Clinical scenario

An 18 year-old patient presents with partial thickness burns over the feet. A pain score of 7/10 was reported at triage along with a significant fear of needles. Adequate first aid has been provided already, and the area of burn has been covered in cling film, but the patient remains in significant pain. Your ED has recently acquired ‘the green whistle’ device, and a colleague suggests you should go straight for it in this situation.

You have heard at conferences that inhaled methoxyflurane provides excellent analgesia, but you have yet to see it used in clinical practice. You wonder whether there is any evidence supporting the hype, in particular compared with other readily available forms of inhalational analgesia.

Three-part question

In (patients with acute pain secondary to injury) is (inhaled methoxyflurane superior to inhaled nitrous oxide/oxygen 50% mixture) at (reducing patient reported pain score)?

Search strategy

EMBASE, PubMed and CINAHL were searched, with no limitation on date or language, via the National Institute for Health and Care Excellence Healthcare Databases Advanced Search portal (search strategy 445231). The search strategy was reduced to ‘clinical trials only’.

ClinicalTrials.gov was searched for ‘methoxyflurane’.

HDAS search: (pain OR analgesia OR efficacy OR ache OR comfort) AND (methoxyflurane OR methoxiflurane OR penthrox OR penthrane OR pentrane) AND (nitrous OR Entonox OR nitronox OR livopan OR nitralgin) as of eighth June 2018.

Search outcome

ClinicalTrials.gov: eight studies found for: methoxyflurane.

Three completed, two as efficacy and safety (NCT01420159 and NCT00524927) as placebo comparator, one as comparison with tramadol. None in comparison with Entonox. Of the two safety and efficacy trials, two direct papers and a subgroup analysis were published. None of the four trials included Entonox as a rescue therapy, hence not included.

CINAHL (4), Embase (26) and PubMed (50) results.

Total: 80 results, with 18 duplicates. Sixty-two articles reviewed, with 60 excluded, using the Rayyan (1) platform.

• Thirty-three excluded based on title (or abstract, where available).

• Eight were background or discussion type articles.

• Four were in a language other than English, and none of the original articles were accessible for translation.

• Six had no article that could be readily found.

• Three were not direct comparisons.

• Three had an article which was inaccessible.

• One was not head to head.

• One was a review article which referenced another paper already included within the BET.

• One compared variable concentrations of the two drugs.

Two articles directly relevant to the clinical question posed. These reviews are presented in table 1 below:

Comment(s)

Methoxyflurane is a halogenated ether, first used clinically as a volatile inhalation anaesthetic agent in the 1960s.1 Early use noted prolonged postoperative analgesia following anaesthesia, which highlighted a unique advantage over other inhalational agents.2 Over the next decade, use of methoxyflurane as a procedural analgo-sedative flourished, being widely used in obstetrics and dentistry.3 4 However, toxicity concerns arose, and the manufacturer withdrew methoxyflurane from the US market in 1999. The Food and Drug Administration subsequently revoked its licence in 2005.5

Inhaled methoxyflurane continues to be licenced in Australia and New Zealand, where it is primarily used in analgesic doses through a Penthrox inhaler. Recent issues with ED crowding has led to renewed UK interest in methoxyflurane as a potentially safe and effective analgo-sedative, which is easy to administer, patient controlled and requires no enhanced monitoring. These are certainly attractive aspects of any analgesic drug to any busy emergency physician and to any patient.

But what does the evidence say? The STOP! Trial published by Coffey et al 6 is, to date, the largest randomised and double blinded clinical trial comparing Penthrox with placebo, conducted at six EDs within the UK. The results show that methoxyflurane provides effective analgesia; the changes in visual analogue scale score from baseline at all time points was greater with methoxyflurane than with placebo. The greatest treatment effect was seen at 15 min poststudy drug inhalation.

How does it compare witht other readily available inhalational analgesic agents? The evidence in this BET suggests it is potentially comparable but is limited by multiple study weaknesses and a lack of any trials with head-to-head comparison. We are left with indirect extrapolations, selection bias, prehospital data and studies that clearly lack generalisability to an ED environment.

How does it compare with stronger standard analgesia? Not as well by all accounts. Studies such as that by Miiddleton et al 7 suggest methoxyflurane does not provide adequate or definitive analgesia for those in severe pain, when compared with standard IV opiates in a prehospital setting. Again, this evidence has limitations.

In place of the evidence, proponents will often cite the softer benefits of the drug; occlusion of the exhalation port can provide a temporary ‘boost’ in analgesia that can provide procedural cover; the negative inspiratory pressure required to work the device is less than that required to trigger the valve in a standard Entonox cylinder; the Penthrox device is more portable. All these benefits are anecdotal at present and require further study.

Thankfully, this work is ongoing. There are at least three international randomised controlled trials that are currently looking to report interventional research comparing methoxyflurane to current standards of care in traumatic injury.8–10 It is vital that these trials report clinical effectiveness and measures of cost-effectiveness and patient flow metrics in addition if the anecdotal benefits are to be realised in scientific evidence.