PHARMACOLOGIC TREATMENTS FOR DRUG AND ALCOHOL DEPENDENCE

ADDICTIVE DISORDERS 0193-953X/99 $8.00 + .OO

PHARMACOLOGIC TREATMENTS FOR DRUG AND ALCOHOL

DEPENDENCE

Henry R. Kranzler, MD, Hetal Amin, MD, Vania Modesto-Lowe, MD, MPH, and Cheryl Oncken, MD

Although psychosocial methods remain the most widely used approach for the treatment of patients with substance-use disorders, pharmacotherapy has come to play an increasing role in such treatment. Individual and group counseling and 12-step programs are basic ele- ments of most rehabilitation programs for alcohol and drug dependence. Although medications are commonly used to treat withdrawal from alcohol, sedatives, opioids, or nicotine, their role in the rehabilitation of patients dependent on these substances remains limited. Notable exceptions to this include opioid-agonist maintenance and medications used to treat comorbid psychiatric disorders in patients with a substance- use disorder.

This article focuses on medications that serve to augment psychoso- cia1 therapies in the rehabilitative treatment of patients with opioid, nicotine, alcohol, and cocaine dependence. Opioid agonist maintenance treatment has long been used to improve outcomes in opioid addicts. The long-acting agonist L-a-acetylmethadol (LAAM) was recently approved by the US Food and Drug Administration (FDA) for maintenance therapy for patients with opioid dependence, and approval of the partial opioid agonist buprenorphine for this indication is expected soon. These

This work was support by grants AA03510, AA07290, and AA00239 from the National Institute on Alcohol Abuse and Alcoholism.

From the Department of Psychiatry, School of Medicine, University of Connecticut Health Center, Farmington, Connecticut

THE PSYCHIATRIC CLINICS OF NORTH AMERICA

VOLUME 22 NUMBER 2 - JUNE 1999 401

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agents have unique advantages that complement methadone for the maintenance treatment of opioid addicts. Similarly, nicotine replacement, long shown to be efficacious in enhancing smoking cessation rates, is now widely available in a variety of formulations, including the gum and the patch, both of which are approved for over-the-counter sale. The recent approval of a nicotine nasal spray provides a route of administration that may most closely mimic the effects of smoking with respect to rapid rate of nicotine delivery to the brain. Furthermore, the recent approval of bupropion for the treatment of patients with nicotine dependence provides a non-nicotine medication for this indication. With respect to the treatment of patients with alcohol dependence, naltrexone, the only medication other than disulfiram approved for the treatment of patients with alcohol dependence, has not yet had a widespread impact on clinical care. Acamprosate, an agent that is in use in several European countries, is currently being evaluated for the treatment of patients with alcohol dependence in the United States. Unfortunately, in contrast to the treatment of patients with opioid, nicotine, and alcohol dependence, and despite considerable effort, no agent has demonstrated efficacy for the treatment of patients with cocaine dependence.

In the sections that follow, an effort has been made to focus on clinically relevant aspects of a variety of medications with demonstrated efficacy in the treatment of patients with substance-use disorders. The majority of the references in this article are review articles. In this regard, the authors draw most heavily on material that is presented in greater de- tail in reviews of opioid dependence? 32, 34, 35, 39 nicotine dependence,l, 6, l4

alcohol dependence,z, 26 and cocaine dependence.28, 30 The authors refer the reader to these works for a more detailed presentation of these topics and for primary references to the studies that are summarized more generally here.

PHARMACOTHERAPY OF OPlOlD DEPENDENCE

Opioid dependence is a significant public health problem in the United States, with between 600,000 and 1 million people currently addicted to heroin." Such dependence is associated with high rates of social, psychiatric, and medical morbidity.39 Of increasing importance is the fact that intravenous drug use significantly increases the risk for infection with HIV, hepatitis (both B and C), and tuberculosis. The results of a recent survey reflect an epidemic of heroin use, with the number of annual emergency room visits increasing from 36,000 to 76,000 from 1991 to 1995. During this time, the yearly number of heroin- related deaths increased from 2300 to 4000.32

The endogenous opioid system is the primary physiologic system responsible for the pharmacologic effects of opioids, with three main types of opioid receptors in the brain: F, K, and 6. The p receptor mediates the rewarding or euphoric effects of opioids and produces analgesia, respiratory depression, sedation, nausea, vomiting, and mio-

PHARMACOLOGIC TREATMENTS FOR DRUG AND ALCOHOL DEPENDENCE 403

sis. Physical dependence and withdrawal are associated with the extended use of opioids that bind to the p receptor.16

Detoxification and maintenance therapies are the predominant approaches used to treat patients with opioid dependence. The goal of these treatments is to prevent or reduce withdrawal symptoms, craving, and relapse and to restore opioid-dependent patients to normal function- ing.

Detoxification

Detoxification is a process that enables individuals to withdraw from opioids safely, quickly, and comfortably. Medical detoxification from opioids relies on the substitution of a long-acting agonist (e.g., methadone) for a shorter-acting one (e.g., heroin). Clonidine, an a- adrenergic agonist, or a combination of clonidine with the opioid antagonist naltresone, can be used to reduce withdrawal symptoms during detoxifjcation.ls Regardless of the agent used, successful detoxification requires tailoring the program to address the needs of the individual with respect to dosage of the opioid agonist or other medications used, as well as the psychosocial supports that are available. A major problem in brief opioid detoxification programs is the extremely high rate at which patients relapse to illicit opioid use.lS

Maintenance Treatment

Stable abstinence from illicit opioids and improvement in overall health are the major treatment goals of maintenance programs. Metha- done maintenance treatment programs (MMTPs) are the most widely used long-term treatment approach for patients with opioid dependence, with approximately 120,000 patients in maintenance treatment for opioid dependence in more than 750 programs in the United States.24 Although maintenance therapy with naltrexone, an opioid antagonist, is of utility in a minority of highly motivated opioid-dependent patients, poor compliance with the medication has limited its use in the majority of addicts.%

Studies have consistently shown that methadone maintenance reduces mortality, illicit drug use, criminal activity, health care costs, and joblessness among opioid addicts. The median death rate for addicts maintained on methadone is 30% of that for opioid addicts who are not in treatment.32 These programs also provide regular medical care, re- sulting in better general health status, including better pregnancy outcomes. By decreasing the frequency of injection and the sharing of contaminated needles, methadone maintenance also reduces the risk for hepatitis and HIV infection in opioid-dependent patients.42

The effectiveness of MMTPs depends on the dose of methadone administered, the duration and continuity of treatment, and the avail-

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ability of a knowledgeable and empathetic staff and appropriate psychosocial services, including psychotherapy and other counseling ser- v i c e ~ . ~ ~ Patient factors related to better outcomes include lower rates of criminal activity and abuse of other substances, older age of dependence onset, and older age at the time of treatment. Greater motivation for change has also been associated with better outcomes. Barriers to the effective use of methadone maintenance include the stigma associated with opioid-agonist treatment, lack of training for physicians and other health care professionals in addictive services, and burdensome regulations imposed by federal and state government^.^^

Federal guidelines for methadone maintenance among individuals 18 years of age or older include the presence of opioid dependence for more than 1 year and evidence of physiologic ~ i t h d r a w a l . ~ ~ Persons less than age 18 years must have documented evidence of at least two attempts of short-term detoxification or drug-free treatment (the epi- sodes separated by at least 1 week), together with parental or legal guardian consent. Maintenance therapy with methadone is designed to support patients for months or years while they receive counseling to help change their opioid-dependent lifestyles.

Methadone dosage has been directly associated with success rates in preventing heroin use. In maintenance programs, methadone is begun in 25- to 35-mg/d dosages, with adjustment of the dose to alleviate withdrawal, and then is gradually increased to 80 to 120 mg/d." A review of 24 MMTPs throughout the United States concluded that 60 mg of methadone is the lowest daily dosage that is efficacious and that low-dose maintenance (20-40 mg) is inappr~priate.~~

Low birth weight and preterm births are consequences of heroin use during pregnancy. Pregnant women in MMTPs show a reduced risk for maternal and fetal HIV infection and increased infant birth weight compared with women who are not in treatment; however, approximately 60% of infants born to women on methadone maintenance show opioid withdrawal, with the severity of abstinence symptoms correlated with maternal methadone dosage. The dosage of methadone given to pregnant women is 10 to 90 mg/d (mean, 50 mg/d). In the last trimester of pregnancy, an increase in plasma volume and placental metabolism occurs. Hence, the dosage of methadone should be increased during this time.42

Medications Used to Treat Opioid Dependence

Methadone

Methadone, which is primarily a p agonist, was first introduced for the treatment of patients with heroin dependence in the 1960s by Dole and Ny~wander.~" An adequate dose of methadone relieves craving and withdrawal and blocks the euphoric effects of other opioids; its regular use discourages illicit opioid use." Methadone is effective orally; it has


an extended duration of action and persistent effects following repeated administration. It is well absorbed from the gastrointestinal tract and reaches peak concentrations at approximately 4 hours. Ninety percent of methadone is bound to plasma proteins.38 To prevent the precipitation of opioid withdrawal, opioids with mixed agonist-antagonist effects, such as pentazocine, nalbuphine, and butorphanol, should be avoided.42

Inpatient opioid detoxification programs are now reserved for more medically or psychiatrically compromised patients. Inpatients are usually given 10 to 40 mg/d of methadone initially, which is sufficient to control abstinence symptoms. After 2 or 3 days, this dosage is tapered by approximately 5 mg/ d.42 In an outpatient detoxification setting, methadone is usually given in a dose of 5 to 20 mg per day orally, based on the severity of withdrawal, with an additional 5 to 10 mg given if symptoms recur. According to federal regulations, short-term outpatient detoxification can last for up to 30 days, and long-term outpatient detoxification can last for up to 180 days31; however, several studies of the use of methadone for short-term detoxification have shown poor results.42 When methadone is abruptly stopped, the withdrawal symptoms start within 36 to 72 hours (compared with 8-12 h for heroin), with a peak in symptoms 4 to 6 days after the last dose. These withdrawal symptoms subside over the subsequent 10 to 12 days.16

~ - o l -Acetylmethadol

L-a-acetylmethadol, a IJ. receptor agonist that is a derivative of methadone, was first approved by the FDA in 1993 as maintenance therapy for patients with opioid dependence. LAAM, which is administered orally, is similar to methadone in its pharmacologic actions. The drug produces its effects within 2 to 4 hours and is metabolized in the liver into active metabolites, which have a half-life of 72 to 92 hours; hence, LAAM can be given three times a week>*

Treatment with LAAM has certain advantages over traditional methadone maintenance programs. Patients receiving LAAM report a more normal and even feeling than that associated with methadone because LAAM does not produce euphoria. LAAM treatment can reduce the number of clinic visits and thus provide an alternative for patients who find daily clinic visits difficult but who are not ready for complete detoxification. Finally, because no take-home doses are required with LAAM treatment, it reduces opportunities for illicit diversion.8

Drawbacks to the use of LAAM include a long treatment induction period (approximately 2 wk), during which time patients may feel un- comfortable. Given the long duration of activity, a danger of overdose also exists if patients use illicit drugs or if doses of LAAM are given too frequently. Because most patients are unfamiliar with LAAM, they may be anxious over its use, thereby increasing the need for support and counseling during treatment. Also, because of the alternate dosing schedule, the lack of daily contact with health care workers may be counter- productive for certain patients.8

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LAAM has been shown to be equivalent to methadone in terms of suppressing opioid use and encouraging productivity, but retention in treatment with LAAM is less than with methadone. A typical dosage of LAAM is 30 mg to 100 mg orally every 2 or 3 days. Side effects from LAAM include constipation, delayed ejaculation, and impotence.& When LAAM is abruptly discontinued, the withdrawal syndrome is slow in onset and relatively mild in intensity. Normally, LAAM is initiated at a low dosage (e.g., 30 mg/d), which is then increased by 5 to 10 mg/d over the next 2 weeks, at the end of which a therapeutic dosage is achieved. An alternate approach is to stabilize the patient on methadone and then switch to LAAM, which requires that 1.2 to 1.3 times as much LAAM be given as methadone. Comparisons of LAAM with methadone have shown mixed results.8

Buprenorphine

Buprenorphine, a partial opioid agonist and a partial antagonist, is 25 to 50 times more potent than morphine. It is usually given sublingually because its oral bioavailability is low. The half-life of the drug in plasma is approximately 3 hours, at which time 96% of the drug is bound to protein. Although reinforcing at low dosages, buprenorphine can block the intrinsic biologic effects of opioids, thus decreasing heroin use. It does not produce clinically significant levels of physical dependence, shows a lower risk for overdose, and has a better safety profile than does methadone." High doses of the drug produce slight respiratory depression or sedation, and dysphoria can be a problem. When discontinued abruptly, buprenorphine produces mild withdrawal symptoms. Many patients have had their treatment safely and successfully changed from low-dose buprenorphine to naltre~one.~

Buprenorphine has been studied for both detoxification and maintenance treatment. At a dose of 8 mg sublingually, the drug has been shown to be comparable with 60 mg of oral methadone? although it is significantly less effective in reducing craving and maintenance of an opioid-free state than 80 mg of methadone.16 Given its unique profile as a partial p agonist, buprenorphine should soon receive approval from the FDA for use in the treatment of patients with opioid dependence.

Naltrexone

Naltrexone is an opioid antagonist with no intrinsic agonist proper- ties (i.e., it produces no psychoactive effects or dependence). The drug was approved by the FDA in 1985 for the treatment of patients with opioid dependence and in 1994 for the treatment patients with of alcohol dependence. When administered orally, it is well absorbed, with peak plasma levels achieved within an The drug undergoes substantial first-pass metabolism, and although it has a half-life of 3.9 to 10.3 hours, it has an extended duration of effects in the brain.

Side effects commonly include fatigue, nausea, and loss of energy.


Hepatoxicity has been reported at a dosage of 300 mg/d. Because it can precipitate withdrawal symptoms, naltrexone is generally not given for 10 to 14 days after stopping methadone and at least a week after stopping heroin. Clinically, it is useful in patients who have completed opioid withdrawal and want to maintain a drug-free state. The usual dosage of naltrexone is 50 mg/d, or 100 mg on Monday and Wednesday and 150 mg on Friday."

Because of poor compliance, naltrexone maintenance treatment of patients with opioid dependence has been generally unsuccessful in practice. A notable exception to this is its use in opioid-dependent professionals, in whom it can be combined with contingency contracting to enhance c~rnpliance.~~ The development of a sustained-release, in- jectable formulation may also enhance compliance with nal t rex~ne.~~

Another use for naltrexone is in ultrarapid detoxification. This approach, which can be completed in a day or two, involves anesthesia with either midazolam or methohexital, followed by the precipitation of withdrawal with naltrexone. Because these patients do not experience withdrawal symptoms, it has been touted as a "painless" approach to detoxification. OConnor and K ~ s t e n ~ ~ reviewed 12 studies on rapid detoxification and 9 studies on ultrarapid detoxification, concluding that further research is needed on these methods and their long-term outcomes before they can be recommended for widespread use.

Clonidine

Clonidine is an a,-adrenergic receptor agonist that stimulates para- sympathetic outflow via activation of presynaptic a, receptors; these receptors suppress the release of norepinephrine from peripheral nerve endings and effectively block the sympathetic symptoms associated with opioid withdrawal. Noradrenergic activity in brain regions innervated by the locus ceruleus are also suppressed.

Clonidine is well absorbed after oral administration; peak plasma concentrations are reached in 1 to 3 hours, and the elimination half-life of the drug is approximately 12 hours. Adverse effects of clonidine include sedation, hypotension, and bradycardia.

Although clonidine can ameliorate symptoms associated with sympathetic nervous system activity during withdrawal, it cannot suppress symptoms such as craving, lethargy, insomnia, restlessness, and muscle aches.16 On average, opioid detoxification with clonidine can be achieved in 5 to 7 days. Clonidine can be given in doses of 0.1 to 0.2 mg every 4 to 6 hours for mild to moderate withdrawal, with a taper of 0.2 mg/d beginning after the third day." More rapid and effective detoxification can be achieved by combining clonidine with naltrexone. Oxazepam can also used for muscle spasms, and antiemetics are used for symptoms not adequately controlled by other medications. Using a combination of medications results in fewer signs and symptoms of withdrawal and a shorter detoxification period. This may be a cost-effective way to treat patients who desire to begin naltrexone maintenance.18 Other a,-adrener-

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gic agonists, such as lofexidine and guanabenz, also seem to ameliorate aspects of the opioid withdrawal syndrome.

Conclusions on the Pharmacotherapy of Opioid Dependence

Methadone is the most widely prescribed medication for the treatment of patients with opioid dependence and is presently the only medication available for use in both detoxification and maintenance. Although controversy continues to surround the practice of prescribing one dependence-producing drug for another, the acceptance of methadone has been increasing over the past decade. In addition, LAAM seems promising for maintenance therapy, although its utility in long- term maintenance has yet to be established. Buprenorphine has also shown favorable results and is expected to be approved shortly for both detoxification and maintenance. Naltrexone seems to be most useful in opioid-dependent patients who are highly motivated to recover. The utility of a sustained-release formulation of naltrexone, which has shown efficacy in a preliminary study in alcoholic patients,23 is currently being evaluated. Other novel approaches that are not yet in the clinic include nitric oxide synthase inhibitors and glycine antagonists for the treatment of patients with opioid withdrawal. Evaluation of the safety and efficacy of these agents is required before they are made available for clinical use.

Cigarettes are a highly addictive product. Approximately 30% to 50% of occasional cigarette smokers progress to regular use and physical dependence. Although the majority of cigarette smokers would like to quit smoking, only 2% to 3% are able to achieve long-term abstinence each year. The public health implications of cigarette smoking are substantial because half of all smokers die of a smoking-related il1ne~s.I~

PHARMACOTHERAPY OF NICOTINE DEPENDENCE

Nicotine is the addictive substance in cigarette smoke. A bolus of nicotine of approximately 1 to 3 mg is typically delivered to the brain rapidly with each cigarette ~rn0ked.l~ Smoking produces high arterial nicotine concentrations, and maximal venous concentrations of nicotine are reached approximately 2 minutes after smoking.14 The acute effects of smoking include calmness, alertness, and increased concentration, all of which can be positively reinforcing. Moreover, smoking cessation produces withdrawal symptoms in many smokers (i.e., dysphoric or depressed mood, insomnia, irritability, anxiety, frustration, difficulty con- centrating, and increased appetite and weight gain), relief from which is negatively reinf0r~ing.l~ Therefore, both the primary reinforcing effects of smoking and the avoidance of withdrawal symptoms likely sustain tobacco use in most smokers.

Nicotine-replacement therapies were designed to enhance efficacy


rates during smoking cessation by replacing some of the nicotine usually delivered by smoking.14 FDA-approved nicotine replacement therapies for smoking cessation include 2-mg or 4-mg nicotine polacrilex gum, transdermal nicotine, nicotine nasal spray, and the nicotine inhaler. All replacement therapies have been shown to significantly increase smoking cessation success rates in clinical trials. The choice of nicotine- replacement therapy for an individual patient depends on patient prefer- ence, side effects, the presence of other medical conditions, and previous success or failure with a certain type of nicotine-replacement therapy. A review of nicotine medications for smoking cessation follows.

Nicotine-Replacement Therapies

Nicotine Gum

Nicotine polacrilex gum contains nicotine bound to an ion-exchange resin. The gum was the first nicotine-replacement therapy marketed for smoking cessation in the United States, and now 2- and 4-mg doses are available over the counter. Nicotine gum is most beneficial with concurrent behavioral therapy, improving smoking cessation rates by approximately 20% to 40% through 1 year of follow-up. Studies have shown that a fixed gum-chewing schedule (i.e., chewing one piece every 1-2 h) is more efficacious than ad lib dosing. The recommended treatment length for gum chewing is 1 to 3 months; however, some patients may benefit from a longer duration of treatment.'

The gum is designed to be chewed slowly, with intermittent parking of the gum at the side of the mouth; this produces a gradual release of nicotine and avoids adverse effects (e.g., hiccups, heartburn, and stom- ach upset). Approximately 50% of the nicotine in a piece of chewing gum is systemically absorbed. Peak nicotine concentrations are reached approximately 30 minutes after the onset of chewing.14 The starting dose recommended for smokers who smoke fewer than 24 cigarettes per day is 2 mg, with the 4-mg dose recommended for those who smoke more than this amount.14 The gum probably should not be prescribed for persons with temperomandibular joint disease.

Transdermal Nicotine

Transdermal nicotine (i.e., the nicotine patch) is recommended by the Agency for Health Care Policy and Research as first-line nicotine- replacement therapy for patients undergoing smoking cessation.' This approach promotes good patient compliance and requires less clinician time to train patients in the effective use of the product. Transdermal nicotine consistently doubles smoking abstinence rates in clinical trials at the end of treatment and at 6-month foll~w-up.~ Eight weeks of treatment are generally recommended; longer use has not been shown to improve success rates.9 In comparison with other replacement therapies,

410 KRANZLER et a1

transdermal nicotine probably has the lowest abuse potential because few or no withdrawal symptoms occur after patch discontinuation, and patients do not have control over nicotine delivery.

Transdermal nicotine is available in a variety of formulations and dosing schedules (e.g., 15 mg; 11 and 22 mg; and 7, 14, and 21 mg as produced by different manufacturers).6 Peak nicotine concentrations for the various systems are reached 2 to 6 hours after application, and steady-state conditions occur 2 or 3 days after continued patch use.14 With the highest-dose patch (i.e., 21 or 22 mg/d or 15 mg/16 h), approximately 0.9 mg/h of nicotine is delivered through the skin.14

The transdermal system is applied to the skin on the upper body in the morning and removed either before bedtime or the next morning. The highest-dose patch is recommended as a starting dose, unless a patient smokes less than 10 cigarettes per day, for whom an intermediate dose can be used.14 Although dose reduction is usually recommended after 2 to 4 weeks in most formulations, one meta-analysis showed no benefit of dose reduction on patch effi~acy.~ Transdermal nicotine should probably not be used by patients with severe eczema, allergy to adhesive tape, or skin conditions that could be exacerbated by the patch.

Nicotine Nasal Spray

Nicotine nasal spray is a nicotine-delivery system that delivers nicotine through the nasal mucosa. Compared with other delivery systems, nicotine nasal spray most approximates the nicotine pharmacoki- netic profile of smoking. Nicotine nasal spray relieves tobacco craving quickly. One study found that at 1-year follow-up, nicotine nasal spray was 2.6-fold more likely to produce smoking astinence than was placebo. Furthermore, the active spray was most beneficial in highly dependent

One dose (i.e., one spray to each nostril) delivers approximately 1 mg of nicotine, of which 0.5 mg is systemically absorbed. Initially, patients should use one or two doses per hour, not to exceed more than five doses per hour or 40 doses per day.40 This nicotine delivery system delivers nicotine rapidly, with maximal venous nicotine concentrations occurring 5 minutes after the administration of a 2-mg dose.40 Patients with rhinitis, nasal polyps, or sinusitis should not use the nicotine nasal spray for smoking cessation.

Nicotine Inhaler

The nicotine inhaler has also been recently approved in the United States for smoking cessation. This form of nicotine replacement may be useful for some patients because its use is similar to the smoking ritual (i.e., puffing through a cartridge inhaler). This replacement therapy also approximately doubles smoking cessation rates in clinical trials. The recommended treatment period is up to 12 weeks, with a gradual reduc-


tion in the number of cartridges used per day over the subsequent 6 to 12 ~ e e k s . 2 ~

A puffing regimen of 80 deep inhalations over 20 minutes results in a systemic absorption of approximately 2 mg of nicotine through the buccal mucosa; peak nicotine concentrations are reached 15 minutes after the end of inhalation. Clinical trials have evaluated the use of 6 to 16 cartridges per day. This form of nicotine replacement therapy is relatively contraindicated in patients with asthma because nicotine by inhalation can cause bonchoconstriction even though most is absorbed through the buccal muc0sa.2~

Antidepressants

Sustained-release bupropion (Zyban) is a non-nicotine medication that has been shown to be efficacious as an aid to smoking cessation. A multicenter, randomized, double-blind trial in 615 subjects compared the efficacy of placebo with 100 mg/d, 150 mg/d, or 300 mg/d of bupropion for 7 weeks. The quit day was 1 week after the initiation of medication, when steady-state concentrations of the medication were anticipated. At the end of treatment, the quit rates were 19.0%, 28.8%, 38.6%, and 44.2% in the four conditions, respectively. At 1-year follow-up, the quit rate in the 300-mg condition was 23.1% compared with 12.4% in the placebo group.15

Sustained-release bupropion was well tolerated in this study; however, a slightly increased risk for seizures (i.e., l in 1000 smokers) may exist with the medication. Thus, bupropion is relatively contraindicated in patients predisposed to seizures (e.g., those with seizure disorder, head trauma, or alcohol dependen~e).'~

Smokers with current depression (but not those with past depression) were excluded from this study. Because nicotine is postulated to have antidepressant effects and tobacco withdrawal may include depressed mood, some hypothesized that bupropion may be efficacious, in part, because of its beneficial effects on negative mood; however, the study showed no significant difference of the mean change in Beck Depression Inventory scores from baseline to either the second week or end-of-treatment follow-ups among the groups. Consequently, the beneficial effects of bupropion on smoking cessation are likely caused by effects other than those involving depressed m00d.l~ Bupropion is believed to inhibit the neuronal reuptake of dopamine (which may play a role in the reinforcement of addictive drugs) and norepinephrine (which may affect nicotine withdrawal). Because nicotine also facilitates the release of dopamine, norepinephrine, and other neurotransmitters, the two drugs may have similar effects on brain chemistry.15

Other antidepressants currently under investigation for smoking cessation include doxepin and venlafaxine; however, no definitive rec- ommendations regarding these medications for smoking cessation can be made at this time.6 It is also noteworthy that nortriptyline has recently been shown to be efficacious for smoking cessation.lZa

412 KRANZLER et a1

Conclusions on the Pharmacotherapy of Nicotine Dependence

Pharmacotherapy is an integral part of the treatment of patients with tobacco dependence. Although nicotine-replacement therapies and sustained-release bupropion significantly increase smoking cessation rates, the majority of smokers are unable to sustain long-term abstinence (i.e., absolute 1-year quit rates remain low). Additional research on medications, either alone or in combination, to enhance smoking cessation rates and prevent relapse (including long-term maintenance strategies) is warranted. Future studies should also seek to identify specific therapies that are beneficial in treating special populations of smokers (e.g., persons with a comorbid substance use or psychiatric disorder, such as alcoholism, major depression, or an anxiety disorder). Although much knowledge has been gained, much is to be learned in the treatment of tobacco dependence.

MEDICATIONS FOR RELAPSE PREVENTION IN ALCOHOLICS

The greatest challenge for alcoholics in the months after the cessation of drinking is the prevention of relapse to heavy drinking. In this section, alcohol-sensitizing drugs (which make the ingestion of alcohol aversive or hazardous) and drugs that seem to reduce the reinforcing effects of alcohol or the urge or craving to ingest alcohol are discussed. The treatment of persistent psychiatric symptoms may also reduce the risk for relapse to heavy drinking by removing the motivation to use alcohol as "self-medication" to control such symptomszz; however, a discussion of the treatment of dual-diagnosis patients is beyond the scope of this article, and the reader is referred elsewhere for a recent, comprehensive volume on that topic.21

Alcohol-Sensitizing Agents

Alcohol-sensitizing agents, which alter the response of the body to alcohol, make its ingestion unpleasant or toxic.22 Although disulfiram (Antabuse) is the only such agent approved in the United States for the treatment of patients with alcohol dependence, calcium carbamide is used for alcoholism treatment in Canada and Europe. Both agents inhibit aldehyde dehydrogenase, the enzyme that catalyzes the oxidation of acetaldehyde, causing blood acetaldehyde levels to increase. The disulfiram-ethanol reaction (DER) varies in intensity with the dose of disulfiram and the volume of alcohol consumed. The most common symptoms of the DER are warmness and flushing of the skin, especially in the upper chest and face; heart rate increases; palpitations; and decreased blood pressure. Nausea, vomiting, shortness of breath, sweating, dizzi-


ness, blurred vision, and confusion may also occur. Although the syndrome generally lasts approximately 30 minutes and is self-limited, occasionally it may be life-threatening, with rare deaths caused primarily by cardiovascular collapse. Patients should be warned carefully about the hazards of the DER, including the need to avoid over-the-counter preparations with alcohol and drugs that interact adversely with disulfiram. A warning should also be provided regarding the potential for a DER precipitated by alcohol used in cooking.

In addition to its effects on aldehyde dehydrogenase, disulfiram inhibits a variety of other enzymes, including dopamine P-hydroxylase. Thus, in addition to the toxicity of the DER caused by the accumulation of acetaldehyde, adverse effects of disulfiram or its metabolites can occur as a result of multiple drug interactions, alterations in levels of normal body constituents and neurotransmitters, and other toxic effects. Com- mon side effects of disulfiram (independent of the DER) include drowsi- ness, lethargy, peripheral neuropathy, hepatotoxicity, and hypertension.22

Because the risk for side effects and toxic hazards increases as the dosage is increased, the daily dosage prescribed in the United States has been limited to 250 to 500 mg/d; however, efforts to titrate the dose of disulfiram in relation to a challenge dose of ethanol indicate that some patients require in excess of 1 g / d of disulfiram to reach blood levels sufficient to produce the DER.4

Although disulfiram has been used in the treatment of patients with alcohol dependence for many years, few controlled studies have been conducted. In a large, multicenter study conducted by the Veterans Administration Cooperative Studies Group,'O more than 600 male alcoholics were assigned randomly to groups receiving either 1 mg/d of disulfiram or a therapeutic dosage of 250 mg/d or to a control group that was told they were not receiving disulfiram. Patients assigned to the disulfiram groups were told they were being given the drug, but neither patients nor staff knew the dosage. The findings indicated that complete abstinence was related to compliance with drug therapy (in all three groups). Among patients who resumed drinking, those taking a therapeutic dosage of disulfiram had significantly fewer drinking days than did patients in either of the other two groups; however, in terms of length of time to first drink, unemployment rate, social stability, or number of men totally abstinent, no significant difference was found among the three groups. Although disulfiram may be helpful in reducing the frequency of drinking in men who cannot remain abstinent,1° this one finding in favor of disulfiram, 250 mg/d, may have arisen by chance (given the large number of statistical analyses).

Many practitioners believe that, by enhancing compliance with disulfiram, individuals' commitment to abstinence from alcohol can be increased. A trial program of stimulus-control training, role-playing, communication-skills training, and recreational and vocational counseling improved outcomes in disulfiram-treated patients.*'j In summary, although widespread use of disulfiram does not seem justified, the drug

414 KRANZLER et a1

may be useful in selected samples of alcoholics with whom special efforts are made to ensure compliance.

Drugs That Directly Reduce Alcohol Consumption

Several neurotransmitter systems seem to influence the reinforcing or discriminative stimulus effects of ethanol: endogenous opioids; cate- cholamines, especially dopamine; serotonin (5-HT); and excitatory amino acids (e.g., gl~tamate).'~ These systems likely interact in complex ways to produce the reinforcing effects of ethanol.

Opioidergic Agents

Studies in animals of the effects of ethanol on opioid neurotransmission and of opioid antagonists on drinking behavior suggest that some of the reinforcing effects of alcohol may be mediated through opioid neurotransmission.2° These have provided the basis for studies of naltrexone as an adjunct to the psychosocial treatment of patients with alcohol dependence.

Results from two double-blind, placebo-controlled trials of naltrexone in alcoholics have shown it to be efficacious in the prevention of relapse to heavy Based on the findings in these studies, naltrexone was approved by the FDA for the treatment of patients with alcoholism. In these studies, naltrexone was well tolerated and resulted in significantly less craving for alcohol and fewer drinking days. The active medication also limited the progression of drinking from initial sampling of alcohol to operationally defined relapse.

During a post-treatment follow-up period, OMalley et a137 found that the beneficial effects of naltrexone diminished gradually over time. These findings suggest that among patients who respond to the opioid antagonist, a period of medication treatment that extends beyond 3 months may be warranted.

In a recent study, however, Volpicelli et a141 found no overall advantage to naltrexone over placebo in the treatment of patients with alcohol dependence. These investigators found that compliance with naltrexone treatment was variable and that only among highly compliant subjects was the active medication significantly better than placebo with respect to the likelihood of a relapse and on total drinks consumed. These findings are similar to those with disulfiram and underscore the need for efforts to enhance medication compliance among alcoholics if medication therapy is to be of value in the routine clinical care provided to these patients.

In summary, although naltrexone is a promising treatment of patients with alcohol dependence, the number of patients treated in pub- lished double-blind studies of the drug has been modest (n < 300),36, and longer-term outcome studies are lacking. A number of studies are currently underway to further evaluate the range of patient groups for


which naltrexone is efficacious, its optimal duration of use, and the most appropriate psychosocial treatments to be used in combination with the medication.

Serotonergic Agents

Extensive experimental literature links 5-HT neurotransmission to alcohol consumption. In rodents, 5-HT precursors and selective serotonin reuptake inhibitors (SSRIs) consistently decrease ethanol consumption.20 In humans, the data on the effects of SSRIs on alcohol consumption are more limited, and the results are less consistent.20

Studies have shown that most of the drugs in this group are well tolerated and that they reduce drinking in nondepressed, heavy drinkers. The magnitude of the decrease, however, has generally not been large, with reductions often being 15% to 20% from pretreatment levels and the effects limited to subgroups of heavy drinkers or to the early period in treatment. Despite these limitations, a role may emerge for SSRIs in combination with other medications to which patients respond only partially or to support initial abstinence in patients who do not benefit from naltrexone.

Acamprosa te

Acamprosate (calcium acetylhomotaurinate), an amino acid derivative, is a promising therapeutic agent that has been approved for use in a number of European countries and has recently begun to be studied in clinical trials in the United States. Acamprosate affects both y-amino- butyric acid and excitatory amino acid (i.e., glutamate) neurotransmission. Based on its profile of clinical effects, LittletonZ7 has argued that acamprosate works by decreasing craving for alcohol.

Studies conducted in France, Austria, Germany, Belgium, the Neth- erlands, Luxembourg, and Italy have shown acamprosate to be efficacious for the treatment of patients with alcohol In general, these studies have shown an advantage for acamprosate over placebo with respect to retention in treatment, time to first alcohol consumption, and cumulative days of abstinence from alcohol. These effects have been demonstrated during active treatment periods of 3 to 12 months and have been shown to persist for up to 12 months following the cessation of active treatment.

Together, studies of more than 3000 patients provide consistent evidence of the efficacy of acamprosate in alcoholism rehabilitation. Over the period of a year, the drug nearly doubled the rate of abstinence over the 11% observed among placebo patients. Although studies of acamprosate have not used standardized psychotherapeutic approaches, the consistent, although not dramatic, advantage of the active medication can be expected in routine clinical settings; however, as greater efforts are made to provide psychosocial therapies as a context for pharmacotherapy, the effects of adding medication may be greater. Furthermore,

416 KRANZLER et a1

because the medication has a benign side-effect profile, with gastrointestinal symptoms being most prominent, it seems to have a promising future for the treatment of patients with alcohol dependence. As with naltrexone, further studies are needed to identify subgroups of alcoholics who may be most responsive to acamprosate.22

Conclusions on Medications for Relapse Prevention in Alcoholics

Although they have never been in widespread use, aversive agents (e.g., disulfiram) may have clinical utility in combination with psychoso- cia1 approaches that enhance compliance. Such efforts will likely also be of value with medications that directly reduce alcohol consumption. Of this group, naltrexone and acamprosate show the greatest efficacy. Fur- ther research is needed with these agents to identify the circumstances under which they are most efficacious. Specifically, which patient groups, dosage schedules, duration of therapy, and concomitant psychosocial treatments are optimal for these medications is unclear. Fur- thermore, information on strategies for combining medications for relapse prevention (including SSRIs) is needed to maximize the efficacy of pharmacotherapy for relapse prevention in alcoholics.

With the exception of the central role that benzodiazepines play in the treatment of patients undergoing alcohol withdrawal, pharmacotherapy has not yet had a demonstrably large effect on alcoholism treatment; however, recent developments suggest that this situation may change in the near future. As data on the most effective medications and the patients for whom pharmacotherapies are most appropriate accumulate, the challenge for those treating alcoholics will be to combine medication effectively with psychotherapy and self-help group participation.

MEDICATIONS FOR RELAPSE PREVENTION IN COCAINE ABUSERS

Cocaine dependence continues to be a major public health problem in the United States, accounting for significant medical morbidity and psychosocial problems.30 Despite the widespread use of psychosocial interventions in the management of patients with this disorder, high relapse rates and poor treatment responses are common in cocaine- dependent patients.43

Neurochemical Effects of Cocaine

The ability of cocaine to enhance dopaminergic neurotransmission in mesolimbic and mesocortical brain seems to be the basis for the positive reinforcing effects of this drug. Furthermore, symptoms that commonly occur upon cessation of cocaine use (e.g., cocaine craving, depressed mood, and sleep and appetite abnormalities) may serve as


negative reinforcement for cocaine use. Theoretically, for a medication to be effective in preventing relapse in cocaine dependence, it should block the positive and negative reinforcement produced by the drug. In addition to effects on learned behavior, long-term cocaine use may produce other persistent, clinically significant changes in neurotransmitter systems that can be remediated by treatment with medications.

Cocaine acutely enhances dopaminergic neurotransmission by bind- ing to the dopamine transporter protein and inhibiting the presynaptic reuptake of dopamine. Cocaine also potently inhibits the reuptake of norepinephrine and serotonin.@ Despite controversy concerning the existence and nature of a cocaine withdrawal syndrome, the symptoms that develop following cessation of heavy cocaine use have been thought to negatively reinforce cocaine use and have, therefore, been a major target of pharmacologic interventions. In this regard, a number of hypotheses have guided research aimed at identifying medications for use in the treatment of patients with cocaine dependence.

The dopamine depletion hypothesis posits that long-term cocaine use leads to dopamine depletion, which is thought to be a physiologic correlate of cocaine ~ithdrawa1.l~ According to this theory, potentiation of dopaminergic neurotransmission by dopamine agonists should counter the dopamine depletion and, thereby, alleviate cocaine withdrawal symptoms. A variety of agents that enhance dopaminergic transmission (e.g., bromocriptine, amantadine, mazindol, methylphenidate, and bupropion) have been evaluated for this purpose.3o

Another neurobiologic model of cocaine withdrawal symptoms pos- tulates that long-term cocaine use leads to noradrenergic or serotonergic dysfunction. Studies related to this model have examined the efficacy of tricyclic antidepressants (TCAs) in reducing cocaine withdrawal symptoms in an effort to reduce the risk for and severity of relapse to cocaine

33 Carbamazepine, a tricyclic anticonvulsant, has also been studied for the treatment of patients with cocaine dependence.I2 This is based on the hypothesis that kindling is a substrate for cocaine craving and that the antikindling effects of carbamazepine reduce cocaine craving. Finally, buprenorphine, an opioid partial agonist, has been studied for the treatment of patients with comorbid cocaine and opioid dependen~e.~

The variety of pharmacologic agents tested reflect the difficulties in identifying the neurochemical basis of cocaine dependence and the general lack of efficacy of any of the drugs examined. Because cocaine craving is of questionable value as a measure of treatment outcome, studies that focus exclusively on cocaine craving are not reviewed here. In addition, because many medications that seem promising in open trials are found not to be efficacious in controlled studies, this review covers only double-blind, placebo-controlled trials.

Dopaminergic Medications

Bromocriptine was the first dopamine agonist to be studied for the treatment of patients with cocaine dependen~e .~~ Although initial studies

418 KRANZLER et a1

showed this postsynaptic dopamine agonist to be significantly better than placebo in treating patients with cocaine-withdrawal symptoms, subsequent trials showed the medication to be either poorly tolerated or ineffective in reducing withdrawal symptoms or cocaine use.13 Given the lack of consistent findings, evidence to recommend the use of bromocriptine for the treatment of patients with cocaine dependence is inade- quate.

Amantadine, an indirect dopamine agonist, has also been studied for the treatment of patients undergoing cocaine ~ithdrawa1.I~ Most studies of this medication have focused on cocaine abusers, with or without comorbid opiate dependence. Of four controlled trials of amantadine in cocaine abusers, the active medication was found to be superior to placebo in only one. Similarly, methadone-maintained cocaine abusers receiving amantadine fared no better than did patients receiving placebo.17

Other dopaminergic medications that have been studied for the treatment of patients with cocaine dependence include mazindol, methylphenidate, and bupropion. Mazindol is a dopamine and norepinephrine reuptake inhibitor that is FDA-approved as an appetite suppressant. It binds to the dopamine transporter and, given limited abuse liability, was evaluated as a potential antagonist that might block the reinforcing effects of cocaine. Unfortunately mazindol was shown to be no better than placebo on any of the outcome measures when tested in either cocaine abusers or those with comorbid opiate and cocaine dependen~e.~O

Methylphenidate is a dopamine agonist commonly used for the treatment of attention-deficit hyperactivity disorder. Its use in cocaine abusers has been found to be problematic in that rather than reducing cocaine use, it seems to increase craving.30 It may, however, be of use in cocaine-dependent patients with comorbid attention-deficit hyperactivity disorder.

Antidepressants

Based on the rationale that depressive symptoms occurring during cocaine withdrawal may reflect dysregulation of norepinephrine and serotonergic systems, antidepressants have been studied as an adjunct to the psychosocial treatment of patients with cocaine dependence. Desi- pramine and imipramine have been the most widely tested agents for cocaine dependence. Bupropion, a second-generation antidepressant that inhibits dopamine and norepinephrine reuptake, has also been studied for the treatment of patients with cocaine dependence. The rationale for this is that by augmenting dopamine levels, bupropion may alleviate cocaine abstinence symptoms and dysphoria.

Initial trials with desipramine found the medication to be effective in decreasing cocaine use irrespective of a patient’s depression statusz; however, the samples used in these studies were heterogeneous; some


consisted of pure cocaine users, whereas others had substance-use disorders comorbid with other psychiatric disorders. Recent well-controlled studies have not replicated these findings.@ Among these is a 12-week, randomized, placebo-controlled trial comparing the single and combined effects of cognitive-behavioral treatment with desipramine on cocaine use in 139 cocaine 'abusers. Although desipramine significantly reduced cocaine use over 6 weeks, no effect was found at the end of the 12- week

Because of the heterogeneity of cocaine abusers, recent trials have sought to identify homogeneous subgroups?, 33 Cocaine-dependent patients with comorbid major depression comprise a subgroup that is of interest, particularly in relation to their response to antidepressant medication. A study by Carroll et aP showed desipramine to be no better than placebo in reducing cocaine use by cocaine abusers, irrespective of the presence of comorbid major depression; however, depressed patients treated with desipramine had a significantly greater reduction in depressive symptoms compared with those receiving placebo? These findings were replicated by Nunes et aP3 with the TCA imipramine.

In summary, although imipramine and desipramine do not seem to reduce cocaine use by cocaine abusers, they have been found to be efficacious antidepressants in this patient population. Similarly, bupropion was no more effective than was placebo in treating cocaine dependence in patients on methadone maintenance30; however, bupropion has not been tested in depressed patients with cocaine-use disorders.

To date, few controlled trials of SSRIs have been conducted in cocaine abusers.** Two randomized, double-blind, placebo-controlled trials examined the effects of fluoxetine on cocaine-dependent patients (n = 228) and on patients with cocaine and opiate dependence (n = 21)." In these studies, fluoxetine was not found to be useful in decreasing cocaine use.

Carbamazepine

Carbamezapine, an anticonvulsant used in the treatment of patients with a wide variety of neurologic and psychiatric disorders, has also been studied for the treatment of patients with cocaine dependence. Observations that cocaine induces neuronal kindling led Halikas et all2 to postulate an association between kindling induced by cocaine and craving for the drug. Because carbamazepine prevents neuronal kindling, it was hypothesized to reduce cocaine craving and therefore to be of value in the treatment of patients with cocaine dependence.

In a placebo-controlled, crossover trial with 32 crack cocaine users unmotivated for treatment, a modest but significant reduction in cocaine- positive urine specimens during carbamazepine treatment was observed. Greater improvement was associated with carbamazepine levels of 4 p,g/ mL or more; however, three subsequent double-blind, placebo-controlled trials failed to replicate these findings, with carbamazepine being shown

420 KRANZLER et a1

to be no better than placebo in decreasing cocaine use (reviewed in Halikas et all2).

Recently, in a double-blind study, 150 cocaine abusers were randomly assigned to receive placebo; carbamazepine, 400 mg; or carbamazepine, 800 mg.12 In this study, 400 mg/d of carbamazepine led to a significant decrease in the rate of cocaine-positive urine specimens, but the 800-mg/d dosage had no such effects. In attempting to understand these divergent findings, Halikas et all2 argue that high attrition rates in the negative studies limits the ability to interpret the findings. Taken together, however, these findings do not provide enough support for the use of carbamazepine in the treatment of patients with cocaine dependence.

Buprenorphine

Based on animal studies showing a reduction in cocaine self-administration in rodents and monkeys as a consequence of treatment with buprenorphine, this partial opiate agonist has been studied for the treatment of patients with comorbid cocaine and opioid dependence. Two double-blind, randomized trials showed buprenorphine (2-8 mg / d) to be no more efficacious than methadone (20-65 mg/d) in decreasing cocaine use among patients with comorbid opioid dependen~e.~

Conclusions on Medications for Relapse in Cocaine Abusers

Most medications studied for the treatment of patients with cocaine dependence have targeted the treatment of withdrawal states. For instance, because patients are particularly vulnerable to relapse during early cocaine abstinence because of the presence of dysphoria and other depressive symptoms, the use of antidepressants was thought to be of value by reducing depressive symptoms and cocaine craving, thereby decreasing the risk for relapse. Unfortunately, initial reports that TCAs facilitate abstinence have not been replicated; however, their use seems justifiable in the subgroup of cocaine abusers with comorbid major depression. Similarly, the use of newer antidepressants (e.g., fluoxetine or bupropion) for patients with cocaine dependence without comorbid major depression does not seem to be justified.

Of the many neurochemical theories proposed to explain cocaine withdrawal, the dopamine depletion hypothesis has had the greatest influence in the evaluation of pharmacologic agents affecting dopaminergic transmission (e.g., amantadine, bromocriptine, methylphenidate, bupropion, and mazindol). Trials with these agents have also failed to provide consistent support for their use. A similar lack of consistent support has been obtained in trials of carbamazepine and buprenorphine. Although no single agent has consistently shown positive results


for the treatment of patients with cocaine dependence, some subgroups of cocaine abusers (i.e., those with comorbid major depression) may benefit from pharmacotherapy.

Heterogeneity among cocaine abusers has complicated the search for pharmacologic agents to treat the disorder. In addition to psychiatric comorbidity, factors, such as route of administration and severity of dependence, may also be important in determining treatment response. For example, intranasal and intravenous users may respond differently to TCAS.~~ Other methodologic issues identified in pharmacologic trials for cocaine dependence have been high rates of attrition and of placebo response and the use of multiple outcome measures, including psycho- pathologic symptoms, subjective cocaine effects, craving, cocaine use, and treatment retention.

Apart from methodologic issues, conceptual barriers may impede progress toward the identification of efficacious medications for cocaine abuse. For instance, controversies exist regarding the existence of a cocaine withdrawal syndrome and the clinical relevance of cocaine craving; however, reductions in putative withdrawal symptomatology and cocaine craving have been major goals of pharmacotherapy. Future pharmacotherapy studies should focus on reducing the positive reinforcing effects of cocaine and base the determination of efficacy on the reduction of cocaine use.

Pharmacotherapy remains a relatively underused strategy for the treatment of patients with psychoactive substance-use disorders. This is partly because of a widely held view among the public and the substance-abuse treatment community that substance-use disorders are non- medical and should be treated through nonpharmacologic means. Fur- thermore, the pharmaceutical industry has been slow in developing medications for the treatment of patients with these disorders because of skepticism over the potential profitability of such medications. These factors have limited research activity in this area, with much of the impetus for study of these medications coming from the National Insti- tute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, where the substantial public health implications of medications development for substance-use disorders have been recognized. Despite limitations, considerable advances in medication development for patients with substance-use disorders have occurred in recent years, and more can be expected in the near future. This is most evident in the treatment of patients with nicotine and opioid dependence, for whom several pharmacologic options exist. Recently renewed interest in the pharmacologic treatment of patients with alcohol dependence is likely to advance that therapeutic area substantially with time. Ongoing efforts should focus on identifying new compounds, systematically assessing them for activity in specific substance-use disorders, and educating the

422 KRANZLER et a1

public and the treatment community about the substantial benefits that can accrue from medication development for patients with substance- use disorders.

References

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Address reprint requests to Henry R. Kranzler, MD

University of Connecticut Health Center 263 Farmington Avenue, MC2103

Farmington, CT 06030

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PHARMACOLOGIC TREATMENTS FOR DRUG AND ALCOHOL DEPENDENCE

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