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Bedside Snapshot (ED/EMS/Prehospital)
  • Core dose: 3 mL via handheld inhaler (the "Green Whistle"); patient self-administers under supervision; max 6 mL/day, 15 mL/week
  • Onset/duration: Analgesia within 6-8 breaths; effects persist ~30 minutes after stopping inhalation; each 3 mL dose lasts approximately 25-30 minutes
  • Key danger: Nephrotoxicity at high cumulative doses (>2.5 MAC hours historically); avoid in pre-existing renal disease, diabetes mellitus; do NOT use on consecutive days; avoid with tetracyclines
  • Special: Non-opioid alternative for acute trauma pain; portable and disposable device; patient controls depth of analgesia; warn of potential headache, dizziness, and fruity smell; maintain adequate ventilation; contraindicated with known malignant hyperthermia susceptibility
💡 The "Green Whistle": Named for the distinctive green color of the Penthrox inhaler. Originally used as a general anesthetic in the 1960s-70s, now repurposed at low analgesic doses. Popular in Australian/New Zealand EMS since the 1970s; approved in UK/Ireland/EU for trauma pain.
Brand & Generic Names
  • Generic Name: Methoxyflurane
  • Brand Names: Penthrox, Penthrane (discontinued anesthetic formulation)
  • Common Nicknames: "Green Whistle," "Penthrane Whistle"
Medication Class

Volatile halogenated ether, inhaled analgesic (subanesthetic dose), general anesthetic (historic use)

Pharmacology

Mechanism of Action:

  • Positive allosteric modulator of GABAA and glycine receptors in the CNS
  • At subanesthetic concentrations, provides potent analgesia and sedation without loss of consciousness
  • Exact mechanism not fully defined; likely involves multiple molecular targets in brain and spinal cord
  • High lipid solubility allows rapid CNS penetration and persists in fat compartments, providing sustained analgesia

Pharmacokinetics:

  • Onset: Rapid—analgesia after 6-8 breaths (within 1-2 minutes)
  • Duration: Effects last approximately 30 minutes after cessation; may persist longer due to high lipid solubility
  • Metabolism: ~70% hepatically metabolized via O-demethylation to fluoride ions and dichloroacetic acid (DCAA)—metabolites responsible for historical nephrotoxicity at anesthetic doses
  • Elimination: Metabolites excreted renally; slow release from fat stores
  • MAC: 0.16% (extremely potent; analgesic doses are well below anesthetic threshold)
ℹ️ Key Property: Blood:Gas partition coefficient of 12 (high solubility) means slow induction/emergence as an anesthetic, but excellent for sustained low-dose analgesia.
Indications
  • Primary indication: Emergency relief of moderate to severe acute pain due to trauma
  • Prehospital analgesia (ambulance services, military field medicine)
  • Short painful procedures (wound care, dressing changes, fracture reduction, IUD insertion)
  • Labor analgesia (historic use)
  • Burns dressing changes
  • Alternative to nitrous oxide (Entonox) when contraindicated (chest injuries, pneumothorax)
💡 Prehospital Advantage: Unlike Entonox, methoxyflurane is safe in chest trauma/pneumothorax and doesn't require bulky cylinders—the Penthrox inhaler fits in a pocket.
Conditions Treated
  • Acute traumatic pain (fractures, dislocations, lacerations)
  • Procedural pain (minor surgeries, wound debridement)
  • Burns
  • Renal colic
  • Visceral pain (prehospital abdominal pain)
  • Musculoskeletal injuries
  • Gynecological procedures (IUD insertion/removal)
Dosing & Administration

Available Forms:

  • Penthrox inhaler: 3 mL single-use vial with handheld device
  • Activated charcoal chamber (AC chamber) clips to mouthpiece to absorb exhaled vapors

Dosing:

Patient Population Single Dose Maximum Daily Maximum Weekly
Adults 3 mL inhaled PRN 6 mL (two doses) 15 mL
Children ≥5 years 3 mL inhaled PRN (with supervision) 6 mL 15 mL

Administration Technique:

  • Patient holds device and breathes through mouthpiece, controlling depth of inhalation
  • Dilution hole can be covered intermittently for stronger effect
  • Use AC chamber to reduce environmental vapor exposure
  • Patient remains conscious and in control throughout
  • Must be administered under direct medical supervision
⚠️ Dosing Limits: Do NOT exceed 6 mL in 24 hours or 15 mL in 7 days. Do NOT use on consecutive days. Risk of nephrotoxicity increases with cumulative exposure.
Contraindications

Absolute Contraindications:

  • Known hypersensitivity to methoxyflurane or other fluorinated anesthetics
  • Personal or family history of malignant hyperthermia
  • Pre-existing renal impairment or nephropathy
  • Diabetes mellitus (increased nephrotoxicity risk)
  • Use within 5 days of prior methoxyflurane administration
  • Concurrent tetracycline antibiotics (synergistic nephrotoxicity)
  • Altered level of consciousness (patient cannot self-administer safely)

Relative Contraindications:

  • Hepatic impairment
  • Concurrent use of other potentially nephrotoxic agents
  • Patients taking enzyme-inducing drugs (may increase toxic metabolites)
  • Cardiovascular instability (though generally hemodynamically well-tolerated)
Adverse Effects

Common (at analgesic doses):

  • Headache
  • Dizziness, lightheadedness
  • Drowsiness, somnolence
  • Nausea
  • Euphoria or feeling of relaxation
  • Cough

Rare/Serious (typically at anesthetic doses):

  • Nephrotoxicity: High-output renal failure, nephrogenic diabetes insipidus (dose-dependent, seen historically with anesthetic use >2.5 MAC hours)
  • Hepatotoxicity: Rare, dose-dependent
  • Malignant hyperthermia: Potential trigger in susceptible individuals
  • Respiratory depression (at high concentrations)
  • Hypotension
  • Amnesia
ℹ️ Safety at Analgesic Doses: No significant nephrotoxicity has been reported with cumulative doses up to 6 mL (analgesic use). Toxicity was primarily seen at prolonged anesthetic exposure (>2.5 MAC hours).
Drug Interactions

Major Interactions:

  • Tetracyclines: Contraindicated—synergistic nephrotoxicity, potentially fatal
  • Other nephrotoxic drugs: NSAIDs, aminoglycosides, vancomycin—use caution, may potentiate renal effects
  • Enzyme inducers: Phenytoin, carbamazepine, rifampin—may increase formation of nephrotoxic metabolites

Moderate Interactions:

  • CNS depressants: Opioids, benzodiazepines, alcohol—additive sedation
  • Other volatile anesthetics: Additive effects if used concurrently
Clinical Pearls
💡 Non-Opioid Advantage: Methoxyflurane provides effective analgesia without opioid-related concerns (respiratory depression ceiling, constipation, dependence). Ideal for opioid-sparing prehospital protocols.
💡 Patient Self-Titration: The unique benefit of the Green Whistle is patient control—they inhale as needed and stop when pain is controlled, providing built-in dosing safety.
💡 Chest Trauma Advantage: Unlike nitrous oxide (Entonox), methoxyflurane does NOT expand air-filled spaces. Safe to use with pneumothorax, chest injuries, bowel obstruction.
💡 Pediatric Use: Approved for children ≥5 years old in many countries. The simple inhaler device is well-tolerated and easy for children to use with supervision.
💡 Occupational Exposure: Use the activated charcoal (AC) chamber attachment to minimize provider exposure. NIOSH recommends exposure limit of 2 ppm over 60 minutes.
Special Populations

Pregnancy (Category C in Australia):

  • May be used during labor for analgesia
  • Historically used in obstetrics without significant fetal effects at analgesic doses
  • Cross-references should be made to local guidelines

Pediatrics:

  • Approved for children ≥5 years old
  • Same dosing as adults (3 mL per dose)
  • Must be under direct supervision
  • Child must be able to follow instructions for self-administration

Geriatrics:

  • Use with caution in elderly patients
  • Consider reduced renal function—may increase toxicity risk
  • Monitor for excessive sedation

Renal Impairment:

  • Contraindicated in pre-existing renal disease

Hepatic Impairment:

  • Use with caution; monitor for adverse effects
References
  • 1. Jephcott C, Grummet J, Nguyen N, Spruyt O. A review of the safety and efficacy of inhaled methoxyflurane as an analgesic for outpatient procedures. Br J Anaesth. 2018;120(5):1040-1048.
  • 2. Grindlay J, Babl FE. Review article: Efficacy and safety of methoxyflurane analgesia in the emergency department and prehospital setting. Emerg Med Australas. 2009;21(1):4-11.
  • 3. McLennan JV. Is methoxyflurane a suitable battlefield analgesic? J R Army Med Corps. 2007;153(2):111-113.
  • 4. Babl FE, Jamison SR, Spicer M, Bernard S. Inhaled methoxyflurane as a prehospital analgesic in children. Emerg Med Australas. 2006;18(4):404-410.
  • 5. Mazze RI. Methoxyflurane revisited: tale of an anesthetic from cradle to grave. Anesthesiology. 2006;105(4):843-846.
  • 6. Australian Medicines Handbook. Methoxyflurane. 2025 Edition.
  • 7. National Prescribing Service (Australia). Methoxyflurane (Penthrox) for analgesia. NPS RADAR. 2010.
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