Component 3: Naltrexone and Topiramate Combined for the Treatment of Cocaine and Alcohol Dependence Finding an effective pharmacological treatment for a difficult problem such as dual cocaine and alcohol dependence may require innovative strategies including the combination of two medications that can address the addiction through complementary mechanisms of action. For example, the combination of naltrexone and topiramate. Naltrexone, by blocking mu opiate receptors, reduces the rewarding properties of alcohol and reduces alcohol craving. It has been proven to be effective for preventing relapse in alcoholics. Recently, we found that naltrexone at a higher dose than commonly used to treat alcohol dependence may be moderately effective for reducing relapse to cocaine and alcohol in dually addicted cocaine and alcohol dependent patients. Topiramate raises brain GABA levels and facilitates GABAergic neurotransmission and may, therefore, reduce the rewarding properties of both cocaine and alcohol as well as reduce cocaine and alcohol craving. In two independently-conducted placebo-controlled trials, topiramate has shown to be effective for the treatment of 1) cocaine dependence and also 2) alcohol dependence. Thus, both naltrexone and topiramate appear to act on the brain reward center, although by two distinctly different mechanisms of action. Therefore, the combination of the two medications may have a more robust effect, than either medication alone. The proposed project will evaluate the efficacy of combining high-dose naltrexone and topiramate for the treatment of dual cocaine and alcohol dependence in a double-blind, placebo-controlled, 14-week trial involving 200 DSM-FV alcohol and cocaine dependent subjects. The study will be a 4-cell design (50 subjects per cell) where each of the two medications (naltrexone + topiramate) will be given alone, or in combination, and compared to placebo. The primary hypotheses are: 1 .Naltrexone-treated subjects and (separately)topiramate-treated subjects, compared to placebo-treated subjects, will have more abstinent days, fewer heavy drinking days (measured by the timeline followback), and a greater reduction in cocaine use (measured by fewer benzoylecgonine positive urine samples); and 2. Subjects treated with the combination of naltrexone and topiramate will have more abstinent days, fewer heavy drinking days, and a greater reduction in cocaine use, compared to subjects treated with a single medication, as well as placebo-treated subjects.
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