Genetic and Brain Mechanisms of Naltrexone's Treatment Efficacy for Alcoholism

Genetic and Brain Mechanisms of Naltrexone?s Treatment Efficacy for Alcoholism

The overarching aim of this trial is to evaluate naltrexone's efficacy in light of genetic variation and brain response to alcohol cues utilizing a neuroimaging paradigm. This trial has four specific aims. First, this trial will evaluate whether the presence of the OPRM1 Asp40 allele substitution is associated with improved treatment response to naltrexone in treatment-seeking alcoholics. Second, it will evaluate whether there is a difference in the naltrexone dampening of the alcohol cue-induced brain activation dependent on OPRM1 genotype. Third, it will explore whether alcohol cue-induced brain activation dampening by naltrexone might be a mediating factor in the treatment effects of naltrexone, the OPRM1 gene, or their interaction that might be observed in the first aim. Finally, this trial will evaluate the effect of medication compliance, or adverse effects, on the observed medication by genotype treatment response. A secondary aim will measure medication compliance and side effects based on OPRM1 genotype.

Study Overview

• Status: Completed
• Conditions: Alcohol Dependence
• Intervention / Treatment: Drug: Placebo; Drug: Naltrexone 50 Mg

• Study Type: Interventional
• Enrollment (Actual): 358
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina, Center for Drug and Alcohol Programs
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

1. Age 18 70
2. Subjects will meet criteria for primary alcohol dependence
3. Consumes, on average, at least 5 standard drinks per day for men and 4 drinks per day for women in the 90 days pre-screening. Has at least 50% of days as heavy drinking days (as defined above).
4. Able to maintain sobriety for four days (with or without the aid of alcohol detoxification medications) as determined by self report and breathalyzer measurements
5. Able to read and understand questionnaires and informed consent
6. Lives within approximately 50 miles of the study site

Exclusion Criteria

1. Currently meets DSM IV criteria for any other psychoactive substance dependence disorder except nicotine dependence
2. Any psychoactive substance abuse, except marijuana, nicotine, and cocaine, within the last 30 days as evidenced by subject report, collateral report, or urine drug screen. May meet cocaine abuse criteria, but not dependence, and also must have two sequential urines free of illicit substances
3. Meets DSM IV criteria for current and active axis I disorders of major depression, panic disorder, obsessive compulsive disorder, post traumatic stress syndrome, bipolar affective disorder, schizophrenia, or any other psychotic disorder or organic mental disorder
4. Meets DSM IV current criteria for dissociative disorder or eating disorders
5. Has current suicidal ideation or homicidal ideation
6. Need for maintenance or acute treatment with any psychoactive medication, except a stable dose (at least one month) of antidepressants
7. Need for maintenance on anti-seizure medications (including topiramate and gabapentin)
8. Use of disulfiram, acamprosate, or naltrexone in the last two weeks
9. Clinically significant medical problems such as cardiovascular, renal, GI, or endocrine problem that would impair participation or limit medication ingestion
10. Hepatocellular disease indicated by elevations of SGPT (ALT) and SGOT (AST) of at least 3.0 times normal at screening and/or after 5 days abstinence
11. Sexually active female of child-bearing potential who is pregnant (by urine HCG), nursing, or who is not willing to use a reliable form of birth control
12. Has current charges pending for a violent crime (not including DUI-related offenses)
13. Does not have a stable living situation
14. African American heritage due to low prevalence of Asp40 (also see Inclusion of Women and Minorities section)

Exclusion Criteria of fMRI Procedure

1. Having metal objects in the body that are deemed unsafe in the MRI environment.
2. Severe claustrophobia that cannot be managed with support and encouragement.
3. Morbid obesity such that placement in the MRI scanner is impossible.
4. History of significant head injury leading to unconsciousness.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: A118G A/A with Naltrexone; Individuals with the OPRM1 genotype Asn40 are given naltrexone 50 mg after 2 days at 25 mg for 16 weeks with Medication Management 9 visits in 16 weeks	Drug: Naltrexone 50 Mg; Naltrexone 25 or 50 mg per titration schedule
Placebo Comparator: A118G A/A with Placebo; Individuals with the OPRM1 genotype Asn40 are given Placebo for 16 weeks with Medication Management in 16 weeks	Drug: Placebo; placebo
Active Comparator: A118G Any G with Naltrexone; Individuals with the OPRM1 genotype Any G (Asp) are given naltrexone 50 mg after 2 days of naltrexone 25 mg for 16 weeks with Medication Management 9 visits in 16 weeks	Drug: Naltrexone 50 Mg; Naltrexone 25 or 50 mg per titration schedule
Placebo Comparator: A118G Any G with Placebo; Individuals with the OPRM1 genotype Any G (Asp) are given 50 mg naltrexone after 2 days at 25 mg for 16 weeks with Medication Management 9 visits in 16 weeks	Drug: Placebo; placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percent Heavy Drinking Days by mu Opioid Receptor Gene	Time Line Follow-Back drinking collected at each of 9 visits (weeks 1, 2, 3, 4, 6, 8, 10, 12 and 16)

Collaborators and Investigators

• Sponsor: Medical University of South Carolina
• Collaborators: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Investigators: Principal Investigator: Raymond F Anton, MD, Medical University of South Carolina

Publications and helpful links

General Publications

• Schacht JP, Randall PK, Latham PK, Voronin KE, Book SW, Myrick H, Anton RF. Predictors of Naltrexone Response in a Randomized Trial: Reward-Related Brain Activation, OPRM1 Genotype, and Smoking Status. Neuropsychopharmacology. 2017 Dec;42(13):2640-2653. doi: 10.1038/npp.2017.74. Epub 2017 Apr 14. Erratum In: Neuropsychopharmacology. 2017 Dec;42(13):2654.

Helpful Links

• Predictors of Naltrexone Response in a Randomized Trial: Reward-Related Brain Activation, OPRM1 Genotype, and Smoking Status.

Study record dates

Study Major Dates

• Study Start: June 1, 2009
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: June 11, 2009
• First Submitted That Met QC Criteria: June 11, 2009
• First Posted (Estimate): June 15, 2009

Study Record Updates

• Last Update Posted (Actual): July 10, 2018
• Last Update Submitted That Met QC Criteria: June 12, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: Genetics; Alcohol Dependence; Naltrexone; Alcoholism; Substance Abuse
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Alcoholism; Physiological Effects of Drugs; Peripheral Nervous System Agents; Sensory System Agents; Narcotic Antagonists; Alcohol Deterrents; Naltrexone
• Other Study ID Numbers: ANTON-1R01AA017633-01A1