Comparison of inhalational methoxyflurane, intranasal fentanyl, and intravenous morphine for treatment of prehospital acute pain in Norway (PreMeFen): a randomised, non-inferiority, three-arm, phase 3 trial
Authors' conclusion
Inhalational methoxyflurane is non-inferior to intranasal fentanyl and intravenous morphine for acute pain management in the prehospital environment, assessed 10 min after administration.
Study context
- Population
- Patients aged 18–69 years and 70 years and older with traumatic or medical acute pain Numeric Rating Scale (NRS) 4 or higher, ground ambulance service, Innlandet Hospital Trust, Norway281 per-protocol
- Participants
- 338 patients
- Comparison
- Inhalational methoxyflurane vs intranasal fentanyl vs IV morphine
- Methoxyfluranen = 112
- Fentanyln = 115reference
- Morphinen = 111reference
- Primary endpoint
- Change in pain NRS score from baseline (per protocol; non-inferiority margin 1.3)
- Follow-up
- 10 min after treatment start
Methodological detailsopen-label, non-inferiority, three-arm, phase 3
- Open-label
- Non-inferiority
- Three-arm
- Phase 3
Primary result
As reported in the abstract
Change in NRS score · 10 min
Methoxyflurane
−3.31
mean · SD 2.67
Fentanyl
−1.98
mean · SD 2.28
Morphine
−2.74
mean · SD 2.12
Difference (95% CI)
Methoxyflurane vs Fentanylnon-inferior; adjusted for baseline
−1.33(−2.01 to −0.64)
Methoxyflurane vs Morphinenon-inferior; adjusted for baseline
−0.36(−1.03 to 0.31)
Fentanyl vs Morphinenot non-inferior; adjusted for baseline
0.91(0.27–1.55)
Non-inferiority margin 1.3 as printed, not drawn
Safety
Adverse events
- Adverse events: of 109 morphine, 112 fentanyl, 111 methoxyflurane
Serious adverse events
- Treatment-related deaths
- 0
- Two serious AEs (respiratory depression grade 2, loss of consciousness grade 3) in the same methoxyflurane patient
Original publication
Comparison of inhalational methoxyflurane, intranasal fentanyl, and intravenous morphine for treatment of prehospital acute pain in Norway (PreMeFen): a randomised, non-inferiority, three-arm, phase 3 trial. Lancet. Published 20 November 2025. doi:10.
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