Peripheral opioid receptor antagonism alleviates fentanyl-induced cardiorespiratory depression and is devoid of aversive behavior.

Summary

A peripherally restricted μ-opioid receptor antagonist (naloxone methiodide) both prevented and reversed fentanyl-induced respiratory depression in vivo to a degree comparable to naloxone, but without aversive behaviors. Electrophysiologic and circuit-level data implicate peripheral MORs and ascending inputs to the nucleus of the solitary tract, suggesting a therapeutic path to reverse OIRD while minimizing CNS-mediated withdrawal and aversion.

Key Findings

• Naloxone methiodide (peripherally restricted) prevented and reversed fentanyl-induced respiratory depression comparably to naloxone.
• Peripheral MOR antagonism did not elicit aversive behaviors seen with naloxone.
• nTS neuronal activity changes after fentanyl were attenuated by peripheral antagonism, implicating ascending peripheral inputs in OIRD pathophysiology.

Clinical Implications

If translated clinically, peripherally restricted MOR antagonists could reverse fentanyl overdoses without precipitating severe CNS-mediated withdrawal or aversion, potentially improving EMS and perioperative rescue strategies.

Limitations

• Preclinical animal data; human pharmacokinetics, dosing, and safety profiles require evaluation.
• Scope limited to fentanyl; generalizability to other opioids needs confirmation.

Future Directions

First-in-human studies of peripherally restricted MOR antagonists for OIRD reversal, dose-ranging, and comparative effectiveness versus naloxone in EMS and perioperative settings.