• STOP!: a randomised, double-blind, placebo-controlled study of the efficacy and safety of methoxyflurane for the treatment of acute pain

    by Alan Batt. Last modified: 16/07/14



    Coffey F1, Wright J2, Hartshorn S3, Hunt P4, Locker T5, Mirza K6, Dissmann P4. STOP!: a randomised, double-blind, placebo-controlled study of the efficacy and safety of methoxyflurane for the treatment of acute pain. Emerg Med J. 2014 Aug;31(8):613-8. PMID: 24743584.




    To evaluate the short-term efficacy and safety of methoxyflurane for the treatment of acute pain in patients presenting to an emergency department (ED) with minor trauma.


    STOP! was a randomised, double-blind, multicentre, placebo-controlled study conducted at six sites in the UK. A total of 300 patients, 90 of whom were adolescent patients (age 12-17 years), were randomised 150:150 to receive either methoxyflurane via a Penthrox inhaler or placebo. The primary end point of the study was the change in pain intensity as measured using the visual analogue scale (VAS) from baseline to 5, 10, 15 and 20 min after the start of study drug inhalation. Patients were supplied with one inhaler containing 3 mL methoxyflurane or 5 mL placebo after enrolment and initial assessments. Age group (adolescent/adult) and baseline VAS score were controlled for in the statistical analyses.


    A total of 149 patients received methoxyflurane, and 149 patients received placebo. Demographic and baseline characteristics were comparable between the groups. Methoxyflurane reduced pain severity significantly more than placebo (p<0.0001) at all time points tested, with the greatest estimated treatment effect of -18.5 mm (adjusted change from baseline) seen at 15 min after the start of treatment. Methoxyflurane was well tolerated, with the majority of adverse reactions being mild, transient and in line with anticipated pharmacological action.


    The results of this study suggest that methoxyflurane administered via the Penthrox inhaler is an efficacious, safe, and rapidly acting analgesic.

    Trial Registration


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    Alan Batt

    Alan Batt

    Paramedic, educator, researcher
    Alan is a critical care paramedic, paramedic educator and prehospital researcher, currently working around the world as an educator and researcher. He has previously worked and studied across Europe, North America and the Middle East. He holds a Graduate Certificate in Intensive Care Paramedic Studies, and an MSc in Critical Care. His main interests are in care of the elderly, end-of-life care, patient safety, professionalism (including role and identity), and paramedic education.

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    5 thoughts on “STOP!: a randomised, double-blind, placebo-controlled study of the efficacy and safety of methoxyflurane for the treatment of acute pain

    • jasonhoran says:

      So, methoxyflurane works better than NOTHING. Surprise, surprise. Next question is how does it compare to current standard effective treatments. It’s a bit surprising that the researchers were allowed to give pretend pain relief to adolescents and adults, although they were allowed rescue medications and take-up was high in the placebo group (16.8% v 1.3%). Next thing to do is compare it to standard effective treatments and compare efficacy, like oramorph or intranasal fentanyl or whatever.

      The difference in the drop in the pain scale between methoxyflurane and placebo was 15.1mm on a 100mm VAS, that means that people getting their treatment dropped their pain score by an average of 1.5/10 more in the treatment group than the placebo. So even when the methoxyflurane pain score dropped by up to 35mm, placebo dropped by nearly 20mm.

      The side-effect section is a bit confusing. 36.2% of patients had some sort of drug-related adverse or emergent event from methoxyflurane. However 13.4% in the placebo group had a similar event? What would the rate be for what we now use as standard treatment?

      A good head-to-head with a reasonable comparator is what’s needed before you’d consider changing practice.

      • Alan Batt Alan Batt says:

        Totally agree with your comments Jason, what would be the reasonable comparator in your opinion?

        I guess it’s jurisdiction dependent, but for Ireland, I’d say that Entonox would be a valid comparator as opposed to opioids.

    • jasonhoran says:

      I don’t know about Entonox. It is good for right here and now but once you stop using it, the effect diminishes quickly. Haven’t used methoxyflurane but I’d expect it to be in a similar league to opiates, with respect to effect. Taking into account ease of administration, I’d like to compare it to fentanyl, either intranasal or buccal lozenge. Also, you could easily do up placebo fentanyl and you could do a proper RCT, so everyone gets either i) methoxyflurane whistle and atomised saline or ii) placebo whistle (as above) and atomised fentanyl. So you have a workable trial there…

      In our ED, we’re looking at increasing our use of fentanyl, particularly with children with significantly painful injuries. We use it ad-hoc but with good effect, we just want to make it our standard of care. Would love to see it dished out like smarties.

      • Alan Batt Alan Batt says:

        Interesting, good point about effect with regards to duration and onset – and I guess it carries a respiratory depression risk as do opiods, but has milder haemodynamic effects.

        I don’t have any experience with methoxyflurane either. It has just been approved for use here in UAE (as has Fentanyl), so may get some experience with it in the near future.

    • jasonhoran says:

      Both IN and buccaly fentanyl as well as inhaled methoxyflurane have appeared on the drug schedule released on 2nd of July at both Advanced Paramedic and Paramedic level.

      Ref S.I. 300/2014 Medicinal Products (Prescription and Control of Supply) (Amendment) Regulations 2014

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