• Filippo D'Amico, Eoin Kelleher, Jacopo D'Andria Ursoleo, Andrey G Yavorovskiy, Stefano Turi, Sara Zaffaroni, Viviana Teresa Agosta, Silvia Ajello, and Giovanni Landoni.
• Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy.
• J Clin Anesth. 2025 Feb 8; 102: 111772111772.

Study ObjectiveSubstance P is a neuropeptide with a pivotal role in pain transmission and modulation. Preclinical studies suggest that targeting substance P and inhibiting its receptor, neurokinin 1 (NK-1), is a potential avenue for pain relief. When translated into clinical settings, these preliminary findings yielded mixed results. This meta-analysis of randomized controlled trials (RCTs) aims to investigate whether a preemptive administration of NK-1 antagonists may reduce postoperative pain.DesignWe searched PubMed, Cochrane and EMBASE from inception to January 3, 2025, for studies comparing NK-1 antagonists versus placebo or standard care that reported data on postoperative pain. The primary outcome was pain at two hours after surgery measured through a 0-10 numeric scale. Secondary outcomes were postoperative pain at 24 and at 48 h and postoperative morphine equivalent consumption.SettingHospitals.Main ResultsThe search strategies identified 13 RCTs with a total of 1959 patients. All studies reported a single preoperative administration of NK-1 antagonists. NK-1 antagonists reduced postoperative pain two hours (n = 8; MD -0.62; 95 % CI: -0.91, -0.32; P < 0.001; I2 = 0 %) and at 24 h (n = 9; MD -0.65; 95 % CI: -1.22, -0.09; P = 0.02; I2 = 86 %) but not 48 h after surgery. Morphine equivalent consumption was similar in the two groups.ConclusionsPreoperative single-administration of NK-1 antagonists reduces postoperative pain. The observed pain reduction pattern is consistent with the pharmacokinetics (half-life 9-12 h) of these inhibitors and with data from preclinical studies.Copyright © 2025 Elsevier Inc. All rights reserved.

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