Nassima Ait-Daoud

Oral topiramate for treatment of alcohol dependence: a randomised controlled trial

BACKGROUND Topiramate, a sulphamate fructopyranose derivative, might antagonise alcohols rewarding effects associated with abuse liability by inhibiting mesocorticolimbic dopamine release via the contemporaneous facilitation of gamma-amino-butyric acid activity and inhibition of glutamate function. We aimed to see whether topiramate was more effective than placebo as a treatment for alcohol dependence. METHODS We did a double-blind randomised controlled 12-week clinical trial comparing oral topiramate and placebo for treatment of 150 individuals with alcohol dependence. Of these 150 individuals, 75 were assigned to receive topiramate (escalating dose of 25-300 mg per day) and 75 had placebo as an adjunct to weekly standardised medication compliance management. Primary efficacy variables were: self-reported drinking (drinks per day, drinks per drinking day, percentage of heavy drinking days, percentage of days abstinent) and plasma gamma-glutamyl transferase, an objective index of alcohol consumption. The secondary efficacy variable was self-reported craving. FINDINGS At study end, participants on topiramate, compared with those on placebo, had 2.88 (95% CI -4.50 to -1.27) fewer drinks per day (p=0.0006), 3.10 (-4.88 to -1.31) fewer drinks per drinking day (p=0.0009), 27.6% fewer heavy drinking days (p=0.0003), 26.2% more days abstinent (p=0.0003), and a log plasma gamma-glutamyl transferase ratio of 0.07 (-0.11 to -0.02) less (p=0.0046). Topiramate-induced differences in craving were also significantly greater than those of placebo, of similar magnitude to the self-reported drinking changes, and highly correlated with them. INTERPRETATION Topiramate (up to 300 mg per day) is more efficacious than placebo as an adjunct to standardised medication compliance management in treatment of alcohol dependence.

A preliminary randomized, double-blind, placebo-controlled study of the safety and efficacy of ondansetron in the treatment of methamphetamine dependence

Methamphetamine dependence is an increasing public health problem in the United States. No efficacious medication for methamphetamine dependence has been developed. As ondansetron, a 5-HT3 receptor antagonist and modulator of cortico-mesolimbic dopamine function, has been shown to reduce some of the rewarding effects of d-amphetamine in animal and human laboratory studies, we decided to test whether it would be superior to placebo at reducing methamphetamine use. In a preliminary, multi-site, randomized, double-blind, 8-wk controlled trial, 150 methamphetamine-dependent men and women received ondansetron (0.25 mg, 1 mg, or 4 mg b.i.d.) or placebo. Participants were assessed on several measures of methamphetamine use including urine methamphetamine level up to three times per week. As a psychosocial adjunct to the medication condition, cognitive behavioural therapy also was administered three times per week. Ondansetron was well tolerated and was less likely than placebo to be associated with serious adverse events. Nevertheless, none of the ondansetron doses was superior to placebo at decreasing any of the measures of methamphetamine use, withdrawal, craving, or clinical severity of methamphetamine dependence. Our preliminary results do not support the utility of ondansetron, at the doses tested, as a treatment for methamphetamine dependence. These findings should be viewed in light of the possibility that a less intensive cognitive behavioural therapy regimen might have yielded more positive results in this initial phase II trial exploring for the efficacy of ondansetron.

A Pilot Evaluation of the Safety and Tolerability of Repeat Dose Administration of Long‐Acting Injectable Naltrexone (Vivitrex®) in Patients With Alcohol Dependence

BACKGROUND : Oral naltrexone is currently used as part of a treatment regimen for alcohol-dependent patients, but its clinical utility is hampered by poor patient adherence. A long-acting injectable naltrexone formulation (Vivitrex) was designed to facilitate patient adherence by providing an extended duration of therapeutic naltrexone over 1 month, thereby eliminating the need for daily dosing. METHODS : A multicenter, randomized, double-blind, placebo-controlled pilot study was conducted to evaluate the safety and tolerability of intramuscular repeat dose administration of this extended-release naltrexone formulation in DSM-IV alcohol-dependent patients. Thirty patients were randomized to treatment with injectable naltrexone (400 mg; n = 25) or a matching placebo injection (n = 5) and were dosed once every 28 days over 4 months. Psychosocial treatment was offered to patients in both treatment groups. Outcome measures related to drinking activity and trough plasma concentrations of naltrexone and its primary metabolite, 6-beta-naltrexol, were evaluated. RESULTS : Injectable naltrexone was generally safe and well tolerated. Reported adverse events were mild to moderate and resolved without intervention; only two patients discontinued due to adverse events. The most common adverse events (nausea and headache) occurred at a similar rate for patients in both treatment groups. Pharmacokinetic analysis confirmed that therapeutic levels of naltrexone were delivered throughout the four 1-month treatment cycles. CONCLUSIONS : The results of this pilot study provide the basis and methods for a larger, more definitive trial to determine the utility of this long-acting injectable naltrexone formulation in the treatment of alcohol-dependent patients.

Topiramate for the treatment of methamphetamine addiction: a multi-center placebo-controlled trial

AIMS   Topiramate has shown efficacy at facilitating abstinence from alcohol and cocaine abuse. This double-blind, placebo-controlled out-patient trial tested topiramate for treating methamphetamine addiction. DESIGN   Participants (n = 140) were randomized to receive topiramate or placebo (13 weeks) in escalating doses from 25 mg/day [DOSAGE ERROR CORRECTED] to the target maintenance of 200 mg/day in weeks 6-12 (tapered in week 13). Medication was combined with weekly brief behavioral compliance enhancement treatment. SETTING   The trial was conducted at eight medical centers in the United States. PARTICIPANTS   One hundred and forty methamphetamine-dependent adults took part in the trial. MEASUREMENTS   The primary outcome was abstinence from methamphetamine during weeks 6-12. Secondary outcomes included use reduction versus baseline, as well as psychosocial variables. FINDINGS   In the intent-to-treat analysis, topiramate did not increase abstinence from methamphetamine during weeks 6-12. For secondary outcomes, topiramate reduced weekly median urine methamphetamine levels and observer-rated severity of dependence scores significantly. Subjects with negative urine before randomization (n = 26) had significantly greater abstinence on topiramate versus placebo during study weeks 6-12. Topiramate was safe and well tolerated. CONCLUSIONS   Topiramate does not appear to promote abstinence in methamphetamine users but can reduce the amount taken and reduce relapse rates in those who are already abstinent.

Review of treatment for cocaine dependence.

Cocaine dependence is a complicated, destructive, and often chronic illness that is difficult to treat. In this article we review the challenges in treating cocaine dependence, as well as recent developments and future directions in psychosocial and pharmacological treatment relevant to treatment of cocaine dependence. Cocaine is one of the most addictive drugs because of its immediate and powerful rewarding effects. Often, cocaine dependent individuals experience difficulty abstaining due to cognitive impairments from repeated cocaine use, strong use-related social and environmental cues, and high levels of life stress. Cocaine use also affects areas of the brain related to motor function, learning, emotion, and memory, further complicating the administration of effective interventions. In addition, development of treatments for cocaine dependence has been complicated by the tendency for abusers not to complete treatment programs and their propensity for relapse. Despite these challenges, some treatment approaches, such as cognitive behavioral therapy (CBT) and medications have shown promise in successfully treating cocaine dependence. However, individually, each of these treatments exhibit weakness in longitudinal studies where long-term abstinence is the primary outcome of interest. Although other treatments are being explored, thus far, the combination of CBT and pharmacotherapy has elicited the best results for treating cocaine dependence with respect to patient retention and relapse prevention following abstinence. No treatment method has yet been shown to completely and effectively treat cocaine dependence. More research is necessary to test treatment programs and garner further information in order to better understand and treat cocaine dependence.

Topiramate in the New Generation of Drugs: Efficacy in the Treatment of Alcoholic Patients

Predicated upon a neuropharmacological conceptual model, there is now solid clinical evidence to support the efficacy of topiramate for the treatment of alcohol dependence. Topiramate treatment can be initiated whilst the alcohol-dependent individual is still drinking - just when crisis intervention is most likely to be needed by a patient with or without his or her family asking the health practitioner for assistance. Because topiramate can be paired with a brief intervention, there is now the exciting possibility of treating most alcohol- dependent individuals in office-based practice or generic treatment settings. Topiramates additional effects on other impulsedyscontrol disorders make it a particularly interesting compound for the treatment of other comorbid drug or psychiatric disorders. Additionally, future studies should explore whether topiramate can be combined with other putative therapeutic agents to increase its efficacy. One notable clinical challenge in the development of topiramate as a pharmacotherapy to treat alcohol dependence is the determination of the smallest dose that can result in efficacy, thereby achieving the optimum balance between therapeutic benefit and adverse event profile. Animal data do provide support for topiramates general anti-drinking effects but also indicate that its mechanisms of action might rely on several complex pharmacobehavioral changes. Additional preclinical studies are needed to elucidate more clearly the basic mechanistic processes that underlie topiramates efficacy as a treatment for alcohol dependence. Preclinical information that topiramate may have differential effects based on genetic vulnerability opens up the possibility of future methods to optimize treatment.

Topiramate for the Treatment of Cocaine Addiction: A Randomized Clinical Trial

IMPORTANCE 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. OBJECTIVE To determine the efficacy of topiramate vs placebo as a treatment for cocaine dependence. DESIGN, SETTING, AND PARTICIPANTS 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. INTERVENTIONS 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. MAIN OUTCOMES AND MEASURES 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. RESULTS 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). CONCLUSIONS AND RELEVANCE 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.

Ondansetron reduces mood disturbance among biologically predisposed, alcohol-dependent individuals.

BACKGROUND Early-onset alcoholics (EOA) differ from late-onset alcoholics (LOA) by developing problem drinking during youth, experiencing severe behavioral problems, having a familial disease history, and possessing a tendency toward subsyndromal mood disturbance, including symptoms of depression, anxiety, and hostility. Subsyndromal mood disturbance is, therefore, an important component of the early-onset syndrome and may be mediated by serotonin dysfunction. Therefore, the serotonin-3 antagonist ondansetron, which has been shown to be effective at improving drinking outcomes and promoting abstinence among EOA, presumably by ameliorating serotonin dysfunction, also may exert its beneficial effects by alleviating mood disturbance among EOA. METHODS After one lead-in week of single-blind placebo administration, subjects underwent 11 weeks of double-blind outpatient treatment using a 2 x 4 factorial design that examined age of onset (EOA versus LOA) and medication dose (placebo, or ondansetron 1, 4, or 16 microg/kg twice daily) combined with weekly standardized group cognitive-behavioral therapy. The placebo lead-in week was used to adjust for study entrance effects but not for excluding subjects. Assessments of mood were performed by using the overall score and subscales of the Profile of Mood States both at screening and at weekly intervals during the study. RESULTS Subsyndromal mood disturbance was shown to be an important component of early-onset alcoholism. Ondansetron (16 microg/kg twice daily) showed greater therapeutic efficacy at alleviating symptoms of overall mood disturbance, fatigue, vigor, confusion/bewilderment, and depression among EOA compared with LOA. EOA-associated improvements in mood disturbance seemed to be independent of drinking behavior. CONCLUSIONS Ondansetron has been shown to be an effective treatment for early-onset alcoholism. Ondansetrons ability to improve symptoms of depression, anxiety, and hostility among EOA may make an additional contribution to its therapeutic effect. Mechanistic studies are needed to delineate more clearly the relationship between serotonin dysfunction and pathophysiology among various subtypes of alcohol-dependent individuals.

Effects of acute topiramate dosing on methamphetamine-induced subjective mood

Clinical studies have shown that topiramate, a sulphamate-substituted fructopyranose derivative, might be an efficacious treatment for alcohol dependence, smoking cessation within an alcohol-dependent population, and cocaine dependence. Mechanistically, topiramates therapeutic effects have been hypothesized to be due to inhibition of cortico-mesolimbic dopamine function, the primary substrate that governs the acquisition, maintenance, and reinstatement of goal-directed behaviour towards seeking abused drugs. Predicated on this hypothesis, we tested in 10 methamphetamine-dependent individuals (three females) whether low- or high-dose (15 or 30 mg i.v.) methamphetamine-induced positive subjective effects and reinforcement can be antagonized by low- or high-dose (100 or 200 mg orally) topiramate using a placebo-controlled, cross-over, factorial design. Methamphetamine administration was associated with orderly, prototypical, and significant increases on measures of stimulation, euphoria, craving, and reinforcement; however, some dysphoric symptoms also emerged. Topiramate alone showed a non-significant trend towards mild reductions in positive mood and reinforcement; yet topiramate appeared to accentuate the appreciation of methamphetamine-induced stimulation and euphoria significantly, but not craving or reinforcement. The experimental combination of topiramate and methamphetamine appeared to be safe and well tolerated, with few adverse events. Acute dosing with up to 200 mg topiramate appears to enhance, rather than attenuate, the positive subjective effects of methamphetamine. Perhaps this indicates a partial inhibition of methamphetamines reinforcing effects. Thus, testing chronically administered or higher doses, or both, of topiramate would be necessary to determine conclusively whether or not it can attenuate the positive subjective and reinforcing effects of methamphetamine.

Emerging Biomarkers : New directions and clinical applications

This article summarizes content proceedings of a symposium held at the 2004 Research Society on Alcoholism Scientific Annual Meeting in Vancouver, Canada. The chairs were Friedrich M. Wurst and Raye Litten. The presentations were (1) Introduction, by Raye Litten; (2) Direct Ethanol Metabolites--On the Threshold From Science to Routine Use, by Friedrich M. Wurst; (3) Sialic Acid Index of Plasma Apolipoprotein J (SIJ) as a Viable Marker for Chronic Alcohol Consumption, by Philippe Marmillot; (4) The Emergence of Ethyl Glucuronide (EtG) Testing as a Tool in Monitoring Healthcare Professionals, by Gregory E. Skipper; (5) Application of Biomarkers for Alcohol Use Disorders in Clinical Practice, by Tim Neumann; (6) Utility of Biomarkers in Assessing the Efficacy of Medications for Treating Alcoholism, by Marty Javors; and (7) Discussion, by Raye Litten.