Oral Premedication with Tapentadol versus Pregabalin for Acute Postoperative Pain in Lower Limb Surgery Under Neuraxial Anesthesia: A Pilot Randomized Controlled Trial
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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 µ -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 50 mg orally every 12 hours (Group A, n = 23) or pregabalin 75 mg 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 × 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 timepoint. The LMM revealed a significant main effect of Time ( F 4,181.6 = 23.61, p < 0.001) and a borderline-significant Group × Time interaction in the continuous-time sensitivity model ( F 1,187.6 = 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 100 mg/day provided superior postoperative analgesia compared with pregabalin 75 mg/day at the 90-minute PACU timepoint, 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.
Trial registration
ClinicalTrials.gov – NCT07587645 (retrospectively registered).
Highlights
Double-blind pilot RCT compared 72-hour oral premedication with tapentadol versus pregabalin in 46 patients undergoing elective lower limb surgery under neuraxial anesthesia.
Tapentadol-premedicated patients reported significantly lower pain scores at 90 minutes post-PACU arrival (mean NRS difference − 0.91; p = 0.006; Cohen’s d = 0.96, large effect).
The rate of pain increase over the two-hour PACU period was faster in the pregabalin group (Group × Time interaction, continuous model: p = 0.053).
Rescue analgesia was required five times less frequently with tapentadol premedication (4.3% vs. 21.7%).
Both agents were well tolerated; nausea and vomiting were present in 17.4% of the patients in both groups. No hypersensitivity reactions occurred in either arm.
Figure 1: Graphical Abstract – CONSORT
Figure 1:CONSORT flow diagram.
Enrollment, allocation, and analysis of participants in the pilot randomized controlled trial comparing oral premedication with tapentadol versus pregabalin for acute postoperative pain in elective lower limb surgery under neuraxial anesthesia.
