Targeting the Carotid Body Function With Big-K-Channel Blocker ENA-001 in Opioid-Induced Respiratory Depression: A Scoping Review

Abstract

Opioids, most intravenous anesthetics and various illicit substances can cause fatal respiratory depression by depressing central respiratory networks. ENA-001, a ventilatory modulator targeting the carotid bodies, has emerged as a potential countermeasure without impairing analgesia or hypnosis. We conducted a literature review to evaluate the efficacy and safety of ENA-001. This scoping review summarizes the current evidence base for ENA-001 from in vitro, animal experiments, and human volunteer studies. A comprehensive search was conducted across several electronic databases to identify all available literature describing its effects as a respiratory stimulant and as a reversal agent of drug-induced respiratory depression. We identified eight relevant publications, four describing data in humans and four using animal models (mice, rats, and non-human primates). ENA-001 increased ventilation and attenuated respiratory depression induced by morphine and the combination of xylazine and fentanyl. The primary site of action was localized to the carotid bodies, specifically the pore-forming α-subunit of the KCa1.1 (BK) channel. In humans, ENA-001 increased minute ventilation and reduced end-tidal carbon dioxide under poikilocapnic conditions. In experimental human models of alfentanil- and propofol-induced respiratory depression, ENA-001 significantly improved isohypercapnic minute ventilation and fully restored the hypoxic ventilatory response, respectively, without impairing sedation or analgesia. Across all studies, the safety profile was favorable, with no serious adverse events reported. In conclusion, ENA-001 is a first-in-class, peripherally acting respiratory stimulant that effectively reverses drug-induced respiratory depression. These findings support its continued clinical development for opioid- and anesthetic-induced respiratory compromise.