Comparative risk of psychiatric comorbidities associated with codeine and tramadol in patients with hip osteoarthritis: a nationwide population-based cohort study

Background: Weak opioids are often prescribed for osteoarthritis (OA), yet their comparative psychiatric risks are not well established. We aimed to comprehensively compare the composite psychiatric risks associated with codeine and tramadol in patients diagnosed with hip OA. Methods: We conducted a nationwide, population-based retrospective cohort study, using Korean Health Insurance Review and Assessment Service database on patients diagnosed with hip OA between 2014 and 2017. We included patients who received either opioid, with a total of 22 651 patients (of whom 4533 codeine and 18 118 tramadol users) after 1:4 propensity score matching (PSM). We applied Cox proportional hazards models to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) for incident psychiatric outcomes. Results: Codeine use was associated with a significantly lower hazard of composite psychiatric disorders (aHR = 0.86; 95% CI = 0.78-0.96), particularly anxiety (aHR = 0.81; 95% CI = 0.69-0.95), and showed a borderline reduction in sleep disorders (aHR = 0.81; 95% CI = 0.65-1.00, P = 0.048) after adjustment for age, sex, comorbidities, and concomitant medications. Subgroup analyses revealed consistently lower psychiatric risk among patients with a high comorbidity burden (Charlson's comorbidity index ≥3), cardiovascular disease, or those without concomitant psychotropic medications. Sensitivity analyses using inverse probability treatment weighting and 1:1 PSM demonstrated broadly similar patterns, although statistical significance varied across models. No clear duration-response relationship was observed. Conclusions: Codeine was associated with lower hazards of anxiety and sleep disorders in several analyses. These findings suggest that strengthening opioid stewardship through structured psychiatric risk assessment and individualised prescribing may enhance patient safety. Further controlled studies incorporating detailed clinical data are warranted to validate these associations and to better define their implications for long-term opioid management and policy development.