Disproportionate Reporting of Sudden Cardiac Death with Methadone in the FDA Adverse Event Reporting System (FAERS): A Case–Non-Case Study

Abstract

Background. Methadone can prolong cardiac repolarization, but outcome-specific reporting of sudden cardiac death has not, to our knowledge, been evaluated with contemporary data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS).

Objective. To quantify disproportionate reporting of sudden cardiac death with methadone in FAERS and to test its stability across exposure definitions, report clustering, and comparators.

Methods. We performed a report-level case–non-case disproportionality analysis of the openFDA Drug Adverse Event API. Methadone exposure was defined by a medicinal-product query and sudden cardiac death by its Medical Dictionary for Regulatory Activities (MedDRA) Preferred Term. Reporting odds ratios (RORs), proportional reporting ratios (PRRs), 95% confidence intervals (CIs), and Fisher exact tests were calculated. Four sensitivity analyses used harmonized and exact exposure definitions, an identical-signature clustering proxy, and exclusive buprenorphine reports as an active comparator.

Results. Among 20,692,690 searchable reports (52,462 mentioning methadone), 89 contained both methadone and sudden cardiac death. The primary ROR was 10.65 (95% CI 8.62–13.14) and the PRR was 10.63 (95% CI 8.61–13.12). Sensitivity RORs ranged from 6.82 to 9.29; every lower 95% CI bound exceeded 1. Fifty-six reports carried duplicate-related metadata, and 57 unique clinical signatures were identified.

Conclusion. Methadone and sudden cardiac death showed a consistent signal of disproportionate reporting in FAERS across exposure, clustering, and comparator assumptions. The signal supports focused pharmacovigilance and case review but does not estimate incidence, establish causality, or determine the cause of an individual death.