Inhaled Methoxyflurane versus Intravenous Morphine for Severe Trauma Pain in the Emergency Setting: Subgroup Analysis of MEDITA, a Multicenter, Randomized, Controlled, Open-Label Trial

Antonio Voza; Germana Ruggiano; Sossio Serra; Giuseppe Carpinteri; Gianfilippo Gangitano; Fabio Intelligente; Elisabetta Bonafede; Antonella Sblendido; Alberto Farina; Amedeo Soldi; Andrea Fabbri; MEDITA Study Group

doi:10.2147/JPR.S240911

Inhaled Methoxyflurane versus Intravenous Morphine for Severe Trauma Pain in the Emergency Setting: Subgroup Analysis of MEDITA, a Multicenter, Randomized, Controlled, Open-Label Trial

J Pain Res. 2020 Mar 6:13:491-502. doi: 10.2147/JPR.S240911. eCollection 2020.

Affiliations

¹ Emergency Department, IRCCS Humanitas Research Teaching Hospital, Milan, Italy.
² Emergency Medicine Department, Santa Maria Annunziata Hospital, Florence, Italy.
³ Emergency Department, Maurizio Bufalini Hospital, Cesena, Italy.
⁴ Department of Emergency Medicine, Policlinico G. Rodolico University Hospital, Catania, Italy.
⁵ Emergency Department, Infermi Hospital, Rimini, Italy.
⁶ YGHEA, Division of Ecol Studio s.p.a., Bologna, Italy.
⁷ Medical Affairs Department, Mundipharma Pharmaceuticals Srl, Milan, Italy.
⁸ Department of Emergency Medicine, Morgagni-Pierantoni Hospital, Forlì, Italy.

Abstract

Purpose: Opioid analgesics remain the cornerstone of treatment for severe trauma pain in the emergency setting, but there are barriers to their use. This post hoc analysis of a previously reported trial (MEDITA) investigated the efficacy and safety of low-dose methoxyflurane versus intravenous (IV) morphine for severe trauma pain.

Patients and methods: MEDITA was a Phase IIIb, randomized, active-controlled, parallel-group, open-label study in Italian pre-hospital units and emergency departments (EudraCT: 2017-001565-25; NCT03585374). Adult patients (N=272) with moderate-to-severe trauma pain (score ≥4 on the Numerical Rating Scale [NRS]) were randomized 1:1 to inhaled methoxyflurane (3 mL) or standard analgesic treatment (SAT; IV paracetamol 1g or ketoprofen 100mg for moderate pain [NRS 4-6] and IV morphine 0.1mg/kg for severe pain [NRS ≥7]). Analyses were performed for the severe pain subgroup. The primary efficacy variable was the overall change from baseline in visual analog scale (VAS) pain intensity at 3, 5 and 10min post-randomization. Non-inferiority of methoxyflurane versus morphine was concluded if the upper 95% confidence interval (CI) for the treatment difference was <1; superiority was concluded if the upper 95% CI was <0.

Results: Ninety-three patients (methoxyflurane: 49; SAT: 44) were included in the severe pain intention-to-treat population. The reduction in VAS pain intensity over the first 10min was superior for methoxyflurane versus morphine (adjusted mean treatment difference: -5.54mm; 95% CI: -10.49, -0.59mm; p=0.029). Median time to onset of pain relief was 9min for methoxyflurane and 15min for morphine. Patients rated treatment efficacy and physicians rated treatment practicality "Excellent" or "Very good" for more methoxyflurane-treated patients (42.8% and 67.3%) than morphine-treated patients (18.1% and 22.8%). Adverse events, all non-serious, were reported in 20.4% of methoxyflurane-treated patients and in 4.8% of morphine-treated patients.

Conclusion: Methoxyflurane provided superior short-term pain relief to IV morphine in patients with severe trauma pain and offers an effective non-narcotic treatment option.

Keywords: acute pain; analgesic; emergency department; methoxyflurane; morphine; prehospital.

Grants and funding

The study was funded by Mundipharma Pharmaceuticals srl. The study sponsor was involved in the study design and data interpretation but had no role in data collection or analysis. The sponsor reviewed the report and provided funding for medical writing assistance. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Costs for article processing and Open Access were funded by Mundipharma Pharmaceuticals srl.