CYP2D6 Metaboliser Status and Postoperative Analgesic Response to Tramadol in South African Arthroplasty Patients

Background Individualised pain management strategies rather than purely empiric analgesic escalation, has become a topic of importance in precision medicine. African populations carry the greatest global CYP2D6 genetic diversity, yet remain under-represented in pharmacogenetic studies. No prospective South African data exist evaluating CYP2D6 phenotype and tramadol analgesic response in postoperative settings. This study therefore aimed to determine the association between postoperative pain scores and CYP2D6 metaboliser status in South African participants receiving tramadol after total knee arthroplasty (TKA) or total hip arthroplasty (THA). Methods Fifty adults received immediate-release oral tramadol 50 mg according to a standardised institutional postoperative analgesic protocol after elective TKA or THA. Pain intensity was measured on an 11-point Numerical Rating Scale (NRS) immediately before, and two hours after the first postoperative tramadol dose. Genotyping from whole blood was performed using the Agena Bioscience Veridose and Copy Number Variation panels to determine CYP2D6 phenotype. Plasma tramadol and O-desmethyltramadol (M1) concentrations were quantified by liquid chromatography-tandem mass spectrometry (LC–MS/MS). Results CYP2D6 phenotyping identified 36 normal metabolisers (72%), 11 intermediate metabolisers (22%), and 3 poor metabolisers (6%). Among participants who achieved a clinically significant analgesic response (≥3-point NRS reduction; n=25), 96% were normal metabolisers, 4% intermediate metabolisers, and none were poor metabolisers. (Fisher's exact p<0.001). M1 concentrations and M1:tramadol ratios differed significantly across phenotypes (p=0.010 and p<0.001, respectively). Conclusion A significant association was observed between tramadol analgesic response and metaboliser status. In resource-limited settings, the M1:tramadol ratio may reflect underlying CYP2D6 metaboliser status, potentially supporting more individualised analgesic prescribing.