Drug-specific effects of anxiety on high-dose oxycodone: age as a modifier for oxycodone response

To investigate the association between preoperative anxiety and opioid tolerance in patients undergoing primary hip arthroplasty, focusing on heterogeneity across opioid types and the mechanisms underlying this association, this retrospective cohort study identified 1763 such patients from the Medical Information Mart for Intensive Care IV database. Of these, 198 patients were identified as anxious based on an anxiety diagnosis at admission. Opioid tolerance was assessed by evaluating dosage patterns of morphine, oxycodone, and tramadol. Multivariable logistic regression, Johnson-Neyman, and restricted cubic spline analysis were employed to evaluate the associations and interactions. Transcriptomic data from a rat neuropathic pain model (GSE53897) were used to analyze differential pathways between morphine and oxycodone treatments. Preoperative anxiety was significantly associated with high-dose oxycodone use across model 1 [odds ratio (OR) = 2.025], model 3 (OR = 1.786), and model 4 (OR = 1.679), but not with high-dose morphine or tramadol. Exploratory age analyses revealed that this association exhibited marked age specificity: it persisted only in patients aged less than or equal to 75 years ( P < 0.05) and was nonsignificant in those more than 75 years, with effect strength diminishing with increasing age. Mechanistic analysis revealed different gene profiles and enriched biological pathways between morphine and oxycodone treatment groups, suggesting a molecular basis for treatment heterogeneity. In hip arthroplasty patients, preoperative anxiety was an independent risk factor for oxycodone tolerance, and this effect was age-modulated, significant only in patients aged less than or equal to 75 years. Integrating psychological status and age into pain management strategies deserves consideration in clinical practice.