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


If you’ve ever watched Bondi Rescue, you may have seen the Aussie lifeguards getting injured surfer dudes to suck on the ‘green whistle’ (and if you watch the video above, perform sketchy shoulder relocations). Methoxyflurane (or it’s better known brand name ‘Penthrox®’) has been used in Australia for pain relief for several decades. Initially used as an anaesthetic, concern grew over it’s nephrotoxic effects, but sub-anaesthetic doses were noted to be effective as an analgesic.

Though observational data has reported methoxyflurane to be an effective method of pain relief in the prehospital setting, no randomised controlled trial (as far as I can find), has been performed in this environment.

The STOP! trial was published in the EMJ in 2014. This was a randomised, double blind, placebo-controlled study of the efficacy and safety of methoxyflurane for the treatment of acute pain. There was also an interesting editorial published at the same time that I strongly recommend you read too.

While this study wasn’t published really recently (2014), I thought it was worth looking at, as methoxyflurane is starting to make an introduction in European EMS systems and it also provides an interesting study to do a critical appraisal of.

This study was offered to me as evidence for the introduction of methoxyflurane in a UK ambulance service during a twitter exchange, so I thought I should have a look.

We looked at this study at our last #PHJC and we had Dr Duncan Bootland (@dbootland), an Emergency Medicine Consultant from Brighton and Sussex University Hospitals and Kent, Surrey and Sussex Air Ambulance Trust, also author of ‘Critical Appraisal – from papers to patient’ (shameless plug for you, Duncan) come and lead a fantastic session.

While I can’t do justice to Duncan’s excellent appraisal of this study, I stole a lot of his points and decided to take a look at the study, using the BestBets critical appraisal tool for RCTs.

Obectives and design

The objectives of the study are clearly stated at the start of the study:

‘This double-blind, randomised, controlled clinical study was conducted to investigate the safety and efficacy of methoxyflurane at analgesic doses in patients aged ≥12 years presenting to the ED with pain associated with minor to moderate trauma.’

If we look at the hierarchy of evidence, we see that randomised controlled trials are the gold standard for evaluating effectiveness of treatments. Good start!


The authors were quite clever in how they went about ensuring that the study was double-blinded, so that neither the patient nor the provider knew which treatment they were given. As anyone that has used methoxyflurane will tell you, it has a distinct (rather unpleasant and nauseating) odour to it. To try and reduce selection bias, a drop of methoxyflurane was placed on every inhaler given to participants, placebos and all.

While this may reduce selection bias, it also brings in to question a rather big issue. Why did the authors compare against placebo? The results of this study tells us that methoxyflurane is better than, well, nothing! Does that surprise you? Probably not. Does this help us in deciding whether we should incorporate this drug into clinical practice? I don’t think so.  Normally placebo controlled trials are used when no proven effective therapy exists, however there are a number of options for analgesia that could have been used as a comparator (nitrous oxide, or Entonox, comes to mind as the best comparator). The authors seemed to have put more importance on the trial being double-blinded rather than finding out whether it’s better or worse than a comparative treatment.

The editorial in the EMJ provides a really interesting view on this, and questions the ethical implications when you take into consideration the Declaration of Helsinki. Not only does the study not answer a question of clinical importance, but it withheld treatment from patients in pain.

Another point worth mentioning is that this study was funded by Medical Developments International (MDI), who manufacture Penthrox®. Industry-funded trials are more likely to produce positive results (see Ben Goldacre’s book – Bad Pharma). While this shouldn’t mean you completely disregard the study, it should certainly get your inner-sceptic raising a critical eye-brow.



The outcomes the authors were interested in were safety and effectiveness.

Effectiveness was measured by a change in pain intensity using a visual analogue scale (VAS) from baseline to 5, 10 and 20 minutes from drug inhalation.

Safety was measured by any treatment-emergent adverse event. A 14-day post-treatment safety follow-up was made, as well as laboratory samples for haematology. Whether 14-day follow-up is long enough to detect long term effects is a question worth asking.

Participants and setting

The patients enrolled were over the age of 12, suffering minor trauma (fractures, lacerations, burns, dislocations, contusions or injury due to foreign bodies) with a pain score of ≥ 4 or ≤7.

The setting of the study was six Emergency Department sites in the UK. So, this wasn’t set in the prehospital setting. This needs to be recognised and caution be taken in deciding whether these results can or should be generalised to a different setting (prehospital) with different clinical staff administering the drug, with the patient at a different point of their injury and experience of pain. I’m not saying we can never generalise research generated from in-hospital settings to the prehospital setting, but we need to think carefully about the implications.

A power calculation was reported to have been performed to determine study size. 303 patients were screened, with 91% of patients completing the study, including the 14-day safety assessments.

Results & Discussion

The study found that methoxyflurane is an effective analgesic compared with placebo, reducing pain severity by 30%, with a short onset time from first inhalation.

Drug-related treatment emergent adverse events were reported in 36.2% of the methoxyflurane group compared with 13.4% in the placebo group. Ooh, that doesn’t sound great actually…

The discussion section considers the results in relation to other literature on the subject and acknowledges some of the limitations mentioned in this appraisal. The authors mention that comparing methoxyflurane to an active comparator would have been preferable, but felt that the study being double-blinded was more important. Here, I would disagree.

The authors conclude that methoxyflurane is efficacious. While there were more adverse reactions in the methoxyflurane group, none of the incidents were deemed serious, therefore the authors also conclude that the drug is safe.

Where do we go from here?

So, based on the results of this study, should methoxyflurane be introduced to UK ambulance services, as has been suggested? I would probably say – no.

So what next? Well, a suggestion would be a systematic review of all of the available literature on the prehospital use of methoxyflurane. As I mentioned, to my knowledge there is no prehospital based RCT on methoxyflurane, so this would probably just include observational studies (if you know of a prehospital RCT, please let me know!).

Then, a randomised controlled trial, set in the prehospital setting, with a better comparator, for instance nitrous oxide (Entonox), and maybe larger sample and longer follow-up period to detect any adverse events.

I have no idea as to the costs of methoxyflurane, especially in comparison to what is currently used by ambulance services, so perhaps an economic evaluation might be helpful too. I know talking about money may sound cold-hearted when it comes to helping relieve pain, but it’s an important consideration. We’re already starting to see the introduction of methoxyflurane in ambulance services in the UK.  Is it responsible for our resource scarce ambulance services to start using tax-payers money on a drug with limited evidence behind it? Is it right/safe/ethical to be giving it to patients with the current level of evidence? These are questions that need serious thought.

The ambulance service I work for briefly introduced methoxyflurane and then later re-called it, so I have seen it at work and, anecdotally, it seemed to be effective. It does stink, and colleagues reported getting headaches when using it in small, unventilated spaces (such as the back of an ambulance).

I can see many draws for the use of methoxyflurane in the prehospital setting. It’s portable and easy to store (unlike Entonox). If found to be effective and safe for use with children, it would provide a much-needed alternative option to current analgesia available to UK ambulances services.

With the current level of research and evidence that I can find, I would be cautious in jumping ahead and start introducing it widely across ambulance services in the UK.

Lets see what happens.






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