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

Penthrox® provides rapid pain relief within 6–10 inhalations.^1,11 The STOP! study showed that 84.6% of patients achieved pain relief within 10 inhalations, with a median time to first pain relief of 4 minutes.² The recent InMEDIATE study conducted in Spain demonstrated an onset to analgesia for Penthrox® of 3 minutes.⁵⁴

The median onset to analgesia for Penthrox® was 4 minutes in the STOP! Study and 3 minutes in the Spanish InMEDIATE study.^2,54 Onset to analgesia for other established analgesics (not evaluated in head-to-head comparisons with Penthrox) indicate onset to meaningful analgesia with intra-nasal fentanyl of 11 minutes,¹³ oromucosal fentanyl of 16 minutes¹³ intravenous morphine sulphate of 5 minutes¹² and intramuscular morphine of 20 minutes,¹² and is comparable to nitrous oxide with an onset of effect of 3–5 minutes.⁴⁴

Recovery from Penthrox® is rapid.^58,62,63 Psychomotor tests performed on healthy volunteers have demonstrated a return to normal 30 minutes after cessation of Penthrox® treatment.⁵⁸

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 and a study of Penthrox® in mountain rescue is ongoing.⁶⁴

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.

Elderly patients have been included in randomised, controlled studies of Penthrox®.^54,55 A subanalysis of the inMEDIATE study compared the use of Penthrox® with standard analgesic treatment among patients at least 65 years old. Patients treated with Penthrox® (n=33) achieved significantly faster pain relief in less than half the time of those treated with standard care (n=26). Time to first pain relief was 5.55 vs 12.38 minutes, and time to first meaningful pain relief of 12.57 vs 25.07 minutes, respectively (p<0.001).⁶⁰

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.

Penthrox® has been compared with standard of care (SoC). Although there was variation among sites, this was most frequently nonsteroidal anti-inflammatory drugs for moderate pain and intravenous non-opioid and opioid analgesics for severe pain in Spain (inMEDIATE study) or IV paracetamol or ketoprofen for moderate pain and IV morphine for severe pain in Italy (MEDITA study).^54,55

Penthrox® has been investigated in randomised, controlled studies.

In a head-to-head study vs. SoC analgesia in patients in Spain with trauma pain of at least 4 on the 11-point NRS at baseline, the mean decrease in pain intensity was greater for Penthrox® (n=156) than SoC (n=149) at all time points, with a significant treatment difference overall up to 20 min (repeated measures model: 2.5 vs. 1.4; treatment difference: 1.0; 95% CI: 0.8, 1.3; p<0.001) (inMEDIATE).⁵⁴ The mean NRS score at baseline was 7.6 in the Penthrox® group and 7.5 in the standard treatment group.

In a head-to-head study vs. SoC in patients in Italy with trauma pain of at least 4 on the 11-point NRS at baseline, there was a mean treatment difference of -5.94 mm (95% CI -8.83, -3.06mm) with Penthrox® (n=135) over standard treatment (n=135). Median pain relief was faster with Penthrox® at 9 minutes compared with 15 minutes with standard treatment (MEDITA).⁵⁵

MEDITA is a head-to-head study of Penthrox® vs SoC in trauma pain in Italy. The study included an analysis of 177 patients with moderate baseline pain of between 4 and 6 on the NRS (Penthrox®, n=86; SoC, n=91). The overall change in VAS pain intensity in the first 10 minutes was significantly greater in the Penthrox® group compared with the SoC group (mean treatment difference of -5.97 (95% CI -9.55, -2.39; p=0.001) with superiority of Penthrox® from 3 minutes.⁵⁵

MEDITA is a head-to-head study of Penthrox® vs SoC in trauma pain in Italy. The study included an analysis of 93 patients with severe baseline pain of 7 or above on the NRS (Penthrox®, n=49; SoC, n=44). The overall change in VAS pain intensity in the first 10 minutes was significantly greater in the Penthrox® group compared with the standard SoC group (mean treatment difference of -5.54 (95% CI -10.49, -0.59; p=0.029) with superiority of Penthrox® at 5 minutes.⁵⁵

The InMEDIATE study of Penthrox® vs SoC for trauma pain in Spain reported findings from a subanalysis among patients with severe pain of 7 or more on the NRS. The decrease from baseline was significantly larger for Penthrox® (n=89) than standard treatment (n=76) at all time points (3, 5, 10, 15 and 20 minutes) (p<0.001), with the largest treatment difference reported at 10 minutes.⁶¹

Penthrox® has used as multimodal analgesia in the PenASAP trial which is a head-to-head study of efficacy and safety of Penthrox® plus SoC vs placebo (n=178) plus SoC (n=173). Pain relief was achieved in 35 minutes with Penthrox® plus SoC but was not reached in the SoC plus placebo group (p<0.01).⁵⁶

In an observational study by Umana and colleagues, Penthrox® (n=30) and propofol (n=52) were used in patients with shoulder dislocation. Penthrox® was shown to successfully facilitate dislocation reduction in 80% of patients vs 98% for propofol with a shorter median recovery time compared with propofol (30 minutes vs 47 minutes, respectively; p<0.004). This led to a significantly shorter length of stay in the emergency department (70.5 with Penthrox® vs 135 minutes with propofol; p<0.001).⁵⁷

Data from randomised, controlled trials show that both patients and clinicians are highly satisfied with Penthrox®. In a head-to-head trial of Penthrox® (n=156) vs SoC (n=149), Penthrox® exceeded patient and clinician expectations in 77% and 72% of cases compared with only 38% and 19% for SoC (inMEDIATE).⁵⁴ In another study of Penthrox® (n=135) vs SoC (n=135), Penthrox® was rated as ‘excellent’, ‘very good’ or ‘good’ by significantly more patients in the Penthrox® group, compared to the SoC group (72.7% vs 60.9%; p=0.001) and significantly more healthcare professionals rated the practicality of methoxyflurane as ‘excellent’, ‘very good’ or ‘good’, compared to SAT (90.3% vs 64.4%; p<0.001).⁵⁵

Yes. The STOP! Study was the pivotal study for Penthrox® assessed by the regulators. Penthrox® (n=149) significantly reduced pain severity vs placebo (n=149) (p<0.0001) at all time points up to 20 minutes.²

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 or patients with a known family history of severe adverse reactions after being administered with inhaled anaesthetics.
• 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 6 million doses being administered in Australia and New Zealand since launch.⁵³ 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 adsorbs exhaled methoxyflurane to reduce by more than 86% 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®.