Background

Methoxyflurane is a volatile fluorinated hydrocarbon that was widely used as an inhalational anaesthetic in the 1960s. Its use as an anaesthetic agent declined in the 1970s due to evidence that deep or prolonged methoxyflurane anaesthesia was associated with a dose related nephrotoxicity.1 Sub-anaesthetic doses of methoxyflurane have been shown to provide an analgesic effect without any evidence of adverse renal events.2 In Australia, sub-anaesthetic doses of methoxyflurane have been used as an analgesic in the prehospital setting and emergency departments for over thirty years.

A 2009 literature review of methoxyflurane use in ED and prehospital settings concluded that it likely provided effective analgesia without significant adverse events at analgesic doses. The authors noted that while this conclusion was supported by a large volume of observational and non-controlled published literature, there had been no published randomised controlled trials studying the use of methoxyflurane as an analgesic.3

Recently interest in methoxyflurane as an analgesic for acute pain has increased. In 2014, the STOP! trial was conducted across 6 sites in the UK. It was a randomised, double-blind, placebo-controlled study of the efficacy and safety of methoxyflurane for the treatment of acute traumatic pain. It randomised 300 patients with minor traumatic injuries to Penthrox or placebo and recorded subsequent pain intensity. Patients receiving Penthrox had significantly reduced pain intensity across all time points (100mm VAS = -17.4 mm; 95% confidence interval: -22.3 to -12.5 mm; p < 0.0001) and it was found to be generally well tolerated, with the majority of adverse events being mild and transient.4

Subsequent papers have expanded upon this by demonstrating its usefulness in elderly trauma patients.5 This increase in research activity has resulted in a recently published meta-analysis which combined findings from four randomised controlled trials: STOP!, PenASAP, MEDITA and InMEDIATE (the paper covered today). Together these studies gathered data from over 1000 patients. The results of the meta-analysis demonstrated that methoxyflurane related analgesia was superior to standard care (overall estimate treatment effect = 11.88 (95% CI=9.75-14.00); P<0.0001) and concluded that methoxyflurane can be considered as an alternative to standard analgesia for trauma pain in adult patients.6

Further research is ongoing into methoxyflurane’s potential applications. The METEORA trial is looking at methoxyflurane use in HEMS and hostile environments,7 MAGPIE is examining its use in paediatrics,8 and the ANEMON-SIRO3 study is examining its use in acute myocardial infarction as a replacement for morphine, which is known to have inhibitory effects on some antiplatelets.9

However, despite increasing evidence of its benefits, concerns remain regarding its potential harms to both patients and risks associated to clinicians from occupational exposure. These relate to methoxyflurane triggered increased fluoride production and subsequent hepatotoxicity.10 The device is fitted with an activated carbon chamber to reduce environmental exposure.11 This requires the patient to breath out through the whistle for this to work.

A real world study looking at occupational exposure of 138 ED nurses working in 2 French EDs where methoxyflurane was used regularly found there was 900-fold lower than recommended maximum exposure level of 15ppm.12 In addition, a small study measuring serum fluoride in 12 paramedics over a twenty-four month period showed that the serum fluoride levels remained in the healthy range throughout.13

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