Liposomal Bupivacaine via Combined Sciatic and Saphenous Block after Lower Extremity Procedures: a Randomized, Double-Blind, Phase 3 Trial

Abstract

Category: Bunion; Midfoot/Forefoot Introduction/Purpose: Combined sciatic and saphenous nerve blocks are commonly used for pain management after lower extremity procedures. Liposomal bupivacaine (LB) is a formulation of the local anesthetic bupivacaine that gradually releases bupivacaine for prolonged periods of analgesia. The objective of this phase 3 multicenter, randomized, double-blind, active- controlled study (NCT04518462) was to evaluate the postoperative analgesic effect of combined sciatic and saphenous nerve blocks with LB with or without admixed bupivacaine hydrochloride (HCl) versus bupivacaine HCl alone in adults undergoing bunionectomy or other lower extremity procedures. Methods: This study enrolled 2 parallel cohorts: pharmacokinetics, pharmacodynamics, efficacy, and safety were assessed in cohort 1 (bunionectomy), and efficacy and safety were further assessed in cohort 2 (bunionectomy, other lower extremity procedures). Eligibility criteria included American Society of Anesthesiologists physical status classification ≤3 and body mass index ≥18 to < 40 kg/m2. Participants were randomized 1:1:1 to receive LB 266 mg admixed with saline (LB266), LB 266 mg admixed with bupivacaine HCl 50 mg (LB266-ADMIX), or bupivacaine HCl 100 mg (BUP100), administered as a combined sciatic and saphenous block. No additional regional blocks were administered. For 96 hours after surgery, rescue medication included nonsteroidal anti- inflammatory drugs and acetaminophen and escalation to opioids if necessary. The primary endpoint was the area under the curve (AUC) of the numerical rating scale (NRS) pain intensity scores 0-96 hours after surgery. Total postsurgical opioid consumption 0- 96 hours after surgery was a secondary endpoint. Results: In total, 119 participants were enrolled (LB266: n=40; LB266-ADMIX: n=41; BUP100: n=40). The least squares mean (LSM) AUC of the NRS pain intensity score was nonsignificantly lower 0-96 hours after surgery for LB266 versus BUP100 (LSM [standard error], 286.9 [32.9] vs 348.6 [34.4]; LSM difference vs BUP100, −61.7 [95% confidence interval (CI), −147.0, 23.6]; P=0.1564). LB266 pain intensity scores were significantly higher 6-18 hours after surgery but were significantly lower at 36-96 hours than BUP100 (Figure). Cumulative opioid consumption differences 0-96 hours after surgery for LB266 versus BUP100 were not significant (LSM [95% CI], 20.7 [13.5, 31.7] vs 19.8 [12.7, 31.0]; P=0.8857). Mirroring pain scores, opioid consumption with LB266 versus BUP100 was higher at 0-24 hours but lower 24-96 hours (Figure); adverse events were similar. Conclusion: Cumulative pain intensity and opioid consumption were not significantly different between the LB266 and BUP100 groups 0-96 hours after surgery; however, consistent with the known mechanism of LB, pain intensity scores were significantly lower with LB266 36-96 hours after surgery, and opioid consumption was significantly lower 24-96 hours after surgery.