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

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.

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

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)