Role of genetic polymorphisms on opioid safety and efficacy in cancer pain: A systematic review and meta-analysis.

Pain is one of the most prevalent and challenging symptoms in cancer, and opioids remain central to its management. Genetic factors are thought to underlie interindividual variability in opioid response, yet findings across pharmacogenomic studies have been inconsistent. We conducted a systematic review and seven meta-analyses across 24 independent populations (n = 4190), evaluating the three most frequently studied variants, OPRM1 rs1799971, ABCB1 rs1045642, and COMT rs4680, in patients with cancer receiving opioids. Opioid dose requirements were meta-analysed for all three variants; pain scores and adverse effects were additionally meta-analysed for OPRM1, as data were insufficient for COMT and ABCB1. We also qualitatively reviewed evidence across the remaining tabled loci and additional candidate genes (e.g., CYP2D6, UGT2B7, CYP3A4, CYP3A5, OPRK1, OPRD1, HTR3B, and STAT6) from 73 studies. Across all three variants, overall dose meta-analyses showed no significant associations. Sensitivity analysis excluding a clear outlier study attenuated but did not eliminate this association. The exception emerged in a subgroup restricted to acute pain, where OPRM1 rs1799971 GG carriers required significantly higher opioid doses than AA carriers - an effect absent in chronic pain. Beyond dose, OPRM1 meta-analyses of pain scores and adverse effects (nausea, vomiting, constipation) were also non-significant, while qualitative evidence for COMT, ABCB1, and additional candidate genes was heterogeneous and often underpowered. These findings suggest that the effects of individual common variants on opioid requirements in cancer pain are modest and context-dependent; the OPRM1 rs1799971 GG genotype was the notable exception, showing higher opioid consumption specifically in acute postoperative settings (standardised mean difference [SMD] +0.61; 95% CI 0.04-1.18). This study represents the first meta-analysis to comprehensively evaluate the role of OPRM1, COMT, and ABCB1 polymorphisms in patients with cancer.