Are opioid receptor antagonists adequate for "Opioid" overdose in a changing reality?

What Is Known And Objective: Deaths due to opioid-induced respiratory depression (OIRD) continue to rise despite intense regulatory and professional actions. COVID-19 has only worsened this situation. An opioid receptor antagonist (ORA) such as naloxone is the most common intervention for OIRD. However, with increasing overdose from highly potent illicit opioids and polysubstance abuse, appraisal of the adequacy of ORA seems warranted and timely.

Comment: OIRD results from the binding of an excess number of agonist molecules to opioid receptors. Mechanistically, it makes sense to reverse this by displacing agonist molecules by administering an ORA. But realistically, the trend to higher-potency agonists and polysubstance abuse diminishes the effectiveness of this approach. We are left facing a crisis without a solution.

What Is New And Conclusion: For the increasingly common OIRD from highly potent illicit agonists and polysubstance overdose, ORAs are correspondingly less effective. Alternatives are needed-soon.