The role of inhaled methoxyflurane in acute pain management

References

• Tomlin PJ. Methoxyflurane. Br J Anaesth. 1965;37(9):706–709.
   PubMed Web of Science ®Google Scholar
• Stephen CR. Clinical applications of methoxyflurane. Acta Anaesthesiol Scand Suppl. 1966;24:215–222.
   PubMedGoogle Scholar
• Mazze RI. Methoxyflurane revisited: tale of an anesthetic from cradle to grave. Anesthesiology. 2006;105(4):843–846.
   PubMed Web of Science ®Google Scholar
• Tomi K, Mashimo T, Tashiro C, et al. Alterations in pain threshold and psychomotor response associated with subanaesthetic concentrations of inhalation anaesthetics in humans. Br J Anaesth. 1993;70(6):684–686.
   PubMed Web of Science ®Google Scholar
• Crandell WB, Pappas SG, Macdonald A. Nephrotoxicity associated with methoxyflurane anesthesia. Anesthesiology. 1966;27(5):591–607.
   PubMed Web of Science ®Google Scholar
• Cousins MJ, Mazze RI. Methoxyflurane nephrotoxicity. A study of dose response in man. JAMA. 1973;225(13):1611–1616.
   PubMed Web of Science ®Google Scholar
• Kharasch ED, Schroeder JL, Liggitt HD, Park SB, Whittington D, Sheffels P. New insights into the mechanism of methoxyflurane nephrotoxicity and implications for anesthetic development (part 1): identification of the nephrotoxic metabolic pathway. Anesthesiology. 2006;105(4):726–736.
   PubMed Web of Science ®Google Scholar
• Kharasch ED, Schroeder JL, Liggitt HD, Ensign D, Whittington D. New insights into the mechanism of methoxyflurane nephrotoxicity and implications for anesthetic development (part 2): identification of nephrotoxic metabolites. Anesthesiology. 2006;105(4):737–745.
   PubMed Web of Science ®Google Scholar
• Mazze RI, Trudell JR, Cousins MJ. Methoxyflurane metabolism and renal dysfunction: clinical correlation in man. Anesthesiology. 1971;35(3):247–252.
   PubMed Web of Science ®Google Scholar
• Desmond JW. Methoxyflurane nephrotoxicity. Can Anaesth Soc J. 1974;21(3):294–307.
   PubMedGoogle Scholar
• Jones NO. Methoxyflurane nephrotoxicity: a review and a case report. Can Anaesth Soc J. 1972;19(2):152–159.
   PubMedGoogle Scholar
• Urgena RB, Gergis SD. Nephrotoxicity from methoxyflurane anaesthesia: a 6-year retrospective study. Br J Anaesth. 1973;45(4):358–362.
   PubMed Web of Science ®Google Scholar
• US Federal Register. Determination that Penthrane (methoxyflurane) inhalation liquid, 99.9 percent, was withdrawn from sale for reasons of safety or effectiveness. Available from: https://www.federalregister.gov/documents/2005/09/06/05-17559/determination-that-penthrane-methoxyflurane-inhalation-liquid-999-percent-was-withdrawn-from-sale. Accessed July 19, 2018.
   Google Scholar
• Australian Therapeutic Goods Administration Approved Product Information for Penthrox; 2016. Available from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/PICMI?OpenForm&t=pi&q=methoxyflurane. Accessed July 19, 2018.
   Google Scholar
• New Zealand Datasheet for Penthrox; 2017. Available from: http://www.medsafe.govt.nz/profs/datasheet/p/penthroxinh.pdf. Accessed July 19, 2018.
   Google Scholar
• Penthrox® Summary of Product Characteristics. Available from: https://www.medicines.org.uk/emc/medicine/31391. Accessed July 19, 2018.
   Google Scholar
• Medical Developments International. European Penthrox® Update, 12 August 2016. Available from: http://www.medicaldev.com/wp-content/uploads/2016/08/ASX-Announcement_European-Penthrox-Update_120816.pdf. Accessed July 19, 2018.
   Google Scholar
• 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(11):2012–2031.
   PubMed Web of Science ®Google Scholar
• Mclennan JV. Is methoxyflurane a suitable battlefield analgesic? J R Army Med Corps. 2007;153(2):111–113.
   PubMedGoogle Scholar
• Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. Acute Pain Management: Scientific Evidence. 4th ed 2015. Available from: https://www.clinicalguidelines.gov.au/portal/2505/acute-pain-management-scientific-evidence. Accessed July 19, 2018.
   Google Scholar
• ACT Ambulance Service. Clinical Management Guidelines 2: Pain Management. July 2017. Available from: http://cdn.esa.act.gov.au/wp-content/uploads/CMG-2-PAIN-MANAGEMENT-July-2017.pdf. Accessed July 19, 2018.
   Google Scholar
• Queensland Ambulance Service. Drug Therapy Protocols: Methoxyflurane. April 2018. Available from: https://www.ambulance.qld.gov.au/docs/clinical/dtprotocols/DTP_Methoxyflurane.pdf. Accessed July 19, 2018.
   Google Scholar
• St John Ambulance Australia (Western Australia). Clinical Practice Guidelines for Ambulance Care in Western Australia, Version 11. Available from: http://www.fair-go.com/docs/Clinical%20Practice%20Guidelines%20V11%2022.07.11.pdf. Accessed July 19, 2018.
   Google Scholar
• Ambulance Victoria. Clinical Practice Guidelines for Ambulance and MICA Paramedics. Available from: http://ambulance.vic.gov.au/paramedics/clinical-practice-guidelines. Accessed July 19, 2018.
   Google Scholar
• 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(8):613–618.
   PubMed Web of Science ®Google Scholar
• Buntine P, Thom O, Babl F, Bailey M, Bernard S. Prehospital analgesia in adults using inhaled methoxyflurane. Emerg Med Australas. 2007;19(6):509–514.
   PubMed Web of Science ®Google Scholar
• 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(4):439–447.
   PubMed Web of Science ®Google Scholar
• Gillis M, Keirens A, Steinkamm C, Verbelen J, Muysoms W, Reynders N. The use of methoxyflurane (Penthrox) in the emergency department. Reg Anesth Pain Med. 2008;33(Suppl 1):e247.
   Google Scholar
• Konkayev AK. Evaluation of clinical effectiveness of inhalatory analgesic “Penthrox” for pain relief in ankle injuries. Arch Balkan Med Union. 2013;48:239–243.
   Google Scholar
• Oxer HF, Wilkes G. Methoxyflurane is a safe, easy, effective analgesic for prehospital pain relief. Prehosp Disast Med. 2007;22:s77.
   Google Scholar
• Lim KJH, Koh ZX, Zafirah NA. Clinical evaluation of Penthrox® (methoxyflurane) and tramadol for the Singapore Emergency Ambulance Service. Abstract presented at the Society for Emergency Medicine in Singapore Annual Scientific Meeting; February 27–28, 2016; Singapore.
   Google Scholar
• 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(2):148–153.
   PubMed Web of Science ®Google Scholar
• Babl FE, Jamison SR, Spicer M, Bernard S. Inhaled methoxyflurane as a prehospital analgesic in children. Emerg Med Australas. 2006;18(4):404–410.
   PubMedGoogle Scholar
• Bendall JC, Simpson PM, Middleton PM. Effectiveness of prehospital morphine, fentanyl, and methoxyflurane in pediatric patients. Prehosp Emerg Care. 2011;15(2):158–165.
   PubMed Web of Science ®Google Scholar
• 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.
   Google Scholar
• Blair HA, Frampton JE. Methoxyflurane: a review in trauma pain. Clin Drug Investig. 2016;36(12):1067–1073.
   PubMed Web of Science ®Google Scholar
• Blair HA, Frampton JE. Methoxyflurane inhalation vapour in trauma pain: a profile of its use in the EU. Drugs Therapy Perspect. 2017;33(9):403–408.
   Google Scholar
• Bijur PE, Latimer CT, Gallagher EJ. Validation of a verbally administered numerical rating scale of acute pain for use in the emergency department. Acad Emerg Med. 2003;10(4):390–392.
   PubMed Web of Science ®Google Scholar
• Todd KH, Funk KG, Funk JP, Bonacci R. Clinical significance of reported changes in pain severity. Ann Emerg Med. 1996;27(4):485–489.
   PubMed Web of Science ®Google Scholar
• Gallagher EJ, Liebman M, Bijur PE. Prospective validation of clinically important changes in pain severity measured on a visual analog scale. Ann Emerg Med. 2001;38(6):633–638.
   PubMed Web of Science ®Google Scholar
• Hoffman GA, Harrington A, Fields HL. Pain and the placebo: what we have learned. Perspect Biol Med. 2005;48(2):248–265.
   PubMed Web of Science ®Google Scholar
• Porter KM, Siddiqui MK, Sharma I, Dickerson S, Eberhardt A. Management of trauma pain in the emergency setting: low-dose methoxyflurane or nitrous oxide? A systematic review and indirect treatment comparison. J Pain Res. 2018;11:11–21.
   PubMed Web of Science ®Google Scholar
• Spruyt O, Westerman D, Milner A, Bressel M, Wein S. A randomised, double-blind, placebo-controlled study to assess the safety and efficacy of methoxyflurane for procedural pain of a bone marrow biopsy. BMJ Support Palliat Care. 2014;4(4):342–348.
   PubMedGoogle Scholar
• Gaskell AL, Jephcott CG, Smithells JR, Sleigh JW. Self-administered methoxyflurane for procedural analgesia: experience in a tertiary Australasian centre. Anaesthesia. 2016;71(4):417–423.
   PubMed Web of Science ®Google Scholar
• Grummet J, Huang S, Konstantatos A, Frydenberg M. The “green whistle”: a novel method of analgesia for transrectal prostate biopsy. BJU Int. 2012;110(Suppl 4):85–88.
   PubMedGoogle Scholar
• Huang S, Pepdjonovic L, Konstantatos A, Frydenberg M, Grummet J. Penthrox alone versus Penthrox plus periprostatic infiltration of local analgesia for analgesia in transrectal ultrasound-guided prostate biopsy. ANZ J Surg. 2016;86(3):139–142.
   PubMed Web of Science ®Google Scholar
• Lee C, Woo HH. Penthrox inhaler analgesia in transrectal ultrasound-guided prostate biopsy. ANZ J Surg. 2015;85(6):433–437.
   PubMed Web of Science ®Google Scholar
• Moss A, Parrish FJ, Naidoo P, et al. Self-administered, inhaled methoxyflurane improves patient comfort during nasoduodenal intubation for computed tomography enteroclysis for suspected small bowel disease: a randomized, double-blind, placebo-controlled trial. Clin Radiol. 2011;66(2):125–131.
   PubMed Web of Science ®Google Scholar
• Nguyen NQ, Toscano L, Lawrence M, et al. Patient-controlled analgesia with inhaled methoxyflurane versus conventional endoscopist-provided sedation for colonoscopy: a randomized multicenter trial. Gastrointest Endosc. 2013;78(6):892–901.
   PubMed Web of Science ®Google Scholar
• Nguyen NQ, Toscano L, Lawrence M, et al. Portable inhaled methoxyflurane is feasible and safe for colonoscopy in subjects with morbid obesity and/or obstructive sleep apnea. Endosc Int Open. 2015;3(5):E487–E493.
   PubMedGoogle Scholar
• Wasiak J, Mahar PD, Paul E, Menezes H, Spinks AB, Cleland H. Inhaled methoxyflurane for pain and anxiety relief during burn wound care procedures: an Australian case series. Int Wound J. 2014;11(1):74–78.
   PubMed Web of Science ®Google Scholar
• Anwari JS, Khalil L, Terkawi AS. Efficacy of the methoxyflurane as bridging analgesia during epidural placement in laboring parturient. Saudi J Anaesth. 2015;9(4):370–375.
   PubMedGoogle Scholar
• Jephcott C, Grummet J, Nguyen N, Spruyt O. A review of the safety and efficacy of inhaled methoxyflurane as an analgesic for outpatient procedures. Br J Anaesth. 2018;120(5):1040–1048.
   PubMed Web of Science ®Google Scholar
• Dayan AD. Analgesic use of inhaled methoxyflurane: evaluation of its potential nephrotoxicity. Hum Exp Toxicol. 2016;35(1):91–100.
   PubMed Web of Science ®Google Scholar
• Jacobs IG. Health effects of patients given methoxyflurane in the prehospital setting: a data linkage study. Open Emerg Med J. 2010;3:7–13.
   Google Scholar
• Australian Government Department of Health Therapeutic Goods Administration. Database of Adverse Event Notifications (DAEN). Available from: https://www.tga.gov.au/database-adverse-event-notifications-daen. Accessed July 19, 2018.
   Google Scholar
• 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(1):57–63.
   PubMed Web of Science ®Google Scholar
• 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.
   Google Scholar
• O’Rourke KM, Mcmaster S, Lust KM. A case of hepatitis attributable to repeated exposure to methoxyflurane during its use for procedural analgesia. Med J Aust. 2011;194(8):423–424.
   PubMed Web of Science ®Google Scholar
• Frangos J, Mikkonen A, Down C. Derivation of an occupational exposure limit for an inhalation analgesic methoxyflurane (Penthrox(®). Regul Toxicol Pharmacol. 2016;80:210–225.
   PubMed Web of Science ®Google Scholar
• Ruff R, Kerr S, Kerr D, Zalcberg D, Stevens J. Occupational exposure to methoxyflurane administered for procedural sedation: an observational study of 40 exposures. Br J Anaesth. 2018;120(6):1435–1437.
   PubMed Web of Science ®Google Scholar
• de Francisco CP. Pentrane dependence: a case report. Br J Psychiatry. 1971;119(553):609–610.
   PubMed Web of Science ®Google Scholar
• Min KW, Cain GD, Sabel JS, Gyorkey F. Methoxyflurane hepatitis. South Med J. 1977;70(11):1363–1364.
   PubMed Web of Science ®Google Scholar
• Klemmer PJ, Hadler NM. Subacute fluorosis: a consequence of abuse of an organofluoride anesthetic. Ann Intern Med. 1978;89(5 Pt 1):607–611.
   PubMed Web of Science ®Google Scholar
• Okuno T, Takeda M, Horishi M, Okanoue T, Takino T. Hepatitis due to repeated inhalation of methoxyflurane in subanaesthetic concentrations. Can Anaesth Soc J. 1985;32(1):53–55.
   PubMedGoogle Scholar
• Novak MA, Roth AS, Levine MR. Calcium oxalate retinopathy associated with methoxyflurane abuse. Retina. 1988;8(4):230–236.
   PubMed Web of Science ®Google Scholar
• Brennan RP, Pearlstein AE, Miller SA. Computed tomography of the kidneys in a patient with methoxyflurane abuse. J Comput Assist Tomogr. 1988;12(1):155–156.
   PubMed Web of Science ®Google Scholar
• Australian Government National Health and Medical Research Council. Emergency care acute pain management manual. 2011. Available from: https://www.nhmrc.gov.au/guidelines-publications/cp135. Accessed July 19, 2018.
   Google Scholar
• The College of Emergency Medicine. Management of pain in adults 2014. Available from: https://www.rcem.ac.uk/docs/College%20Guidelines/5w.%20Management%20of%20Pain%20in%20Adults%20(Revised%20December%202014).pdf. Accessed July 19, 2018.
   Google Scholar
• Berben SA, Meijs TH, van Dongen RT, et al. Pain prevalence and pain relief in trauma patients in the Accident & Emergency department. Injury. 2008;39(5):578–585.
   PubMed Web of Science ®Google Scholar
• 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(5):970–984.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMedGoogle Scholar
• Carter D, Sendziuk P, Eliott JA, Braunack-Mayer A. Why is pain still under-treated in the emergency department? Two new hypotheses. Bioethics. 2016;30(3):195–202.
   PubMed Web of Science ®Google Scholar
• 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(3):228–238.
   PubMed Web of Science ®Google Scholar
• 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 yr retrospective study. Br J Anaesth. 2013;110(1):96–106.
   PubMed Web of Science ®Google Scholar
• Thomas D, Kircher J, Plint AC, et al. Pediatric pain management in the emergency department: the Triage nurses’ perspective. J Emerg Nurs. 2015;41(5):407–413.
   PubMed Web of Science ®Google Scholar
• 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. Epub 2018 Jun 02.
   Google Scholar
• Rickard C, O’Meara P, Mcgrail M, Garner D, Mclean A, Le Lievre P. A randomized controlled trial of intranasal fentanyl vs intravenous morphine for analgesia in the prehospital setting. Am J Emerg Med. 2007;25(8):911–917.
   PubMed Web of Science ®Google Scholar
• Crellin D, Ling RX, Babl FE. Does the standard intravenous solution of fentanyl (50 microg/mL) administered intranasally have analgesic efficacy? Emerg Med Australas. 2010;22(1):62–67.
   PubMed Web of Science ®Google Scholar
• Hansen MS, Dahl JB. Limited evidence for intranasal fentanyl in the emergency department and the prehospital setting: a systematic review. Dan Med J. 2013;60(1):A4563.
   PubMed Web of Science ®Google Scholar
• Murphy A, O’Sullivan R, Wakai A, et al. Intranasal fentanyl for the management of acute pain in children. Cochrane Database Syst Rev. 2014;10(10):CD009942.
   Google Scholar
• Karlsen AP, Pedersen DM, Trautner S, Dahl JB, Hansen MS. Safety of intranasal fentanyl in the out-of-hospital setting: a prospective observational study. Ann Emerg Med. 2014;63(6):699–703.
   PubMed Web of Science ®Google Scholar
• Yeaman F, Oakley E, Meek R, Graudins A. Sub-dissociative dose intranasal ketamine for limb injury pain in children in the emergency department: a pilot study. Emerg Med Australas. 2013;25(2):161–167.
   PubMed Web of Science ®Google Scholar
• Andolfatto G, Willman E, Joo D, et al. Intranasal ketamine for analgesia in the emergency department: a prospective observational series. Acad Emerg Med. 2013;20(10):1050–1054.
   PubMed Web of Science ®Google Scholar
• Yeaman F, Meek R, Egerton-Warburton D, Rosengarten P, Graudins A. Sub-dissociative-dose intranasal ketamine for moderate to severe pain in adult emergency department patients. Emerg Med Australas. 2014;26(3):237–242.
   PubMed Web of Science ®Google Scholar
• Graudins A, Meek R, Egerton-Warburton D, Oakley E, Seith R. The PICHFORK (Pain in Children Fentanyl or Ketamine) trial: a randomized controlled trial comparing intranasal ketamine and fentanyl for the relief of moderate to severe pain in children with limb injuries. Ann Emerg Med. 2015;65(3):248–254.
   PubMed Web of Science ®Google Scholar
• Reynolds SL, Studnek JR, Bryant K, et al. Study protocol of a randomised controlled trial of intranasal ketamine compared with intranasal fentanyl for analgesia in children with suspected, isolated extremity fractures in the paediatric emergency department. BMJ Open. 2016;6(9):e012190.
   PubMed Web of Science ®Google Scholar
• Peura DA. Gastrointestinal safety and tolerability of nonselective nonsteroidal anti-inflammatory agents and cyclooxygenase-2-selective inhibitors. Cleve Clin J Med. 2002;69(Suppl 1):SI31–SI39.
   PubMed Web of Science ®Google Scholar
• Dijkstra BM, Berben SA, van Dongen RT, Schoonhoven L. Review on pharmacological pain management in trauma patients in (pre-hospital) emergency medicine in the Netherlands. Eur J Pain. 2014;18(1):3–19.
   PubMed Web of Science ®Google Scholar
• Entonox Summary of Product Characteristics. Available from: http://www.mhra.gov.uk/spc-pil/?prodName=ENTONOX%20MEDICINAL%20GAS&subsName=NITROUS%20OXIDE&pageID=SecondLevel. Accessed July 19, 2018.
   Google Scholar
• Nolan JP, Baskett PJF. Analgesia and anaesthesia. Skinner DV, editor. Cambridge, UK: Cambridge Textbook of Accident and Emergency Medicine. Cambridge University Press. 1997:188–189.
   Google Scholar
• Komessaroff D. Pre-hospital pain relief: Penthrane or Entonox. Aust J Emerg Care. 1995;2:28–29.
   Google Scholar
• 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(7):920–925.
   PubMed Web of Science ®Google Scholar
• Ducassé JL, Siksik G, Durand-Béchu M, et al. Nitrous oxide for early analgesia in the emergency setting: a randomized, double-blind multicenter prehospital trial. Acad Emerg Med. 2013;20(2):178–184.
   PubMed Web of Science ®Google Scholar
• Chaplin S, Zeppetella G. Instanyl: intranasal fentanyl for treating breakthrough pain. Prescriber. 2010;21(6):40–42.
   Google Scholar
• Nguyen NQ, Burgess J, Debreceni TL, Toscano L. Psychomotor and cognitive effects of 15-minute inhalation of methoxyflurane in healthy volunteers: implication for post-colonoscopy care. Endosc Int Open. 2016;4(11):E1171–E1177.
   PubMedGoogle Scholar
• Sokoloff C, Daoust R, Paquet J, Chauny JM. Is adequate pain relief and time to analgesia associated with emergency department length of stay? A retrospective study. BMJ Open. 2014;4(3):e004288.
   PubMed Web of Science ®Google Scholar
• Oxford League Table of Analgesics in Acute Pain. Available from: http://www.jr2.ox.ac.uk/bandolier/booth/painpag/Acutrev/Analgesics/Leagtab.html. Accessed July 19, 2018.
   Google Scholar
• Mundipharma Pharmaceuticals SL. A phase IIIb open randomized clinical trial to compare pain relief between methoxyflurane and standard of care for treating patients with trauma pain in Spanish emergency units. Available from: https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-000338-70/ES. EudraCT number 2017-000338-70. Accessed July 19, 2018.
   Google Scholar
• Borobia Pérez AM, Capilla Pueyo R, Casal Codesido JR, et al. InMEDIATE Group. 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.
   Google Scholar
• Mundipharma Pharmaceuticals srl. Efficacy and safety of methoxyflurane vaporized (PENTHROX®) in the treatment of acute trauma pain in pre-hospital setting and in the emergency department in Italy: a multicentre, randomized, controlled, open-label study. Available from: https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-001565-25/IT. EudraCT number 2017-001565-25. Accessed July 19, 2018.
   Google Scholar
• 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). Available from: https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-004290-41/GB. EudraCT number 2016-004290-41. Accessed July 19, 2018.
   Google Scholar