INVITED EDITORIAL
DISULFIRAM, COCAINE, AND ALCOHOL: TWO OUTCOMES FOR THE PRICE OF ONE?
1 National Addiction Centre, Maudsley Hospital/Institute of Psychiatry, King's College London, London SE5 8BB, UK and 2 Division of Substance Abuse, Yale University School of Medicine, West Haven CT 06516, USA
* Author to whom correspondence should be addressed at: E-mail: M.Gossop{at}iop.kcl.ac.uk.
The concurrent abuse of cocaine and alcohol is a common phenomenon, and is increasingly recognized as a difficult clinical issue. Several effective pharmacotherapies for substance dependence disorders have been identified, though the search for an effective pharmacotherapy for cocaine dependence has proved difficult. However, it has been suggested that disulfiram may offer a promising treatment option.
The randomized, placebo-controlled study of Carroll et al. (2004)
provides some of the strongest evidence to date regarding the effectiveness of disulfiram treatment in reducing cocaine use. In a large general outpatient sample, cocaine users were assigned either to disulfiram treatment or to a placebo condition to control for medication expectancies. All participants were cautioned not to drink alcohol during the study. Participants assigned to disulfiram reduced their cocaine use more than the placebo group, and the results were confirmed by urine analysis. Adverse effects of disulfiram were generally mild and these did not differ significantly from the placebo condition.
An interesting question is whether the effects of disulfiram upon cocaine use are indirect and associated with the aversive effects of disulfiram when alcohol is used, or whether disulfiram may also have direct effects on cocaine use which are independent of its effects on alcohol. The rewarding effects of both cocaine and alcohol are mediated by the mesolimbic pathway, with the two substances acting synergistically to increase dopaminergic activity. Disulfiram increases brain dopamine concentrations by inhibition of dopamine-catabolizing enzymes (particularly dopamine beta hydroxylase), and it is possible that disulfiram could exert a direct effect through its action on dopaminergic mechanisms (McCance-Katz et al., 1998).
Although disulfiram may have direct mechanisms of action on brain substrates related to addiction, its effectiveness in the treatment of alcohol dependence is undoubtedly related to its deterrent effect. Because alcohol and cocaine are so often taken together, early studies used disulfiram specifically to tackle alcohol use among cocaine users (Carroll et al., 1998): it was assumed that reductions in alcohol use would reduce alcohol-related cues for cocaine use, lessen problems of alcohol-related impairments in judgement, and reduce exposure to cocaethylene, a product of the combined use of alcohol and cocaine which produces euphoric effects indistinguishable from those of cocaine, and which has a half-life three times that of cocaine.
Carroll et al. (2004) found that disulfiram's effects on cocaine use were evident among those who abstained from alcohol during the trial. One explanation could be, if disulfiram did indeed have an action on cocaine use, that those who did not drink tended to be more compliant with their study medication. For patients who drank alcohol, cocaine outcomes for disulfiram were not statistically significantly different from placebo. For this reason, disulfiram therapy might, paradoxically, be particularly appropriate for the treatment of cocaine problems among drug users who are not regular or problematic drinkers. Further research is required to determine if disulfiram is more effective in the treatment of specific subgroups of cocaine users.
A study in this issue of Alcohol and Alcoholism (Gossop et al., 2006) confirms that heavy drinking is common among cocaine users, but also shows differences in alcohol consumption between users of cocaine powder and crack cocaine. Cocaine powder users reported more frequent heavy drinking than crack users, and drinking often involved excessive amounts over prolonged periods. So disulfiram may be better suited for use with crack users (i.e. less alcohol involvement in their cocaine use). Similarly, where cocaine misuse occurs in conjunction with heroin dependence, rates of alcohol abstinence can be surprisingly high. In a national study of drug treatment, more than a third of drug dependent patients reported abstinence from alcohol during the 3 months prior to treatment (Gossop et al., 2003). Where disulfiram is used to treat substance misusers with combined cocaine and alcohol problems, efforts should be made to enhance patient commitment to alcohol abstinence.
As with other substance misuse treatments, and especially with treatments for cocaine problems, treatment adherence is a relevant issue for disulfiram therapy. Carroll et al. (2004) found that compliance with medication was related to cocaine use outcomes: only half of their sample completed the course of treatment, with lower treatment adherence rates among the alcoholic participants who drank while taking disulfiram. When these patients experienced a disulfiram reaction, they effectively broke the medication masking, and many either stopped taking disulfiram entirely, or discontinued it when they wanted to drink alcohol or use cocaine. In this respect, the effect of disulfiram treatment in cocaine abusers may be mediated by its impact on alcohol use. Instead of reducing cocaine use through first stopping drinking, the aversive effects of disulfiram may have led drinkers to stop taking disulfiram. On the other hand, because patients who did not drink alcohol continued to be ‘blind’ to their medication, they may have continued to take the active medication sufficiently to benefit from an anti-cocaine effect.
Where a pharmacotherapy targets more than a single problem substance, this represents an important additional bonus. However, even the most powerful pharmacotherapies for substance use disorders may not be effective if provided as ‘stand-alone’ interventions. Treatment outcomes have been shown to be improved when pharmacotherapies are provided in conjunction with appropriate psychosocial treatments, and behavioural therapies can also be used to enhance treatment adherence and effectiveness.
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Carroll, K. M., Nich, C., Ball, S. A. et al. (1998). Treatment of cocaine and alcohol dependence with psychotherapy and disulfiram. Addiction 93, 713–728.[CrossRef][Web of Science][Medline]
Carroll, K. M., Fenton, L., Ball, S. et al. (2004) Efficacy of disulfiram and cognitive behavior therapy in cocaine-dependent outpatients. Archives of General Psychiatry 61,264–272.
Gossop, M., Browne, N., Stewart, D. et al. (2003) Alcohol use outcomes and heavy drinking at 4–5 years among a treatment sample of drug misusers. Journal of Substance Abuse Treatment 25, 135–143.[CrossRef][Web of Science][Medline]
Gossop, M., Manning, V., Ridge, G. (2006) Concurrent use of alcohol and cocaine: differences in patterns of use and problems among users of crack cocaine and cocaine powder. Alcohol and Alcoholism.
McCance-Katz, E. F., Kosten, T. R., Jatlow, P. M. (1998) Disulfiram effects on acute cocaine administration. Drug and Alcohol Dependence 52, 27–39.[CrossRef][Web of Science][Medline]
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