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Methoxyflurane

Methoxyflurane is a fluorinated isopropyl ether that acts as an inhaled volatile anesthetic and analgesic, providing rapid-onset pain relief and muscle relaxation through central nervous system depression.^[1] It is administered via a portable, self-contained inhaler device, delivering low concentrations (typically 0.2–0.5%) for short-term use in conscious patients, with effects beginning within 6–8 breaths and lasting up to 30 minutes per dose.^[2] Originally synthesized in 1958 and introduced clinically in the early 1960s as a general anesthetic for surgical induction and maintenance, methoxyflurane induces hypnosis, immobility, and amnesia at higher doses (up to 2–3%) but was largely discontinued for this purpose by the 1970s due to dose-dependent nephrotoxicity from its metabolites.^[3]^[4] In its modern application, methoxyflurane is approved and widely used at sub-anesthetic doses for the emergency management of moderate to severe acute trauma pain, burns, and procedural discomfort in prehospital, emergency department, and ambulatory settings, particularly in Australia, New Zealand, over 55 countries worldwide including Canada (approved 2022) and the UK, but not approved for human use in the United States due to historical safety concerns.^[5]^[2]^[6] Marketed under the brand name Penthrox, it offers a non-opioid alternative that patients can self-administer, with strict dosing limits of no more than 6 mL (two 3 mL doses) per day and 15 mL per week to minimize risks of renal and hepatic injury.^[7] Clinical studies demonstrate its efficacy in reducing pain scores by 30–50% within 5–10 minutes, comparable to or faster than intravenous opioids or standard analgesics, while maintaining hemodynamic stability and low sedation levels.^[8]^[9] The pharmacology of methoxyflurane involves inhalation-induced diffusion into the bloodstream and brain, where it modulates GABA_A receptors and inhibits excitatory neurotransmission, though the exact mechanism remains incompletely understood.^[4] It undergoes hepatic metabolism via cytochrome P450 enzymes to form dichloroacetic acid and other fluoride-containing compounds, which can cause reversible renal dysfunction if cumulative exposure exceeds safe thresholds; monitoring of renal function is recommended for repeated use.^[10] Common side effects include dizziness, nausea, and somnolence, with rare instances of hypersensitivity or environmental exposure concerns for healthcare providers.^[11] Despite its historical challenges, low-dose methoxyflurane's portability, ease of use, and opioid-sparing profile have solidified its role in acute pain protocols, supported by decades of real-world safety data from tens of millions of administrations worldwide as of 2025.^[2]

Medical Uses

General Anesthesia

Methoxyflurane, introduced in the early 1960s, served as an inhalational anesthetic for the induction and maintenance of general anesthesia in surgical settings, delivering deep hypnosis and profound analgesia suitable for a range of procedures. Its high lipid solubility enables effective central nervous system depression, supporting stable anesthetic depths during operations. Clinically, it was administered via vaporizers in oxygen or nitrous oxide-oxygen mixtures, with induction typically achieved through progressive increases in concentration to avoid excessive respiratory depression. The agent's potency is notable, with a minimum alveolar concentration (MAC) of 0.16% in humans—substantially lower than halothane's 0.75%—indicating superior anesthetic strength on a volume basis and allowing lower inspired concentrations for equivalent effect. For full surgical anesthesia, maintenance typically involves 0.2–0.5% methoxyflurane in oxygen, sustaining unconsciousness and immobility for the procedure's duration, often several hours, while permitting adjustments for lighter or deeper planes as needed.^[12] Methoxyflurane induces significant muscle relaxation by altering neuronal excitability in the central nervous system, which aids endotracheal intubation and enhances surgical conditions through reduced skeletal muscle tone. This property was particularly valued in historical applications for procedures requiring good abdominal relaxation without supplemental neuromuscular blockers. Due to evolving safety profiles, its role in general anesthesia has diminished, shifting toward low-dose uses for analgesia.^[4]

Acute Pain Management

Methoxyflurane is primarily used at low doses (approximately 0.2-0.5%) for self-administered analgesia in conscious patients experiencing moderate to severe acute pain, particularly in emergency and pre-hospital settings, without inducing loss of consciousness.^[2] It is indicated for trauma-related pain, such as fractures or soft tissue injuries, and procedural pain including shoulder dislocation reduction, intrauterine device (IUD) insertion, endometrial biopsy, and other minor gynecological interventions.^[13]^[14] Additionally, it has emerging applications for acute oral emergencies, such as dental abscesses or post-extraction pain in outpatient care.^[15] Clinical studies demonstrate methoxyflurane's efficacy in providing rapid pain relief, with onset typically within 4–5 minutes and significant reductions in visual analog scale (VAS) pain scores compared to placebo.^[16] In trauma patients, randomized controlled trials have shown it outperforms placebo, achieving mean VAS reductions of 18-20 mm greater than controls at 15 minutes post-administration.^[17] For procedural pain, such as dislocation reductions, it offers analgesia comparable to standard sedation techniques while allowing quicker recovery.^[18] In 2025, methoxyflurane received approval in Ireland for use in children aged 6 years and older for trauma-related acute pain, following the MAGPIE trial which confirmed its superior pain reduction over placebo in pediatric populations.^[19]^[20] Systematic reviews published that year supported its role in managing acute oral pain during emergency dental procedures, highlighting consistent efficacy and tolerability.^[15] For gynecological procedures, reviews affirmed its benefits in outpatient settings like hysteroscopy and IUD placement, with reduced pain scores and high patient satisfaction.^[6] As a non-opioid analgesic, methoxyflurane serves as an alternative in pre-hospital care for both adults and children, with 2025 trials demonstrating cost-effective pain control in trauma scenarios and confirming safety profiles without increased risks of adverse events.^[21]^[22] These developments underscore its value in resource-limited environments, delivered via portable handheld inhalers for patient-controlled administration.^[2]

Administration and Dosage

Delivery Methods

Methoxyflurane is primarily administered via a handheld, disposable inhaler device known as the Penthrox inhaler, which allows for patient self-administration in clinical and prehospital settings. The device consists of a plastic inhaler body with a wick for vaporization, a one-way valve to prevent exhalation into the inhaler, and an optional attachment point for supplementary gases. To prepare the inhaler, the contents of a 3 mL bottle of methoxyflurane are poured into the base while the device is tilted at a 45° angle and rotated to ensure even distribution onto the wick.^[23]^[7] An activated carbon (AC) chamber is inserted into the dilutor hole on the top of the inhaler prior to use, which adsorbs exhaled methoxyflurane vapor to minimize occupational and environmental exposure. The inhaler entrains room air through the dilutor hole for dilution during inhalation, typically delivering a concentration of 0.2–0.5% methoxyflurane; for a stronger effect, the patient can cover the dilutor hole with a finger to reduce air entrainment. In clinical settings, supplementary oxygen can be delivered by attaching tubing to the base of the inhaler, allowing dilution with oxygen instead of air while maintaining the device's portability.^[2]^[7]^[24] Patients are instructed to hold the inhaler upright, place the mouthpiece between their lips, and inhale slowly and deeply for 3–5 breaths, followed by a 15–20 second pause before repeating if needed, to achieve onset of effect within 6–10 breaths. Administration should occur in a well-ventilated area, and the device is designed for intermittent use to control dosing. After use, the inhaler is sealed and disposed of as pharmaceutical waste according to local regulations, as it cannot be refilled or reused.^[23]^[25]^[26] For pediatric use, the same Penthrox inhaler is employed, with approvals in Europe as of 2025 extending its application to children aged 6 years and older following clinical trials demonstrating safety and efficacy in acute trauma pain relief. These trials utilized the standard device without modifications, emphasizing supervised self-administration to ensure appropriate technique and monitoring for side effects like dizziness.^[19]^[20]

Dosing Regimens

Methoxyflurane is primarily used in low doses for analgesia via self-administration using a portable inhaler device. The standard analgesic dose is up to 3 mL per session, providing approximately 20-30 minutes of relief with continuous inhalation or up to 1 hour with intermittent use; a second 3 mL dose may be administered if needed, but the total should not exceed 6 mL in a single day or 15 mL in one week to minimize risks.^[25]^[2] Formerly used for general anesthesia (though rarely employed today due to nephrotoxicity concerns), methoxyflurane was vaporized and delivered in a carrier gas such as oxygen or an oxygen-nitrous oxide mixture, with concentrations typically ranging from 0.5% to 2% by volume, titrated to the desired depth of anesthesia based on patient response and monitoring.^[4] The 2025 European Methoxyflurane Guideline (EMHG) reinforces these limits for safe use in emergency settings, recommending a maximum of 2 doses (6 mL total) per day and 5 doses (15 mL total) per week to prevent nephrotoxicity from cumulative exposure.^[27] In pediatric patients aged 6 years and older, dosing follows similar protocols to adults at up to 6 mL per day, as demonstrated effective and safe in the 2025 MAGPIE trial conducted in Ireland, though clinicians should consider weight-based adjustments and enhanced monitoring for repeated administrations to ensure safety.^[20]^[25]

Pharmacology

Pharmacokinetics

Methoxyflurane is administered via inhalation and exhibits rapid absorption through the pulmonary vasculature, facilitated by its high lipid solubility. This property is quantified by a blood:gas partition coefficient ranging from 10.2 to 14.1, with a typical value of approximately 12, which allows for efficient uptake into the bloodstream despite the relatively high solubility in blood compared to less soluble inhalational agents. At low analgesic doses delivered through a handheld inhaler, onset of action occurs within minutes, enabling self-administration for short-term pain relief.^[25]^[28] Following absorption, methoxyflurane distributes rapidly to the central nervous system and other lipid-rich tissues due to its high oil:gas partition coefficient of about 825 and low water solubility (water:gas partition coefficient of 4.5). This preferential partitioning into adipose tissue contributes to its potential for accumulation with repeated or prolonged exposure, although at recommended low doses for analgesia (up to 6 mL per day), tissue accumulation is minimal and recovery is prompt. The drug equilibrates quickly with the brain, supporting its analgesic effects without significant delay in low-concentration scenarios.^[25] Methoxyflurane undergoes hepatic metabolism primarily via cytochrome P450 2E1 (CYP2E1), with minor contributions from CYP2A6, producing metabolites including inorganic fluoride ions, dichloroacetic acid, and difluoromethoxyacetic acid. Methoxyflurane may also undergo metabolism in kidney microsomes, contributing to local fluoride formation.^[29] Approximately 50-70% of absorbed methoxyflurane is metabolized, with the absolute production of fluoride and other metabolites being lower at analgesic doses due to limited total uptake. Excretion occurs through the lungs as unchanged drug (approximately 30-40% of uptake) and as carbon dioxide from metabolism, with the remainder (~60%) eliminated renally as metabolites such as fluoride (about 8% of uptake) and organic fluorine compounds (about 29% of uptake). The apparent elimination half-life for analgesic effects, based on blood concentration decline, is 15-60 minutes, allowing for rapid recovery post-administration.^[30]^[31]^[32]^[29]

Pharmacodynamics

Methoxyflurane, an inhalational anesthetic, primarily exerts its effects through modulation of neurotransmitter systems in the central nervous system (CNS). It acts as a positive allosteric modulator of GABA_A and glycine receptors, enhancing inhibitory synaptic transmission and contributing to hypnosis and muscle relaxation.^[4] Additionally, methoxyflurane inhibits excitatory glutamate receptors, including NMDA receptors, thereby reducing neuronal excitability and supporting its analgesic and anesthetic properties.^[33] These molecular interactions disrupt normal neuronal signaling, leading to a reduction in gap junction conductance by altering channel opening and closing times, which further diminishes cell-to-cell communication in neural tissues.^[10] The pharmacological actions of methoxyflurane are dose-dependent, allowing for targeted use in analgesia or anesthesia. At low doses (equivalent to approximately 0.59 MAC-hours), it provides effective analgesia via activation of spinal and supraspinal pathways, suppressing pain transmission without inducing significant sedation or loss of consciousness.^[34] In contrast, higher doses (around 1-2 MAC) produce general anesthesia by broadly depressing CNS activity, including inhibition of thalamic and cortical transmission as well as spinal motor neurons, resulting in unconsciousness, amnesia, and immobility.^[10] This selectivity enables self-administration for acute pain relief while reserving higher exposures for surgical settings. Systemically, methoxyflurane induces mild cardiovascular depression, characterized by reduced myocardial contractility, cardiac output, and arterial blood pressure, though it does not typically cause arrhythmias or significant pulmonary vascular changes.^[35] On the respiratory side, it has no notable depression of respiratory drive at analgesic doses.^[2] Furthermore, methoxyflurane exhibits additive effects with other inhalational anesthetics, lowering their required minimum alveolar concentration (MAC) and facilitating combined use in clinical practice.^[2]

Adverse Effects

Nephrotoxicity

Methoxyflurane undergoes hepatic metabolism to produce inorganic fluoride ions, which are the primary mediators of its nephrotoxic effects. At anesthetic doses, this metabolism results in elevated serum fluoride concentrations exceeding 50 µmol/L, leading to vasopressin-resistant polyuria and high-output renal failure characterized by impaired urine concentrating ability and tubular dysfunction.^[36]^[29]^[37] The nephrotoxicity is dose-dependent, with clinical manifestations including polyuria, elevated blood urea nitrogen (BUN), and serum creatinine levels, typically appearing hours to days post-exposure. Frequent or repeated exposure increases the risk of nephrotoxicity, with recommendations to limit cumulative doses through daily (≤6 mL) and weekly (≤15 mL) restrictions to stay below nephrotoxic thresholds.^[25]^[2] Recent real-world studies, including a 2023 post-authorization safety study of over 100,000 administrations, confirm no increased risk of nephrotoxicity with low-dose use compared to standard analgesics.^[11] Monitoring involves serial assessment of serum fluoride levels and renal function tests, such as BUN and creatinine, particularly in patients receiving higher doses, to detect early signs of toxicity. In contrast, low-dose analgesic regimens limited to less than 6 mL per administration remain below the nephrotoxic threshold, with 2025 guidelines recommending no more than 6 mL per day and 15 mL per week to ensure safety.^[27]^[38]

Hepatotoxicity

Hepatotoxicity associated with methoxyflurane is a rare adverse effect, primarily observed in the context of high-dose anesthetic use rather than low-dose analgesic administration. Elevated liver transaminases occur in less than 1% of cases, with severe hepatitis or hepatic failure reported in fewer than 1 in 10,000 exposures based on post-marketing surveillance data. Recent real-world studies, including a 2023 post-authorization safety study of over 100,000 administrations, confirm no increased risk of hepatotoxicity with low-dose use compared to standard analgesics.^[31]^[12]^[11] The mechanism of methoxyflurane-induced hepatotoxicity is thought to involve immune-mediated reactions, similar to those seen with halothane, where metabolism by hepatic cytochrome P450 enzymes (primarily CYP2E1 and CYP2A6) produces reactive intermediates that trigger hypersensitivity.^[39]^[40] These metabolites may lead to hepatocellular necrosis, with histologic findings resembling viral hepatitis, including eosinophilic infiltrates in some instances.^[39] Risk factors include repeated or prolonged exposure to methoxyflurane, prior history of liver injury from halogenated anesthetics, and pre-existing hepatic impairment, which may exacerbate susceptibility due to altered metabolism.^[31]^[25] Enzyme-inducing agents, such as chronic alcohol use, can increase the production of toxic metabolites, heightening the risk.^[31] Incidence appears higher with anesthetic doses compared to subanesthetic analgesic levels, where such events are exceptionally uncommon.^[11] Clinically, hepatotoxicity may present with transient elevations in liver enzymes, nausea, jaundice, and fever, typically emerging 2–14 days post-exposure, though fulminant cases with hepatic failure have been documented.^[39]^[41] Symptoms often resolve upon discontinuation, but severe instances can progress to hepatorenal syndrome or death, particularly with multiple exposures.^[42] In low-dose analgesic settings, such as emergency pain management, reports of significant liver injury remain minimal, with no increased incidence compared to standard analgesics in large cohort studies.^[11]^[12]

Other Effects

Common transient side effects of methoxyflurane inhalation include dizziness, nausea, somnolence, and cough, which are typically mild and resolve shortly after discontinuation.^[31]^[43]^[44] At higher analgesic doses, methoxyflurane may cause mild cardiovascular effects such as hypotension and bradycardia, though these are infrequent and not associated with significant clinical impact in low-dose self-administration.^[12]^[25] Respiratory effects are generally minimal, with initial airway irritation often manifesting as cough during inhalation, but overall no clinically significant depression of respiratory function; rare instances of laryngospasm have been noted in animal studies with volatile anesthetics like methoxyflurane.^[2]^[45] Neurologically, methoxyflurane can induce euphoria or disorientation during analgesic use, contributing to its dissociative properties and potential for abuse as a halogenated hydrocarbon, though supervised low-dose administration minimizes misuse risks.^[31]^[46]

Contraindications and Precautions

At-Risk Populations

Methoxyflurane is contraindicated in patients with clinically significant renal impairment (e.g., eGFR <45 mL/min), due to the risk of exacerbated nephrotoxicity from fluoride ion release during metabolism.^[47] It is also absolutely contraindicated in individuals susceptible to malignant hyperthermia, a genetic condition that can be triggered by volatile anesthetics like methoxyflurane, potentially leading to life-threatening hypermetabolism.^[27] Additionally, recent high-dose exposure to methoxyflurane or other halogenated anesthetics is an absolute contraindication, as it increases the cumulative risk of renal and hepatic damage.^[7] Relative contraindications include pregnancy, classified as category C, where animal studies have shown adverse effects on fetal development, though human data are limited, necessitating careful risk-benefit assessment.^[25] In the elderly, methoxyflurane requires caution due to age-related declines in renal function and heightened susceptibility to hypotension and bradycardia.^[7] Patients with pre-existing liver disease also warrant relative contraindication, as prior exposure to methoxyflurane has been associated with hepatic injury, potentially worsening underlying conditions.^[25] For pediatric patients, methoxyflurane is approved for use in children aged 6 years and older in Australia, New Zealand, and as of August 2025 in Ireland for acute trauma pain, with strict dose limits to mitigate risks of sedation and respiratory effects; however, approvals vary by region, with some such as the UK still restricting to 18 years and older as of July 2025.^[7]^[48]^[2] Genetic factors influencing metabolism, such as variants in the CYP2E1 enzyme responsible for methoxyflurane biotransformation, may alter fluoride production and toxicity risk, though clinically significant polymorphisms are rare. Special monitoring is essential for at-risk groups like ICU patients or those with repeated trauma, where cumulative exposure should not exceed 15 mL per week to prevent irreversible renal damage; regular assessment of renal function is recommended in these scenarios.^[7]

Drug Interactions

Methoxyflurane, acting as a central nervous system (CNS) depressant, can potentiate the effects of other CNS depressants, including opioids, benzodiazepines, and additional anesthetic agents. This interaction results in additive sedation, impaired respiratory function, and increased risk of respiratory depression, necessitating careful monitoring and dose adjustments during concurrent use.^[4]^[49] Inducers of the cytochrome P450 2E1 (CYP2E1) enzyme, such as isoniazid and chronic ethanol consumption, accelerate the metabolism of methoxyflurane to its nephrotoxic metabolites, including inorganic fluoride and dichloroacetic acid. This enhanced biotransformation elevates serum fluoride levels, thereby increasing the potential for nephrotoxicity, and such combinations should be avoided.^[50]^[25]^[51] Concurrent administration of methoxyflurane with other nephrotoxic drugs, particularly aminoglycoside antibiotics like gentamicin and amikacin, can lead to synergistic renal impairment due to cumulative effects on kidney function. Clinical reports have documented severe nephrotoxicity in such cases, underscoring the need to avoid or closely monitor these combinations.^[52]^[53]^[54] While methoxyflurane is metabolized primarily by CYP2E1 and to a lesser extent by CYP2C9 and CYP3A4, it does not significantly inhibit or induce these or other cytochrome P450 enzymes, limiting interactions to those affecting its own metabolism rather than broadly impacting other drugs.^[4]^[37]

Chemical Properties

Molecular Structure

Methoxyflurane has the molecular formula C₃H₄Cl₂F₂O and is systematically known as 2,2-dichloro-1,1-difluoroethyl methyl ether.^[10]^[55] This compound is a halogenated ether characterized by a central oxygen atom linking a methyl group (CH₃-) and a 2,2-dichloro-1,1-difluoroethyl group (CF₂CHCl₂-).^[10] The ether linkage and extensive halogen substitution on the ethyl moiety contribute to its volatility as an inhalational agent.^[56] Industrially, methoxyflurane is synthesized starting from 1,1-difluoro-2,2,2-trichloroethane, which undergoes dehydrochlorination with potassium hydroxide to yield 1,1-dichloro-2,2-difluoroethylene; this alkene then reacts with methanol in the presence of a base to form the final ether product.^[57] As an achiral molecule lacking stereocenters, methoxyflurane exhibits no optical isomers.^[10]

Physical and Chemical Characteristics

Methoxyflurane is a colorless, volatile liquid at standard temperature and pressure, with a characteristic ethereal odor.^[10] Its boiling point is 104.6 °C, and it has a melting point of -35 °C.^[58] The density is 1.426 g/mL at 25 °C, and its refractive index is 1.386.^[59] The vapor pressure of methoxyflurane is 23 mmHg at 20 °C, contributing to its suitability for inhalation delivery via low-concentration vaporization.^[60]^[61] It exhibits low solubility in water, with values less than 1 mg/mL at ambient temperatures, but demonstrates high lipophilicity, evidenced by an octanol-water partition coefficient (log P) of 2.55.^[10]^[58] Methoxyflurane is chemically stable under normal conditions of storage, including exposure to air, light, moisture, and alkali, with no significant decomposition reported.^[10] It is considered non-flammable in clinical use despite a flash point of 37 °C and a lower explosive limit of 7% in air at elevated temperatures, due to its low vapor pressure limiting ignition risks.^[62]^[59] Environmentally, as a halogenated hydrocarbon containing chlorine and fluorine, methoxyflurane has a low ozone depletion potential (approximately 0.001); however, this impact is minimized by its restricted, low-volume applications in medicine.^[63]

History

Development and Early Use

Methoxyflurane, a fluorinated ether anesthetic, was first synthesized in 1948 by chemist William T. Miller Jr. and his colleagues at Columbia University as part of research extending from their Manhattan Project work on organofluorine compounds.^[64] The first human clinical trials of methoxyflurane took place in 1960, led by anesthesiologists J.F. Artusio Jr. and Alan Van Poznak at St. Vincent's Hospital in New York. Their study involved administering the agent to 25 patients undergoing various surgical procedures, demonstrating effective anesthesia with concentrations of 0.3% to 0.7% in oxygen or nitrous oxide-oxygen mixtures. These trials highlighted methoxyflurane's ability to provide deep surgical anesthesia without significant respiratory depression or flammability risks.^[65] Building on this, additional early evaluations confirmed its utility in neurological surgery, where it offered stable hemodynamic conditions.^[66] Methoxyflurane received U.S. Food and Drug Administration approval in 1962 under the brand name Penthrane, marketed by Abbott Laboratories for use in obstetrics and general surgery. Its popularity stemmed from a blood-gas partition coefficient of approximately 1.4, lower than ether's 1.9, which contributed to relatively smooth induction and recovery despite its high potency (minimum alveolar concentration of 0.16%). Compared to ether, methoxyflurane produced minimal cardiovascular depression, preserving blood pressure and heart rate during induction, while offering potent analgesia and muscle relaxation ideal for prolonged operations.^[67]^[2] Throughout the 1960s, initial studies expanded its application, particularly in obstetrics and general surgery. Trials for cesarean sections showed methoxyflurane enabled rapid onset of analgesia with low maternal and fetal concentrations, facilitating safer deliveries when combined with nitrous oxide. In general surgery, reports from over 500 cases underscored its efficacy for procedures requiring deep relaxation, such as abdominal explorations, with fewer excitatory effects than earlier agents. These findings established methoxyflurane as a preferred option for self-administered analgesia in labor and routine operations during its early adoption phase.^[68]^[69]

Regulatory Changes

In the 1970s, methoxyflurane faced increasing regulatory scrutiny due to reports of nephrotoxicity associated with high-dose anesthetic use, leading to its gradual withdrawal from general anesthesia in several countries.^[70] In the United States, the Food and Drug Administration (FDA) formally determined in 2005 that Penthrane (methoxyflurane inhalation liquid, 99.9%) had been withdrawn from sale for safety reasons, primarily irreversible kidney damage linked to fluoride ion release during metabolism at anesthetic doses.^[67] However, Australia permitted continued low-dose use for analgesia, recognizing the reduced risk at sub-anesthetic levels below 6 mL per day.^[37] Regulatory reintroduction focused on its analgesic potential in emergency settings. The Therapeutic Goods Administration (TGA) in Australia approved Penthrox (methoxyflurane 3 mL inhaler) in 1975 for self-administered relief of moderate to severe pain in conscious patients, establishing it as a standard prehospital option.^[37] In Europe, the European Medicines Agency (EMA) authorized low-dose methoxyflurane in 2015 via a centralized procedure for emergency relief of moderate to severe trauma pain in conscious adults, marketed as Penthrox with strict dosing to avoid toxicity.^[11] As of 2025, updates have expanded its applications while emphasizing safety. The Health Products Regulatory Authority (HPRA) in Ireland approved pediatric indications for Penthrox in August 2025 for children aged 6 years and older, facilitating national approvals across European member states for acute trauma pain relief in this population.^[48] Concurrently, the European Malignant Hyperthermia Group (EMHG) reinforced dosing limits in January 2025, recommending no more than two 3 mL doses (6 mL total) per day and five doses per week to minimize risks of nephrotoxicity and occupational exposure.^[27] Globally, methoxyflurane has shifted from a broad-spectrum anesthetic to a niche inhaled analgesic for acute pain management, with approvals in over 30 countries but ongoing monitoring for abuse potential due to its central nervous system effects; in regions like Australia, it is classified as a Schedule 4 controlled substance requiring prescription oversight.^[2]^[31]

Legal Status and Availability

Global Approvals

Methoxyflurane's regulatory status varies significantly across the globe, primarily reflecting its historical use as an anesthetic versus its modern application as a low-dose analgesic for emergency relief of moderate to severe pain. In Australia, it has been classified as a Schedule 4 prescription-only medicine since the 1970s and is widely available for self-administered emergency analgesia in conscious adults and children, with inclusion on the Pharmaceutical Benefits Scheme since 2008 to support its use in prehospital settings.^[71]^[72] New Zealand mirrors this approval, permitting its use for similar indications in emergency care without restrictions on pediatric application.^[2] In Europe, the European Medicines Agency (EMA) granted centralized marketing authorization for methoxyflurane (as Penthrox) in 2015, approving it for the emergency relief of moderate to severe pain in conscious adults with trauma or medical conditions requiring analgesia, excluding general anesthesia.^[73] This approval has facilitated its availability across multiple member states, including the UK and Ireland, where it is marketed for self-administration via a handheld inhaler. Recent extensions include a pediatric indication approved by the Health Products Regulatory Authority (HPRA) in Ireland in August 2025 for children aged 6 years and older, with similar regulatory processes underway in the UK to broaden access for younger patients.^[48] In the United States, methoxyflurane was withdrawn from the market in 2005 by the Food and Drug Administration (FDA) for use as an anesthetic due to concerns over nephrotoxicity and hepatotoxicity at higher doses, and it has not received approval for low-dose analgesic indications.^[67] This effectively restricts civilian access, though limited military use persists and phase 3 trials for nasal formulations were permitted to resume in 2022 under FDA oversight.^[74] Canada approved low-dose methoxyflurane inhalation (as Penthrox) in April 2018 through Health Canada for short-term relief of moderate to severe acute pain associated with trauma in conscious adults, marking its reintroduction after prior withdrawal for anesthetic use due to toxicity risks.^[46]^[75] In other regions, approvals exist in over 55 countries including parts of Latin America, South Africa, and the Middle East for emergency analgesia as of 2025, but it remains banned or withdrawn in several nations, such as the US, primarily owing to historical concerns over renal and hepatic toxicity from prolonged or high-dose exposure.^[13]^[6]

Brand Names and Access

Methoxyflurane is commercially available primarily under the brand name Penthrox, a 3 mL self-administered inhaler developed and manufactured by Medical Developments International (MDI) for emergency pain relief.^[76] Penthrox is distributed by Mundipharma in regions including Australia and much of Europe, where it serves as the standard formulation for low-dose analgesic use in conscious adults with trauma-related pain.^[77] Historically, methoxyflurane was marketed as Penthrane by Abbott Laboratories in the 1960s as a general anesthetic, though this higher-dose product was discontinued in many markets due to safety concerns related to nephrotoxicity.^[2] Generic versions of methoxyflurane are available in limited markets, primarily for veterinary applications or through active pharmaceutical ingredient suppliers, but human-use generics remain scarce outside branded products like Penthrox.^[78] Access to methoxyflurane varies by region, with Penthrox classified as a Schedule 4 prescription medicine in Australia, typically supplied to emergency services, paramedics, and healthcare professionals for use in pre-hospital and emergency department settings.^[79] In Australia, it is not available over-the-counter to the general public but is authorized for self-administration under supervision in acute trauma scenarios, facilitating rapid deployment without immediate physician involvement.^[25] Elsewhere, such as in Europe (including the UK, Ireland, France, and Belgium) and Canada, Penthrox requires a prescription and is restricted to medical supervision for moderate to severe acute pain in adults.^[7] The approximate cost per Penthrox inhaler in Australia ranges from $67 to $93, depending on subsidized pricing through the Pharmaceutical Benefits Scheme or commercial suppliers, making it an accessible option for emergency kits despite procurement restrictions.^[80]^[81] The supply chain for Penthrox emphasizes safety through disposable, single-use inhalers containing exactly 3 mL of methoxyflurane, designed to deliver a limited analgesic dose and prevent refills or overuse that could lead to adverse effects.^[82] This tamper-evident packaging ensures controlled distribution, primarily through medical suppliers to hospitals, ambulances, and emergency services, minimizing diversion risks.^[83] As of 2025, expansions in pediatric indications have increased availability, with approvals such as Ireland's Health Products Regulatory Authority extending use to children aged 6 years and older for emergency pain relief following successful clinical trials, integrating Penthrox into pediatric emergency kits across adopting regions.^[48]^[19]

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STEP 2: Fill & Rotate. Tilt the PENTHROX Inhaler to a 45° angle and pour the total contents of one PENTHROX bottle into the base of the Inhaler whilst rotating.
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E. Partition Coefficients ; Methoxyflurane, 12.0, 970.0 ; Halothane, 2.54, 224.0 ; Isoflurane, 1.46, 91.0 ; Enflurane, 2.0, 96.0.
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