Understanding Treatment Response With Naltrexone Among White Alcoholics (DEFINE II)

• Improvement in quality of life (MOS SF-12), alternative drinking measures, biological markers of heavy drinking (CDT and GGT) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
• Asp40 gene variant and family history of alcohol problems. [ Time Frame: once ] [ Designated as safety issue: No ]

This is a study involving treatment for alcohol dependence among males of European or Asian decent. The ultimate aim of this line of investigation is to further establish a genetic link between alcohol dependence and treatment by defining an endophenotype associated with treatment response. The study will combine two inpatient alcohol challenge sessions along with 12 weeks of outpatient treatment using random assignment to either naltrexone or placebo.

Despite the well-established efficacy of naltrexone, there are significant variations in individual responses to naltrexone. A critical question remains: under what circumstances and for which patients will naltrexone be most beneficial? Recent work at our center provides evidence that the mu-opioid receptor (OPRM1) gene polymorphism A118G (Asn40Asp) imparts a significant change in treatment response. We have shown that patients with Asn40 variant (absence of heavy drinking -73.9% v/s 49% response). To further consolidate our knowledge, we wish to test the relationship between A118G polymorphism and the subjective/objective measures to alcohol among alcoholics treated with naltrexone. This work is focused on subjects of European or Asian decent as the A118G polymorphism occurs in less than 1% of those of African decent.

Up to 40 subjects will be recruited. The study is divided into two phases. For the first phase (Phase I) subjects are admitted to the UPenn Translational Research Center and receive two alcohol challenge sessions after pretreatment with naltrexone or placebo. Phase II continues with 12 weeks of outpatient treatment, immediately following the sessions, after random assignment to naltrexone or placebo.

• Drug: naltrexone
  phase 1: 30 or 50 mg of naltrexone prior to challenge session; phase 2: 50mg/day for 12 weeks
  Other Name: ReVia
• Drug: placebo
  placebo pills
• Other: alcohol
  190 proof alcohol prepared to 11% volume mixed with fruit juice

• Experimental: P1A
  Phase 1: Placebo then naltrexone prior to alcohol challenge sessions
  Interventions:

  • Drug: naltrexone
  • Other: alcohol
• Placebo Comparator: P1B
  Phase 1: placebo prior to alcohol challenge sessions
  Interventions:

  • Drug: placebo
  • Other: alcohol
• Experimental: P2A
  Phase 2: naltrexone treatment
  Intervention: Drug: naltrexone
• Placebo Comparator: P2B
  Phase 2: placebo
  Intervention: Drug: placebo

Inclusion Criteria:

1. Males 21 years of age or older of European or Asian decent.
2. Has a current DSM IV diagnosis of alcohol dependence as determined by the Structural Clinical Interview for DSM IV (SCID-IV Mini).
3. Drank an average of 21 drinks/week in the 60 days prior to treatment and had at least 2 occasions of heavy drinking (5 or more drinks on a given day for men), as measured by the Timeline Followback (TLFB).
4. Has adequate vision, hearing, and ability to communicate to allow study participation.
5. Successfully completes detoxification as manifested by at least 48 consecutive hours of no self-reported alcohol use immediately prior to admission to the inpatient unit.
6. Has signed a witnessed informed consent
7. Scores below an 8 on the Clinical Inventory of Withdrawal for Alcohol (CIWA) prior to starting naltrexone/placebo; and 8) Can speak, print, and understand English.

Exclusion Criteria:

1. Meets DSM-IV criteria for dependence on any substance other than alcohol or nicotine in the last 6 months.
2. Tests positive on the urine drug screen for opioids, cocaine, or amphetamine at the screening visit (only 1 repeat test permitted).
3. Meets current or lifetime DSM-IV criteria for bipolar affective disorder, schizophrenia, or any psychotic disorder
4. The presence of unstable or serious medical illness, including history of stroke, seizure disorder, severe liver disease (AST or ALT > 5x normal at the time of randomization), or unstable cardiac disease
5. Has taken any psychotropic medications (including disulfiram) regularly within the last seven days prior to randomization (14 days for fluoxetine) or needs immediate treatment with a psychotropic medication (with the exception of detoxification medications or benadryl used sparingly for sleep)
6. Over age 64 and has evidence of severe cognitive impairment as evidenced by a Mini-mental status exam (MMSE) score <24
7. Has suicidal or homicidal ideation necessitating inpatient hospitalization
8. Has been abstinent more than 14 days prior to Phase 1
9. Is of African Descent
10. Meets current DSM-IV criteria for for major depression (non-substance induced), PTSD, or panic disorder.
11. Has significant hematological, pulmonary, endocrine, cardiovascular, renal, or gastrointestinal disease.