Higher naloxone dosing in a quantitative systems pharmacology model that predicts naloxone-fentanyl competition at the opioid mu receptor level
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.
| Errataetall: |
ErratumIn: PLoS One. 2020 Sep 29;15(9):e0240148. - PMID 32991627 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
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| Enthalten in: |
PloS one - 15(2020), 6 vom: 09., Seite e0234683 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Moss, Ronald B [VerfasserIn] |
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| Links: |
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| Themen: |
36B82AMQ7N |
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| Anmerkungen: |
Date Completed 28.08.2020 Date Revised 28.08.2020 published: Electronic-eCollection ErratumIn: PLoS One. 2020 Sep 29;15(9):e0240148. - PMID 32991627 Citation Status MEDLINE |
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| doi: |
10.1371/journal.pone.0234683 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Analgesics, Opioid |2 NLM | |
| 650 | 7 | |a Narcotic Antagonists |2 NLM | |
| 650 | 7 | |a Receptors, Opioid, mu |2 NLM | |
| 650 | 7 | |a Naloxone |2 NLM | |
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| 650 | 7 | |a Fentanyl |2 NLM | |
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| 700 | 1 | |a Friedrich, Christina |e verfasserin |4 aut | |
| 700 | 1 | |a Reed, Mike |e verfasserin |4 aut | |
| 700 | 1 | |a Carlo, Dennis J |e verfasserin |4 aut | |
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