Methoxyflurane Versus Standard of Care for Acute Trauma-Related Pain in the Emergency Setting: Protocol for a Randomised, Controlled Study in Italy (MEDITA)

Andrea Fabbri, Giuseppe Carpinteri, Germana Ruggiano, Elisabetta Bonafede, Antonella Sblendido, Alberto Farina, Amedeo Soldi, MEDITA Study Group, Germana Ruggiano, Isabella Bartoli, Giuseppe Carpinteri, Andrea Fabbri, Francesco Bermano, Maurizio Chiesa, Daniela Mura, Mario Oppes, Peppino Masciari, Davide Torti, Vittorio Iorno, Antonio Voza, Piero Paolini, Sossio Serra, Gianfilippo Gangitano, Raffaella Francesconi, Andrea Fabbri, Giuseppe Carpinteri, Germana Ruggiano, Elisabetta Bonafede, Antonella Sblendido, Alberto Farina, Amedeo Soldi, MEDITA Study Group, Germana Ruggiano, Isabella Bartoli, Giuseppe Carpinteri, Andrea Fabbri, Francesco Bermano, Maurizio Chiesa, Daniela Mura, Mario Oppes, Peppino Masciari, Davide Torti, Vittorio Iorno, Antonio Voza, Piero Paolini, Sossio Serra, Gianfilippo Gangitano, Raffaella Francesconi

Abstract

Introduction: Low-dose methoxyflurane, administered via a hand-held inhaler, has been used for short-term pain relief in emergency medicine in Australia and New Zealand for over 40 years, and was recently approved in Europe for the rapid relief of moderate-to-severe trauma-related pain in adults. There is currently a lack of data for methoxyflurane versus active comparators, therefore this trial will investigate the efficacy and safety of inhaled methoxyflurane compared with standard of care (SoC) in the treatment of acute trauma-related pain in pre-hospital and ED settings in Italy.

Methods: MEDITA (Methoxyflurane in Emergency Department in ITAly) is a Phase IIIb, prospective, randomised, active-controlled, parallel-group, open-label, multicentre trial. A total of 272 adult patients with moderate-to-severe pain [score ≥ 4 on the Numerical Rating Scale (NRS)] due to limb trauma will be randomised 1:1 to receive 3 mL methoxyflurane (self-administered by the patient via inhalation under supervision of a trained person) or medications that currently comprise the SoC in Italy [intravenous (IV) morphine for severe pain (NRS ≥ 7); IV paracetamol or ketoprofen for moderate pain (NRS 4-6)], administered as soon as possible after randomisation.

Planned outcomes: Pain intensity will be measured using a 100-mm visual analogue scale (VAS) at baseline (time of randomisation) and at intervals up to 30 min. Time of onset of pain relief as reported by the patient and use of rescue medication will be recorded. The patient will rate the efficacy and the healthcare professional will rate the practicality of study treatment at 30 min after randomisation using a 5-point Likert scale. Adverse events will be recorded until safety follow-up at 14 ± 2 days. Vital signs will be measured at baseline, 10 and 30 min. The primary aim is to demonstrate non-inferiority of methoxyflurane versus SoC for the change in VAS pain intensity from baseline (randomisation) to 3, 5 and 10 min.

Trial registration: EudraCT number: 2017-001565-25. Clinicaltrials.gov identifier: NCT03585374.

Funding: Mundipharma Pharmaceuticals srl.

Keywords: Acute pain; Analgesic; Emergency department; Inhaled analgesic; Injury; Methoxyflurane; Penthrox; Pre-hospital; Trauma.

Figures

Fig. 1
Fig. 1
Methoxyflurane inhaler with activated carbon chamber

References

    1. EuroSafe. Injuries in the European Union: summary of injury statistics for the years 2012–2014, 6th Edition. 2016. . Accessed 06 Sept 2018.
    1. Berben SAA, Schoonhoven L, Meijs THJM, van Vugt AB, van Grunsven PM. Prevalence and relief of pain in trauma patients in emergency medical services. Clin J Pain. 2011;27:587–592. doi: 10.1097/AJP.0b013e3182169036.
    1. Berben SA, Meijs TH, van Dongen RT, et al. Pain prevalence and pain relief in trauma patients in the Accident and Emergency Department. Injury. 2008;39:578–585. doi: 10.1016/j.injury.2007.04.013.
    1. Cordell WH, Keene KK, Giles BK, Jones JB, Jones JH, Brizendine EJ. The high prevalence of pain in emergency medical care. Am J Emerg Med. 2002;20:165–169. doi: 10.1053/ajem.2002.32643.
    1. Todd KH, Ducharme J, Choiniere M, et al. Pain in the emergency department: results of the pain and emergency medicine initiative (PEMI) multicenter study. J Pain. 2007;8:460–466. doi: 10.1016/j.jpain.2006.12.005.
    1. Albrecht E, Taffe P, Yersin B, Schoettker P, Decosterd I, Hugli O. Undertreatment of acute pain (oligoanalgesia) and medical practice variation in prehospital analgesia of adult trauma patients: a 10 year retrospective study. Br J Anaesth. 2013;110:96–106. doi: 10.1093/bja/aes355.
    1. Pierik JG, IJzerman MJ, Gaakeer MI, et al. Pain management in the emergency chain: the use and effectiveness of pain management in patients with acute musculoskeletal pain. Pain Med. 2015;16:970–984. doi: 10.1111/pme.12668.
    1. Diβmann PD, Maignan M, Cloves PD, Gutierrez Parres B, Dickerson S, Eberhardt A. A review of the burden of trauma pain in emergency settings in Europe. Pain Ther. 2018 doi: 10.1007/s40122-018-0101-1.
    1. Pierik JGJ, IJzerman MJ, Gaakeer MI, Vollenbroek-Hutten MMR, Doggen CJM. Painful discrimination in the emergency department: risk factors for underassessment of patients’ pain by nurses. J Emerg Nurs. 2017;43:228–238. doi: 10.1016/j.jen.2016.10.007.
    1. Motov SM, Khan AN. Problems and barriers of pain management in the emergency department: are we ever going to get better? J Pain Res. 2008;2:5–11.
    1. The College of Emergency Medicine. Management of pain in adults. 2014. . Accessed 06 Sept 2018.
    1. Komessaroff D. Pre-hospital pain relief: penthrane or entonox. Aust J Emerg Care. 1995;2:28–29.
    1. Entonox summary of product characteristics. 2018. . Accessed 06 Sept 2018.
    1. Casamayor M, DiDonato K, Hennebert M, Brazzi L, Prosen G. Administration of intravenous morphine for acute pain in the emergency department inflicts an economic burden in Europe. Drugs Context. 2018;7:212524. doi: 10.7573/dic.212524.
    1. Raccomandazioni Intersocietarie Italiane (SIAARTI, SIMEU, SIS 118, AISD, SIARED, SICUT, IRC) sulla gestione del dolore in emergenza. 2014. . Accessed 06 Sept 2018.
    1. Penthrox® summary of product characteristics. 2016. . Accessed 06 Sept 2018.
    1. Cousins MJ, Mazze RI. Methoxyflurane nephrotoxicity. A study of dose response in man. JAMA. 1973;225:1611–1616. doi: 10.1001/jama.1973.03220410023005.
    1. Dayan AD. Analgesic use of inhaled methoxyflurane: evaluation of its potential nephrotoxicity. Hum Exp Toxicol. 2016;35:91–100. doi: 10.1177/0960327115578743.
    1. Australian Therapeutic Goods Administration approved Product Information for Penthrox. 2016. . Accessed 06 Sept 2018.
    1. New Zealand Datasheet for Penthrox. 2017. . Accessed 06 Sept 2018.
    1. Medical Developments International. European Penthrox® Update, 12 August 2016. 2016. . Accessed 06 Sept 2018.
    1. Coffey F, Wright J, Hartshorn S, 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. 2014;31:613–618. doi: 10.1136/emermed-2013-202909.
    1. 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!) Adv Ther. 2016;33:2012–2031. doi: 10.1007/s12325-016-0405-7.
    1. Konkayev AK. Evaluation of clinical effectiveness of inhalatory analgesic “Penthrox” for pain relief in ankle injuries. Arch Balkan Med Union. 2013;48:239–243.
    1. Chin R, Maccaskill M, Browne G. A randomised control trial of inhaled methoxyflurane pain relief, in children with upper limb fracture. J Paediatr Child Health. 2002;38:A13. doi: 10.1046/j.1440-1754.2002.00011.x.
    1. Middleton PM, Simpson PM, Sinclair G, Dobbins TA, Math B, Bendall JC. Effectiveness of morphine, fentanyl, and methoxyflurane in the prehospital setting. Prehosp Emerg Care. 2010;14:439–447. doi: 10.3109/10903127.2010.497896.
    1. Bendall JC, Simpson PM, Middleton PM. Effectiveness of prehospital morphine, fentanyl, and methoxyflurane in pediatric patients. Prehosp Emerg Care. 2011;15:158–165. doi: 10.3109/10903127.2010.541980.
    1. Buntine P, Thom O, Babl F, Bailey M, Bernard S. Prehospital analgesia in adults using inhaled methoxyflurane. Emerg Med Australas. 2007;19:509–514.
    1. Babl F, Barnett P, Palmer G, Oakley E, Davidson A. A pilot study of inhaled methoxyflurane for procedural analgesia in children. Paediatr Anaesth. 2007;17:148–153. doi: 10.1111/j.1460-9592.2006.02037.x.
    1. Babl FE, Jamison SR, Spicer M, Bernard S. Inhaled methoxyflurane as a prehospital analgesic in children. Emerg Med Australas. 2006;18:404–410.
    1. Craig M, Jeavons R, Probert J, Benger J. Randomised comparison of intravenous paracetamol and intravenous morphine for acute traumatic limb pain in the emergency department. Emerg Med J. 2012;29:37–39. doi: 10.1136/emj.2010.104687.
    1. Sin B, Wai M, Tatunchak T, Motov SM. The use of intravenous acetaminophen for acute pain in the Emergency Department. Acad Emerg Med. 2016;23:543–553. doi: 10.1111/acem.12921.
    1. Eken C, Serinken M, Elicabuk H, Uyanik E, Erdal M. Intravenous paracetamol versus dexketoprofen versus morphine in acute mechanical low back pain in the emergency department: a randomised double-blind controlled trial. Emerg Med J. 2014;31:177–181. doi: 10.1136/emermed-2012-201670.
    1. Borobia Pérez AM, Capilla Pueyo R, Casal Codesido JR, InMEDIATE Group et al. Phase IIIb, open label randomised clinical trial to compare pain relief between methoxyflurane and standard of care for treating patients with trauma pain in Spanish Emergency Units (InMEDIATE): Study protocol. IBJ Clin Pharmacol. 2017;1:e0008.
    1. Johnston S, Wilkes GJ, Thompson JA, Ziman M, Brightwell R. Inhaled methoxyflurane and intranasal fentanyl for prehospital management of visceral pain in an Australian ambulance service. Emerg Med J. 2011;28:57–63. doi: 10.1136/emj.2009.078717.
    1. Oxer HF. Effects of Penthrox® (methoxyflurane) as an analgesic on cardiovascular and respiratory functions in the pre-hospital setting. J Mil Veterans Health. 2016;24:14–20.
    1. Jacobs IG. Health effects of patients given methoxyflurane in the prehospital setting: a data linkage study. Open Emerg Med J. 2010;3:7–13. doi: 10.2174/1876542401003010007.
    1. Hjermstad MJ, Fayers PM, Haugen DF, et al. Studies comparing Numerical Rating Scales, Verbal Rating Scales, and Visual Analogue Scales for assessment of pain intensity in adults: a systematic literature review. J Pain Symptom Manag. 2011;41:1073–1093. doi: 10.1016/j.jpainsymman.2010.08.016.
    1. Jensen MP, Karoly P. The measurement of clinical pain intensity: a comparison of six methods. Pain. 1986;27:117–126. doi: 10.1016/0304-3959(86)90228-9.
    1. Ho K, Spence J, Murphy M. Review of pain measurement tools. Ann Emerg Med. 1996;27:427–431. doi: 10.1016/S0196-0644(96)70223-8.
    1. Tveita T, Thoner J, Klepstad P, Dale O, Jystad A, Borchgrevink PC. A controlled comparison between single doses of intravenous and intramuscular morphine with respect to analgesic effects and patient safety. Acta Anaesthesiol Scand. 2008;52:920–925. doi: 10.1111/j.1399-6576.2008.01608.x.
    1. Ducassé JL, Siksik G, Durand-Béchu M. Nitrous oxide for early analgesia in the emergency setting: a randomized, double-blind multicentre prehospital trial. Acad Emerg Med. 2013;20:178–184. doi: 10.1111/acem.12072.
    1. Medical Developments International Limited. A randomised, double-blind, multicentre, placebo controlled study to evaluate the safety and efficacy of methoxyflurane (PENTHROX®) for the treatment of acute pain in children and adolescents from 6 to less than 18 years of age (presenting to an Emergency Department with minor trauma). 2017. . EudraCT number 2016-004290-41. Accessed 06 Sept 2018.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다