S3170 NK-1 Receptor Blockade Yields a Promising Boost in Nausea Response Without Added Serious Harm in Gastroparesis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Introduction: Refractory nausea cripples nearly half of gastroparesis patients and remains the symptom least improved by existing prokinetics. Pre-clinical data implicate vagal-afferent NK-1 neuropeptide signaling, yet human evidence has been sparse and fragmented. We therefore synthesized every randomized trial testing NK-1 receptor antagonists in diabetic or idiopathic gastroparesis—a drug class currently licensed only for chemotherapy-induced emesis—to deliver the first aggregate efficacy-and-safety estimate in this population. Methods: A systematic search of PubMed, Embase, Scopus, and Cochrane Library identified randomized controlled trials (RCTs) that compare the efficacy and safety of drugs blocking NK-1 receptor for treatment of diabetic or idiopathic gastroparesis through May 2025. Data were analyzed using RevMan 4.2.1. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using Mantel-Haenszel methods. Random- or fixed-effects models were applied based on heterogeneity (Higgins’ I2). Statistical significance was set at P < 0.05. Risk of bias was assessed using RoB 2.0. Results: Across 3 randomized, placebo-controlled trials (Jesse 2021, Jesse 2024, Pankaj 2018; n = 479), NK-1 receptor antagonists increased the likelihood of achieving a clinically meaningful nausea response by 44% versus placebo (48.9% vs 33.7%; pooled RR 1.44; 95% CI 0.97-2.14; P = 0.07; I2 = 60%), although this improvement narrowly missed statistical significance. Any treatment-emergent adverse events occurred in 40.9% (99/242) of active-drug recipients versus 31.6% (75/237) of controls, a non-significant 36% relative increase (RR 1.36; 95% CI 0.91-2.02; P = 0.13; I2 = 57%). Any serious side-effect rates remained low and statistically comparable (1.6% vs 1.3%; pooled RR 1.22; 95% CI 0.33-4.49; P = 0.76; I2 = 0%). Conclusion: We observed a clinically meaningful 15-point absolute rise in nausea responders that narrowly missed statistical significance, without an increase in serious adverse events. This directionally favorable effect, coupled with a comparable safety profile, positions NK-1 blockade as a biologically plausible, gastric-motility-independent option for patients who fail dopamine- or serotonin-targeted agents. Heterogeneity—driven by small sample sizes and variable responder definitions—highlights the urgent need for adequately powered phase III trials using unified endpoints. Until such data mature, clinicians may consider off-label NK-1 use in carefully selected cases.