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