Modulation of Pharmacologically Induced Alcohol Craving in Recently Detoxified Alcoholics
Condition: Alcoholism
MeSH terms: Alcoholism
Study type: Interventional
Phase: Phase 2

Summary: 
      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....
    

Detailed description: 
      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.
    

Intervention name(s): Acamprosate; Yohimbine; mCPP; Saline
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): orally administered tablet, 333mg, three times daily for a minimum of 2 weeks (14 days); Intravenous infusion of yohimbine (0.4 mg/kg) administered once over 10 minutes; Intravenous infusion of mCPP (0.05 mg/kg) over 10 minutes, two times, for a total of 0.1 mg/kg; Intravenous infusion of 0.9% sodium chloride solution over 10 minutes, three times during the study (2 times for the "Saline Infusion" milestone, and one time immediately following the "Yohimbine Infusion" milestone)
Other intervention name(s): Campral; Yohimbe; Yocon; Yohimex; Aphrodyne; 3-CPP; CPP; Normal Saline Flush; Sodium Chloride
Intervention MeSH terms: Acamprosate; Yohimbine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Chemical Stressor; Alcoholism; Yohimbine; Acamprosate; Craving