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Andrea Fabbri,1 Alberto M Borobia,2 Agnes Ricard-Hibon,3 Frank Coffey,4 Aurore Caumont-Prim,5 François Montestruc,5 Amedeo Soldi,6 Susana Traseira Lugilde,7 Sara Dickerson8 1Department of Emergency Medicine, Morgagni-Pierantoni Hospital, Forli, Italy; 2Clinical Pharmacology Department, La Paz University Hospital, School of Medicine, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain; 3Emergency Department SAMU-SMUR 95, CHG Pontoise-Beaumont/Oise, Pontoise, France; 4DREEAM: Department of Research and Education in Emergency Medicine, Acute Medicine and Major Trauma, Nottingham University Hospitals NHS Trust, Nottingham, UK; 5eXYSTAT, Malakoff, France; 6Mundipharma Pharmaceuticals Srl, Milan, Italy; 7Mundipharma Pharmaceuticals S.L., Madrid, Spain; 8Mundibiopharma Limited, Cambridge, UKCorrespondence: Sara DickersonMundibiopharma Limited, Cambridge Science Park, Milton Road, Cambridge CB4 0AB, UKTel +44 1223 397684Email Sara.Dickerson@mundipharma.comPurpose: Undertreatment of trauma-related pain is common in the pre-hospital and hospital settings owing to barriers to the use of traditional standard of care analgesics. Low-dose methoxyflurane is an inhaled non-opioid analgesic with a rapid onset of pain relief that is approved for emergency relief of moderate-to-severe trauma-related pain in adults. This analysis was performed to compare the efficacy and safety of low-dose methoxyflurane with standard of care analgesics in adults with trauma-related pain.Methods: A meta-analysis was performed on pooled data from randomized controlled trials identified via a systematic review. The primary endpoint was the pain intensity difference between baseline and various time intervals (5, 10, 15, 20, and 30 minutes) after initiation of treatment.Results: The pain intensity difference was statistically superior with low-dose methoxyflurane compared with standard of care analgesics (overall estimated treatment effect=11.88, 95% CI=9.75– 14.00; P< 0.0001). The superiority of low-dose methoxyflurane was demonstrated at 5 minutes after treatment initiation and was maintained across all timepoints. Significantly more patients treated with methoxyflurane achieved response criteria of pain intensity ≤ 30 mm on a visual analog scale, and relative reductions in pain intensity of ≥ 30% and ≥ 50%, compared with patients who received standard of care analgesics. The median time to pain relief was shorter with methoxyflurane than with standard of care analgesics. The findings were consistent in a subgroup of elderly patients (aged ≥ 65 years).Conclusion: Methoxyflurane can be considered as an alternative to standard of care analgesics in pre-hospital and hospital settings for treatment of adult patients with acute trauma-related pain.Keywords: acute pain, inhaled analgesic, emergency service, wounds and injury, pain management, analgesia

Keith M Porter,1 Anthony D Dayan,2 Sara Dickerson,3 Paul M Middleton4,5 1Trauma Department, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, UK; 2Independent Consultant, London, UK; 3Medical Affairs, Mundipharma International Limited, Cambridge, UK; 4Emergency Medicine Research Unit, Liverpool Hospital, Sydney, NSW, Australia; 5Distributed Research in Emergency and Acute Medicine (DREAM) Collaboration, Sydney, NSW, Australia Abstract: Methoxyflurane is an inhaled analgesic administered via a disposable inhaler which has been used in Australia for over 40 years for the management of pain associated with trauma and for medical procedures in children and adults. Now available in 16 countries worldwide, it is licensed in Europe for moderate to severe pain associated with trauma in conscious adults, although additional applications are being made to widen the range of approved indications. Considering these ongoing developments, we reviewed the available evidence on clinical usage and safety of inhaled analgesic methoxyflurane in trauma pain and in medical procedures in both adults and children. Published data on methoxyflurane in trauma and procedural pain show it to be effective, well tolerated, and highly rated by patients, providing rapid onset of analgesia. Methoxyflurane has a well-established safety profile; adverse events are usually brief and self-limiting, and no clinically significant effects on vital signs or consciousness levels have been reported. Nephrotoxicity previously associated with methoxyflurane at high anesthetic doses is not reported with low analgesic doses. Although two large retrospective comparative studies in the prehospital setting showed inhaled analgesic methoxyflurane to be less effective than intravenous morphine and intranasal fentanyl, this should be balanced against the administration, supervision times, and safety profile of these agents. Given the limitations of currently available analgesic agents in the prehospital and emergency department settings, the ease of use and portability of methoxyflurane combined with its rapid onset of effective pain relief and favorable safety profile make it a useful nonopioid option for pain management. Except for the STOP! study, which formed the basis for approval in trauma pain in Europe, and a few smaller randomized controlled trials (RCTs), much of the available data are observational or retrospective, and further RCTs are currently underway to provide more robust data. Keywords: analgesia, clinical safety, Penthrox, procedural pain, review, trauma

Carsten Bantel,1 Shiva S Tripathi,2 David Molony,3 Tony Heffernan,3 Susmita Oomman,4 Vivek Mehta,5 Sara Dickerson6 1Chelsea and Westminster Hospital NHS Foundation Trust, London, 2Royal Preston Hospital, Preston, UK; 3Mallow Primary Healthcare Centre, Mallow, Ireland; 4Withybush General Hospital, Haverfordwest, 5Pain & Anaesthesia Research Centre, Barts Health NHS Trust, London, 6Mundipharma International Limited, Cambridge, UK Background: Opioids are an effective treatment for moderate-to-severe pain. However, they are associated with a number of gastrointestinal side effects, most commonly constipation. Laxatives do not target the underlying mechanism of opioid-induced constipation (OIC), so many patients do not have their symptoms resolved. Fixed-dose prolonged-release (PR) oxycodone/naloxone (OXN) tablets contain the opioid agonist oxycodone and the opioid antagonist naloxone. Naloxone blocks the action of oxycodone in the gut without compromising its analgesic effects.Aim: To evaluate the effectiveness of PR OXN in patients with severe pain who had laxative-refractory OIC with their previous opioid.Methods: The study was carried out in 13 centers across the UK and Ireland, using a bespoke online tool to capture patients’ data. Patients were reviewed according to normal clinical practice of each center and rated any changes in their constipation and quality of life (QoL) since starting PR OXN. Any change in patients’ laxative use was also recorded.Results: One hundred and seven patients were entered into the database, and 81 went on to attend at least one review. Of these, 54 (66.7%) reported an improvement in constipation and 50 (61.7%) reported an improvement in QoL since starting PR OXN. Fifty-seven patients (70.4%) said they had reduced laxative intake; 48 (59.3%) only needed laxatives as required.Conclusion: PR OXN reduced symptoms of constipation, improved QoL and reduced laxative intake in patients with OIC. It has a potential place early in any treatment strategy for severe pain in patients using opioids, particularly in patients who may be predisposed to constipation. Keywords: laxatives, opioid, opioid-induced constipation, oxycodone/naloxone, PR OXN, real-world data, severe pain

Keith M Porter,1 Mohd Kashif Siddiqui,2 Ikksheta Sharma,2 Sara Dickerson,3 Alice Eberhardt4 1University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; 2Parexel International Ltd, Chandigarh, India; 3Mundipharma International Ltd, Cambridge, UK; 4Mundipharma GmbH, Limburg, Germany Background: Low-dose methoxyflurane and nitrous oxide (N2O; 50:50 with oxygen) are both self-administered, self-titrated, rapid-acting, nonnarcotic, and noninvasive inhalational agents with similar onset times of pain relief. The aim of this review was to compare the clinical efficacy, safety, and tolerability of these analgesics in emergency care. Materials and methods: A systematic literature search and review according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were performed using Embase, Medline, the Cochrane Library, several clinical trial registers, and emergency-medicine conference material. Results: Although both compounds have been used for many years in emergency care, the search found only a few controlled studies and no head-to-head trials performed in this setting. Two double-blind, randomized studies comparing their respective study medication (low-dose methoxyflurane or N2O) to placebo were identified that could be compared in an indirect approach by using placebo as a bridging comparator. Both agents provided rapid pain relief to trauma patients, with no significant differences between them; both treatments were generally well tolerated. Conclusion: Both low-dose methoxyflurane and N2O are suitable options for the pain treatment of trauma patients in the emergency setting. Due to the ease of administration and portability, inhaled low-dose methoxyflurane, however, may not only offer advantages in emergency situations in remote or difficult-to-reach locations and mass-casualty situations but also be of significant value in urban and rural environments. Keywords: methoxyflurane, nitrous oxide, trauma, pain treatment, emergency

Author(s): T. Kovachy [1]; P. Asenbaum [1]; C. Overstreet [1]; C. A. Donnelly [1]; S. M. Dickerson [1]; A. Sugarbaker [1]; J. M. Hogan [1]; M. A. Stamper-Kurn (corresponding author) [...]