Psychiatric, Cardiovascular and Skeletal Risks of Codeine versus Oxycodone in Hip Osteoarthritis: A Population-Based Cohort Study

Jeongmin Lee,1– 3,* Yujin Kim,1– 3,* Eunjung Choo,4 Sooyoung Shin,4,5 Yeo Jin Choi1– 3 1Department of Regulatory Science, Graduate School, Kyung Hee University, Seoul, Korea; 2Institute of Regulatory Innovation through Science (IRIS), Kyung Hee University, Seoul, Korea; 3Department of Pharmacy, College of Pharmacy and Institute of Integrated Pharmaceutical Sciences, Kyung Hee University, Seoul, Korea; 4Department of Pharmacy, College of Pharmacy, Ajou University, Suwon, Korea; 5Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University, Suwon, Korea*These authors contributed equally to this workCorrespondence: Yeo Jin Choi, Department of Pharmacy, College of Pharmacy and Institute of Integrated Pharmaceutical Sciences, Kyung Hee University, 26 Kyungheedae-ro, Dongdamun-gu, Seoul, 02447, Korea, Tel +82 2 961 0532, Fax +82 2 961 9580, Email [email protected] Sooyoung Shin, Department of Pharmacy, College of Pharmacy, Ajou University, Suwon, 16488, Korea, Tel +82 31 219 3456, Fax +82 31 219 3435, Email [email protected]/Objectives: Hip osteoarthritis (OA) induces chronic pain and disability in aging populations. Opioids are increasingly prescribed for refractory hip OA pain; however, comparative safety data are limited. This study aimed to compare the psychiatric, cardiovascular and skeletal outcomes between codeine and oxycodone in patients with hip OA.Methods: A population-based retrospective cohort using Korean Health Insurance Review and Assessment Service (HIRA) claims data was performed in hip OA (M16) patients who initiated codeine or oxycodone. Propensity score matching (PSM) was applied with sensitivity analyses performed using inverse probability of treatment weighting (IPTW). Outcomes included composite psychiatric outcomes (depression, anxiety, bipolar disorder, sleep disorders, and schizophrenia), major adverse cardiovascular outcomes (MACE; myocardial infarction, stroke, cardiovascular death/arrest, heart failure hospitalization), and fractures. Hazard ratios (HR) with 95% confidence intervals (CIs) were estimated using Cox proportional hazard models.Results: A total of 16,162 patients were included in the cohort after 1:1 PSM. Codeine was associated with a higher risk of psychiatric disorders (HR 1.11, 95% CI 1.04– 1.19), particularly anxiety (HR 1.14, 95% CI 1.03– 1.26) and sleep disorders (HR 1.15, 95% CI 1.02– 1.30). Risks of MACE (HR 1.02, 95% CI 0.92– 1.14) and death (HR 1.03, 95% CI 0.92– 1.14) were comparable between groups. Codeine was associated with a higher risk of non-femoral fractures (HR 1.10, 95% CI 1.04– 1.16). Subgroup analyses revealed differentiated risks across age, sex, comorbidities, and concomitant medications.Conclusion: Codeine use in patients with hip osteoarthritis was associated with a higher risk of psychiatric disorders and distinct fracture patterns. The observed risks varied according to patient characteristics, comorbidities, and concomitant medications, emphasizing the need for individualized opioid prescribing strategies that incorporate psychiatric monitoring, fracture risk assessment, and patient-specific factors. Further controlled studies integrating clinical, lifestyle, and genetic data are warranted to confirm these findings and refine personalized opioid therapy in hip osteoarthritis.Keywords: oxycodone, codeine, MACE, anxiety, sleep disorder, fracture