Evaluating the Clinical Impact of CYP2C19 and CYP2D6 on Amitriptyline Outcomes in a Real-World Chronic Pain Cohort

Abstract

BackgroundAmitriptyline is widely prescribed for chronic pain, yet treatment response and tolerability vary substantially. Genetic variation in CYP2C19 and CYP2D6 influences amitriptyline metabolism, but evidence linking pharmacogene status to clinical outcomes in chronic pain populations remains limited. Importantly, amitriptyline is typically prescribed at lower doses for chronic pain (10-50 mg/day) than for depression (75-150 mg/day), which may attenuate observable pharmacogenomic effects. We investigated whether CYP2C19 and CYP2D6 derived metaboliser phenotypes were associated with self-reported effectiveness and tolerability of amitriptyline. MethodsWe conducted a cross-sectional analysis within the Australian Genetics of Depression Study. Participants reporting chronic pain, amitriptyline use, treatment response data, and genotype data were included (n=1146). Pharmacogene variants were annotated using PharmCAT, and plausible diplotypes were harmonised using averaged gene-activity scores and a CPIC-guided framework to assign final metaboliser phenotypes. Associations with effectiveness and tolerability were examined using multinomial and binary logistic regression models adjusted for age and sex. ResultsReported effectiveness was generally low: 46.0% reported amitriptyline worked not at all well, 36.6% moderately well, and 17.4% very well. Among participants with tolerability data, 53% discontinued treatment because of side effects. CYP2D6 phenotype was not associated with effectiveness or discontinuation. CYP2C19 intermediate metabolisers showed nominally reduced odds of discontinuation, although this did not survive multiple-testing correction. ConclusionsCYP2C19 and CYP2D6 derived phenotypes were not strongly associated with amitriptyline effectiveness or tolerability in this chronic pain cohort with comorbid mental health disorders, suggesting that low-dose prescribing and titration-based management may attenuate pharmacogenomic effects in routine care.