The Need for an Agnostic Pharmacologic Approach to Polysubstance Overdose

The Need for an Agnostic Pharmacologic Approach to Polysubstance Overdose

Background:

As the opioid overdose crisis has transitioned to a polysubstance overdose crisis, the available medications to treat the resulting respiratory depression (RD) may be becoming less effective.  The use of xylazine, an α₂-agonist, has become increasingly prevalent in polysubstance overdoses.  Xylazine releases neurotransmitters in the central nervous system resulting in sedation, analgesia and euphoria as well as decreases in peripheral vascular resistance, heart rate and blood pressure.  When fentanyl is adulterated or associated with xylazine (FAAX), patients experience enhanced euphoria as well as life threatening side effects such as RD.  Xylazine is not an opioid and thus, naloxone nor nalmefene will reverse its effects.  Therefore, in cases of FAAX-induce RD, opioid-receptor antagonists may be less effective. 


Purpose/Objectives:

A first step in addressing the current overdose-death challenge is an understanding that dealing with polysubstance use deaths changes the treatment dynamics.  In particular, more effective options for treating polysubstance-induced respiratory depression need to be developed.  Ideally, such an agent should (1) stimulate respiration independently of (i.e., be ‘agnostic’ to) the cause, (2) not reverse opioid pain-relief, (3) be effective against both hypoxia (low O₂) and hypercapnia (high CO₂), (4) have a rapid onset of action, and (4) have a good safety profile, including minimal central nervous system activity.

 

Method: Review of preclinical and clinical study data to demonstrate the effects of an agnostic respiratory stimulant, ENA-001.

Results: In contradistinction to receptor blockade by an antagonist, which is hampered by ever-more-potent opioid agonists and polysubstance-induced respiratory depression, a new approach is needed. Such an approach should be ‘agnostic’ to the cause, and therefore ideally universally effective. A new respiratory stimulant currently in development is ENA- 001.  It acts by a novel mechanism – inhibition of the large-conductance Ca²⁺/voltage-activated BK (big K⁺ channels) located in chemosensory glomus cells of the carotid bodies (i.e., a peripheral site of action). It has been shown to safely increase minute ventilation in a dose-dependent manner, and to reverse opioid, benzodiazepine, isoflurane, and propofol-induced respiratory depression in animal models and recent human studies.

Conclusions: Antagonism of BK channels in the carotid bodies might be a safe and effective way of addressing the complexities of polysubstance overdoses.

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