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

PLoS One. 2020 Jun 16;15(6):e0234683. doi: 10.1371/journal.pone.0234683. eCollection 2020.


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.

MeSH terms

  • Analgesics, Opioid / metabolism
  • Binding, Competitive*
  • Computer Simulation
  • Dose-Response Relationship, Drug
  • Drug Overdose / drug therapy
  • Fentanyl / metabolism*
  • Fentanyl / toxicity
  • Humans
  • Models, Theoretical*
  • Naloxone / administration & dosage*
  • Naloxone / therapeutic use
  • Narcotic Antagonists / administration & dosage
  • Receptors, Opioid, mu / metabolism*
  • Treatment Outcome


  • Analgesics, Opioid
  • Narcotic Antagonists
  • Receptors, Opioid, mu
  • Naloxone
  • Fentanyl

Grant support

This study was funded by Adamis Pharmaceuticals. RBM and DJC are employees of Adamis Pharmaceuticals and have equity in the company. MMP, RB, KK,CF, and MR are employees of Rosa & Co and have equity in the company. The funder provided support in the form of salaries for authors RBM and DJC, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.