Methoxyflurane: The Inhaled Analgesic the United States Does Not Have

Methoxyflurane is the analgesic that makes American clinicians envious at international conferences. A colleague in Melbourne, London, Toronto or Madrid hands a patient a small green plastic inhaler, the patient breathes through it themselves, and within a minute or two a procedure that would have required an oral premedication and a driver becomes tolerable. The device is called Penthrox, it is not available in the United States, and there are specific, non-trivial reasons for that which are worth understanding even though you cannot use it.

I want to be unambiguous at the outset, because this is the kind of article that gets misread: methoxyflurane is not approved in the United States for any indication, it cannot lawfully be obtained or used in US practice, and importation is not a workaround. Nothing below should be read as suggesting otherwise. What follows is a practice-gap piece — what the rest of the world has, why we do not have it, and what that tells you about the inhaled rung of a comfort plan generally.

What it actually is

Penthrox is a single-use, hand-held inhaler — the "green whistle" — loaded by a healthcare professional with 3 mL of 99.9% methoxyflurane. The patient holds it and inhales through it. It is used with an activated carbon chamber that adsorbs exhaled vapour, which is not an optional accessory; more on that below.

Self-administration is the design. The patient controls the dose. If the patient becomes drowsy, they stop inhaling, and the concentration falls. This is the same architecture that makes patient-delivered nitrous oxide safe, and it is why a non-anesthetist can supervise it.

Duration. Continuous inhalation of one 3 mL bottle provides analgesia for roughly 25 to 30 minutes. Intermittent inhalation — which is how it is typically used for a procedure — stretches that out.

The potency question, resolved properly

There is a persistent confusion about how methoxyflurane compares to nitrous oxide, and it is worth settling with numbers because the two intuitions people hold are both wrong.

Minimum alveolar concentration, MAC, is the standard measure of inhalational anesthetic potency. Lower MAC means more potent.

On that measure methoxyflurane is roughly 650 times more potent than nitrous oxide. That is not a rhetorical flourish; it is 104 divided by 0.16. Nitrous oxide's MAC is above 100%, which is precisely why nitrous cannot serve as a sole general anesthetic at one atmosphere — you cannot deliver enough of it and still deliver oxygen.

Now the two caveats that must never be dropped from that comparison.

MAC measures anesthetic potency, not analgesic potency. A 650-fold ratio in MAC does not translate into 650 times the pain relief. The two properties dissociate.

Penthrox is deliberately used at sub-anesthetic doses. A single 3 mL inhaler delivers on the order of 0.3 MAC-hours. The maximum weekly analgesic exposure — five inhalers — is roughly 0.59 MAC-hours. For context, the threshold below which nephrotoxicity has not been demonstrated sits around 2 MAC-hours. The analgesic product lives an order of magnitude below the dose at which the drug's famous problem appears.

So the correct statement is not "it is like nitrous" and not "it is a general anesthetic in a tube." It is: a far more potent agent than nitrous oxide, used at a deliberately tiny fraction of an anesthetic dose, to produce analgesia and light anxiolysis while the patient remains conscious and in control of the delivery.

Why the United States does not have it

This is the part most people get wrong, and the history is genuinely instructive.

Methoxyflurane was approved in the United States — as Penthrane, a volatile general anesthetic at the same 99.9% concentration, used in surgical anesthesia for decades. It was associated with serious, irreversible and sometimes fatal nephrotoxicity, dose-related, and mediated by inorganic fluoride ions generated when the drug is demethylated in the liver. Distribution in the US and Canada ended in 1999, and in September 2005 the FDA formally determined that Penthrane had been withdrawn from sale for reasons of safety or effectiveness — a Federal Register determination that has the practical consequence of preventing FDA from accepting or approving generic applications for methoxyflurane inhalation liquid at that concentration.

The low-dose analgesic inhaler is a separate development program with a separate dose-response profile. The fluoride numbers tell the story cleanly:

• No nephrotoxicity demonstrated below serum inorganic fluoride of about 40 µmol/L (≈ 2 MAC-hours).
• Clinical toxicity above roughly 90 µmol/L.
• After a single 3 mL analgesic dose, serum levels did not exceed about 10 µmol/L.

That is a drug whose danger is entirely a matter of dose, and whose analgesic formulation sits a long way below the threshold. It is also why the regulators who have approved it have wrapped it in unusually strict ceilings.

Penthrox was placed on clinical hold in the US; that hold was lifted in 2022, and the manufacturer has been pursuing a Phase 3 trial in trauma pain. As of writing I find no evidence of US marketing approval. If that changes, it will change through the normal approval pathway, and the practical facts below will change with it.

Where it is approved, and for what

The approved indications are narrower than the enthusiasm suggests, and they differ by market in a way that matters:

• United Kingdom: "Emergency relief of moderate to severe pain in conscious patients aged 6 years and older with trauma and associated pain."
• Australia: "Self administration to conscious haemodynamically stable patients with trauma and associated pain, under supervision by personnel trained in its use."
• Canada: "short-term relief of moderate to severe acute pain, associated with trauma or interventional medical procedures, in conscious adult patients."

Canada is the outlier and the one that matters for our purposes: it is the only one of the three whose indication explicitly extends to procedural pain rather than trauma. The Canadian monograph also states plainly that use as an anesthetic agent is contraindicated, and that the product is not for breakthrough chronic pain or repetitive pain.

The safety architecture

The dose ceilings are meticulous, and they are market-specific — cite the right ones for the right jurisdiction.

• Canada: maximum 6 mL (two bottles) in a single administration or across 48 hours; maximum 15 mL (five bottles) over three months; treatments not repeated at intervals shorter than three months.
• United Kingdom: maximum 6 mL per day, 15 mL per week.

The Canadian product monograph carries a Serious Warnings and Precautions box:

"Supratherapeutic doses of methoxyflurane inhalation, have been shown to lead to serious, irreversible nephrotoxicity in a dose-related manner… Dosing limitations should be followed meticulously to prevent or limit risk of nephrotoxicity."

Very rare hepatotoxicity has also been reported.

Contraindications include altered level of consciousness from any cause; clinically significant renal impairment; history of liver dysfunction after previous methoxyflurane or other halogenated anesthetics; hypersensitivity to halogenated anesthetics; known or genetically susceptible malignant hyperthermia, or a history of severe adverse reactions in the patient or relatives; clinically evident haemodynamic instability; and clinically evident respiratory impairment. It is not indicated in pregnancy or the peripartum period.

Driving. This is where a common assumption fails. Unlike nitrous oxide — where rapid offset is the central practical advantage — the methoxyflurane labelling explicitly states that it may adversely influence the ability to drive and use machines, and that patients experiencing dizziness should be advised not to drive or operate machinery during administration. The patient information carries the same warning about feeling dizzy or drowsy afterwards. Do not carry across the "no driver needed" argument from nitrous.

Occupational exposure. The labelling is direct about this: clinicians regularly exposed to patients using the inhaler should follow occupational health guidance for inhalational agents, and the inhaler should always be used with the activated carbon chamber. Repeated use without it creates additional risk, and elevated liver enzymes have been reported in repeatedly exposed staff. In a clinic doing multiple procedures a day, staff exposure is not a theoretical concern.

The honest evidence position for aesthetics

Here is where I have to be blunt, because the aesthetic trade conversation about this drug has run ahead of the data.

There is a 2024 review in Skin Therapy Letter — Johnston and colleagues, on inhaled analgesia with methoxyflurane in dermatologic settings — which proposes a long list of applications: full-face ablative and non-ablative fractional resurfacing, laser tattoo removal, laser hair removal, radiofrequency microneedling, radiofrequency and ultrasound skin tightening, sclerotherapy, dermal filler injection, intralesional injection, PRP for hair loss, botulinum toxin injection, photodynamic therapy.

That same review states that no studies have been published on methoxyflurane use during dermatologic procedures.

It is an expert proposal extrapolated from emergency medicine, burn care and endoscopy — not dermatologic evidence. None of it is on-label anywhere. There are registered trials in other procedural settings, including urologic procedures, hysteroscopy, nasal fracture reduction, sinus procedures and dental emergencies, and at least one registration in outpatient aesthetic surgery and facial filler. Trial registrations are not results, and none of those programmes has reported in a way that changes the position for a US aesthetic practice.

So the accurate summary is: plausible mechanism, strong procedural track record in other specialties, no published aesthetic efficacy data, and unavailable in the United States regardless.

What a US injector should take from this

Three things.

Understand the inhaled rung generally. The argument for inhaled analgesia in aesthetic practice is not about a particular molecule. It is about a delivery architecture: patient-controlled, self-limiting, fast on, fast off, no driver logistics, no controlled-substance record. In the United States that architecture is available — it is nitrous oxide. The companion piece in this cluster covers nitrous properly, including the parts most practices overlook, which are scavenging, ventilation and state regulation.

Recognise it when a patient describes it. Patients who have had procedures in Australia, the UK, Canada or much of Europe may tell you they were given "a green whistle" or "the pain inhaler." Knowing what that was, and being able to explain why you cannot offer the same thing, is a better answer than a blank look.

Read the international literature with the gap in mind. When a study out of Australia or the UK reports comfort outcomes in laser resurfacing or thread lifting, check what analgesia they used before you compare their results to yours. A procedure that is tolerable under inhaled methoxyflurane may not be tolerable under your protocol, and that difference is not a technique difference.

The procedures where this question bites hardest are the long thermal and traction-based ones — laser resurfacing, thread lifting and scalp restoration work — and the comfort strategy for those is taught inside Empire Medical Training's hands-on curriculum alongside the technique itself.

This discussion reflects Dr. Jennifer Thomas-Goering's clinical perspective as taught in Empire Medical Training's hands-on curriculum. Methoxyflurane is not approved for use in the United States. Regulatory status, indications and dose ceilings are jurisdiction-specific and must be verified against the applicable national labelling. This article is educational and is not a substitute for training.

Dr. Jennifer Thomas-Goering, DO, MBA is a board-certified anesthesiologist, clinical lead instructor and executive committee member at Empire Medical Training, and founder of an aesthetics practice in Ann Arbor, Michigan.

Frequently Asked Questions

Is methoxyflurane available in the United States?

No. Methoxyflurane is not approved in the US for any indication. It was formerly marketed as Penthrane, a general anesthetic, which was discontinued in 1999; in 2005 the FDA formally determined it had been withdrawn for reasons of safety or effectiveness. The low-dose analgesic inhaler is a separate program that has not received US marketing approval.

How potent is methoxyflurane compared with nitrous oxide?

By minimum alveolar concentration, methoxyflurane is roughly 650 times more potent — MAC of about 0.16% versus 104% for nitrous oxide. But MAC measures anesthetic potency, not analgesic potency, and the analgesic inhaler delivers a deliberately sub-anesthetic dose of about 0.3 MAC-hours, far below the threshold at which nephrotoxicity has been demonstrated.

Why was methoxyflurane withdrawn as an anesthetic?

Dose-related, serious and sometimes irreversible nephrotoxicity, caused by inorganic fluoride released during hepatic metabolism. Sustained general-anesthetic exposure generates fluoride levels well into the toxic range. The analgesic formulation produces serum fluoride levels roughly an order of magnitude lower, which is the pharmacologic basis for treating it as a different risk proposition — within strict dose ceilings.

Can patients drive after methoxyflurane?

The labelling warns that it may adversely affect the ability to drive and operate machinery, and advises patients experiencing dizziness not to do so. This is a meaningful contrast with nitrous oxide, where rapid offset is the central practical advantage. Do not assume the two inhaled agents behave the same way on discharge.

Is there evidence for methoxyflurane in aesthetic procedures?

Not yet. A 2024 dermatology review proposes a wide range of aesthetic applications but states explicitly that no studies have been published on methoxyflurane use during dermatologic procedures. Registered trials exist in other procedural specialties, and at least one in outpatient aesthetic surgery, but registrations are not results.

Disclaimer

This article reflects the clinical opinions and experience of Dr. Jennifer Thomas-Goering, DO, MBA, an independent faculty member contributing to Empire Medical Training's curriculum. The views expressed are the author's own and do not necessarily represent those of Empire Medical Training.

It is professional education, not medical advice, and is no substitute for hands-on training or independent clinical judgment. Licensed clinicians remain responsible for their own patient selection, technique and outcomes, for verifying current product labelling, and for practising within their scope and applicable law. Empire Medical Training accepts no liability for reliance on this content.

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