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

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.

Molecular Mechanisms of Action of Novel Psychoactive Substances (NPS). A New Threat for Young Drug Users with Forensic-Toxicological Implications

“…Contrarily to morphine, which has antagonistic interactions with 5HT 3A receptors [ 32 ], interaction of fentanyl with 5HT 1A and 2A receptors might lead to additional toxicity due to serotonin syndrome, especially in combination with other drugs active on the serotonin system [ 33 ]. This might explain why rescue therapy with naloxone (receptor antagonist) are noneffective, or less effective than what expected [ 34 , 35 , 36 ].…”

The Novel Tetra-Specific Drug C-192, Conjugated Using UniStac, Alleviates Non-Alcoholic Steatohepatitis in an MCD Diet-Induced Mouse Model

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Fact vs. fiction: naloxone in the treatment of opioid-induced respiratory depression in the current era of synthetic opioids

“…The implications of these differences for treating OIRDs have been investigated in preclinical studies and systems pharmacology modeling of the relationship between plasma naloxone levels and μ-opioid receptor occupancy. One study in rhesus monkeys found a direct correlation between the plasma levels achieved with higher doses of IM naloxone and the degree of μ-opioid receptor blockade observed in the basal ganglia and thalamus with an 0.06-mg/kg naloxone IM dose producing a mean 56% occupancy by naloxone of the μ-opioid receptors in the basal ganglia and 47% in the thalamus ( 54 ). Doses of 0.14 and 0.28 mg/kg increased the percentage of occupied receptors to 74 and 75% in the basal ganglia and 65 and 74% in the thalamus, respectively.…”