2021 FDA Science Forum
Reversal of High Potency Synthetic Opioid Overdose: Literature Review
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Contributing OfficeCenter for Drug Evaluation and Research
Abstract
Opioid misuse and abuse have long been public health issues in the United States, but recent increases in overdose-related deaths caused the U.S. Department of Health and Human Services to declare the opioid crisis a national public health emergency. The purpose of this project was to evaluate the landscape of available information and scientific considerations surrounding intranasal, intramuscular, and intravenous routes of opioid antagonist development addressing prescription opioid overdose reversal, and illicit highly potent opioid overdose reversal. A literature search of the PubMed database was conducted using keywords in order to review historical and current scientific knowledge of synthetic opioid overdose reversal. Additionally, publicly available regulatory documents were evaluated from the websites of CDC, DEA, FDA, NIDA, and the Federal Register. In vitro binding data at the µ-opioid receptor suggest carfentanil, a veterinary tranquilizer, has the highest affinity. Pharmacokinetic and pharmacodynamic data regarding illicit highly potent synthetic opioids are uncharacterized, making it difficult to determine the most appropriate reversal therapy. However, pharmacokinetics of fentanyl, a synthetic prescription opioid, and its pharmacodynamic effects on respiration have been characterized over the last several decades, which could serve as a model. Additionally, pharmacodynamics of opioid antagonists such as naloxone and nalmefene on fentanyl-induced respiratory depression are described in the literature. Nalmefene is labeled to be effective in reversing fentanyl’s respiratory effects when administered perioperatively. A preclinical study in African green monkey suggests naloxone may be able to protect against carfentanil overdose. Effects of carfentanil, considered to be the most potent synthetic opioid currently known, were reversed with IV bolus naloxone. After carfentanil administration, nalmefene and naloxone block its effects. Using these limited data, model-informed drug development (MIDD) can play an important role in future research towards better antagonist development and application. We identify knowledge gaps in science of opioid overdose reversal that need to be addressed for successful development of therapies.
