Version July 2025
Pain (moderate to severe, acute): Inhalation: Initial: 3 mL inhaled intermittently to achieve adequate analgesia; typical duration of analgesia is ~25 to 60 minutes depending on frequency of inhalation. May repeat an additional 3 mL dose if needed; maximum: 6 mL over a 48-hour period. Do not use on consecutive days. Use lowest effective dosage. A treatment course should be limited to a total dose of 15 mL over a 3-month period. Do not repeat treatment courses more frequently than at 3-month intervals.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution at the lowest effective dose. Use is contraindicated in patients with clinically significant renal impairment.
There are no dosage adjustments provided in the manufacturer's labeling; however, methoxyflurane is metabolized in the liver. Use with caution in patients with hepatic impairment. Use is contraindicated in patients who have shown signs of liver dysfunction after previous methoxyflurane use or other halogenated anesthetics.
Refer to adult dosing; use minimum effective dose.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%: Nervous system: Dizziness (8% to 30%), headache (22%)
1% to 10%:
Cardiovascular: Flushing (2%), hypertension (2%)
Dermatologic: Skin rash (1%)
Endocrine & metabolic: Increased lactate dehydrogenase (1%)
Gastrointestinal: Xerostomia (2%)
Genitourinary: Dysmenorrhea (1%)
Infection: Influenza (1%), viral infection (1%)
Nervous system: Amnesia (1%), anxiety (2%), depression (2%), drowsiness (≤5%), dysarthria (1%), euphoria (4%), falling (1%), impaired consciousness (≤2%), intoxicated feeling (1%), migraine (1%), peripheral sensory neuropathy (2%)
Neuromuscular & skeletal: Back pain (2%), sprain (1%)
Respiratory: Cough (1%)
<1%:
Dermatologic: Pruritus (oral)
Gastrointestinal: Dysgeusia, hunger, oral discomfort, sialorrhea
Nervous system: Disturbance in attention, fatigue, hangover effect, paresthesia, psychiatric disturbance (inappropriate effect, verbigeration), relaxation, shivering
Ophthalmic: Diplopia
Postmarketing:
Cardiovascular: Presyncope
Endocrine & metabolic: Increased uric acid
Hepatic: Hepatic failure, hepatic injury, hepatitis, hepatotoxicity, increased liver enzymes, jaundice
Hypersensitivity: Hypersensitivity reaction
Nervous system: Agitation, choking sensation, confusion, disorientation, dissociative reaction, drug abuse, emotional lability, restlessness
Ophthalmic: Blurred vision, nystagmus disorder
Renal: Increased blood urea nitrogen, increased serum creatinine, kidney failure
Respiratory: Hypoxia, oxygen saturation decreased, respiratory depression
Hypersensitivity to methoxyflurane, other halogenated anesthetics, or any component of the formulation; use as an anesthetic agent; renal impairment (clinically significant); hemodynamic instability (clinically evident); respiratory impairment (clinically evident); altered consciousness due to any cause, including head injury, drugs, or alcohol; history of liver dysfunction after previous methoxyflurane or other halogenated anesthetics; malignant hyperthermia or genetic susceptibility to malignant hyperthermia or a history of severe adverse reactions in either patient or relatives.
Concerns related to adverse effects:
• Cardiovascular effects: May cause dose-related bradycardia and hypotension; use with caution in elderly patients with hypotension or bradycardia. Effects are likely not significant with analgesia doses.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating heavy machinery).
• Hepatic effects: [Canadian Boxed Warning]: Very rare cases of hepatotoxicity, including hepatic injury and failure, have been reported when used for analgesic purposes; increased hepatic enzymes have also been reported. Avoid use in patients who show signs of liver damage after previous exposure to methoxyflurane or halogenated anesthetics. Use with caution in patients with underlying hepatic conditions or risk factors for hepatic dysfunction.
• Renal toxicity: [Canadian Boxed Warning]: Supratherapeutic doses have led to serious, irreversible nephrotoxicity in a dose-related manner; dosing limitations should be followed meticulously to prevent or limit the risk of nephrotoxicity; increased BUN or SCr has also been reported. Consecutive day use is not recommended due to nephrotoxic potential. Risk may also be increased when the rate of metabolism is increased, such as with coadministration with hepatic enzyme inducers or genetic variations that result in rapid metabolism. Use with caution and at the lowest effective dose in geriatric patients and patients with known risk factors or clinical conditions that would predispose to renal injury.
• Respiratory depression: May cause respiratory depression.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment; systemic exposure and risk of toxicity may be increased.
• Renal impairment: Use with caution in patients with renal impairment; use lowest effective dose due to risk of nephrotoxicity.
Special populations:
• Older adult: Use with caution in older adults; use lowest effective dose due to risk of nephrotoxicity.
• Obesity: Use with caution in obese patients due to the distribution into and slow release from fat tissue.
Special handling:
• Occupational exposure: Elevation of liver enzymes, blood urea nitrogen and serum uric acid have been reported in health workers regularly exposed to patients using methoxyflurane. To reduce occupational exposure, always attach the activated carbon chamber to inhaler, which adsorbs exhaled methoxyflurane.
Other warnings/precautions:
• Abuse/misuse/diversion: Use of higher than recommended doses may be a risk factor for substance use disorder, abuse, and misuse, potentially leading to overdose and death (Porter 2018; manufacturer's labeling).
• Appropriate use: Methoxyflurane is not appropriate for relief of chronic or repetitive pain.
• Butylated hydroxytoluene: Contains butylated hydroxytoluene, a stabilizer, which may cause local skin reactions (eg, contact dermatitis) or irritation to the eyes and mucous membranes.
Not available in the US
May be product dependent
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Inhalation:
Penthrox: 99.9% (3 mL)
Inhalation: May be self-administered under supervision of health care provider. Attach activated carbon chamber to dilutor hole on inhaler. Holding the methoxyflurane bottle upright, remove bottle cap by hand. Alternatively, may use the base of the inhaler to loosen the cap with a 1/2 turn, then remove cap by hand and separate inhaler from bottle. Tilt the inhaler to a 45° angle and slowly pour the contents of one bottle into the base while rotating to ensure wick is adequately saturated. Instruct patient to inhale and exhale through the inhaler mouthpiece. First few breaths should be gentle, then patient can breathe normally through inhaler. If stronger analgesia is required, cover diluter hole on the activated carbon chamber with finger during inhalation. Inhale intermittently; continuous administration will reduce time of analgesia.
Note: Not approved in the United States.
Pain (moderate to severe, acute): Short-term relief of moderate to severe acute pain, associated with trauma or interventional medical procedures, in conscious adults
Penthrox brand name for methoxyflurane [Australia, New Zealand, United Kingdom] may be confused with Penamox brand name for amoxicillin [multiple international markets].
ALERT: Canadian Boxed Warning: Health Canada-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling.
Substrate of CYP2A6 (Minor), CYP2E1 (Minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential;
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Acrivastine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Alcohol (Ethyl): May increase CNS depressant effects of Methoxyflurane. Alcohol (Ethyl) may increase metabolism of Methoxyflurane. Specifically, this increased metabolism may lead to increased production of nephrotoxic metabolites. Risk X: Avoid
Alizapride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Aminoglycosides: May increase nephrotoxic effects of Methoxyflurane. Risk X: Avoid
Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Amphotericin B: Methoxyflurane may increase nephrotoxic effects of Amphotericin B. Risk X: Avoid
Articaine: May increase CNS depressant effects of CNS Depressants. Management: Consider reducing the dose of articaine if possible when used in patients who are also receiving CNS depressants. Monitor for excessive CNS depressant effects with any combined use. Risk D: Consider Therapy Modification
Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Barbiturates: May increase nephrotoxic effects of Methoxyflurane. Barbiturates may increase metabolism of Methoxyflurane. Risk X: Avoid
Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Blonanserin: CNS Depressants may increase CNS depressant effects of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider Therapy Modification
Brexanolone: CNS Depressants may increase CNS depressant effects of Brexanolone. Risk C: Monitor
Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromopride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromperidol: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Buclizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Buprenorphine: CNS Depressants may increase CNS depressant effects of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider Therapy Modification
BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Cannabinoid-Containing Products: CNS Depressants may increase CNS depressant effects of Cannabinoid-Containing Products. Risk C: Monitor
Cetirizine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk D: Consider Therapy Modification
Chloral Hydrate/Chloral Betaine: CNS Depressants may increase CNS depressant effects of Chloral Hydrate/Chloral Betaine. Management: Consider alternatives to the use of chloral hydrate or chloral betaine and additional CNS depressants. If combined, consider a dose reduction of either agent and monitor closely for enhanced CNS depressive effects. Risk D: Consider Therapy Modification
Chlormethiazole: May increase CNS depressant effects of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider Therapy Modification
Chlorphenesin Carbamate: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
CNS Depressants: Methoxyflurane may increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Colistimethate: May increase nephrotoxic effects of Methoxyflurane. Risk X: Avoid
CYP2B6 Inducers (Moderate): May increase metabolism of Methoxyflurane. Specifically, this increased metabolism may lead to increased production of nephrotoxic metabolites. Risk X: Avoid
Dantrolene: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Daridorexant: May increase CNS depressant effects of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification
DexmedeTOMIDine: CNS Depressants may increase CNS depressant effects of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider Therapy Modification
Difelikefalin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Difenoxin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dihydralazine: CNS Depressants may increase hypotensive effects of Dihydralazine. Risk C: Monitor
Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dothiepin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Doxylamine: CNS Depressants may increase CNS depressant effects of Doxylamine. Risk C: Monitor
DroPERidol: May increase CNS depressant effects of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider Therapy Modification
Emedastine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk C: Monitor
Entacapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Esketamine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Flunarizine: CNS Depressants may increase CNS depressant effects of Flunarizine. Risk X: Avoid
Flunitrazepam: CNS Depressants may increase CNS depressant effects of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider Therapy Modification
HydrOXYzine: May increase CNS depressant effects of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider Therapy Modification
Iodinated Contrast Agents: May increase nephrotoxic effects of Methoxyflurane. Risk X: Avoid
Isoniazid: May increase metabolism of Methoxyflurane. Specifically, this increased metabolism may lead to increased production of nephrotoxic metabolites. Risk X: Avoid
Ixabepilone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kava Kava: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ketotifen (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kratom: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Lemborexant: May increase CNS depressant effects of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider Therapy Modification
Levocetirizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lisuride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofepramine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofexidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Loxapine: CNS Depressants may increase CNS depressant effects of Loxapine. Management: Consider reducing the dose of CNS depressants administered concomitantly with loxapine due to an increased risk of respiratory depression, sedation, hypotension, and syncope. Risk D: Consider Therapy Modification
Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Melitracen [INT]: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methotrimeprazine: CNS Depressants may increase CNS depressant effects of Methotrimeprazine. Methotrimeprazine may increase CNS depressant effects of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider Therapy Modification
Metoclopramide: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor
Moxonidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Nabilone: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Nalfurafine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Nonsteroidal Anti-Inflammatory Agents: May increase nephrotoxic effects of Methoxyflurane. Risk X: Avoid
Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid
Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Opicapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Opioid Agonists: CNS Depressants may increase CNS depressant effects of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification
Opipramol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Orphenadrine: CNS Depressants may increase CNS depressant effects of Orphenadrine. Risk X: Avoid
Oxomemazine: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Oxybate Salt Products: CNS Depressants may increase CNS depressant effects of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider Therapy Modification
OxyCODONE: CNS Depressants may increase CNS depressant effects of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification
Paliperidone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Paraldehyde: CNS Depressants may increase CNS depressant effects of Paraldehyde. Risk X: Avoid
Perampanel: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Periciazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Pipamperone: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Piribedil: CNS Depressants may increase CNS depressant effects of Piribedil. Risk C: Monitor
Pizotifen: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Polymyxin B: Methoxyflurane may increase nephrotoxic effects of Polymyxin B. Risk X: Avoid
Pramipexole: CNS Depressants may increase sedative effects of Pramipexole. Risk C: Monitor
Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Rilmenidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ropeginterferon Alfa-2b: CNS Depressants may increase adverse/toxic effects of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider Therapy Modification
ROPINIRole: CNS Depressants may increase sedative effects of ROPINIRole. Risk C: Monitor
Rotigotine: CNS Depressants may increase sedative effects of Rotigotine. Risk C: Monitor
Sevoflurane: May increase nephrotoxic effects of Methoxyflurane. Risk X: Avoid
Suvorexant: CNS Depressants may increase CNS depressant effects of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification
Tetracyclines: May increase nephrotoxic effects of Methoxyflurane. Risk X: Avoid
Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid
Trimeprazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Zolpidem: CNS Depressants may increase CNS depressant effects of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider Therapy Modification
Zuranolone: May increase CNS depressant effects of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider Therapy Modification
Methoxyflurane crosses the placenta (Clark 1970; Siker 1968); serum fluoride concentrations may be increased in neonates at birth.
Use during labor may cause dose-related central nervous system or respiratory depression in the newborn (Clark 1970).
Methoxyflurane is not indicated for use during pregnancy or the peripartum period, including labor.
It is not known if methoxyflurane is present in breast milk.
The manufacturer recommends that caution be exercised when administering methoxyflurane to breastfeeding patients.
Liver function; renal function; blood pressure; heart rate; pain relief; signs/symptoms of CNS depression (drowsiness, pallor, and muscle relaxation).
Halogenated volatile anesthetic, when inhaled at low concentrations, produces an analgesic effect. Exact mechanism in analgesia has not been elucidated; potential factors contributing to the analgesic activity include effects on substance P and beta-endorphin.
Onset of action: Rapid (5 minutes).
Duration of action: 25 to 30 minutes (continuous inhalation); ~60 minutes (intermittent inhalation).
Distribution: Highly lipophilic; diffuses into fatty tissues and is released slowly over days.
Metabolism: Hepatic; dechlorination and o-demethylation via CYP2E1, 2B6, and 2A6 to free fluoride, oxalic acid, difluoromethoxyacetic acid and dichloroacetic acid.
Half-life: Intermittent inhalation: Methoxyflurane: 3.16 hours (range: 1.06 to 7.89 hours); Metabolite: 33 hours (range: 23.5 to 51.2 hours).
Time to peak: Intermittent inhalation: 15 minutes (range: 4.8 to 45 minutes).
Excretion: Urine (~60%, as metabolites); respiratory (~40%, unaltered or as carbon dioxide).
