A Scoping Review of Inhaled Methoxyflurane for Acute Traumatic Pain

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 Methoxyflurane, an inhaled anesthetic first developed in the 1960s but later withdrawn due to dose-related nephrotoxicity, has been repurposed internationally at substantially lower sub-anesthetic doses as an analgesic delivered via a compact,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.

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.

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.

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.