Oxidative stress mediates associations between preoperative psychosocial phenotype and pain-related outcomes at 6 months following total knee arthroplasty: a longitudinal cohort study

Objective: Greater preoperative depression, anxiety, and pain catastrophizing are associated with more severe long-term pain following total knee arthroplasty (TKA). In a secondary analysis of previously reported data, we tested the hypothesis that these associations are mediated by oxidative stress (OS). Design: A mixed between/within-subjects longitudinal cohort design. Setting: A single academic medical center. Subjects: Osteoarthritis patients (n = 91; 62.6% female) undergoing unilateral TKA. Methods: We assessed depression, anxiety, and catastrophizing, as well as markers of central sensitization (widespread pain, temporal summation of pain) preoperatively. Blood samples were then obtained immediately prior to intraoperative tourniquet placement for quantification of in vivo biomarkers of systemic OS, F-2-isoprostanes and isofurans. Post-TKA pain intensity (numeric rating scale worst pain [NRS], McGill Pain Questionnaire-2 [MPQ-2]) and function (PROMIS Pain Interference) were assessed at 6months following TKA. Results: Greater preoperative depression, catastrophizing, and widespread pain were associated with higher intraoperative combined OS (F-2-isoprostanes+isofurans/2), which was in turn associated with higher post-TKA pain intensity and worse function (P<.05). All preoperative phenotype predictors except anxiety were correlated positively with post-TKA pain and/or function (P<.05). Bootstrapped mediation analyses revealed significant (P<.05) indirect (mediated) effects of depression (NRS Worst Pain, MPQ-2, PROMIS Pain Interference), anxiety (MPQ-2, PROMIS Pain Interference), and catastrophizing (PROMIS Pain Interference) on adverse long-term post-TKA outcomes via elevated OS. Central sensitization-related predictors demonstrated only direct effects (P<.05) on post-TKA outcomes that were independent of OS mechanisms. Conclusions: Results suggest that the adverse impact of depression, anxiety, and pain catastrophizing on post-TKA pain and functional outcomes are mediated in part by elevated OS.