topiramate and Cocaine-Related-Disorders

Extending from the triple wave epidemic of opioid-related overdose deaths, a fourth wave of high mortality involving methamphetamine and cocaine use has been gathering force. This article provides a review of the published literature on stimulants including epidemiology, pharmacology, neurobiology, medical and psychiatric consequences, withdrawal management, and medical and behavioral treatments.

Topics: Adrenergic alpha-2 Receptor Antagonists; Adult; Anticonvulsants; Behavior Therapy; Bupropion; Central Nervous System Stimulants; Cocaine-Related Disorders; Cognitive Dysfunction; Comorbidity; Dopamine Uptake Inhibitors; Female; Humans; Illicit Drugs; Male; Mental Disorders; Methamphetamine; Mirtazapine; Neurobiology; Neurodegenerative Diseases; Opiate Overdose; Substance Withdrawal Syndrome; Topiramate; Transgender Persons; United States

The literature on topiramate use in cocaine-dependent patients was reviewed.. Six randomized, double-blind, controlled clinical trials evaluating the use of topiramate in patients who were cocaine dependent were analyzed. The results from the studies indicated that topiramate, when used in combination with cognitive behavioral therapy, may be effective in reducing short-term cocaine use and should be considered as a possible treatment option. Other trials suggested that topiramate was not effective in patients with a dual diagnosis of opioid and cocaine dependence. Two trials suggested that short-term abstinence assisted by pharmacotherapy is a predictor of longer-term (6 months and 1 year, respectively) abstinence. Cocaine use is dependent on multiple factors; therefore, a reduction in use or craving is not definitively associated with abstinence. However, decreased use reduces potential patient harm and the amount of money spent on illicit cocaine. The findings of this literature review should be used to encourage the completion of more trials that are appropriately designed. Topiramate was shown to be effective for increasing cocaine abstinence, the proportion of cocaine nonuse days, and the proportion of patients to attain 3 consecutive weeks of cocaine abstinence and decreasing the abuse liability of cocaine. Conflicting results in clinical trials do not provide a definitive answer regarding topiramate's efficacy in managing cocaine dependence.. Available research neither validates nor invalidates the hypothesis that topiramate is efficacious in attaining abstinence in cocaine-dependent patients.

Topics: Anticonvulsants; Cocaine-Related Disorders; Humans; Randomized Controlled Trials as Topic; Time Factors; Topiramate; Treatment Outcome

To assess the efficacy of topiramate in treating cocaine use disorder (i.e. retention, efficacy, safety and craving reduction) through a systematic review and meta-analysis.. We searched six scientific databases from inception to 23 December 2014 with no date limits. Data were reviewed, extracted and analysed systematically. Studies were included if they were peer-reviewed randomized control trials with participants meeting diagnostic criteria for cocaine dependence or cocaine use disorder, with the treatment arm involving topiramate with or without psychosocial intervention, and the control arm involving no intervention or psychosocial intervention with or without placebo. A random-effects meta-analytical model was computed.. Five studies met inclusion criteria (n = 518). Topiramate was compared with placebo (four studies) and no medication (one study). In a meta-analysis, we observed no significant differences between topiramate and placebo in improving treatment retention risk ratio (RR) = 0.85; 95% confidence interval (CI) = 0.60-1.22, P = 0.38. However, compared with a placebo, use of topiramate was associated with increased continuous abstinence in two of five studies (RR = 2.43; 95% CI = 1.31-4.53, P = 0.005). No differences were observed in frequency of adverse effects reported between topiramate and placebo (RR = 1.06; 95% CI = 0.91-1.23, P = 0.48). Topiramate was associated significantly (P < 0.05) with a reduction in craving in only one of five studies.. Evidence does not currently support the use of topiramate to improve treatment retention for cocaine use disorder, although it may extend cocaine abstinence with a similar risk of adverse events compared with placebo.

Topics: Anticonvulsants; Cocaine-Related Disorders; Craving; Fructose; Humans; Randomized Controlled Trials as Topic; Topiramate; Treatment Outcome

Topiramate (TPM) is an antiepileptic drug able to play a role in both neurological and psychiatric disorders. TPM facilitates gamma-aminobutyric acid (GABA) transmission and inhibits glutamatergic transmission (i.e. AMPA/kainate receptors). Several studies reported that the modulation of GABAergic and glutamatergic synaptic transmission may reduce cocaine reinforcement. Therefore, TPM could be used in the management of cocaine dependence.

Topics: Animals; Central Nervous System Agents; Cocaine-Related Disorders; Fructose; Humans; Topiramate

There are no FDA-approved pharmacotherapies for treating cocaine addiction; thus, developing drugs to treat cocaine dependence is an unmet critical need. Fortunately, there are a number of drugs that are currently in Phase II clinical trial/s. This is due in part to the advances from in vivo imaging in humans which provided a roadmap of the neurochemistry of the cocaine-dependent brain. Most drugs currently in Phase II clinical trials attempt to modulate the disturbed neurochemistry in cocaine dependents to resemble those of healthy individuals. These predominantly modulate dopamine, serotonin, glutamate, GABA or noradrenaline signalling.. This review summarizes the therapeutic potential of each drug as evidenced by clinical and preclinical studies. It also discusses their utility in terms of bioavailability and half-life.. Amphetamine salts and topiramate clearly stand out in terms of their potential efficacy in treating cocaine addiction. The efficacy of topiramate was closely associated with regular cognitive-behavioural therapy (CBT), which highlights the importance of a combined effort to promote abstinence and enhance retention via CBT. Cognitive/psychological screening appears necessary for a more symptom-based approach with more reasonable outcomes other than abstinence (e.g., improved quality of life) in treating cocaine addiction.

Topics: Amphetamines; Animals; Brain; Clinical Trials, Phase II as Topic; Cocaine-Related Disorders; Drug Design; Fructose; Humans; Quality of Life; Topiramate

Cocaine dependence is characterized by compulsive drug seeking and high vulnerability to relapse. Overall, cocaine remains one of the most used illicit drugs in the world. Given the difficulty of achieving sustained recovery, pharmacotherapy of cocaine addiction remains one of the most important clinical challenges. Recent advances in neurobiology, brain imaging and clinical trials suggest that certain medications show promise in the treatment of cocaine addiction. The pharmacotherapeutic approaches for cocaine dependence include medications able to target specific subtypes of dopamine receptors, affect different neurotransmitter systems (i.e. noradrenergic, serotonergic, cholinergic, glutamatergic, GABAergic and opioidergic pathways), and modulate neurological processes. The systematic reviews concerning the pharmacological treatment of cocaine dependence appear to indicate controversial findings and inconclusive results. The aim of future studies should be to identify the effective medications matching the specific needs of patients with specific characteristics, abandoning the strategies extended to the entire population of cocaine dependent patients. In the present review we summarize the current pharmacotherapeutic approaches to the treatment of cocaine dependence with a focus on the new patents.

Topics: Acetylcysteine; Atomoxetine Hydrochloride; Baclofen; Benzhydryl Compounds; Buprenorphine; Cocaine-Related Disorders; Fructose; Humans; Modafinil; Ondansetron; Patents as Topic; Propylamines; Topiramate

To critically review the literature on topiramate in the treatment of substance-related disorders.. A PubMed search of human studies published in English through January 2009 was conducted using the following search terms: topiramate and substance abuse, topiramate and substance dependence, topiramate and withdrawal, topiramate and alcohol, topiramate and nicotine, topiramate and cocaine, topiramate and opiates, and topiramate and benzodiazepines.. 26 articles were identified and reviewed; these studies examined topiramate in disorders related to alcohol, nicotine, cocaine, methamphetamine, opioids, Ecstasy, and benzodiazepines.. Study design, sample size, topiramate dose and duration, and study outcomes were reviewed.. There is compelling evidence for the efficacy of topiramate in the treatment of alcohol dependence. Two trials show trends for topiramate's superiority over oral naltrexone in alcohol dependence, while 1 trial suggests topiramate is inferior to disulfiram. Despite suggestive animal models, evidence for topiramate in treating alcohol withdrawal in humans is slim. Studies of topiramate in nicotine dependence show mixed results. Human laboratory studies that used acute topiramate dosing show that topiramate actually enhances the pleasurable effects of both nicotine and methamphetamine. Evidence for topiramate in the treatment of cocaine dependence is promising, but limited by small sample size. The data on opioids, benzodiazepines, and Ecstasy are sparse.. Topiramate is efficacious for the treatment of alcohol dependence, but side effects may limit widespread use. While topiramate's unique pharmacodynamic profile offers a promising theoretical rationale for use across multiple substance-related disorders, heterogeneity both across and within these disorders limits topiramate's broad applicability in treating substance-related disorders. Recommendations for future research include exploration of genetic variants for more targeted pharmacotherapies.

Topics: Alcohol-Related Disorders; Amphetamine-Related Disorders; Cocaine-Related Disorders; Fructose; Humans; Neuroprotective Agents; Opioid-Related Disorders; Substance-Related Disorders; Tobacco Use Disorder; Topiramate

Cocaine dependence continues to be a significant public health problem in the United States. The number of regular cocaine users has not declined significantly in the United States since 1992. Although counseling remains the treatment of choice for cocaine dependence, many cocaine-dependent patients do not respond completely to standard drug counseling. Therefore, the development of new and more effective treatments for cocaine dependence is a research priority. Progress in the understanding of the neurobiology of cocaine dependence has led to the discovery of several promising medications that have already shown encouraging results in controlled clinical trials. Other promising compounds are just becoming available for clinical trials. The use of novel psychosocial techniques such as contingency management seems to increase the efficacy of several medications used to treat cocaine dependence. New medications and new psychosocial techniques are leading to significant improvements in the treatment of cocaine dependence.

Topics: Behavior Therapy; Clinical Trials as Topic; Cocaine-Related Disorders; Fructose; Humans; Topiramate; United States

Neuroscientific developments have promulgated interest in developing efficacious medications for the treatment of substance dependence. Previous pharmacological strategies that involve the use of relatively specific medications to alter corticomesolimbic dopaminergic neuronal activity--the critical pathway for expression of the reinforcing effects of abused drugs--have yielded modest efficacy in the treatment of alcohol dependence, and no medication has been established as a treatment for cocaine dependence. Since corticomesolimbic dopaminergic neurons interact with other neurotransmitters that modulate the effects of dopamine in the nucleus accumbens, would it not be possible to control these dopaminergic effects more reliably with a medication that acts contemporaneously on more than one neuromodulator of dopaminergic function? Further, since the long-term use of either alcohol or cocaine results in neuronal adaptations as a result of sensitisation, would the chances of effective therapy not be bolstered by administering a medication that was also able to mitigate these chronic effects? Thus, a new conceptual approach is needed. My proposal is that a medication--in this case topiramate--that principally potentiates inhibitory GABA(A) receptor-mediated input and antagonises excitatory glutamatergic afferents to the corticomesolimbic dopaminergic system should have therapeutic potential in treating either alcohol or cocaine dependence or perhaps both. This is because the principal neurochemical effects of topiramate would not only serve to decrease the acute reinforcing effects of alcohol or cocaine, but might also facilitate cessation of their use following a period of long-term use by decreasing neuronal sensitisation. This overview highlights the scientific concepts and clinical evidence for the development of topiramate in the treatment of alcohol dependence and introduces preliminary evidence to indicate that it might also have utility in treating cocaine dependence. Finally, to place the material on topiramate in context, information has been included on the utility and development of other medications that modulate GABA- or glutamate-mediated neuronal systems for the treatment of alcohol or cocaine dependence.

Topics: Alcoholism; Animals; Cocaine-Related Disorders; Fructose; gamma-Aminobutyric Acid; Glutamic Acid; Humans; Neuroprotective Agents; Topiramate

Cocaine use disorder (CUD) remains a substantial public health problem with no clearly effective pharmacotherapy available. In a prior trial, combined amphetamine and topiramate treatment significantly reduced cocaine use among individuals demonstrating the most frequent use at baseline. This trial targeted such frequent users.. A double-blind, randomized placebo-controlled trial, testing the combination of mixed amphetamine salts extended-release (MAS-ER) and topiramate or placebo over a 12-week medication phase was conducted. The two-site outpatient trial included 127 adults (96 males) with CUD using at least 9 days in the prior month. MAS-ER was titrated to a maximum dose of 60 mg/day and topiramate to a maximum dose of 100 mg twice/day. The primary outcome was the proportion of individuals who achieved three consecutive abstinent weeks at the end of the study (EOS) as measured by urine toxicology and self-report.. The proportion of participants achieving three abstinent weeks at the EOS was significantly (P = .03) larger in the treatment (14.1%) compared to the placebo group (0.0%), while controlling for baseline cocaine use, sex, current alcohol use disorder, and site. Of note, due to conservative cardiac safety-parameters a considerable number of individuals in the treatment group were discontinued from study medication (20.3%).. While these findings provide further evidence that the combination of MAS-ER and topiramate is efficacious in promoting abstinence in CUD adults with frequent use it remains possible that the combination treatment is no more effective than either treatment alone. Despite this, the study provides a valuable "proof of concept."

Topics: Amphetamines; Cocaine-Related Disorders; Delayed-Action Preparations; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Medication Adherence; Middle Aged; Salts; Topiramate; Treatment Outcome

Topiramate has been studied in the treatment of substance use disorders and is often used off-label in the treatment of other disorders with impaired impulse control. We sought to determine whether impulsiveness could predict topiramate treatment response in individuals with cocaine use disorder (CUD).. In a post-hoc analysis of a 12-week, double-blind, randomized, placebo-controlled trial of topiramate for CUD, we examined the relationship between response to treatment and participants' baseline score on the Barrett Impulsiveness Scale (BIS-11). During the original trial, topiramate was titrated up to 300 mg/day over 6 weeks and maintained for 6 weeks. All participants received weekly cognitive behavioral therapy.. Individuals with total BIS-11 scores above the median had 11.2% more cocaine-free days with topiramate versus placebo (Bonferroni corrected p = 0.047). Individuals with first-order factor scores above the median in self-control (Bonferroni corrected p = 0.020) and at or below the median in attention (Bonferroni corrected p = 0.022), and second-order factor scores at or below the median in attentional (Bonferroni corrected p = 0.024) and motor impulsiveness (Bonferroni corrected p = 0.046) were all associated with a greater improvement with topiramate.. The results indicate an association between higher within-group impulsiveness and response to topiramate for CUD. The subscore findings may suggest a complex interaction between effectiveness and known cognitive side effects. The finding that trait impulsiveness is associated with treatment response is a promising discovery that may help guide treatment for CUD.. This analysis suggests a possible endophenotype based on impulsiveness that can predict treatment response to topiramate. (Am J Addict 2019;XX:1-6).

Topics: Adult; Anticonvulsants; Cocaine-Related Disorders; Cognitive Behavioral Therapy; Double-Blind Method; Female; Humans; Impulsive Behavior; Male; Middle Aged; Patient Selection; Psychological Techniques; Self-Control; Topiramate; Treatment Outcome

We performed a double-blind, randomized, placebo-controlled trial to assess the efficacy of topiramate in the treatment of crack cocaine dependence.. Sixty men who were dependent on cocaine (DSM-IV) (exclusive use of crack cocaine) were selected. The subjects were randomly assigned to either a topiramate group (subjects received 50-200 mg of topiramate per day for 12 weeks) or a control group (subjects received placebo). The initial daily treatment dose was 50 mg, and this dose was increased weekly at increments of 25 to 50 mg, based on the subject's tolerability, to a maximum of 200 mg. All of the subjects also participated in motivational interviews and group therapy. The primary outcome measures were detection of benzoylecgonine in the urine, study retention, frequency of cocaine smoking, amount of cocaine use, and mean amount of money spent on cocaine per week. The study was conducted from February 2013 to February 2014.. Twenty-nine subjects in the topiramate group and 29 subjects in the control group completed the study. Longitudinal assessment revealed that retention was not significant (odds ratio [OR] = 1.072, P = .908) between the 2 groups. Negative results from a urine test for benzoylecgonine (a cocaine metabolite), which is a measure of cocaine abstinence, were more frequently obtained from the topiramate group (OR = 8.687, P < .001). Topiramate reduced the quantity of cocaine used (mean reduction = -3.108 g, P < .001), the frequency of cocaine use (mean = -0.784 times per week, P = .005), and the amount of money spent on cocaine (mean [US dollars] = -$25.38, P = .015; this variable did not achieve statistical significance after Bonferroni correction) compared with the placebo during the 12 weeks (or 84 days) of the assessment. However, the differences in reductions between the 2 groups in the quantity of cocaine used, the frequency of cocaine use, and money spent on cocaine over time (time × group interaction) were present only during the first 4 weeks, and none of these variables by 12 weeks. The studied groups did not differ with regard to secondary end points, such as study dropout and the number of subjects who reported side effects.. The present findings indicate that topiramate is effective and safe and thus reinforce previous data suggesting that topiramate is a potentially useful treatment for crack cocaine dependence. However, we found that topiramate is only useful as an adjunctive treatment during the first 4 weeks of the treatment. Future studies with larger samples are needed to confirm these results.. Registro Brasileiro de Ensaios Clínicos (ReBEC) RBR-3vwfjs and UTN: U1111-1131-4443.

Topics: Adult; Anticonvulsants; Cocaine-Related Disorders; Combined Modality Therapy; Crack Cocaine; Double-Blind Method; Drug Administration Schedule; Fructose; Humans; Male; Motivational Interviewing; Psychotherapy, Group; Topiramate; Treatment Outcome; Young Adult

An intronic polymorphism in the delta-opioid receptor gene (OPRD1) was previously associated with cocaine dependence in African-Americans. However, it is not known if the polymorphism (rs678849) is associated with dependence-related phenotypes within the cocaine dependent population.. Cocaine and alcohol dependent subjects were randomized to either topiramate or placebo. Abstinence from cocaine use was confirmed by urine drug screens for benzoylecgonine three times per week. Cocaine withdrawal and craving were assessed at randomization using the Cocaine Selective Severity Assessment (CSSA) and Minnesota Cocaine Craving Scale (MCCS), respectively. Subjects were also interviewed using the Addiction Severity Index (ASI). Genotype at rs678849 was determined for 105 African-American subjects and compared to cocaine abstinence, as well as scores for CSSA, MCCS, and ASI.. African-American patients with the C/T or T/T genotypes (n=40) were more likely to be abstinent at the first urine drug screen and more likely to be abstinent for the week prior to randomization compared to patients with the C/C genotype (n=65). Subjects carrying the T allele were also more likely to have abstinent weeks over the course of the trial compared to those with the C/C genotype (RR=1.88, 95% CI=1.59-2.22, p=0.0035). No effects of rs678849 genotype on withdrawal, craving, or addiction severity were observed.. A polymorphism in OPRD1 appears to be associated with both cocaine dependence and cocaine use during treatment in African-Americans. Follow-up studies to confirm the effect on cocaine use are warranted.

Topics: Adult; Alcoholic Intoxication; Alleles; Black or African American; Cocaine-Related Disorders; Female; Follow-Up Studies; Fructose; Genetic Variation; Genotype; Humans; Male; Middle Aged; Phenotype; Polymorphism, Genetic; Receptors, Opioid, delta; Temperance; Topiramate

Topiramate is being investigated as a potential pharmacotherapy for the treatment of addictive disorders. However, its cognitive side effects raise concerns about its use, especially in populations with cognitive impairment, such as persons with chronic substance use disorders. This study investigated topiramate's cognitive effects in individuals dually dependent on cocaine and opioids as part of a double-blind, randomized, controlled trial of topiramate for cocaine dependence treatment. After 5 weeks of stabilization on daily oral methadone (M = 96 mg), participants were randomized to topiramate (n = 18) or placebo (n = 22). Cognitive testing took place at 2 time points: study weeks 4 through 5 to assess baseline performance and 10 to 13 weeks later to assess performance during stable dosing (300 mg topiramate or placebo). All participants were maintained on methadone at both testing times, and testing occurred 2 hours after the daily methadone plus topiramate/placebo administration. The topiramate and placebo groups did not differ on sex, level of education, premorbid intelligence, methadone dose, or illicit drug use. Topiramate slowed psychomotor and information processing speed, worsened divided attention, reduced n-back working memory accuracy, and increased the false alarm rate in recognition memory. Topiramate had no effects on visual processing, other measures of psychomotor function, risk-taking, self-control, Sternberg working memory, free recall, and metamemory. These findings indicate that topiramate may cause cognitive impairment in this population. This effect may limit its acceptability and use as a treatment in individuals with chronic opioid and cocaine use disorders, among whom preexisting cognitive impairments are common. (PsycINFO Database Record

Topics: Adult; Cocaine-Related Disorders; Cognition Disorders; Diagnosis, Dual (Psychiatry); Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Fructose; Humans; Male; Methadone; Neuropsychological Tests; Opiate Substitution Treatment; Opioid-Related Disorders; Topiramate

Crack-cocaine dependence is a complex disorder with limited treatment options. Topiramate is one of the promising medications with reported reductions in cocaine use and craving in former studies. The present study evaluated the acceptance and effectiveness of topiramate as an add-on to cognitive behavioral therapy (CBT) in crack-cocaine dependent patients.. Seventy-four crack-cocaine dependent outpatients participated in an open-label, randomized feasibility trial. They were randomized to receive either 12-week CBT plus topiramate (200mg/day) or 12-week CBT only. The primary outcome measure was treatment retention. Secondary outcomes included medication adherence, safety, cocaine and other substance use, health, social functioning, and patient satisfaction.. Adherence to topiramate treatment was low. In the intent-to-treat analyses, topiramate neither improved treatment retention nor reduced cocaine and other substance use. Post hoc, exploratory analyses suggested a moderation effect of comorbid opioid dependence, with a significant effect of topiramate on cocaine use reduction only in crack-cocaine dependent patients with comorbid opioid dependence.. Topiramate was safe and well-tolerated in this sample of crack-cocaine dependent patients, but efficacy was not supported probably due to low acceptance of the treatment. Given the equivocal results of previous studies and the negative findings in our study, the potential of topiramate in the treatment of cocaine dependence seems limited.

Topics: Adult; Cocaine-Related Disorders; Cognitive Behavioral Therapy; Combined Modality Therapy; Crack Cocaine; Feasibility Studies; Female; Fructose; Humans; Male; Medication Adherence; Netherlands; Patient Compliance; Patient Satisfaction; Social Behavior; Topiramate; Treatment Outcome; Young Adult

Dual dependence on opiate and cocaine occurs in about 60% of patients admitted to methadone maintenance and negatively impacts prognosis (Kosten et al. 2003. Drug Alcohol Depend. 70, 315). Topiramate (TOP) is an antiepileptic drug that may have utility in the treatment of cocaine dependence because it enhances the GABAergic system, antagonizes the glutamatergic system, and has been identified by NIDA as one of only a few medications providing a "positive signal" warranting further clinical investigation. (Vocci and Ling, 2005. Pharmacol. Ther. 108, 94).. In this double-blind controlled clinical trial, cocaine dependent methadone maintenance patients (N=171) were randomly assigned to one of four groups. Under a factorial design, participants received either TOP or placebo, and monetary voucher incentives that were either contingent (CM) or non-contingent (Non-CM) on drug abstinence. TOP participants were inducted onto TOP over 7 weeks, stabilized for 8 weeks at 300 mg daily then tapered over 3 weeks. Voucher incentives were supplied for 12 weeks, starting during the fourth week of TOP induction. Primary outcome measures were cocaine abstinence (Y/N) as measured by thrice weekly urinalysis and analyzed using Generalized Estimating Equations (GEE) and treatment retention. All analyses were intent to treat and included the 12-week evaluation phase of combined TOP/P treatment and voucher intervention period.. There was no significant difference in cocaine abstinence between the TOP vs. P conditions nor between the CM vs. Non-CM conditions. There was no significant TOP/CM interaction. Retention was not significantly different between the groups.. Topiramate is not efficacious for increasing cocaine abstinence in methadone patients.

Topics: Adolescent; Adult; Cocaine-Related Disorders; Double-Blind Method; Female; Fructose; Humans; Male; Methadone; Middle Aged; Narcotics; Neuroprotective Agents; Opiate Substitution Treatment; Patient Compliance; Substance Abuse Detection; Topiramate; Treatment Outcome; Young Adult

Topiramate increases GABAergic activity and antagonizes the AMPA/kainate subtype of glutamate receptors. Through these mechanisms of action, topiramate may reduce alcohol and cocaine reward and may reduce alcohol and cocaine craving. Topiramate has been shown to reduce drinking in persons with alcohol dependence, and reduce relapse in stimulant-dependent patients. The current trial was intended to test the ability of topiramate to promote cocaine and alcohol abstinence among patients addicted to both drugs.. The study was a double-blind, placebo-controlled, 13-week trial involving 170 cocaine and alcohol dependent subjects. After achieving a period of cocaine and alcohol abstinence, subjects were randomized to topiramate, 300 mg daily, or identical placebo capsules. In addition, subjects received weekly individual psychotherapy. Primary outcome measures included self-reported alcohol and cocaine use, and thrice weekly urine drug screens. Secondary outcome measures included cocaine and alcohol craving, Addiction Severity Index results, cocaine withdrawal symptoms, and clinical global improvement ratings.. Topiramate was not better than placebo in reducing cocaine use on the a priori primary outcome measure, or in reducing alcohol use. Topiramate was not better than placebo in reducing cocaine craving. Topiramate-treated subjects, compared to placebo-treated subjects, were more likely to be retained in treatment and more likely to be abstinent from cocaine during the last three weeks of the trial. Subjects who entered treatment with more severe cocaine withdrawal symptoms responded better to topiramate.. Topiramate plus cognitive behavioral therapy may reduce cocaine use for some patients with comorbid cocaine and alcohol dependence.

Topics: Adolescent; Adult; Aged; Alcoholism; Anticonvulsants; Behavior, Addictive; Cocaine-Related Disorders; Cognitive Behavioral Therapy; Combined Modality Therapy; Double-Blind Method; Female; Fructose; Humans; Male; Middle Aged; Patient Compliance; Secondary Prevention; Severity of Illness Index; Substance Withdrawal Syndrome; Topiramate

No medication has been established as an efficacious treatment for cocaine dependence. We hypothesized that dual modulation of the mesocorticolimbic dopamine system by topiramate-a glutamate receptor antagonist and γ-aminobutyric acid receptor agonist-would result in efficacious treatment for cocaine dependence compared with placebo.. To determine the efficacy of topiramate vs placebo as a treatment for cocaine dependence.. Double-blind, randomized, placebo-controlled, 12-week trial of 142 cocaine-dependent adults in clinical research facilities at the University of Virginia between November 22, 2005, and July 25, 2011.. Topiramate (n = 71) or placebo (n = 71) in escalating doses from 50 mg/d to the target maintenance dose of 300 mg/d in weeks 6 to 12, combined with weekly cognitive-behavioral treatment.. For the efficacy period, weeks 6 to 12, the primary outcome was the weekly difference from baseline in the proportion of cocaine nonuse days; the secondary outcome was urinary cocaine-free weeks, and exploratory outcomes included craving and self- and observer-rated global functioning on the Clinical Global Impression scales.. Using an intent-to-treat analysis, topiramate was more efficacious than placebo at increasing the weekly proportion of cocaine nonuse days, irrespective of whether missing data were not or were imputed conservatively to the baseline value (13.3% vs 5.3%, 95% CI for the estimated mean difference, 1.4%-14.6%, P = .02 or 8.9% vs 3.7%, 95% CI for the estimated mean difference, 0.2%-10.1%, P = .04, respectively). Topiramate also was associated, significantly more than placebo, with increasing the likelihood of urinary cocaine-free weeks (16.6% vs 5.8%; odds ratio, 3.21; 95% CI, 1.24-8.32; P = .02), as well as decreasing craving and improving observer-rated global functioning (all P < .05).. Topiramate is more efficacious than placebo at increasing the mean weekly proportion of cocaine nonuse days and associated measures of clinical improvement among cocaine-dependent individuals.

Topics: Adult; Anticonvulsants; Cocaine-Related Disorders; Cognitive Behavioral Therapy; Combined Modality Therapy; Double-Blind Method; Female; Fructose; Humans; Male; Middle Aged; Placebos; Psychiatric Status Rating Scales; Severity of Illness Index; Time Factors; Topiramate; Treatment Outcome

Topiramate, presumably through antagonism of excitatory glutaminergic pathways and facilitation of inhibitory gamma-aminobutyric acid neurons in the cortico-mesolimbic system, might reduce cocaine's abuse liability. We tested whether topiramate (100 mg twice daily) would reduce the euphoria, subjective mood, craving and preference for cocaine over money induced by low and high doses (0.325 and 0.65 mg/kg i.v., respectively) of experimentally administered cocaine in 24 male and female, cocaine-dependent, non-treatment-seeking research volunteers in a university in-patient laboratory. We utilized a randomized, double-blind, placebo-controlled, within-subject, Latin-square cross-over design in which three experimental challenge doses of low-dose cocaine, high-dose cocaine and placebo were administered in counterbalanced order after 5 days of topiramate or matching placebo pre-treatments separated by a 1-week washout period (2006-2009). After placebo pre-treatments, cocaine produced dose-related increases in euphoria, stimulant effects, craving for more cocaine and monetary value of cocaine in a behavioral preference test of cocaine versus money choice. Topiramate pre-treatment reduced the cocaine-related craving and monetary value of high-dose cocaine while increasing the monetary value, euphoria and stimulant effects of low-dose cocaine. Validated and standardized human experimental methods evaluating the potential for topiramate to alter cocaine's abuse liability suggest that topiramate may reduce the reinforcing effects and craving induced by higher cocaine doses. Low-dose cocaine might appear to have some enhancement of its stimulant properties in the presence of topiramate's prominent sedative effects.

Topics: Adolescent; Adult; Affect; Cocaine; Cocaine-Related Disorders; Cross-Over Studies; Dopamine Uptake Inhibitors; Double-Blind Method; Euphoria; Female; Fructose; Humans; Male; Middle Aged; Neuroprotective Agents; Patient Preference; Reinforcement, Psychology; Topiramate; Young Adult

Cocaine dependence is a substantial public health problem, yet there are no clearly effective medication treatments. Amphetamine and topiramate have both shown promise for the treatment of cocaine dependence in preclinical and early-stage clinical studies.. Eighty-one cocaine-dependent adults were randomized to receive a combination of extended-release mixed amphetamine salts (MAS-ER) and topiramate or placebo for 12 weeks under double-blind conditions. MAS-ER doses were titrated over 2 weeks to a maximum dose of 60 mg daily, and topiramate doses were titrated over 6 weeks to a maximum dose of 150 mg twice daily. All participants received a supportive behavioral intervention. The primary outcome was the proportion of individuals who achieved 3 consecutive weeks of abstinence as measured by urine toxicology confirmed self-report.. The overall proportion of participants who achieved 3 consecutive weeks of abstinence was larger in the extended-release mixed amphetamine salts and topiramate group (33.3%) than in placebo group (16.7%). There was a significant moderating effect of baseline total number of cocaine use days (Wald χ(2) = 3.75, df = 1, p = .05) on outcome, suggesting that the combination treatment was most effective for participants with a high baseline frequency of cocaine use.. The results of this study supported our hypothesis that the combination of MAS-ER and topiramate would be superior to placebo in achieving 3 weeks of consecutive abstinence. These findings provide evidence that the combination of MAS-ER and topiramate is efficacious in promoting abstinence in cocaine-dependent individuals.

Topics: Adolescent; Adult; Amphetamine; Cocaine-Related Disorders; Delayed-Action Preparations; Double-Blind Method; Drug Combinations; Female; Fructose; Humans; Male; Middle Aged; Self Report; Topiramate; Treatment Outcome

Cocaine, particularly in its base form ('crack'), has become one of the drugs of most concern in the Netherlands, being associated with a wide range of medical, psychiatric and social problems for the individual, and with significant public order consequences for society. Available treatment options for cocaine dependent users are limited, and a substantial part of the cocaine dependent population is not reached by the addiction treatment system. Psychosocial interventions for cocaine dependence generally show modest results, and there are no registered pharmacological treatments to date, despite the wide range of medications tested for this type of dependence. The present study (Cocaine Addiction Treatments to improve Control and reduce Harm; CATCH) investigates the possibilities and problems associated with new pharmacological treatments for crack dependent patients.. The CATCH-study consists of three separate randomised controlled, open-label, parallel-group feasibility trials, conducted at three separate addiction treatment institutes in the Netherlands. Patients are either new referrals or patients already in treatment. A total of 216 eligible outpatients are randomised using pre-randomisation double-consent design and receive either 12 weeks treatment with oral topiramate (n = 36; Brijder Addiction Treatment, The Hague), oral modafinil (n = 36; Arkin, Amsterdam), or oral dexamphetamine sustained-release (n = 36; Bouman GGZ, Rotterdam) as an add-on to cognitive behavioural therapy (CBT), or receive a 12-week CBT only (controls: n = 3 × 36). Primary outcome in these feasibility trials is retention in the underlying psychosocial treatment (CBT). Secondary outcomes are acceptance and compliance with the study medication, safety, changes in cocaine (and other drug) use, physical and mental health, social functioning, and patient satisfaction.. To date, the CATCH-study is the first study in the Netherlands that explores new treatment options for crack-cocaine dependence focusing on both abstinence and harm minimisation. It is expected that the study will contribute to the development of new treatments for one of the most problematic substance use disorders.. The Netherlands National Trial Register NTR2576The European Union Drug Regulating Authorities Clinical Trials EudraCT2009-010584-16.

Topics: Benzhydryl Compounds; Clinical Protocols; Cocaine-Related Disorders; Cognitive Behavioral Therapy; Combined Modality Therapy; Crack Cocaine; Delayed-Action Preparations; Dextroamphetamine; Fructose; Modafinil; Netherlands; Outcome and Process Assessment, Health Care; Topiramate

To evaluate anticraving action and tolerability of topiramate in cocaine user treatment.. Male users of inhaled cocaine which met criteria for cocaine dependence (Diagnostic and Statistical Manual of Mental Disorders, fourth edition) were selected for outpatient 12-week, open label trial with topiramate; individual dosage ranged between 25-300 mg/day. Main clinical variables were abstinence rate, craving intensity, frequency and duration, adherence, dropouts, side effects and impulsivity measure through Barratt Impulsivity Scale. Patients received assertive strategic counseling for abstinence assistance and medication monitoring evaluation every two weeks. Comparative analysis was made with intention to treat, missing values were replaced (last observation carried forward), and significance level was 5%.. Adherence to treatment was 57% (at least three evaluations), 32% dropped out (one evaluation). There were no severe side effects. Negative test average was 25.4% (31.2). Significant reduction in craving intensity and duration was observed in 25% of the sample. No statistical significant reduction in craving frequency was observed in 7.1%. Increase in frequency was observed in 10.7% and 82.1% did not present any variation. No significant statistical variations in Barratt Impulsivity Scale or in the total score were found in the final evaluation when compared to baseline.. More randomized placebo-controlled trials with topiramate for cocaine dependants should be performed to evaluate preliminary evidence.

Topics: Adult; Ambulatory Care; Behavior, Addictive; Cocaine-Related Disorders; Fructose; Humans; Male; Medication Adherence; Neuroprotective Agents; Patient Dropouts; Self-Assessment; Substance Withdrawal Syndrome; Topiramate

Cocaine use contines to be a significant public health problem world-wide. However, despite substantial research efforts, no pharmacotherapies are approved for the treatment of cocaine use disorder (CUD).. Studies have identified positive signals for a range of medications for treating CUD. These include long-acting amphetamine formulations, modafinil, topiramate, doxazosin and combined topiramate and mixed amphetamine salts extended-release (MAS-ER). However, valid conclusions about a medication's clinical efficacy require nuanced approaches that take into account behavioural phenotypes of the target population (frequency of use, co-abuse of cocaine and other substances, genetic subgroups, psychiatric comorbidity), variables related to the medication (dose, short-/long-acting formulations, titration speed, medication adherence) and other factors that may affect treatment outcomes. Meta-analyses frequently do not account for these co-varying factors, which contributes to a somewhat nihilistic view on pharmacotherapeutic options for CUD. In addition, the predominant focus on abstinence, which is difficult for most patients to achieve, may overshadow more nuanced therapeutic signals.. While there is an emphasis on finding new medications with novel mechanisms of action for treating CUD, currently available medications deserve further investigation based on the existing literature. Evaluating refined metrics of treatment success in well-defined subgroups of patients, and further exploring combination therapies and their synergy with behavioural/psychosocial interventions, are promising avenues to establishing effective therapies for CUD.

Topics: Amphetamine; Cocaine; Cocaine-Related Disorders; Humans; Substance-Related Disorders; Topiramate

Cocaine use disorder is an unrelenting public health concern. Despite nearly four decades of research, an FDA approved medication is not yet available.. The objective of this human laboratory study was to demonstrate the initial efficacy, safety and tolerability of topiramate-phentermine combinations for cocaine use disorder.. Thirty-one (31) participants with cocaine use disorder completed this mixed-model inpatient laboratory study. Participants were maintained on topiramate (0 [N = 11], 50 [N = 9] or 100 [N = 11] mg/day). Each topiramate group was concurrently maintained on phentermine (0, 15, 30 mg). Drug self-administration, subjective responses and cardiovascular effects following acute doses of intranasal cocaine (0, 40, 80 mg) were determined during separate experimental sessions after at least seven (7) days of maintenance on each condition.. The three groups of participants were well matched demographically and generally did not differ significantly in their responses to a range of doses of intranasal cocaine (0, 10, 20, 40, 80 mg) during a medical safety session. Maintenance on topiramate and phentermine alone significantly decreased cocaine self-administration although these effects were modest in magnitude. Combining topiramate and phentermine robustly decreased cocaine self-administration. Topiramate and phentermine were well tolerated alone and combined, as well as in conjunction with cocaine.. The results of the present study support advancing topiramate-phentermine combinations as a putative pharmacotherapeutic for cocaine use disorder.

Topics: Adult; Cocaine; Cocaine-Related Disorders; Drug Combinations; Female; Fructose; Humans; Male; Middle Aged; Phentermine; Self Administration; Topiramate; Young Adult

Topics: Cocaine; Cocaine-Related Disorders; Crack Cocaine; Fructose; Humans; Topiramate

Topiramate is an anticonvulsant drug which has been evaluated as a therapeutic option for the treatment of cocaine addiction during the last decade.. The purpose of this study was to evaluate the effects of topiramate on the reinforcing actions of cocaine. To this aim, the topiramate-mediated regulation of acquisition and extinction phases of the cocaine conditioned place preference (CPP) was assessed in young-adult mice using three experimental designs.. Topiramate (50 mg/kg, p.o.) was given as follows: (1) during cocaine (1 and 25 mg/kg, i.p.) conditioning sessions (4 days) and cocaine (25 mg/kg) post-conditioning session; (2) 2 weeks before and during cocaine conditioning (25 mg/kg); and (3) during extinction of CPP induced by cocaine (25 mg/kg). In the first experimental design, changes in tyrosine hydroxylase (TH) and dopamine transporter (DAT) gene expressions were measured in the ventral tegmental area (VTA).. Topiramate significantly increased cocaine-induced CPP and delayed or failed to produce extinction after the first cocaine reinstatement extinction in the first and second experiments. Furthermore, treatment with topiramate after place conditioning blocked the extinction of cocaine-induced CPP. TH and DAT gene expression in the VTA was significantly lower both with topiramate alone and in combination with cocaine compared with animals receiving only cocaine.. These findings suggest that topiramate increases the rewarding properties of cocaine, at least in part, by regulating dopaminergic signaling in the mesolimbic circuit. Consequently, the results of this study do not support the use of topiramate for the treatment of problems related to cocaine dependence.. • Topiramate increases the rewarding properties of cocaine in CPP • Topiramate alters dopaminergic signaling in the mesolimbic circuit • Topiramate delays the extinction of cocaine-induced CPP • TH and DAT gene expression in the VTA decreases with topiramate and/or with cocaine • Results show that it should limit the use of topiramate in cocaine-dependent subjects.

Topics: Analysis of Variance; Animals; Anticonvulsants; Cocaine; Cocaine-Related Disorders; Disease Models, Animal; Dopamine Uptake Inhibitors; Fructose; Male; Mice; Reward; Topiramate; Ventral Tegmental Area

Cocaine abuse is a major public health problem with multiple-related complications. Indeed, cocaine can affect almost every organ of the human body, but little is known about its effects on the visual system. The main purpose of this work was to study if topiramate was able to reverse changes in retinal metabolism and retinal function induced by chronic cocaine exposure in adult rats.. Sixteen Wistar rats were treated with a daily oral dose of cocaine during 36 days. Sixteen rats receiving NaCl 0.9% served as controls. Eight control and eight cocaine animals were administered topiramate from day 18 to day 36 of the experiment. Malondialdehyde (MDA), glutathione (GSH) and glutamate content, as well as glutathione peroxidase (GPx) activity in retina tissue homogenates were determined. Retinal function was assessed by electroretinogram (ERG).. Glutamate concentration was increased in the retinas of cocaine-treated rats. No changes in oxidative stress parameters were observed in the retinas of cocaine-treated rats when compared with the control ones. Cocaine induced a decrease in the a-wave and b-wave ERG amplitude. The administration of topiramate reversed cocaine-induced increase in glutamate concentration and had little effect on a-wave and b-wave ERG amplitude. Topiramate, a drug used during the last decade for the treatment of epileptic seizures, is able to reverse the cocaine-induced alterations observed in retinal glutamate concentration.. We can conclude that retinal glutamate metabolism and function may be affected by exposure to cocaine. We confirm that topiramate, a treatment recently proposed for cocaine dependence, is also able to recover partially cocaine-induced changes in the retina.

Topics: Animals; Anticonvulsants; Chronic Disease; Cocaine; Cocaine-Related Disorders; Energy Metabolism; Fructose; Male; Oxidation-Reduction; Rats, Wistar; Retina; Topiramate; Vasoconstrictor Agents; Visual Acuity

Topics: Adult; Cocaine-Related Disorders; Fructose; Humans; Male; Neuroprotective Agents; Schizophrenia; Topiramate

Different mechanisms have been suggested for cocaine toxicity including an increase in oxidative stress but the association between oxidative status in the brain and cocaine induced-behaviour is poorly understood. Nuclear factor kappa B (NFkappaB) is a sensor of oxidative stress and participates in memory formation that could be involved in drug toxicity and addiction mechanisms. Therefore NFkappaB activity, oxidative stress, neuronal nitric oxide synthase (nNOS) activity, spatial learning and memory as well as the effect of topiramate, a previously proposed therapy for cocaine addiction, were evaluated in an experimental model of cocaine administration in rats. NFkappaB activity was decreased in the frontal cortex of cocaine treated rats, as well as GSH concentration and glutathione peroxidase activity in the hippocampus, whereas nNOS activity in the hippocampus was increased. Memory retrieval of experiences acquired prior to cocaine administration was impaired and negatively correlated with NFkappaB activity in the frontal cortex. In contrast, learning of new tasks was enhanced and correlated with the increase of nNOS activity and the decrease of glutathione peroxidase. These results provide evidence for a possible mechanistic role of oxidative and nitrosative stress and NFkappaB in the alterations induced by cocaine. Topiramate prevented all the alterations observed, showing novel neuroprotective properties.

Topics: Animals; Cocaine; Cocaine-Related Disorders; Disease Models, Animal; Dopamine Uptake Inhibitors; Frontal Lobe; Fructose; Learning Disabilities; Male; Memory Disorders; Neuroprotective Agents; NF-kappa B; Oxidative Stress; Rats; Rats, Wistar; Topiramate

Self-mutilation is direct and deliberate harm to one's body without conscious intent to die. It is observed in both men and women with various psychiatric disorders, but most of those who self-mutilate are women diagnosed with borderline personality disorder. Cocaine addiction is a significant worldwide public health problem, associated with somatic, psychological, psychiatric, socioeconomic and legal complications. Amphetamine use, but not cocaine use, has previously been associated with severe self-injurious behavior.. We report here a case of a female patient with recurring self-injurious behavior ("the pleasure of bleeding") induced by cocaine abuse.. The clinical characteristics of self-mutilation are manifold and there is a lack of agreement about its etiology. The complex behavior associated with cocaine abuse may be one cause of self-mutilation. Dysfunction of the inhibitory brain circuitry caused by drug addiction could explain why this cocaine-addicted patient loses control and self-mutilates during cocaine use.

Topics: Administration, Inhalation; Adult; Cocaine; Cocaine-Related Disorders; Female; Forearm; Fructose; Hemorrhage; Humans; Neuroprotective Agents; Self Mutilation; Topiramate; Treatment Outcome

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.

Topics: Adolescent; Adult; Chi-Square Distribution; Cocaine; Cocaine-Related Disorders; Double-Blind Method; Female; Fructose; Humans; Male; Middle Aged; Pilot Projects; Topiramate