Abstract
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.
Highlights
Mortality from drug overdoses has reached epidemic proportions in the U.S (>70,000 in 2017), exceeding the number of yearly deaths during the peak of the AIDS epidemic [1]
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]
Using [11 C]carfentanil ([11 C]CFN, [13]), we employed preclinical positron emission tomography (PET) imaging to investigate receptor occupancy (RO) of NLX administered by IM injection at three different doses in two mature rhesus monkeys, and we compared our imaging findings with the plasma levels of NLX in the monkeys determined by quantitative LC-MS/MS
Summary
Mortality from drug overdoses has reached epidemic proportions in the U.S (>70,000 in 2017), exceeding the number of yearly deaths during the peak of the AIDS epidemic [1]. 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. Molecules 2020, 25, 1360 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]. Using [11 C]carfentanil ([11 C]CFN, [13]), we employed preclinical positron emission tomography (PET) imaging to investigate RO of NLX administered by IM injection at three different doses in two mature rhesus monkeys, and we compared our imaging findings with the plasma levels of NLX in the monkeys determined by quantitative LC-MS/MS
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