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).

INTRODUCTION: 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 Methoxyflurane in Emergency Department in ITAly (MEDITA) trial investigated the analgesic efficacy, practicality and safety of methoxyflurane versus standard analgesic treatment (SAT) for acute trauma pain. METHODS: This was a 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 3 mL or SAT [intravenously administered (IV) morphine 0.1 mg/kg for severe pain (NRS ≥ 7); IV paracetamol 1 g or IV ketoprofen 100 mg for moderate pain (NRS 4-6)]. The primary endpoint was overall change in visual analogue scale (VAS) pain intensity from baseline (time of randomisation) to 3, 5 and 10 min. Non-inferiority and superiority of methoxyflurane versus SAT were concluded if the upper 95% confidence interval (CI) for the treatment comparison (methoxyflurane-SAT) was less than 1 and less than 0, respectively. RESULTS: Between 8 February 2018 and 8 February 2019, 272 patients were randomised (136 per treatment group). A total of 270 patients (mean age 51 years; 49% male; 34% with severe pain; mean baseline VAS 67 mm) were treated and analysed for efficacy and safety. Superiority of methoxyflurane was demonstrated for moderate-to-severe pain (adjusted mean treatment difference - 5.94 mm; 95% CI - 8.83, - 3.06 mm), moderate pain (- 5.97 mm; 95% CI - 9.55, - 2.39 mm) and severe pain (- 5.54 mm; 95% CI - 10.49, - 0.59 mm). Median onset of pain relief was 9 min for methoxyflurane and 15 min for SAT. Practicality of methoxyflurane treatment was rated "Excellent", "Very Good" or "Good" by 90% of clinicians vs. 64% for SAT. Adverse events (all non-serious) were reported by 17% of methoxyflurane-treated patients and 3% of SAT-treated patients. CONCLUSION: 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: Trial registered with EudraCT (2017-001565-25) on 2 March 2018 and ClinicalTrials.gov (NCT03585374) on 13 July 2018. FUNDING: Mundipharma Pharmaceuticals S.r.l.

Methoxyflurane Versus Standard of Care for Acute Trauma-Related Pain in the Emergency Setting: Protocol for a Randomised, Controlled Study in Italy (MEDITA).

INTRODUCTION: Low-dose methoxyflurane, administered via a hand-held inhaler, has been used for short-term pain relief in emergency medicine in Australia and New Zealand for over 40 years, and was recently approved in Europe for the rapid relief of moderate-to-severe trauma-related pain in adults. There is currently a lack of data for methoxyflurane versus active comparators, therefore this trial will investigate the efficacy and safety of inhaled methoxyflurane compared with standard of care (SoC) in the treatment of acute trauma-related pain in pre-hospital and ED settings in Italy. METHODS: MEDITA (Methoxyflurane in Emergency Department in ITAly) is a Phase IIIb, prospective, randomised, active-controlled, parallel-group, open-label, multicentre trial. A total of 272 adult patients with moderate-to-severe pain [score ≥ 4 on the Numerical Rating Scale (NRS)] due to limb trauma will be randomised 1:1 to receive 3 mL methoxyflurane (self-administered by the patient via inhalation under supervision of a trained person) or medications that currently comprise the SoC in Italy [intravenous (IV) morphine for severe pain (NRS ≥ 7); IV paracetamol or ketoprofen for moderate pain (NRS 4-6)], administered as soon as possible after randomisation. PLANNED OUTCOMES: Pain intensity will be measured using a 100-mm visual analogue scale (VAS) at baseline (time of randomisation) and at intervals up to 30 min. Time of onset of pain relief as reported by the patient and use of rescue medication will be recorded. The patient will rate the efficacy and the healthcare professional will rate the practicality of study treatment at 30 min after randomisation using a 5-point Likert scale. Adverse events will be recorded until safety follow-up at 14 ± 2 days. Vital signs will be measured at baseline, 10 and 30 min. The primary aim is to demonstrate non-inferiority of methoxyflurane versus SoC for the change in VAS pain intensity from baseline (randomisation) to 3, 5 and 10 min. TRIAL REGISTRATION: EudraCT number: 2017-001565-25. Clinicaltrials.gov identifier: NCT03585374. FUNDING: Mundipharma Pharmaceuticals srl.

Prospective, Multicentre Trial of Methoxyflurane for Acute Trauma-Related Pain in Helicopter Emergency Medical Systems and Hostile Environments: METEORA Protocol.

INTRODUCTION: The inhalational analgesic low-dose methoxyflurane has been widely used by Australian ambulance services since 1975 and is now approved in Europe for emergency relief of moderate-to-severe trauma-related pain in conscious adult patients. The use of methoxyflurane in hostile environments is of special interest given its portability, ease of use and rapid onset of action. This trial will investigate the efficacy, tolerability and practicality of use of inhaled methoxyflurane in patients with moderate-to-severe trauma-related pain rescued from hostile mountainous environments by the Helicopter Emergency Medical Service (HEMS) in Italy. METHODS: METEORA is a phase IIIb, prospective, single-arm, multicentre trial. Approximately 200 adult patients with a pain score of at least 4 on the numerical rating scale (NRS) due to limb trauma rescued by HEMS will be enrolled. Patients will receive up to 2 × 3 mL methoxyflurane, self-administered by the patient by inhalation under medical supervision. Rescue medication will be permitted if required. PLANNED OUTCOMES: Pain intensity will be measured using a 100-mm visual analogue scale (VAS) at baseline, at 5, 10, 15, 20, 30, 45 and 60 min after the start of methoxyflurane inhalation and when positioning the patient on a spinal board or stretcher; and also using the NRS at enrolment and at 10 min. Use of rescue medication (yes/no) will be recorded. The patient will rate efficacy and the healthcare professional will rate practicality of methoxyflurane treatment at 30 and 60 min using a 5-point Likert scale. Vital signs will be measured at baseline, 10, 30 and 60 min. Assessments after 30 min will only be performed for patients using a second inhaler. Adverse events will be recorded until safety follow-up at 3 ± 1 days. The primary endpoint is the percentage of patients achieving at least 30% improvement from baseline in VAS pain intensity within the first 10 min of methoxyflurane administration. TRIAL REGISTRATION: EudraCT number: 2017-004601-40. FUNDING: Mundipharma Pharmaceuticals, srl. Plain language summary available for this article.

A water soluble CoQ10 formulation improves intracellular distribution and promotes mitochondrial respiration in cultured cells.

BACKGROUND: Mitochondria are both the cellular powerhouse and the major source of reactive oxygen species. Coenzyme Q(10) plays a key role in mitochondrial energy production and is recognized as a powerful antioxidant. For these reasons it can be argued that higher mitochondrial ubiquinone levels may enhance the energy state and protect from oxidative stress. Despite the large number of clinical studies on the effect of CoQ(10) supplementation, there are very few experimental data about the mitochondrial ubiquinone content and the cellular bioenergetic state after supplementation. Controversial clinical and in vitro results are mainly due to the high hydrophobicity of this compound, which reduces its bioavailability. PRINCIPAL FINDINGS: We measured the cellular and mitochondrial ubiquinone content in two cell lines (T67 and H9c2) after supplementation with a hydrophilic CoQ(10) formulation (Qter®) and native CoQ(10). Our results show that the water soluble formulation is more efficient in increasing ubiquinone levels. We have evaluated the bioenergetics effect of ubiquinone treatment, demonstrating that intracellular CoQ(10) content after Qter supplementation positively correlates with an improved mitochondrial functionality (increased oxygen consumption rate, transmembrane potential, ATP synthesis) and resistance to oxidative stress. CONCLUSIONS: The improved cellular energy metabolism related to increased CoQ(10) content represents a strong rationale for the clinical use of coenzyme Q(10) and highlights the biological effects of Qter®, that make it the eligible CoQ(10) formulation for the ubiquinone supplementation.