Aims: To measure and evaluate clinical response to nasal naloxone in opioid overdoses in the pre-hospital environment.

Design: Randomised, controlled, double-dummy, blinded, non-inferiority trial, and conducted at two centres. Participants were included by ambulance staff in Oslo and Trondheim, Norway, and treated at the place where the overdose occurred. Participants were men and women age above 18 years with miosis, rate of respiration ≤8/min, and Glasgow Coma Score <12/15 were included. Informed consent was obtained through a deferred-consent procedure.

Intervention and comparator: A commercially available 1.4 mg/0.1 mL intranasal naloxone was compared with 0.8 mg/2 mL naloxone administered intramuscularly. 

Measurements: The primary end-point was restoration of spontaneous respiration of ≥10 breaths/min within 10 minutes. Secondary outcomes included time to restoration of spontaneous respiration, recurrence of overdose within 12 hours and adverse events.

Findings: In total, 201 participants were analysed in the per-protocol population. Heroin was suspected in 196 cases. With 82% of the participants being men, 105 (97.2%) in the intramuscular group and 74 (79.6%) in the intranasal group returned to adequate spontaneous respiration within 10 minutes after one dose. The estimated risk difference was 17.5% in favour of the intramuscular group. The risk of receiving additional naloxone was 19.4% higher in the intranasal group. Adverse reactions were evenly distributed, except for drug withdrawal reactions, where the estimated risk difference was 6.8% in favour of the intranasal group in a post hoc analysis.

Conclusion: Intranasal naloxone (1.4 mg/0.1 mL) was less efficient than 0.8 mg intramuscular naloxone for return to spontaneous breathing within 10 minutes in overdose patients in the pre-hospital environment when compared head-to-head. Intranasal naloxone at 1.4 mg/0.1 mL restored breathing in 80% of participants after one dose and had few mild adverse reactions.