Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Department of Anesthesiology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Addict Biol. 2024 Jan;29(1):e13355. doi: 10.1111/adb.13355.
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.
OPRM1 基因 A118G SNP 的等位基因变异改变了阿片类药物信号；然而，评估等位基因差异如何影响阿片类药物的作用还很缺乏。本人类实验室范式研究了 AA 与 AG/GG 基因型是否决定了阿片类药物的反应特征。接受过有限阿片类药物暴露的个体（N=100）完成了为期五天的、在个体内、双盲、安慰剂对照、住院研究。参与者入院（第 1 天），接受 4 毫克氢吗啡酮（第 2 天），并以随机顺序接受 0 毫克、2 毫克和 8 毫克氢吗啡酮（第 3-5 天），并完成自我报告的视觉模拟量表（VAS）评分和李克特量表、观察 VAS 以及基线和给药后 6.5 小时的生理反应。结果作为时间的峰值/谷值效应进行分析，作为基因型的函数（可用于 N=96 名个体；AG/GG=13.5%，AA=86.4%）。AG/GG 基因型的参与者认为低剂量和中剂量的氢吗啡酮的正面影响更大（例如，良好影响 VAS、滑行、驱动、友好、健谈、刺激），负面影响更小（例如，皮肤瘙痒、恶心、嗜睡），并且与 AA 基因型的人相比，观察到更健谈和精力充沛。AG/GG 基因型的人在舒张压和心率方面的生理反应性较低，但核心体温的变化比 AA 基因型的人更大。AA 基因型的人在各剂量下也表现出更典型的激动剂作用；AG/GG 基因型的人对 2 毫克和 4 毫克的反应有限。数据表明，与 AA 基因型的人相比，AG/GG 基因型的人对氢吗啡酮的反应更愉快，不愉快的反应更少。未来的研究应该在临床人群中复制这些实验室发现，以支持阿片类药物处方的精准医学方法。
