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. 2020 Mar 17;25(6):1360.
doi: 10.3390/molecules25061360.

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

Peter J H Scott  1 , Robert A Koeppe  1 , Xia Shao  1 , Melissa E Rodnick  1 , Alexandra R Sowa  1 , Bradford D Henderson  1 , Jenelle Stauff  1 , Phillip S Sherman  1 , Janna Arteaga  1 , Dennis J Carlo  2 , Ronald B Moss  2
Affiliations

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

Peter J H Scott et al. Molecules. .

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.

Keywords: [11C]carfentanil; carfentanil; fentanyl; naloxone; opioid; overdose; pharmacokinetics; positron emission tomography; receptor occupancy.

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Conflict of interest statement

D.J.C. and R.B.M. are employees of Adamis Pharmaceuticals who funded this study and provided naloxone.

Figures

Figure 1
Figure 1
Representative transverse (top row), sagittal (middle row), and coronal (bottom row) monkey positron emission tomography (PET) images of a [11C]CFN baseline scan and following blocking studies with low (0.06 mg/kg), medium (0.14 mg/kg), and high (0.28 mg/kg) doses of naloxone (NLX). Images are distribution volume ratio (DVR) images summed 0–60 min following intravenous (IV) injection of the radiotracer. BG = basal ganglia, THAL = thalamus, CTX = cortex.
Figure 2
Figure 2
Mean % RO by intramuscular (IM) Dose.
Figure 3
Figure 3
Plasma NLX levels 30 min after three different IM doses.
Figure 4
Figure 4
The relationship (r = 0.80) between NLX plasma level and RO in the basal ganglia and thalamus.
See this image and copyright information in PMC

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