The Pharmacogenomics of Opioid Response in Cancer Pain: From Receptor Polymorphisms to Tumour-Mediated Interference—A Narrative-Critical Review

Cancer pain affects more than half of all oncology patients and represents one of the most challenging therapeutic problems in modern medicine. Despite the central role of opioids in cancer pain management—codified by the WHO analgesic ladder—the clinical response to these agents is highly variable between individuals. Pharmacogenomics promises to explain this heterogeneity by identifying functionally relevant genetic polymorphisms in genes encoding opioid receptors, metabolizing enzymes, and membrane transport proteins. However, after two decades of intensive research, clinical translation of genetic data into actionable prescribing strategies remains elusive. A narrative-critical review of the literature was conducted by searching PubMed, Scopus, and Web of Science databases from inception to March 2026, using the search terms “opioid,” “pharmacogenomics,” “pharmacogenetics,” “cancer pain,” “polymorphism,” and individual gene names (OPRM1, CYP2D6, COMT, ABCB1, SLC22A1, UGT2B7, and others). Reference lists of included articles were hand-searched for additional relevant studies. Inclusion was restricted to English-language articles reporting original data or systematic reviews on genetic polymorphisms and opioid response, with priority given to studies conducted in cancer pain populations. Clinical practice guidelines from CPIC, NCCN, ESMO, EAPC, and ASCO were consulted for current recommendations. This narrative-critical review examines the evidence on genetic polymorphisms relevant to opioid response in cancer pain, covering three functional categories: (1) pharmacodynamic genes, including opioid receptors (OPRM1, OPRD1, OPRK1) and neuromodulatory targets (COMT, KCNJ6, MC1R); (2) pharmacokinetic enzymes (CYP2D6, CYP3A4/5, UGT2B7); and (3) membrane transporters, including ABC efflux pumps (ABCB1, ABCG2, ABCC2) and SLC uptake carriers (SLC22A1, SLCO1B1, SLC6A4, SLC6A2). A dedicated section addresses the direct and indirect interference of the tumour itself—through the tumour microenvironment, neuroimmune signalling, epigenetic reprogramming, and cancer-induced organ dysfunction—on opioid pharmacogenomics. The overall evidence is poor and fragmented, a finding intrinsic to the extraordinary diversity, large number, and context-dependent biological activity of the polymorphisms identified. The tumour itself acts as a pervasive confounder that systematically distorts genotype–phenotype relationships. The path forward requires a paradigm shift from candidate-gene association studies to system pharmacogenomics and multi-omic integration.