Toward Developing Alternative Opioid Antagonists for Treating Community Overdose: A Model‐Based Evaluation of Important Pharmacological Attributes

In response to increased illicit use of synthetic opioids, various μ-receptor antagonist formulations, with varied pharmacological characteristics, have been and are being developed. To understand how pharmacologic characteristics such as absorption rate and clearance rate affect reversal in treating community opioid overdose, we used our previously published translational opioid model. We adapted this model with in vitro receptor binding data and clinical pharmacokinetic data of three intranasal nalmefene formulations along with an intranasal naloxone formulation to study the reversal of fentanyl and carfentanil-induced respiratory depression in chronic opioid users. Nalmefene has a longer plasma half-life and slower unbinding from the μ-receptor compared to naloxone. For a more rapid reversal of acute overdose-induced respiratory depression, a fast-absorbing antagonist formulation may be of greater utility than a slow-absorbing one containing the same dosage of the antagonist. For preventing renarcotization caused by a long opioid exposure, a slow-clearing antagonist with slow unbinding from the receptor may be of value. While a more potent antagonist with a longer half-life may have the potential to facilitate recovery from respiratory depression for overdose with synthetic opioids, such interventions may also lead to longer and more pronounced withdrawal. This emphasizes the need for a nuanced consideration of several facets while choosing a μ-receptor antagonist, dose, and formulation to treat community opioid overdose cases.