You’re in the rapid response vehicle, having just handed over a 2 year old with a femoral fracture. As you clear the hospital, a call comes in: 8 year old, fall from slide, deformed left arm, conscious and breathing. When you arrive in the house you find him lying on the sofa, with bruising and deformity of his left elbow. The paracetamol and ibuprofen given by his mother has not controlled his pain*, so you take out a methoxyflurane inhaler and explain to him to suck in and blow out through ‘the whistle’. After a few breaths he begins to relax.
Methoxyflurane is a fluorinated hydrocarbon, used as an inhaled anaesthetic in the ’60s and early ’70s, until it fell out of favour after case reports describing renal failure at anaesthetic doses. But, when given in small doses, methoxyflurane has excellent analgesic properties, with no nephrotoxic side effects. It has been used extensively in Australia and New Zealand by prehospital clinicians as a self-administered analgesic for short-term pain relief in adults and children. After being licenced in 2015 in the UK and Ireland for the emergency relief of moderate to severe pain in conscious adults with trauma, methoxyflurane was included in the Irish prehospital CPG for EMTs, paramedics and advanced paramedics with permission under the seventh amendment to allow its use in children.
Added as a liquid to a Penthrox® inhaler, methoxyflurane vaporises, to be inhaled on demand. It has revolutionised prehospital pain control due to its quick onset and easy, pain free administration and, because of its light weight, crews can carry it over rough ground easily. Known as ‘the green whistle‘, each 3ml dose is quoted to last between 20 and 30 minutes, but in practice can sometimes last up to 45 minutes or an hour, depending on a child’s respiratory rate and depth and the way in which they self-administer. The Irish prehospital CPGs allow two inhalers to be administered in 24 hours to a patient, so when there’s an extended journey time, methoxyflurane inhalers used back-to-back can provide up to two hours of analgesia, which can be supplemented by the simple analgesics, paracetamol and ibuprofen, or morphine, fentanyl and ketamine, as needed.
But what’s the evidence for methoxyflurane in children?
Pop methoxyflurane in the PubMed search bar, and a lot comes up. It’s safe, it works, but there are surprisingly few randomised controlled trials (RCTs) that include children. A couple of observational studies are noteworthy. An Australian study in the prehospital setting, published in 2006 by Franz Babl and colleagues, describes an observational case series of 105 children, ranging in age from 15 months to 17 years, who received methoxyflurane while by being conveyed to hospital by ambulance. The children’s pain scores dropped from 7.9 to 4.5, with few side effects, although there was a tendency towards deep sedation in the under 5s. The following year Babl’s team published an ED-based observational case series of 14 children aged 6 to 13 years with extremity injuries who received methoxyflurane for painful procedures in the hospital setting. Although methoxyflurane was a useful analgesic agent, Babl’s team found it did not work as well as a procedural analgesic for fracture reduction.
The first double-blind RCT of methoxyflurane in children was published almost two decades ago by Chin et al in 2002. Forty-one children over the age of 5 with upper limb fractures were randomised to receive either methoxyflurane or placebo. Unsurprisingly, methoxyflurane resulted in a lower pain score at 10 minutes than placebo. Adverse events weren’t reported, but the apparent safety and efficacy of methoxyflurane demonstrated in this study paved the way the some bigger and better RCTs.
A better known, and more recent, RCT involving children was the STOP! trial, published in the EMJ in 2014. This randomised, double-blind placebo-controlled trial was conducted at six EDs in the UK. Three hundred patients, 90 between the ages of 12 and 17, with minor trauma (such as burns, fractures, dislocations and lacerations), were randomised to receive either methoxyflurane or saline via an inhaler. In a nifty way to keep the patients, doctors and nurses blinded to which drug was being administered, a drop of methoxyflurane was added to the outside of every inhaler so both drug devices smelled the same. Pain scores dropped significantly lower in the methoxyflurane group, with a median onset of action of 4 minutes. But what about those adolescents? Although 45 12 to 17 year olds were included in each group, their data wasn’t analysed separately, and children under the age of 12 were excluded from the study, so although we can probably assume methoxyflurane works well and is safe in adolescents, more trials would be helpful.
Segue to the Magpie trial, which is currently recruiting in the UK and Ireland via the PERUKI network. This international multi-centre randomised, double-blind placebo-controlled trial is specifically investigating the efficacy and safety of methoxyflurane in children and young people so that its UK license can be extended to include children. Like STOP!, participants are being randomised to either methoxyflurane or placebo (again saline) via an inhaler. To ensure younger children are well represented in the study data, the study team are aiming to recruit higher numbers of 6 to 11 year olds than adolescents, with a recruitment target of 220 children and adolescents in total. We’re awaiting the results eagerly…
*A top tip on top up dosing
This child had been given 500mg of paracetamol and 280mg of ibuprofen by his mother before the crew arrived. He was 8 years old, with an estimated weight of 31kg. Based on Irish CPGs allowing a paracetamol dose of 20mg/kg (620mg) and ibuprofen dose of 10mg/kg (310mg) he was underdosed. It’s important to top-up simple analgesics as part of your approach to pain relief in children.
But what happened to the 8 year old?
You check CSMs (circulation, sensation and movement) before and after applying a splint and transfer him to the ambulance on a stretcher. His pain is very well controlled, and he asks his mother to take a photo for his friends. This sentence is hard for him to say and he gets the giggles. You transfer him uneventfully to hospital where he’s diagnosed with a supracondylar fracture.
Read more about assessing pain, prehospital analgesia in children and the evidence behind intranasal fentanyl in part 1 of the DFTB prehospital analgesia series.
Hartshorn, S., & Middleton, P. M. (2019). Efficacy and safety of inhaled low-dose methoxyflurane for acute paediatric pain: A systematic review. Trauma, 21(2), 94–102. https://doi.org/10.1177/1460408618798391
Babl FE, Jamison SR, Spicer M, Bernard S. Inhaled methoxyflurane as a prehospital analgesic in children. Emerg Med Australas. 2006;18(4):404-410. doi:10.1111/j.1742-6723.2006.00874.x
Babl FE, Barnett P, Palmer G, Oakley E and Davidson A. A pilot study of inhaled methoxyflurane for procedural analgesia in children. Pediatric Anesthesia. 2007;17:148-153. doi:10.1111/j.1460-9592.2006.02037.x
Chin, R, McCaskill, M, Browne, G A randomized controlled trial of inhaled methoxyflurance pain relief in children with upper limb fracture. J Paediatr Child Health 2002; 38: A13–A13.
Hartshorn, S., Barrett, M.J., Lyttle, M.D. et al. Inhaled methoxyflurane (Penthrox®) versus placebo for injury-associated analgesia in children—the MAGPIE trial (MEOF-002): study protocol for a randomised controlled trial. Trials 20, 393 (2019). https://doi.org/10.1186/s13063-019-3511-4