Efficacy and Safety Comparison of Ulinastatin Versus Flurbiprofen Axetil for Preemptive Analgesia in Reducing Opioid Burden After Total Knee Arthroplasty: A Randomized Controlled Trial

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Background: Total knee arthroplasty (TKA) poses a significant challenge for acute pain. Opioid-based analgesia carries substantial risks, whereas non-steroidal anti-inflammatory drugs (NSAIDs) have adverse effects and ceiling effects. Ulinastatin may be a novel treatment option with improved efficacy and safety. Purpose: To compare the efficacy and safety of single preoperative administration of ulinastatin (UTI), flurbiprofen axetil (FA), and control (saline) in reducing opioid consumption and adverse events in TKA. Patients and Methods: In this prospective, double-blind, placebo-controlled trial, 150 TKA patients were randomized to receive intravenous UTI (30 IU), FA (100 mg), or saline 15 minutes before skin incision. Standardized postoperative analgesia utilizes patient-controlled intravenous analgesia (PCIA) to maintain visual analog scale (VAS) scores ≤ 30 mm. The primary outcome was cumulative morphine consumption within 72 h postoperatively, while the secondary outcomes included adverse reactions and inflammatory factor levels (IL-6 and IL-10). Results: The final analysis included 149 patients. Median 72-hour morphine consumption was significantly lower with UTI (29.00 [22.50– 33.50] mg) than with FA (40.00 [27.50– 60.50] mg) and the control (54.40 [46.40– 82.80] mg, P < 0.001). VAS scores showed no intergroup differences ( P > 0.05). UTI reduced total adverse reactions (24.5%) versus FA (48.0%, P = 0.015) and control (52.0%, P = 0.005), specifically lowering vomiting (4.1 vs 20.0%), gastrointestinal discomfort (6.1 vs 26.0%), and delirium (4.1 vs 30.0%). UTI suppressed IL-6 and IL-10 elevation better than control (ΔIL-6:0.00 vs 1.63 pg/mL, P = 0.003; ΔIL-10:2.20 vs 19.92 pg/mL, P < 0.001). Conclusion: Single preoperative UTI significantly reduced postoperative morphine consumption (~48%) and adverse reaction risks compared with FA and control by modulating the balance of proinflammatory and anti-inflammatory factors (IL-6 and IL-10). UTI provides an efficient and safe alternative, supporting its inclusion in enhanced recovery after surgery (ERAS) analgesia strategies.