Analgesic use of inhaled methoxyflurane: Evaluation of its potential nephrotoxicity

Hum Exp Toxicol. 2016 Jan;35(1):91-100. doi: 10.1177/0960327115578743. Epub 2015 Apr 28.


Methoxyflurane is a volatile, halogenated analgesic, self-administered in a controlled low dose from the Penthrox(®) inhaler for short-term pain relief. It was formerly used in significantly higher doses to produce anaesthesia, when it caused a specific type of dose-related renal tubular damage. The pathogenesis of the renal damage and clinical use of methoxyflurane are discussed here with evidence that a low but effective analgesic dose is not associated with the risk of renal adverse effects. The maximum dose employed to produce analgesia is limited to methoxyflurane 6 mL/day and 15 mL/week, producing a minimum alveolar concentration (MAC) of 0.59 MAC-hours. Renal damage is due to the metabolism of methoxyflurane and release of fluoride ions. Exposure of humans to methoxyflurane ≤2.0 MAC-hours, resulting in serum fluoride ≤40 µmol/L, has not been associated with renal tubular toxicity. The safety margin of analgesic use of methoxyflurane in the Penthrox ((®)) inhaler is at least 2.7- to 8-fold, based on methoxyflurane MAC-hours or serum fluoride level, with clinical experience suggesting it is higher. It is concluded from clinical experience in emergency medicine, surgical procedures and various experimental and laboratory investigations that the analgesic use of methoxyflurane in subanaesthetic doses in the Penthrox inhaler does not carry a risk of nephrotoxicity.

Keywords: Methoxyflurane; analgesia; clinical safety; fluoride; nephrotoxicity; renal tubular damage.

Publication types

  • Review

MeSH terms

  • Anesthetics, Inhalation / adverse effects*
  • Anesthetics, Inhalation / chemistry
  • Anesthetics, Inhalation / pharmacology*
  • Animals
  • Humans
  • Kidney Diseases / chemically induced*
  • Methoxyflurane / adverse effects*
  • Methoxyflurane / chemistry
  • Methoxyflurane / pharmacology*


  • Anesthetics, Inhalation
  • Methoxyflurane