Preemptive multimodal analgesia (PMA) is commonly employed for pain control after total knee arthroplasty (TKA). However, the optimal timing for initiating PMA remains unclear. This study aimed to compare the efficacy of PMA administered at different time points before TKA. In this prospective, double-blind, placebo-controlled, randomized trial, 120 patients who underwent TKA were randomized into three groups. PMA (200mg celecoxib and 150mg pregabalin administered every 12h) was initiated 48h (group A), 24h (group B), and 1h (group C) before surgery. The primary outcome was the postoperative administration of morphine hydrochloride as a rescue analgesic. Secondary outcomes included time to first rescue analgesia, postoperative pain assessed using the visual analog scale (VAS), functional recovery assessed by knee motion range and ambulation distance, time until hospital discharge, and complication rates. Compared with group C, groups A and B exhibited significantly lower morphine consumption within 24h after surgery, lower total morphine consumption, longer time to first rescue analgesia, and superior range of knee motion on the day of surgery. Groups A and B did not exhibit significant differences in these outcomes. The three groups did not differ significantly in postoperative VAS pain scores, ambulation distance, length of hospital stay, or complication rates. In comparison with PMA starting at 1h preoperatively, initiating PMA at 24 and 48h preoperatively provided better postoperative pain relief. Considering the aim of minimizing the amount of ineffective medication received by patients, initiating PMA at 24h preoperatively may be a more favorable option for patients undergoing TKA. However, the clinical significance of our results and the optimal starting time for PMA require further investigation.
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