Development of therapeutics to treat fentanyl overdose using a validated animal model

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PROJECT SUMMARY: According to the Centers for Disease Control (CDC), synthetic opioids are currently the most common cause of overdose death in the U.S, while heroin and prescription opioid deaths have decreased significantly since 2017. Despite the widespread availability of naloxone, deaths from fentanyl and fentanyl analogues (F/FA) continue to rise in parallel with increasing reports of F/FA resistance to naloxone. High doses of rapidly injected F/FA cause airway obstruction from vocal cord closure (VCC) and severe chest wall rigidity (CWR) within 2 minutes, effects that persist for up to 10 minutes and appear to be resistant to naloxone. In contrast, morphine- derived opiates (e.g. heroin) cause respiratory depression and mild muscle rigidity that is responsive to naloxone, but are not known to cause VCC in humans. This suggests distinct pharmacological mechanisms underlying F/FA-induced VCC, compared to morphine-induced respiratory depression mediated by mu opioid receptors. In support of this hypothesis, our published pharmacological data demonstrate F/FA, but not morphine or naloxone, have affinity for off-site targets that may regulate these F/FA-induced effects. The in vitro data include F/FA concentrations that may be physiologically relevant to humans, based on available models of brain lipid concentrations for F/FA. Additionally, we have demonstrated in our animal model that these fentanyl-induced effects are resistant to high dose naloxone and may involve these off-site receptor targets. This preliminary data suggests the development of effective therapies for overdose require a biological model that re-conceptualizes the underlying causes of F/FA overdose deaths to include VCC, in addition to respiratory depression. Therefore, the goal of this Phase I proposal is to complete the validation of a comprehensive animal model replicating the rapid fentanyl toxicity effects seen clinically in humans and the preliminary identification of formulations that address VCC. There are currently no Federal Drug Administration approved treatments that target these F/FA toxicity effects, and this project directly addresses the need for the development of a new class of therapeutics, specific to F/FA overdose.