The effect of Neurokinin-1 receptor antagonists on postoperative pain: A meta-analysis of randomized controlled trials

Study objective: Substance 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 metaanalysis of randomized controlled trials (RCTs) aims to investigate whether a preemptive administration of NK-1 antagonists may reduce postoperative pain. Design: We 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. Setting: Hospitals. Main results: The 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. Conclusions: Preoperative 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.