Association between opioid analgesics and learning disorders: a disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) and EudraVigilance databases

Background: Opioid analgesics are widely used, but their long-term neurocognitive safety, particularly concerning prenatal exposure in children, is poorly understood. This study aimed to investigate the reporting association between opioid use and learning disorders and to characterize this pharmacovigilance signal, with a focus on the pediatric population. Methods: We analyzed adverse event reports from the U.S. Food and Drug Administration’s Adverse Event Reporting System (FAERS) database (2004–2025), with external validation performed on the EudraVigilance (EV) database. Cases were identified using the MedDRA High-Level Term “Learning disorders.” A multi-algorithm disproportionality analysis [reporting odds ratio (ROR), proportional reporting ratio, information component, empirical Bayes geometric mean] was performed, including an all-drug screening, age-stratification, and a detailed clinical characterization of pediatric cases (<18 years). Results: Among 9666 reports of learning disorders in FAERS, opioids were the most prominent drug class. Oxycodone (ROR 46.79) and hydrocodone-containing products (ROR up to 62.24) showed the strongest signals. This signal was persistent across all age groups. In an in-depth analysis of 65 pediatric opioid-related cases, prenatal exposure was the most frequently reported exposure context, collectively accounting for 72.3% of cases. These pediatric cases were overwhelmingly reported by consumers or lawyers (95.4%) and frequently associated with severe outcomes like congenital anomalies (32.3%). Conclusion: This large-scale analysis identifies a strong and persistent signal of disproportionate reporting for learning disorders associated with opioids. In the pediatric population, these reports are frequently linked to prenatal exposure and severe outcomes. These hypothesis-generating findings highlight a potential safety concern that warrants further investigation in controlled epidemiological studies. While causality cannot be established, the results suggest the importance of cautious prescribing of opioids to women of childbearing potential and support considering neurodevelopmental follow-up for prenatally exposed children.