The Effect of Naltrexone on Alcohol Craving and on Brain Activity During Alcohol Infusion
Condition: Alcohol Dependence; Alcoholism
MeSH terms: Alcoholism
Study type: Interventional
Phase: Early Phase 1

Summary: 
      This study will determine whether naltrexone, a medicine used to treat alcoholism, can lessen
      the craving for alcohol during alcohol withdrawal and examine how the drug affects brain
      activity during alcohol infusion.

      People between 21 and 50 years of age who are right-handed, alcohol-dependent, and have at
      least one family member with a history of alcoholism, may be eligible for this study.

      Participants are admitted to the NIH Clinical Center for 1 month for the following
      procedures:

      Screening

        -  Medical history, alcohol-use history and family history of alcoholism

        -  Physical examination, psychological tests and blood tests

        -  Medicine to lessen alcohol withdrawal symptoms, if necessary

      Days 1-7

        -  Alcohol detoxification

        -  Medical and psychological evaluations

        -  Assignment to naltrexone or placebo group

      Days 7 through 28

        -  Drug treatment: Take naltrexone or placebo capsule every morning

        -  Additional alcohol-dependence treatment: Cognitive and behavioral therapies and
           participation in self-help groups, such as Alcoholics Anonymous

        -  Weekly questionnaires to measure mood and desire for alcohol

        -  Blood tests

        -  Alcohol craving stimulation test (day 7): Subjects handle and sniff water and then their
           favorite alcoholic beverage. They then rate their urge to drink alcohol and their level
           of anxiety and their heart rate is measured.

        -  Alcohol infusion test (day 9): Subjects have an MRI scan during infusion through a vein
           of saline (salt water), followed by infusion of alcohol. For this test, a catheter
           (plastic tube) is placed in a vein in each arm, one for administering the saline and
           then alcohol; the other for drawing blood samples to measure blood alcohol level and
           body chemistries. Before, during and after the infusion, subjects are asked to respond
           to questions about their feelings, cravings and mood changes.

      Follow-up

      Subjects are asked to participate in a 3-month outpatient assessment program involving five
      outpatient visits (at 1, 2, 4, 8 and 12 weeks after discharge). At each visit, they fill out
      questionnaires and to take a breathalyzer test and blood and urine tests for drugs. They may
      continue naltrexone therapy and weekly group therapy sessions during this time. Subjects who
      do not participate in the assessment program are contacted at home by phone once a week for 1
      month and then every other week for the next 2 months to monitor alcohol abstinence.

      ...
    

Detailed description: 
      Alcoholism is a chronic, progressive, brain disorder with a profound impact on individuals'
      lives and economic cost to society. The positive reinforcing effect of alcohol is a key
      element in the transitional development from alcohol intake to alcohol addiction. Findings
      from animal and human studies indicate that the rewarding properties of ethanol arise in part
      from a complex interaction between alcohol, endogenous opioids, and dopamine (DA) systems.
      Acute administration of ethanol increases the release of opioid peptides, which in turn,
      increases the release of DA in the mesocorticolimbic system. Naltrexone (NTX), an opioid
      receptor antagonist, has been studied widely in both preclinical and clinical research for
      the treatment of alcoholism. Numerous clinical studies have shown that short-term use of NTX
      on alcohol-dependent patients effectively prevents relapse and reduces the level of craving.
      Genetic studies have suggested that individuals with mu-opioid receptors (OPRMs) encoded by
      the 118G gain-of function variant allele experience a greater therapeutic response to NTX.
      There are no data utilizing functional Magnetic Resonance Imaging (fMRI) to study the effect
      of NTX on brain activity during an intravenous (IV) infusion of ethanol.

      Objectives:

      To study the effect of NTX on the blood oxygen level dependent (BOLD) response in the ventral
      striatum area of the brain in response to an ethanol infusion.

      To study the effect of NTX on cue reactivity (CR) to alcohol-associated cues.

      Study population:

      Alcohol-dependent patients between the ages of 21-50 years.

      Design:

      All participants will complete a screening telephone interview before coming to the NIAAA
      Inpatient Unit. The interviewer will inform eligible participants about the requirements and
      procedures associated with current protocols. Following admission to NIAAA Inpatient Unit,
      all participants will be enrolled in the Assessment and Treatment of People with Alcohol
      Drinking Problems protocol (#05-AA-0121). Protocol 05-AA-0121 will allow us to evaluate each
      participant's general medical and psychiatric conditions and provide standard of care for
      treatment seeking alcoholics.

      Participants, who fulfill the specific requirements of the NTX protocol, will be thoroughly
      informed about the nature of the study before obtaining an informed consent. Consented
      participants will be randomized, using a double-blind design, to receive either 50 mg of NTX
      per day or placebo. Medications will be administered at 8:00 AM on a daily basis by the
      nursing staff.

      Prior to the challenge procedures (CR on Day 7 and fMRI/ethanol infusion on Day 9), a
      clinical nurse specialist who is not involved with the protocol will re-consent each
      participant when they are not in acute withdrawal. The re-consenting process will provide
      reassurance that participants understand the requirements and implications associated with
      participation in the CR and fMRI/ethanol infusion procedures. Individuals who elect not to
      participate in the CR and fMRI/ethanol infusion sessions will be discharged from the
      in-patient unit and encouraged to continue treatment in the NIAAA Outpatient Clinic for the
      next three months.

      Participants who elect to remain in the study will take part in the CR session on Day 7 and
      fMRI/ethanol infusion session on Day 9 (procedures are described on Page 13 under study
      procedures). Following the fMRI/ethanol infusion session, participants will remain in the
      hospital for approximately three weeks to monitor their craving and take part in our
      inpatient treatment program for alcoholism. During the post-challenge hospitalization, all
      participants will be offered 50 mg of NTX once a day. Following discharge from the hospital,
      participants will be encouraged to continue treatment in NIAAA Outpatient Clinic for three
      months.

      Outcome Measures:

      BOLD response during the ethanol infusion challenge.

      BOLD brain response to emotional facial stimuli.

      Self-reported Alcohol Urge Questionnaires (AUQ), Penn Alcohol Craving Scale (PACS), Obsessive
      Compulsive Drinking Scale (OCDS) and Profile of Mood Status (POMS).

      Hormonal responses to the ethanol challenge: plasma ACTH, cortisol, and beta-endorphin.

      Subjective responses to the ethanol challenge as rated by stimulation, sedation, high, and
      intoxication questionnaires.

      Cue-induced craving during the CR session.
    

Intervention name(s): Naltrexone
Intervention type(s): Drug
Intervention MeSH terms: Naltrexone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Alcohol; Naltrexone; fMRI; Alcoholism; Alcoholics; Alcohol Dependence