Higher doses of naloxone are needed in the synthetic opioid era

Moss, Ronald B.; Carlo, Dennis J.

doi:10.1186/s13011-019-0195-4

Cited by 117 publications

(120 citation statements)

References 28 publications

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“…associated with underdosing of naloxone is an unsuccessful reversal of opioid toxicity leading to death, which outweighs the risk of opioid withdrawal [33]. This model supports the notion that higher doses of naloxone are required as a countermeasure to the new synthetic opioid epidemic [34]. Table. (TIF)…”

Section: Plos Onesupporting

confidence: 59%

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

et al. 2020

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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.

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Section: Plos Onesupporting

confidence: 59%

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

et al. 2020

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“…Currently, in spite of community awareness and increased access to naloxone, deaths from synthetic opioids have reached record highs and do not seem to be slowing (Baumann et al, 2018;Skolnick, 2018). This fact is coupled with increasing reports of unsuccessful resuscitation attempts with naloxone following F/FA exposure, or successful resuscitation attempts only via multiple and escalating doses (Schumann et al, 2008;Fairbairn et al, 2017;Baumann et al, 2018;Moss and Carlo, 2019). These reports are further confounded by the fact that F/FAs are being combined with multiple illicit drugs (e.g., heroin, fentanyl, carfentanil, and Xanax) of unknown quantity, quality, synthesis, and combination, and the fact that these illicit drugs are not easily assayed.…”

Section: Naloxonementioning

confidence: 99%

Noradrenergic Mechanisms in Fentanyl-Mediated Rapid Death Explain Failure of Naloxone in the Opioid Crisis

Torralva

Janowsky

2019

J Pharmacol Exp Ther

116

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In December 2018, the Centers for Disease Control declared fentanyl the deadliest drug in America. Opioid overdose is the single greatest cause of death in the United States adult population (ages 18-50), and fentanyl and its analogs [fentanyl/ fentanyl analogs (F/FAs)] are currently involved in .50% of these deaths. Anesthesiologists in the United States were introduced to fentanyl in the early 1970s when it revolutionized surgical anesthesia by combining profound analgesia with hemodynamic stability. However, they quickly had to master its unique side effect. F/FAs can produce profound rigidity in the diaphragm, chest wall and upper airway within an extremely narrow dosing range. This clinical effect was called wooden chest syndrome (WCS) by anesthesiologists and is not commonly known outside of anesthesiology or to clinicians or researchers in addiction research/medicine. WCS is almost routinely fatal without expert airway management. This review provides relevant clinical human pharmacology and animal data demonstrating that the significant increase in the number of F/FA-induced deaths may involve a-adrenergic and cholinergic receptor-mediated mechanical failure of the respiratory and cardiovascular systems with rapid development of rigidity and airway closure. Although morphine and its prodrug, heroin, can cause mild rigidity in abdominal muscles at high doses, neither presents with the distinct and rapid respiratory failure seen with F/FA-induced WCS, separating F/FA overdose from the slower onset of respiratory depression caused by morphine-derived alkaloids. This distinction has significant consequences for the design and implementation of new pharmacologic strategies to effectively prevent F/FA-induced death. SIGNIFICANCE STATEMENT Deaths from fentanyl and F/FAs are increasing in spite of availability and awareness of the opioid reversal drug naloxone. This article reviews literature suggesting that naloxone may be ineffective against centrally mediated noradrenergic and cholinergic effects of F/FAs, which clinically manifest as severe muscle rigidity and airway compromise (e.g., wooden chest syndrome) that is rapid and distinct from respiratory depression seen with morphine-derived alkaloids. A physiologic model is proposed and implications for new drug development and treatment are discussed.

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“…Lastly, we observed a significant correlation between percent RO and plasma NLX plasma levels and, taken together, these results support the notion that higher doses of IM NLX result in higher mu RO. Given that higher doses of naloxone could be needed to treat overdoses due to more potent synthetic opioids such as fentanyl and carfentanil [8,9], development of higher dose forms of naloxone is warranted in light of the findings in this study.…”

Section: Discussionmentioning

confidence: 99%

“…Naloxone (NLX) is the first line of treatment and an effective countermeasure in the event of an opioid overdose because, as a mu receptor antagonist, it is capable of rapid reversal of opioid toxicity [3]. Currently approved doses of NLX include 4 mg intranasal (IN) and 2 mg intramuscular (IM) [4] but, to date, there have been numerous reports suggesting that multiple doses of NLX may be required for successful reversal of opioid toxicity, especially when treating overdoses due to more potent synthetic opioids such as fentanyl and carfentanil that have entered the illicit drug market recently [5][6][7][8][9]. To address this issue, we previously reported that a higher dose of intramuscular naloxone (5 mg ZIMHI) has greater systemic exposure compared to the current community dose of naloxone (2 mg intramuscular and 4 mg intranasal) [10].…”

Section: Introductionmentioning

confidence: 99%

The Effects of Intramuscular Naloxone Dose on Mu Receptor Displacement of Carfentanil in Rhesus Monkeys

et al. 2020

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Naloxone (NLX) is a mu receptor antagonist used to treat acute opioid overdoses. Currently approved doses of naloxone to treat opioid overdoses are 4 mg intranasal (IN) and 2 mg intramuscular (IM). However, higher mu receptor occupancy (RO) may be required to treat overdoses due to more potent synthetic opioids such as fentanyl and carfentanil that have entered the illicit drug market recently. To address this need, a higher dose of NLX has been investigated in a 5 mg IM formulation called ZIMHI but, while the effects of intravenous (IV) and IN administration of NLX on the opioid mu receptor occupancy (RO) have been studied, comparatively little is known about RO for IM administration of NLX. The goal of this study was to examine the effect of IM dosing of NLX on mu RO in rhesus macaques using [11C]carfentanil positron emission tomography (PET) imaging. The lowest dose of NLX (0.06 mg/kg) approximated 51% RO. Higher doses of NLX (0.14 mg/kg, 0.28 mg/kg) resulted in higher mu RO of 70% and 75%, respectively. Plasma levels were 4.6 ng/mL, 16.8 ng/mL, and 43.4 ng/mL for the three IM doses, and a significant correlation between percent RO and plasma NLX level was observed (r = 0.80). These results suggest that higher doses of IM NLX result in higher mu RO and could be useful in combating overdoses resulting from potent synthetic opioids.

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Higher doses of naloxone are needed in the synthetic opioid era

Cited by 117 publications

References 28 publications

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

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

Noradrenergic Mechanisms in Fentanyl-Mediated Rapid Death Explain Failure of Naloxone in the Opioid Crisis

The Effects of Intramuscular Naloxone Dose on Mu Receptor Displacement of Carfentanil in Rhesus Monkeys

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