Cocaine Dependence
Conditions
Keywords
cocaine dependence, disulfiram, clinical trial, methadone maintenance, pharmacogenetics, dopamine beta-hydroxylase
Brief summary
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.
Interventions
DRUGDisulfiram
Disulfiram at 0, 250, 375, or 500 mg/day for 12 weeks
Sponsors
National Institute on Drug Abuse (NIDA)
University of Arkansas
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cocaine Use Over Time | thrice weekly for 12 weeks | 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) |
Secondary
| Measure | Time frame |
|---|---|
| Retention | 14 weeks |
Countries
United States
Participant flow
Recruitment details
Recruitment occurred between April 2006 and September 2011. Opioid- or nonopioid dependent treatment seekers recruited via newspaper ads, radio ads, flyer, word-of-mouth and referrals and attended the Treatment Research Unit, initially located in an off-campus facility and then relocated to the the Psychiatric Research Institute (12/08).
Pre-assignment details
Participants underwent either a two-week induction onto methadone (if opioid dependent) or a two-week baseline period prior to randomization to the treatment arms and receiving medication starting in week 3. Those receiving at \>1 dose of medication and completing assessments at at least 2 time points during week 3 were include in the analyses.
Participants by arm
| Arm | Count |
|---|---|
| Placebo microcrystalline cellulose | 27 |
| Disulfiram 250 disulfiram at 250 mg/day | 25 |
| Disulfiram 375 Disulfiram at 375 mg/day | 30 |
| Disulfiram 500 Disulfiram at 500 mg/day | 25 |
| Total | 107 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Pre-randomization Baseline/Induction | Inconsistent attendance | 1 | 0 | 0 | 0 |
| Pre-randomization Baseline/Induction | noncompliance (missed med/urine) | 6 | 0 | 0 | 0 |
| Pre-randomization Baseline/Induction | Withdrawal by Subject | 4 | 0 | 0 | 0 |
| Randomization to Disulfiram/ Pre-admin | noncompliance - missed med/urines | 2 | 2 | 6 | 4 |
| Randomization to Disulfiram/ Pre-admin | noncompliance with alcohol use | 1 | 0 | 0 | 0 |
| Randomization to Disulfiram/ Pre-admin | suicidal ideation | 1 | 0 | 0 | 0 |
| Randomization to Disulfiram/ Pre-admin | work schedule conflict | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Disulfiram 250 | Disulfiram 375 | Placebo | Disulfiram 500 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants | 30 Participants | 27 Participants | 25 Participants | 107 Participants |
| Age Continuous | 39.8 years STANDARD_DEVIATION 11.3 | 39.4 years STANDARD_DEVIATION 10.1 | 43.0 years STANDARD_DEVIATION 12.4 | 40.4 years STANDARD_DEVIATION 10.1 | 40.6 years STANDARD_DEVIATION 11 |
| Region of Enrollment United States | 25 participants | 30 participants | 27 participants | 25 participants | 107 participants |
| Sex: Female, Male Female | 10 Participants | 13 Participants | 10 Participants | 8 Participants | 41 Participants |
| Sex: Female, Male Male | 15 Participants | 17 Participants | 17 Participants | 17 Participants | 66 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 20 | 12 / 23 | 10 / 24 | 11 / 21 |
| serious Total, serious adverse events | 1 / 20 | 1 / 23 | 1 / 24 | 0 / 21 |
Outcome results
Primary
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)
Time frame: thrice weekly for 12 weeks
Population: number is based on those who participated long enough to have assessments completed at two time points during the disulfiram phase
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Cocaine Use Over Time | 0.01 slope (change in prob of coc-pos utox/d) |
| Disulfiram 250 | Cocaine Use Over Time | 0.007 slope (change in prob of coc-pos utox/d) |
| Disulfiram 375 | Cocaine Use Over Time | -0.01 slope (change in prob of coc-pos utox/d) |
| Disulfiram 500 | Cocaine Use Over Time | 0.007 slope (change in prob of coc-pos utox/d) |
Comparison: Used placebo group as contrast to determine whether slopes of disulfiram groups differed from slope of placebo group datap-value: <0.05Repeated Measures Logistic Regression
Secondary
Retention
Time frame: 14 weeks
Population: those who were entered the disulfiram phase,e tc.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Retention | 8.3 Weeks | Standard Deviation 5.4 |
| Disulfiram 250 | Retention | 9.0 Weeks | Standard Deviation 4.9 |
| Disulfiram 375 | Retention | 6.4 Weeks | Standard Deviation 4.7 |
| Disulfiram 500 | Retention | 8.3 Weeks | Standard Deviation 4.8 |
p-value: <0.05t-test, 2 sided