A double-blind, placebo-controlled trial of tiagabine for the treatment of cocaine dependence.

BACKGROUND: The potential efficacy of tiagabine for treating cocaine dependence is suggested by both pre-clinical research and two small clinical trials. METHOD: One hundred and forty one participants who met DSM-IV criteria for cocaine dependence were enrolled into this 12-week, double blind, placebo controlled outpatient trial. Participants received either tiagabine (20 mg/day) or matching placebo. All participants received 1h of manualized individual cognitive behavioral therapy on a weekly basis. Outcome measures included cocaine use as determined by self-report confirmed with urine benzoylecgonine (BE) results, and qualitative and quantitative urine toxicology measures. Safety measures included adverse events, EKGs, vital signs, and laboratory tests. RESULTS: Seventy-nine participants (i.e., 56%) completed the 12-week trial. The safety results suggest that tiagabine was safe and generally well tolerated by the participants. Participants in both groups improved significantly on cocaine craving and global functioning, with no significant differences between the groups. There were no significant changes in cocaine use as measured by self-report confirmed by urine BE or by quantitative urine toxicology results. Qualitative urine toxicology results suggest a possible weak effect for tiagabine in reducing cocaine use. CONCLUSION: These results suggest that tiagabine, at a dose of 20 mg/day, did not have a robust effect in decreasing cocaine use.

A double-blind, placebo-controlled trial of reserpine for the treatment of cocaine dependence.

BACKGROUND: Cocaine's increase of dopamine is strongly associated with its reinforcing properties and, thus, agents that reduce dopamine have received much attention as candidate cocaine-dependence treatments. The potential efficacy of reserpine, a dopamine depletor, for treating cocaine dependence is suggested by both pre-clinical research and a small clinical trial. METHOD: One hundred and nineteen participants who met DSM-IV criteria for cocaine dependence were enrolled into this 12-week, double-blind, placebo-controlled outpatient trial. Participants received either reserpine (0.5 mg/day) or matching placebo. All participants received 1h of manualized individual cognitive behavioral therapy on a weekly basis. Outcome measures included cocaine use as determined by self-report confirmed with urine benzoylecgonine results, cocaine craving, addiction severity index scores, and clinical global impression scores. Safety measures included adverse events, EKGs, vital signs, laboratory tests, and the Hamilton Depression Inventory. RESULTS: Seventy-nine participants (i.e., 66%) completed the 12-week trial. The safety results suggest that reserpine was safe and well tolerated by the participants. The efficacy measures indicated no significant differences between reserpine and placebo. CONCLUSION: These results do not support the efficacy of reserpine as a cocaine-dependence treatment.

Efficacy screening trials of paroxetine, pentoxifylline, riluzole, pramipexole and venlafaxine in cocaine dependence.

AIMS: The two studies presented here were conducted to assess the efficacy of paroxetine, pentoxifylline, riluzole, venlafaxine and pramipexole as medications for the treatment of cocaine dependence. DESIGN: A multi-arm, modified blinded, placebo-controlled design was used. SETTING: The studies were conducted at the Boston VA Healthcare System and the Boston University School of Medicine Medication Development Research Unit (MDRU). PARTICIPANTS: Participants met criteria for cocaine dependence during a 2-week screening period. INTERVENTION: Following random assignment to one of the treatment groups, subjects received active medication or placebo for 8 weeks in combination with cognitive behavioral counseling. In the first study the efficacy of the antidepressant paroxetine (20 mg daily), the phosphodiesterase inhibitor pentoxifylline (1200 mg daily) and the glutamate release inhibitor riluzole (100 mg daily) was assessed. The antidepressant venlafaxine (150 mg daily) and the dopamine agonist pramipexole (1.5 mg daily) were evaluated in the second study. MEASUREMENTS: Urine benzoylecgonine (BE) concentrations, self-report of cocaine use and global impression scores served as primary outcome measures. Secondary measures included assessments of cocaine craving and psychiatric functioning. Adverse events were monitored during the treatment period. FINDINGS: None of the active medications produced greater reductions in urine BE concentrations over the treatment period than did placebo. There were trends for BE levels to become reduced in the pentoxifylline group during the first 4 weeks of treatment and for Addiction Severity Index (ASI) drug composite scores to be lower in the pentoxyfylline group at end-point compared to the placebo group. Significant within-group reductions in reported cocaine use and craving were found for all treatment groups, but none of the active medications were superior to placebo on these measures. The accuracy of self-reported cocaine use declined over the study period. Overall, the active medications were well tolerated. CONCLUSIONS: This study does not support the use of paroxetine, pentoxifylline, riluzole, venlafaxine or pramipexole for the treatment of cocaine dependence. However, these results need to be interpreted with caution because of the small size and lack of homogeneity of the experimental groups.

A medication screening trial evaluation of reserpine, gabapentin and lamotrigine pharmacotherapy of cocaine dependence.

AIMS: To conduct a preliminary evaluation of the safety and efficacy of reserpine, gabapentin or lamotrigine versus an unmatched placebo control as a treatment for cocaine dependence. DESIGN: A 10-week out-patient study using the Cocaine Rapid Efficacy and Safety Trial (CREST) study design. SETTING: The study was conducted at the Cincinnati Medication Development Research Unit (MDRU). PARTICIPANTS: Participants met Diagnostic and Statistical Manual version IV (DSM-IV) criteria for cocaine dependence. Sixty participants were enrolled, with 50 participants completing the final study measures. INTERVENTION: The targeted daily doses of medication were reserpine 0.5 mg, gabapentin 1800 mg and lamotrigine 150 mg. All participants received 1 hour of manualized individual cognitive behavioral therapy on a weekly basis. MEASUREMENTS: Primary outcome measures of efficacy included urine benzoylecgonine (BE) level, Cocaine Clinical Global Impression scale--observer and self-report of cocaine use. Safety measures included adverse events, electrocardiograms (ECGs), vital signs and laboratory tests. FINDINGS: Subjective measures of cocaine dependence indicated significant improvement for all study groups. Urine BE results indicated a significant improvement for the reserpine group (P < 0.05) and non-significant changes for the other study groups. No pattern of physical or laboratory abnormalities attributable to treatment with any of the medications was identified. There were three serious adverse events reported, none of which were related to study procedures. The medications appeared to be tolerated well. CONCLUSIONS: The present findings suggest that reserpine may be worthy of further study as a cocaine dependence treatment.

A placebo-controlled screening trial of tiagabine, sertraline and donepezil as cocaine dependence treatments.

AIMS: To conduct a preliminary evaluation of the safety and efficacy of tiagabine, sertraline or donepezil versus an unmatched placebo control as a treatment for cocaine dependence. DESIGN: A 10-week out-patient study was conducted using the Cocaine Rapid Efficacy and Safety Trial (CREST) study design. SETTING: This study was conducted at the Cincinnati Medication Development Research Unit (MDRU) and at an affiliated site in Dayton, Ohio. PARTICIPANTS: Participants met Diagnostic and Statistical Manual version IV (DSM-IV) criteria for cocaine dependence. Sixty-seven participants were enrolled with 55 completing final study measures. INTERVENTION: The targeted daily doses of medication were tiagabine 20 mg, sertraline 100 mg and donepezil 10 mg. All participants received 1 hour of manualized individual cognitive behavioral therapy on a weekly basis. MEASUREMENTS: Primary outcome measures of efficacy included urine benzoylecgonine (BE) level, Cocaine Clinical Global Impression Scale-Observer and self-report of cocaine use. Safety measures included adverse events, ECGs, vital signs and laboratory tests. FINDINGS: Subjective measures of cocaine dependence indicated significant improvement for all study groups. Generalized estimating equations analysis indicated that the tiagabine group showed a trend toward a significant decrease in urine BE level from baseline to weeks 5-8 (P = 0.10) and non-significant changes for the other study groups. No pattern of physical or laboratory abnormalities attributable to treatment with any of the medications was identified. There were three serious adverse events reported, none of which were related to study procedures. CONCLUSIONS: The present findings suggest that tiagabine may be worthy of further study as a cocaine dependence treatment.

Randomized controlled pilot trial of cabergoline, hydergine and levodopa/carbidopa: Los Angeles Cocaine Rapid Efficacy Screening Trial (CREST).

AIM: This study tested three dopaminergic medications against a common unmatched placebo condition: hydergine 1 mg three times daily (n = 15); levodopa/carbidopa 25/100 mg three times daily (n = 15); cabergoline 0.5 mg per week (n = 15); and placebo three times daily (n = 15) as potential pharmacotherapies for cocaine dependence. DESIGN: The four-parallel group, Cocaine Rapid Efficacy Screening Trial (CREST) design featured a 2-week baseline period followed by randomization to an 8-week medication condition that included 1 hour per week of cognitive behavioral drug counseling. A safety evaluation was conducted 4 weeks after termination. MEASURES: Outcomes included cocaine metabolites measured in urine, retention and self-reports for drug use, cocaine craving, clinical improvement, mood and HIV risk behaviors. RESULTS: Participants assigned to receive cabergoline provided more urine samples negative for cocaine metabolites (42.4%) than those assigned to receive placebo (25.0%), a statistically significant difference after controlling for baseline differences in self-reported cocaine use (F = 2.95, df = 3; P = 0.05). Cabergoline-treated participants demonstrated a significant improvement over placebo from baseline to week 8 when measured using the Addiction Severity Index (ASI) employment subscale (overall change = - 0.09, SD = 0.10, t = 2.36, P < 0.05). Safety and adverse event measures showed similar rates and types of complaints by treatment condition. CONCLUSIONS: These results, combined with the apparent safety of cabergoline when used with this population, provide empirical support for conducting a larger study of the medication.

Cocaine Rapid Efficacy Screening Trials (CREST): lessons learned.

AIMS: The Cocaine Rapid Efficacy Screening Trials (CREST) were designed by the National Institute on Drug Abuse Division of Treatment Research and Development (NIDA, DT R&D) to rapidly screen a number of medications potentially useful for the treatment of cocaine dependence. DESIGN: Each CREST trial was designed to compare several medications in a single trial against an unmatched placebo. The placebo group was included in each trial to avoid the nearly universal positive response to medications seen in open-label trials. In addition, a common set of procedures and outcome measures were employed throughout to increase comparability of results obtained from different trials and from different times. PARTICIPANTS: In all, 18 medications were screened in seven different trials, conducted in four different sites throughout the United States involving 398 cocaine-dependent patients. FINDINGS: Three medications were found to be promising enough to include in subsequent larger trials. Common statistical procedures for evaluating medications were developed to facilitate comparisons across sites and across time. A portion of the data were pooled and analyzed, which yielded some useful insights into cocaine dependence and its treatment. Finally, a review of individual trials together with the pooled analysis revealed several potential improvements for future screening trials. CONCLUSIONS: Overall, the CREST trials proved to be useful for rapidly screening medications for treatment of cocaine dependence, but several modifications in design should be made before this framework is applied further.

An open-label pilot study of methylphenidate in the treatment of cocaine dependent patients with adult attention deficit/hyperactivity disorder.

A multi-site, open-label study of methylphenidate for treating patients with comorbid diagnoses of attention deficit/hyperactivity disorder and cocaine dependence was performed. Forty-one participants, who met DSM-IV criteria for adult attention deficit/hyperactivity disorder and cocaine dependence, were enrolled into this ten week outpatient study. The targeted total daily dose of methylphenidate was 60 mg (20 mg TID). Participants received individual substance abuse therapy throughout the trial. Safety measures included adverse events, vital signs, and electrocardiograms. Methylphenidate's efficacy was assessed by both objective and subjective measures. Seventy percent of the participants completed final study measures. Safety measures indicated that methylphenidate was well tolerated by the participants. Subjective efficacy measures suggested that participants evidenced improvement in both cocaine dependence and adult attention deficit/hyperactivity disorder symptoms. Quantitative benzoylecgonine indicated that only those participants categorized as being compliant showed improvement. A double-blind, placebo-controlled study of methylphenidate for this population may be warranted.