Higher naloxone dosing in a quantitative systems pharmacology model that predicts naloxone-fentanyl competition at the opioid mu receptor level

Abstract

Rapid resuscitation of an opioid overdose with naloxone, an opioid antagonist, is critical. We developed an opioid receptor quantitative systems pharmacology (QSP) model for evaluation of naloxone dosing. In this model we examined three opioid exposure levels that have been reported in the literature (25 ng/ml, 50 ng/ml, and 75 ng/ml of fentanyl). The model predicted naloxone-fentanyl interaction at the mu opioid receptor over a range of three naloxone doses. For a 2 mg intramuscular (IM) dose of naloxone at lower fentanyl exposure levels (25 ng/ml and 50 ng/ml), the time to decreasing mu receptor occupancy by fentanyl to 50% was 3 and 10 minutes, respectively. However, at a higher fentanyl exposure level (75 ng/ml), a dose of 2 mg IM of the naloxone failed to reduce mu receptor occupancy by fentanyl to 50%. In contrast, naloxone doses of 5 mg and 10 mg IM reduced mu receptor occupancy by fentanyl to 50% in 5.5 and 4 minutes respectively. These results suggest that the current doses of naloxone (2 mg IM or 4 mg intranasal (IN)) may be inadequate for rapid reversal of toxicity due to fentanyl exposure and that increasing the dose of naloxone is likely to improve outcomes.

Clinical Pharmacology, Toxicity, and Abuse Potential of Opioids

“…Opioids mediate most of their desired and adverse effects through binding and activation of opioid receptors, and toxicity may therefore be reversed with an opioid receptor antagonist, most commonly naloxone 169 . Naloxone is a competitive antagonist at all opioid receptors, with the highest affinity at the μ‐opioid receptor, which reverses respiratory depression 82 .…”

Overdoses due to fentanyl and its analogues (F/FAs) push naloxone to the limit

“…At 75 ng/ mL fentanyl, 2 mg IM naloxone failed to reduce fentanyl occupancy at MOR by 50% (Figure 1). 15 This suggests that in some cases of high-dose F/FA use, naloxone may not be adequate to compete, and that simply increasing the naloxone dose may not improve results. 15 In an animal model, fentanyl produced apnoea within 14 s, followed by a low tidal volume with slow frequency.…”

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

“…Prior to IMF, naloxone was reported to be almost 100% effective in reversing respiratory depression 33 . However, as the opioid crisis has progressed, reports of a need for increasing doses and repeated doses have emerged.…”