Overdose Reversal Challenges and Priorities in the Era of Synthetic Opioids: Insights from the Respire Expert Forum

The opioid overdose crisis in the US is marked by illicitly manufactured high-potency synthetic opioids (HPSOs), like fentanyl/fentanyl analogs, combined with other illicit substances. The year preceding July 2024 recorded over 65,000 opioid overdose fatalities, with 92% involving synthetic opioids, excluding methadone. HPSOs render overdoses challenging to reverse. The multidisciplinary Reversing Synthetic Opioid Overdose (RESPIRE) Expert Forum discussed challenges and solution pathways for HPSO overdose reversal. The RESPIRE Expert Forum convened on July 9, 2024, where insights from eight multidisciplinary experts were gathered and summarized. The experts unanimously agreed that the goal of overdose reversal is to rapidly restore breathing to avoid irreversible neurological injury and that saving a life outweighs the risk of precipitated withdrawal. HPSOs exhibit increased potency and lipophilicity, resulting in rapid onset and risk of re-narcotization, requiring reversal strategies/agents addressing these properties. Intranasal (IN) naloxone (3 mg, 4 mg) is accessible over the counter. Prescription IN nalmefene possesses high potency at the µ-opioid receptor, fast onset, and long duration of action. These properties help reverse HPSO overdose in general and may be particularly advantageous in opioid-naïve victims in whom rapid onset and prolonged duration are required while precipitated withdrawal is of lesser concern. Rapid onset may be advantageous in settings where emergency response times may be delayed and the potential for permanent injury or death is precipitated. Prolonged duration of action may be advantageous when hospital transit times are long or when resource constrained medical settings prevent observation for re-narcotization. Both medications are available to first responders and bystanders. Saving a life is the highest priority in overdose reversal. Fast onset of action is a key differentiator of any reversal agent in the context of HPSO. IN nalmefene may provide beneficial outcomes in certain overdose victims, locales, and care settings. Bystander education and easy access to IN reversal agents are critical to combat community HPSO overdoses.