The real-world safety profile of amitriptyline: A comprehensive pharmacovigilance analysis based on the large-scale FDA adverse event reporting system database

Despite its established efficacy, the long-term safety profile of amitriptyline among broad patient populations remains insufficiently characterized. We thoroughly characterized the real-world safety profile of amitriptyline through a systematic analysis of the FDA Adverse Event Reporting System (FAERS). Adverse events were collected from Q1 2004 to Q1 2026, and four disproportionality algorithms—reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS)—were employed to identify safety signals. Weibull distribution modeling was used to assess temporal trends, with subgroup analyses stratified by age and sex. Among 5301 amitriptyline-related cases involving 20,451 adverse events, risk signals were identified for psychiatric, nervous system, and cardiac disorders. Analysis confirmed recognized risks, including somnolence, confusional state, drug interaction, and xerostomia. Additional risk signals were identified for potential drug abuse or misuse and for serious adverse events not currently listed on package insert, like aspiration pneumonia, cardiorespiratory arrest, and specific congenital anomalies (e.g., syndactyly, polydactyly, and adactyly). Temporal analysis revealed 52.84% of events occurred within 30 days, whereas 26.14% occurred beyond six months. Subgroup analyses revealed distinct susceptibility patterns: cardiovascular events were more common in females, neuropsychiatric events (e.g., migraine, nightmares) in males; fetal exposure was concerning in pediatric populations, suicide and overdose predominant among adults, and confusion and drug interactions prominent in elderly patients. This pharmacovigilance study confirmed amitriptyline's established adverse reactions and highlighted previously under-characterized risks. These findings recommended implementing integrated risk management in clinical practice to improve patient safety.