Modulation of Pharmacologically Induced Alcohol Craving in Recently Detoxified Alcoholics

Alcoholism

Chemical Stressor, Alcoholism, Yohimbine, Acamprosate, Craving

This study will determine if acamprosate, a drug approved to treat alcoholism, decreases alcohol cravings in alcohol-dependent subjects following infusions of yohimbine and mCPP. Yohimbine causes anxiety and may provoke a desire for alcohol; mCPP induces a feeling of having had a few drinks, which often creates a desire for more drinks. If acamprosate can prevent a craving following these stimuli, then the effectiveness of new experimental drugs for treating alcoholism can be tested for their ability to block yohimbine or mCPP-induced cravings. This type of investigation would be less expensive and less time-consuming than conducting clinical trials with alcohol-dependent people. People between 21 and 65 years of age who are alcohol-dependent and have been drinking regularly for at least 1 month before entering the study may be eligible to participate. Participants are admitted to the NIH Clinical Center for about 35 days, during which time they are asked to participate in an alcohol treatment program. They may request passes to leave the hospital during the day but must return overnight. Upon return to the hospital, subjects are required to take a breathalyzer test for alcohol and urine screen for drug use. Participants found to have used drugs or consumed alcohol while away from the hospital are terminated from the study. Participants are randomly assigned to take acamprosate or placebo pills three times a day for about 2 weeks. They are then given three intravenous (through a vein) infusions, 5 to 7 days apart, each containing either yohimbine, mCPP or placebo. The drugs are infused for 20 minutes following a 1-hour infusion of saline (salt water). Subjects complete two questionnaires - an alcohol urge questionnaire to assess the desire for alcohol and a PASS rating scale to assess anxiety - several times during the study and during the infusions....

Objective: The objective of the present study is to establish, in our laboratory, a published model of pharmacologically induced alcohol craving, and carry out an initial evaluation of its predictive validity for efficacy in treatment of alcoholism. Two pharmacological challenges are tested: 1. The alpha2-adrenergic antagonist yohimbine, which reliably induces reinstatement of alcohol seeking in experimental animals, but has produced less clear results in humans. 2. The serotonergic compound mCPP, which has been reported to robustly increase alcohol craving in human alcoholics, but for which animal data are less clear. Our objective study is to evaluate craving responses to infusion of yohimbine or mCPP using optimal assessment tools and subject population, and establish their sensitivity to the clinically effective alcoholism medication acamprosate. Study Population: The study will be carried out in 60 subjects aged 21-65 years, with alcohol dependence as their primary complaint, and without other serious medical or psychiatric conditions. An additional inclusion criterion will be elevated trait anxiety as measured by the Spielberger Trait Anxiety Inventory. Subjects will be admitted to the NIAAA research inpatient unit at the NIH Clinical Research Center (CRC) through the platform training and natural history protocol (05-AA-0121 Assessment and Treatment of People with Alcohol Drinking Problems ), which provides basic assessments and standard withdrawal treatment if needed. Patients will enter into the present protocol once such treatment, if needed, is completed. Design: Following inclusion, subjects will be randomized to acamprosate (n=25) or placebo (n=25), receiving either 3 tablets of 333mg acamprosate three times daily, or receiving identically looking placebo. Following a minimum of 2 weeks of treatment, subjects will undergo three challenge sessions, a minimum of 5 days apart, with yohimbine, m-CPP or placebo infusion, in counterbalanced order. Outcome Measures: During the challenge sessions, subjective cravings for alcohol will be assessed using the Alcohol Urge Questionnaire. Neuroendocrine and cardiovascular measures will be collected for exploratory purposes.

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