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, Multicentre Trial in Italy (MEDITA)

Abstract

Background: Inhaled low-dose methoxyflurane is approved in Europe for emergency relief of moderate-to-severe trauma-related pain in adults, but data versus active comparators are sparse. The Phase IIIb MEDITA trial investigated the analgesic efficacy, practicality and safety of methoxyflurane versus standard analgesic treatment (SAT) for acute trauma pain. Methods: Randomised, active-controlled, parallel-group, open-label trial conducted in 15 Italian emergency units. Adults with limb trauma and pain score ≥4 on Numerical Rating Scale (NRS) were randomised 1:1 to inhaled methoxyflurane 3mL or SAT (intravenous [IV] morphine 0.1mg/kg for severe pain [NRS ≥7]; IV paracetamol 1g or IV ketoprofen 100mg for moderate pain [NRS 4-6]). Primary endpoint was overall change in visual analogue scale (VAS) pain intensity from baseline (time of randomisation) to 3, 5 and 10min. Non-inferiority and superiority of methoxyflurane versus SAT were concluded if the upper 95% confidence interval (CI) for the comparison was <1 and <0, respectively. Findings: Between February 8, 2018, and February 8, 2019, 272 patients were randomised (136 per group). 270 patients (mean age 51 years; 49% male; 34% with severe pain; mean baseline VAS: 67mm) were treated and analysed. Superiority of methoxyflurane was demonstrated for moderate-to-severe pain (adjusted mean treatment difference: -5·94mm; 95% CI: -8·83, -3·06mm), moderate pain ( 5·97mm; 95% CI: 9·55, -2·39mm) and severe pain (-5·54mm; 95% CI: -10·49, -0·59mm). Median onset of pain relief was 9min for methoxyflurane and 15min for SAT. Practicality of methoxyflurane treatment was rated Excellent, Very or Good by 90% of clinicians vs. 64% for SAT. 17% of methoxyflurane-treated patients and 3% of SAT-treated patients reported adverse events (all non-serious). Interpretation: Methoxyflurane provided superior pain relief to SAT in patients with moderate-to-severe trauma pain and may offer a simple, fast, effective non-opioid treatment option. Trial Registration: This trial is registered with EudraCT (2017- 001565-25) and ClinicalTrials.gov (NCT03585374). Funding Statement: The study was funded by Mundipharma Pharmaceuticals srl. Costs for article processing and Open Access were funded by Mundipharma Pharmaceuticals srl. Declaration of Interests: Sebastiano Mercadante, Antonio Voza, Sossio Serra, Germana Ruggiano, Giseppe Carpinteri, Gianfilippo Gangitano, Fabio Intelligente and Andrea Fabbri have nothing to disclose. Elisabetta Bonafede is an employee of the clinical research organisation that conducted the study. Antonella Sblendido, Amedeo Soldi and Alberto Farina are employees of Mundipharma Pharmaceuticals srl. Ethics Approval Statement: The study was approved by the Italian Medicines Agency (AIFA). The trial was conducted in accordance with the principles established in the Declaration of Helsinki and the International Conference on Harmonization guidelines for good clinical practice. All trial documents and procedures were approved by the appropriate ethics committees at each site, and written informed consent (or verbal witnessed consent) was obtained from all patients before initiation into the study.