Real world safety of methoxyflurane analgesia in the emergency setting: a comparative hybrid prospective-retrospective post-authorisation safety study.

BACKGROUND: Low-dose analgesic methoxyflurane (Penthrox®) was approved in Europe for emergency relief of moderate to severe pain in conscious adults with trauma in 2015. A comparative post-authorisation safety study (PASS) was conducted to assess the risk of hepatotoxicity and nephrotoxicity with methoxyflurane during routine clinical practice. METHODS: This was a comparative hybrid prospective-retrospective cohort study. The comparative cohorts consisted of adults who were given methoxyflurane (methoxyflurane cohort) or another analgesic (concurrent cohort) routinely used for moderate to severe trauma and associated pain in the emergency setting (ambulance and Emergency Department) in the UK between December 2016 and November 2018. Hepatic and renal events were captured in the ensuing 12 weeks. A blinded clinical adjudication committee assessed events. A historical comparator cohort (non-concurrent cohort) was identified from patients with fractures in the English Hospital Episode Statistics (HES) accident and emergency database from November 2013 and November 2015 (before commercial launch of methoxyflurane). Hepatic and renal events were captured in the ensuing 12 weeks via linkage with the Clinical Practice Research Datalink (CPRD) and HES hospital admissions databases. RESULTS: Overall, 1,236, 1,101 and 45,112 patients were analysed in the methoxyflurane, concurrent and non-concurrent comparator cohorts respectively. There was no significant difference in hepatic events between the methoxyflurane and concurrent cohorts (1.9% vs. 3.0%, P = 0.079) or between the methoxyflurane and non-concurrent cohorts (1.9% vs. 2.5%, P = 0.192). Renal events were significantly less common in the methoxyflurane cohort than in the concurrent cohort (2.3% vs. 5.6%, P < 0.001). For methoxyflurane versus non-concurrent cohort the lower occurrence of renal events (2.3% vs. 3.2%, P = 0.070) was not statistically significant. Multivariable adjustment did not change these associations. CONCLUSIONS: Methoxyflurane administration was not associated with an increased risk of hepatotoxicity or nephrotoxicity compared with other routinely administered analgesics and was associated with a reduced risk of nephrotoxicity compared with other routinely administered analgesics. TRIAL REGISTRATION: Study registered in the EU PAS Register (ENCEPP/SDPP/13040).

Inhaled methoxyflurane (Penthrox®) versus placebo for injury-associated analgesia in children-the MAGPIE trial (MEOF-002): study protocol for a randomised controlled trial.

BACKGROUND: Pain from injuries is one of the commonest symptoms in children attending emergency departments (EDs), and this is often inadequately treated in both the pre-hospital and ED settings, in part due to challenges of continual assessment and availability of easily administered analgesic options. Pain practices are therefore a key research priority, including within the field of paediatric emergency medicine. Methoxyflurane, delivered via a self-administered Penthrox® inhaler, belongs to the fluorinated hydrocarbon group of volatile anaesthetics and is unique among the group in having analgesic properties at low doses. Despite over 30 years of clinical acute analgesia use, and a large volume of evidence supporting its safety and efficacy, there is a paucity of randomised controlled trial data for Penthrox®. METHODS: This is an international multi-centre randomised, double-blind, placebo-controlled phase III trial assessing the efficacy and safety of methoxyflurane delivered via the Penthrox® inhaler for the management of moderate to severe acute traumatic pain in children and young people aged 6-17 years. Following written informed consent, eligible participants are randomised to self-administer either inhaled methoxyflurane (maximum dose of 2 × 3 ml) or normal saline placebo (maximum dose 2 × 5 ml). Patients, treating clinicians and research nurses are blinded to the treatment. The primary outcome is the change in pain intensity at 15 min after the commencement of treatment, as measured by the Visual Analogue Scale (VAS) or the Wong-Baker FACES® Pain Rating scale, with the latter converted to VAS values. Secondary outcome measures include the number and proportion of responders who achieve a 30% reduction in VAS score compared to baseline, rescue medication requested, time and number of inhalations to first pain relief, global medication performance assessment by the patient, clinician and research nurse, and evaluation of adverse events experienced during treatment and during the subsequent 14 ± 2 days. The primary analysis will be by intention to treat. The total sample size is 110 randomised and treated patients per treatment arm. DISCUSSION: The Methoxyflurane AnalGesia for Paediatric InjuriEs (MAGPIE) trial will provide efficacy and safety data for methoxyflurane administered via the Penthrox® inhaler, in children and adolescents who present to EDs with moderate to severe injury-related pain. TRIAL REGISTRATION: EudraCT, 2016-004290-41 . Registered on 11 April 2017. ClinicalTrials.gov, NCT03215056 . Registered on 12 July 2017.