Fentanyl can result in rapid respiratory failure with resulting brain hypoxia and ultimately death. Rapid naloxone systemic treatment, resulting in decreased fentanyl binding to the mu receptors, is critical for a successful reversal and resuscitation.
The idea that higher concentrations of fentanyl exposure may require higher doses of naloxone treatment is supported by data from the field suggesting that multiple administrations of naloxone are required for overdose resuscitations. In one report, the use of multiple administrations of naloxone increased 98% during a 29 week period that included COVID-19 pandemic, compared to the previous period reported by EMS providers (12).
This report, and others (13), support the notion that acutely administered higher doses of naloxone are needed for rapid and adequate clinical reversal, particularly when higher systemic exposure of the potent synthetic opioids occur.
Using an opioid receptor QSP model, we predicted naloxone-fentanyl interaction at the mu-opioid receptor over a range of four naloxone doses. We examined four levels of fentanyl exposure in the plasma found in overdose patients. The high receptor mu occupancy of fentanyl at the doses observed in this model, without naloxone administration, is consistent with reports of the potency of this synthetic opioid and its relation to a recent spike in overdoses and deaths.
The results of model simulations suggest that at higher exposure levels of fentanyl, capable of resulting in respiratory depression and death (75 ng/ml), the currently approved lower doses of naloxone (2 mg IM and 4 mg IN) may be inadequate for a rapid, successful reversal. Most importantly, at the highest exposure levels of fentanyl (100 ng/ml) examined in this simulation, the highest IN dose available (8 mg IN and 4 mg IM) may be inadequate for successful resuscitation. In these simulations, a drop to 50% occupancy at the highest fentanyl exposure was not achieved within 15 minutes with the highest IN dose (8 mg IN 4 mg IM).
The model includes some assumptions but is consistent with other studies suggesting that the mu receptor occupancy by fentanyl increases with an increase in systemic fentanyl exposure (3) and that naloxone receptor occupancy increases as the naloxone dose increases (3).
The model demonstrates that these observations are consistent with a receptor competition mechanism and helps quantify the additional benefit of the higher 5 mg and 10 mg IM doses. These analyses support the idea that higher doses of naloxone (5 mg IM and 10 mg IM), as examined in this model, are superior in many overdose situations when compared to the current naloxone doses (2 mg IM or 4 mg IN, 4 mg IM or 8 mg IN).