The usual starting dose is to vaporise one 3 mL bottle in the inhaler.¹ The STOP! study demonstrated that the majority of patients obtained effective pain relief with just one 3 mL bottle,⁷ with less than 20% requesting a second inhaler.⁷ Patients are able to assess their own level of pain and titrate the amount of Penthrox® inhaled for adequate pain control. The lowest effective dose for pain relief should be used.¹

The maximum daily dose is 6 mL (2 x 3 mL bottles).¹ If the first 3 mL bottle is finished, patients may use a second bottle if required.¹

The maximum dose per week is 15 mL (5 x 3 mL bottles).¹ It is not recommended to administer Penthrox® on consecutive days. The frequency at which Penthrox® can be safely used has not been established.¹

One 3 mL bottle of Penthrox® provides approximately 25–30 minutes of analgesia if used continuously.¹ For adults in the pivotal STOP! study the median duration of effect of the first Penthrox® inhaler was 54 minutes (range 30–120 minutes).¹¹ For patients who require it, a second bottle of methoxyflurane may be used to further increase the duration of analgesia.¹ The maximum dose per day for Penthrox® is 6 mLs i.e. two bottles.¹

If stronger analgesia is required, patients can cover the dilutor hole on the top of the Activated Charcoal (AC) chamber with their finger to prevent dilution of methoxyflurane with external air and inhale a stronger concentration of methoxyflurane.¹

For the majority of patients, one Penthrox® inhaler will be sufficient to provide effective analgesia.¹¹ In the pivotal clinical study STOP! the use of a second inhaler in the adult sub-group was evaluated. In this study, only 25% of patients required a second inhaler and 75% of patients required only one Penthrox® inhaler.¹¹

If a patient requires further analgesia once the first inhaler is exhausted, either a second 3 mL bottle of methoxyflurane can be added to the initial inhaler or a new primed inhaler can be provided to the patient.¹

Patients should be able to detect when the Penthrox® device is empty as there will be a diminishing amount of vapour available to inhale and a reduced effect.¹⁵

Penthrox® can be used alongside other analgesics such as opioids or NSAIDs. However, when using Penthrox® with CNS depressants, the patient should be monitored for additional depressant effects.¹⁶ In a pre-hospital study, use of Penthrox® in combination with morphine or fentanyl was effective with no apparent differences in adverse events.¹⁷

The Penthrox inhaler is for single patient use and should be discarded after use.¹ For individual patients requiring a second 3 mL dose of methoxyflurane, they should either be given a new inhaler primed with 3 mL of methoxyflurane or an additional 3 mL bottle can be added to the original inhaler. In both cases the Penthrox inhaler should be discarded after use;¹ for most patients however, a single bottle in a single inhaler is adequate for analgesia.¹¹

The number of inhalations required to empty the Penthrox inhaler of methoxyflurane has not been formally undertaken, however, it is known that with continuous use, one Penthrox inhaler will last for approximately 25–30 minutes.¹ Normal respiratory rate ranges from 16–20 breaths per minute,¹⁸ and if an average of 15 breaths is assumed then it can be assumed that the Penthrox inhaler would be emptied in around 375–450 breaths, dependent of course on the depth of breathing of the patient.

Penthrox is a single use device and should be disposed of after use. Composition of components of Penthrox are as follows:¹⁹

• Penthrox device: inhaler device — high-density polyethylene (HDPE) (Type 2 plastic); one-way valve – polyethylene terephthalate (PET) (Type 1 plastic); wick – needle punched polypropylene (Type 5 plastic); wrist band – cotton.
• Glass Penthrox bottle: brown/amber glass; cap – polyoxymethylene (POM); wadding – PET lined low-density polyethylene (LDPE)
• Activated Carbon (AC) chamber: polycarbonate material; Activated Carbon – non-recyclable; PET valves.

It is recommended that recycling guidelines in each country and within each local authority are consulted regarding recycling of the Penthrox inhaler. However, it is recommended that:

• The cotton wrist strap is removed from the device and considered non-recyclable.
• The Penthrox inhaler device can then be recycled as a mixed plastic.
• The empty glass bottle is recyclable as glass; residual methoxyflurane will dissipate and so will not present an issue.
• The AC chamber is not recyclable.

Once the Penthrox inhaler is exhausted it should be placed and sealed within the plastic bag that is provided and should be disposed of responsibly as part of clinical waste.¹

36 months.¹

Penthrox is stable at a temperature range of -20°C to 40°C and no deterioration of Penthrox is noted at the higher temperature.²⁰ Methoxyflurane remains liquid at -20°C (the melting point of methoxyflurane is -35°C). Stability at a range of temperatures may facilitate use of Penthrox in temperature hostile environments e.g. mountainous regions.²¹

Penthrox is stable across a wide range of temperatures from -20°C to 40°C and has been used to manage pain in extreme conditions such as high altitudes.²¹ Whilst no formal studies for Penthrox use at altitude currently exist, it has been used at altitude in the Himalayas and in the ski fields of Australia and New Zealand, and no issues with use, such as vaporisation, have been observed. It is currently recommended for use in mountain rescue by the International Commission for Mountain Emergency Medicine (ICAR-MEDCOM).²²

No. In the EU, Penthrox is not licensed for use in patients under 18 years of age due to lack of safety and efficacy data.¹ The licensed indication in Europe differs from Australia where Penthrox can be used in children.²³

Analgesic doses of methoxyflurane (3–6 mL) are not thought to have a significant effect on blood pressure or heart rate.¹ However, Penthrox should be used with caution in the elderly due to a potential reduction in blood pressure.¹ As the elderly may also have reduced renal function, the lowest effective dose of Penthrox should be used.

The use of Penthrox is contraindicated in patients with clinically significant renal impairment.¹ This should be defined by the medical judgement of the treating healthcare professional.

Penthrox is contraindicated in patients who have a history of showing signs of liver damage after previous methoxyflurane use or halogenated hydrocarbon anaesthesia.¹

Penthrox should be used with caution in patients with hepatic impairment or risks for hepatic dysfunction, as methoxyflurane is metabolised extensively in the liver.¹

Penthrox should be used with caution in patients receiving additional medication which can induce hepatic enzymes such as alcohol or isoniazid, phenobarbital or rifampicin and certain antibiotics (e.g. tetracycline, gentamicin, colistin, polymyxin B and amphotericin B).¹

Repeated exposure at frequent intervals and prior exposure to halogenated anaesthesia (including methoxyflurane) may increase the risk of hepatotoxicity.¹ Clinical judgement should be exercised cautiously when Penthrox is to be used more frequently than once every three months.¹

No specific studies of Penthrox in asthma have been conducted, but Penthrox can be used in patients where respiratory function is normal. It is not recommended for use in patients whose oxygen saturation is reduced¹ such as might be expected during an active asthmatic episode.

Penthrox is rapidly distributed to the bloodstream after inhalation and forms a reservoir in fatty tissues from which it disperses over several days.¹ The effects of Penthrox in acute trauma pain in patients who are obese, underweight, very tall or very petite have not been investigated. Penthrox has been used (although not in trauma pain) in morbidly obese patients (BMI≥35 kg/m2) with or without obstructive sleep apnoea undergoing colonoscopy.²⁴ In these patients (n=85) analgesia was successful in all cases and rates of cardiorespiratory events were uncommon affecting only 2%, and there was no impact on renal or hepatic parameters.²⁴

There is no specific contraindication to using Penthrox in pregnancy.¹ However, as with all medicines care should be exercised when administered during pregnancy, especially during the first trimester. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.¹ Penthrox is not licensed for use in obstetrics, however historically a number of studies have investigated the use of methoxyflurane in labouring women.^25-28 There has been a single published report of neonatal respiratory depression following extended methoxyflurane analgesic use in a labouring woman.¹ When methoxyflurane was used at low concentrations and was administered for short periods of time there have been limited effects to the neonate reported and no foetal complications.¹ More recently Penthrox has been used as a bridge to epidural placement during labour;²⁹ in Europe, Penthrox is not licensed for use in medical procedures.

Caution should be exercised when Penthrox is administered to a nursing mother.¹ There is insufficient information on the excretion of methoxyflurane in human milk.

Penthrox is contraindicated in patients with an altered level of consciousness due to head injury.¹

Penthrox is not contraindicated in pneumothorax but it is contraindicated in patients with clinically evident respiratory depression.¹ Patients with a pneumothorax who display respiratory depression would not be appropriate for treatment with Penthrox. By contrast, nitrous oxide/oxygen mixes are contraindicated in any patients with gas entrapment within the body cavity, including pneumothorax, air embolism etc.³⁰ The use of Penthrox in patients with evident pneumothorax remains at the discretion of the administering healthcare professionals taking into account the points raised above.

The STOP! study was the pivotal study for Penthrox agreed with the regulators.

Rescue medication was available to all patients upon request at any time during and after treatment. The type of rescue medication that could be used within the study was paracetamol or intravenous, intranasal or oral opioids. The use of rescue medication and the time to rescue medication use was a secondary endpoint.^2,7

The pivotal STOP! study included patients with pain scores of VAS 4–7.² There have also been studies from Australia and Belgium where Penthrox has been used in patients with baseline VAS pain scores >7.^17,31,32,33

• In a study by Buntine et al.³³ of Penthrox in adults in the pre-hospital setting [Buntine 2007] patients had a median pain score of approximately 8 which was reduced by 2.32 points in musculoskeletal pain and 3.43 in patients with back pain within 5 minutes, rising to 2.57 and 4.27 within 20 minutes, respectively which were statistically significant (p<0.0001) versus baseline.³³
• A second pre-hospital study by Middleton et al.¹⁷ demonstrated effective analgesia with Penthrox in patients with a median pain score of 8.3 (n=19,235) in patients receiving Penthrox with a mean reduction in pain of 3.2.¹⁷
• In a study in the Emergency Department in the Netherlands by Gillis et al.,³² 59 patients with an average pain score of 7.6 received Penthrox and experienced significant pain reductions at 15 and 30 minutes of 2.3 and 3.3, respectively.³²
• In a second hospital study for Penthrox in the Emergency Department by Bendall et al.³¹ patients were included if they had a pain score VAS 7–10 (median VAS 8), and reduced pain to a median VAS of 4, but this study did include patients for which Penthrox is not currently licensed, such as children.¹

Penthrox should not be used in the following settings:¹

• Use as an anaesthetic agent
• Hypersensitivity to PENTHROX or any fluorinated anaesthetic.
• Malignant hyperthermia: patients with known or genetically susceptible to malignant hyperthermia or a history of severe adverse reactions in either patient or relatives.
• Patients who have a history of showing signs of liver damage after previous methoxyflurane use or halogenated hydrocarbon anaesthesia.
• Clinically significant renal impairment.
• Altered level of consciousness due to any cause including head injury, drugs, or alcohol.
• Clinically evident cardiovascular instability.
• Clinically evident respiratory depression.

Penthrox has no clinically relevant effects on vital signs at analgesic doses,¹⁴ but caution should be exercised in elderly patients with hypotension or bradycardia. The lack of effect on vital signs is important in an emergency trauma setting where minimal negative impact of medications on patient physiology is desirable. Penthrox is not associated with respiratory depression.^1,14

Risk to healthcare workers with Penthrox due to exposure to methoxyflurane has not been observed despite more than 5 million doses being administered in Australia and New Zealand since launch.³ Maximum exposure levels (MEL) have been established for Penthrox of 15 ppm, working exposures for healthcare providers over the course of an 8-hour shift are 0.23 ppm and modelled concentrations of Penthrox in ambulances and treatment rooms is 1.5 ppm.³⁴ The MEL for Penthrox is more than 50 times higher than the exposure experienced by healthcare workers.³⁴ In addition, Penthrox is supplied with an Activated Charcoal (AC) chamber which adsorb exhaled methoxyflurane to reduce by more than 80% fugitive methoxyflurane emissions, reducing the risk of occupational exposure.³⁴

Methoxyflurane is not a controlled drug,¹⁶ therefore it is not subject to the safe custody requirements, controlled drug register and retaining of invoices for two years.

Methoxyflurane in Penthrox is not flammable;³⁵ despite extensive use of Penthrox in Australia for more than 40 years no incidence of fire or explosion linked to Penthrox has been reported.³⁶ The flashpoint (the lowest temperature at which a liquid is sufficiently gaseous to form an ignitable mixture) of methoxyflurane in air is 63°C,³⁷ but tests of the combustibility of Methoxyflurane in Penthrox did not demonstrate any propensity to ignite at 75°C.³⁶ The Penthrox inhaler has been constructed of materials that are non-flammable.³⁶

Methoxyflurane was first used at high doses as an anaesthetic in the early 1960s.³⁸ However, following reports of dose-related renal tubular damage³⁹ its use as an anaesthetic ceased by the late 1970s. The nephrotoxicity associated with high dose methoxyflurane is thought to be due to the production of fluoride ions from metabolism in the liver and kidney.⁴⁰ It is important to note that this is a dose-related effect only seen at high anaesthetic doses. Analgesic dose Penthrox® is significantly lower than anaesthetic dose – at least 6-fold below the upper safety limit.³ Please see the below table for further details.³

Table adapted from Dayan et al 2016³

This is supported by clinical data where a large linked cohort study with Penthrox⁴¹ and other clinical studies^2,42 have reported no incidences of nephrotoxicity with Penthrox. Please note that the SmPC contains a warning that dose-related nephrotoxicity has been associated with methoxyflurane in large doses over prolonged periods and that at analgesic doses increased serum uric acid, increased urea nitrogen, increased creatinine and renal failure have been observed.

Although methoxyflurane was discontinued in the USA by 1999, the FDA formally withdrew methoxyflurane from sale in 2005 with specific intent to prevent Abbreviated New Drug Applications (ANDAs) which do not require extensive clinical studies programmes to secure a licence.^.”]43 The FDA withdrawal is specific to Penthrane (methoxyflurane) which was licensed by Abbott Laboratories. It was used as general anaesthesia in procedures lasting four hours or less or for self-administered analgesia in obstetrics and minor surgical procedures using the hand-held inhaler – the Analgizer. The FDA withdrawal was undertaken in response to Abbott’s withdrawal from sale of Penthrane following incidences of dose-related nephrotoxicity and hepatotoxicity.⁴⁴ Cases of dose-related nephrotoxicity when methoxyflurane was used as an anaesthetic were first reported by Crandell in 1966 and subsequent reports have followed in surgery^39,45-51 and in prolonged use as an analgesic in obstetrics for labouring women.^47,52 The FDA have stated that new clinical studies will be required before methoxyflurane can be considered for reintroduction to the USA. It is important to note that the recommended loading dose of methoxyflurane of the Analgizer was 15 mL with further dosing possible during procedures. This is above the maximum dose of 6 mL per day or 15 mL in one week for Penthrox.