• Steven L Shafer, Sam L Teichman, Ira J Gottlieb, Neil Singla, Harold S Minkowitz, David Leiman, Benjamin Vaughn, and John F Donovan.
• Professor Emeritus, Department of Anesthesiology, Perioperative and Pain Medicine Stanford University, Stanford, California, USA steven.shafer@stanford.edu.
• Anesthesiology. 2024 Apr 25.

BackgroundNonopioid management of postsurgical pain remains a major unmet need. Few studies have evaluated TRPV1 agonists for analgesia after surgery. We studied intraoperative vocacapsaicin, a novel prodrug of the TRPV1 agonist capsaicin, in a validated model of postsurgical pain.MethodsThis was a triple-blinded, randomized, placebo-controlled, dose-ranging trial in patients undergoing bunionectomy. We randomized patients 1:1:1:1 to surgical site administration of 14 mL of placebo or one of three vocacapsaicin concentrations: 0.30, 0.15, or 0.05 mg/mL. The prespecified primary endpoint was the area-under-the-curve of the Numerical Rating Scale (NRS) pain score at rest through 96 hours for the 0.3 mg/mL group. Prespecified ordered, secondary endpoints for the 0.3 mg/mL group included percent of patients who did not require opioids from 0-96 hours, total opioid consumption through 96 hours, and the area-under-the-curve of the NRS pain score for the first week.ResultsWe randomized 147 patients. During the first 96 hours, vocacapsaicin 0.30 mg/mL reduced pain at rest by 33% vs. placebo (primary endpoint, 95% CI [10%, 52%], effect size (Cohen's D) = 0.61, p = 0.005). Twenty-six percent of patients receiving vocacapsaicin 0.30 mg/mL did not require postoperative opioids for analgesia (p=0.025) vs. 5% of patients receiving placebo. Vocacapsaicin 0.30 mg/mL reduced opioid consumption over the first 96 hours by 50% vs. placebo (95% CI [26%, 67%], effect size = 0.76, p = 0.002). Vocacapsaicin 0.30 mg/mL reduced pain over the first week by 37% vs. placebo (95% CI [12%, 57%], effect size = 0.62, p = 0.004). Treatment effect persisted for at least 2 weeks. All study endpoints showed an administered concentration vs. response relationship. Vocacapsaicin was well-tolerated with no differences between groups in any safety parameter.ConclusionsA single, local administration of vocacapsaicin during surgery reduced pain and opioid consumption for at least 96 hours after surgery compared to control.Trial RegistrationClinicalTrials.gov NCT03599089.Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Anesthesiologists.

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