Alcohol Dependence
Conditions
Keywords
Alcohol Dependence, Alcoholism, Naltrexone, Substance Abuse, Genetics
Brief summary
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.
Interventions
DRUGNaltrexone 50 Mg
Naltrexone 25 or 50 mg per titration schedule
DRUGPlacebo
placebo
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Medical University of South Carolina
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| 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) |
Countries
United States
Participant flow
Recruitment details
358 Subjects were recruited via media advertisements and clinical referrals and 355 provided a blood sample for A118G genotyping.
Pre-assignment details
A118G genotyping was performed for 355 of these, 259 were A/A (Asn40) allele and 96 were any G (asp). Of the 259 Asn40 subjects, 89 were selected to participate 5 met exclusion criteria and 7 were lost or declined. Of the 96 Asp subjects, 9 met exclusion; 12 were lost or declined.
Participants by arm
| Arm | Count |
|---|---|
| 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
Naltrexone 50 MG: Naltrexone 25 or 50 mg per titration schedule | 35 |
| A118G A/A With Placebo Individuals with the OPRM1 genotype Asn40 are given Placebo for 16 weeks with Medication Management in 16 weeks
Placebo: placebo | 38 |
| 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
Naltrexone 50 MG: Naltrexone 25 or 50 mg per titration schedule | 38 |
| 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
Placebo: placebo | 35 |
| Total | 146 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Allocation | No post randomization data | 3 | 1 | 0 | 2 |
| Available for Analysis | Adverse Event | 1 | 2 | 1 | 0 |
| Available for Analysis | Death | 1 | 0 | 0 | 0 |
| Available for Analysis | Protocol Violation | 0 | 0 | 1 | 0 |
| Available for Analysis | Required Medical Treatment | 0 | 1 | 2 | 0 |
| Available for Analysis | Required more treatment | 0 | 2 | 0 | 1 |
| Available for Analysis | Withdrawal by Subject | 6 | 6 | 6 | 10 |
Baseline characteristics
| Characteristic | A118G Any G With Naltrexone | Total | A118G A/A With Placebo | A118G A/A With Naltrexone | A118G Any G With Placebo |
|---|---|---|---|---|---|
| Age, Continuous | 50.3 years STANDARD_DEVIATION 10.2 | 49.3 years STANDARD_DEVIATION 10.1 | 46.3 years STANDARD_DEVIATION 10.8 | 51.1 years STANDARD_DEVIATION 8.2 | 49.7 years STANDARD_DEVIATION 10.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 38 Participants | 144 Participants | 38 Participants | 34 Participants | 34 Participants |
| Sex: Female, Male Female | 13 Participants | 45 Participants | 12 Participants | 9 Participants | 11 Participants |
| Sex: Female, Male Male | 25 Participants | 101 Participants | 26 Participants | 26 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 38 | 0 / 35 | 0 / 35 | 1 / 38 |
| other Total, other adverse events | 16 / 38 | 20 / 35 | 30 / 35 | 29 / 38 |
| serious Total, serious adverse events | 0 / 38 | 0 / 35 | 0 / 35 | 0 / 38 |
Outcome results
Primary
Percent Heavy Drinking Days by mu Opioid Receptor Gene
Time frame: Time Line Follow-Back drinking collected at each of 9 visits (weeks 1, 2, 3, 4, 6, 8, 10, 12 and 16)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| A118G A/A With Naltrexone | Percent Heavy Drinking Days by mu Opioid Receptor Gene | Month 1 | 11.0 percentage of days | Standard Error 3.5 |
| A118G A/A With Naltrexone | Percent Heavy Drinking Days by mu Opioid Receptor Gene | Month 2 | 11.7 percentage of days | Standard Error 4.5 |
| A118G A/A With Naltrexone | Percent Heavy Drinking Days by mu Opioid Receptor Gene | Month 3 | 10.4 percentage of days | Standard Error 4.4 |
| A118G A/A With Naltrexone | Percent Heavy Drinking Days by mu Opioid Receptor Gene | Month 4 | 11.4 percentage of days | Standard Error 4.7 |
| A118G A/A With Placebo | Percent Heavy Drinking Days by mu Opioid Receptor Gene | Month 2 | 25.8 percentage of days | Standard Error 4.4 |
| A118G A/A With Placebo | Percent Heavy Drinking Days by mu Opioid Receptor Gene | Month 3 | 23.0 percentage of days | Standard Error 4.3 |
| A118G A/A With Placebo | Percent Heavy Drinking Days by mu Opioid Receptor Gene | Month 4 | 18.1 percentage of days | Standard Error 4.5 |
| A118G A/A With Placebo | Percent Heavy Drinking Days by mu Opioid Receptor Gene | Month 1 | 18.0 percentage of days | Standard Error 3.4 |
| A118G Any G With Naltrexone | Percent Heavy Drinking Days by mu Opioid Receptor Gene | Month 3 | 16.9 percentage of days | Standard Error 4.3 |
| A118G Any G With Naltrexone | Percent Heavy Drinking Days by mu Opioid Receptor Gene | Month 2 | 15.5 percentage of days | Standard Error 4.4 |
| A118G Any G With Naltrexone | Percent Heavy Drinking Days by mu Opioid Receptor Gene | Month 4 | 18.3 percentage of days | Standard Error 4.5 |
| A118G Any G With Naltrexone | Percent Heavy Drinking Days by mu Opioid Receptor Gene | Month 1 | 11.8 percentage of days | Standard Error 3.4 |
| A118G Any G With Placebo | Percent Heavy Drinking Days by mu Opioid Receptor Gene | Month 4 | 28.7 percentage of days | Standard Error 4.6 |
| A118G Any G With Placebo | Percent Heavy Drinking Days by mu Opioid Receptor Gene | Month 2 | 19.7 percentage of days | Standard Error 4.5 |
| A118G Any G With Placebo | Percent Heavy Drinking Days by mu Opioid Receptor Gene | Month 1 | 18.7 percentage of days | Standard Error 3.6 |
| A118G Any G With Placebo | Percent Heavy Drinking Days by mu Opioid Receptor Gene | Month 3 | 25.0 percentage of days | Standard Error 4.4 |
Comparison: A linear mixed model with unstructured variance/covariance matrices was used to evaluate the primary outcome measure.p-value: 0.724Mixed Models Analysis
Comparison: This is a test of the main effect of medication, with a null hypothesis of no difference between Naltrexone and Placebo groups.p-value: 0.023Mixed Models Analysis