppress withdrawal symptoms at least as well
as methadone, causes less severe withdrawal than heroin or methadone when abruptly stopped, allows for
outpatient use, and is safe when used by experienced physicians.
Recent studies on rapid antagonist induction under general anesthesia have revealed little benefit while
leading to significant adverse events.
Various alternatives to current detoxification strategies, including the use of tramadol, ibogaine,
acupuncture, and others, require further study before their routine use can be supported.
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SUGGESTED READING
American Society of Addiction Medicine: http://www.asam.org
Center for Substance Abuse Treatment: Detoxification and Substance Abuse Treatment. TIP Series #45 (DHHS
Publ No SMA-06-4131). Rockville, MD, Substance Abuse and Mental Health Services Administration, 2006
National Institute on Drug Abuse: http://www.nida.nih.gov
Substance Abuse and Mental Health Services Administration National Clearinghouse for Alcohol and Drug
Information: http://ncadi.samhsa.gov
Substance Abuse and Mental Health Services Administration Substance Abuse Treatment Facility Locator:
http://dasis3.samhsa.gov
Copyright © 2008 American Psychiatric Publishing, Inc. All Rights Reserved.
Course Content
Introduction to Opioid Detox and Recovery
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Understanding Opioid Addiction
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The Detoxification Process: What to Expect
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The Role of Medication-Assisted Treatment (MAT)
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Opioid Detox Basics Quiz
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Support Systems and Resources for Recovery
Understanding Opioid Addiction: Causes and Effects
Safe Detox Practices: Strategies and Protocols
Support Systems and Coping Mechanisms in Recovery
Long-term Recovery: Sustaining Sobriety and Preventing Relapse
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