Analgesic use of inhaled methoxyflurane

Abstract

<jats:p> Methoxyflurane is a volatile, halogenated analgesic, self-administered in a controlled low dose from the Penthrox<jats:sup>®</jats:sup> 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<jats:sup><jats:sup>®</jats:sup></jats:sup> 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. </jats:p>

Methoxyflurane Analgesia in Adult Patients in the Emergency Department: A Subgroup Analysis of a Randomized, Double-blind, Placebo-controlled Study (STOP!)

“…Similarly, in patients receiving methoxyflurane as procedural analgesia for bone marrow biopsy, blood analysis of urea and electrolytes was no different between those patients receiving methoxyflurane and those receiving placebo [35]. These observations are consistent with the findings of Dayan [17], who reviewed laboratory and clinical data relevant to nephrotoxicity and methoxyflurane and concluded that low-dose use of methoxyflurane for analgesia has a large safety margin (at least 2.7- to 8-fold based on methoxyflurane MAC-hours or serum fluoride level) and does not carry a risk of causing renal dysfunction or damage. Furthermore, over 5 million doses of Penthrox have been sold with no pharmacovigilance-related trends suggesting nephrotoxicity.…”

“…In a much larger controlled observational study of patients receiving analgesia during ambulance transport, comparing 17,629 patients receiving methoxyflurane with 118,141 patients not receiving methoxyflurane, no link between methoxyflurane use for emergency analgesia and renal disease (or hepatic disease) was observed [16]. Whilst the literature and post-marketing surveillance in Australia suggest that nephrotoxicity and/or hepatotoxicity of methoxyflurane at analgesic doses is not a risk [16, 17], a study is underway in the UK to understand hepatotoxicity in the pre-hospital and ED settings.…”

“…Laboratory evidence also shows a large safety margin for analgesic use of methoxyflurane in the Penthrox inhaler [a dose of 6 mL/day and 15 mL/week results in exposure of 0.59 methoxyflurane minimum alveolar concentration (MAC)-hours, which is well below the reported level of risk of nephrotoxicity of 2.0 MAC-hours [14]]. Therefore, it has been concluded that the use of methoxyflurane in analgesic doses does not carry a risk of nephrotoxicity [17]. …”

“…Due to the physiochemical characteristics of methoxyflurane, absorption is rapid, providing fast onset of analgesic action (usually within 6–10 inhalations) to treat acute pain rapidly [13, 17]. The portability of the Penthrox inhaler and self-administration by the patient mean that it has practical advantages over alternatives such as nitrous oxide.…”

Methoxyflurane (Penthrox®)—a case series of use in the prehospital setting

“…-a case series of use in the prehospital setting noted that it exhibited excellent analgesic properties in much lower doses than those used for anaesthesia (Cousins and Mazze, 1973). The upper limit of safety for methoxyflurane has been determined to be 2 MAC (minimal alveolar concentration)-hours (Dayan, 2016). Doses below 2 MAC-hours have not been associated with nephrotoxicity.…”