Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2024 Jan;29(1):e13355.
doi: 10.1111/adb.13355.

Polymorphisms in the A118G SNP of the OPRM1 gene produce different experiences of opioids: A human laboratory phenotype-genotype assessment

Kelly E Dunn  1 , Andrew S Huhn  1 , Patrick H Finan  2 , Ami Mange  3 , Cecilia L Bergeria  1 , Brion S Maher  4 , Jill A Rabinowitz  4 , Eric C Strain  1 , Denis Antoine  1
Affiliations
Randomized Controlled Trial

Polymorphisms in the A118G SNP of the OPRM1 gene produce different experiences of opioids: A human laboratory phenotype-genotype assessment

Kelly E Dunn et al. Addict Biol. 2024 Jan.

Abstract

Allelic variations in the A118G SNP of the OPRM1 gene change opioid signaling; however, evaluations of how allelic differences may influence opioid effects are lacking. This human laboratory paradigm examined whether the AA versus AG/GG genotypes determined opioid response profiles. Individuals with limited opioid exposure (N = 100) completed a five-day within-subject, double-blind, placebo-controlled, residential study. Participants were admitted (Day 1), received 4 mg hydromorphone (Day 2) and 0 mg, 2 mg and 8 mg hydromorphone in randomized order (Days 3-5) and completed self-reported visual analog scale (VAS) ratings and Likert scales, observed VAS, and physiological responses at baseline and for 6.5 h post-dose. Outcomes were analysed as peak/nadir effects over time as a function of genotype (available for N = 96 individuals; AG/GG = 13.5%, AA = 86.4%). Participants with AG/GG rated low and moderate doses of hydromorphone as significantly more positive (e.g., Good Effects VAS, coasting, drive, friendly, talkative, stimulation) with fewer negative effects (e.g., itchy skin, nausea, sleepiness), and were also observed as being more talkative and energetic relative to persons with AA. Persons with AG/GG were less physiologically reactive as determined by diastolic blood pressure and heart rate, but had more changes in core temperature compared with those with AA. Persons with AA also demonstrated more prototypic agonist effects across doses; persons with AG/GG showed limited response to 2 mg and 4 mg. Data suggest persons with AG/GG genotype experienced more pleasant and fewer unpleasant responses to hydromorphone relative to persons with AA. Future studies should replicate these laboratory findings in clinical populations to support a precision medicine approach to opioid prescribing.

Trial registration: ClinicalTrials.gov NCT02360371.

Keywords: A118G; OPRM1; addiction; hydromorphone; opioid; phenotype; risk.

PubMed Disclaimer

Conflict of interest statement

No authors have direct competing interests to report. In the past 3 years, KED has consulted or served as an advisor to study protocols with companies Mind Med, Inc. DemeRx, Cessation Therapeutics, and Indivior and has received funding through her university from the National Institute on Drug Abuse and Cure Addiction Now. ASH has consulted for Gilgamesh and received research funding from Indivior through his University. PHF has served on an advisory board for Ninnion Therapeutics. CLB has received research funding through her university from Canopy Growth Corporation and Pear Therapeutics. ECS has served on advisory boards and received grant funding or supplies for studies from, and/or consulted with: Ashley Addiction Treatment, Cerevel Therapeutics, Clearmind Medicine, Fast‐Track Drugs & Biologics, Masimo Corporation, UpToDate, Otsuka Pharmaceutical Development and Commercialization, and Pear Therapeutics.

Figures

FIGURE 1
FIGURE 1
Significant gene‐based outcomes collapsed across dose. Data represent mean ratings (Y‐axis) collapsed across dose as a function of minutes post‐dose (x‐axis) for persons with the AA (closed) or AG/GG (open) version of the A118G SNP for outcomes related to patient‐reported talkativeness (F[14,1286] = 2.37, p = 0.003; top), drive (F[14,1286] = 2.12, p = 0.009; middle) and nervousness (F[14,1286] = 2.68, p = 0.001; bottom)
FIGURE 2
FIGURE 2
Significant gene‐based interactions. Mean ratings (Y‐axis) as a function of dose over minutes post‐dose (x‐axis) for persons with the AA (circle) and AG/GG (square) alleles of the A118G SNP for patient‐reported ratings of good effects (F[14,1286] = 2.8, p = 0.001; top panel), observed levels of energy (F[42,3245] = 1.7, p = 0.004; middle panel), and observed levels of inactivity (F[42,3245] = 1.6, p = 0.004, bottom panel)
See this image and copyright information in PMC

Comment in

References

    1. Association SAaMH . Highlights for the 2021 National Survey on drug use and health. National Survey on Drug Use and Health; 2022. https://www.samhsa.gov/data/sites/default/files/2022-12/2021NSDUHFFRHigh...
    1. Higgins C, Smith BH, Matthews K. Substance misuse in patients who have comorbid chronic pain in a clinical population receiving methadone maintenance therapy for the treatment of opioid dependence. Drug Alcohol Depend. 2018;193:131‐136. doi:10.1016/j.drugalcdep.2018.08.038 - DOI - PubMed
    1. Lasagna L, Mosteller F, Von Felsinger JM, Beecher HK. A study of the placebo response. Am J Med. 1954;16(6):770‐779. doi:10.1016/0002-9343(54)90441-6 - DOI - PubMed
    1. Bickel WK, Bigelow GE, Preston KL, Liebson IA. Opioid drug discrimination in humans: stability, specificity and relation to self‐reported drug effect. J Pharmacol Exp Ther. 1989;251(3):1053‐1063. - PubMed
    1. Dunn KE, Barrett FS, Brands B, Marsh DC, Bigelow GE. Individual differences in human opioid abuse potential as observed in a human laboratory study. Drug Alcohol Depend. 2019;205:107688. doi:10.1016/j.drugalcdep.2019.107688 - DOI - PMC - PubMed

Publication types

Associated data