Effectiveness and tolerability of perioperative interventions to prevent chronic pain after knee or hip replacement surgery: A systematic review with network and component network meta-analysis of randomized controlled trials

Abstract

Background: Chronic pain is a common complication after musculoskeletal and orthopedic surgeries. We conducted a systematic review with network and component network meta-analysis of randomized trials to assess the effectiveness and tolerability of perioperative pharmacological interventions for preventing chronic pain after knee or hip replacement surgery. Methods: We searched MEDLINE, Embase, PsycInfo, CINAHL, and CENTRAL to February 2025. Eligible trials enrolled adults undergoing knee or hip replacement, randomized them to any pharmacotherapy, combination, or placebo to reduce post-surgical pain, and assessed pain ≥3 months post-surgery. Outcomes included the proportion of patients reporting chronic post-surgical pain (CPSP), pain severity, physical and emotional functioning, and drop out rates. Analyses used frequentist random-effects models for network and an additive component network meta-analysis (CNMA). We assessed the certainty evidence following GRADE guidance using CINeMA platform. Findings: We included 59 trials (7,705 patients). At 3–6 months, epidural corticosteroid injection may reduce CPSP compared to usual care (risk ratio [RR] 0.35, 95% CI 0.14–0.90; risk difference 11.7% fewer patients, low certainty). At 6–12 months, wound infiltration of corticosteroids probably had little to no effect on pain intensity (mean difference [MD] −0.31, 95% CI −0.57 to −0.05, moderate certainty). At longest follow-up, ketamine may slightly improve physical function (MD 10.77, 95% CI 5.21–16.33, low certainty). Other interventions showed little to no effect on pain or functioning. CNMA indicated corticosteroids reduced CPSP risk (incremental RR 0.58, 95% CI 0.39–0.86). Benefits were primarily observed in knee replacement surgeries. None of the interventions influenced dropout or tolerability. Conclusions: Low to moderate certainty evidence suggests epidural corticosteroid injection may reduce CPSP after knee/hip replacement, while most pharmacotherapies show minimal benefit. CNMA found the steroid component reduced CPSP risk; ketamine, nefopam, and steroids each improved physical function. Future research should prioritize large, randomized trials and identification of modifiable predictors of CPSP.