CLINICAL QUESTION

Is disulfiram effective in the treatment of cocaine dependence?

EVIDENCE-BASED ANSWER

Disulfiram appears to increase point abstinence (i.e., the number of abstinent participants at completion of treatment) compared with placebo (risk ratio [RR] = 1.58; 95% CI, 1.05 to 2.36; number needed to treat [NNT] = 6). Disulfiram does not appear to affect frequency of cocaine use, amount of use, continuous abstinence, or drop-out rate compared with no treatment or placebo.¹ (Strength of Recommendation: C, consensus, usual practice, disease-oriented evidence, case series for studies of treatment or screening, and/or opinion.)

DISCUSSION

Cocaine use disorder is defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5) as cocaine use plus clinically significant impairment or distress caused by at least two of the following criteria from four groups in the preceding 12 months: (1) physiologic criteria, including craving, tolerance, and withdrawal; (2) loss of control of cocaine use; (3) cocaine use taking precedence over other activities (e.g., responsibilities at home, work, or school); and (4) other negative consequences from cocaine use.² Cocaine dependence, or cocaine use disorder, affects millions of people globally, and approximately 21.5 million people aged 15 to 64 years used cocaine at least once in 2020.³ Among people 12 years and older in the United States in 2021, the latest year for which statistics are available, 4.8 million people reportedly used cocaine and 996,000 people used crack cocaine.⁴

Disulfiram was initially synthesized in 1881 for use in industrial processes and was found to be effective in treating alcohol use disorder because it inhibits the enzyme aldehyde dehydrogenase.^1,5 Disulfiram may be effective for cocaine dependence by decreasing synthesis of norepinephrine, thus improving the functioning of mesolimbic circuits disrupted in cocaine dependence.¹ The authors of this review sought to assess the effectiveness of disulfiram in the treatment of cocaine dependence.

This Cochrane review included 13 randomized controlled trials (RCTs) with 1,191 participants with cocaine dependence according to DSM criteria (DSM-III-R; DSM-IV, DSM-5).¹ The mean duration of treatment was 11.7 weeks (range = 8 to 12 weeks). Most participants were male (72.1%; range = 48% to 100%), and the mean age range was 28.6 to 41.6 years. Eleven of the RCTs were conducted in the United States, most at a single institution. Five RCTs enrolled people with comorbid alcohol misuse or dependence, and six RCTs included people with comorbid opioid dependence or opioid use disorder receiving treatment with methadone. The amount of cocaine used was variously measured by weight in grams, weight expressed in bags or dimes, or in terms of money spent purchasing cocaine. Disulfiram dosages ranged from 62.5 mg per day to 400 mg per day, with most studies using 250 mg per day. Participants in all of the RCTs received psychosocial treatment.

Disulfiram was compared with no pharmacotherapy, placebo, or naltrexone (Revia).¹ Primary outcomes assessed included frequency of cocaine use, amount of cocaine use, continuous abstinence from cocaine, point abstinence from cocaine, dropout for any reason, dropout due to adverse events, any adverse event, and serious adverse events. Secondary outcomes assessed were individual adverse events, craving, severity of dependence, or psychiatric symptoms/psychological distress (e.g., depression, anxiety).

Compared with placebo, disulfiram appeared to increase point abstinence at the end of treatment (RR = 1.58; 95% CI, 1.05 to 2.36; NNT = 6; two RCTs; n = 142).1 Disulfiram did not appear to impact frequency of use, amount of use, continuous abstinence, or drop-out rate compared with no pharmacotherapy or placebo. In studies comparing disulfiram with naltrexone, disulfiram may have reduced the frequency of cocaine use (mean difference = −1.90 days; 95% CI, −3.37 to −0.43; two data sets; 123 participants), although it had little to no effect on the amount of use, and the evidence was rated as low.

Currently, no pharmacotherapy has been approved by the U.S. Food and Drug Administration for cocaine dependence.¹

No current guidelines recommend the use of disulfiram for treating cocaine dependence or cocaine use disorder. There are several potential adverse effects associated with disulfiram, including hepatotoxicity, cardiovascular and psychiatric complications, and disulfiram-alcohol interaction.1 Given the potential adverse effects and lower strength of evidence from this systematic review, clinicians should use caution when considering this treatment.

The practice recommendations in this activity are available at https://www-cochrane-org.lib3.cgmh.org.tw:30443/CD007024.