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      Efficacy, Practicality, and Safety of Inhaled Methoxyflurane in Elderly Patients with Acute Trauma Pain: Subgroup Analysis of a Randomized, Controlled, Multicenter, Open-Label Trial (MEDITA)

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          Acute trauma pain management in the elderly population is a challenge. Inhaled methoxyflurane represents a promising treatment option; however, data in the elderly population are limited.

          Patients and Methods

          Subgroup, post hoc analysis including 69 patients aged ≥65 years from a randomized, active-controlled, open-label study in the emergency setting. Key inclusion criterion was moderate-to-severe pain (Numerical Rating Scale [NRS] score ≥ 4]) secondary to trauma in a single limb. Patients received inhaled methoxyflurane (3 mL) or standard analgesic treatment (SAT; IV paracetamol 1 g or ketoprofen 100 mg for moderate pain [NRS 4–6] and IV morphine 0.1mg/kg for severe pain [NRS ≥7]). The primary endpoint was the overall change in visual analog scale (VAS) pain intensity from randomization to the next 3, 5, and 10 min. Secondary endpoints included time to onset of pain relief (TOPR), efficacy up to 30 min, judgment of operators and patients, and safety.


          Pain reduction over time was similar in both groups. Median TOPR was shorter for methoxyflurane (9 min; 95% CI: 7.8, 10.2 min) than SAT (15 min; 95% CI: 10.2, 19.8 min). In terms of treatment satisfaction, patients and operators rated treatment efficacy and practicality, respectively, as “Excellent” or “Very good” 5.7 times and 3.4 times more frequently than SAT. A similar rate of adverse events (methoxyflurane: 6 events; SAT: 7 events) was recorded, all non-serious. No clinically significant changes in vital signs parameters were observed, and methoxyflurane did not result in cases of bradycardia or hypotension.


          In elderly patients with trauma pain, inhaled methoxyflurane shows similar pain relief and safety compared to SAT, offering advantages in terms of onset of effect and user’s satisfaction. Although this analysis presents some methodological limitations, it provides the first specific evidence of the use of inhaled methoxyflurane in the elderly population.

          Trial Registration

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

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          Most cited references 11

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          The stress response to trauma and surgery

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            Pain management in the elderly population: a review.

            The elderly population comprises the fastest growing segment of the world's population. As patients age, the incidence and prevalence of certain pain syndromes increase. Pain may be underreported as some elderly patients incorrectly believe that pain is a normal process of aging. A comprehensive pain assessment includes a thorough medical history and physical examination, review of systems and pertinent laboratory results, imaging studies, and diagnostic tests. Pain physicians should have a broad range of understanding of the pharmacologic and physiological changes that occur in the geriatric population. The present review on pain management in the elderly focuses on relevant information for the pain clinician. Included are appropriate pain assessment, physical examination, pathophysiologic changes in the elderly, pharmacokinetic and pharmacodynamic changes, and present pain management modalities. Elderly patients present with increased fat mass, decreased muscle mass, and decreased body water, all of which have important ramifications on drug distribution. Hepatic phase I reactions involving oxidation, hydrolysis, and reduction appear to be more altered by age than phase II conjugation such as acetylation, glucuronidation, sulfation, and glycine conjugation. There is a predictable age-related decline in cytochrome P-450 function and, combined with the polypharmacy that much of the elderly population experiences, this may lead to a toxic reaction of medications. One of the newer opiates, oxymorphone, has recently been studied as it is metabolized in a non-cytochrome P-450 pathway and therefore bypasses many of the drug-drug interactions common to the elderly. A multidisciplinary approach is recommended to investigate all possible options for optimal management, including pharmacotherapy, interventional procedures, physical rehabilitation, and psychological support.
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              STOP!: a randomised, double-blind, placebo-controlled study of the efficacy and safety of methoxyflurane for the treatment of acute pain

              Objective To evaluate the short-term efficacy and safety of methoxyflurane for the treatment of acute pain in patients presenting to an emergency department (ED) with minor trauma. Methods STOP! was a randomised, double-blind, multicentre, placebo-controlled study conducted at six sites in the UK. A total of 300 patients, 90 of whom were adolescent patients (age 12–17 years), were randomised 150:150 to receive either methoxyflurane via a Penthrox inhaler or placebo. The primary end point of the study was the change in pain intensity as measured using the visual analogue scale (VAS) from baseline to 5, 10, 15 and 20 min after the start of study drug inhalation. Patients were supplied with one inhaler containing 3 mL methoxyflurane or 5 mL placebo after enrolment and initial assessments. Age group (adolescent/adult) and baseline VAS score were controlled for in the statistical analyses. Results A total of 149 patients received methoxyflurane, and 149 patients received placebo. Demographic and baseline characteristics were comparable between the groups. Methoxyflurane reduced pain severity significantly more than placebo (p<0.0001) at all time points tested, with the greatest estimated treatment effect of −18.5 mm (adjusted change from baseline) seen at 15 min after the start of treatment. Methoxyflurane was well tolerated, with the majority of adverse reactions being mild, transient and in line with anticipated pharmacological action. Conclusion The results of this study suggest that methoxyflurane administered via the Penthrox inhaler is an efficacious, safe, and rapidly acting analgesic. Trial registration number: NCT01420159.

                Author and article information

                J Pain Res
                J Pain Res
                Journal of Pain Research
                16 July 2020
                : 13
                : 1777-1784
                [1 ]Emergency Department, Maurizio Bufalini Hospital , Cesena, Italy
                [2 ]Emergency Department, IRCCS Humanitas Research Teaching Hospital , Rozzano, Milan, Italy
                [3 ]Emergency Medicine Department, Santa Maria Annunziata Hospital , Florence, Italy
                [4 ]Department of Emergency Medicine, Morgagni-Pierantoni Hospital , Forlì, Italy
                [5 ]YGHEA, CRO Division of Ecol Studio Bioikos S.r.l ., Bologna, Italy
                [6 ]Medical Affairs Department, Mundipharma Pharmaceuticals Srl , Milan, Italy
                Author notes
                Correspondence: Alberto Farina Medical Affairs Department, Mundipharma Pharmaceuticals Srl , Milan, ItalyTel +39 02 3182881 Email alberto.farina@mundipharma.it
                © 2020 Serra et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 3, Tables: 2, References: 14, Pages: 8
                Funded by: Mundipharma Pharmaceuticals srl, Milan, Italy
                The study was sponsored and funded by Mundipharma Pharmaceuticals srl, Milan, Italy. The study sponsor was involved in study design and overview, data interpretation, and report revision. The sponsor had no role in data collection or analysis. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Editorial costs were funded by Mundipharma Pharmaceuticals srl.
                Original Research


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