David W Oslin1, Shirley H Leong2, Kevin G Lynch3, Wade Berrettini3, Charles P O'Brien3, Adam J Gordon4, Margaret Rukstalis5. 1. Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia2Mental Illness Research, Education, and Clinical Center, Center of Excellence for Substance Abuse Treatment and Evaluation, Philadelphia Veterans Affairs. 2. Mental Illness Research, Education, and Clinical Center, Center of Excellence for Substance Abuse Treatment and Evaluation, Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania. 3. Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia. 4. Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania4Mental Illness Research, Education, and Clinical Center, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania5Center for Health Equity Researc. 5. Department of Psychiatry, Wake Forest University, Winston-Salem, North Carolina.
Abstract
IMPORTANCE: Alcohol use disorder is one of the leading causes of disability worldwide. While effective pharmacological treatments exist, they are efficacious only in certain individuals, contributing to their limited use. Secondary analysis of clinical trial data suggests that a functional polymorphism (rs1799971, Asn40Asp) of the µ-opioid receptor gene (OPRM1) is associated with the risk of relapse to heavy drinking following treatment with the opioid antagonist naltrexone. OBJECTIVE: To prospectively examine whether rs1799971 is predictive of naltrexone treatment response. DESIGN, SETTING, AND PARTICIPANTS: We conducted a 12-week, double-blind, randomized clinical trial of naltrexone vs placebo in individuals with alcohol dependence (intent-to-treat analysis). Participants were randomly assigned to study treatment based on the presence of 1 or 2 copies of the Asp40 allele compared with those homozygous for the Asn40 allele (2 × 2 cell design). Recruitment occurred between January 2009 and September 2013. All participants were seen in an outpatient clinical setting. A convenience sample of participants (n = 221) was recruited from 5 sites. All participants met DSM-IV criteria for alcohol dependence, with no concurrent psychotic or manic symptoms, no use of concurrent psychotropic medications, and no current dependence on illicit substances. INTERVENTIONS: The study drug was naltrexone (50 mg) given once daily or corresponding placebo. MAIN OUTCOMES AND MEASURES: The primary study outcome measure was relapse to heavy drinking measured using the timeline follow-back method. RESULTS: There was no evidence of a genotype × treatment interaction on the primary outcome of heavy drinking (P = .32). In the Asn40 group, the observed effect of naltrexone was similar to that in previous trials (odds ratio, 0.69; 95% CI, 0.41-1.18; P = .17), with a very small naltrexone effect in the Asp40 group (odds ratio, 1.10; 95% CI, 0.52-2.31; P = .80), contrary to the pattern expected a priori. A significant reduction in heavy drinking occurred across all groups (P = .001). Other drinking outcomes, and all secondary outcomes, demonstrated similar time effects, with no genotype × treatment interaction. CONCLUSIONS AND RELEVANCE: The results of this study do not support the hypothesis that the Asp40 allele moderates the response to naltrexone treatment. It is premature to use the Asn40Asp polymorphism as a biomarker to predict the response to naltrexone treatment of alcohol dependence. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00831272.
RCT Entities:
IMPORTANCE: Alcohol use disorder is one of the leading causes of disability worldwide. While effective pharmacological treatments exist, they are efficacious only in certain individuals, contributing to their limited use. Secondary analysis of clinical trial data suggests that a functional polymorphism (rs1799971, Asn40Asp) of the µ-opioid receptor gene (OPRM1) is associated with the risk of relapse to heavy drinking following treatment with the opioid antagonist naltrexone. OBJECTIVE: To prospectively examine whether rs1799971 is predictive of naltrexone treatment response. DESIGN, SETTING, AND PARTICIPANTS: We conducted a 12-week, double-blind, randomized clinical trial of naltrexone vs placebo in individuals with alcohol dependence (intent-to-treat analysis). Participants were randomly assigned to study treatment based on the presence of 1 or 2 copies of the Asp40 allele compared with those homozygous for the Asn40 allele (2 × 2 cell design). Recruitment occurred between January 2009 and September 2013. All participants were seen in an outpatient clinical setting. A convenience sample of participants (n = 221) was recruited from 5 sites. All participants met DSM-IV criteria for alcohol dependence, with no concurrent psychotic or manic symptoms, no use of concurrent psychotropic medications, and no current dependence on illicit substances. INTERVENTIONS: The study drug was naltrexone (50 mg) given once daily or corresponding placebo. MAIN OUTCOMES AND MEASURES: The primary study outcome measure was relapse to heavy drinking measured using the timeline follow-back method. RESULTS: There was no evidence of a genotype × treatment interaction on the primary outcome of heavy drinking (P = .32). In the Asn40 group, the observed effect of naltrexone was similar to that in previous trials (odds ratio, 0.69; 95% CI, 0.41-1.18; P = .17), with a very small naltrexone effect in the Asp40 group (odds ratio, 1.10; 95% CI, 0.52-2.31; P = .80), contrary to the pattern expected a priori. A significant reduction in heavy drinking occurred across all groups (P = .001). Other drinking outcomes, and all secondary outcomes, demonstrated similar time effects, with no genotype × treatment interaction. CONCLUSIONS AND RELEVANCE: The results of this study do not support the hypothesis that the Asp40 allele moderates the response to naltrexone treatment. It is premature to use the Asn40Asp polymorphism as a biomarker to predict the response to naltrexone treatment of alcohol dependence. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00831272.
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