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Three Part Question

In [patients with acute pain] is [methoxyflurane better than nitrous oxide/oxygen 50% mixture] at [reducing patient reported pain score]

Clinical Scenario

An 18 year old presents with partial thickness burns over the feet, with a self-reported pain score of 7/10 and a significant fear of needles. Adequate first aid has been provided already and burns covered in clingfilm. All of the cylinders of Entonox are currently being used by other patients in the Emergency Department. You've been told the ED has acquired 'the green whistle' device for inhaling methoxyflurane but haven't used it in clinical practice, and wonder how good it is in comparison to Entonox?

Search Strategy

EMBASE, PubMed and CINAHL were searched, with no limitation on date or language, via the NICE Healthcare Databases Advanced Search portal (search strategy 445231).

ClinicalTrials.gov was searched for 'methoxyflurane'.
HDAS Search: “((pain OR analgesia OR efficacy OR ache OR comfort).ti,ab AND (methoxyflurane OR methoxiflurane OR penthrox OR penthrane OR pentrane).ti,ab) AND (nitrous OR Entonox OR nitronox OR livopan OR nitralgin).ti,ab" as of 8th June 2018

Search Outcome

ClinicalTrials.gov: 8 studies found for: methoxyflurane
3 completed, 2 as efficacy and safety (NCT01420159 and NCT00524927) as placebo comparator, 1 as comparison with tramadol. None in comparison to Entonox. Of the two safety and efficacy trials, two direct papers and a sub-group 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. 62 articles reviewed, with 60 excluded, using the Rayyan(1) platform.
- 33 excluded based on title (or abstract, where available)
- 8 were background or discussion type articles
- 4 were in a language other than English, and none of the original articles were accessible for translation
- 6 had no article that could be readily found
- 3 were not direct comparisons
- 3 had an article which was inaccessible
- 1 was not head to head
- 1 was a review article which referenced another paper already included within the BET
- 1 compared variable concentrations of the two drugs

2 articles directly relevant to the clinical question posed.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Porter KM et al 2018 United Kingdom	Two studies: 1. Methoxyflurane v.s. Placebo(2) (?12 yrs, pain score ?4 - ?7 at time of admission to emergency departments [multi-centre, within UK] on numerical rating scale [NRS] due to minor trauma) 2. Nitrous Oxide/Oxygen 50% v.s. Medical Air(3) (?18 yrs, pain score 4-6 inclusive on NRS, from trauma, on pre-hospital assessment at two centres, France)	1+ (SR with indirect comparison of treatments from two RCTs)	1. Change on visual analogue scale [VAS] at 5, 10, 15, 20, 30 minutes from baseline and then every 30 minutes until discharge or rescue analgesia used. Primary efficacy measured at 15 minutes.	1. 303 screened with 149 randomized to each arm completing to 20min VAS	1. Funded by two pharmaceutical companies (Mundipharma International Ltd and Parexel International). Three of the four authors disclosed either funding or employment by the pharmaceutical industry. 2. No mention of explanation to patients regarding ability to temporarily increase analgesia delivered by covering dilutor hole. 3. Both studies neglect to note the use of other analgesic agents or adjuncts such as ice, NSAIDs or paracetamol etc. 4. No note of time since painful trauma onset (with associated risks of injury complication or windup) 5. Both studies use a ‘middle range’ of self-reported pain scores. Both forms of analgesia compared may be used clinically in worse self-reported values of pain as an interim treatment.
			2. ‘pain relief’ defined as NRS ?3 at 15 minutes with NRS measured every 5 minutes.	2. 648 screened, 30 randomized to each arm
				Collated results from both papers were compared with standardised median differences (SMD) of -0.15, -0.26 and -0.2 at 5, 10 and 15 minutes respectively. All SMDs had 95% confidence intervals crossing one and P values >0.05.
Rosen M et al 1969 United Kingdom	Women in labour in eight maternity centres, Wales. Randomised by day of the week barring Sundays (midwife’s choice), comparison of entonox apparatus (50% mix) v.s. 0.35% concentration in air of methoxyflurane)	2+	1. ‘Mothers opinion of pain relief during and then after labour’ as one of: complete, considerable, slight or none.	1. 598 in methoxyflurane arm, 265 in Entonox arm. 1257 in total, but 394 in trichloroethylene group excluded. No significant difference between methoxyflurane and Entonox across all four rating scales. Pre-delivery, multiparous mothers stated labour was ‘better than previous’ in 55% with methoxyflurane and 35% with Entonox but after delivery, 30% of all multips changed choice, with inter-drug difference remaining but no longer significant.	Unable to blind (a persistent issue between comparison drugs) Absence of standardised measure of pain such as NRS or VAS Could consider peak and trough pain score rather than during and after to reduce recall bias Midwives added to initial choices for degree of co-operation Midwife discretion regarding cessation of inhalation. No mention of method of delivery for Entonox (mouthpiece or facemask), presumed facemask administration of methoxyflurane)
			2. ‘Midwives opinion of pain relief’ as one of excellent, good, adequate or inadequate	2. Midwives opinion of ‘excellent’ was 14% with methoxyflurane and 7% with Entonox (P<0.01)

Comment(s)

The current preparation of methoxyflurane commercially available and licensed for clinical use is Penthrox (3mL methoxyflurane), which is stated to deliver 0.3 MAC hours(4); quoted as MAC x duration in hours, in the form of a hand-held self-administered unit. The ‘Cardiff’ Inhaler, which most articles refer to when discussing methoxyflurane in it’s former anaesthetic setting, delivers a concentration of 0.35(5) with fresh gas flows ranging from 5-40lpm. This was tested through minute volumes of 7, 10 and 20lpm at a respiratory rate of 24 breaths per minute (British Standards Institution) The most common mixture of nitrous oxide available in the emergency setting (pre hospital and emergency department) is Entonox, a branded preparation of 50% nitrous oxide and oxygen. Modern anaesthetic machines have the ability to provide bespoke mixtures of nitrous oxide to oxygen with safeguards to mitigate delivery of a hypoxic mixture. The systematic review iterates what this BET has shown which is there has not been a head to head comparison of methoxyflurane with Entonox, however has pragmatically compared both indirectly, as a result of the systematic review from 2018, as well as directly in 1969. Admittedly, the modern Penthrox inhalational device is patient administered with the ability to temporarily increase analgesia through covering a diluter hole, whilst the Cardiff inhaler from 1969 was a midwife administered fixed concentration device. Whilst Entonox was used in the 1969 study, it does not specify method of delivery e.g. use of a facemask or a mouthpiece delivery system.

Clinical Bottom Line

Both methoxyflurane and Entonox provide analgesia to moderate painful stimuli, but have not had any head to head comparison in the literature. Both are likely to provide similar experiences of pain relief, with the ability for self-titrating an increased inhaled concentration with the ‘green whistle’ an additional benefit in patients with a similar breathing rate. (Grade C Recommendation) Entonox is widely available in emergency departments and ambulance services; given clinical contexts, other factors may prove more influential in the clinician or employing organisation’s choice of inhaled analgesia, including cost per unit, portability, clinical training of clinician, availability of other health care professions and analgesic agents and clinical environment/permissibility amongst others. References 1. Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan-a web and mobile app for systematic reviews. Syst Rev [Internet]. 2016;5(1):1–10. Available from: http://dx.doi.org/10.1186/s13643-016-0384-4 2. Coffey F, Wright J, Hartshorn S, Hunt P, Locker T, Mirza K, et al. STOP!: a randomised, double-blind, placebo-controlled study of the efficacy and safety of methoxyflurane for the treatment of acute pain. Emerg Med J [Internet]. 2014 Aug 1;31(8):613 LP-618. Available from: http://emj.bmj.com/content/31/8/613.abstract 3. Ducassé JL, Siksik G, Durand-Béchu M, Couarraze S, Vallé B, Lecoules N, et al. Nitrous oxide for early analgesia in the emergency setting: A randomized, double-blind multicenter prehospital trial. Acad Emerg Med. 2013;20(2):178–84. 4. Dayan AD. Analgesic use of inhaled methoxyflurane: Evaluation of its potential nephrotoxicity. Hum Exp Toxicol [Internet]. 2016;35(1):91–100. Available from: https://doi.org/10.1177/0960327115578743 5. Jones PL, Molloy MJ, Rosen M. The Cardiff Penthrane Inhaler. A vaporizer for the administration of methoxyflurane as an obstetric analgesic. Br J Anaesth. 1971 Feb;43(2):190–9.

References

1. Porter, Keith M. Siddiqui, Mohd Kashif Sharma, Ikksheta Dickerson, Sara Eberhardt, Alice Management of trauma pain in the emergency setting: Low-dose methoxyflurane or nitrous oxide? A systematic review and indirect treatment comparison Journal of Pain Research 20 December 2017 Volume 2018:11 Pages 11—21
2. Rosen, M. Mushin, W. W. Jones, P. L. Jones, E. V. Field Trial of Methoxyflurane, Nitrous Oxide, and Trichloroethylene as Obstetric Analgesics British Medical Journal 02 August 1969