Understanding: What Schedule Drug is Methoxyflurane?

October 8, 2025 •

4 min read

While methoxyflurane has been used for decades in regions like Australia and New Zealand as a low-dose analgesic, its regulatory status and classification are far from uniform globally. The answer to 'what schedule drug is methoxyflurane?' depends entirely on a country's unique regulatory history, its past use as an anesthetic versus a modern analgesic, and its specific risk assessment.

Quick Summary

Methoxyflurane's legal scheduling is not uniform globally, varying from a Schedule 4 prescription-only medicine in Australia to being withdrawn for safety reasons in the U.S.. This variation is due to its history as a high-dose anesthetic causing renal toxicity versus its modern use as a low-dose inhaled analgesic.

Key Points

Jurisdictional Variation: The drug scheduling of methoxyflurane varies significantly by country, reflecting different regulatory histories and safety assessments.
Not a US Controlled Substance: Methoxyflurane is not a scheduled drug under the U.S. Controlled Substances Act but was withdrawn from the market entirely for safety reasons in 2005.
Australian Schedule 4: In Australia, methoxyflurane is a Schedule 4 (Prescription Only) medicine, widely used as a supervised analgesic in emergency settings.
Low-Dose Analgesic: Modern use of methoxyflurane is at sub-anesthetic doses via a self-administered inhaler (Penthrox) for pain relief, minimizing the renal toxicity associated with older, high-dose anesthetic use.
Safety Profile: The international use of low-dose methoxyflurane has established a favorable safety profile with mild, self-limiting side effects, unlike the severe effects seen historically at high doses.
Ongoing US Research: Despite the U.S. ban, a Phase 3 clinical trial was initiated in 2022 to potentially reintroduce methoxyflurane as an analgesic, which could lead to a change in its U.S. status.

The Historical Context of Methoxyflurane

Methoxyflurane is a fluorinated hydrocarbon volatile liquid that was first introduced in the 1960s as a powerful inhalation general anesthetic. It gained popularity due to its potency and non-explosive properties. However, by the late 1960s and 1970s, reports of dose-dependent nephrotoxicity (kidney damage) began to emerge. This toxicity was linked to the metabolism of methoxyflurane, which releases nephrotoxic fluoride ions. With the introduction of safer alternatives, its use as a general anesthetic declined significantly, and it was eventually pulled from the market in some regions entirely.

Following its discontinuation as an anesthetic, methoxyflurane found a second life at much lower, analgesic doses, particularly in the pre-hospital and emergency care settings. Administered via a patient-controlled inhaler, notably the 'green whistle' (Penthrox), it provides rapid relief for moderate to severe pain in conscious patients with trauma. This modern application relies on sub-anesthetic doses, which are associated with a low incidence of the renal and hepatic toxicity seen with earlier, higher-dose applications.

International Drug Scheduling of Methoxyflurane

The United States: Withdrawn for Safety

In the U.S., methoxyflurane is not a scheduled drug under the Controlled Substances Act, but that's because it was intentionally withdrawn from sale for safety reasons. In 2005, the Food and Drug Administration (FDA) formally determined that the risks of the drug outweighed its potential benefits, leading to its removal from the market. The FDA stated that its use for anesthesia was associated with serious and sometimes fatal nephrotoxicity and hepatotoxicity. Since then, methoxyflurane has effectively been banned for general use in the U.S., although a Phase 3 clinical trial was permitted in 2022 to evaluate its reintroduction as a low-dose analgesic.

Australia and New Zealand: A Long-Standing Schedule 4 Drug

In stark contrast to the U.S., methoxyflurane (marketed as Penthrox) is widely used in Australia and New Zealand as a fast-acting analgesic for trauma-related pain and procedures. In Australia, it is classified as a Schedule 4 (S4) poison under the national poisons standard, meaning it is a 'prescription-only medicine'. Its use is authorized for healthcare professionals and trained emergency workers, like paramedics and ski patrollers, under strict guidelines and supervision. Its long history and established safety profile at analgesic doses have made it a standard part of their emergency medicine toolkit.

Europe and the UK: Prescription Only Medicine

Methoxyflurane has also been approved for use as an analgesic in Europe, including the United Kingdom. In these regions, it is classified as a Prescription Only Medicine (POM). Its use is regulated and typically reserved for moderate-to-severe trauma pain relief in conscious adult patients. Regulatory authorities like the European Medicines Agency (EMA) authorized its use based on modern clinical trial data that supported its efficacy and safety profile at analgesic doses.

Canada: Prescription Only Status

In Canada, methoxyflurane is also available by prescription only (℞-only) for short-term relief of moderate to severe acute pain. The product is regulated and is not classified under the federal Controlled Drugs and Substances Act. Its use is supported by international data on safety and efficacy in analgesic settings, distinguishing it from the anesthetic-dose risks that led to its withdrawal elsewhere.

Factors Influencing Methoxyflurane's Global Status

Several key factors contribute to the varied drug scheduling and availability of methoxyflurane across different nations:

Risk vs. Benefit Assessment: Regulatory bodies assess the potential risks (like historical nephrotoxicity) against the benefits (rapid non-opioid pain relief). The interpretation of this balance has varied significantly.
Dose-Dependent Toxicity: The distinction between high, anesthetic doses (toxic) and low, analgesic doses (safe) is critical. Some countries have accepted this distinction, while the U.S. FDA, as of 2005, did not.
Alternative Analgesics: The availability and prevalence of alternative pain management options, such as intravenous opioids or nitrous oxide, influence how necessary and valuable methoxyflurane is perceived.
Standard of Care: The establishment of methoxyflurane as a standard practice in pre-hospital care, as seen in Australia, has created a long history of safe use that influences ongoing policy.

Comparison of Methoxyflurane Regulations by Country


Country/Region	Regulatory Status	Primary Use	Availability	Reason for Status
United States	Withdrawn for Safety	Historical Anesthetic	Not Available for civilian use	Historical concerns over nephrotoxicity at anesthetic doses
Australia	Schedule 4 (Prescription Only)	Inhaled Analgesic	Widely Available	Long history of safe use at low doses; regulated via prescribing
European Union	Prescription Only Medicine (POM)	Inhaled Analgesic	Widely Available	Approved based on clinical evidence for low-dose analgesic safety
Canada	Prescription Only (℞-only)	Inhaled Analgesic	Available	Approved for analgesic use based on international data

Conclusion: A Global Divergence in Policy

In conclusion, the simple question, 'what schedule drug is methoxyflurane?', reveals a complex global patchwork of pharmaceutical policy driven by history, safety concerns, and reassessments of risk. While it is effectively banned in the U.S. due to past anesthetic-dose toxicity, it has become a standard, regulated analgesic in Australia and parts of Europe, where its safety at low doses is well-established and accepted based on decades of use. As clinical trials continue in the U.S., its status may change, but its current regulatory landscape serves as a potent reminder of how national authorities can diverge on interpreting risk versus benefit for the same medication. For a more detailed look at the clinical use of methoxyflurane as an analgesic, consult the extensive review available from the National Institutes of Health (NIH).

Frequently Asked Questions

No, methoxyflurane is not a scheduled substance under the U.S. Controlled Substances Act, but this is because the Food and Drug Administration (FDA) withdrew it from the market for safety reasons in 2005. It is effectively banned for general civilian use.

In Australia, methoxyflurane (Penthrox) is a Schedule 4 medicine. This means it is a prescription-only medicine and must be administered under supervision by trained health professionals.

The difference is due to varying regulatory histories and risk assessments. Its original use as a high-dose anesthetic caused renal toxicity, which led some countries like the U.S. to ban it. In contrast, other countries have accepted its use at much safer, low-dose analgesic concentrations.

The 'green whistle' is the colloquial name for the Penthrox inhaler, a self-administered device used to deliver low-dose methoxyflurane for pain relief. It is widely used in countries like Australia and Canada for emergency pain management.

The U.S. FDA withdrew methoxyflurane in 2005 due to reports of severe and sometimes fatal nephrotoxicity (kidney damage) and hepatotoxicity (liver damage) when it was used at the higher doses required for general anesthesia.

Yes, in several countries like Australia, paramedics and other emergency services personnel are trained and authorized to administer low-dose methoxyflurane (Penthrox) for pain relief in trauma patients.

When used as an anesthetic, methoxyflurane is administered at higher concentrations to induce unconsciousness, which led to toxicity. As an analgesic, it is used at very low, sub-anesthetic doses to provide pain relief while the patient remains conscious, which has a much safer profile.