Periarticular Injection Cocktails for Pain Management After Total Knee Arthroplasty: A Systematic Review of Randomized Controlled Trials.

BACKGROUND: Total knee arthroplasty (TKA) is a common and effective treatment for end-stage knee osteoarthritis, but postoperative pain remains a major barrier to recovery and may increase opioid use. Periarticular infiltration (PAI) with multimodal drug cocktails is a promising analgesic strategy, though the optimal formulation remains unclear. METHODS: A systematic review was conducted in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Embase, and CENTRAL were searched from inception through June 1, 2025, for randomized controlled trials (RCTs) evaluating local infiltration analgesia in TKA. Studies were included if they compared multimodal PAI cocktails to placebo, nerve blocks, or alternative cocktails and reported clinical or economic outcomes. Dual independent screening, data extraction, and risk of bias assessment (using the JADAD scale) were performed. There were 78 RCTs comprising 8,515 patients that met inclusion criteria. RESULTS: Compared to placebo, PAI cocktails consistently reduced postoperative pain and opioid consumption and improved early functional outcomes. In comparisons with nerve blocks, pain control was generally equivalent, though opioid use slightly favored nerve blocks. Head-to-head comparisons between different cocktail formulations showed no consistently superior combination, though cocktails containing corticosteroids were associated with improved analgesia. Liposomal bupivacaine (LB) demonstrated comparable effectiveness to standard cocktails and nerve blocks in most studies, with several trials reporting meaningful benefits in pain reduction, opioid sparing, and patient satisfaction. Only one study reported LB to be more cost-effective than adductor canal block. Study heterogeneity limited pooled analysis and direct formulation comparisons. CONCLUSION: Multimodal PAI improves early postoperative outcomes after TKA, especially versus placebo. Corticosteroid-containing cocktails may provide added benefit, but variation in formulations, dosing, and outcomes prevents identification of a single optimal regimen. The LB is a promising component, with some studies showing better pain control, lower opioid use, and higher patient satisfaction. Standardized, high-quality trials with economic endpoints are still needed.