Randomized clinical trial of disulfiram for cocaine dependence or abuse during buprenorphine treatment.
BACKGROUND
Disulfiram may be efficacious for treating cocaine dependence or abuse, possibly through inhibiting dopamine β-hydroxylase (DβH). Consequently, this randomized, placebo-controlled clinical trial of disulfiram during buprenorphine maintenance treatment evaluated the study hypothesis that disulfiram is superior to placebo and explored whether disulfiram response is greatest for participants with a single nucleotide polymorphism coding for genetically low DβH (T-allele carriers).


METHODS
We randomized 177 buprenorphine-treated opioid dependent participants with cocaine dependence or abuse to 12 weeks of double-blind treatment with disulfiram 250mg daily (n=91) or placebo (n=86). Of 155 participants genotyped, 84 were CC-homozygous, and 71 CT or TT genotypes. Primary outcomes included days per week cocaine use, number of cocaine-negative urine tests, and maximum consecutive weeks of cocaine abstinence. We analyzed an intention-to-treat comparison between disulfiram and placebo. We also explored potential pharmacogenetic interactions and examined treatment responses of four participant groups based on medication (disulfiram or placebo) by genotype (CC-homozygous or T-allele carrier) classification.


RESULTS
Disulfiram participants reported significantly less frequent cocaine use; the differences in cocaine-negative urine tests or consecutive weeks abstinence were not significant. Frequency of cocaine use was lowest in disulfiram-treated T-allele carriers; differences in cocaine-negative urine tests or consecutive weeks abstinence were not significant among the four medication-genotype groups.


CONCLUSIONS
The findings provide limited support for the efficacy of disulfiram for reducing cocaine use and suggest that its mechanism of action may involve inhibition of DβH. Further studies of its efficacy, mechanism of action, and pharmacogenetics of response are warranted.
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States. Electronic address: richard.schottenfeld@yale.edu.
Richard S
RS
Schottenfeld
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States.
Marek C
MC
Chawarski
Departments of Genetics and Psychiatry and Behavioral Sciences, Emory University School of Medicine, United States.
Joseph F
JF
Cubells
Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto, Faculty of Medicine, Canada.
Tony P
TP
George
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States.
Jaakko
J
Lappalainen
Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine and Michael E. DeBakey VA Medical Center, United States.
Thomas R
TR
Kosten
D000293:Adolescent; D000328:Adult; D000427:Alcohol Deterrents / Q000009:adverse effects / Q000627:therapeutic use*; D000437:Alcoholism / Q000188:drug therapy / Q000235:genetics / Q000523:psychology; D000483:Alleles; D002047:Buprenorphine / Q000009:adverse effects / Q000627:therapeutic use*; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000235:genetics / Q000523:psychology; D004247:DNA / Q000235:genetics; D003627:Data Interpretation, Statistical; D004221:Disulfiram / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009292:Narcotic Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D009293:Opioid-Related Disorders / Q000150:complications; D010597:Pharmacogenetics; D016133:Polymerase Chain Reaction; D018401:Sample Size; D016896:Treatment Outcome; D055815:Young Adult
D000427:Alcohol Deterrents; D009292:Narcotic Antagonists; D002047:Buprenorphine; D004247:DNA; D004221:Disulfiram
Buprenorphine pharmacogenetics; Cocaine abuse or dependence; DBH genotype; Disulfiram