A Scoping Review of Inhaled Methoxyflurane for Acute Traumatic Pain

Michael T Le; Joshua J Oliver; Julie A Rizzo; Michael S Patzkowski

doi:10.1093/milmed/usag446

A Scoping Review of Inhaled Methoxyflurane for Acute Traumatic Pain | ResearchHub

Abstract Introduction Acute pain after trauma remains a major challenge in emergency department, prehospital, and operational medicine settings. Methoxyflurane, an inhaled anesthetic first developed in the 1960s but later withdrawn due to dose-related nephrotoxicity, has been repurposed internationally at substantially lower sub-anesthetic doses as an analgesic delivered via a compact, hand-held inhaler. This review aims to characterize the available evidence regarding its efficacy, safety, and operational applications for adoption in U.S. civilian and military trauma systems. Materials and Methods A scoping review was conducted using the PRISMA-ScR checklist. PubMed and Google Scholar were used to identify relevant literature from 1960 to 2025. Studies were eligible if they reported on the use of methoxyflurane for acute traumatic pain. Our initial search yielded 31 potential studies, of which 22 met inclusion for this review. Of those, there were 5 systematic reviews, 13 randomized controlled trials, 2 prospective observational studies, and 2 retrospective observational studies. There were 2 articles that focused on the pediatric population. Two trials are currently ongoing, 1 a systematic review comparing speed to onset of pain relief of methoxyflurane vs. the usual care and another study analyzing use and effectiveness in prehospital helicopter transport. Results Across studies, methoxyflurane consistently demonstrated clinically meaningful rapid analgesia onset and greater efficacy than placebo and other standard selected analgesic strategies, particularly within the first 10-20 minutes. Available short-term safety data at contemporary analgesic dosages were reassuring, with few adverse events, primarily mild and transient side effects. Studies also confirmed effective patient self-administration of methoxyflurane with minimal occupational exposure risk. Conclusion Current evidence suggests that methoxyflurane is an effective, well-tolerated, and rapid-acting analgesic for acute trauma. Current evidence supports short-term, episodic use within approved dosing limits, with favorable safety data in both adult and pediatric populations. The favorable safety profile, ease of self-administration, and non-opioid mechanism make it a potentially valuable therapy in emergency and prehospital settings. Future studies should assess usability, safety, and efficacy of methoxyflurane to define its operational use in the prehospital deployed combat setting.

External reference records

Hot off the press: the RAMPED trial—methoxyflurane for analgesia in the emergency department

10.1111/acem.14257 · 2021

Inhaled methoxyflurane provides greater analgesia and faster onset of action versus standard analgesia in patients with trauma pain: InMEDIATE: a randomized controlled trial in emergency departments

10.1016/j.annemergmed.2019.07.028 · 2020

STOP!: a randomised, double-blind, placebo-controlled study of the efficacy and safety of methoxyflurane for the treatment of acute pain

10.1136/emermed-2013-202909 · 2014

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

10.1016/s0140-6736(25)01575-2 · 2026

Prospective, multicentre trial of methoxyflurane for acute trauma-related pain in helicopter emergency medical systems and hostile environments: METEORA protocol

10.1007/s12325-018-0816-8 · 2018

Inhaled methoxyflurane versus intravenous morphine for severe trauma pain in the emergency setting: subgroup analysis of MEDITA, a multicenter, randomized, controlled, open-label trial

10.2147/jpr.s240911 · 2020

Evaluation of the effectiveness and costs of inhaled methoxyflurane versus usual analgesia for prehospital injury and trauma: non-randomised clinical study

10.1186/s12873-022-00664-y · 2022

The role of inhaled methoxyflurane in acute pain management

10.2147/oaem.s181222 · 2018

Effectiveness of inhaled methoxyflurane in acute pain in an emergency department – a systematic review of randomized controlled trials

10.1016/j.ajem.2025.04.021 · 2025

Inhaled methoxyflurane (Penthrox®) versus placebo for injury-associated analgesia in children—the MAGPIE trial (MEOF-002): study protocol for a randomised controlled trial

10.1186/s13063-019-3511-4 · 2019

The safety of methoxyflurane for emergency pain relief in children and adolescents: a retrospective cohort study

10.1080/10903127.2024.2397519 · 2025

Analgesic efficacy, practicality and safety of inhaled methoxyflurane versus standard analgesic treatment for acute trauma pain in the emergency setting: a randomised, open-label, active-controlled, multicentre trial in Italy (MEDITA)

10.1007/s12325-019-01055-9 · 2019

Real world safety of methoxyflurane analgesia in the emergency setting: a comparative hybrid prospective-retrospective post-authorisation safety study

10.1186/s12873-023-00862-2 · 2023

Usability and effectiveness of inhaled methoxyflurane for prehospital analgesia – a prospective observational study

10.1186/s12873-021-00565-6 · 2022

Methoxyflurane in pre-hospital settings: a review of clinical effectiveness, cost-effectiveness and guidelines

2018

Clinical assessment and risk stratification for prehospital use of methoxyflurane versus standard analgesia in adult patients with trauma pain

10.4103/tjem.tjem_229_22 · 2023

Determination of equi-analgesic doses of inhaled methoxyflurane versus intravenous fentanyl using the cold pressor test in volunteers: a randomised, double-blinded, placebo-controlled crossover study

10.1016/j.bja.2020.12.045 · 2021

Efficacy and safety of methoxyflurane: managing trauma associated pain in UK SAR helicopter paramedic practice

10.12968/jpar.2017.9.3.108 · 2017

Analgesic effectiveness of methoxyflurane inhaler during genicular nerve block in knee osteoarthritis: a randomized controlled trial

10.1136/rapm-2024-105777 · 2025

Self-administered methoxyflurane for procedural analgesia: experience in a tertiary Australasian centre

10.1111/anae.13377 · 2016

Inhaled methoxyflurane (Penthrox) for analgesia in trauma: a systematic review protocol

10.1186/s13643-021-01600-0 · 2021

Additional external references

No additional external references are available.

A Scoping Review of Inhaled Methoxyflurane for Acute Traumatic Pain

Referenced works

Cited by

External reference records

Additional external references