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Am Fam Physician. 2004;69(1):195-203

Research on the neurophysiology of alcohol dependence indicates facilitated dopamine neurotransmission. Johnson and colleagues postulated that topiramate might effectively treat alcohol dependence through several mechanisms, including the ability to decrease extracellular release of dopamine in the midbrain and antagonism of glutamate activity at the neuroreceptors.

The authors conducted a randomized, double-blind, placebo-controlled clinical trial for 12 weeks using topiramate in dosages of up to 300 mg daily. The 150 participants, who were 21 to 65 years of age, met criteria in Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) for alcohol dependence, had diagnostic scores on tests of alcohol-use disorders, and reported drinking at least 21 (for participating women) or 35 (for participating men) standard drinks per week in the 90 days before the study. To be included in the study, participants had to have urine toxicology screens that were negative for narcotics, amphetamines, or sedative hypnotics. A long list of exclusion criteria included a current serious medical or psychologic disorder, biochemical abnormality, or coercion into attempting abstinence (e.g., to avoid imprisonment or maintain employment).

After a comprehensive intake assessment, participants were randomly assigned to treatment with topiramate or placebo. The starting dosage of topiramate, 25 mg daily, was escalated over eight weeks to 300 mg daily. If tolerated, this dosage was maintained for the final four weeks of the study. All patients received brief behavior compliance-enhancement treatment weekly from nurse practitioners who dispensed medications, and adherence was checked weekly by physicians. Patient compliance with the study was assessed by breath alcohol measurements and other indicators of drinking at the weekly visits, plus counts of returned pill packs.

The primary outcome of self-reported drinking was assessed by the number of drinks per day, the percentage of heavy drinking days, and the number of days of abstinence. Patients also reported cravings using a standardized 14-item scale. Objective evidence of drinking was obtained by checking the plasma γ-glutamyl transferase concentration.

The 107 men and 43 women enrolled in the study were 42 years of age on average, and nearly two thirds were white. The participants reported an average of 12.69 to 14.73 years of problems with alcohol use and intakes of 9.59 to 8.85 drinks per day during the 90 days before the study. The treatment and placebo groups were comparable in all significant respects. By the end of the study, both groups showed highly significant reductions over baseline in objective and subjective measures of drinking. Patients receiving topiramate were significantly more successful than those taking placebo in reducing the number of drinks per day, the number of drinks on each drinking day, the percentage of heavy drinking days, and measures of γ-glutamyl transferase. They also significantly increased the percentage of abstinent days compared with the placebo group.

The significant differences between the groups became apparent at weeks 6 and 8 and increased as the study progressed. Compared with the placebo group, by the end of the study the patients treated with topiramate reported having 2.88 fewer drinks per day, 3.10 fewer drinks per drinking day, 27.6 fewer days of heavy drinking, and 26.2 more days of abstinence. Changes in the γ-glutamyl transferase ratio indicated significantly decreased alcohol intake in the treated group. These differences between the groups also were apparent in measures of cravings during treatment.

Results were reported on the assignment of 75 patients to each group, but only 55 patients in the topiramate group and 48 in the placebo group completed the study. Dizziness, paresthesia, psychomotor slowing, memory impairment, and weight loss were reported more frequently by patients taking topiramate, but only three patients withdrew from the topiramate group and five from the placebo group because of adverse effects.

The authors conclude that topiramate is more effective than placebo as an adjunct treatment of alcohol dependence in a 12-week program. The effect appears to become significant at dosages of 200 mg daily but increases over time as the dosage is increased to a maximum of 300 mg daily; therefore, independent effects of time and dosage cannot be segregated. They call for further studies of this approach to the treatment of alcohol dependence.

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