Methoxyflurane, sold under the brand name Penthrox (the "green whistle") among others, is an inhaled medication primarily used to reduce pain following an injury. It may also be used to reduce pain associated with minor medical procedures. Onset of pain relief is rapid and a standard dose typically lasts for up to 30 minutes. Use is only recommended with direct medical supervision. Common side effects include anxiety, headache, sleepiness, cough, and nausea. Serious side effects may include kidney problems, liver problems, low blood pressure, and severe anaesthetic reactions such as malignant hyperthermia. It may be used during pregnancy or breastfeeding, however there may be additional harmful side effects. It is only recommended in those who have a normal level of consciousness and stable blood pressure and heart rate. It is classified as a volatile anaesthetic. It was first made in 1948 by William T. Miller and came into medical use in the 1960s. It was used as a general anesthetic from its introduction in 1960 until the late 1970s. In 1999, the manufacturer discontinued methoxyflurane in the United States, and in 2005 the Food and Drug Administration withdrew it from the market, due to reports of nephrotoxicity and hepatotoxicity. As of April 2025, it is used in New Zealand, Australia, Canada, Ireland, and the United Kingdom for acute pain.
Medical use
Methoxyflurane is used for relief of moderate or severe pain as a result of trauma. It may also be used for short episodes of pain as a result of procedures. Each dose lasts approximately 30 minutes. Pain relief begins after 6–8 breaths and continues for several minutes after stopping inhalation. The maximum recommended dose is 6 milliliters per day or 15 milliliters per week because of the risk of kidney problems, and it is not recommended to be used on consecutive days. Despite the potential for kidney problems when used at anesthetic doses, no significant adverse effects have been reported when it is used at the lower doses (up to 6 milliliters) used for pain relief. Due to the risk of kidney toxicity, methoxyflurane is contraindicated in people with pre-existing kidney disease or diabetes mellitus, and is not recommended to be administered in conjunction with tetracyclines or other potentially nephrotoxic or enzyme-inducing drugs. It is self-administered to children and adults using a hand-held inhaler device. A non-opioid alternative to morphine, it is also easier to use than nitrous oxide. A portable, disposable, single-use inhaler device, along with a single 3 milliliter brown glass vial of methoxyflurane allows people who are conscious and hemodynamically stable (including children over the age of 5 years) to self-administer the medication, under supervision. In prehospital care Penthrox offers an alternative to Entonox, it being smaller, lighter and not contraindicated with chest injuries.
Side effects
The current consensus is that the use of methoxyflurane should be restricted only to healthy individuals and only at dosages less than 2.5 MAC hours. The National Institute for Occupational Safety and Health maintains a recommended exposure limit for methoxyflurane as waste anesthetic gas of 2 ppm (13.5 mg/m3) over 60 minutes. The Australian Medicines Handbook recommends no more than 6mL in one day, and no more than 15mL in a 7-day period.
Kidney An association between methoxyflurane and acute kidney injury was first reported in a 1964 case study of three patients. Another report was published in 1966, in which 17 of 95 patients (18%) who received methoxyflurane as a general anaesthetic developed vasopressin and fluid challenge-resistant high-output kidney failure (production of large volumes of poorly concentrated urine) and deranged serum electrolytes. Most of these cases resolved within 2–3 weeks, but evidence of renal dysfunction persisted in some patients for more than one year. Compared with halothane, methoxyflurane produces dose-dependent abnormalities in kidney function. The authors showed that subclinical nephrotoxicity occurred following methoxyflurane at minimum alveolar concentration (MAC) for 2.5 to 3 hours (2.5 to 3 MAC hours), while overt toxicity was present in all patients at dosages greater than 5 MAC hours. This study provided a model that would be used for the assessment of the nephrotoxicity of volatile anesthetics for the next two decades. Furthermore, the concurrent use of tetracyclines and methoxyflurane has been reported to result in fatal renal toxicity.
Liver Reports of severe and even fatal hepatotoxicity related to the use of methoxyflurane began to appear in 1966.
Mechanism The biodegradation of methoxyflurane begins immediately. The kidney and liver toxicity observed after anesthetic doses is attributable to one or more metabolites produced by O-demethylation of methoxyflurane. Products of this catabolic process include methoxyfluoroacetic acid (MFAA), dichloroacetic acid (DCAA), and inorganic fluoride. Methoxyflurane nephrotoxicity is dose dependent and irreversible, resulting from O-demethylation of methoxyflurane to fluoride and DCAA. It is not entirely clear whether the fluoride itself is toxic—it may simply be a surrogate measure for some other toxic metabolite. The concurrent formation of inorganic fluoride and DCAA is unique to methoxyflurane biotransformation compared with other volatile anesthetics, and this combination is more toxic than fluoride alone. This may explain why fluoride formation from methoxyflurane is associated with nephrotoxicity, while fluoride formation from other volatile anesthetics (such as enflurane and sevoflurane) is not.
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