Downloaded from http://emj.bmj.com/ on November 15, 2015 - Published by group.bmj.com
Commentary
Methoxyflurane is a better painkiller than placebo: but do we want to know more? Simon Carley,1,2 Richard Body1,3 Recently the journal published a multicentre, randomised, controlled trial on the use of methoxyflurane for acute pain.1 Methoxyflurane is a volatile anaesthetic agent which, at low doses, has analgesic properties. It has been in widespread use as an analgesic in Australasia since as early as 1968 and there have been trials of its use in a variety of settings.2 In the UK and USA it does not currently have a license following safety concerns that it might precipitate renal failure.3 The trial concludes that methoxyflurane is an efficacious, safe and rapidly acting analgesic. The data presented do seem to support those assertions, although a trial of this size will not reliably detect rare events related to safety. Readers must now ask some interesting and important questions about whether these findings are sufficient to justify clinical implementation. The trial aimed to evaluate the short term efficacy of methoxyflurane for treating patients presenting to the emergency department with minor trauma and moderate acute pain. Bearing that in mind, readers should consider what evidence would persuade them that using inhaled methoxyflurane is better than our current approach. At present, patients with moderate acute pain are likely to receive some analgesia. This should, therefore, lead us to ask whether comparing methoxyflurane to placebo is sufficient to justify its use in practice. Without comparing methoxyflurane with active controls (as used in practice), can we really know whether it provides more or less analgesia than the alternatives? Importantly, 36.2% of patients who received methoxyflurane 1
Central Manchester University Hospitals Foundation NHS Trust, Manchester, UK; 2Manchester Metropolitan University, Manchester, UK; 3University of Manchester, Manchester, UK Correspondence to Professor S Carley, Emergency Department, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK; [email protected]
610
developed a drug related treatment emergent adverse event compared with 13.4% in the placebo group. Without an active control, it is difficult to know how this compares with the side effect profile of regular oral analgesia and which option patients would prefer overall. Clearly there are scientific reasons why an active control may have been preferable to placebo. As an exercise in the consideration of the ethical issues, readers may be interested to note the guidance provided in the Declaration of Helsinki (box 1). Of course, it is important to recognise that this trial received appropriate approval from a research ethics committee. We must
Box 1 Guidance from the Declaration of Helsinki on the use of placebo control4 “The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best proven intervention(s), except in the following circumstances: ▸ where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or ▸ where for compelling and scientifically sound methodological reasons the use of any intervention less effective than the best proven one, the use of placebo or no intervention is necessary to determine the efficacy or safety of an intervention and the patients who receive any intervention less effective than the best proven one, placebo or no intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention. Extreme care must be taken to avoid abuse of this option.”
therefore assume and can be reassured that the issue was appropriately considered prior to commencing the trial and that placebo control was deemed to be ethically justified. It is important to consider, for example, that to maintain blinding with an active control the methoxyflurane group would need to receive placebo oral analgesia, which may have affected the provision of rescue analgesia. Readers must make up their own minds as to whether the methodological justifications given for placebo use in any trial are balanced against the requirements to provide known effective therapies to patients. While placebo control may be an efficient design to deliver answers to certain clinical questions, we must also consider whether such questions are indeed the most relevant to our practice and whether we most need comparison with the best alternative therapy prior to considering clinical implementation. Competing interests None. Provenance and peer review Commissioned; not externally peer reviewed.
To cite Carley S, Body R. Emerg Med J 2014;31:610. Received 8 February 2014 Accepted 12 February 2014 Published Online First 17 April 2014
▸ http://dx.doi.org/10.1136/emermed-2013-202909 Emerg Med J 2014;31:610. doi:10.1136/emermed-2014-203690
REFERENCES 1
2
3
4
Coffey F, Wright J, Hartshorn S, et al. 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;31: 613–18. Grindlay J, Babl FE. Efficacy and safety of methoxyflurane analgesia in the emergency department and prehospital setting. Emerg Med Australas 2009;21:4–11. Fairhurst R. The use of inhaled methoxyflurine as an analgesic in prehospital care. Emerg Med J 2011;28:171. World Medical Association. Declaration of Helsinki— ethical principles for medical research involving human subjects. 2013. http://www.wma.net/en/ 30publications/10policies/b3/ (accessed 2 Feb 2014).
Carley S, et al. Emerg Med J August 2014 Vol 31 No 8
Downloaded from http://emj.bmj.com/ on November 15, 2015 - Published by group.bmj.com
Methoxyflurane is a better painkiller than placebo: but do we want to know more? Simon Carley and Richard Body Emerg Med J 2014 31: 610 originally published online April 17, 2014
doi: 10.1136/emermed-2014-203690 Updated information and services can be found at: http://emj.bmj.com/content/31/8/610
These include:
References Email alerting service
This article cites 2 articles, 1 of which you can access for free at: http://emj.bmj.com/content/31/8/610#BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
Commentary
Methoxyflurane is a better painkiller than placebo: but do we want to know more? Simon Carley,1,2 Richard Body1,3 Recently the journal published a multicentre, randomised, controlled trial on the use of methoxyflurane for acute pain.1 Methoxyflurane is a volatile anaesthetic agent which, at low doses, has analgesic properties. It has been in widespread use as an analgesic in Australasia since as early as 1968 and there have been trials of its use in a variety of settings.2 In the UK and USA it does not currently have a license following safety concerns that it might precipitate renal failure.3 The trial concludes that methoxyflurane is an efficacious, safe and rapidly acting analgesic. The data presented do seem to support those assertions, although a trial of this size will not reliably detect rare events related to safety. Readers must now ask some interesting and important questions about whether these findings are sufficient to justify clinical implementation. The trial aimed to evaluate the short term efficacy of methoxyflurane for treating patients presenting to the emergency department with minor trauma and moderate acute pain. Bearing that in mind, readers should consider what evidence would persuade them that using inhaled methoxyflurane is better than our current approach. At present, patients with moderate acute pain are likely to receive some analgesia. This should, therefore, lead us to ask whether comparing methoxyflurane to placebo is sufficient to justify its use in practice. Without comparing methoxyflurane with active controls (as used in practice), can we really know whether it provides more or less analgesia than the alternatives? Importantly, 36.2% of patients who received methoxyflurane 1
Central Manchester University Hospitals Foundation NHS Trust, Manchester, UK; 2Manchester Metropolitan University, Manchester, UK; 3University of Manchester, Manchester, UK Correspondence to Professor S Carley, Emergency Department, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK; [email protected]
610
developed a drug related treatment emergent adverse event compared with 13.4% in the placebo group. Without an active control, it is difficult to know how this compares with the side effect profile of regular oral analgesia and which option patients would prefer overall. Clearly there are scientific reasons why an active control may have been preferable to placebo. As an exercise in the consideration of the ethical issues, readers may be interested to note the guidance provided in the Declaration of Helsinki (box 1). Of course, it is important to recognise that this trial received appropriate approval from a research ethics committee. We must
Box 1 Guidance from the Declaration of Helsinki on the use of placebo control4 “The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best proven intervention(s), except in the following circumstances: ▸ where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or ▸ where for compelling and scientifically sound methodological reasons the use of any intervention less effective than the best proven one, the use of placebo or no intervention is necessary to determine the efficacy or safety of an intervention and the patients who receive any intervention less effective than the best proven one, placebo or no intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention. Extreme care must be taken to avoid abuse of this option.”
therefore assume and can be reassured that the issue was appropriately considered prior to commencing the trial and that placebo control was deemed to be ethically justified. It is important to consider, for example, that to maintain blinding with an active control the methoxyflurane group would need to receive placebo oral analgesia, which may have affected the provision of rescue analgesia. Readers must make up their own minds as to whether the methodological justifications given for placebo use in any trial are balanced against the requirements to provide known effective therapies to patients. While placebo control may be an efficient design to deliver answers to certain clinical questions, we must also consider whether such questions are indeed the most relevant to our practice and whether we most need comparison with the best alternative therapy prior to considering clinical implementation. Competing interests None. Provenance and peer review Commissioned; not externally peer reviewed.
To cite Carley S, Body R. Emerg Med J 2014;31:610. Received 8 February 2014 Accepted 12 February 2014 Published Online First 17 April 2014
▸ http://dx.doi.org/10.1136/emermed-2013-202909 Emerg Med J 2014;31:610. doi:10.1136/emermed-2014-203690
REFERENCES 1
2
3
4
Coffey F, Wright J, Hartshorn S, et al. 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;31: 613–18. Grindlay J, Babl FE. Efficacy and safety of methoxyflurane analgesia in the emergency department and prehospital setting. Emerg Med Australas 2009;21:4–11. Fairhurst R. The use of inhaled methoxyflurine as an analgesic in prehospital care. Emerg Med J 2011;28:171. World Medical Association. Declaration of Helsinki— ethical principles for medical research involving human subjects. 2013. http://www.wma.net/en/ 30publications/10policies/b3/ (accessed 2 Feb 2014).
Carley S, et al. Emerg Med J August 2014 Vol 31 No 8
Downloaded from http://emj.bmj.com/ on November 15, 2015 - Published by group.bmj.com
Methoxyflurane is a better painkiller than placebo: but do we want to know more? Simon Carley and Richard Body Emerg Med J 2014 31: 610 originally published online April 17, 2014
doi: 10.1136/emermed-2014-203690 Updated information and services can be found at: http://emj.bmj.com/content/31/8/610
These include:
References Email alerting service
This article cites 2 articles, 1 of which you can access for free at: http://emj.bmj.com/content/31/8/610#BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
