Pharmacovigilance analysis of central nervous system adverse events associated with sevoflurane and drug interactions: a disproportionality study based on the FDA adverse event reporting system (FAERS) database

Sevoflurane is rarely administered as monotherapy in clinical anesthesia practice, yet the safety profile of its drug-drug interactions (DDIs) remains incompletely characterized in real-world settings. To systematically identify and quantify disproportionality signals for central nervous system (CNS) adverse events associated with sevoflurane combinations using the FDA Adverse Event Reporting System (FAERS) database.

Reports from 2004 Q1 to 2025 Q2 listing sevoflurane as primary suspect were extracted and deduplicated. Disproportionality analysis employed Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) to detect signals, supplemented by Bayesian methods (EBGM and IC) for multi-method validation. A hierarchical approach progressed from broad CNS adverse event screening to drug class-level and individual drug-level analyses. Interaction Reporting Odds Ratio (IOR) models quantified synergistic interaction signals under both PS-restricted and role-independent frameworks, with the Ω shrinkage measure applied as a Bayesian validation method for all IOR signals.

Among 4,129 sevoflurane reports (2,903 concomitant use, 1,226 quasi-monotherapy), multiple significant signals emerged. Intravenous anesthetics and opioid analgesics demonstrated the highest signal rates (44.4% each). Movement disorders, particularly dystonia, exhibited the strongest signals across multiple drug classes. Morphine combination with sevoflurane showed a notably high dystonia signal (ROR: 66.64). IOR analysis identified supra-additive interactions: morphine-dystonia (IOR: 9.46), fentanyl-dystonia (IOR: 2.96), and propofol-confusional state (IOR: 2.56). Ω shrinkage validation confirmed fentanyl-dystonia and propofol-confusional state as true synergistic signals. The role-independent analysis identified seven additional supra-additive IOR signals, with morphine-dystonia retaining significance across both frameworks. Sensitivity analyses confirmed the robustness of the core signals.

Sevoflurane DDIs might be associated with multiple CNS adverse event signals, particularly movement and consciousness disorders. Dual-method validation using IOR and Ω shrinkage measure enhanced signal discrimination and reduced false-positive risk. These findings warrant clinical vigilance in vulnerable populations and prospective validation studies.