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Three Part Question

In [Adult patients who present to ED with moderate to severe pain due to traumatic limb injuries] is [methoxyflurane better than standard care] at [reducing pain, decreasing length of stay in ED and reduce treatment side effects]

Clinical Scenario

A 70-year-old patient is brought to the Emergency Department (ED) with a fracture dislocation of her ankle. Despite standard analgesic treatment (SAT) including 10mg of Morphine intravenously (IV), 1gr of Paracetamol (IV) and nitrous oxide, the patient is still in moderate pain. There is significant delay in organising reduction and cast application under sedation. The patient is asking for more analgesia and the paramedics state that they have heard Methoxyflurane can provide effective pain relief for patients with similar injuries in out of hospital settings. Methoxyflurane is currently not adopted or available as part of SAT in the ED.

Search Strategy

An online search was conducted in October 2020 via online library access at Manchester Metropolitan University using the EBSCOhost platform. This enabled a selection of multiple databases including MEDLINE, AMED - The Allied and Complementary Medicine Database, OpenDissertations, CINAHL, eBook Collec-tion (EBSCOhost), Education Abstracts (H.W. Wilson). The search terms entered were as follows: (“penthrox or methoxyflurane”) and (“pain management or pain relief or pain control or pain reduction”) and (“emergency department or emergen-cy room or accident and emergency or accident & emergency or a & e”) and (“traumatic injury or trauma patients or physical trauma).
The search was restricted to papers available within the last 10 years and excluded children, adolescents and pre-hospital settings.
Search of The Cochrane Central Register of Controlled Trials (CENTRAL) re-turned 0 results. BestBets search revealed 1 article submitted in 2018 comparing Penthrox with Nitrous oxide in acute pain management outside the context of trauma and 1 article in 2018 attempting to compare penthrox to nitrous oxide in management of pain in shoulder dislocation with no relevant papers being found.

Search Outcome

A total of 16 articles were found. After reviewing abstracts, full texts and associated references, 8 papers were deemed to be relevant. Of these there were 4 randomised controlled trials (RCT), 1 systematic literature review, 1 prospective observa-tional trial, 1 retrospective study, 1 sub-group analyses and one Phase 4 prospective trial which is still ongoing

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Ricard-Hibon, A, Lecoules N, Jacquin L et al 2020 France	351 patients over 18 years of age with moderate to severe pain due to limb trauma. 178 received inhaled Methoxyflurane (m)and standard analgesic treatment (SAT) and and 173 received placebo with SAT	Phase 3b Randomised, double-blind, multi-centre, open-label, placebo-controlled conducted across 8 emergency departments	safety	Most adverse events were of mild (111/147) intensity	assessment and treatment bias (according to investigators' choice)
			efficacy	Median time to pain relief 35 minutes (95% CI 28-62) with most pro-nounced effect in patients with severe pain p<0.001
			satisfaction with use	Increased satis-faction for pa-tient, nurse and physician (p < 0.001)
Coffey F, Dissmann P, Mirza K, Lomax M 2016 UK	204 adults over 18 years of age, with minor limb trauma (fractures, dislocations, burns, contusions, lacerations) 103 methoxyflurane vs 101 placebo group	Phase 3, randomised double blind, multi centre, placebo-controlled across 6 Emergency departments	safety	(mostly dizziness/headache) were reported by 42.2% of patients receiving methoxyflurane and 14.9% of patients receiving placebo; none caused withdrawal and the majority were mild and transient.	Unclear as to why a pain score of up to 7 was included and not higher.Limited clinical laboratory sampling to identify if any hepatic or nephrotoxicity present post use
			satisfaction with use	'Excellent', 'Very Good' or 'Good' by 77.6% of patients, 74.5% of physicians and 72.5% of nurses
Mercandante 2019 Italy	270 adults over age 18 moderate -severe pain minor single trauma (fracture, dislocation, crush injury or contusion	Phase 3b randomised, open-label, multi-centre, active-controlled, parallel group 16 Emergency departments	safety	minor and transient side effects	Possible intrinsic bias
			efficacy	Median time to onset of pain relief 9mins vs 15mins SAT
			user satisfaction	Staff and patients (p<0.001)
Borobia et al 2020 Spain	305 adults over age 18 moderate to severe pain due to limb injuries (limbs, fracture, swelling, dislocation, contusion, burns, laceration) 156 methoxyflurane vs SAT	Phase 3b Randomised con-trolled trial, open label, multi-centre, active-controlled 13 Emergency departments and 1 pre-hospital setting	safety	minor and transiet	Risks participants and researchers bias Variation in SAT offered Patients in sever pain not offered opioids Funded by Multipharma
			efficacy	median time to onset of pain relief 3 mins vs 10 mins SAT
			user satisfaction	Patients 77% vs 38% SAT and Clinicians 72% vs 19% SAT
			overall pain reduction	-2.47 on NRS (numerical rating scale) scale at 20 mins vs 1.39 control (difference 1: CI 0.84-1.32)
Porter et al 2018 UK	4 studies (none of which compare nitrous oxide with methoxyflurane)	Systematic litera-ture review Indirect treatment comparison level of evidence 2b	efficacy	No statistical difference at 5,10 and 15 mins	Insufficient studies Questionable methodology of the studies being analysed Multiple interventions
Viglino et al 2019 France	200 adults over age 18 years (median 32 years) moderate to severe pain due to minor limb trauma (fracture, contusion, sprain, wound, burn, dislocation)	Prospective, observational	safety	frequent (64%) but not serious adverse events	Observer bias, selective patients (young, benign limb trauma) Received funding from 2 Multipharma companies which market methoxyflurane
			efficacy	66/200 had pain score <3 on NRS at 15 mins whilst overall reduction in pain over 60mins was significant (p<0.001)
			user satisfaction	good level of satisfaction without statistical data
Campbell et al 2020 Canada	49 adults over age 18 moderate to sever pain with minor limb trauma 87.8% (sprain 40.8% and fracture 32.7%)	Phase 4 real world ongoing trial prospective open label, multi centred	safety	no serious adverse events	Ongoing trial, no data in abstract regarding what rescue medication was given, no information in the abstract regarding how much improvement of pain was reported on NRS
			efficacy	5 mins post administration methoxyflurane 80.4% pain relief 15 mins 91.3% 100% by 30mins
			user satisfaction	>80% of pa-tients rated good, very good or excel-lent within 20mins post start of treat-ment
Serra et al 2020 Italy	69 adults over age 65 years moderate to severe pain due to trauma to a single limb	Sub-group, post hoc analysis of MEDITA trial for patients >age 65	safety	no serious adverse events	Small sample size with no power calculation Post hoc study Intrinsic bias
			efficacy	median time of pain relief 9mins vs 15mins for SAT
			user satisfaction	Patients 64 %(Methoxyflu-rane) vs 6% (SAT) Clinicians (60% vs 17.7%)

Comment(s)

Acute trauma pain is frequently overlooked and inadequately assessed or under-treated. Oligoanalgesia (under-treatment of pain) is problematic and is influenced by pain severity, patients’ characteristics and available resources.Recent recommendations by the European Society for Emergency Medicine (EU-SEM, 2020) advocate the use of inhaled methoxyflurane (1x3mls vials with max dose of 2x3mls vials) or Nitrous oxide alongside Paracetamol PO/IV, NSAIDs Po/IV and Opioids IV in the pharmacological management of acute moderate to severe pain in adults. It has been also licensed for use in the UK since 2015. Methoxyflurane is a low dose non-opioid volatile fluorinated hydrocarbon, which is self-administered by patients via a portable inhalation device. Risks from hepatic and renal toxicity in the past have been linked to doses exceeding that of the recommended for use in the ED. Studies identified most common side effects to be dizziness, somnolence and headache which were transient with discontinuation of its use. Serra et al (2020) showed no significant adverse effects in those over 65 but more research in this subgroup of patients is needed. Despite minor side effect, satisfaction with its use amongst clinicians and patients is consistently high throughout the studies. Coffey et al (2016) were amongst the first to show that when compared with placebo, methoxyflurane was effective and safe for the management of moderate to severe pain due to minor trauma. Median time to first pain relief was four minutes and maximum effect was achieved within 15 minutes. Studies by Mercadante et al (2019) and Borobia et al (2020) comparing methoxyflurane to standard analgesic treatment (SAT) may be more clinically relevant , as pain management in ED is often multi-modal. Both studies demonstrate that methoxyflurane is more effective than SAT in reducing pain from baseline (p<0.001), with effective and superior analgesia maintained up to 60 minutes post-administration (Borobia et al 2020). The efficacy of methoxyflurane vs nitrous oxide alone in trauma pain has not been extensively researched. Porter et al (2018) suggest that it is as effective as nitrous oxide in providing rapid pain relief in trauma and is well tolerated by patients, however only 4 studies were included in their review with significant differences in methodology and neither or which compared methoxyflurane with nitrous oxide.

Clinical Bottom Line

Evidence supports consideration for use of low dose inhaled Methoxyflurane (Penthrox) in the adult population presenting to ED, either as a first-line or as part of multi-modal analgesic treatment for moderate to severe pain secondary to acute traumatic limb injury. It is non-narcotic, easy to administer, acts rapidly, has no serious adverse effects and is highly rated amongst patients and clinicians.

References

1. Ricard-Hibon, A, Lecoules N, Jacquin L et al Inhaled methoxyflurane for the management of trauma related pain in patients admitted to hospital emergency departments: a randomised, double-blind placebo-controlled trial (PenASAP study) European Journal of Emergency Medicine 27:414-421
2. Coffey F, Dissmann P, Mirza K, Lomax M Methoxyflurane analgesia in adult patients in the Emergency Department: a subgroup analysis of a randomized, double-blind, placebo- controlled study (STOP!) Advances in Therapy 33:2012-31
3. Mercadante S, Voza A, Serra S, et al Analgesic efficacy, practicality and safety of inhaled methoxyflurane versus standard analgesic treatment for acute trauma pain in the emergency setting: a randomised, open-label, active-controlled, Advances in Therapy 36:3030-46
4. Borobia AM, Collado SG, Cardona CC, et al. Inhaled methoxyflurane provides greater analgesia and faster onset of action versus standard of care analgesia in patients with trauma pain. InMEDIATE: a randomized con-trolled trial in Emergency Unit Annals in Emergency Med 75(3):315-328.
5. Porter K, Siddiqui M. Sharma I et al Management of trauma pain in the emergency setting: low-dose methoxyflurane or ni-trous oxide? A systematic review and indirect treatment comparison Journal of Pain Research 11:(11-21)
6. Viglino, D, Masson, N.T, Verdetti, A. et al Multimodal oral analgesia for non-severe trama patients: evaluation of a triage-nurse led directed protocol combining methoxyflurane, paracetamol and oxycodone Internal and Emergency medicine 14:1139-1145
7. Campbell, S, Simard, E, Arcand A, Blagrove et al A phase IV real world study on the use of low dose methoxyflurane (penthrox) for the treatment of moderate to severe trauma pain in the Canadian emergency department (ADVANCE-ED): an interim report on CJEM Scientific abstracts 22:S1 P129
8. Serra S, Voza A, Ruggiano G. et al Efficacy, Practicality and safety of Inhaled Methoxyflurane in Elderly patients with Acute Trauma pain : Subgroup analysis of a Randomised controlled, Multicentre, Open-Label Trail (MEDITA) Journal of Pain Research 13: 1777-1784