Background Extended-release naltrexone is an established pharmacological strategy for preventing relapse in alcohol use disorder (AUD), yet substantial interindividual variability in treatment response remains unexplained. The δ-opioid receptor (DOR), encoded by the OPRD1 gene, has been implicated in modulating affective states, stress reactivity, and reinforcement mechanisms—key factors in relapse vulnerability. This study evaluated the association between the OPRD1 rs4654327 polymorphism and clinical outcomes of extended-release naltrexone in patients with AUD. Methods A non-randomized, prospective observational study was conducted in 100 patients with AUD in clinical remission who received six monthly injections of extended-release naltrexone over 180 days. Genotyping for rs4654327 was performed using allele-specific real-time PCR. Primary outcomes included remission duration, relapse frequency, treatment completion, and changes in alcohol craving assessed by the Penn Alcohol Craving Scale (PACS). Secondary analyses explored craving phenomenology and motivational profiles. Results In the prespecified A/A vs. G-carrier model, G-allele carriers showed a trend toward shorter remission duration and higher relapse risk compared with A/A (OR = 2.37; p = 0.022), but these associations did not remain significant after Bonferroni correction. End-of-treatment alcohol craving, assessed by the PACS on Day 150, was lower in A/A homozygotes than in G-allele carriers and survived correction across the six prespecified A/A vs. G-carrier tests (4.1 ± 2.4 vs. 6.6 ± 3.8; p_adj ≈ 0.002). Treatment completion showed a borderline association (84.2% vs. 60.5%; Pearson χ² p = 0.007; Fisher’s exact p = 0.011). Behavioral and affective craving components were more frequent among G-allele carriers, whereas ideational craving predominated in A/A homozygotes; however, this craving-component distribution was significant only before correction (p = 0.026, p_adj = 0.156). Conclusion In this modest prospective cohort, OPRD1 rs4654327 showed exploratory signals of association with clinical outcomes during extended-release naltrexone treatment. When restricted to the six prespecified A/A vs. G-carrier tests (m = 6), PACS at Day 150 survived Bonferroni correction (p_adj ≈ 0.002); treatment completion was borderline. The G/G subgroup was underpowered. Larger, adequately powered studies are required before considering clinical implementation. Clinical trial number Not applicable.

OPRD1 rs4654327 and Outcomes of Extended-Release Naltrexone in Alcohol Use Disorder: An Exploratory Prospective Pharmacogenetic Study

期刊论文
发表日期：

2026年6月30日

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Valentin Skryabin,
Sergei Miroshkin,
Anton Masyakin,
Sergei Pozdniakov,
Valentina Ivanchenko,
Valery Shipitsin

摘要

Background

Extended-release naltrexone is an established pharmacological strategy for preventing relapse in alcohol use disorder (AUD), yet substantial interindividual variability in treatment response remains unexplained. The δ-opioid receptor (DOR), encoded by the OPRD1 gene, has been implicated in modulating affective states, stress reactivity, and reinforcement mechanisms—key factors in relapse vulnerability. This study evaluated the association between the OPRD1 rs4654327 polymorphism and clinical outcomes of extended-release naltrexone in patients with AUD.

Methods

A non-randomized, prospective observational study was conducted in 100 patients with AUD in clinical remission who received six monthly injections of extended-release naltrexone over 180 days. Genotyping for rs4654327 was performed using allele-specific real-time PCR. Primary outcomes included remission duration, relapse frequency, treatment completion, and changes in alcohol craving assessed by the Penn Alcohol Craving Scale (PACS). Secondary analyses explored craving phenomenology and motivational profiles.

Results

In the prespecified A/A vs. G-carrier model, G-allele carriers showed a trend toward shorter remission duration and higher relapse risk compared with A/A (OR = 2.37; p = 0.022), but these associations did not remain significant after Bonferroni correction. End-of-treatment alcohol craving, assessed by the PACS on Day 150, was lower in A/A homozygotes than in G-allele carriers and survived correction across the six prespecified A/A vs. G-carrier tests (4.1 ± 2.4 vs. 6.6 ± 3.8; p_adj ≈ 0.002). Treatment completion showed a borderline association (84.2% vs. 60.5%; Pearson χ² p = 0.007; Fisher’s exact p = 0.011). Behavioral and affective craving components were more frequent among G-allele carriers, whereas ideational craving predominated in A/A homozygotes; however, this craving-component distribution was significant only before correction (p = 0.026, p_adj = 0.156).

Conclusion

In this modest prospective cohort, OPRD1 rs4654327 showed exploratory signals of association with clinical outcomes during extended-release naltrexone treatment. When restricted to the six prespecified A/A vs. G-carrier tests (m = 6), PACS at Day 150 survived Bonferroni correction (p_adj ≈ 0.002); treatment completion was borderline. The G/G subgroup was underpowered. Larger, adequately powered studies are required before considering clinical implementation.

Clinical trial number

Not applicable.