Topiramate in the Treatment of Alcohol Use Disorders

Sarah T. Melton, PharmD

Disclosures

October 01, 2015

Question

What is the evidence for using topiramate for alcoholism?

Sarah T. Melton, PharmD
Associate Professor of Pharmacy Practice, Gatton College of Pharmacy, East Tennessee State University, Johnson City, Tennessee

Alcohol use disorders occur frequently in clinical practice, and US Food and Drug Administration (FDA)-approved pharmacotherapies (eg, disulfiram, naltrexone, acamprosate) are only moderately effective. Long-term consumption of alcohol causes alterations in several neurotransmitter systems, including gamma-aminobutyric acid (GABA), glutamate, N-methyl-D-aspartate (NMDA), dopamine, and norepinephrine.[1] Ongoing research into alternative pharmacotherapies targets these neurotransmitter systems to decrease alcohol cravings and compulsions with the goal of preventing the long-term detrimental effects of chronic alcohol abuse.

In nonalcoholics, extracellular dopamine release is blocked by GABA neurons in both the ventral tegmental area and nucleus accumbens (areas of the brain associated with pleasure and addiction, the "reward pathway"). Acute drinking decreases the firing of GABA neurons, producing an increase in neuronal activity and release of dopamine. Dopamine release is associated with the reward pathway in the brain.[2] In chronic alcohol abuse, decreased inhibition of GABA in the nucleus accumbens results in a hyperexcitable state of GABA neurons in the ventral tegmental area.

Topiramate is an anticonvulsant with neuroprotective effects. While the exact mechanism of action of topiramate in the treatment of alcohol use disorders is unknown, several mechanisms have been proposed.

Topiramate facilitates GABAA-mediated inhibitory impulses and at the same time antagonizes glutamate receptors. Glutamate antagonism suppresses ethanol-induced dopamine release from the nucleus accumbens, which blocks the reinforcing effects of alcohol abuse.[2] Topiramate is thought to inhibit ventral tegmental area-GABA neuronal activity due to increased GABA tone in the nucleus accumbens. Through these mechanisms, topiramate may decrease dopamine activity in the reward pathway with alcohol ingestion and reduce withdrawal symptoms.[2,3]

The safety and efficacy of topiramate in patients with alcohol use disorders have been evaluated in placebo and active control trials. All but two studies reported positive findings in patients with alcohol use disorders.[4,5]

Overall, topiramate has shown efficacy using dosing regimens of 75-300 mg/day. Topiramate was compared with placebo in three large, randomized, double-blind, placebo-controlled trials with more than 600 patients.[6,7,8] Compared with placebo, topiramate reduced the number of drinks per day and the number of heavy drinking days and increased days of abstinence. In addition, topiramate reduced craving for alcohol and demonstrated a greater reduction of serum gamma-glutamyl transpeptidase (GGT) levels, an objective biologic marker of chronic alcohol abuse.[6,7]

It is important to note that all studies used behavioral interventions along with topiramate. Patient-reported outcomes with the use of topiramate included improved overall well-being and life satisfaction, decreased compulsion and seeking habits, and reduced harmful drinking consequences.[6,7,9]

A recent double-blind, placebo-controlled, randomized trial examined the efficacy of topiramate 200 mg in heavy drinkers whose treatment goal was to reduce drinking to safe levels.[10] The trial also evaluated pharmacogenetic effects of topiramate in this population. Brief counseling was provided to patients in both treatment arms as adjunctive therapy to reduce drinking days and increase days of abstinence. The authors found that topiramate treatment significantly reduced heavy drinking days and increased abstinent days compared with placebo. A key finding of this trial has important implications for the personalized treatment of heavy drinking; the analysis showed that only patients with a specific genotype found in approximately 40% of European-Americans benefited from treatment with topiramate.[10]

Topiramate has been compared with oral naltrexone and disulfiram for alcohol use disorders in several studies. Three studies showed that topiramate at mean doses of 200 mg/day trended toward better outcomes than naltrexone in reducing intake of alcohol and cravings.[8,11,12] In an open-label trial, topiramate was less efficacious than disulfiram.[13] No direct comparison of topiramate and acamprosate has been published.

The therapeutic effect of topiramate can be seen as early as the fourth week of treatment. Slow dose titration may increase adherence and produce a milder adverse-effect profile. The initial dose of topiramate is 25 mg/day orally with weekly titration by 25 mg/day to a maximum dose of 300 mg/day.[9] Topiramate has been effective in patients who were abstinent or still drinking alcohol. About 20% of patients in clinical trials discontinued therapy because of adverse effects.[6,7,9] The most common adverse effects included paresthesias, anorexia, disturbance in memory or concentration (especially word-naming difficulties and decreased attention), taste perversion, and pruritus.[7] Adverse effects can be minimized by slowly titrating to an effective dose over 6-8 weeks. Up to 10% of patients will experience concentration difficulties even with slow dose titration.[7,9]

In conclusion, topiramate is efficacious in the treatment of alcohol use disorders and is an alternative treatment to FDA-approved medications. Clinical trials demonstrate significant, although moderate, benefits of topiramate for abstinence and heavy drinking outcomes. Topiramate also appears to have positive effects on GGT and alcohol craving. Use of topiramate may be limited by dose-related adverse effects, requiring weekly dosage titration to effective doses of 100-300 mg/day.

Pharmacotherapy with topiramate in patients with alcohol use disorders should be accompanied by counseling or psychotherapy for best outcomes. In the future, genotyping in patients with alcohol use disorders might help predict which patients may respond to topiramate.

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