Double-blind comparison of carbamazepine and placebo for treatment of cocaine dependence. A randomized double-blind study of carbamazepine in the treatment of cocaine abuse. Effects of phenytoin on cocaine self-administration in humans. A placebo-controlled screening trial of olanzapine, valproate, and coenzyme Q10/L-carnitine for the treatment of cocaine dependence. A randomized placebo-controlled trial of gabapentin for cocaine dependence. Tiagabine increases cocaine-free urines in cocaine-dependent methadone-treated patients: results of a randomized pilot study. Carbamazepine treatment for cocaine dependence. Clinical efficacy of gabapentin versus tiagabine for reducing cocaine use among cocaine dependent methadone-treated patients. Carbamazepine treatment of cocaine dependence: a placebo-controlled trial. A pilot trial of topiramate for the treatment of cocaine dependence. Phenytoin in the treatment of cocaine abuse: a double-blind study. A placebo-controlled screening trial of tiagabine, sertraline and donepezil as cocaine dependence treatments.
This study was conducted to determine the effectiveness of carbamazepine (CBZ) for treatment of cocaine dependence. Sixty-two (CBZ = 28, placebo = 34) cocaine-dependent (DSM-III-R criteria) volunteers consented to be treated for eight weeks with standardized outpatient individual counseling twice a week plus double-blind CBZ or inactive placebo. During the 8-week trial, both groups showed increased number of urine samples negative for cocaine, significantly (P < 0.01) decreased self-reported cocaine use (money spent and grams used), and decreased Beck Depression Inventory and Symptom Check List-90-Revised (SCL-90-R) total scores. However, there were no significant differences between CBZ and placebo. This study does not support the effectiveness of CBZ for outpatient treatment of cocaine dependence. A 12-week, randomized, double-blind, placebo-controlled, fixed-dose outpatient study of carbamazepine (400 mg and 800 mg) in the treatment of cocaine dependence was performed. Data were analyzed with respect to both treatment condition and carbamazepine serum levels. Outcome variables included subject retention, cocaine urinalysis, self-reported cocaine use, cocaine craving, patient and clinical global impressions, the Drug Impairment Rating Scale for Cocaine, and side effects. Compared with placebo, the 400 mg treatment condition exhibited a greater decrease in the rate of positive cocaine urinalyses and a reduction in intensity and duration of craving over the course of the study. Higher serum carbamazepine levels were associated with a lower rate of positive cocaine urinalysis, fewer days of self-reported cocaine use, briefer craving episodes, and greater subject interval retention. The clinical and methodologic implications of these findings and of the study design are discussed. The goal of this pilot study was to determine the effects of phenytoin on cocaine self-administration in a human laboratory model. Subjects were randomized to either phenytoin (n = 6) or placebo (n = 7). Those assigned to phenytoin treatment received a single oral loading dose of 20 mg/kg. The phenytoin and placebo treatment groups did not differ in the number of tokens valued at $5, exchanged for cocaine. Similarly, the cardiovascular and subjective response to cocaine administration did not show a statistically significant treatment effect. In this laboratory model, phenytoin did not alter either the self-administration or effects of cocaine. To conduct a medication screening trial on the efficacy of olanzapine, valproate or coenzyme Q10/L-carnitine combination versus placebo for the treatment of cocaine dependence.
                A four-arm, modified blinded, parallel group study in an out-patient setting using the Cocaine Rapid Efficacy and Safety Trials (CREST) study design.
                The study was performed at the New York Medications Development Research Unit (MDRU).
                All participants met Diagnostic and Statistical Manual version IV (DSM-IV) criteria for cocaine dependence and provided at least two urine samples positive for benzoylecgonine (BE) during the 2-week screening period. Sixty-eight participants were enrolled with 39 completing the study.
                After a 2-week screening period, 68 subjects were assigned randomly to receive either olanzapine (10 mg/day), valproate (1500 mg/day), coenzyme Q10 (200 mg/day) and L-carnitine (500 mg/day) combination or placebo for an 8-week treatment period. All subjects also received individual cognitive behavioral counseling during treatment.
                Primary outcome measures included quantitative urine benzoylecgonine (BE) levels, self-report of drug use, and global impression scores. Secondary outcomes included cocaine craving, study retention and related psychosocial measures. Safety measures included adverse event monitoring, vital signs, and extrapyramidal side-effects tests.
                Study retention was similar across all treatment groups, and all groups showed improvement across most measures of treatment efficacy over the duration of the study. None of the study medications, however, were superior to placebo on any of the primary or secondary outcome measures. Cocaine use, as measured by urine BE levels and self-report, was not significantly lower than placebo in any of the drug treatment groups. All study medications were equally well tolerated, and few medication side effects were observed.
                This pilot study does not support the effectiveness of olanzapine, valproate or coenzyme Q10/L-carnitine combination for the treatment of cocaine dependence. In laboratory animals, augmentation of GABA neurotransmission results in inhibition of cocaine self-administration and inhibition of reinstatement to cocaine-seeking behaviors. If parallel effects were observed in humans, GABA-ergic medication should be effective both in the abstinence-induction as well as in the relapse-prevention phase of cocaine dependence treatment. Gabapentin is an anticonvulsant medication that increases human brain GABA levels. We evaluated the safety and efficacy of gabapentin combined with relapse-prevention therapy in the treatment of cocaine-dependent individuals.
                The study involved 129 individuals with cocaine dependence. Of the 99 participants, who were randomized into a double-blind trial 88% were males, 66% were minorities and with an average age of 39 years (range 22-58 years). After 2 weeks of placebo lead-in, participants were randomized to receive either gabapentin 3200 mg (1600 mg bid) or placebo for 12 weeks, followed by 2 weeks of placebo lead-out. Prior to randomization, participants were stratified into four groups based on the principal route of cocaine use (smokers versus intranasal users) and the level of cocaine use during the 2 weeks of lead-in (high level versus low level). Throughout the 16 weeks study, participants received weekly individual relapse-prevention therapy. The outcome measures included: days of cocaine use and a binary indicator of abstinence based on urine toxicology test, self-reported cocaine craving and retention in treatment.
                Forty-nine percent of randomized patients completed 12 weeks of the trial. Retention did not differ by treatment group but cocaine-smokers dropped out of treatment at a significantly faster rate than intranasal users. For the entire sample, odds of cocaine use over the course of the study did not differ between gabapentin- and placebo-treated individuals. There was a significant difference in the odds of cocaine use between high and low-use groups, with the odds in high-use groups decreasing over time and odds in the low-use groups gradually increasing over the course of the study, such that by the end of the study low and high users were similarly likely to use cocaine. In the low-use group, there was a non-significant trend suggesting that gabapentin-treated subjects had more favorable outcome compared to placebo-treated individuals. There was no treatment effect on abstinence rates, craving or other substance use. Gabapentin at 3200 mg/day was very well tolerated in this group of cocaine-dependent participants.
                When combined with weekly individual relapse-prevention therapy, gabapentin 1600 mg bid was no more effective than placebo in the treatment of cocaine dependence. When reviewed in conjunction with other published studies, gabapentin and other GABA enhancing anticonvulsant medications may deserve further study as relapse-preventive agents in cocaine-dependent individuals who achieve abstinence early in treatment. We sought to evaluate the safety and efficacy of the GABAergic agent tiagabine in reducing cocaine use among methadone-treated patients.
                Ten-week randomized double-blind placebo-controlled trial.
                Opiate Treatment Research Program, Veteran's Affairs Connecticut Healthcare System in West Haven, Connecticut, USA.
                The participants were 45 cocaine-dependent methadone-treated patients who were predominately Caucasian (75.6%), male (77.8%) and never married (53%) with an average age of 38 years (SD = 6.5).
                Comparison groups received tiagabine 12 mg/day (n = 15), tiagabine 24 mg/day (n = 15) or placebo (n = 15).
                Baseline assessments included the Structured Clinical Interview for DSM-IV, the Addiction Severity Index, a urine drug test, self-reported use and opiate withdrawal scales. Urine drug tests were performed thrice weekly.
                Treatment retention was over 80% for all treatment groups. The sample mean (+/- SE) of cocaine-free urines for the first week after study entry and before tiagabine was started was 1.16 (0.19) urines/week. During weeks 9 and 10 cocaine-free urines increased significantly from baseline by 33% with high-dose tiagabine (24 mg/day), by 14% with low-dose tiagabine (12 mg/day) and decreased by 10% with placebo (hierarchical linear model, Z= 2.03; P < 0.05). Self-reported cocaine use also decreased significantly more with active medications than with placebo.
                Tiagabine at 24 mg/day was well tolerated among these methadone-treated patients with only one reporting headache. Tiagabine appears to be a promising GABAergic medication that moderately improves cocaine-free urines. We report on a double-blind, placebo-controlled study of carbamazepine (CBZ) treatment for cocaine dependence. A previously reported uncontrolled study found CBZ to be a beneficial pharmacotherapy for cocaine dependence. Statistical analyses were performed on data from 82 subjects who were randomized to 10 weeks' treatment with either CBZ, titrated to 4-12 micrograms/ml, (n = 37) or placebo (n = 45). The two treatment groups did not differ for primary outcome measures of retention time in treatment, urine samples positive for cocaine metabolite, subject reported desire for cocaine or for subject reported side-effects. CBZ was not an effective treatment in this study. GABAergic medications appear to reduce the reinforcing effects of cocaine by attenuating cocaine-induced dopamine release. This study evaluated gabapentin and tiagabine compared to placebo in reducing cocaine taking behavior.
                A total of 76 treatment seeking, cocaine dependent, methadone-treated, predominately Caucasian male subjects were randomly assigned to tiagabine 24 mg/day (N=25), gabapentin 2400 mg/day (N=26) or placebo (N=25) in a 10-week double-blind placebo-controlled trial. Study medications were slowly increased to their full dosages by the end of week 5 and maintained through week 10. The primary outcome measure was thrice-weekly drug free urine samples.
                Treatment retention was significantly less for the gabapentin group relative to the other groups (log rank=5.29, d.f.=1, p=0.02). The proportion of cocaine-free urine samples during weeks 6-10 was significantly larger in the tiagabine treated group (p<0.05). The longitudinal data showed significant change in thrice-weekly cocaine free urines that reached a greater abstinent rate for the tiagabine treated group (22%) compared to gabapentin (5%) or placebo (13%) treated groups. Mixed-effects ordinal regression models showed a significant tiagabine by time interaction compared to gabapentin (Z=2.48, d.f.=1, p=0.01) and placebo (Z=3.90, d.f.=1, p=0.0001). The gabapentin group did not differ from placebo.
                Gabapentin showed poor treatment retention and ineffectiveness in reducing cocaine use. Tiagabine significantly reduced cocaine taking behavior compared to placebo or gabapentin among methadone-stabilized cocaine abusers. Cocaine-induced kindling, which has been hypothesized to underlie cocaine-induced craving, is reversed by carbamazepine treatment. Though preliminary studies showed carbamazepine to be useful for relapse prevention in cocaine-dependent subjects, more recent studies have failed to replicate those findings. We conducted a randomized, double-blind, placebo-controlled trial of carbamazepine 600 mg/day in 40 cocaine-dependent males. During active treatment there were no significant effects of carbamazepine on cocaine use, alcohol consumption, anxiety or depressive symptoms. At three months post-treatment carbamazepine-treated subjects reported fewer drinking days. We conclude that carbamazepine at this dose level is probably not efficacious for treatment of cocaine dependence. Both GABAergic and glutamatergic neurons appear to be important modulators of the brain reward system and medications that affect GABA and glutamatergic neurotransmission may reduce the rewarding properties of cocaine and reduce cocaine craving. Topiramate, an anticonvulsant, raises cerebral GABA levels, facilitates GABAergic neurotransmission and inhibits glutametergic activity at AMPA/kainite receptors. Thus, it may be useful for treating cocaine dependence.
                The efficacy of topiramate for cocaine dependence was tested in a 13-week, double-blind, placebo-controlled pilot trial (n = 40). Topiramate was titrated gradually over 8 weeks to a dose of 200 mg daily. The primary outcome measure was cocaine abstinence verified by twice weekly urine benzoylecgonine tests (UBT).
                Eighty-two percent of subjects completed the trial. Analysis of the UBT using a GEE model showed that after week 8, when the dose titration was completed, topiramate-treated subjects were more likely to be abstinent from cocaine compared to placebo-treated subjects (Z = 2.67, P = 0.01). Topiramate-treated subjects were also more likely to attain 3 weeks of continuous abstinence from cocaine (chi2 = 3.9, d.f. = 1, P = 0.05).
                Topiramate may be effective for the treatment of cocaine dependence. To evaluate the effectiveness of phenytoin in the treatment of cocaine abuse.
                A 12-week, double-blind, placebo-controlled outpatient study of phenytoin in the treatment of cocaine abuse was conducted. Sixty cocaine-using subjects were randomly assigned to a daily fixed dose of 300 mg phenytoin or placebo. Forty-four subjects initiated treatment and returned for weekly visits. Primary measures of outcome included weekly quantitative and qualitative cocaine urinalysis, self-reported cocaine use, global functioning and improvement, craving intensity, and subject retention.
                Cocaine use, as measured both by weekly urinalysis and self-report, was significantly lower in the phenytoin group. The phenytoin group was also rated as significantly less impaired and more improved than the placebo group. Craving intensity was lower in the phenytoin group, but the difference was not statistically significant. Among phenytoin subjects, serum phenytoin levels above 6.0 micrograms/ml were associated with lower rates of positive cocaine urine specimens and longer cocaine-free periods. No differences were observed between groups in study retention.
                These findings suggest that phenytoin may be useful in the treatment of cocaine abuse. Further studies are needed to replicate these findings. 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.
                A 10-week out-patient study was conducted using the Cocaine Rapid Efficacy and Safety Trial (CREST) study design.
                This study was conducted at the Cincinnati Medication Development Research Unit (MDRU) and at an affiliated site in Dayton, Ohio.
                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.
                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.
                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.
                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.
                The present findings suggest that tiagabine may be worthy of further study as a cocaine dependence treatment.
Although caution is needed when assessing results from a limited number of small clinical trials at present there is no current evidence supporting the clinical use of anticonvulsants medications in the treatment of cocaine dependence. Aiming to answer the urgent demand of clinicians, patients, families, and the community as a whole for an adequate treatment for cocaine dependence, we need to improve the primary research in the field of addictions in order to make the best possible use out of a single study and to investigate the efficacy of other pharmacological agent.