Inhaled methoxyflurane for the management of trauma related pain in patients admitted to hospital emergency departments: a randomised, double-blind placebo-controlled trial (PenASAP study)

Abstract

Background Oligo-analgesia is common in the emergency department (ED). This study aimed at reporting, when initiated by triage nurse, the superior efficacy of inhaled methoxyflurane plus standard of care (m-SoC) analgesia versus placebo plus SoC (p-SoC) for moderate-to-severe trauma-related pain in the hospital ED. Methods A randomised, double-blind, placebo-controlled trial was conducted at eight EDs. Adults with pain score ≥4 (11-point numerical rate scale, NRS) at admission were randomised to receive one or two inhalers containing m-SoC or p-SoC. Primary outcome measure was time until pain relief ≤30 mm, assessed on the 100-mm Visual Analogic Scale (VAS). Results A total of 351 patients were analysed (178 m-SoC; 173 p-SoC). Median pain prior to first inhalation was 66 mm, 75% had severe pain (NRS 6–10). Median time to pain relief was 35 min [95% confidence interval (CI), 28–62] for m-SoC versus not reached in p-SoC (92 – not reached) [hazard ratio), 1.93 (1.43–2.60), P < 0.001]. Pain relief was most pronounced in the severe pain subgroup: hazard ratio, 2.5 (1.7–3.7). As SoC, 24 (7%) patients received weak opioids (6 versus 8%), 4 (1%) strong opioid and 44 (13%) escalated to weak or strong opioids (8 versus 17%, respectively, P = 0.02). Most adverse events were of mild (111/147) intensity. Conclusions In this study, we report that methoxyflurane, initiated at triage nurse as part of a multimodal analgesic approach, is effective in achieving pain relief for trauma patients. This effect was particularly pronounced in the severe pain subgroup.

<p>Role of Inhaled Methoxyflurane in the Management of Acute Trauma Pain</p>

“…Several randomized controlled trials have been recently conducted, comparing methoxyflurane to placebo 28 or to standard analgesic treatments 29,30 (either defined by protocol or by the investigators) and in the context of multimodal analgesia. 31 All have reported consistent results: low-dose methoxyflurane is an effective analgesic and provides pain relief faster than the comparators (i.e., time to first pain relief 3-5 minutes; 6-10 inhalations). Methoxyflurane is generally well tolerated, with mild and transient adverse events (mainly headache and dizziness).…”

“…Data from the control arms of the studies that compared methoxyflurane to standard treatment as per investigator choice also showed that trauma pain is often undertreated in current clinical practice, and there is no established standard of care (e.g., in the inMEDIATE study 29 only 23% of the patients with severe pain [>7 on the NRS scale] received opioids in the standard of care arm or as a rescue medication; in the PenASAP study 31 patients in the control arm did not achieve pain control).…”

“…While indirectly confirming that trauma pain undertreatment is still an unresolved issue in many EDs across Europe, the results of the PenASAP study establish inhaled methoxyflurane as a viable option in the context of multi-modal pain management strategies in trauma patients. 31 METEORA Study -Methoxyflurane in Hostile Environments METEORA, a phase 3b, prospective, single-arm, multicenter trial, was designed to assess whether inhaled methoxyflurane is effective, safe and practical in treating trauma pain (fracture, dislocation, crushing or contusion) in hostile environments, given its specific characteristics (portability, easy use and rapid pain relief). This currently ongoing study will enroll approximately 200 patients with a single limb trauma (based on clinical suspicion) and moderate to severe pain in the context of rescue missions performed by the Helicopter Emergency Medical Service (HEMS) in Italy.…”

Low-Dose Methoxyflurane versus Standard of Care Analgesics for Emergency Trauma Pain: A Systematic Review and Meta-Analysis of Pooled Data

“…The analysis therefore included five publications describing four RCTs: STOP!, 15 , 19 InMEDIATE, 16 MEDITA, 17 and PenASAP. 18 A flowchart of study identification and selection is shown in Figure 1 .

Figure 1 PRISMA flow diagram for study selection.

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“…The PenASAP study (NCT03798899) was a randomized, double-blind study comparing methoxyflurane (plus standard of care) with placebo (plus standard of care) in patients presenting to the French emergency department with moderate-to-severe trauma-related pain. 18 The primary outcome was time to pain relief. A summary of the key outcomes from these studies is given in Table 1 .…”