Pharmacogenetics of Disulfiram for Cocaine
Study Details
Study Description
Brief Summary
Previous research has shown that disulfiram, a medication sometimes used for treating alcoholism, discourages cocaine use among cocaine addicts who are undergoing methadone treatment. By blocking the enzyme dopamine beta hydroxylase (DBH), disulfiram increases levels of dopamine and produces an unpleasant sense of hyperstimulation and discomfort in cocaine users. This study will evaluate the effectiveness of disulfiram in preventing drug relapse among cocaine and opiate addicts with varying inherited levels of DBH.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
Dopamine, a type of neurotransmitter, is the brain's "feel good" chemical. The amount of dopamine in the body may be an important factor in how cocaine addicts respond to treatment. Disulfiram, like cocaine, enhances dopamine activity. Upon taking disulfiram, subsequent intake of cocaine may elevate dopamine to excessive levels that produce extreme discomfort. DBH is an enzyme that breaks down dopamine. A particular variation in the DBH gene can affect the amount of dopamine that is released in the body. Therefore, cocaine addicts with varying DBH genes may respond differently to treatment. The purpose of this study is to compare the effectiveness of disulfiram in preventing relapse among methadone-maintained individuals addicted to both cocaine and opioids who may have different DBH genes.
This 17-week study will begin with a 2-week methadone stabilization period. Participants will then be randomly assigned to receive a daily dose of either 250 mg of disulfiram or placebo for 12 weeks, while concurrently receiving methadone treatment. All participants will stop receiving study medication at Week 14, at which point they will undergo a 4-week methadone detoxification period. Participants will report cocaine and other drug use, as well as any cocaine cravings that they experience. Cocaine levels will be monitored throughout the study with urine tests. The DBH gene of each participant will be examined to determine its specific make-up and any particular variations.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Disulfiram, Methadone (w/lactose) & CBT Participants are randomly assigned to receive a daily dose of 250 mg of disulfiram for 12 weeks, while concurrently receiving methadone treatment. All participants will stop receiving study medication at week 14, at which point they will undergo a 4-week methadone detoxification period. |
Drug: Disulfiram
Disulfiram 250 mg/day by mouth daily during study weeks 2-13. Disulfiram discontinued during study weeks 14-15.
Other Names:
Drug: Methadone
Initial dose 25 mg; increased by 5 mg at each subsequent daily dosing until 60 mg maintenace dose reached.
Other Names:
Behavioral: CBT
1-hour weekly, individual, manual-guided Cognitive Behaviorial Therapy.
Other Names:
Other: Lactose
Lactose was added to both the active disulfiram and placebo doses so they tasted identical.
Other Names:
|
| Active Comparator: Placebo, Methadone (w/lactose) & CBT Participants are randomly assigned to receive a daily dose of a sugar pill to mimic the experimental drug disulfiram for 12 weeks, while concurrently receiving methadone treatment. All participants will stop receiving all medication at week 14, at which point they will undergo a 4-week methadone detoxification period. |
Drug: Methadone
Initial dose 25 mg; increased by 5 mg at each subsequent daily dosing until 60 mg maintenace dose reached.
Other Names:
Behavioral: CBT
1-hour weekly, individual, manual-guided Cognitive Behaviorial Therapy.
Other Names:
Other: Lactose
Lactose was added to both the active disulfiram and placebo doses so they tasted identical.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Urine Toxicology for Cocaine. [Thrice weekly, baseline through week 14.]
Secondary Outcome Measures
- Retention by Treatment Condition. [12 weeks]
Treatment retention for full 12 weeks of study.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Meets DSM-IV diagnosis criteria for opioid dependence, as determined by documentation of prior treatment for addiction; signs of withdrawal; self-reported history of dependence for at least 1 year; and a positive urine test for opioids
-
Meets DSM-IV diagnosis criteria for cocaine dependence, as determined by self-reported use of cocaine at least once weekly for at least 1 month prior to study entry; a positive urine test for cocaine; and a score greater than 3 on the Severity Dependence Scale
-
If female, willing to use contraception throughout the study
Exclusion criteria:
-
Meets DSM-IV diagnosis criteria for dependence on any drugs other than opiates, cocaine, or tobacco
-
Current major psychiatric illness, including schizophrenia, bipolar disorder, or other psychotic disorder
-
Current suicidal or homicidal ideation
-
Current use of a prescribed psychotropic medication that cannot be discontinued
-
History of or current major medical illness, including major heart, kidney, endocrine, or liver disorder; abnormal liver function (SGOT or SGPT levels three times greater than normal);
-
High risk factor for heart disease, seizure disorders, or any illness for which disulfiram or methadone treatment would be inadvisable
-
Currently taking metronidazole or clotrimazole
-
Pregnant or breastfeeding
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Michael E. DeBakey VA Medical Center | Houston | Texas | United States | 77030 |
Sponsors and Collaborators
- Baylor College of Medicine
- National Institute on Drug Abuse (NIDA)
- Yale University
Investigators
- Principal Investigator: Thomas R. Kosten, MD, Baylor College of Medicine
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- NIDA-18197-2
- P50DA018197-02
Study Results
Participant Flow
| Recruitment Details | The 74 opioid and cocaine dependent subjects were drawn from a sample of 93 candidates who entered into a 2-week screening period for stabilization on methadone maintenance between 2005 and 2006 at Yale University (n=40) and then from between 2006 and 2008 at Baylor College of Medicine (n=53). |
|---|---|
| Pre-assignment Detail | Eleven subjects were excluded prior to randomization because they did not have at least one urine toxicology positive for opiates or cocaine metabolites during the two-week screening. Another eight subjects were lost to follow-up prior to randomization. |
| Arm/Group Title | Disulfiram | Placebo |
|---|---|---|
| Arm/Group Description | 250 mg/day with methadone daily during study weeks 2-13. Medication will be discontinued during study weeks 14-15. | Inactive medication (placebo) with methadone daily during study weeks 2-13. Inactive medication will be discontinued during study weeks 14-15. |
| Period Title: Overall Study | ||
| STARTED | 34 | 40 |
| COMPLETED | 26 | 35 |
| NOT COMPLETED | 8 | 5 |
Baseline Characteristics
| Arm/Group Title | Disulfiram | Placebo | Total |
|---|---|---|---|
| Arm/Group Description | 250 mg/day with methadone daily during study weeks 2-13. Medication will be discontinued during study weeks 14-15. | Inactive medication (placebo) with methadone daily during study weeks 2-13. Inactive medication will be discontinued during study weeks 14-15. | Total of all reporting groups |
| Overall Participants | 34 | 40 | 74 |
| Age (Count of Participants) | |||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
34
100%
|
40
100%
|
74
100%
|
| >=65 years |
0
0%
|
0
0%
|
0
0%
|
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
37.5
(10.5)
|
40
(10)
|
38.75
(10)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
10
29.4%
|
12
30%
|
22
29.7%
|
| Male |
24
70.6%
|
28
70%
|
52
70.3%
|
| Region of Enrollment (participants) [Number] | |||
| United States |
34
100%
|
40
100%
|
74
100%
|
Outcome Measures
| Title | Urine Toxicology for Cocaine. |
|---|---|
| Description | |
| Time Frame | Thrice weekly, baseline through week 14. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 74 cocaine and opioid-codependent (DSM-V) subjects were stabilized on methadone for 2 weeks and subsequently randomized into disulfiram (250mg/day, n=34) and placebo groups (n=40) for 10 weeks. We genotyped the DBH gene polymorphism that reduces DBH enzyme levels and evaluated its role for increasing cocaine free urines with disulfiram. |
| Arm/Group Title | Placebo CC | Placebo CT/TT | Disulfiram CC | Disulfiram CT/TT |
|---|---|---|---|---|
| Arm/Group Description | Subjects who received placebo with a genotype of CC. | Subjects who received placebo with genotype CT/TT. | Subjects who received Disulfiram with genotype CC. | Subjects who received Disulfiram with genotype CT/TT. |
| Measure Participants | 21 | 19 | 17 | 17 |
| Mean (Standard Error) [% cocaine + urines over 2 week blocks] |
84
(5)
|
68
(5)
|
56
(5)
|
67
(5)
|
| Title | Retention by Treatment Condition. |
|---|---|
| Description | Treatment retention for full 12 weeks of study. |
| Time Frame | 12 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| 74 cocaine and opioid-codependent(DSM-V)subjects were stabilized on methadone for 2 weeks and subsequently randomized into disulfiram (250 mg/day, n=34) and placebo groups (n=40) for 10 weeks. We genotyped the DBH gene polymorphism that reduced DBH enzyme levels and evaluated its role for increasing cocaine free urines with disulfiram. |
| Arm/Group Title | Disulfiram | Placebo |
|---|---|---|
| Arm/Group Description | 250 mg/day with methadone daily during study weeks 2-13. Medication will be discontinued during study weeks 14-15. | Inactive medication (placebo) with methadone daily during study weeks 2-13. Inactive medication will be discontinued during study weeks 14-15. |
| Measure Participants | 34 | 40 |
| Number [% of subjects who complete 12 wks study] |
77
|
87
|
Adverse Events
| Time Frame | ||||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | Disulfarim | Placebo | ||
| Arm/Group Description | 250 mg/day with methadone daily during study weeks 2-13. Study medicine discontinued during study weeks 14-15. | Inactive medicine (placebo)with methadone during study weeks 2-13. Inactive medicine discontinued during study weeks 14-15. | ||
All Cause Mortality |
||||
| Disulfarim | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Disulfarim | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/34 (0%) | 0/40 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Disulfarim | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/34 (8.8%) | 1/40 (2.5%) | ||
| Psychiatric disorders | ||||
| Suicide gesture. | 0/34 (0%) | 0 | 1/40 (2.5%) | 1 |
| Renal and urinary disorders | ||||
| Reduced sexual functioning. | 1/34 (2.9%) | 1 | 0/40 (0%) | 0 |
| Vascular disorders | ||||
| Arm numbness. | 1/34 (2.9%) | 1 | 0/40 (0%) | 0 |
| Arm numbness and back rash. | 1/34 (2.9%) | 1 | 0/40 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Thomas R. Kosten, M.D. |
|---|---|
| Organization | Baylor College of Medicine |
| Phone | (713) 794-7032 |
| kosten@bcm.edu |
- NIDA-18197-2
- P50DA018197-02