Oral Premedication with Tapentadol versus Pregabalin for Acute Postoperative Pain in Lower Limb Surgery Under Neuraxial Anesthesia: A Pilot Randomized Controlled Trial

Abstract Background: Acute postoperative pain affects more than 80% of surgical patients, with orthopedic lower limb procedures consistently associated with severe pain intensity and high opioid requirements. Preemptive analgesia with oral agents has been proposed to attenuate central and peripheral sensitization prior to surgical incision. Tapentadol, a dual-mechanism -opioid receptor agonist and norepinephrine reuptake inhibitor, and pregabalin, a voltage-gated calcium channel modulator, represent pharmacologically distinct premedication options; however, direct comparative data in this surgical context are lacking. This pilot randomized controlled trial aimed to compare the analgesic efficacy and safety of 72-hour oral premedication with tapentadol versus pregabalin in patients undergoing elective lower limb surgery under neuraxial anesthesia. Methods: In this double-blind, parallel-group pilot trial, 46 patients scheduled for elective lower limb surgery under neuraxial anesthesia were randomized equally to receive tapentadol 50mg orally every 12 hours (Group A, n = 23) or pregabalin 75mg orally every 24 hours (Group B, n = 23), initiated 72 hours before surgical incision. The primary outcome was postoperative pain intensity assessed using the Numeric Rating Scale (NRS, 0-10) at post-anesthesia care unit (PACU) arrival (T0) and at 30 (T1), 60 (T2), 90 (T3), and 120 (T4) minutes thereafter. Secondary outcomes included Verbal Rating Scale (VRS) scores, rescue morphine consumption, and safety. The primary longitudinal analysis used a linear mixed model (LMM) with Group, Time, and Group x Time interaction as fixed effects and a random intercept per patient; between-group contrasts at each timepoint were derived from estimated marginal means with Holm correction. Effect sizes are reported as Cohen's d. Results: All 46 patients completed the study with no missing data. Both groups were pain-free at T0 (NRS=0). Pain scores diverged progressively from T1 onward, with the pregabalin group reporting consistently higher NRS values at every time point. The LMM revealed a significant main effect of Time (F4,181.6 = 23.61, p < 0.001) and a borderline-significant Group x Time interaction in the continuous-time sensitivity model (F1,187.6 = 3.79, p = 0.053). Post-hoc contrasts identified a statistically significant, large effect between-group difference at T3 (mean NRS difference -0.91, p = 0.006, Cohen's d = -0.96) and a medium-effect trend at T2 (d = -0.59, p = 0.089). Rescue analgesia was required by 4.3% of tapentadol patients versus 21.7% of pregabalin patients. Nausea and vomiting were equally present in both groups (17.4%). No hypersensitivity reactions were observed in either arm. Conclusions: Seventy-two-hour oral premedication with tapentadol 100mg/day provided superior postoperative analgesia compared with pregabalin 75 mg/day at the 90-minute PACU time point, with a large effect size and a fivefold reduction in rescue analgesia requirements. Both agents were well tolerated. These pilot data support the conduct of a fully powered, multicenter randomized controlled trial to confirm the analgesic superiority of tapentadol premedication in orthopedic lower limb surgery.