Systematic analysis of adverse reactions associated with dantrolene treatment: From clinical features to molecular mechanisms

Dantrolene, 1st synthesized in 1967, is widely used for treating malignant hyperthermia (MH), neuroleptic malignant syndrome, and spasticity. However, comprehensive analysis of its adverse effects and underlying mechanisms remains limited. This study aims to analyze dantrolene-associated adverse events (AEs) using pharmacovigilance databases, with particular focus on subgroup analysis comparing MH versus non-MH patients, and investigate their underlying molecular mechanisms. We analyzed AEs from 3 pharmacovigilance databases (U.S. Food and Drug Administration Adverse Event Reporting System [2004-2024], Japanese Adverse Drug Event Report [2004-2023], Canada Vigilance Adverse Reaction Online Database [1991-2019]) and conducted differential gene expression analysis using GEO datasets (GSE184769, GSE227229). Signal detection employed disproportionality analysis using reporting odds ratio (ROR), proportional reporting ratio, Bayesian confidence propagation neural network, and Empirical Bayesian Geometric Mean indices. Analysis revealed significant respiratory and musculoskeletal AEs. Respiratory failure was consistently reported across databases (ROR: 29.33-46.29), while musculoskeletal complications included rhabdomyolysis (ROR: 14.05) and compartment syndrome (ROR: 80.52). MH patients showed increased risks of muscular weakness (ROR: 19.00), respiratory failure (ROR: 5.48), and pulmonary edema (ROR: 22.18). Molecular analysis identified IL6 and ALB as key mediators of respiratory effects, while Adgrl1 and Adgrl2 emerged as crucial regulators of muscle function. Our study quantified differential dantrolene susceptibility, revealing significantly higher AE risks in MH versus non-MH patients: muscular weakness (ROR: 19.00), respiratory failure (ROR: 5.48), and pulmonary edema (ROR: 22.18). Molecular analysis demonstrated that mutant ryanodine receptor 1 channels amplify IL6/ALB-mediated respiratory effects and disrupt Adgrl1/2-regulated muscle function, establishing the mechanistic basis for MH patient vulnerability and supporting MH-specific dosing strategies.