Cocaine abuse and dependence may be initiated and perpetuated by a wide range of physiologic, behavioral, and sociocultural factors. Recent treatment-center evaluations of urban, economically disadvantaged cocaine abusers revealed that 73 percent had one or more personality disorders. Accordingly, the use of existing medications and the development of new ones should be based on accurate diagnosis and a consideration of the multiple interactive processes that may have contributed to the genesis and continuation of cocaine abuse and dependence.

A number of drugs have been used to treat cocaine-related problems, in part because of the postulated role of antecedent disorders in the genesis of chronic abuse, as well as the neurobiologic consequences of abuse and dependence. For example, clinical observations of dysphoric mood changes during cocaine intoxication and withdrawal have led to the use of antidepressant drugs to treat cocaine abuse and dependence. However, the diversity of patterns of use and routes of administration, as well as the concurrent abuse of other drugs, complicates judgments about the efficacy of medication. The conclusions of studies of drugs in persons who use cocaine intranasally (by insufflation) may not apply to persons who inhale cocaine (as crack) or use intravenous cocaine, alone or in combination with opiates. Moreover, drugs that appear to be effective in cocaine abusers may not be useful in treating cocaine dependence.

The evaluation of drug efficacy must be based on the severity of illness. The Addiction Severity Index is one test that facilitates the grading of substance-abuse disorders and is important for research on the treatment of cocaine abuse and dependence. Judgments about drug efficacy can only be made in relation to ratings of the biobehavioral severity of cocaine abuse or dependence.

This position was clearly articulated in a recent review of research and clinical perspectives on the treatment of cocaine abuse and dependence that was prepared for the National Institute on Drug Abuse. This report emphasized the need to pay more attention to research design, the analysis of treatment methods, research on treatment, and the specification of important diagnostic and demographic characteristics of patients participating in studies of pharmacologic or behavioral treatment.

Many approaches to the treatment of cocaine abuse and dependence have also been used in treating patients with alcoholism and other substance-abuse disorders. There has been interest in comparing the effectiveness of drug therapy with that of psychotherapy, as well as with behavioral treatments of cocaine abuse and dependence. In this review we primarily discuss pharmacotherapeutic approaches to the management of cocaine abuse and dependence, but some recent advances in behavioral treatment are also described. The rationale for the use of various classes of medications is presented in the following sections, with data on treatment outcome. Any assessment of the efficacy of therapy for cocaine abuse and dependence is complicated by the high frequency of abuse of other substances.

Antidepressant Drugs

Dysphoric moods are frequently reported after the cessation of cocaine use. Clinical observations of depression have provided a rationale for exploring the effectiveness of antidepressant drugs in treating cocaine abuse. Although depression may precede or follow cocaine use, it was hypothesized that ameliorating symptoms of depression might decrease such use. Desipramine, an antidepressant, has been used for both cocaine detoxification and the maintenance of abstinence. A 1984 report that this drug was safe and effective in treating cocaine abuse led to a placebo-controlled, double-blind assessment of the relative efficacy of desipramine in 72 cocaine-dependent persons treated at an outpatient clinical facility. The results indicated that desipramine was beneficial, but in subsequent trials it was found not to be effective in treating patients with cocaine dependence. The assessment of this treatment is complicated by the fact that many cocaine abusers often abuse other substances, such as opiates, and there is considerable disagreement about the effectiveness of desipramine for patients who abuse or are dependent on opiates. At present, desipramine appears to be most effective for persons with diagnosed cocaine abuse who have antecedent or consequent symptoms of severe depression. Desipramine is often ineffective in treating cocaine dependence. The results of two recent clinical trials indicated that fluoxetine is ineffective in treating cocaine dependence with or without concurrent dependence on opiates. Other antidepressant drugs, including imipramine and trazodone, have also been used, but they have more adverse effects than desipramine.

Drugs Affecting Dopaminergic Function
The rationale for the use of dopamimetic drugs to treat cocaine abuse and dependence is based in part on the effects of cocaine on dopamine-transporter systems; cocaine blocks the reuptake of dopamine and acts as an indirect dopamine agonist. Moreover, chronic exposure to cocaine is postulated to affect dopaminergic function in the brain adversely (dopamine depletion). A less toxic drug similar to cocaine could be substituted for cocaine in a manner analogous to the use of methadone in opiate-abuse treatment. Unfortunately, the relative effectiveness of dopamimetic drugs in treating cocaine abuse and dependence is often severely compromised by adverse effects, including gastrointestinal disorders such as nausea and abdominal pain, headaches, cardiovascular instability, hypertension, and psychosis-like illness. A number of agonists and antagonists for highly selective dopamine D1, D2, and D3 receptors have also been developed, and although preclinical studies show many to be effective in reducing cocaine use, none are approved for clinical use.

Bromocriptine, a dopamimetic drug used to treat hyperprolactinemia, has been evaluated in both open and placebo-controlled trials. Bromocriptine was reported to decrease the craving for cocaine during detoxification and to reduce dysphoria during both detoxification and abstinence. The dopamine agonist methylphenidate was found to increase rather than decrease the craving for cocaine. Amantadine has also been used in the detoxification of cocaine-dependent patients. An encouraging report of the effectiveness of amantadine in reducing cocaine craving was not confirmed by a double-blind, placebo-controlled study. Both open and placebo-controlled, double-blind studies designed to compare amantadine with desipramine as a treatment for patients in methadone-maintenance programs who also had cocaine abuse or dependence indicated that both drugs increased the time during which patients remained in the programs.

Mazindol inhibits the binding of cocaine to dopamine transporters in the brain. In controlled studies, mazindol neither attenuated the subjective effects associated with intravenous cocaine use in abusers of the drug nor reduced cocaine-induced craving. Bupropion, an antidepressant, was no more effective than placebo in treating cocaine dependence in patients in methadone-maintenance programs. Flupentixol, a dopamine-receptor antagonist, has antidepressant effects at low doses and neuroleptic effects at high doses. Initial open-label studies suggest that flupentixol may be useful in treating cocaine abuse and dependence.

Tryptophan and tyrosine, dietary amino acid precursors of dopamine, have been administered in open-label studies for both cocaine detoxification and the maintenance of abstinence. However, there is no evidence that either is effective for the treatment of cocaine abuse and dependence. In a placebo-controlled, double-blind study, levodopa and carbidopa together did not attenuate symptoms of abstinence after the cessation of cocaine use.

Opioid Antagonists and Mixed Agonist–Antagonists

One rationale for the use of opioid antagonists (such as naltrexone) or opioid mixed agonist–antagonists (such as buprenorphine) to treat cocaine abuse and dependence is that these conditions may be preceded or accompanied by abuse of or dependence on opiates. Endogenous opioid systems in the brain may also be involved in the reinforcing effects of other abused substances, including cocaine and alcohol. Compliance with naltrexone therapy for opiate abuse and dependence has been poor, however, even when there is no cocaine abuse or dependence. No clinical trials of the effectiveness of naltrexone in treating cocaine abuse and dependence have been conducted as yet, but naltrexone appeared more effective than methadone in reducing the abuse of cocaine by opiate-dependent patients. Naltrexone has usually been ineffective in reducing cocaine self-administration in preclinical studies.

In contrast, the opioid-agonist properties of buprenorphine appear to make it more acceptable to patients than naltrexone, even though the two drugs antagonize opioid effects equally well. Buprenorphine is currently under review by the Food and Drug Administration (FDA) for the treatment of opioid dependence, and initial clinical trials were encouraging. In preclinical studies, buprenorphine reduced cocaine use significantly.71,90 Clinical studies of inpatients have demonstrated that buprenorphine is safe in combination with cocaine. Ongoing clinical trials suggest that buprenorphine reduces cocaine abuse as well as opiate abuse in patients who are dependent on both drugs according to the criteria in the third edition of the Diagnostic and Statistical Manual of Mental Disorders, revised.

Carbamazepine

Carbamazepine is an anticonvulsant drug used to treat seizure disorders. In an open trial, 200 to 800 mg of carbamazepine two to four times daily suppressed the craving for cocaine and decreased cocaine use, but carbamazepine was no more effective than placebo in several subsequent clinical trials.