What is the evidence for the analgesic effectiveness, safety, and patient/clinician satisfaction of inhaled methoxyflurane compared to placebo or standard care analgesics in patients presenting to the emergency department with acute traumatic pain?
AMSTAR Rating
Summary
Patient Population:
Six main randomized controlled trials (RCTs) (n = 1083) plus two subgroup publications met eligibility criteria, evaluating pediatric, adolescent, and adult patients presenting to emergency care settings with moderate-to-severe acute traumatic pain (baseline visual analog scale [VAS] scores typically 63–66 mm or numeric rating scale [NRS] scores ≥4 to ≥8). Average age was 41.4 years. Conditions managed included minor and major extremity trauma, acute shoulder dislocations, fractures, lacerations, and burns.
Intervention:
Inhaled low-dose methoxyflurane (3 mL self-administered via a handheld Penthrox whistle inhaler, with a second inhaler provided if required up to maximum recommended clinical doses).
Comparison:
Matched placebo inhalers containing normal saline (5 mL via Penthrox inhaler) or standard care ED analgesia protocols (including parenteral opioids such as IV morphine, fentanyl, tramadol, oxycodone, IM ketorolac, or non-opioid regimens like IV acetaminophen/paracetamol and NSAIDs).
Outcome:
All included trials demonstrated superior or equivalent analgesic effectiveness for inhaled methoxyflurane compared to placebos and standard care options.
Methoxyflurane produced rapid onset of pain relief, with initial onset occurring within 1 to 5 minutes (median time to relief 1–5 min vs. 10–20 min for standard care) and significant VAS pain reductions reaching up to 30.4 mm on a 100-mm scale (or up to 5.75 points on an 11-point NRS scale).
Over 95% of patients, physicians, and nurses rated methoxyflurane treatment as ‘Good’, ‘Very Good’, or ‘Excellent’, significantly outperforming placebo and active comparators.
Methoxyflurane exhibited a highly favorable safety profile; adverse events were mild, transient, and self-limiting (predominantly mild dizziness, drowsiness, and transient sedation), with no reports of significant respiratory depression, hypotension, hepatotoxicity, or nephrotoxicity.
Guideline Recommendations
| Source | Recommendation |
|---|---|
| EUSEUM guidelines, 2020 | Support Use |
Outcomes Assessed
- Benefit
- Harm
- Inconclusive
Pain Relief
Reduced up to 30.4mm on 100mm VAS
Onset 1-5 minutes
Patient, Nurse, Physician satisfaction
Positive (>95%)
Safety Profile
Acceptable (minor transient dizziness, sedation)
Relevant Clinical Info
Borobia AM, Collado AG, Morales-Molina JA, et al. Inhaled methoxyflurane provides greater analgesia and faster onset of action versus standard analgesia in patients with trauma pain: InMEDIATE: a randomized controlled trial in emergency departments. Ann Emerg Med. 2020;75(3):315-328. doi: 10.1016/j.annemergmed.2019.07.025.
Borobia et al. (2020) conducted the landmark InMEDIATE trial across 14 emergency departments in Spain, evaluating a total sample size of 305 conscious adult patients presenting with acute moderate-to-severe traumatic pain. Participants were randomized to receive either inhaled methoxyflurane (𝑛=156) or standard ED pain management (𝑛=149), where 70% of standard care patients received intravenous first-line analgesics (including parenteral NSAIDs, acetaminophen, and opioids). Methoxyflurane demonstrated a significantly faster median time to initial pain relief (3 minutes vs. 10 minutes for standard care; 𝑝<0.001; and achieved greater mean reductions in NRS pain scores at all early time points up to 20 minutes. Furthermore, clinician satisfaction (72% vs. 19%) and patient satisfaction (77% vs. 38%) were markedly higher in the methoxyflurane group, while adverse events were mild and transient with zero reported severe treatment-emergent complications.
Participant Information
of participants
were Male
The sample size was 1083
There were 6 studies used.
