Disulfiram for Cocaine Abuse

This study examines the influence of dopamine beta-hydroxylase enzyme activity on the clinical efficacy of the novel pharmacotherapy, disulfiram, for treating cocaine dependence in cocaine-dependent patients, some of whom are opioid dependent and maintained on an FDA-approved opioid agonist. Cocaine dependence as well as co-morbid cocaine and opioid-dependence is associated with more public health issues and poorer treatment prognosis when admitted to methadone maintenance. Yet no effective pharmacotherapies have been developed to treat cocaine dependence to date. One novel pharmacotherapy, disulfiram, has shown some promise as a treatment for this disorder in several clinical trials at a dose of 250 mg/day or more (e.g., Carroll et al., 1998, 2004). This 14-week, randomized, double blind clinical trial will provide treatment for up to160 cocaine-dependent individuals, aged 18-65 years. Participants who are opioid dependent will be stabilized on methadone maintenance during the first 2 weeks and baseline cocaine use will be assessed; participants will be stratified by DBH genotype and randomly assigned to receive disulfiram at either 0, 250, 375 or 500 mg/day. During induction onto methadone for opioid dependent individuals, participants are administered increasing doses of methadone on a daily basis until maintenance doses are attained. At the beginning of week 3, participants receive methadone, if relevant, plus disulfiram or placebo disulfiram according to their randomized assignments, and are maintained on study medication(s) through week 14. At the end of the study, participants will undergo detoxification from the opioid agonist, if relevant, and active/placebo medication over a 4- to 6-week period. All participants receive weekly 1-hour psychotherapy (Cognitive Behavioral Treatment) with experienced clinicians specifically trained to deliver the therapy and who will receive ongoing supervision. Participants undergo a delay discounting session during week 1. The primary outcomes will be retention, reduction in opioid and cocaine use, as assessed by self-report and confirmed by thrice-weekly urinalyses, and disulfiram side-effects profile. Secondary outcomes will include reductions in other illicit drug and alcohol use, and improvements in psychosocial functioning. The prognostic relevance of genotype at the DBH locus, DβH activity, etc., on response to disulfiram will be examined.

Study Overview

• Status: Completed
• Conditions: Cocaine Dependence
• Intervention / Treatment: Drug: Disulfiram

• Study Type: Interventional
• Enrollment (Actual): 118
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• current users of cocaine, including having a cocaine-positive urine
• self-reported use of > 7 gm during the preceding 6 months and > 1 time/week in at least one month preceding study entry
• meet DSM-IV criteria for cocaine dependence

Exclusion Criteria:

• current diagnosis of alcohol dependence
• significant medical conditions such as abnormal liver function
• active hepatitis
• hypertension
• a current cardiac condition or high risk of cardiovascular disease
• seizure disorders
• any another significant underlying medical condition which would contraindicate disulfiram or methadone treatment
• meeting DSM-IV psychiatric classifications for schizophrenia, bipolar disorder, or other psychotic disorders
• exhibiting current suicidality or homicidality
• pregnancy
• current use of a prescribed psychotropic medication (e.g., antidepressants, anxiolytics, antipsychotics, anticonvulsants, etc.) which cannot be discontinued current use of medications such as anticoagulants, isoniazid, metronidazole, clotrimazole, and paraldehyde.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 1; microcrystalline cellulose	Drug: Disulfiram; Disulfiram at 0, 250, 375, or 500 mg/day for 12 weeks
Experimental: 2; disulfiram at 250 mg/day	Drug: Disulfiram; Disulfiram at 0, 250, 375, or 500 mg/day for 12 weeks
Experimental: 3; Disulfiram at 375 mg/day	Drug: Disulfiram; Disulfiram at 0, 250, 375, or 500 mg/day for 12 weeks
Experimental: 4; Disulfiram at 500 mg/day	Drug: Disulfiram; Disulfiram at 0, 250, 375, or 500 mg/day for 12 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cocaine Use Over Time	Urine toxicology results (dichotomous: positive or negative) for the presence of cocaine/cocaine metabolite during the disulfiram phase of the study. The change in the probability of a cocaine positive urine sample per day was assessed for each dose compared with placebo and slopes for each dose condition were calculated from Repeated Measures Genearlized Linear Models on a Binomial distribution (thus a Repeated Measures Logistic Regression)	thrice weekly for 12 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Retention	14 weeks

Collaborators and Investigators

• Sponsor: University of Arkansas
• Collaborators: National Institute on Drug Abuse (NIDA)
• Investigators: Principal Investigator: Alison Oliveto, Ph.D., University of Arkansas

Study record dates

Study Major Dates

• Study Start: April 1, 2007
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: November 2, 2006
• First Submitted That Met QC Criteria: November 2, 2006
• First Posted (Estimate): November 3, 2006

Study Record Updates

• Last Update Posted (Estimate): November 13, 2013
• Last Update Submitted That Met QC Criteria: September 6, 2013
• Last Verified: September 1, 2013

More Information

Terms related to this study

• Keywords: pharmacogenetics; clinical trial; cocaine dependence; methadone maintenance; disulfiram; dopamine beta-hydroxylase
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Cocaine-Related Disorders; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Alcohol Deterrents; Acetaldehyde Dehydrogenase Inhibitors; Disulfiram
• Other Study ID Numbers: NIDA-13441; DPMC (Other Identifier: NIDA); R01DA013441 (U.S. NIH Grant/Contract); 5R01DA013441-02 (U.S. NIH Grant/Contract); 5R01DA013441-03 (U.S. NIH Grant/Contract); 5R01DA013441-04 (U.S. NIH Grant/Contract); 5R01DA013441-06 (U.S. NIH Grant/Contract); 1R01DA013441-01A1 (U.S. NIH Grant/Contract); 7R01DA013441-05 (U.S. NIH Grant/Contract); 5R01DA013441-09 (U.S. NIH Grant/Contract); 5R01DA013441-10 (U.S. NIH Grant/Contract); 5R01DA013441-08 (U.S. NIH Grant/Contract)