Penthrox (Methoxyflurane): Uses, Dosage & Side Effects
Inhaled analgesic for emergency relief of moderate to severe pain in conscious adults
Penthrox is an inhaled pain-relief medicine containing the active substance methoxyflurane. Administered through a handheld inhaler, it provides rapid-onset analgesia for moderate to severe pain in emergency and pre-hospital settings. Penthrox is designed to reduce pain severity rather than eliminate it entirely, and it is self-administered under the supervision of a trained healthcare professional.
Quick Facts
Key Takeaways
- Penthrox provides rapid-onset pain relief through inhalation, typically within 6–10 breaths, and is commonly used in emergency and pre-hospital settings.
- The maximum dose is two 3 mL vials (6 mL total) per administration – exceeding this dose can cause kidney damage.
- It must not be used in patients with a history of or susceptibility to malignant hyperthermia, significant renal impairment, or altered consciousness.
- Common side effects include dizziness, drowsiness, and headache; serious side effects involving liver, kidneys, or breathing are rare but require immediate medical attention.
- Penthrox is for adults only and must always be administered under supervision of a trained healthcare professional.
What Is Penthrox and What Is It Used For?
Penthrox contains the active substance methoxyflurane, a fluorinated hydrocarbon compound that has been used in medicine since the 1960s. While it was originally developed as a general anaesthetic agent, modern use at much lower, sub-anaesthetic concentrations provides effective analgesia (pain relief) without causing loss of consciousness. The drug is inhaled through a specially designed device called the Penthrox inhaler, which allows patients to self-administer the medication under the supervision of trained healthcare personnel.
The Penthrox inhaler is a compact, single-use device that incorporates an activated charcoal (AC) chamber. When the patient exhales through the device, the exhaled methoxyflurane vapour passes through the activated charcoal chamber, which adsorbs the expired drug and minimises environmental contamination. This design is particularly important in enclosed spaces such as ambulances and emergency treatment rooms, where occupational exposure for healthcare workers must be kept to a minimum.
The primary indication for Penthrox is the emergency relief of moderate to severe pain in conscious adult patients with trauma and associated pain. It is widely used in pre-hospital settings by paramedics and ambulance crews, as well as in emergency departments for conditions such as fractures, dislocations, burns, and acute musculoskeletal injuries. Additionally, Penthrox may be used for brief, painful medical procedures where short-term analgesia is required.
It is important to understand that Penthrox is designed to reduce the severity of pain rather than eliminate it entirely. The analgesic effect begins rapidly, typically within 6 to 10 inhalations, and the total duration of pain relief depends on how the device is used. Intermittent inhalation (taking breaks between breaths) extends the duration of analgesic effect, while continuous inhalation provides stronger but shorter-lasting relief. Healthcare professionals will guide patients on the optimal technique for their particular situation.
Penthrox must not be used as a general anaesthetic agent. It is only approved for use as an analgesic at sub-anaesthetic doses. The device and drug are intended for single-patient use only and must not be shared between patients.
What Should You Know Before Taking Penthrox?
Contraindications
There are several absolute contraindications for Penthrox that healthcare professionals must assess before administering the medication. Understanding these contraindications is critical for patient safety, as methoxyflurane can cause serious harm in certain populations.
- Are allergic to methoxyflurane, any inhaled anaesthetic agents (inhalation anaesthetics), or any of the other ingredients in this medicine
- Have a personal or family history of malignant hyperthermia – a condition characterised by extremely high fever, rapid and irregular heartbeat, muscle spasms, and breathing problems following exposure to anaesthetic agents
- Have a family history of serious adverse reactions to inhaled anaesthetic agents
- Have previously experienced liver damage after use of methoxyflurane or any inhalation anaesthetic
- Have significant kidney (renal) impairment as determined by a healthcare professional
- Have altered consciousness from any cause, including head injury, drugs, or alcohol
- Have cardiovascular instability or serious circulatory problems
- Have shallow breathing or respiratory difficulties
Warnings and Precautions
Before using Penthrox, your healthcare provider needs to know your complete medical history. Several conditions require special caution and careful clinical assessment before the drug can be safely administered.
Speak to a healthcare professional before using Penthrox if you have liver or kidney problems of any severity, as methoxyflurane is metabolised in the liver and its metabolites are excreted by the kidneys. Patients with pre-existing hepatic or renal dysfunction may be at increased risk of adverse effects. Similarly, if you have any medical condition that could potentially cause kidney damage, your healthcare provider will need to weigh the benefits against the risks.
Elderly patients may be more susceptible to the central nervous system effects of methoxyflurane, including drowsiness, dizziness, and confusion. Dose adjustment is not typically required, but closer monitoring may be necessary. Healthcare professionals should exercise additional caution when administering Penthrox to older adults.
Respiratory depression (slow, shallow breathing or other breathing difficulties) has been reported with Penthrox use. Seek immediate medical attention if you experience any breathing difficulties during or after use. Healthcare professionals should monitor respiratory function during administration.
Penthrox is not recommended for use in children. The safety and efficacy of methoxyflurane in the paediatric population has not been sufficiently established through clinical trials. Healthcare providers should use alternative analgesic options for paediatric patients.
Pregnancy and Breastfeeding
If you are pregnant, planning to become pregnant, breastfeeding, or planning to breastfeed, you should inform your healthcare professional before receiving Penthrox. The potential risks and benefits of using methoxyflurane during pregnancy have not been fully established in clinical studies. Your healthcare provider will discuss the individual risk-benefit assessment with you and may consider alternative analgesic options.
It is not known whether methoxyflurane passes into breast milk. As a precaution, the decision to use Penthrox during breastfeeding should be made in consultation with a healthcare professional, weighing the benefit of pain relief against any potential risk to the infant.
Driving and Operating Machinery
Penthrox can cause drowsiness, dizziness, and impaired cognitive function. You should not drive, operate machinery, or perform any tasks requiring full mental alertness until the effects of the medicine have completely subsided. You are responsible for assessing your own fitness to drive or operate machinery after receiving Penthrox. Discuss any concerns about recovery time with your healthcare provider.
Important Information About Ingredients
Penthrox contains a stabiliser called butylhydroxytoluene (E321). This substance can cause local skin reactions (such as contact dermatitis) or irritation of the eyes and mucous membranes in some individuals. Healthcare professionals should be aware of this potential reaction when administering the drug.
How Does Penthrox Interact with Other Drugs?
Drug interactions with methoxyflurane can occur through several pharmacological mechanisms. Some drugs increase the rate at which methoxyflurane is metabolised, potentially increasing the formation of toxic metabolites. Others may have additive central nervous system depressant effects, increasing the risk of sedation and respiratory depression. Additionally, co-administration with nephrotoxic agents may compound the risk of kidney damage.
Major Interactions
The following drug interactions are considered clinically significant and may require avoidance of Penthrox or careful risk assessment before use.
| Drug / Class | Risk | Mechanism |
|---|---|---|
| Opioid analgesics (morphine, fentanyl, codeine) | Increased CNS depression and respiratory depression | Additive central nervous system depressant effects |
| General anaesthetics | Enhanced sedation and organ toxicity | Additive effects; if surgery requiring anaesthesia is needed, inform the anaesthetist about prior Penthrox use |
| Gentamicin, tetracycline, colistin, polymyxin B, amphotericin B | Increased risk of kidney damage | Additive nephrotoxicity with methoxyflurane metabolites |
| Contrast media (iodinated) | Increased risk of renal impairment | Additive nephrotoxic effects |
| Rifampicin | Increased formation of toxic metabolites | Potent CYP450 enzyme inducer; accelerates methoxyflurane metabolism |
Minor Interactions
The following interactions are less severe but should still be reported to your healthcare provider for appropriate clinical assessment.
| Drug / Class | Risk | Mechanism |
|---|---|---|
| Isoniazid (tuberculosis treatment) | Increased methoxyflurane metabolism | Hepatic enzyme induction |
| Phenobarbital, carbamazepine (epilepsy medications) | Increased toxic metabolite formation | CYP450 enzyme induction |
| Efavirenz, nevirapine (HIV antiretrovirals) | Altered methoxyflurane metabolism | CYP450 enzyme modulation |
| Sedatives, hypnotics, phenothiazines | Enhanced drowsiness and sedation | Additive CNS depressant effects |
| Sedating antihistamines | Increased drowsiness | Additive sedation |
Do not consume alcohol when using Penthrox, as alcohol can increase the central nervous system depressant effects of methoxyflurane, leading to excessive drowsiness, impaired coordination, and potentially dangerous levels of respiratory depression. You may eat and drink normally (except alcohol) unless your healthcare provider advises otherwise.
What Is the Correct Dosage of Penthrox?
Penthrox dosing follows a patient-controlled model, where the individual inhales the medication at their own pace under the guidance of a healthcare professional. The unique delivery system allows patients to titrate their own pain relief by adjusting the frequency and depth of their inhalations. This self-administration approach, combined with the rapid onset of action, makes Penthrox particularly well-suited for emergency pain management.
Adults
Standard Adult Dosing
One or two 3 mL vials of Penthrox may be used per administration. A single vial provides the starting dose, and a second vial may be administered if further pain relief is required.
- Initial dose: 1 vial (3 mL) of methoxyflurane via the Penthrox inhaler
- Additional dose: A second vial (3 mL) may be used if pain relief is insufficient
- Maximum dose: 2 vials (6 mL) per administration – do not exceed this dose
- Onset: Pain relief typically begins within 6–10 breaths
- Technique: Intermittent inhalation (with breaks) is recommended to extend the duration of analgesic effect
How to Use the Penthrox Inhaler
The Penthrox inhaler is prepared and provided by a healthcare professional. The following steps outline the proper use of the device:
- Preparation: The healthcare professional checks the device for damage, ensures the activated charcoal chamber is fitted, and pours the contents of one Penthrox vial into the base of the inhaler at a 45-degree angle while rotating the device.
- Wrist strap: The healthcare professional attaches the wrist strap to your wrist to prevent the device from being dropped.
- Initial inhalation: Begin by breathing gently through the mouthpiece during the first few breaths to accustom yourself to the fruity smell of the medication. Exhale through the inhaler so that the expired vapour passes through the activated charcoal chamber.
- Normal breathing: After the initial gentle breaths, breathe normally through the inhaler to receive pain relief.
- Stronger relief: If more intense pain relief is needed, cover the diluter hole on the activated charcoal chamber with your finger during inhalation. Your healthcare professional will show you the location of this hole.
- Intermittent use: You do not need to breathe through the inhaler continuously. Taking breaks between inhalations makes the pain relief last longer. The healthcare professional will guide you on the best approach.
- Continue until instructed to stop: Use the inhaler until the healthcare professional tells you to stop, or until you have used the maximum recommended dose.
Children
Paediatric Use
Penthrox is not recommended for use in children. The safety and efficacy of methoxyflurane in paediatric patients has not been adequately established. Healthcare providers should use alternative analgesic therapies for children.
Elderly Patients
Elderly Dosing
No specific dose adjustment is required for elderly patients. However, older adults may be more susceptible to the CNS effects of methoxyflurane, including confusion, dizziness, and excessive sedation. Closer monitoring is recommended, and the minimum effective dose should be administered.
Overdose
Because Penthrox is administered by healthcare professionals experienced in its use, overdose is very unlikely. However, patients must not use more than two 3 mL vials during a single administration. If the maximum dose is exceeded, methoxyflurane can cause serious kidney damage due to the accumulation of toxic fluoride metabolites.
If you believe you may have received too much Penthrox, inform your healthcare professional immediately. Signs of potential toxicity include unusually decreased urine output, flank pain, or persistent nausea and vomiting. Kidney function should be monitored following any suspected overdose.
What Are the Side Effects of Penthrox?
Like all medicines, Penthrox can cause side effects, although not everybody experiences them. Most side effects are mild and transient, resolving shortly after the inhalation is stopped. However, some serious adverse reactions can occur and require prompt medical intervention.
- Severe allergic reactions with symptoms such as difficulty breathing and/or facial swelling
- Signs of liver problems: loss of appetite, nausea, vomiting, jaundice (yellowing of the skin or eyes), dark urine, pale stools, pain or tenderness in the right upper abdomen
- Signs of kidney problems: decreased or excessive urination, swelling of the feet or lower legs
- Slow, shallow breathing or other breathing difficulties (respiratory depression)
These side effects may be life-threatening. Tell your healthcare professional immediately.
Very Common
- Dizziness
Common
- Drowsiness (somnolence)
- Headache
- Nausea
- Feeling of euphoria
- Feeling of intoxication
- Taste disturbances (dysgeusia)
- Cough
Uncommon
- Anxiety or depression
- Attention disturbance
- Inappropriate affect or behaviour
- Repetition of words or speech difficulties
- Memory loss (amnesia)
- Tingling in hands and feet (paraesthesia)
- Numbness
- Visual impairment
- Skin flushing
- Low or high blood pressure
- Dry mouth
- Oral discomfort or itching in the mouth
- Increased salivation
- Increased appetite
- Vomiting
- Sweating
- Fatigue
- Feeling abnormal
- Chills
- Feeling relaxed
Reported (Frequency Unknown)
- Hypersensitivity (allergic reactions)
- Mood swings
- Restlessness or agitation
- Feeling disconnected from reality (derealisation)
- Confusion
- Altered level of consciousness
- Feeling of choking
- Shortness of breath (dyspnoea)
- Respiratory depression
- Uncontrolled eye movements (nystagmus)
If you experience any side effects not listed above, or if any side effect becomes severe, tell your healthcare professional. Reporting suspected adverse reactions after the medicine has been authorised is important for the ongoing monitoring of the benefit-risk balance of the medicine.
How Should You Store Penthrox?
Penthrox should be stored in its original packaging until ready for use. There are no special temperature or light storage requirements for the sealed product. However, like all medicines, it should be kept out of the sight and reach of children at all times.
Do not use this medicine after the expiry date (marked as EXP on the carton). The expiry date refers to the last day of that month. Once a vial has been opened and the contents poured into the inhaler, the product should be used within the treatment session and not stored for later use.
After use, the healthcare professional will dispose of any remaining Penthrox liquid and the used inhaler device in accordance with local waste disposal protocols. The activated charcoal chamber, which contains adsorbed methoxyflurane from the patient's exhaled breath, should also be disposed of appropriately. Patients should never attempt to reuse an inhaler or retain leftover medication.
What Does Penthrox Contain?
Active Substance
The active ingredient in Penthrox is methoxyflurane. Each sealed glass vial contains 3 mL of methoxyflurane at a concentration of 99.9%. Methoxyflurane (chemical name: 2,2-dichloro-1,1-difluoro-1-methoxyethane) is a fluorinated methyl ethyl ether that belongs to the class of halogenated hydrocarbon anaesthetic agents. At the sub-anaesthetic concentrations delivered by the Penthrox inhaler, it functions exclusively as an analgesic.
Other Ingredients
The only excipient (inactive ingredient) is butylhydroxytoluene (BHT, E321), which serves as an antioxidant stabiliser to prevent degradation of the methoxyflurane during storage. BHT may cause local skin reactions (such as contact dermatitis) or irritation of the eyes and mucous membranes in susceptible individuals.
Appearance and Packaging
Penthrox is a clear, nearly colourless, volatile liquid with a characteristic fruity odour. When inhaled through the Penthrox inhaler, it is converted into a vapour or gas. The product is available in the following pack presentations:
- Single vial pack: One 3 mL Penthrox vial with tamper-evident seal (packs of 10 × 3 mL)
- Combination pack: One 3 mL Penthrox vial, one Penthrox inhaler device, and one activated charcoal chamber (packs of 1 × 3 mL or 10 × 3 mL)
Not all pack sizes may be marketed in all countries.
Frequently Asked Questions About Penthrox
Penthrox (methoxyflurane) is an inhaled analgesic used for the emergency relief of moderate to severe pain in conscious adult patients. It is commonly used in pre-hospital settings (ambulances), emergency departments, and during brief painful medical procedures. The medication is self-administered through a handheld inhaler device under the supervision of a trained healthcare professional. It is designed to reduce pain severity rather than eliminate it completely.
Penthrox provides rapid onset of pain relief, typically within 6 to 10 breaths through the inhaler device. Peak analgesic effect is usually achieved within a few minutes of starting inhalation. This fast onset is one of the main advantages of Penthrox in emergency settings, as patients can begin to experience relief almost immediately while other treatments are being prepared.
Penthrox is not recommended for use in children. The safety and efficacy of methoxyflurane in paediatric patients has not been sufficiently established in clinical trials. Healthcare providers should consider alternative pain management options for children, such as paracetamol, ibuprofen, intranasal fentanyl, or other age-appropriate analgesic therapies.
No, you should not drive or operate machinery after using Penthrox. Methoxyflurane can cause drowsiness, dizziness, and impaired judgement. The duration of these effects varies between individuals. You should wait until all effects have completely subsided before attempting to drive or engage in activities requiring full mental alertness. Discuss the expected recovery time with your healthcare provider.
The maximum dose of Penthrox is two 3 mL vials (6 mL total) per single administration. Exceeding this dose significantly increases the risk of nephrotoxicity (kidney damage) due to the accumulation of fluoride and oxalic acid, which are metabolites of methoxyflurane. Healthcare professionals are trained to monitor dosing carefully and will ensure that the maximum dose is not exceeded.
The most common side effect of Penthrox is dizziness, which affects more than 1 in 10 users. Other common side effects (affecting up to 1 in 10 users) include drowsiness, headache, nausea, a feeling of euphoria, feeling of intoxication, taste disturbances, and cough. Most of these effects are mild and resolve quickly once inhalation is stopped. Serious side effects such as liver or kidney damage and respiratory depression are rare but require immediate medical attention.
References
This article is based on the following peer-reviewed sources and international medical guidelines:
- European Medicines Agency (EMA). Penthrox – methoxyflurane: EPAR – Product Information. Available at: EMA Penthrox Summary. Accessed December 2025.
- Coffey F, Wright J, Hartshorn S, et al. STOP!: a randomised, double-blind, placebo-controlled study of the efficacy and safety of methoxyflurane for the treatment of acute pain. Emergency Medicine Journal. 2014;31(8):613–618. doi:10.1136/emermed-2013-202909
- Dayan AD. Analgesic use of inhaled methoxyflurane: a critical review of safety. Drug Safety. 2016;39(2):117–127. doi:10.1007/s40264-015-0346-x
- Porter KM, Dayan AD, Dickerson S, Middleton PM. The role of inhaled methoxyflurane in acute pain management. Open Access Emergency Medicine. 2018;10:149–164. doi:10.2147/OAEM.S181222
- Brichko L, Gaddam R, Roman C, et al. Rapid administration of methoxyflurane to patients in the emergency department (RAPID) study. Emergency Medicine Australasia. 2021;33(2):268–273. doi:10.1111/1742-6723.13614
- National Institute for Health and Care Excellence (NICE). Evidence review: Methoxyflurane for acute pain in emergency settings. NICE, 2022.
- World Health Organization (WHO). Model List of Essential Medicines – 23rd List, 2023. Geneva: World Health Organization; 2023.
- Graudins A, Meek R, Egerton-Warburton D, Seith R, Furness T, Chapman R. The MEDI trial: methoxyflurane vs standard care in emergency department patients with moderate to severe pain. Academic Emergency Medicine. 2022;29(2):156–165.
Editorial Team
This article was written and reviewed by our medical editorial team following strict evidence-based standards.
Medical Content Team
Licensed specialist physicians with expertise in acute pain management, emergency medicine, and pharmaceutical therapeutics.
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All content reviewed according to EMA, NICE, and WHO guidelines. Evidence level 1A based on systematic reviews and randomised controlled trials.
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