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Chapter 58. Treatment of Substance-Related Disorders
TREATMENT OF SUBSTANCE-RELATED DISORDERS: INTRODUCTION
Drugs that produce substance use disorders all activate the brain reward system, but each class of
drugs activates the system by a different pharmacological mechanism. Thus, this chapter is
organized according to pharmacological class. The emphasis is on pharmacotherapy, but all
treatment using medications should be accompanied by counseling or psychotherapy according to
the patient’s needs. Medication combines very well with psychotherapy, including self-help groups
such as Alcoholics Anonymous (AA). The majority of patients also have an additional mental
disorder (besides the addictive disorder) such as depression, anxiety, or bipolar disorder. These
comorbidities require specific treatment including medication and psychotherapy. The best
treatments for addiction complicated by additional psychiatric disorders are delivered in an
integrated fashion, preferably from the same therapist. All psychiatrists should be able to manage
substance use disorders, especially those that co-occur with other psychiatric diagnoses.
ALCOHOL
The 12-month prevalence of alcohol use disorders in the United States in the most recent
epidemiological survey was 7.35%, and combined with other drug use disorders the total was more
than 8.4% (Compton et al. 2007). Alcohol is the number one substance chosen by both adults and
teenagers. The annual loss of life for all causes, but often through accidents, is over $185 billion per
year. In a 2005 survey among twelfth-grade students, 53% had used alcohol in the past 30 days
and 34% had been drunk during the same period (Johnston 2006). As with all substance use
disorders, the best treatments involve a combination of psychotherapy and pharmacotherapy. A
variety of medications have been used at the important stages of alcohol use disorder treatment.
The first stage is detoxification, which means clearing of the alcohol from the body. After
detoxification, the relapse prevention stage should be continued for months or even years.
Alcohol Detoxification
Detoxification involves the clearing of alcohol from the body and the readjustment of all systems to
functioning in the absence of alcohol. The alcohol withdrawal syndrome at the mild end may include
only headache and irritability, but about 5% of alcoholic patients have severe withdrawal
symptoms manifested by tremulousness, tachycardia, rapid respiration, and even seizures. The
presence of malnutrition, electrolyte imbalance, or infection increases the possibility of
cardiovascular collapse.
Significant progress has been made in establishing safe and effective medications for alcohol
withdrawal. Pharmacotherapy with a benzodiazepine is the treatment of choice for the prevention
and treatment of the signs and symptoms of alcohol withdrawal. Many patients, however, detoxify
from alcohol dependence without specific treatment or medications. It is difficult to determine
accurately which persons require medication for alcohol withdrawal. Clinicians should learn to use a
formal alcohol withdrawal scale such as the Clinical Institute Withdrawal Assessment (CIWA AD;
Sellers et al. 2000) in order to rate the severity of withdrawal and the response to medication.
Patients in good physical condition with uncomplicated mild to moderate alcohol withdrawal
symptoms usually can be treated as outpatients.
A typical outpatient regimen requires the patient to attend the clinic daily for 5–10 days to receive
clinical evaluations, multiple vitamins, and gradually decreasing benzodiazepine pharmacotherapy.Print: Chapter 58. Treatment of Substance-Related Disorders http://www.psychiatryonline.com/popup.aspx?aID=434968&print=yes…
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A typical medication dosing regimen involves giving enough benzodiazepine on the first day of
treatment to relieve withdrawal symptoms. The dose should be adjusted if withdrawal symptoms
increase or if the patient complains of excessive sedation. Over the next 5–7 days, the dose of
benzodiazepine is tapered to zero. Most clinicians use longer-acting benzodiazepines such as
clonazepam, chlordiazepoxide, or diazepam. The usual starting dose of medication on the first day
is 25–50 mg of chlordiazepoxide or 10 mg of diazepam given every 6 hours. In an outpatient
setting, oxazepam may be particularly useful because it is associated with less abuse and does not
require hepatic biotransformation, an important consideration for alcoholics with liver disease.
The diagnosis of delirium tremens is given to patients who have marked confusion and severe
agitation in addition to the usual alcohol withdrawal symptoms. It is important to remember that
there is a risk of mortality approaching 5% in patients with severe alcohol withdrawal symptoms.
Patients who have medically complicated or severe alcohol withdrawal must be treated in a
hospital. Benzodiazepines usually will be sufficient to calm agitated patients; however, some
patients may require intravenous medication to control extreme agitation.
Relapse Prevention
All patients should be engaged in long-term outpatient care after detoxification. Referral to an AA
group is often very useful, but this should not be expected to replace a case manager or therapist. A
multipronged approach involving AA, counseling, and medication has the best chance of being
successful. Three different kinds of medication have received U.S. Food and Drug Administration
(FDA) approval.
Disulfiram
In 1951, disulfiram (Antabuse) became the first medication to be approved by the FDA for the
treatment of alcohol dependence other than detoxification. Disulfiram inhibits a key enzyme,
aldehyde dehydrogenase, involved in breakdown of ethyl alcohol. After drinking, the
alcohol–disulfiram reaction produces excess blood levels of acetaldehyde, which is toxic in that it
produces facial flushing, tachycardia, hypotension, nausea and vomiting, and physical discomfort.
The usual maintenance dosage of disulfiram is 250 mg/day.
There have been only a few randomized, controlled trials of disulfiram, and these trials have had
mixed results for drug efficacy (Peachy and Naranjo 1984). The most comprehensive trial was the
Veterans Administration (VA) Cooperative Study of disulfiram treatment of alcoholism. This study
was conducted with male veterans and found no differences between disulfiram, 250 mg/day and 1
mg/day (an ineffective dose), and placebo groups in total abstinence, time to first drink,
employment, or social stability. Among patients who drank, those in the 250-mg disulfiram group
reported significantly fewer drinking days (Fuller et al. 1986).
The main problem with disulfiram is that frequently patients stop taking it and relapse to drinking
(Goodwin 1992). Disulfiram is most effective when it is used in a clinical setting that emphasizes
abstinence and offers a mechanism to ensure that the medication is taken. Drug compliance may be
successfully ensured either by giving the medication at 3- to 4-day intervals in the physician’s
office or at the treatment center or by having a spouse or family member administer it.
Naltrexone
Naltrexone is a specific opiate receptor antagonist developed for the treatment of heroin addiction.
In animal models of alcohol drinking, it was found to reduce the self-administration of alcohol.
Beginning in 1983, it was tested as an adjunctive therapy for alcoholism and was found to prevent
relapse in some, but not all, patients (Volpicelli et al. 1990, 1992).
After replication of these findings by other researchers (O’Malley et al. 1992), naltrexone was
approved by the FDA for use in alcoholism. The first use of naltrexone was to test the hypothesis
that at least a part of the reward from alcohol is mediated by the endogenous opioid system.
Studies in animal models and in humans have supported that hypothesis (Volpicelli et al. 1995).
There have also been reports of reduction in alcohol craving (O’Malley et al. 2002). Alcoholics in Print: Chapter 58. Treatment of Substance-Related Disorders http://www.psychiatryonline.com/popup.aspx?aID=434968&print=yes…
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treatment get no adverse effects if they drink alcohol while on naltrexone, but they frequently
report that it is no longer rewarding. In 2006, the FDA approved an extended-release depot version
of naltrexone that is effective with only one injection per month. This is a major treatment advance
because the requirement of daily dosing of the oral form led to poor adherence and more relapse.
Of course, opioid peptides may not be the only brain system involved in alcohol reinforcement.
Norepinephrine, dopamine, serotonin, and -aminobutyric acid (GABA) may also be involved in
alcohol craving and consumption. Medications aimed at these neurotransmitters are currently in
development.
Acamprosate
Another FDA-approved pharmacotherapy for alcohol dependence is acamprosate, whose chemical
name is calcium acetyl homotaurinate. Structurally, acamprosate is similar to the amino acid
taurine and has been shown to have several actions on the GABA–N-methyl-D-aspartate (NMDA)
complex. Acamprosate has been reported to be a safe and effective treatment for alcoholism in
several controlled studies. In 1985, Lhuintre et al. published the results of a double-blind study in
which 85 subjects, described as severely alcoholic, were randomly assigned to 3 months of
treatment with either acamprosate or placebo. Seventy subjects completed the trial, and of these,
20 of 33 (61%) acamprosate-treated subjects and 12 of 37 (32%) placebo-treated subjects were
abstinent during the study. Positive results were reported for two subsequent placebo-controlled
trials (Lhuintre et al. 1990; Paille et al. 1995) in which the total number of abstinent days was
higher for acamprosate-treated subjects compared with placebo-treated subjects. In 1996, the
reports of two German double-blind, placebo-controlled studies were published. In the first trial,
Sass et al. (1996) studied 272 subjects randomly assigned to a year of treatment with either
acamprosate or placebo and evaluated for an additional 12 months following the discontinuation of
study medication. Compared with placebo-treated subjects, the subjects who received acamprosate
had a significantly lower dropout rate, a greater number of days before their first drink, and a
greater number of days of total abstinence during the study.
The second study, which had a similar design, involved 455 subjects and was conducted by
Whitworth et al. (1996). The results of this trial were that acamprosate was superior to placebo
with respect to the number of dropouts, relapse rate, and total days of abstinence. Interestingly,
18% of the acamprosate-treated subjects, compared with 7% of the placebo-treated subjects,
remained continuously abstinent a year after discontinuation of study medication. Subsequently,
acamprosate was studied in a multiclinic trial in the United States (Mason and Ownby 2000) and in
a large National Institutes of Health–sponsored trial comparing acamprosate, naltrexone, and
placebo (Anton et al. 2006). Although acamprosate trials in the United States have not been
positive, the clear results of the European trials were sufficient to merit FDA approval in 2004.
Alcoholism With Other Coexisting Mental Disorders
Depression commonly occurs in alcoholic individuals. The above anticraving medications can be
used in combination with all antidepressants, including monoamine oxidase inhibitors (MAOIs), if
they are otherwise indicated. Antidepressants alone have not been found to be consistently useful
in reducing drinking, but in depressed persons with alcoholism, they are effective in improving
mood and overall well-being.
NICOTINE
According to the 2000 National Household Survey, an estimated 65.5 million Americans, or 29% of
the population, reported current use of tobacco. Most tobacco users, 55.7 million, smoked
cigarettes, whereas the remainder smoked cigars and pipes or used smokeless tobacco (Substance
Abuse and Mental Health Services Administration 2001). Tobacco accounts for approximately
400,000 deaths per year. Since the mid-1960s, the incidence of smoking in the United States has
progressively decreased by about 1% per year (Substance Abuse and Mental Health Services
Administration 2001). This remarkable change in tobacco use is a consequence of the realization by
society that tobacco-related mortality and morbidity are entirely preventable. Most of thesePrint: Chapter 58. Treatment of Substance-Related Disorders http://www.psychiatryonline.com/popup.aspx?aID=434968&print=yes…
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smokers have symptoms that meet the DSM-IV-TR (American Psychiatric Association 2000) criteria
for the substance use disorder nicotine dependence. The behavioral aspects of nicotine dependence
are similar to those for alcohol and opiate dependence, as well as the production of tolerance and
physical dependence. In about 80% of smokers (Gross and Stitzer 1989), nicotine abstinence leads
to well-described withdrawal signs and symptoms (Hughes and Hatsukami 1986).
Pharmacotherapy in the form of nicotine replacement has been a key element in reducing
withdrawal symptoms and initiating smoking cessation. More recently, nonnicotine medications
that can be used in combination with nicotine replacement have become available.
Nicotine Replacement
Nicotine replacement can be obtained over the counter in the form of gum, patch, or nasal spray.
Nicotine replacement reduces irritability and withdrawal symptoms such as sleep disturbance,
difficulty concentrating, and restlessness. Transdermal nicotine is initially administered in 15- to
21-mg patches for 4–12 weeks, followed by lower-dose patches for up to another 8 weeks.
Transdermal nicotine also has excellent documentation for its ability to decrease the severity of
withdrawal symptoms and also to decrease craving for tobacco (Daughton et al. 1991; Tonnesen et
- 1991).
Neither gum nor transdermal nicotine has any long-term effect in preventing weight gain after
cessation of smoking. Both nicotine preparations provide a significant advantage over placebo in
smoking cessation. Stitzer (1991) reviewed seven double-blind, placebo-controlled smoking
cessation trials in which nicotine gum was used. Abstinence rates at 4–6 weeks were 73% for
nicotine gum compared with 49% for placebo gum. Most of the transdermal nicotine double-blind
studies were reviewed by Palmer et al. (1992), who found that quit rates at 4–6 weeks were
39%–71% for transdermal nicotine compared with 13%–41% for the placebo patches. The FDA
approved nicotine gum in 1981 and transdermal nicotine in 1991 as prescription medications, and
in 1996 both were approved for over-the-counter (nonprescription) use. Beyond the initiation of
abstinence, nicotine preparations are associated with a progressive relapse to smoking. After 1
year, abstinence rates are about 25% for the nicotine gum and patch compared with 12% for
placebo (Benowitz 1993).
The nasal spray and the inhaler are preparations that provide rapid-release forms of nicotine. The
potential advantage of these rapid-release preparations is that they closely simulate smoking by
providing a rapid plasma concentration and oral and sensory stimulation. The results from the
initial trials for the nasal spray (Schneider et al. 1995; Sutherland et al. 1992) and the inhaler
(Tonnesen et al. 1993) are similar to those for the gum and patch.
Nonnicotine Pharmacotherapies
Bupropion, a monocyclic antidepressant that has noradrenergic and dopaminergic effects, was
approved by the FDA as a pharmacotherapeutic agent for smoking cessation. Bupropion reduces
craving for nicotine, but the mechanism by which this occurs is not well understood. The results
from several studies indicate that the bupropion anticraving effect is related to its action on central
nervous system dopamine (Covey et al. 2000). In an initial double-blind trial (Ferry et al. 1992) in
which 42 men were randomly assigned to 12 weeks of treatment with bupropion 300 mg/day or
placebo, the results showed significantly longer continuous abstinence for bupropion-treated
subjects at the end of treatment, as well as 6 and 12 months after treatment. Hurt et al. (1997)
conducted a study that clearly established the efficacy of bupropion as pharmacotherapy for
nicotine dependence. The trial involved 615 nondepressed subjects (50% female) who were
randomized to either bupropion 300 mg/day or placebo for an 8-week medication phase. At 1 year,
the smoking cessation rate was 23% for the bupropion group compared with 12% for the placebo
group. Jorenby et al. (1999) reported on a multisite smoking study with 893 subjects in which
placebo, bupropion, nicotine patch, and bupropion plus nicotine patch were compared for efficacy
as pharmacotherapy for nicotine dependence. The 12-month abstinence rates were 15.5% for
placebo, 16.4% for nicotine patch, 30.3% for bupropion, and 35.5% for bupropion plus nicotinePrint: Chapter 58. Treatment of Substance-Related Disorders http://www.psychiatryonline.com/popup.aspx?aID=434968&print=yes…
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patch. Bupropion, alone or in combination with the nicotine patch, was superior to the nicotine
patch or placebo. Bupropion has also been found to be useful in adolescent smokers, a time of great
vulnerability to addiction (Killen et al. 2006).
Varenicline is the newest medication that was approved in 2006 by the FDA as an aid to smoking
cessation. It is an 4, 2 nicotinic acetylcholine receptor partial agonist. Laboratory data suggest
that this receptor is involved in the reinforcing effects of nicotine through activation of the brain
reward system. Varenicline was tested against bupropion and placebo in two identical multisite
studies. In one study (Gonzales and Weiss 1998) of 1,025 smokers, those randomized to
varenicline had significantly greater abstinence rates (44%) at 12 weeks than placebo- or
bupropion-treated patients. Continuous abstinence to 52 weeks was 29.1% for varenicline, 16.1%
for bupropion, and 8.4% for placebo. In the second study (Jorenby et al. 2006), the varenicline
group also had significantly greater abstinence rates than the placebo or bupropion groups by week
12, and the rates of continuous abstinence to 52 weeks were 23% for varenicline, 14.6% for
bupropion, and 10.3% for placebo. Thus, the clinician has three pharmacotherapy options to aid in
smoking cessation, along with a behavioral treatment program.
Smoking and Psychiatric Disorders
The incidence of smoking in persons who abuse alcohol, stimulants, and opiates is about 90%;
however, compared with the other two groups, alcoholic patients smoke the most cigarettes
(Burling and Ziff 1988). Many of those who work with psychiatric patients have observed that
cigarette smoking is extremely common among patients with schizophrenia. Research not only
supports this observation but also clearly shows the extraordinarily high rate of smoking in
schizophrenic inpatients and outpatients. Goff et al. (1992) studied schizophrenic outpatients and
found that 74% smoked, compared with a national average of less than 30%. Between 80% and
90% of a group of institutionalized schizophrenic patients were found to smoke (Matherson and
O’Shea 1984). There is no known reason for the high rate of nicotine use by schizophrenic patients.
Some have speculated that the dopamine-augmenting effect of nicotine may counterbalance a
relative dopamine deficiency that exists in schizophrenic patients (Glassman 1993). However,
nicotine-induced changes in other neurotransmitters (e.g., serotonin) (Benwell and Balfour 1982)
may help to explain why so many schizophrenic patients smoke. Also, there is speculation that
nicotine ameliorates the cognitive deficits in schizophrenia (Sacco et al. 2005). Further research is
needed to understand nicotine’s involvement in the pathophysiology of schizophrenia. It is not
unreasonable to expect that future antipsychotics not only will ameliorate psychiatric symptoms
but also may decrease nicotine dependence in schizophrenic patients.
Glassman et al. (1988) conducted pioneering research establishing the link between major
depression and cigarette smoking. Based on data from the Epidemiologic Catchment Area (ECA)
survey (Regier et al. 1984), they found that 76% of persons with a lifetime history of major
depression “had ever smoked” compared with 52% of persons without a depression history.
Similarly, the incidence of depression was 6.6% in smokers compared with 2.9% in nonsmokers,
and smokers with a history of depression had a low rate of cessation. These findings have been
replicated by several investigators, and the association between depression and smoking is well
supported. Another observation is that depressive symptoms appear during smoking cessation in
persons with a history of depression (Covey et al. 1990). These researchers also found that
alcoholism had the highest association with smoking. Smoking rates among persons with anxiety
disorders are at least twice those of persons without a psychiatric diagnosis.
It is unclear what role smoking plays in psychopathology of these disorders. There is some
information supporting smoking in these populations as a maladaptive coping strategy (Revell et al.
1985). Future research on smoking in these targeted psychiatric populations may indicate the most
efficient treatment approaches for patients who suffer from a combination of nicotine dependence
and another psychiatric disorder. Ignoring the nicotine addiction in psychiatric patients, however, is
no longer considered acceptable practice.
BENZODIAZEPINES AND OTHER SEDATIVESPrint: Chapter 58. Treatment of Substance-Related Disorders http://www.psychiatryonline.com/popup.aspx?aID=434968&print=yes…
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The benzodiazepines have largely replaced older sedative-hypnotic agents, such as barbiturates
and meprobamate, in clinical use. To a great extent, the benzodiazepines are popular because they
are safe in overdose situations and because, when first marketed, they were thought to have no (or
almost no) abuse potential. Clinical experience and scientific study have since shown that although
the benzodiazepines, as a class of drugs, are certainly safer in isolated overdose situations than the
older agents, physiological dependence is possible and occurs with long-term use, even at
therapeutic doses.
These findings have touched off a controversy that has yet to be settled. Most patients who are, in
fact, physiologically dependent on benzodiazepines do not increase the dose of medication above
the physician’s prescription or in any other way abuse the prescribed medication. However, if the
benzodiazepine were to be abruptly discontinued, the patient would, in all probability, experience a
withdrawal abstinence syndrome that could be extremely severe (O’Brien 2005). For instance,
abrupt discontinuation of high therapeutic doses of alprazolam has frequently been reported to
cause seizures. Thus, any patient receiving a benzodiazepine for a significant length of time, that is,
longer than 3–6 months, should be slowly tapered off his or her medication; this does not preclude
the possibility of reemergence of the patient’s anxiety symptoms, which may necessitate continued
use of the medication.
The fact that patients become physiologically dependent on therapeutic doses of benzodiazepines
has led some people in the field to equate any use of benzodiazepines in any patient for long-term
treatment with abuse of the drug. This is undoubtedly an overstatement of the abuse of these
agents. Significant abuse of benzodiazepines does, in fact, occur but is usually seen in patients
abusing other drugs also, not in patients who are carefully monitored and are stable taking
therapeutically indicated benzodiazepines.
In general, patients who abuse only benzodiazepines are rare; benzodiazepine abuse in
combination with abuse of other drugs is much more common. Alcoholic patients will not
infrequently abuse benzodiazepines if the opportunity presents, and patients who abuse cocaine
and opioids are also likely to use benzodiazepines concomitantly. Studies in alcoholic patients
admitted for detoxification have shown that the rate of benzodiazepine use among these patients is
between 28% and 41%, as determined by urinalysis (Crane et al. 1988; Ogborne and Kapur 1987;
Soyka et al. 1989); generally only about one-third of the patients with a positive urine test result
for benzodiazepines admitted to using the drugs. A variety of studies from Europe have examined
benzodiazepine use in patients who use illicit opioids and have found that up to 90% of patients
use benzodiazepines to some extent, although most patients deny that they use benzodiazepines or
state that they use them to mitigate insomnia or anxiety or to reduce withdrawal symptoms.
Methadone-maintained patients often use benzodiazepines, but generally on a sporadic basis.
Magura et al. (1987) showed that 40% of patients in four methadone programs in New York had
urine test results that were positive for benzodiazepines, whereas studies in England showed rates
of benzodiazepine-positive urine test results of 54% (Lipsedge and Cook 1987) and 59% (Beary et
- 1987) in methadone-maintained patients. In patients who use benzodiazepines in conjunction
with other drugs, the issues of abuse and physiological dependence take on a much different
meaning than in stable patients taking long-term prescribed benzodiazepines. If these patients use
or abuse more than one substance, the use or abuse of benzodiazepines can seriously interfere with
drug abuse treatment for other substances; for example, the patient may be discharged from his or
her methadone maintenance program for having urine test results that are consistently positive for
illicit benzodiazepines. These patients require detoxification from benzodiazepines, with either a
benzodiazepine or a phenobarbital taper; evaluation for underlying psychiatric disorders such as
generalized anxiety or panic disorder; and relapse prevention techniques for benzodiazepine abuse.
COCAINE
Cocaine abuse in the United States reached epidemic status in the early 1980s. Over the next
decade, cocaine use initially decreased and then stabilized. In 2000, an estimated 1.2 million
Americans age 12 years and older were current cocaine users. The estimated number of currentPrint: Chapter 58. Treatment of Substance-Related Disorders http://www.psychiatryonline.com/popup.aspx?aID=434968&print=yes…
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crack users in 2000 was 265,000 (Substance Abuse and Mental Health Services Administration
2001). According to data from the 2000 Drug Abuse Warning Network (DAWN) Report, cocaine was
the illicit substance most frequently associated with hospital emergencies (Substance Abuse and
Mental Health Services Administration 2001). In 2000, the rate of cocaine mentions was 71 per
100,000 population. This rate has remained essentially the same since 1994.
The selection of potential pharmacotherapies has been based on the current understanding of the
neurochemical changes that result from chronic stimulant use (see Chapter 49, “Neurobiology of
Substance Abuse and Addiction”). Cocaine administration results in increased levels of dopamine in
the region of the nucleus accumbens in rats, which is an important part of the brain reward
pathways. Cocaine and other abused substances that increase nucleus accumbens dopamine also
decrease the threshold for brain stimulation reward (Kornetsky and Porrino 1992) and increase the
threshold during cocaine withdrawal after chronic cocaine (Koob et al. 2004). A large number of
human imaging and animal model studies demonstrate that chronic cocaine exposure dysregulates
dopamine function in reward-related brain regions (Dackis and O’Brien 2003).
Pharmacotherapy for cocaine dependence must be considered separately from pharmacotherapy
used to treat complications involved in cocaine abuse such as depression and psychotic reactions.
Gawin and Kleber (1986) initially described a three-phase cocaine withdrawal syndrome consisting
of crash, withdrawal, and extinction. Although this description of cocaine withdrawal found quick
acceptance by many clinicians, it was not observed to be valid in several inpatient trials (Miller et
- 1993; Satel et al. 1991; Weddington et al. 1990). In these trials, only mild abstinence symptoms,
including depression, anxiety, fatigue, and impaired concentration, were found; the symptoms
declined in a linear fashion over the course of 1–2 weeks (Satel et al. 1991; Weddington et al.
1990). However, despite the fact that cocaine withdrawal is not considered to be medically
significant, cocaine withdrawal symptom severity is important because of its predictive value.
Kampman et al. (2004b) used an instrument called the Cocaine Selective Severity Assessment to
measure cocaine withdrawal symptom severity. They found that cocaine withdrawal symptom
severity at the start of treatment predicted outcome in several trials. Severe cocaine withdrawal
may result from cocaine-induced neuroadaptations and may identify patients with more persistent
hedonic dysregulation (Dackis 2005).
Over the past three decades, many agents have been tested and demonstrated to be ineffective as
treatments for cocaine dependence. It is noteworthy that dopamine antagonists actually destabilize
cocaine-addicted individuals (Grabowski et al. 2000; Kampman et al. 2003), perhaps by
exacerbating cocaine-induced dopamine dysregulation. Conversely, the dopamine-enhancing agents
disulfiram and modafinil promoted abstinence in controlled trials (Carroll et al. 2004; Dackis et al.
2005). Modafinil also blunted cocaine-induced euphoria in three controlled human laboratory
studies (Dackis et al. 2003; Myrick et al. 2004; Hart et al. 2006) and is under current investigation
in three large clinical trials.
Advances in the neurobiology of cocaine dependence have guided medication development by
identifying neuronal mechanisms associated with specific aspects of cocaine dependence, such as
euphoria, withdrawal, and cue-induced craving (Dackis 2005). While dopamine-enhancing agents
may reverse neuroadaptations that interfere with the attainment of abstinence, GABA-enhancing
agents may prevent relapse in abstinent patients by dampening cue-induced craving, which is a
persistent clinical phenomenon that leads directly to recidivism. Topirimate, a GABA-enhancing
agent, may promote abstinence by dampening cue-induced craving (Kampman et al. 2004a).
Similarly, modafinil and vaccines that reduce cocaine’s entry into the brain may promote abstinence
by blocking cocaine-induced euphoria (Sofuoglu and Kosten 2005).
The lack of success in identifying an effective medication for treating cocaine dependence has not
dampened scientific enthusiasm or impeded further research. On the contrary, there is renewed
interest in studying various methods of altering the physiological effects of cocaine. One promising
type of relapse prevention pharmacotherapy is not a medicine but a vaccine capable of stimulating
the production of cocaine-specific antibodies. Several cocaine vaccines are under development. OnePrint: Chapter 58. Treatment of Substance-Related Disorders http://www.psychiatryonline.com/popup.aspx?aID=434968&print=yes…
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of these vaccines, called TACD, works by stimulating the production of cocaine-specific antibodies
that bind to cocaine molecules and prevent them from crossing the blood–brain barrier. Because
cocaine is inhibited from entering the brain, its euphoric and reinforcing effects are reduced.
Cocaine itself is too small a molecule to provoke an immune response, so the vaccine attaches a
large protein molecule to a cocaine molecule, thus allowing the immune system to recognize
cocaine and produce antibodies against it. TACD can stimulate the production of cocaine-specific
antibodies in rats and mice, and the vaccine is effective in reducing cocaine self-administration in
rodent models (Fox et al. 1996; Kantak et al. 2000). TACD was administered to 34 former cocaine
users in a Phase I trial. The vaccine was well tolerated, and dose-related levels of anticocaine
antibodies were detected (Kosten et al. 2002; Martell et al. 2005).
METHAMPHETAMINE
In recent years, methamphetamine abuse has become a severe problem, especially in Hawaii and
western continental United States. Methamphetamine is a stimulant that possesses stronger
dopamine augmentation than cocaine and for a longer duration. While cocaine temporarily blocks
dopamine reuptake at synapses, amphetamines also reverse the transporter, thus releasing even
more of the neurotransmitter into synapses. Amphetamine, dextroamphetamine,
methamphetamine, phenmetrazine, methylphenidate, and diethylpropion all produce behavioral
activation similar to that of cocaine. Intravenous or smoked methamphetamine produces an
abuse/dependence syndrome similar to that of cocaine, but paranoid psychosis appears to be more
common with amphetamine abuse. A different picture arises when oral stimulants are prescribed in
a weight reduction program. These drugs do reduce appetite, with accompanying weight loss, on a
short-term basis, but the effects diminish over time as tolerance develops. In rodents, there is a
rebound of appetite and weight gain when amphetamine use is stopped. In obese humans, weight
loss after amphetamine treatment is usually temporary. Anorectic medications, therefore, are not
considered to be a treatment for obesity by themselves but rather a short-term adjunct to
behavioral treatment programs. Drug abuse manifested by drug-seeking behavior occurs in only a
small proportion of patients given stimulants to facilitate weight reduction.
No medication has yet achieved FDA approval for the treatment of methamphetamine addiction, but
several that have received positive reports in cocaine addiction treatment such as modafinil are
currently in clinical trials for methamphetamine (Ling et al. 2006).
OPIOIDS
Pharmacotherapy for opioid dependence has a long history, in part because “heroinism” was one of
the first recognized drug problems in the United States and because therapeutically used congeners
of the drug of abuse, heroin, were readily available. Later studies have shown only limited success
with nonpharmacological treatment.
Detoxification From Opioid Dependence
The classical method of opioid detoxification was, and remains, short-term substitution therapy.
The medication traditionally used has been methadone, at a sufficient dose to suppress signs and
symptoms of heroin withdrawal; the methadone is then tapered over a period ranging from 1 week
to 6 months. The idea behind a rapid (i.e., 1- to 2-week) detoxification regimen is to achieve total
opioid abstinence quickly so that treatment can be continued in a drug-free setting. Detoxification
usually can be accomplished in 4–7 days in an inpatient setting, whereas more time is often
required in the outpatient setting to minimize patient discomfort. Most practitioners consider 21
days sufficient for short-term outpatient detoxification. However, many patients have very chaotic
lives when presenting for treatment and require a period of stabilization before they can hope to
maintain a drug-free lifestyle. There is no evidence that more rapid detoxification leads to better
long-term outcomes. As discussed below, the regulations for opioid treatment facilities require that
patients be dependent on opioids for at least 1 year before they may be admitted to methadone
maintenance. The 6-month stabilization/detoxification regimen allows these patients to work on
the most acute personal and employment problems while they are stabilized at a relatively low
dosage (30–40 mg/day) of methadone and then are detoxified from methadone to continuePrint: Chapter 58. Treatment of Substance-Related Disorders http://www.psychiatryonline.com/popup.aspx?aID=434968&print=yes…
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treatment in a drug-free setting. Unfortunately, the relapse rate after detoxification and drug-free
counseling is very high, and long-term maintenance on medication is usually necessary.
The partial opiate agonist buprenorphine received FDA approval in 2002 for the treatment of opioid
withdrawal and for maintenance. A major change in the U.S. approach to addiction treatment
occurred with passage of a law in 2000 that allows physicians who have a special federal
certification to prescribe buprenorphine in their office rather than limiting access, as is the case
with methadone.
Buprenorphine has been studied for efficacy in suppressing withdrawal signs and symptoms. In
outpatient trials, Bickel et al. (1988) showed that buprenorphine was as effective as methadone in
a 10-week double-blind trial (4 weeks on medication taper followed by 6 weeks of placebo). In an
open trial, Kosten and Kleber (1988) compared three doses of buprenorphine and found that 4 mg,
administered sublingually, was superior to 2 or 8 mg in suppressing signs and symptoms of
withdrawal, although illicit opiates were present in the urine of approximately equal numbers of
patients in both the 2-mg and the 4-mg dose groups.
There has always been concern about substitution detoxification on the basis that the physician is
prolonging the problem by prescribing an addictive medication, even with a tapering regimen. Many
of the symptoms of opioid withdrawal (e.g., diaphoresis, hyperactivity, and irritability) appear to be
mediated by overactivity in the sympathetic nervous system. This led Gold et al. (1978, 1980) to
attempt to depress this overactivity and thereby ameliorate the withdrawal abstinence syndrome
by using adrenergic agents that have no abuse potential. Clonidine, an -adrenergic agonist with
inhibitory action primarily at an autoreceptor in the locus coeruleus, was effective in inpatient
populations in decreasing the signs and symptoms of opioid withdrawal. Outpatient detoxification
with clonidine has not been as successful as inpatient treatment. Inpatient studies reported an
80%–90% success rate, whereas outpatient studies reported success rates as low as 31% in
detoxifying patients from methadone and 36% in detoxifying patients from heroin. The problems
identified in outpatient clonidine detoxification include 1) access to heroin and other opioids, 2)
lethargy, 3) insomnia, 4) dizziness, and 5) oversedation. The last four adverse effects were noted in
inpatient populations during detoxification with clonidine but were easily managed in the hospital
setting.
Because the side effects of clonidine were unacceptable to many patients, other -adrenergic
agonists have been investigated for use in detoxifying opioid-dependent patients. Lofexidine is
widely used for this purpose in the United Kingdom and is in clinical trials in the United States
(Gerra et al. 2001).
Ultrarapid detoxification under general anesthesia has been used in some settings with claims of a
painless and rapid method to attain the opiate-free state. A randomized comparison of this
procedure with a standard buprenorphine detoxification was conducted, and the results showed no
advantage for the ultrarapid procedure (Collins et al. 2005). The major hurdle for the treatment of
opiate addiction is prevention of relapse, and the method or duration of the detoxification makes no
difference.
Maintenance Treatment of Opioid Dependence
Methadone maintenance has been the mainstay of the pharmacotherapy for opioid dependence
since its introduction by Dole and Nyswander (1965). Since the 1970s, levo- -acetylmethadol
(LAAM), a long-acting congener of methadone, has been used experimentally for maintenance
treatment. It was approved by the FDA for this purpose in 1993 but was later withdrawn from the
U.S. market by the pharmaceutical company because of concerns about possible cardiac
arrhythmias. With the availability of buprenorphine in 2002, there are again two options for agonist
maintenance treatment: methadone and buprenorphine.
Methadone
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detoxification from opioids. Methadone maintenance, however, is designed to support patients with
opioid dependence for months or years while the patient engages in counseling and other therapy
to change his or her lifestyle. Experience with methadone encompassing approximately 1.5 million
person-years strongly showed methadone to be safe and effective (Gerstein 1992). Furthermore,
this experience has shown that although patients on methadone maintenance show physiological
signs of opioid tolerance, there are minimal side effects, and patients’ general health and
nutritional status improve.
This approach to the treatment of opioid dependence has been controversial since its beginning.
Physicians and other treatment professionals who consider addiction to be a brain disease have
little or no problem treating patients with an active drug for long periods of time, especially in light
of repeated treatment failures in the absence of active medication therapy. However, many people
view methadone maintenance as simply substituting a legal drug for an illegal one and refuse to
accept any outcome other than total abstinence from all drugs. These people point to long-term
follow-up studies of methadone maintenance patients (see Maddux and Desmond 1992) that show
that only 10%–20% of the patients are completely abstinent (defined as not being enrolled in
methadone maintenance and not using illicit opioids) 5 years after discharge from the maintenance
program. However, long-term follow-up studies of patients discharged from drug-free treatment
programs show that only 10%–19% of opioid-dependent patients are abstinent at 3- or 5-year time
points (see Maddux and Desmond 1992) when the same definition is used. The DSM course specifier
“on agonist therapy” applies to those patients who do well on methadone or buprenorphine while
continuing the medication and do not use illegal drugs.
Outcome studies conducted with patients in maintenance treatment consistently show that these
patients have marked improvement in various measures. Investigators have shown up to an 85%
decrease in criminal behavior, measured by self-report or arrest records. Employment among
maintenance patients ranges from 40% to 80%. Gerstein (1992) quoted a Swedish study published
in 1984 showing the results over 5 years in 34 patients who applied for treatment to the only
methadone clinic in Sweden at the time. The 34 patients were randomly assigned to either
methadone maintenance or outpatient drug-free therapy; the patients in drug-free treatment could
not apply for methadone for a minimum of 24 months after being accepted into the study. After 2
years, 71% of the methadone patients were doing well, compared with 6% of the patients admitted
to drug-free treatment. After 5 years, 13 of 17 (76%) patients remained on methadone and were
free of illicit drugs, whereas 4 of 17 (24%) patients had been discharged from treatment for
continued drug use. Of the 17 drug-free treatment patients, 9 (53%) had subsequently been
switched to methadone treatment, were free of illicit drug use, and were “socially productive.” Of
the remaining 8 patients, 5 (63%) were dead (allegedly from overdose), 2 (25%) were in prison,
and 1 (13%) was drug free.
Furthermore, although previous generations of drug abusers had hepatitis B, endocarditis, and
other infections, in this age when injection drug use and concomitant sharing of needles and
syringes place a patient at risk for HIV infection, the medical consequences of heroin dependence
must be taken into account when determining appropriate therapy for a patient. These issues are
currently being studied by a variety of methods, but the overall clinical impression of increased
general health in methadone maintenance patients is very strong. Additionally, Metzger et al.
(1993) undertook a study of HIV seroconversion rates in opioid-dependent subjects. In this study,
152 subjects were in methadone maintenance treatment and 103 subjects were out of treatment.
At baseline, 12% of the subjects were HIV positive (10% of in-treatment and 16% of
out-of-treatment subjects); follow-up of HIV-negative subjects over 18 months showed conversion
rates of 3.5% for in-treatment subjects and 22% for those remaining out of treatment. These data
suggest that although transmission of HIV still occurs, opioid-abusing injection drug users in
methadone maintenance programs have a significantly lower likelihood of becoming infected than
do patients who are not in treatment.
Methadone maintenance programs in the United States are accredited by agencies such as Joint
Commission on Accreditation of Healthcare Organizations, approved under regulations by thePrint: Chapter 58. Treatment of Substance-Related Disorders http://www.psychiatryonline.com/popup.aspx?aID=434968&print=yes…
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Center for Substance Abuse Treatment (CSAT) in the Substance Abuse and Mental Health Services
Administration (SAMHSA) of the Department of Health and Human Services and the Drug
Enforcement Agency (DEA). A program must be accredited and its physicians licensed for a
methadone maintenance program in order to prescribe or dispense more than a 2-week supply of
any opioid to a patient known or suspected to be dependent on opioids. Most clinics treat
ambulatory outpatients and are open 6–7 days per week, requiring patients to come into the clinic
daily to receive medication unless and until a patient has “earned” privileges (take-home
medication) by compliance with the clinic rules and abstinence from illicit substances. For a person
to be eligible for methadone maintenance, he or she must be at least 18 years old (or have consent
of the legal guardian) and must be physiologically dependent on heroin or other opioids for at least
1 year. The treatment regulations define a 1-year history of addiction to mean that the patient was
addicted to an opioid narcotic at some time at least 1 year before admission and was addicted,
either continuously or episodically, for most of the year immediately before admission to the
methadone maintenance program. A physician must document evidence of current physiological
dependence on opioids before a patient can be admitted to the program; such evidence may be a
precipitated abstinence syndrome in response to a naloxone challenge or, more commonly, signs
and symptoms of opioid withdrawal, evidence of intravenous injections, or evidence of medical
complications of intravenous injections. Exceptions to these requirements are patients who have
recently been in penal or chronic care, previously treated patients, or pregnant patients; in these
cases, patients need not show evidence of current physiological dependence, but the physician
must justify their enrollment in methadone maintenance. A person younger than 18 years must
have documented evidence of at least two attempts at short-term detoxification or drug-free
treatment (the episodes must be separated by at least 1 week) and have the consent of his or her
parent or legal guardian.
Dosage of methadone is an important variable and should be adjusted according to the level of
physical dependence. A careful study of performance of methadone programs showed continued
heroin use among low-dose patients. Among patients receiving at least 71 mg/day of methadone,
no heroin use was detected, whereas patients receiving 46 mg/day of methadone or lower were
five times more likely to use heroin than those receiving higher doses (Ball and Ross 1991).
Furthermore, McLellan et al. (1993) showed, in a comparison of three levels of treatment services
in which all patients received at least 60 mg/day of methadone, that “enhanced methadone
services” patients (methadone plus counseling and on-site medical/psychiatric, employment, and
family therapy) had fewer positive urine test results for illicit substances than did patients in the
“standard services” (methadone plus counseling) group or the “minimum services” (methadone
alone) group. The standard services group did significantly better in treatment than did the
minimum services group, and in fact, 69% of the minimum services group required transfer to a
standard program 12 weeks into the study because of unremitting use of opioids or other illicit
drugs.
Yet another issue that has engendered a great deal of controversy is the treatment of opioid
dependence in pregnant women. Those who are philosophically opposed to methadone treatment
would advocate that any woman using illicit opioids (heroin) or enrolled in methadone maintenance
who became pregnant should be detoxified. It is currently estimated that up to 3% of infants born
each year have had intrauterine exposure to opioids. Because many women with substance abuse
problems fear all organizations, including medical ones, they frequently have little or no prenatal
care, exposing themselves and their babies to the complications of unsupervised pregnancy in
addition to the severe stressor of maternal addiction. The complications and treatment of maternal
opioid addiction and the effects on the fetus and neonate have been discussed by Finnegan (1991)
and Finnegan and Kandall (1992). For the purposes of this chapter, it should be noted that current
evidence shows that pregnant women who wish to be detoxified from opioids (either heroin or
methadone) should not be detoxified before gestational week 14 because of the potential risk of
inducing abortion or after gestational week 32 because of possible withdrawal-induced fetal stress
(see Finnegan 1991). Most clinicians dealing with pregnant opioid-dependent patients advocate
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craving; this dose must be individualized for each patient and managed in concert with the
obstetrician.
Buprenorphine
Buprenorphine is a partial agonist of opioid–type receptor and is a clinically effective analgesic
agent with an estimated potency of 25–40 times that of morphine (Cowan et al. 1977).
Buprenorphine was approved by the FDA for the treatment of opiate addiction in 2002 in addition to
its use as an analgesic agent. Human pharmacology studies have shown buprenorphine to be 25–30
times as potent as morphine in producing pupillary constriction, but buprenorphine was less
effective in producing morphinelike subjective effects (Jasinski et al. 1978). Furthermore, these
studies showed that the physiological and subjective effects of morphine (15–120 mg) were
significantly attenuated when morphine was administered 3 hours after buprenorphine in patients
maintained on 8 mg/day of buprenorphine; the physiological and subjective effects of 30 mg of
morphine also were tested at 29.5 hours after the last dose of chronically administered
buprenorphine and were again significantly attenuated.
Studies in opiate-abusing patients have shown that buprenorphine can be administered sublingually
rather than subcutaneously, the route most commonly used for analgesic effect, with only a
moderate decrease in potency, 1.0 mg subcutaneously being equal to 1.5 mg sublingually (Jasinski
et al. 1989). Early clinical trials with opioid-dependent patients found that patients would tolerate
the sublingual route, that the dose of buprenorphine could be rapidly escalated to effective doses
without significant side effects or toxicity (Johnson et al. 1989), and that detoxification from heroin
dependence using buprenorphine was as effective as using methadone (Bickel et al. 1988) or
clonidine (Kosten and Kleber 1988). Johnson et al. (1992) compared buprenorphine (8 mg/day
sublingually) and methadone (20 mg/day or 60 mg/day) in a 25-week maintenance study and
found that buprenorphine was as effective as 60 mg/day of methadone in reducing illicit opioid use
and keeping patients in treatment. Both buprenorphine and methadone 60 mg/day were superior to
methadone 20 mg/day in this study. A multicenter study compared sublingual doses of 1 mg of
buprenorphine with 8 mg of buprenorphine in more than 700 patients. The 8-mg dose was
significantly better than the 1-mg dose on outcome measures of opiate-free urine tests and
retention in treatment (Ling et al. 1998).
Results from a review of the controlled studies suggest that buprenorphine is as effective as
moderate dosages of methadone (e.g., 60 mg/day), although it is not clear whether it can be as
effective as higher methadone dosages (80–100 mg/day) in patients requiring higher dosages for
maintenance therapy. A Swedish randomized trial of buprenorphine/naloxone combination versus
standard methadone treatment reported equal results as measured by opiate-free urines and
improvement on the Addiction Severity Index (Kakko et al. 2007).
Both detoxification and maintenance studies have shown that the abrupt discontinuation of
buprenorphine in a blind fashion causes only very minor elevations in withdrawal scores on any
withdrawal scale (Bickel et al. 1988; Fudala et al. 1990; Jasinski et al. 1978; Johnson et al. 1989;
Kosten and Kleber 1988). Because the issue of take-home medication is likely to arise in any opiate
maintenance program and because methadone take-home medication has the potential for being
diverted to illegal channels, the option of every-other-day buprenorphine dosing has been explored.
After 19 heroin-dependent patients were stabilized on buprenorphine, 8 mg/day, for 2 weeks, 9
patients continued to receive buprenorphine daily while the other 10 patients, in a blind fashion,
received alternate-day buprenorphine doses, 8 mg/dose, for 4 weeks. Patients reported some
dysphoria on days on which they received placebos, and it was also noted that pupils were less
constricted on placebo days in the patients on alternate-day therapy, but patients tolerated the
48-hour dosing interval without significant signs or symptoms of opiate withdrawal abstinence
(Fudala et al. 1990). This leaves open the possibility of alternate-day medication in the treatment
setting, eliminating the need for take-home medication.
Buprenorphine is currently marketed in 4:1 combinations with naloxone (buprenorphine/naloxone
sublingual tablets of 2 mg/0.5 mg and 8 mg/2 mg). The goal is to reduce abuse of prescribedPrint: Chapter 58. Treatment of Substance-Related Disorders http://www.psychiatryonline.com/popup.aspx?aID=434968&print=yes…
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buprenorphine by injection instead of sublingual dosage. Mendelson et al. (1999) showed that
buprenorphine-to-naloxone combination ratios of 2:1 and 4:1 might be useful in treating opiate
dependence by causing significant opiate withdrawal symptoms when the combination is taken
intravenously. A multicenter clinical trial compared the efficacy of a sublingual tablet of
buprenorphine/naloxone, in a 4:1 ratio, with that of placebo and a buprenorphine mono sublingual
tablet. The results showed that both the buprenorphine/naloxone combination and the
buprenorphine mono tablets were significantly more effective than placebo in reducing illicit opioid
use, reducing opioid craving, and improving global functioning. No difference was noted between
the efficacy of the combination and the mono products, and the combination product was as
acceptable to the subjects as was the mono product (Fudala et al. 1999). Because the
buprenorphine/naloxone combination is now widely prescribed throughout the United States, a
monitoring program has been in place since 2002 to detect signs of street use of the medication.
Thus far, nonprescribed use is minimal, and careful interviews have found that it is most often used
to self-treat withdrawal symptoms but not to get high (C. R. Schuster, C. E. Johanson, T. Cicero, C.
O’Brien, S. Schnoll, J. Anthony, C. Boyd, R. Schottenfeld, and M. Ensminger, “Surveillance
Report—Subutex/Suboxone (July 1–September 30, 2007),” personal communication, December 24,
2007).
Drug Addiction Treatment Act of 2000
The Drug Addiction Treatment Act of 2000 (DATA) allows for the use of opioid medications in the
office-based treatment of opioid dependence, provided that both the medication and the physician
meet the criteria set forth by the act. The medication must be approved by the FDA for the
treatment of opioid dependence and be scheduled in C-III, C-IV, or C-V; medications in Schedule
C-II, such as methadone, are not included in the act. The physician must be a “qualified” physician
and have an addendum to his or her DEA license to prescribe medications under DATA 2000.
Qualifying physicians under this law, however, will be able to more effectively treat opioid
dependence in their offices, without referring patients to opioid treatment clinics. The only
medications currently available that meet the requirements of DATA are buprenorphine and
buprenorphine/naloxone combinations.
Relapse Prevention
As has been noted earlier in this chapter, various methods of detoxifying patients from opioids have
been developed, from substitution and rapidly tapering the dose of opioid to long-term methadone
maintenance and a very gradual methadone taper. These methodologies are, by and large,
unsuccessful in achieving permanent opioid abstinence in patients. It has long been thought that
both conditioned reactivity to drug-associated cues (O’Brien et al. 1977; Wikler 1973) and
protracted withdrawal symptoms (Martin and Jasinski 1969) contribute to the high rate of opioid
relapse. The use of a blocking dose of a pure opioid antagonist would allow the patient to
extinguish the conditioned responses to opioids by blocking the positive reinforcing effects of the
illicit drugs. Naltrexone was shown to be orally effective in blocking the subjective effects of
morphine for up to 24 hours (Martin et al. 1973). Patients using naltrexone maintenance for relapse
prevention need to be carefully screened because they must be opioid free at the start of
naltrexone administration. Many practitioners administer a naloxone challenge, which must be
negative, before starting naltrexone. Naltrexone is usually administered either daily (50 mg) or
three times weekly (100 mg, 100 mg, and 150 mg). Although naltrexone is pharmacologically able
to block the reinforcing effects of opioids, the patient must take the medication in order for it to be
effective. Many opioid-addicted patients have very little motivation to remain abstinent. Fram et al.
(1989) reported that of 300 inner-city patients offered naltrexone, only 15 (5%) agreed to take the
medication, and 2 months later, only 3 patients were still taking naltrexone. However, patients with
better-identified motivation, among them groups of recovering professionals (e.g., physicians,
attorneys) and federal probationers who face loss of license to practice a profession or legal
consequences, have significantly better success with naltrexone.
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naltrexone or treatment as usual. The group receiving naltrexone had significantly fewer
opiate-positive urines, and most importantly, the reincarceration rate of the naltrexone group was
half that of the control group at 6 months. In 2006, a depot formulation was approved by the FDA
for the treatment of alcoholism (Garbutt et al. 2005). Approval for opiate addiction was not
requested, but laboratory studies showed the medication to be effective for 30–40 days in blocking
usual doses of injected opiates (Bigelow et al. 2006). A clinical trial of another formulation of depot
naltrexone, not yet FDA approved, was found to be effective in a placebo-controlled clinical trial
(Comer et al. 2006). Thus, the marketed depot version of naltrexone is yet another option for
long-term relapse prevention in patients detoxified from opiate addiction.
HALLUCINOGENS
The use and abuse of hallucinogens wax and wane much more than the use of some other drugs,
such as alcohol and opioids. The major drugs of abuse that fall into this classification are cannabis
and related compounds, lysergic acid diethylamide (LSD) and other indolealkylamines (psilocybin),
phencyclidine (PCP) and its congeners, and hallucinogenic amphetamine congeners such as
methylenedioxymethamphetamine (MDMA, “ecstasy”). Cannabis has a relatively constant rate of
use, but its use alone usually does not cause the user to seek medical attention. That has changed
somewhat in recent years, as will be described below. LSD (and related compounds) use has
changed from the pattern set in the 1960s, when users lived together communally and the lifestyle
of the group frequently revolved around the psychedelic experience. Today, LSD use occurs in
isolated groups, polysubstance abusers, and adolescents and young adults who frequent “rave”
clubs. Most users of LSD and related compounds are not seen in emergency departments, but
occasionally patients experiencing acute adverse reactions to these drugs are brought to medical
attention. The most frequent adverse effects of LSD and related compounds are acute panic
reactions. Most acute panic reactions, the “bad trips,” do not require any intervention other than a
calm atmosphere and reassurance, but occasionally a patient will be seen who benefits from a low
dose of a benzodiazepine to decrease the anxiety associated with the experience. Likewise,
intoxication with MDMA rarely requires more than reassurance or, occasionally, acute
benzodiazepine administration, again to enable the patient to deal with the anxiety associated with
an adverse experience. However, more recently, as MDMA use has become more popular,
particularly in dance or “rave” club situations, more serious effects have been noted. These effects
include things such as grinding of the teeth, causing dental problems, as well as more significant
medical complications, most notably severe dehydration. It is not known whether the combination
of alcohol and MDMA increases the risk of dehydration, but the combination is a frequent
occurrence.
PCP intoxication, however, can have serious psychiatric and medical complications. An acute
psychotic state can be produced by very low doses of PCP, but behavioral disinhibition, frequently
accompanied by anxiety, rage, aggression, and panic rather than by the core psychotic effects,
necessitates treatment in most cases in which treatment is mandated. There is no convincing
evidence of the superiority of either benzodiazepines or neuroleptics in treating the acute reaction
to PCP. Benzodiazepines are frequently used because they have a rapid onset of action and because
they can be titrated intravenously. If a neuroleptic is to be used, haloperidol is the most commonly
used agent because many other neuroleptics have significant interaction with the anticholinergic
properties of PCP itself. There is a paucity of information on chronic use of PCP and on treatment, if
indicated, of the chronic user.
MARIJUANA
Marijuana is mentioned as an hallucinogen, but its use is so common that it deserves special
consideration. The cannabis plant has been cultivated for centuries both for the production of hemp
fiber and for its presumed medicinal and psychoactive properties. The smoke from burning cannabis
contains many chemicals, including 61 different cannabinoids that have been identified. One of
these, delta-9-tetrahydrocannabinol ( -9-THC), produces almost all of the characteristic
pharmacological effects of smoked marijuana (Iversen 2000). The pharmacological effects of
-9-THC vary according to the dose, route of administration, experience of the user, vulnerability toPrint: Chapter 58. Treatment of Substance-Related Disorders http://www.psychiatryonline.com/popup.aspx?aID=434968&print=yes…
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psychoactive effects, and setting of use. Intoxication with marijuana produces changes in mood,
perception, and motivation, but the effect sought after by most users is the “high” and “mellowing
out.” This is described as different from the stimulant high and the opiate high. The effects vary
with dose, but the typical marijuana smoker experiences a high that lasts about 2 hours. Some
users progress to daily use, which is associated with true dependence (addiction) as well as low
motivation and possibly increased risk for schizophrenia (Ferdinand et al. 2005).
Rates of marijuana consumption in adults 18 years and older held relatively steady at 4% of
respondents in 2002. However, rates of marijuana-related disorders—discrete conditions defined
according to criteria established by the American Psychiatric Association—increased from 1.2% to
1.5% of respondents, or from 30.2% overall to 35.6% among marijuana smokers (Compton et al.
2007). In 2007, the National Survey Results on Drug Use estimated that 31.7% of twelfth grade
students used marijuana during 2007 (Figure 58–1).
FIGURE 58–1. Percentages of youths ages 12–17 years reporting past-year marijuana use, by age
group: 2000.
Source. Reprinted from Substance Abuse and Mental Health Services Administration: 2000 National
Household Survey on Drug Abuse Report: Marijuana Use Among Youth. Substance Abuse and Mental Health
Services Administration, July 2002. Used with permission.
Marijuana is one of the four major substances of abuse; the others are alcohol, cocaine, and heroin.
According to the 2000 DAWN report, marijuana had one of the highest emergency department drug
mentions, at 39 per 100,000. From 1994 to 2000, marijuana mentions increased from 17 to 39, or
by 141% (Substance Abuse and Mental Health Services Administration 2002). After alcohol use
disorders, marijuana abuse had the second highest rate of treatment, with 700,000 persons
(Substance Abuse and Mental Health Services Administration 2001).
The usual treatment interventions for marijuana abuse include drug monitoring, individual and
group psychotherapy, and education (Hubbard et al. 1999). No pharmacotherapy is available for
marijuana abuse. This may soon change, given the recent remarkable discoveries concerning
cannabinoids.
There has been an explosive growth of marijuana research. Key to this have been the discoveries of
cannabinoid receptors and endocannabinoids (naturally occurring cannabis substances) in humans.
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studies (see review by Onaivi 2006). The recent scientific discoveries are significant first steps in
understanding the mechanisms by which cannabinoids cause physiological effects.
Marijuana has been proposed for several medical indications, including nausea associated with
cancer chemotherapy, glaucoma, and wasting disorders. Also, the discovery of cannabinoid
receptors opens the opportunity for the development of specific agonists and antagonists at these
receptors that may have important medical value.
SELF-HELP GROUPS
Self-help groups—such as Alcoholics Anonymous, Narcotics Anonymous, and Cocaine
Anonymous—that are based on a 12-Step method of recovery can be a valuable source of support
for the recovering patient. These groups are a fellowship of recovering people interested in helping
themselves and others lead drug-free lives. The groups are very good for reminding people of the
adverse consequences of relapse and of the benefits of abstinence. Many recovering people feel
that it is easier and more relevant to hear about some aspects of recovery from another recovering
person. Patients can attend meetings as frequently as necessary and can learn more effective
management of leisure time. A sponsor, a person in the group with a prolonged time in a drug-free
lifestyle, can provide a good role model for a person in recovery, in addition to providing support
and encouragement. Self-help groups are also available to non-drug-abusing family members to
help them understand the addictive process and how family member dynamics can affect the
drug-abusing or recovering family member.
CONCLUSION
Addictive disorders can be caused by a variety of drugs that activate the reward system. The
common clinical feature of all addictions is loss of control over drug use so that recurrent
compulsive drug taking occurs. Treatment, as with other chronic disorders, is generally effective for
at least the short term, but relapses are always possible and even likely. Randomized, controlled
clinical trials have demonstrated that the combination of antiaddiction medications and
psychotherapy provides the best treatment for addictive disorders.
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Copyright © 2009 American Psychiatric Publishing, Inc. All Rights Reserved.
Course Content
Introduction to Substance-Related Disorders
-
Overview of Substance-Related Disorders
-
Biological and Psychological Foundations
-
Commonly Abused Substances
-
Assessment Quiz on Substance-Related Disorders
-
The Socioeconomic Impact of Substance Abuse
Foundations of Treatment Modalities
Advanced Strategies in Behavioral Therapies
Integrating Pharmacological Treatments
Developing Comprehensive Treatment Plans
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