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Adverse Events in Acute Pain Clinical Trials: A Mix of the Study Drug and Rescue
Abstract   Peer reviewed

Adverse Events in Acute Pain Clinical Trials: A Mix of the Study Drug and Rescue

Gabriella P. Nutter and John T. Farrar
The journal of pain, v 41(Supplement), 105875
Mar 2026
DOI: https://doi.org/10.1016/j.jpain.2025.105875

Abstract

Adverse events (AEs) are an important consideration in the use of pain therapeutics. AE reports from studies evaluating acute pain analgesic drugs may misrepresent safety data by failing to account for the concomitant use of rescue medication. If safety data does not account for the administration of rescue we cannot differentiate the likely culprit. We found no publications with AEs compared with and without use of rescue. Using individual participant data from the FDA Document Archiving, Reporting, and Regulatory Tracking System (DARRTS), we identified five acute pain dental extraction trials with adequate data to investigate this issue. In these trials (60% female and ages 18-24 years), nausea and vomiting events occurred more frequently after the administration of opioid rescue, independent of exposure time to the study drug. In four harmonized studies of acetaminophen/ibuprofen (n=636), nausea reporting increased by 10.2% after rescue, vomiting by 6.7%, and dizziness by 3.9%. Similarly, in participants who received 15, 30, and 60mg of meloxicam (n=150), nausea increased by 19.6%, 10.3%, and 8.8% and vomiting by 13.3%, 10.3%, and 3%, respectively, following administration of rescue. Although frequencies were small, no differences were noted in other AEs. Since opioids are known to commonly cause nausea and vomiting, it is likely that they are the cause, although the interaction of the study drug with the opioids cannot be ruled out. Improved recording and reporting of the timing of AEs as they occur in the context of rescue is needed to accurately establish the true safety of analgesic drugs.

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