Inhaled Analgesic — Acute Pain Pregnancy: Avoid — limited data; methoxyflurane crosses placenta; inorganic fluoride may affect fetal renal development; if essential for acute pain in pregnancy, use under specialist supervision with minimum effective dose

Methoxyflurane

Brand names: Penthrox

Adult dose

Dose: 3 mL solution in Penthrox inhaler; patient self-administers via handheld inhaler with activated carbon chamber

Route: Inhalation (patient-controlled, handheld inhaler)

Frequency: As needed during painful procedure or acute episode; 3 mL per episode; maximum 2 bottles (6 mL) in 24 hours; maximum 15 mL per week

Max: 6 mL in any 24-hour period; 15 mL per week; do not exceed — nephrotoxicity risk with repeated use

Analgesic onset in 6–10 breaths; effects begin within 30 seconds; activate carbon chamber dilutor to minimise occupational exposure; patient must hold inhaler themselves — inability to hold = adequately sedated, stop; do NOT use in enclosed spaces without scavenging

Paediatric dose

Route: Inhalation

Frequency: As adult

Max: 3 mL per episode; maximum 6 mL/24 hours

Licensed from age 6 years (MHRA 2020 paediatric extension); same device and dose as adults — children can self-administer if able to hold inhaler correctly; particularly useful for wound care and fracture assessment in paediatric ED

Dose adjustments

Renal

Avoid in pre-existing renal impairment — methoxyflurane is metabolised to inorganic fluoride (nephrotoxic at high concentrations); single analgesic doses rarely cause clinically significant renal impairment in healthy kidneys but avoid if eGFR <60

Hepatic

Use with caution in hepatic impairment — methoxyflurane undergoes hepatic metabolism; avoid in severe impairment or known hepatic disease

Clinical pearls

STOP! trial (Lancet 2017): 300 patients with acute minor trauma in 4 Australian EDs — methoxyflurane non-inferior to IV morphine for pain relief at 5 minutes (NRS reduction 3.5 vs 3.7); significantly faster onset than IV morphine (no IV access required); 93% patient satisfaction; transformed pre-hospital and ED acute pain management across Europe and Australia
Patient-controlled safety mechanism: the inhaler requires continuous active grip — if patient becomes excessively sedated they drop the device and drug delivery ceases automatically; this makes methoxyflurane uniquely safe for self-administered analgesia; no reversal agent required
Nephrotoxicity context: analgesic doses produce inorganic fluoride levels well below the nephrotoxic threshold (50 μmol/L); historical nephrotoxicity concerns arose from prolonged anaesthetic doses (>70 MAC-hours) used in the 1960–70s; a 3 mL analgesic dose produces only ~10–15 μmol/L fluoride — multiple times below the toxic threshold
Occupational exposure protection: the integrated activated carbon chamber in the Penthrox inhaler captures exhaled methoxyflurane before it enters room air — reduces staff occupational exposure by ~95%; still recommended to use in well-ventilated areas or with additional scavenging in enclosed spaces; occupational exposure limit is 15 ppm (8-hour TWA)
Ideal ED indications: wound debridement and irrigation, fracture manipulation (prior to IV access), joint dislocation reduction, burns dressings, cannulation in needle-phobic patients, nasogastric tube insertion — any painful procedure where fast onset analgesia is needed without IV access

Contraindications

Known hypersensitivity to methoxyflurane or halogenated anaesthetics
Personal or family history of malignant hyperthermia
Pre-existing renal impairment (eGFR <60)
Altered level of consciousness or unable to self-administer
Hepatic impairment
Cardiovascular instability (relative)
Concurrent nephrotoxic drugs (aminoglycosides, NSAIDs — avoid combination)

Side effects

Dizziness (most common)
Headache
Somnolence
Nausea
Transient amnesia
Euphoria
Nephrotoxicity (dose-dependent — fluoride metabolite; risk at high/repeated doses)
Hepatotoxicity (rare — with repeated anaesthetic-level exposure)
Malignant hyperthermia (rare — halogenated agent class risk)

Interactions

Nephrotoxic drugs (aminoglycosides, NSAIDs, ciclosporin, vancomycin) — avoid concurrent use; additive fluoride-mediated nephrotoxicity
CNS depressants (opioids, benzodiazepines, alcohol) — additive sedation; patient may lose ability to hold inhaler — built-in safety mechanism
Other halogenated anaesthetics — avoid combining

Monitoring

Level of consciousness (patient must remain able to hold inhaler)
Pain score (NRS) before, during, and after
Oxygen saturation if concerns about sedation
Renal function (U&E) if repeated use >1 episode/week
Occupational exposure monitoring for healthcare staff (regular Penthrox users)

Reference: BNFc; BNF 90; MHRA Approval Penthrox 2015; MHRA Paediatric Extension 2020; Coffey et al. Lancet 2017 (STOP! trial); SPC Penthrox; RCEMlearning Methoxyflurane module; NICE Evidence Review 2019. Verify against your local formulary and the latest BNF before prescribing.

Curated clinical cross-links plus same-class fallbacks.

Calculators

Pathways