Methoxyflurane

Why this drug is interesting

Methoxyflurane occupies an unusual position in the emergency formulary. It is the only drug most of us use that was withdrawn from its original indication for organ toxicity and then successfully reintroduced for a different one — not because the toxicity was disproved, but because the dose was cut by more than an order of magnitude and hedged with hard caps.

That history is not trivia. Every counterintuitive item on the label — why the ceiling is expressed per week rather than per dose, why consecutive days are discouraged, why it is explicitly unsuitable for breakthrough pain in chronic conditions, why sevoflurane afterwards is a problem — descends directly from what happened in the 1960s. A clinician who knows the story does not need to memorise the caps.

History and development

Methoxyflurane was first synthesised in 1958 by the Dow Chemical Company, and evaluated clinically by the Cornell anaesthetists Joseph Artusio and Alan Van Poznak, who published the first clinical evaluation in man in Anesthesiology in 1960.¹⁰ Abbott introduced it in 1962 and marketed it as the non-toxic replacement for halothane.

Uptake was rapid. It was non-flammable, non-explosive, gave profound analgesia and muscle relaxation, and had a benign early safety record. Somewhere between 12 and 15 million anaesthetics were administered.

How the safety signal was established

The unravelling took a decade, and is a genuinely instructive case study in pharmacovigilance — worth the detail because the pattern recurs.

Decline, and the parallel analgesic story

Methoxyflurane fell out of anaesthetic use through the late 1970s. Abbott nonetheless manufactured Penthrane until 2001, and it lost FDA approval in 2005.

The analgesic story ran alongside. Robert Wexler at Abbott developed the Analgizer in 1968 — a disposable self-administration inhaler used widely until the early 1970s, in a manner that anticipated modern patient-controlled analgesia. It was withdrawn in 1974, but methoxyflurane analgesia continued in Australia and New Zealand as the Penthrox inhaler, in use since 1975 and first-line for moderate-to-severe pain in several ambulance services. European licensing followed the STOP! trial in the mid-2010s.²

Pharmacokinetics

The physical chemistry drives everything else about this drug.

The oil/gas figure of 825 is the reason a sub-anaesthetic analgesic dose is even possible. The blood/gas figure of 13 is why it was hopeless in theatre — Van Poznak's remark that it had the volatility of peanut butter captures the problem neatly.

Absorption

Vapour is rapidly transported from lung to blood, hence the rapid analgesic onset. After a single 3 mL dose inhaled intermittently over an hour: arterial t-max 0.25 h (range 0.08–0.75), C-max 32.39 µg/mL, AUC 28.95 h·µg/mL.¹

Distribution

High lipophilicity means ready diffusion into fat, forming a reservoir released slowly over days. This is the pharmacokinetic root of the cumulative-dose problem — the fat depot keeps feeding substrate to biotransformation long after the patient has left the department.

Metabolism

Hepatic dechlorination and O-demethylation via CYP2E1, CYP2B6 and CYP2A6, producing free fluoride, oxalic acid, difluoromethoxyacetic acid and dichloroacetic acid. Methoxyflurane is far more susceptible to metabolism than other halogenated methyl ethyl ethers — published estimates of the fraction metabolised range from about 50% to 75%⁶ — which is an order of magnitude more than isoflurane.

Elimination

Parent drug

Venous median half-life 3.16 h (range 1.06–7.89); concentrations back to baseline by 24 h

Inorganic fluoride

Median t-max 1.5 h; median half-life 33.3 h (range 23.5–51.2); significant venous concentrations still present at 48 h

Excretion

~60% of uptake appears in urine as organic fluorine, fluoride and oxalic acid; remainder exhaled unchanged or as CO₂

Sub-populations

• Children exposed to a low anaesthetic dose had serum fluoride under 62% of adult concentrations at all time points to 48 h.
• A single 3 mL analgesic dose given as instructed produces serum inorganic fluoride below 10 µmol/L, against the historically determined nephrotoxic threshold of above 40 µmol/L.¹

That roughly fourfold margin is the entire safety case for the modern product. It is a margin around a single correctly-used dose — which is precisely why it cannot be assumed to hold for repeated exposure.

Pharmacodynamics

At class level, halogenated ethers potentiate GABA-A and glycine receptor currents, inhibit NMDA receptors, and activate two-pore-domain potassium channels including TREK-1. The relative contribution of each to analgesia, as distinct from immobility and hypnosis, is not established for methoxyflurane specifically.

Clinical profile

What is well characterised is the clinical behaviour. At analgesic doses there may be some decrease in blood pressure, sometimes with bradycardia, though rhythm is usually regular, and the myocardium is only minimally sensitised to adrenaline. The cardiovascular depression that is a genuine class effect at anaesthetic doses does not appear meaningful at analgesic doses — though caution in the elderly is advised.

Secondary CNS effects — sedation, euphoria, amnesia, impaired concentration and coordination — are class effects that also act as a natural ceiling: self-administration is self-limiting, because the patient drops the inhaler as sedation arrives. This is the same safety logic as patient-controlled analgesia, and it is why supervised self-administration is not merely a convenience.

Onset and duration

Onset (adults)

After 6–10 inhalations; children may need additional inhalations

One 3 mL bottle

Up to 25–30 minutes of analgesia with continuous inhalation

Intermittent use

Extends duration beyond the continuous figure

A second bottle

Permitted within the 6 mL daily maximum, but rarely used in a single setting — plan the next analgesic step instead

Indications and dosing

The UK licence is narrow: emergency relief of moderate to severe pain in conscious patients aged 6 years and older with trauma and associated pain.¹ Australasian licensing is broader, extending to analgesia for minor surgical procedures in monitored conscious patients.

Administration

Self-administered under the supervision of a person trained in its use, via the hand-held inhaler. The activated carbon chamber must be fitted — it adsorbs exhaled methoxyflurane and exists specifically to limit occupational exposure. Respiration should be monitored throughout.

Procedural use outside the UK licence

A reasonable observational and small-trial literature has accumulated for colonoscopy, prostate biopsy, dental procedures, bone marrow biopsy, burns dressing changes, external fixator removal, hysteroscopy and interventional radiology. This is off-label in the UK and should be governed accordingly.

Contraindications and interactions

The SmPC list is worth knowing close to verbatim, because several items are counterintuitive.

• Use as an anaesthetic agent
• Hypersensitivity to methoxyflurane, any fluorinated anaesthetic, or the excipients
• Known or genetic susceptibility to malignant hyperthermia
• Known family history of severe adverse reactions to inhaled anaesthetics
• History of liver damage after previous methoxyflurane or halogenated hydrocarbon anaesthesia
• Clinically significant renal impairment
• Altered level of consciousness due to any cause, including head injury, drugs or alcohol
• Clinically evident cardiovascular instability
• Clinically evident respiratory depression

Interactions

Interactions matter more here than for most ED drugs, because they act through metabolic rate — anything that accelerates metabolism accelerates fluoride production.

Complications

Common and expected

Dizziness is very common. Headache, somnolence, dysgeusia, cough, nausea, euphoric mood, fatigue and feeling drunk are common. In the STOP! adult subgroup, treatment-related adverse events were reported by 42.2% receiving methoxyflurane against 14.9% receiving placebo — mostly dizziness and headache, none causing withdrawal, and the majority mild and transient.³

Nephrotoxicity

The historical lesion is a high-output, vasopressin-resistant polyuric renal failure with negative fluid balance, hypernatraemia and rising urea — not oliguric ATN. Recognising that it looks like the opposite of the renal failure clinicians expect is the practical point.

Three mechanistic accounts remain in play, and they are not mutually exclusive:

1. Orthodox — inorganic fluoride is the toxin.
2. Metabolite co-toxicity — renal necrosis from fluoride and dichloroacetic acid together exceeds that from fluoride alone. Because DCAA and fluoride are co-formed uniquely from methoxyflurane, this elegantly explains why other fluoride-generating agents do not cause the lesion.
3. Intrarenal metabolism — Kharasch's work suggests in situ renal defluorination, rather than hepatic metabolism, may be the critical event. The relative paucity of renal sevoflurane defluorination would then account for the absence of clinical sevoflurane nephrotoxicity despite plasma fluoride above 50 µM.¹¹

Hepatotoxicity

Isolated reports exist with analgesic use. The SmPC carries hepatic failure, hepatitis, jaundice and liver injury at unknown frequency. Prior halogenated exposure within three months increases risk — which is part of why the three-month judgement point exists.

Skeletal fluorosis

This is the direct clinical reason behind the weekly cap and the prohibition on breakthrough or repeated-episode use. It is not theoretical.

Respiratory and cardiovascular

Respiratory depression has been reported at analgesic doses and respiration should be monitored. Hypoxia is listed as uncommon. One study found a moderate QTc increase, raising a question of moderately increased risk of sudden cardiac death.

Occupational exposure

The activated carbon chamber exists precisely to adsorb exhaled drug, and multiple use without it creates additional risk. Historically, delivery-suite staff showed elevated liver enzymes, urea and urate when methoxyflurane was used in obstetric analgesia.

Measured staff exposure in modern use is significantly below levels associated with nephrotoxicity. One study of paramedics found no sustained rise in serum fluoride, though a single result above a skeletal fluorosis threshold meant the authors could not exclude a risk of mild skeletal fluorosis.⁶

Other

Abuse potential is low but not zero. Methoxyflurane is also a potent greenhouse gas — an emerging consideration in volatile agent stewardship, raised in a recent Acta Anaesthesiologica Belgica review.

The evidence base

STOP! — the pivotal adult and adolescent trial

Coffey et al., EMJ 2014.² A randomised, double-blind, placebo-controlled study at six UK sites. 300 patients aged 12 and over — 90 of them adolescents aged 12–17 — with minor trauma and pain scoring 4–7 on an 11-point NRS, randomised 1:1 to methoxyflurane (up to 6 mL) or placebo (normal saline), both via the Penthrox inhaler.

Methoxyflurane reduced pain severity significantly more than placebo (p<0.0001) at every time point tested, with the greatest estimated treatment effect of −18.5 mm at 15 minutes.² The published mean VAS changes are reported by subgroup:

In the adult subgroup the greatest comparative effect was a least-squares mean difference of −21.0 mm (95% CI −26.8 to −15.3) at 15 minutes.³ Across the whole trial, 82.4% of methoxyflurane patients reported pain relief at some point against 52.5% on placebo.

In the adult subgroup analysis, median time to first pain relief was 5 minutes against 20 minutes for placebo (HR 2.32, 95% CI 1.63–3.30, p<0.0001), with 79.4% obtaining relief within 1–10 inhalations.³

MAGPIE — the paediatric trial

MEOF-002, published in Injury (2025).⁵ Randomised, double-blind, placebo-controlled, across 11 EDs in the UK and Ireland, in children and young people aged 6–17. Of 4,513 screened, 249 were randomised (127 methoxyflurane, 122 placebo) and 192 treated.

Physician and research-nurse global assessments of medication performance strongly favoured methoxyflurane (OR 5.29 and 5.78 respectively, both p<0.001) — a notably larger effect than the VAS difference, which is itself worth thinking about when a subjective global rating outruns the primary numerical endpoint.

Data below 6 years remain limited to a single observational series, with drowsiness reported in 40% of the under-5 subgroup.

Critical appraisal

If you are taking this to journal club or teaching, five weaknesses in the evidence base are worth naming explicitly.

1. Manufacturer funding throughout. STOP! was funded by Medical Developments International and Mundipharma; the pooled meta-analysis was funded by Mundibiopharma, which was involved at every stage from design to submission, and the STOP! chief investigator has received honoraria from Mundipharma.¹⁴ This does not invalidate the results, but it is the context in which every effect size here was generated.
2. Placebo-controlled, not active-comparator. We know methoxyflurane beats saline. Data against intranasal fentanyl, oral morphine, or a well-executed regional block are far thinner — and those are the actual clinical alternatives.
3. Baseline severity does not match the marketing. STOP! enrolled NRS 4–7 — moderate pain. Extrapolation to severe pain, which is where the pitch usually lands, is not directly supported by the pivotal trial.
4. Blinding was imperfect. The characteristic fruity odour and the CNS effects make assignment guessable, which inflates apparent effect on a subjective endpoint.
5. The paediatric effect size is modest. MAGPIE's −6.8 mm difference sits close to, and arguably below, most estimates of the minimum clinically important difference on a 100 mm VAS — and it was demonstrated in the 9–<18 subgroup, not the full licensed range.

The nephrotoxicity data cut the other way

Where the efficacy literature probably flatters the drug, the safety literature may be too reassuring. The 40–50 µmol/L threshold derives from 1970s anaesthetic-dose studies and was carried across to other agents without revalidation.

Whether it is the right threshold for the modern intermittent-low-dose exposure pattern — particularly given the fat reservoir and the 33-hour fluoride half-life producing accumulation across repeated administrations — has not been properly re-examined. The 2024 fluorosis case suggests it may be optimistic for repeated use.¹²

References

1. 1
   PENTHROX 99.9%, 3 mL inhalation vapour, liquid — Summary of Product Characteristics. electronic Medicines Compendium. Sections 4.1–4.4 verified against the current SmPC 21 Aug 2026 — indication (≥6 years), onset (6–10 inhalations), duration (25–30 min) and the 6 mL/day and 15 mL/week caps all confirmed verbatim. The detailed section 5.2 pharmacokinetic figures below — arterial t-max/C-max/AUC, the 3.16 h parent and 33.3 h fluoride half-lives, and the paediatric fluoride comparison — are reproduced from this SmPC but could not be independently re-retrieved on re-audit, because the emc page truncates before section 5. Treat them as SmPC-sourced but singly-verified.
2. 2
   Coffey F, Wright J, Hartshorn S, et al. STOP!: a randomised, double-blind, placebo-controlled study of the efficacy and safety of methoxyflurane for the treatment of acute pain. Emerg Med J 2014;31(8):613–18. PubMed
3. 3
   Coffey F, Dissmann P, Mirza K, Lomax M. Methoxyflurane analgesia in adult patients in the emergency department: a subgroup analysis of a randomized, double-blind, placebo-controlled study (STOP!). Adv Ther 2016;33(11):2012–31. PubMed
4. 4
   Hartshorn S, Middleton PM. Low-dose methoxyflurane analgesia in adolescent patients with moderate-to-severe trauma pain: a subgroup analysis of the STOP! study. J Pain Res 2019;12:11–21.
5. 5
   Treatment of acute trauma-related pain in children and adolescents with methoxyflurane (Penthrox) compared to placebo (MAGPIE): a randomised clinical trial. Injury 2025. ScienceDirect
6. 6
   Dayan AD. Analgesic use of inhaled methoxyflurane: evaluation of its potential nephrotoxicity. Hum Exp Toxicol 2016;35(1):91–100. Journal
7. 7
   Mazze RI, Shue GL, Jackson SH. Renal dysfunction associated with methoxyflurane anesthesia: a randomized, prospective clinical evaluation. JAMA 1971;216(2):278–88.
8. 8
   Cousins MJ, Mazze RI. Methoxyflurane nephrotoxicity: a study of dose response in man. JAMA 1973;225(13):1611–16.
9. 9
   Crandell WB, Pappas SG, MacDonald A. Nephrotoxicity associated with methoxyflurane anesthesia. Anesthesiology 1966;27(5):591–607.
10. 10
    Artusio JF Jr, Van Poznak A, Hunt RE, et al. A clinical evaluation of methoxyflurane in man. Anesthesiology 1960;21:512–17.
11. 11
    Kharasch ED, Hankins DC, Thummel KE. Human kidney methoxyflurane and sevoflurane metabolism: intrarenal fluoride production as a possible mechanism of methoxyflurane nephrotoxicity. Anesthesiology 1995;82(3):689–99.
12. 12
    Skeletal fluorosis associated with chronic methoxyflurane use — case report. JBMR Plus 2024.
13. 13
    Porter KM, Siddiqui MK, Sharma I, et al. Low-dose methoxyflurane versus standard of care analgesics for emergency trauma pain: a systematic review and meta-analysis of pooled data. J Pain Res 2021;14:11–21. PMC
14. 14
    Funding and competing-interest statements as declared in references 2, 3 and 13.