Abstract
Previous 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. To test whether a dose of naloxone administered intranasally is as effective as the same dose of intramuscularly administered naloxone in reversing opioid overdose. A 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). Clients 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. The 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. A 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. This 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. anzctr.org.au Identifier: ACTRN12611000852954.
Highlights
Naloxone hydrochloride is a highly effective opioid antagonist that has been used in medical practice to reverse the effects of opioid use for more than 40 years.[1]
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)
An 81% increase in hazard for time to respiratory rate of at least 10 and a 65% increase in hazard 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
Summary
Naloxone hydrochloride is a highly effective opioid antagonist that has been used in medical practice to reverse the effects of opioid use for more than 40 years.[1]. The intranasal route for naloxone administration holds promise, with naloxone absorption possible through the nasal mucosa.[9] Published pharmacokinetic data initially suggested that the intranasal route was inefficient compared with the widely used intramuscular route,[10] but recent work with more concentrated forms suggests the intranasal route has slower onset of action but adequate bioavailability after 5 to 20 minutes with a range of naloxone doses.[11,12,13,14,15] These findings are consistent with the results of 2 trials of overdose reversal conducted with paramedics in the out-ofhospital setting,[3,5] with slightly slower overdose reversal times and an increased need for intramuscular rescue doses observed in the intranasal groups in both trials Both studies compared 2 mg of naloxone hydrochloride, but 1 trial used a more concentrated preparation (2 mg per 5 mL3 solution vs 2 mg per 1 mL5 solution); roughly comparable results were found despite the likely waste of dose with the weaker concentration. Neither of these trials allowed for blinding of the paramedics, which may have introduced treatment bias that, in turn, may explain the difference in the treatment effects,[16] including increased propensity to use rescue doses in the intranasal groups.[5]
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