Dataset Information

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

ABSTRACT: Nasal spray formulations of naloxone, a mu-opioid receptor (MOR) antagonist, are currently used for the treatment of opioid overdose. They may have additional therapeutic utility also in the absence of opioid agonist drugs, but the onset and duration of action at brain MORs have been inadequately characterized to allow such projections. This study provides initial characterization of brain MOR availability at high temporal resolution following intranasal (IN) naloxone administration to healthy volunteers in the absence of a competing opioid agonist. Fourteen participants were scanned twice using positron emission tomography (PET) and [¹¹C]carfentanil, a selective MOR agonist radioligand. Concentrations of naloxone in plasma and MOR availability (relative to placebo) were monitored from 0 to 60?min and at 300-360?min post naloxone. Naloxone plasma concentrations peaked at ~20?min post naloxone, associated with slightly delayed development of brain MOR occupancy (half of peak occupancy reached at ~10?min). Estimated peak occupancies were 67 and 85% following 2 and 4?mg IN doses, respectively. The estimated half-life of occupancy disappearance was ~100?min. The rapid onset of brain MOR occupancy by IN naloxone, evidenced by the rapid onset of its action in opioid overdose victims, was directly documented in humans for the first time. The employed high temporal-resolution PET method establishes a model that can be used to predict brain MOR occupancy from plasma naloxone concentrations. IN naloxone may have therapeutic utility in various addictions where brain opioid receptors are implicated, such as gambling disorder and alcohol use disorder.

SUBMITTER: Johansson J

PROVIDER: S-EPMC6785104 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Johansson Jarkko J Hirvonen Jussi J Lovró Zsófia Z Ekblad Laura L Kaasinen Valtteri V Rajasilta Olli O Helin Semi S Tuisku Jouni J Sirén Saija S Pennanen Mirka M Agrawal Arvind A Crystal Roger R Vainio Petri J PJ Alho Hannu H Scheinin Mika M

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20190313 9

Nasal spray formulations of naloxone, a mu-opioid receptor (MOR) antagonist, are currently used for the treatment of opioid overdose. They may have additional therapeutic utility also in the absence of opioid agonist drugs, but the onset and duration of action at brain MORs have been inadequately characterized to allow such projections. This study provides initial characterization of brain MOR availability at high temporal resolution following intranasal (IN) naloxone administration to healthy v ...[more]

PMID: 30867551

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Project description:ImportancePrevious unblinded clinical trials suggested that the intranasal route of naloxone hydrochloride was inferior to the widely used intramuscular route for the reversal of opioid overdose.ObjectiveTo test whether a dose of naloxone administered intranasally is as effective as the same dose of intramuscularly administered naloxone in reversing opioid overdose.Design, setting, and participantsA double-blind, double-dummy randomized clinical trial was conducted at the Uniting Medically Supervised Injecting Centre in Sydney, Australia. Clients of the center were recruited to participate from February 1, 2012, to January 3, 2017. Eligible clients were aged 18 years or older with a history of injecting drug use (n = 197). Intention-to-treat analysis was performed for all participants who received both intranasal and intramuscular modes of treatment (active or placebo).InterventionsClients were randomized to receive 1 of 2 treatments: (1) intranasal administration of naloxone hydrochloride 800 μg per 1 mL and intramuscular administration of placebo 1 mL or (2) intramuscular administration of naloxone hydrochloride 800 μg per 1 mL and intranasal administration of placebo 1 mL.Main outcomes and measuresThe primary outcome measure was the need for a rescue dose of intramuscular naloxone hydrochloride (800 μg) 10 minutes after the initial treatment. Secondary outcome measures included time to adequate respiratory rate greater than or equal to 10 breaths per minute and time to Glasgow Coma Scale score greater than or equal to 13.ResultsA total of 197 clients (173 [87.8%] male; mean [SD] age, 34.0 [7.82] years) completed the trial, of whom 93 (47.2%) were randomized to intramuscular naloxone dose and 104 (52.8%) to intranasal naloxone dose. Clients randomized to intramuscular naloxone administration were less likely to require a rescue dose of naloxone compared with clients randomized to intranasal naloxone administration (8 [8.6%] vs 24 [23.1%]; odds ratio, 0.35; 95% CI, 0.15-0.66; P = .002). A 65% increase in hazard (hazard ratio, 1.65; 95% CI, 1.21-2.25; P = .002) for time to respiratory rate of at least 10 and an 81% increase in hazard (hazard ratio, 1.81; 95% CI, 1.28-2.56; P = .001) for time to Glasgow Coma Scale score of at least 13 were observed for the group receiving intranasal naloxone compared with the group receiving intramuscular naloxone. No major adverse events were reported for either group.Conclusions and relevanceThis trial showed that intranasally administered naloxone in a supervised injecting facility can reverse opioid overdose but not as efficiently as intramuscularly administered naloxone can, findings that largely replicate those of previous unblinded clinical trials. These results suggest that determining the optimal dose and concentration of intranasal naloxone to respond to opioid overdose in real-world conditions is an international priority.Trial registrationanzctr.org.au Identifier: ACTRN12611000852954.

Dataset Information

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

Publications

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

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