Description
Background: Since 2013, the United States Food and Drug Administration (FDA) has issued a sustained series of opioid regulatory actions to curb high-risk prescribing and opioid-related harm. The impact of these actions on real-world prescribing and patient safety outcomes remains uncharacterized. This study aims to synthesize observational data on the real-world impact of FDA opioid regulatory actions and Risk Evaluation and Mitigation Strategies (REMS) on prescribing behavior and patient outcomes. Methods: We conducted a systematic review following the PRISMA 2020 guidelines. We search in Pubmed, Embase and Web of science for studies published between September 2013 and September 2025.The eligible studies included United States based empirical evaluation using interrupted time series (ITS), segmented regression, controlled ITS, pre-post cohort, and repeated cross-sectional designs that accessed prescribing or safety outcomes following FDA labelling or REMS actions. Findings were evaluated across five main prespecified policy areas which include national guidelines and state prescribing limits, pediatric labelling, opioid-benzodiazepine warnings, REMS, and contextual care settings. Results: A total of 1,129 studies were identified, 131 underwent full-text reviews from the databases with 25 meeting the inclusion criteria. There was a fall of 50-70% in codeine prescription for post-tonsillectomy in pediatrics which served as a clear effect of this policy, as well as sharp decline in codeine and tramadol dispensing after the 2017 DSC. There were 40% less patients with overlapping prescriptions by 2019 due to the 2016 opioid-benzodiazepine boxed warnings, and the effects were heightened by the alerts generated by electronic health record clinical decision support. Modest but directionally consistent reductions (relative reductions ranging from 25% to 62%) in high-risk use were produced by REMS programs and boxed warnings. Pre-existing declines in overall and high-dose prescribing and shortened initial days’ supply were increased due to the 2016 CDC guideline and state prescribing limits although transitions to long-term use occasionally rose. Conclusions: Measurable reductions in high-risk prescribing are temporally associated with FDA opioid regulatory actions, with the strongest effect seen in pediatric patients and benzodiazepine co-prescribing. Future evaluations should strengthen causal identification, link prescribing changes to clinical outcomes, and explicitly assess equity across race, rurality, and payer.
Publication Info
2026.