Title: Effect of Opioid Receptor Modulation on Alcohol Self-Administration and Neural Response to Alcohol Cues in Heavy Drinkers: Role of OPRM1 Gene Variation
Condition: AUD
MeSH terms: Alcoholic Intoxication
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      Drugs like nalmefene interfere with opioid receptors. This might reduce drinking. The gene
      OPRM1 determines opioid receptor functions. Researchers want to see if nalmefene affects
      people s responses to alcohol cues. They also want to compare how nalmefene affects people
      with different forms of OPRM1.

      Objectives:

      To test nalmefene s effects on alcohol self-infusion and responses to alcohol cues. To test
      the role of different forms of OPRM1 on these effects.

      Eligibility:

      Healthy heavy drinkers ages 21 60:

      Women: over 15 drinks weekly

      Men: over 20 drinks weekly

      Design:

      Participants will be screened with:

      Medical history

      Physical exam

      Heart, blood, and urine tests

      Questionnaires

      Participants will have three 10-hour visits and one 2-hour follow-up visit. They will take a
      taxi. Visits are about 1 week apart.

      Before visits, participants cannot drink alcohol for 1 day or take medicine for 3 days.

      All study visits:

      Questionnaires

      Heart monitor

      Two-hour alcohol session: A needle guides a thin plastic tube into a vein in each arm. One
      tube receives alcohol. The other draws blood. Participants give themselves alcohol by
      pressing a button on a computer.

      Relaxing at the center until breath alcohol falls below 0.02 percent, or for 3 hours.

      Visits 2 and 3:

      Swallowing nalmefene or placebo.

      One-hour brain MRI: Participants lie on a table with a coil on their head. They press buttons
      in response to computer cues.

      Follow-up visit: participants will discuss their drinking habits.
    

Detailed description: 
      Previous studies have shown that the opioid receptor modulator nalmefene can reduce heavy
      drinking among alcoholics. Genetic variation at the micro-opioid receptor gene locus, OPRM1,
      specifically the A118G polymorphism, is associated with differential subjective responses to
      alcohol. Further, the A118G polymorphism has been shown to moderate the effect of opioid
      receptor modulators on alcohol consumption. However, the role of A118G on nalmefene s
      effectivenes, and the neural substrates underlying nalmefene s therapeutic effect remain to
      be explored in humans.

      Objective: To evaluate the effect of nalmefene on alcohol self-infusion and neural response
      to alcohol cues in healthy male and female heavy drinkers, and to examine the role of the
      OPRM1 A118G polymorphism on this effect.

      Study population: Participants will be 21-60 year-old male and female heavy drinkers in good
      health, as determined by medical history, physical exam, and ECG and lab tests. Participants
      with current Axis-I mood, anxiety or substance use diagnoses, except alcohol dependence, will
      be excluded. Participants will be divided into 2 genotypic groups: Group 1 (AA) will include
      participants homozygous for the major 118A allele (118AA genotype), and group 2 (GX) will
      include participants carrying 1 or 2 copies of the variant 118G allele (118AG or 118GG
      genotype).

      Design: Participants will undergo 3 study sessions. In the first session, participants will
      complete an intravenous alcohol self-administration (IV-ASA) where they will have an open bar
      phase to determine their baseline level of alcohol consumption in the laboratory, as well as
      to obtain data on tolerability and subjective measures of alcohol effects. In the second and
      third sessions, participants will receive a single dose of either nalmefene or placebo, in
      counter-balanced order, before completing functional magnetic resonance imaging (fMRI) scans
      and IV-ASA procedures. The fMRI scans will include a task where participants will see cues
      that indicate the possibility of earning alcohol rewards to examine the neural substrates
      involved in processing alcohol cues, and a task designed to measure neural responses during
      anticipation and processing of aversive events. The difference in alcohol self-infusions
      between the two sessions will be compared between the two genotypic groups.

      Outcome measures: The primary outcome measures are: (1) nalmefene-induced changes in IV
      alcohol self-administration; (2) nalmefene-induced BOLD signal changes in neural regions
      associated with alcohol reward processing, including ventral striatum, amygdala, and
      insula.;Secondary outcome measures include: (1) Nalmefene-induced BOLD signal changes in
      neural processing of aversive stimuli during fMRI; (2) Genotypic modulation (at the OPRM1 118
      location) of nalmefene s effects on primary outcome measures (BOLD signal change during
      alcohol reward processing and IV alcohol self-administration).
    

Intervention name(s): Nalmefene; Placebo
Intervention type(s): Drug; Other
Intervention description(s): Active Drug; Single Dose Placebo
Intervention MeSH terms: Nalmefene
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Other
Keywords: Alcohol Infusion study; Nalmefene; fMRI; Genetics; NIAAA