Intranasal naloxone rapidly occupies brain mu-opioid receptors in human subjects

Johansson, Jarkko; Hirvonen, Jussi; Lovró, Zsófia; Ekblad, Laura L.; Kaasinen, Valtteri; Rajasilta, Olli; Helin, Semi; Tuisku, Jouni; Sirén, Saija; Pennanen, Mirka; Agrawal, Ajai; Crystal, Roger; Vainio, Paula; Alho, Hannu; Scheinin, Mika

doi:10.1038/s41386-019-0368-x

Cited by 35 publications

(43 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As noted in Fig 2, model simulations predicted that a fentanyl overdose exposure level of 25 ng/ml leads to 73% mu receptor occupancy by fentanyl without competition from naloxone. Administration of naloxone leads to rapid reduction in mu receptor occupancy by fentanyl due to competition by naloxone, as would be expected based on naloxone's fast appearance in brain [20,28], and the rapid dissociation rates of fentanyl and naloxone [29]. After administering a 2 mg IM of naloxone, mu receptor occupancy by fentanyl was predicted to decrease to 33% within ten minutes of naloxone being administered.…”

Section: Resultsmentioning

confidence: 88%

“…Because of non-specific binding, concentrations in the brain of fentanyl available for binding to mu receptor are difficult to measure experimentally. Published data for the relationship between naloxone dose and mu receptor occupancy [20], and between fentanyl dose, receptor occupancy, and pain relief [21][22][23] were used to infer brain exposures. For example, a fentanyl plasma level of 5 ng/ml is associated with pain relief [24], and pain relief is evident at mu receptor occupancy above 10% [25].…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2020

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 88%

Section: Methodsmentioning

confidence: 99%

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

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Furthermore, the 2 mg IV dose was associated with a C max plasma level of 38.7 ng/mL. A recent study in humans suggested that 1 mg and 2 mg IV NLX resulted in a mean RO of 54-82% and 71-96%, respectively [18]. The 1 mg and 2 mg IN doses of NLX in that study were associated with C max pharmacokinetic levels of 1.83 ng/mL and 4.33 ng/mL, respectively.…”

Section: Discussionmentioning

confidence: 94%

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

et al. 2020

View full text Add to dashboard Cite

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.

show abstract

“…Absent a clear stoichiometric relationship between occupancy of μ-opioid receptors and plasma concentrations of either naltrexone or its principal metabolite, 6β-naltrexol, 39 additional studies will be required to determine how the shorter plasma half-life of naltrexone observed after intranasal administration affects μ-opioid receptor occupancy in the central nervous system, which is a critical factor contributing to the duration of action of a rescue agent. 16,42 Rabiner et al 39 have hypothesized that the metabolite 6β-naltrexol, a long residence time of both naltrexone and 6β-naltrexol on μ-opioid receptors, and the trapping of these compounds in brain parenchyma could contribute to the anomalously long occupancy of μ-opioid receptors following oral naltrexone. Despite a high affinity at μ-opioid receptors 39 and long plasma half-life following intranasal administration (Table 4), it is unlikely that 6β-naltrexol significantly contributes to the pharmacological effects of naltrexone in the central nervous system.…”

Section: Discussionmentioning

confidence: 99%

“…Imaging studies using [ 11 C]carfentanil have demonstrated that oral naltrexone (50 mg) results in brain μ‐opioid receptor occupancy that is significantly longer (eg, ∼60% occupancy 23‐33 hours postdosing) than would be predicted from its plasma half‐life . By contrast, imaging studies in normal volunteers have demonstrated that occupation of μ‐opioid receptors following either intravenous or intranasal naloxone (t 1/2 , ∼2 hours) mirrors its plasma half‐life. Absent a clear stoichiometric relationship between occupancy of μ‐opioid receptors and plasma concentrations of either naltrexone or its principal metabolite, 6β‐naltrexol, additional studies will be required to determine how the shorter plasma half‐life of naltrexone observed after intranasal administration affects μ‐opioid receptor occupancy in the central nervous system, which is a critical factor contributing to the duration of action of a rescue agent .…”

Section: Discussionmentioning

confidence: 99%

Enhanced Intranasal Absorption of Naltrexone by Dodecyl Maltopyranoside: Implications for the Treatment of Opioid Overdose

Krieter

Gyaw

Chiang

et al. 2019

The Journal of Clinical Pharma

Self Cite

View full text Add to dashboard Cite

Based on its high affinity for μ opiate receptors and reported half‐life after oral administration, the pharmacokinetic properties of intranasal naltrexone were examined to evaluate its potential to treat opioid overdose. This study was prompted by the marked rise in overdose deaths linked to synthetic opioids like fentanyl, which may require more potent, longer‐lived opiate antagonists than naloxone. Both the maximum plasma concentration (C max ) and the time (T max ) to reach C max for intranasal naltrexone (4 mg) were comparable to values reported for a Food and Drug Administration‐approved 4‐mg dose of intranasal naloxone. The addition of the absorption enhancer dodecyl maltoside (Intravail) increased C max by ∼3‐fold and reduced the T max from 0.5 to 0.17 hours. Despite these very rapid increases in plasma concentrations of naltrexone, its short half‐life following intranasal administration (∼2.2 hours) could limit its usefulness as a rescue medication, particularly against longer‐lived synthetic opioids. Nonetheless, the ability to rapidly attain high plasma concentrations of naltrexone may be useful in other indications, including an as‐needed dosing strategy to treat alcohol use disorder.

show abstract

Intranasal naloxone rapidly occupies brain mu-opioid receptors in human subjects

Cited by 35 publications

References 36 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

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

Enhanced Intranasal Absorption of Naltrexone by Dodecyl Maltopyranoside: Implications for the Treatment of Opioid Overdose

Contact Info

Product

Resources

About