Disulfiram-treated patients averaged more than twice as many weeks of abstinence from cocaine as placebo-treated patients during the course of the 12-week trial.

A NIDA-supported study has found evidence that combining disulfiram, a medication long used to treat alcohol addiction, with buprenorphine, a new opiate-addiction treatment medication awaiting approval by the Food and Drug Administration (FDA), can reduce cocaine abuse among the more than 50 percent of heroin-addicted individuals who also abuse cocaine. In the study, patients addicted to both opiates and cocaine who were treated with a combination of disulfiram and buprenorphine achieved 3 weeks of continuous abstinence from cocaine faster and stayed abstinent longer than those who received only buprenorphine.

"This study provides evidence that this well-established treatment for alcoholism, disulfiram, works with the newest opiate treatment medication, buprenorphine, to reduce cocaine abuse in opiate addicts," says Dr. Tony George of Yale University Medical School in New Haven, Connecticut, one of the study's investigators. "Buprenorphine is expected to be used widely to treat heroin addiction once it is approved by FDA. If additional research confirms our results, disulfiram may be a useful adjunct to buprenorphine for physicians to use with patients who also abuse cocaine," he says.

In the study, which was led by Dr. Richard Schottenfeld, also of Yale, 20 patients addicted to heroin and cocaine were treated with buprenorphine for their opiate addiction. Eleven of these patients were randomly assigned to receive disulfiram also, and nine to get placebo pills. Of the 15 patients who completed the 12-week study, the 8 disulfiram-treated patients were abstinent from cocaine for 7.8 weeks compared to 3.3 weeks of abstinence for the 7 placebo-treated patients. Nearly half of the patients in both groups achieved 3 weeks of continuous abstinence, but disulfiram-treated patients achieved that measure after 24.6 days, less than half the 57.8 days it took placebo-treated patients. Opiate use declined in both groups with no significant differences between disulfiram and placebo-treated groups over the course of the study.

Disulfiram and Cocaine, Alcohol, and Heroin Addiction

The findings from this study join a growing body of evidence from other Yale studies in recent years that disulfiram may reduce cocaine abuse among patients who also are addicted to alcohol or heroin, says Dr. Schottenfeld. Initially, scientists began to look at whether disulfiram would reduce cocaine use because of the medication's known aversive effects on alcohol, he explains. Marketed as Antabuse, disulfiram has been used by physicians for more than 40 years to treat alcoholism. Patients who drink alcohol while on this medication can experience unpleasant reactions such as nausea, vomiting, and flushing.

Initial studies at Yale indicated that disulfiram decreases abuse of both cocaine and alcohol in patients who abuse both substances. Those findings are being tested now in a NIDA-funded study at the University of Pennsylvania in Philadelphia. Results from the Philadelphia study could provide independent confirmation of the Yale findings and yield additional information about the strong link between alcohol and cocaine use, says Dr. Maria Majewska of NIDA's Division of Treatment Research and Development. "Some 70 to 80 percent of cocaine-dependent individuals also abuse alcohol," she notes.

Last year, Yale researchers found that disulfiram also reduces cocaine use among opiate-dependent methadone treatment patients who use very little alcohol. "Since the opiate addicts in our new study also used little alcohol, these two studies suggest that disulfiram may be reducing cocaine use directly and not as a result of its effects on alcohol use," Dr. George says.

Exploring How Disulfiram Works

While the main goal of disulfiram research now under way is to confirm disulfiram's efficacy in treating cocaine abuse, researchers also are seeking to increase understanding about how disulfiram works to inhibit this abuse. Understanding this process could lead to development of a new class of cocaine treatment medications that would better target this mechanism with increased efficacy and reduced adverse effects. (See "Large Study Expands Probe of Disulfiram's Effects on Cocaine Use".)

Disulfiram may exert its anticocaine effects by increasing levels of the brain chemical dopamine through blocking the activity of an enzyme called dopamine-b-hydroxylase (DBH) that metabolizes the brain chemical dopamine. Since cocaine also boosts dopamine activity in the brain, the combination of disulfiram and cocaine may raise dopamine to excessive levels, producing a reaction that increases unpleasant effects associated with cocaine, such as anxiety and paranoia, Dr. Schottenfeld hypothesizes. This hypothesis is supported by laboratory studies at Yale in which disulfiram-treated patients had a more sustained physiological response to cocaine and reported that they experienced unpleasant, often anxiety-related, effects from it, he says.

Additional evidence that DBH may play a role in producing aversive reactions to cocaine comes from recent genetic studies at Yale led by Dr. Joseph Cubells. Dr. Cubells found that cocaine-abusing patients whose genetic makeup predicts low levels of DBH were much more paranoid than those with genes predicting high DBH activity. "The more frequent occurrence of this paranoia in low-DBH individuals may result from cocaine interacting with their genetic makeup to produce some form of functional hyperstimulation of their dopamine systems," Dr. Schottenfeld says.

Disulfiram may curb cocaine use through a DBH-mediated increase in dopamine levels in two slightly different but related ways, says Dr. Schottenfeld. When people stop using cocaine they may experience a decline in dopamine function and crave the drug to compensate for this reduction, he says. "In the absence of cocaine, disulfiram may increase dopamine levels sufficiently to reduce the drive to use cocaine," he says. "However, if a patient on disulfiram slips and uses cocaine, the medication may make cocaine's effects so unpleasant they deter further use."

Sources

Carroll, K.M.; Nich, C.; Ball, S.A.; McCance, E.; and Rounsaville, B.J. Treatment of cocaine and alcohol dependence with psychotherapy and disulfiram. Addiction 93(5):713-727, 1998. [Abstract]

Cubells, J.F., et al. A haplotype at the DBH locus associated with low plasma dopamine beta-hydroxylase activity, also associates with cocaine-induced paranoia. Molecular Psychiatry 5(1):56-63, 2000.

George, T.P.; Chawarski, M.C.; Pakes, J.; Carroll, K.M.; Kosten, T.R.; and Schottenfeld, R.S. Disulfiram versus placebo for cocaine dependence in buprenorphine-maintained subjects: a preliminary trial. Biological Psychiatry 47(12):1080-1086, 2000.

McCance-Katz, E.F.; Kosten, T.R.; and Jatlow, P. Disulfiram effects on acute cocaine administration. Drug and Alcohol Dependence 52(1):27-39, 1998.

Petrakis, I.L., et al. Disulfiram treatment for cocaine dependence in methadone-maintained opioid addicts. Addiction 95(2):219-228, 2000. [Abstract]