Systematic review and meta-analysis of the moderating effect of rs1799971 in OPRM1, the mu-opioid receptor gene, on response to naltrexone treatment of alcohol use disorder

Abstract

Background and aims: There is wide inter-individual variability in response to the treatment of alcohol use disorder (AUD) with the opioid receptor antagonist naltrexone. To identify patients who may be most responsive to naltrexone treatment, studies have examined the moderating effect of rs1799971, a single nucleotide polymorphism (SNP) that encodes a non-synonymous substitution (Asn40Asp) in the mu-opioid receptor gene, OPRM1. The aims of this study were to: (1) conduct a systematic review of randomized clinical trials (RCTs); (2) assess the bias of the available studies and gauge publication bias; and (3) meta-analyze the interaction effect of the Asn40Asp SNP on the response to naltrexone treatment.

Methods: We searched for placebo-controlled RCTs that examined the effect of Asn40Asp on the response to naltrexone treatment of heavy drinking or AUD. We tested the hypothesis that the minor (Asp40) allele was associated with a greater reduction in five alcohol consumption measures (relapse to heavy drinking, abstinence, percentage of heavy drinking days, percentage of days abstinent and drinks per day) in naltrexone-treated participants by meta-analyzing the interaction effects using a random effects model.

Results: Seven RCTs met the study criteria. Overall, risk of bias was low and we observed no evidence of publication bias. Of the five alcohol consumption outcomes considered, there was a nominally significant moderating effect of the Asn40Asp SNP only on drinks per day (d = -0.18, P = 0.02). However, the effect was not significant when multiple comparisons were taken into account.

Conclusions: From the evidence to date, it remains unclear whether rs1799971, the OPRM1 Asn40Asp single nucleotide polymorphism, predicts naltrexone treatment response in individuals with alcohol use disorder or heavy drinking.

Keywords: Alcohol use disorder; OPRM1; meta-analysis; naltrexone; pharmacogenetics; pharmacotherapy.

© 2020 Society for the Study of Addiction.

Figures

Figure 1:

Study Selection Flow Diagram Other condition/med=studies focused on a condition other than alcohol dependence or AUD (e.g. epilepsy) or studies focusing on a medication other than naltrexone (e.g. nalmefene). Experimental/lab paradigm= studies not focused on the treatment of alcohol dependence or AUD (e.g. cue paradigm, neuroimaging, etc.) with brief medication administration periods.

Figure 2:

Forest Plot of Heavy Drinking Relapse ROR=ratio of odds ratio, LCL=lower confidence level, UCL=upper confidence level; P=p-value; Wt=weight of each study

Figure 3:

Forest Plot of Abstinence during Study ROR=ratio of odds ratio, LCL=lower confidence level, UCL=upper confidence level; P=p-value; Wt=weight of each study

Figure 4:

Forest Plot of Percentage of Heavy Drinking Days dSMD=difference in standardized mean difference, LCL=lower confidence level, UCL=upper confidence level; P=p-value; Wt=weight of each study

Figure 5:

Forest Plot of Percentage of Days Abstained dSMD=difference in standardized mean difference, LCL=lower confidence level, UCL=upper confidence level; P=p-value; Wt=weight of each study

Figure 6:

Forest Plot of Drinks per Day dSMD=difference in standardized mean difference, LCL=lower confidence level, UCL=upper confidence level; P=p-value; Wt=weight of each study