Addictive disorders, including alcohol, drug, and nicotine dependence, afflict more than 30% of Americans,1 and are associated with considerable morbidity, mortality, social problems, and high health care costs.2-3 One way to reduce the impact of these disorders is through drug and alcohol treatment, defined as medical, psychological, and social interventions to reduce or eliminate the harmful effects of psychoactive substances on the individual, his or her family and associates, and others in society. However, treatment is not always as completely successful as clinicians would wish it to be. Addictive disorders are chronic, relapsing disorders and often require repeated treatment episodes. Sixty percent or more of patients with addictive disorders experience a relapse within the year following treatment.4
In the past several years, there has been increasing interest in the use of pharmacotherapies to improve the effectiveness of treatments for alcoholism and drug dependence. Advances in addiction neurobiology have led to an increased understanding of the neurochemistry of drug and alcohol dependence and to the use of medications to treat these disorders. This article discusses the use of pharmacotherapies in the treatment of addictive disorders, the putative mechanisms of action of the medications, and the evidence for their efficacy.
MECHANISMS OF ACTION OF PHARMACOTHERAPIES
The task of the patient in recovery is to avoid psychoactive substances, to develop better methods of coping with stress and distress, and to improve self-esteem and self-efficacy. Pharmacologic treatment can be used to assist recovery as a component of a comprehensive treatment program that includes psychosocial therapies, such as counseling and self-help groups. Pharmacotherapies can treat alcohol and drug dependence through several mechanisms that may reduce some of the impetus for drug use. These mechanisms and the medications that may operate through these mechanisms are depicted in the table.
Alcohol and drug intoxication are characterized by both pleasurable, stimulating effects and aversive effects. Because the positively reinforcing stimulant effects of alcohol and drugs are thought to initiate and to maintain drug use,5 a pharmacotherapy that reduces the pleasurable, positive reinforcing effects of the drug may decrease alcohol consumption. A pharmacotherapy that increases the aversive or punishing effects of the drug can also decrease consumption by punishing drug ingestion.
The withdrawal syndrome that follows the cessation of the use of drugs and alcohol is unpleasant, is often painful to experience, and may be associated with morbidity and mortality for some drugs, such as sedatives and alcohol. An agent that decreases the distressing symptoms of abstinence and withdrawal can reduce the tendency to relapse.
A craving or an urge to use alcohol and drugs is associated with an increased probability of relapse, particularly early in the posttreatment period.6 Craving can be induced in a number of different ways. In recently abstinent patients, the central nervous system disturbance, sleep disturbance, and dysphoric mood associated with substance withdrawal may elicit craving. However, for some patients external cues, such as exposure to sights, sounds, or smells associated with drug use, and internal cues, such as anger or sadness, can elicit craving for alcohol or drugs after prolonged periods of abstinence. A pharmacotherapy that decreases craving or urge can decrease consumption.
Classes of Pharmacotherapies Used for Addiction Treatment
Alcohol and drug dependence are common in patients with certain psychiatric disorders, especially schizophrenia, panic disorder, and depression.1 A pharmacotherapy that can reduce psychiatric symptoms of the comorbid psychiatric disorder may reduce part of the need to use alcohol or drugs for self-medication.
PHARMACOLOGIC TREATMENT OF ALCOHOL DEPENDENCE
Disulfiram and Calcium Carbimide: Aversive Therapy
Disulfiram and calcium carbimide are examples of medications that can increase the unpleasant, punishing effects of alcohol. Disulfiram irreversibly inhibits the enzyme acetaldehyde dehydrogenase, and causes an accumulation of toxic levels of acetaldehyde whenever alcohol is consumed. Tachycardia, skin flushing, diaphoresis, dyspnea, nausea, and vomiting characterize the distilfiram-alcohol reaction. Hypotension, cardiac problems, and death may occur if large amounts of alcohol are consumed. The possibility of this unpleasant reaction provides a strong deterrent to the consumption of alcohol for some patients.7
Unfortunately, there are few rigorously controlled clinical trials on the efficacy of disulfiram. A large, multicenter, double-blind treatment study comparing the effectiveness of disulfiram with placebo found the medication to be no more effective than placebo.8 More recent studies suggest that direct supervision of disulfiram ingestion and involvement in psychosocial treatment increase its effectiveness. Despite questions about its efficacy and its potential toxicity, many patients and clinicians feel disulfiram can be a useful adjunct to treatment. Some patients use disulfiram episodically during periods of high risk for relapse; others use the medication continuously for years.
Calcium carbimide is a reversible inhibitor of acetaldehyde dehydrogenase that has been used in Canada and European countries to reduce drinking in alcohol-dependent patients.9
Opioid Antagonists: Naltrexone Hydrochloride and Nalmefene Hydrochloride
The observations that opioid antagonists generally reduce alcohol consumption in animals led to the use of the opioid antagonist naltrexone hydrochloride in alcohol-dependent humans. In two 12-week, randomized, placebocontrolled, clinical trials, naltrexone hydrochloride treatment enhanced the effectiveness of psychosocial therapies for recently abstinent alcohol-dependent patients.10·11 Based on these studies, the Food and Drug Administration (FDA) approved naltrexone hydrochloride as an adjunct in the treatment of alcoholism in 1994. Evidence suggests that opioid antagonists may have a dual mechanism of action to reduce alcohol consumption- blockade of positive, reinforcing effects of alcohol and suppression of craving.
Naltrexone hydrochloride is recommended for use in the first 90 days of abstinence, when the risk of relapse is highest; however, it has been shown to be generally safe and well tolerated by alcoholic patients for periods of up to a year. The most common side effects were anxiety, sedation, and nausea in approximately 10% of patients.12 Patients taking naltrexone hydrochloride will be insensitive to opioid effects, including analgesia, although this effect will dissipate within 72 hours of drug discontinuation. The effect can be reversed with carefully monitored high-dose opiates, in case opioid analgesics are required emergently. Although high doses of naltrexone hydrochloride (300 mg daily) have been associated with hepatotoxicity, significant deleterious hepatic effects are rarely observed with 50-mg daily doses. A recently published treatment improvement protocol (TIPS) provides comprehensive information and guidelines on naltrexone hydrochloride treatment.13
Nalmefene hydrochloride is a µ-opioid antagonist that is approved for the reversal of acute opioid intoxication and overdose. A small clinical trial in alcohol-dependent patients comparing two doses of oral nalmefene hydrochloride with placebo found increased abstinence in the higher dose medication group.
Acamprosate is a structural analogue of taurine, which was found to reduce alcohol consumption in several animal models of alcoholism. Acamprosate can reduce the neuronal hyperexcitability of alcohol withdrawal, resulting in reduced withdrawal distress and craving.14 In several European clinical trials involving alcohol-dependent patients, acamprosate reduced relapse drinking and craving for alcohol and had minimal side effects.15 In most of these studies, twice as many patients receiving acamprosate were totally abstinent from alcohol at the end of the treatment period, lasting up to 1 year, than were those receiving placebo.
Acamprosate has now been administered to more than 4,000 alcohol-dependent patients in placebo-controlled, clinical trials in ten European countries. The main adverse effects appear to be diarrhea and headache. An ongoing multicenter clinical trial of acamprosate in the United States is comparing placebo with daily acamprosate doses of 2000 and 3000 mg.
Sedatives and Anticonvulsants
Although benzodiazepines are the most common medications used for alcohol detoxification, most addiction professionals discourage their use as maintenance pharmacotherapies for alcohol dependence, to reduce drinking, and to prevent relapse. In the past, some alcoholics were maintained with daily doses of benzodiazepines or other sedatives in a poorly monitored and uncontrolled fashion, often leading to the development of sedative dependence. The anticonvulsant carbamazepine has been used successfully to treat alcohol withdrawal-16 and is reported to reduce alcohol consumption in alcohol-dependent subjects. A small, double-blind study of 29 alcohol-dependent subjects receiving carbamazepine or placebo showed reduced drinking during medication treatment.
Alcohol has effects on serotonin (5HT) and this has led to the use of serotonergic medications as adjuncts in alcoholism treatment. Buspirone is an anxiolytic with partial agonist activity at the 5HT-Ia receptor and 5HT-2 receptor, and antagonist activity at the dopamine-2 receptor. A double-blind study found that nonanxious alcoholics receiving buspirone did not reduce drinking or experience less craving than those receiving placebo, although the subjects' psychological status improved.17
Selective serotonin reuptake inhibitors (SSRIs), which augment serotonergic function and are used clinically as antidepressants and anxiolytics, also appear to reduce alcohol consumption in animals. Studies on humans who drink heavily found that SSRIs reduce alcohol consumption by 15% to 20%. 18 Other studies with alcohol-dependent patients have yielded less impressive results. A 3-week prospective study on the effects of fluoxetine found reductions in alcohol intake during the first week only. A double-blind study comparing fluoxetine with placebo treatment, in which both groups received cognitive-behavioral psychotherapy, found no difference in drinking for nondepressed patients.19 Although the mechanism of action of SSRIs is unknown, some subjects report decreased desire for and liking of alcohol.
The most widely used pharmacologic treatments for opioid-dependent individuals include pharmacologic maintenance treatments with the opiate agonists methadone hydrochloride and 1-alpha-acetylmethodol (LAAM), maintenance with the partial opiate agonist buprenorphine hydrochloride, and opiate antagonist therapy with naltrexone hydrochloride. All of these medications are best used in the setting of a structured, maintenance treatment program that includes monitored medication administration, periodic, random urine toxicologic screening to assess compliance, and intensive psychological, medical, and vocational services.
Agonist substitution treatments maintain opioid dependence in a safe and controlled manner. Substitution treatments reduce the use of illicit opiates by increasing drug tolerance, thereby decreasing the subjective effects of illicitly administered opiates, and by stabilizing mood, thereby decreasing self-medication. Substitution treatments also provide an incentive for treatment so that patients may be exposed to other therapies.
Methadone Hydrochloride Maintenance
Methadone hydrochloride is a synthetic opiate that is orally active, possesses a long duration of action, produces minimal sedation or "high," and has few side effects at therapeutic doses. Many studies have shown the efficacy of methadone hydrochloride maintenance in the treatment of addicts who are dependent on heroin and other opiates.20 Patients treated with methadone hydrochloride show increased retention in treatment, improved physical health, decreased criminal activity, and increased employment. Methadone hydrochloride is most effective in the context of a program that provides intensive psychosocial and medical services, provides flexibility in methadone hydrochloride dosing, and allows higher doses of methadone hydrochloride.21 The use of methadone hydrochloride for maintenance is highly regulated by government agencies.
Methadone hydrochloride is dissolved in a flavored liquid, and is administered to patients daily, under observation. Long-standing program participants are allowed "take-home" doses of methadone hydrochloride, which they may self-administer. Doses of methadone hydrochloride usually range from 20 to more than 100 mg per day. Higher doses are shown to be generally associated with better retention in treatment. Urine toxicologic screening is performed randomly and periodically to assess compliance with treatment. Counseling and other rehabilitative services are provided on a regular basis.
L-Alpha-Acetylmethodol Acetate (LAAM)
LAAM is a long-acting, orally active opiate with pharmacologic properties that are similar to those of methadone hydrochloride. Studies on LAAM have shown it to be equal to or superior to methadone hydrochloride maintenance in reducing intravenous drug use, when used in the context of a structured maintenance treatment program.22 The advantages of LAAM include a slower onset of effects and a longer duration of action than methadone hydrochloride. This allows LAAM to be administered only 3 times per week, and potentially reduces the use of take-home medications that may be diverted to illegal uses. Patients treated with LAAM should be started on 20 mg administered 3 times weekly, with the dose increased weekly in 10-mg increments as necessary. Doses up to 80 mg 3 times weekly are safe and effective in reducing drug use.
The partial agonist (mixed agonist-antagonist) opiate medication buprenorphine hydrochloride is used medically as an analgesic. The drug has both agonist and antagonist properties-agonist properties predominate at lower doses and antagonist properties predominate at higher doses. These properties have led to its use as a substitution/maintenance treatment of opioid dependence. In the setting of a structured treatment program, daily dosing of buprenorphine has been shown to be effective in the maintenance treatment of narcotics addicts.23 Buprenorphine hydrochloride may also reduce cocaine use (see below). Medication doses usually range O-Om 4 to 16 mg per day, administered sublingually because the medication is not effective orally. Advantages of buprenorphine hydrochloride include a müder withdrawal syndrome on discontinuation and less potential for abuse, as agonist effects diminish at higher doses. Opioid-dependent patients may be started on 2 to 4 mg of buprenorphine hydrochloride immediately after opiates are discontinued, and the dose of buprenorphine hydrochloride titrated to 8 to 16 mg during several days.
Pharmacotherapy with the reversible opioid antagonist naltrexone hydrochloride has been shown to reduce the use of illicit drugs.24 Naltrexone hydrochloride blocks the intoxicating effects of opioids, blocks craving for opioids, and has few effects in individuals not dependent on opioids. There is evidence that opiate antagonists may block craving for alcohol, cocaine, and nicotine as well. The usual dose of naltrexone hydrochloride is 50 mg per day, administered orally, although 3 times weekly dosing with 100, 100, and 150 mg has also been shown to be effective. High doses of naltrexone hydrochloride have been associated with hepatotoxicity; however, few deleterious hepatic effects are observed using a 50 mg per day dose. Other possible side effects include anxiety, sedation, and nausea in some patients. Naltrexone hydrochloride therapy has been shown to be most effective in highly motivated individuals with good social supports. Patients receiving naltrexone hydrochloride must be opiate free for a period of approximately 2 weeks, or they may experience severe opiate withdrawal symptoms. Opiate abstinence can be assessed with urine toxicology screens and by a naloxone hydrochloride challenge test.
Ultra-rapid Opioid Detoxification
The opioid withdrawal syndrome that occurs following cessation of opioid use in dependent persons is characterized by sympathetic hyperactivity, anxiety, agitation, pain, and intense craving for opioids. These are extremely distressing and often lead to reinstitution of opioid use. Reduction of withdrawal signs and symptoms is usually accomplished through slow taper of opiates or the use of blocking agents, such as Clonidine. The administration of opioid antagonists, such as naloxone hydrochloride or naltrexone hydrochloride, during the withdrawal period reduces the duration of withdrawal, but significantly increases withdrawal intensity. Recently, a number of clinicians have combined opioid antagonists and Clonidine with conscious sedation or general anesthesia in a technique called ultra-rapid opioid detoxification (UROD). Using this technique, opioid-dependent patients may be detoxified in less than 24 hours. Proponents of the technique claim that the detoxification is safe and results in long-term abstinence. However, there are few controlled studies to compare the efficacy and safety of UROD with that of more traditional detoxification methods.25
Several pharmacologic agents have been tested as adjuncts in the treatment of cocaine dependence, with the goal of reducing craving and relapse. Although some agents (including the antidepressant desipramine hydrochloride, the dopamine agonist bromocriptine mesylate, the stimulant methylphenidate hydrochloride, and the partial opioid antagonist buprenorphine hydrochloride) have shown initial promise, follow-up studies with these agents have not demonstrated widespread success. Currently, no pharmacologic agent has been approved for the treatment of cocaine dependence.
The antidepressant desipramine has been reported to be efficacious for some cocaine users in reducing craving and helping them to remain abstinent, even when depression is not present. The doses used have been similar to those used in the treatment of depression (50 to 150 mg per day, usually at night). The major side effects include sedation and dry mouth. However, more recent studies have found only minimal, if any, efficacy in the treatment of cocaine dependence.26
Bromocriptine mesylate is a dopamine agonist used in the treatment of Parkinson's disease and prolactin-secreting pituitary tumors. Low doses of bromocriptine mesylate (0.125 mg every 6 hours) have been reported to be helpful in reducing craving and discomfort in the early stages of cocaine abstinence, but not all studies have shown effectiveness. Amantadine hydrochloride, mazindol, and other dopamine agonists have been tried in cocaine dependence, but have not been found to be particularly effective. Recently, the indole alkaloid ibogaine has been shown to decrease stimulant use in animals; it is being tested in cocaine-dependent humans.27
Methylphenidate hydrochloride is a psychomotor stimulant with noradrenergic and dopaminergic effects. Some researchers have reported that methylphenidate hydrochloride may reduce cocaine relapse, particularly in patients who also have attention deficit hyperactivity disorder (ADHD). The doses used are 15 to 60 mg daily. Because methylphenidate hydrochloride is a controlled substance with abuse potential, careful selection of patients is necessary.
Buprenorphine hydrochloride is a partial opiate agonist that has been used for analgesia and maintenance treatment in opiate addicts (see above). Patients with combined opiate and cocaine dependence who receive buprenorphine hydrochloride maintenance treatment show significant reductions in their use of cocaine, compared with patients receiving methadone hydrochloride maintenance.28
Tobacco use is a major public health problem due to its association with cancers and cardiovascular disease. Patients who are unable to quit smoking on their own and to remain abstinent may be helped by pharmacotherapies, including nicotine replacement therapy and antidepressants.
The principle of nicotine replacement therapy is to provide the nicotine-dependent patient with nicotine in a form not associated with the carcinogenic and irritant elements in tobacco products. Two methods of nicotine administration have been approved- nicotine gum and the transdermal nicotine patch. A third method, intranasal nicotine, is under consideration by government agencies. Although nicotine replacement has been used primarily for detoxification and relief of withdrawal symptoms during smoking cessation, some patients use nicotine replacement in a maintenance fashion.
Nicotine Gum. Nicotine gum consists of 2 mg of nicotine complexed to a polacrilex resin matrix, also containing sweeteners and flavors. The gum is placed in the mouth and chewed slowly to release the nicotine from the matrix. When tingling of the mouth or tongue is perceived, chewing should cease for a short period of time, while the gum is held in the mouth. Too rapid chewing releases excess nicotine and may cause nausea and other side effects. The gum is chewed for 20 to 30 minutes and then may be discarded. This method produces nicotine blood levels that rise and fall, partially mimicking smoking. The gum is available by prescription in units of 96 pieces.
Nicotine Transdermal Patches. The nicotine patch consists of various doses of nicotine (7, 14, and 21 mg) impregnated into an adhesive patch for transdermal administration. This method produces nicotine blood levels that are relatively constant throughout the period of application. One patch is applied to uncovered skin each 24hour period and the previous patch is discarded. Some individuals wear the patches during the daytime only and remove them while asleep. Side effects include irritation from the patch and nicotine effects (eg, nausea, cardiac effects). It is important that patients not use tobacco products while using the patch, as toxic nicotine blood levels may occur. The patches are available by prescription.
Bupropion Hydrochloride and Other Antidepressants. Several clinical studies have shown a high incidence of major depression occurring within days to weeks following smoking cessation and nicotine withdrawal. Patients with a personal or a family history of affective illness appear to be at most risk for depression. Antidepressants have been shown to reduce the prevalence of depression and to improve the chances of remaining abstinent from nicotine. Antidepressants reported as effective for smoking cessation block norepinephrine and/or dopamine reuptake and include desipramine hydrochloride, doxepin hydrochloride, and buproprion hydrochloride. Sustained-release bupropion hydrochloride was recently approved by the FDA as a pharmacotherapy for smoking cessation in nondepressed smokers. Bupropion hydrochloride reduces nicotine withdrawal signs and symptoms and may reduce weight gain.29 It can be used together with nicotine replacement for an additive effect.
PHARMACOLOGIC TREATMENT OF COMORBID PSYCHIATRIC DISORDERS
Affective disorders, anxiety disorders, and psychotic disorders are frequently observed in patients with addictive disorders. The treatment of the patient with comorbid psychiatric and substance abuse diagnoses (dual diagnosis) presents a particular challenge to the clinician. The presence of a comorbid psychiatric disorder may result in resistance to addiction treatment because of the need to use drugs and alcohol for self-medication. Appropriate pharmacologic treatment of the psychiatric disorder reduces the need for self-medication and improves the ability to respond to psychosocial treatment. In the case of alcohol dependence, pharmacotherapy of anxiety with buspirone and of depression with antidepressants has been shown to be effective in reducing psychiatric symptoms and maintaining retention in treatment.
FUTURE DIRECTIONS IN PHARMACOTHERAPY FOR ALCOHOL ABUSE AND DEPENDENCE
Several important issues arise in the use of pharmacotherapies for the treatment of alcohol dependence. First, pharmacotherapies should never be used as a sole treatment, but rather as part of a comprehensive treatment program that addresses the psychological, social, and spiritual needs of the patient. Second, compliance with medication is a major factor in the effectiveness of naltrexone hydrochloride, and presumably all pharmacotherapies. Therefore, techniques to enhance compliance are key in the use of pharmacotherapies. Adequate provider and patient education about indications, optimal dosing, and the risks and benefits of pharmacotherapies is necessary to promote compliance. The use of compliance-enhancing injectable, depot forms of medication is being explored for disulfiram and naltrexone hydrochloride. Third, whether a specific pharmacologic agent is best suited for a specific type of patient or for a specific type of alcoholism is unknown. It is possible that multiple medications administered together or in sequence may be required to obtain optimal treatment effectiveness. Finally, the cost effectiveness of medication compared with other forms of therapy will be an important factor in the decision of third-party payers to accept the use of pharmacotherapies, and should be actively studied.
1. Regier DA, Farmer ME, Rae DS. Comorbidity of mental disorders with alcohol and other drug abuse. JAMA 1990;264:2511-2518.
2. McGinnis JM, Foege WH. Actual causes of death in the United States. JAMA. 1993;270:2201-2212.
3. Rice DP. The economic cost of alcohol abuse and alcohol dependence. Alcohol Health Res World. 1990;17:10-11.
4. Brownell KD, Marlatt GA, Lichtenstein E, Wilson GT. Understanding and preventing relapse. Am Psychol. 1986;41:765-782.
5. Wise RA, Bozarth MA. A psychomotor stimulant theory of addiction. Psychiatry Rev. 1987;94:469-492.
6. Rohsenow D, Monti PM1 Abrams DB. Cue elicited urge to drink and salivation in alcoholics: relationship to individual differences and relapse. Advances in Behavior Research Therapy. 1992;14:195-210.
7. Chick J, Gough K, Falkowski W. Disulfiram treatment of alcoholiem. Br J Psychiatry. 1992;161:84-89.
8. Fuller RK, Branchley L, Brightwell DR, et al. Disulfiram treatment of alcoholism: a Veterans Administration cooperative study. JAAiA. 1986;256:1449-1455.
9. Annis HM, Peachey JE. The use of calcium carbimide in relapse prevention counselling: results of a randomized controlled trial. Br J Addict. 1992;87:63-72.
10. Volpiceli! JR, Alterman AI, Hayashida M, O'Brien CP. Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry. 1992;49:876-880.
11. (TMalley SS, Jafle AJ, Chang G, Schottenfeld RS, Meyer RE, Rounsaville B. Naltrexone and coping skille therapy for alcohol dependence. Arch Gen Psychiatry. 1992; 49:881-887.
12. Croop RS, Faulkner EB, Labriola DF. The safety profile of naltrexone in the treatment of alcoholism: results from a multicenter usage study. ArcA Gen Psychiatry. 1997;54:1130-1135.
13. Substance Abuse and Mental Health Services Administration. Treatment Improvement Protocol: Naltrexone in the Treatment of Alcohol Dependence. Washington, DC: Department of Health and Human Services; 1997. Treatment Improvement Protocols (TIPS).
14. Littleton J. Acamprosate in alcohol dependence: how does it work? Addict ion. 1995;90:1179-1188.
15. Sass H, Soyka M, Mann K, Zieglgansberger W. Relapse prevention by acamprosate: results from a placebo-controlled study on alcohol dependence. Arch Gen Psychiatry. 1996;53:673-680.
16. Malcolm R, Ballenger JC, Sturgis ET, Anton R. Double blind controlled trial comparing carbamazepine to oxazepam treatment of alcohol withdrawal. Am J Psychiatry. 1989;146:617-621.
17. Malee E, Malee T, Gagne MA, Dongier M. Buspirone in the treatment of alcohol dependence: a placebo-controlled trial. Alcohol Clin Exp Res. 1996;20:307-312.
18. Naranjo CA, Bremner KE. Clinical pharmacology of serotonin-altering medications for decreasing alcohol consumption. Alcohol Alcohol Suppl- 1993;2:221-229,
19. Kranzler HR, Burleson JA, Körner P1 et al. Placebo-controlled trial of fluoxetine as an adjunct to relapse prevention in alcoholics. Am J Psychiatry. 1995;152:391-397.
20. Senay E. Methadone maintenance treatment. Int J Addictions. 1985;20:803-821.
21. D'Aunno T, Vaughn TE. Variations in methadone treatment practices. JAMA. 1992;267:253-258.
22. Ling W, Rawson RA, Compte« PA. Substitution pharmacotherapies for opioid addiction: from methadone to LAAM and buprenorphine. J Psychoactive Drugs. 1994;26:119-128.
23. Compton PA, Wesson DR, Charuvastra VC, Ling W. Buprenorphine as a pharmacotherapy for opiate addiction. Am J Addict. 1996;5:220-230.
24. Ginzburg HM. Naltrexone: Its Clinical Utility. Rockville. MD: Department of Health and Human Services; 1986. NIDA Treatment Research Report. Vol. (ADM) 86-1358.
25. O'Connor PG1 Kosten TR. Rapid and ultrarapid opioid detoxification techniques. JAMA. 1998;279:229-234.
26. Levin FR, Lehman AF. Meta-analysis of desipramine as an adjunct in the treatment of cocaine addiction. J Clin Psyckopharmacol. 1 99 1 ; 1 1 :374-378.
27. Sershen H1 Hashim A1 Lajtha A. Ibogaine and cocaine abuse: pharmacological interactions at dopamine and serotonin receptors. Brain Res Bull. 1997;42:161-168.
28. Kosten TR, Kleber HD, Morgan C. Treatment of cocaine abuse with buprenorphine. Biol Psychiatry. 1989;26:637639.
29. Hurt RD, Sachs DP, Glover ED, et al. A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med. 1997;337:1195-1202.
Classes of Pharmacotherapies Used for Addiction Treatment