Combination of the BK-Channel Antagonist ENA-001 and Naloxone Is More Effective Than Either Agent Alone in Reversing...

Background Fentanyl overdose in humans produces two life-threatening effects: central μ-opioid receptor (MOR)-mediated hypoventilation and generalized muscle rigidity that further impairs ventilation. Naloxone, the current standard of care, reverses both effects via competitive antagonism at MOR; however, its clinical utility is limited, particularly in the setting of polydrug overdose, where nonopioid mechanism(s) may also contribute to respiratory suppression. ENA-001 restores ventilation as a peripherally directed (carotid body) BK-channel antagonist with a mechanism independent of MOR, and is "agnostic" to the drug cause of respiratory depression. The effectiveness of a combination has not yet been assessed. This study was designed to determine the nature of the pharmacodynamic interaction between naloxone and ENA-001 against fentanyl-induced effects related to overdose toxicity. Specifically, to determine whether their combined effect is neutral, additive, or antagonistic. Methods Fentanyl was administered to adult male Sprague Dawley rats as a single intravenous (i.v.) bolus injection via the lateral tail vein following pretreatment with naloxone and/or ENA-001 administered via intramuscular (i.m.) injection. A timer was started at the time of i.v. fentanyl injection, and hypoventilation and muscle rigidity were recorded to define the duration of early ventilatory suppression and the time to recovery from fentanyl-induced body rigidity. Results Pretreatment with naloxone and ENA-001 together was more effective (p < 0.001) in attenuating fentanyl-induced respiratory suppression than either agent alone (p < 0.05 and 0.01, respectively), and the combination did not compromise the body rigidity recovery timeline. Conclusions In this rat model of fentanyl-induced effects associated with overdose, coadministration of the combination of the opioid antagonist naloxone and the BK channel antagonist ENA-001 represents a potentially more effective treatment of fentanyl overdose than either agent alone.