REVIEW ARTICLE Methoxyflurane toxicity: historical determination and lessons for modern patient and occupational exposure Serah J Allison, Paul D Docherty, Dirk Pons, J Geoffrey Chase ABSTRACT AIM: Historically methoxyflurane was used for anaesthesia. Evidence of nephrotoxicity led to abandonment of this application. Subsequently, methoxyflurane, in lower doses, has re-emerged as an analgesic agent, typically used via the Penthrox inhaler in the ambulance setting. We review the literature to consider patient and occupational risks for methoxyflurane. METHOD: Articles were located via PubMed, ScienceDirect, Google Scholar, Anesthesiology journal and the Cochrane Library. RESULTS: Early studies investigated pharmacokinetics and considered the resulting effects to pose minimal risk. Pre-clinical rodent studies utilised a species not vulnerable to the nephrotoxic fluoride metabolite of methoxyflurane, so nephrotoxicity was not identified until almost a decade after its introduction, and was initially met with scepticism. Further evidence of nephrotoxicity led to abandonment of methoxyflurane use for anaesthesia. Subsequent research suggested there are additional risks potentially relevant to recurrent patient or occupational exposure. Specifically, greater than expected fluoride production after repeated low-dose exposure, increased fluoride production due to medication-caused hepatic enzyme induction, fluoride deposition in bone potentially acting as a slow-release fluoride compartment, which suggests a risk of skeletal fluorosis, and hepatotoxicity. Gestational risk is unclear. CONCLUSIONS: Methoxyflurane poses a potentially substantial health risk in high (anaesthetic) doses, and there are a number of pathways whereby repeated exposure to methoxyflurane in lower doses may pose a risk. Single analgesic doses in modern use generally appear safe for patients. However, the safety of recurrent patient or occupational healthcare-worker exposure has not been confirmed, and merits further investigation. ethoxyflurane is a volatile organic Renal failure was identified in some patients liquid,1 a fluorinated hydrocarbon, anaesthetised with methoxyflurane.10,11 Mthat vaporises readily2 and has Methoxyflurane is estimated to have been historically been used as an anaesthetic responsible for clinical nephrotoxicity in agent from 1958.3 A decade after discovery, approximately 100 patients worldwide, and methoxyflurane was used frequently, mak- death in approximately 20 cases, before its ing up 10% of annual purchases of inhaled near universal discontinuation since the anaesthetics in the USA.3 Sedative and 1970s.12 4,5 analgesic effects were described, which However, methoxyflurane has been prompted an extension of its use outside reintroduced into the contemporary arma- of the operating room for indications such mentarium as an analgesic for emergency or 6–8 9 as labour pain and dressing changes. short procedures. Australasia,13,14 Europe,15 NZMJ 30 April 2021, Vol 134 No 1534 ISSN 1175-8716 © NZMA 76 www.nzma.org.nz/journal REVIEW ARTICLE Canada,16 South Africa17 and, more recently, the following sections of this paper. Only numerous other countries18 allow methoxy- English-language material was reviewed. flurane administration via the Penthrox Reference sections of relevant articles inhaler. This device has been manufactured were examined to identify further relevant by Medical Developments International material for inclusion. Documents included (formerly Medical Developments Australia) in this review range across case reports, since 1978, specifically for analgesic use,19 animal and human prospective observa- and Penthrox is currently the only widely tional studies, experimental trials and other commercially available methoxyflurane literature reviews. administration device. The Penthrox inhaler is a tube into which the methoxyflurane Historic use of medication is poured to soak a wick, with a whistle-like mouthpiece through which the methoxyflurane patient inhales methoxyflurane vapour.20 Early published animal studies were The device features a ‘dilution hole’, which conducted on dogs and determined allows the patient to control the concen- that, with regards to incidence of lethal tration delivered18,21 and can incorporate arrhythmias,29,30 electrolyte disturbances an activated carbon (AC) filter through or liver dysfunction,31 methoxyflurane which the patient is encouraged to exhale. compared favourably with alternative Methoxyflurane has an estimated atmo- inhaled anaesthetic agents. Reports were spheric lifetime of 54 days and a 100-year conflicted with regards to cardiovascular global warming potential four times that and respiratory effects,31–33 although these of carbon dioxide, although it compares risks are not generally discussed in later favourably in that regard against other investigations. Researchers of canine inhalational anaesthetics.22 Administration models noted a slow recovery from anaes- of methoxyflurane via the Penthrox inhaler thesia, with the dogs appearing sluggish has been demonstrated as more effective at until the next day.31 Anaesthetised human relieving pain than placebos and alternative subjects also exhibited slow onset and analgesia in a variety of settings including emergence from anaesthesia.4 Arterial pre-hospital,23,24 clinic,25 and emergency methoxyflurane was approximately double department.26,27 the venous level during early anaesthesia We reviewed the historic literature to (2 to 15 minutes), equilibrating after 100 34 describe the evolution in the understanding minutes. This suggests ready uptake into of the health risks associated with anaes- tissue, confirming laboratory studies that thetic methoxyflurane. Thus we identify had suggested methoxyflurane would have the potential patient and occupational risks high solubility in blood and high uptake in 28 of methoxyflurane in the modern setting, adipose tissue. Methoxyflurane concen- in order to help guide policymakers and tration in subcutaneous fat rose slowly, clinicians who might consider making peaking 5–8 hours after commencement methoxyflurane available in their clinical of anaesthesia and remaining elevated 34 environments. beyond 30 hours after cessation. Overall, these studies suggested that methoxyflurane had a large volume of distribution and Search strategy consequent delayed equilibration between To gain a comprehensive overview of the compartments. historical literature, we sought to locate As methoxyflurane was a new anaes- research and commentary on methoxy- thetic agent, a significant proportion of the flurane administration in any setting for historical animal and human research was any indication by any method other than dedicated to investigating the rate of onset the modern Penthrox inhaler. Articles were of and emergence from anaesthesia,4,31,35,36 located using PubMed, ScienceDirect and the concentration required to achieve Google Scholar and by searching the Anes- adequate anaesthesia1,20,37 and the threshold thesiology journal and Cochrane Library of sedation.36 Early medication safety investi- databases with the term ‘methoxyflurane’. gations included effects on respiration2,4,31,35,38 Articles were selected based on rele- and cardiovascular stability,4,35,38,39 with vance to health effects, as categorised in NZMJ 30 April 2021, Vol 134 No 1534 ISSN 1175-8716 © NZMA 77 www.nzma.org.nz/journal REVIEW ARTICLE methoxyflurane demonstrating reasonable of methoxyflurane into fluoride. Only safety with regards to these concerns. Fischer 344 rats demonstrated biochemical Although many of these historical anaes- and pathological renal changes following thesia studies might not meet modern methoxyflurane anaesthesia.51 In susceptible scientific standards due to the poor quality rats, elevated fluoride was associated with and quantity of data, examination of this dose-related high-output renal failure.43,52,53 literature nonetheless allows identification Therefore, due to the use of a non-sus- and extraction of worthwhile findings. ceptible rat type, preclinical trials had Fluoride-associated health effects unfortunately failed to identify the nephro- toxic potential of methoxyflurane. Methoxyflurane is metabolised by lung and liver tissue into a variety of products,40 Early observations of anaesthetised including fluoride and oxalic acid.20 human subjects also suggested no renal Some medications are known to increase toxicity.35 Nephrotoxicity in clinical use (‘induce’) metabolism pathways in the liver. was suggested by a 1966 case series of 17 Pre-treatment of rat hepatic microsomes patients,10 although unfortunately this first in vitro with phenobarbital, an anticon- report of human methoxyflurane anaes- vulsant therapy,41 caused a 7- to 10-fold thesia-associated nephrotoxicity was met increase in fluoride production in response with scepticism.12 It was a further five to methoxyflurane exposure.40,42 Similarly, years until further incidents of high-output in vivo pre-treatment of rats with pheno- failure were described,54–56 at which time a barbital increased methoxyflurane uptake relationship was identified between serum and fluoride production.43–45 A patient fluoride following methoxyflurane anaes- who had secobarbital prior to receiving thesia and the degree of renal toxicity. In methoxyflurane had peak serum fluoride 1973, strong correlations were identified that was three times that of patients who between methoxyflurane anaesthetic dose, did not receive secobarbital, and the patient increased serum inorganic