Elsevier

The Lancet

Volume 361, Issue 9370, 17 May 2003, Pages 1677-1685
The Lancet

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

https://doi.org/10.1016/S0140-6736(03)13370-3Get rights and content

Summary

Background

Topiramate, a sulphamate fructopyranose derivative, might antagonise alcohol's rewarding effects associated with abuse liability by inhibiting mesocorticolimbic dopamine release via the contemporaneous facilitation of -y-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 γ-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 γ-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.

Introduction

Dopamine pathways that originate in the ventral tegmental area and project to the nucleus accumbens and cortex are widely thought to mediate alcohol's rewarding effects (including craving) associated with its abuse liability.1 Alcohol intake, by decreasing 7-amino-butyric acid receptor activity in the ventral tegmental area, disinhibits γ-amino-butyric acid-mediated tonic inhibition of ventral tegmental area dopamine neurons2 and facilitates dopamine neurotransmission.2 Glutaminergic pathways from the hippocampus and cortex modulate activity of γ-amino-butyric acid in the midbrain.3 Therefore, it is of interest that individuals with chronic alcoholism might have more glutamate binding sites in the brain than people who are not dependent on alcohol,3 including those of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and kainate types in the hippocampus,4 an effect that could result in facilitated dopamine neurotransmission in the midbrain.

Topiramate is a sulphamate fructopyranose derivative that: facilitates γ-amino-butyric acid function through a non-benzodiazepine site on the 7-amino-butyric acid-A receptor,5 thus decreasing extracellular release of dopamine in the midbrain;6 and antagonises glutamate activity at α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and kainate receptors.7

We, therefore, postulated that topiramate would be an effective treatment for alcohol dependence because it had the potential to decrease mesocorticolimbic dopamine activity after alcohol intake and to antagonise chronic changes induced by alcohol at the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and kainate glutamate receptors.

As a proof-of-concept test of this hypothesis, we did a randomised, double-blind, 12-week controlled clinical trial to determine whether topiramate (escalating dose of 25 mg per day to 300 mg per day) would be more effective than placebo at reducing drinking, promoting abstinence, and decreasing craving in individuals who are dependent on alcohol.

Section snippets

Patients

We enrolled 150 men and women who had been diagnosed with alcohol dependence according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM IV).8 Participants were 21-65 years old; scored 8 or greater on the alcohol use disorders identification test,9 which assesses the personal and social harm after alcohol consumption; reported drinking on average at least 21 standard drinks per week for women and at least 35 per week for men, during the 90 days before enrolment; and

Procedures

At baseline (week 0), after providing written informed consent, we assessed participants on: physical health– medical history and physical examination, vital signs (ie, blood pressure, pulse, and temperature), 12-lead electrocardiogram, haematological and biochemical laboratory studies, including a urine drug test; breath alcohol concentration; urine pregnancy test; and psychiatric diagnosis–structured clinical interview for DSM IV;11 age of problem-drinking onset–item B 28 of the comprehensive

Statistical analysis

Power calculations were based on the need to select an ample cell size to detect significant treatment differences between topiramate and placebo as an average of the 12-week drinking outcomes in an analysis of covariance model. Effect sizes were derived from a previous clinical trial in which ondansetron (4 μg/kg twice daily) was more effective than placebo at reducing mean drinks per day (3·13 [95% CI 2·01-4·25] vs 1·56 [0·71-2·41], respectively) in people whose alcohol dependence was of

Role of the funding source

The sponsors of the study had no role in the study design, data collection, data analysis, data interpretation, or the writing of the report.

Results

75 participants in each group received treatment (figure 1). Table 2 shows the participants' baseline characteristics. Self-reported and objective drinking measures were lower at the study end (end of week 12) than at the start of the study (end of week 1) in both groups (p<0-0001 for all comparisons).

Over the course of treatment, topiramate was significantly more effective than placebo at improving drinking outcomes on drinks per day, drinks per drinking day, percentage of heavy drinking days,

Discussion

Our results show that topiramate is more effective than placebo at reducing drinking and promoting abstinence in alcohol-dependent individuals who are seeking treatment. Topiramate's treatment effect on drinking outcome was robust, with increasing differences compared with the placebo as the study progressed. Furthermore, topiramate-induced improvement in self-reported drinking outcomes was corroborated by corresponding decreases in the objective measure, plasma γ-glutamyl transferase.

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