Letter to the Editor
Re: Methoxyflurane use by Ambulance Service Paramedics. Wright S. Response. 2013;40(4):37-43.
I acknowledge the work done by Wright in highlighting the importance of analgesia in paramedic
practice, and in describing variations in pain management guidelines used by Australian ambulance
services. The latter reinforces the need for national evidence-based clinical practice guidelines in the
form that is currently used in the United Kingdom.(1)
The major theme of this article relates to the safety of methoxyflurane, in terms of patient safety
due to concerns about adverse effects, and also paramedic safety due to environmental exposure.
However, much of the data presented is of very low quality or is extrapolated data from research
that is not directly related to the topic, but which has nevertheless been used to strengthen the
author’s claim that there is “conclusive evidence that [methoxyflurane] was both harmful to patients
and to the people administering it.”
Methoxyflurane has been reported to cause dose-dependent nephrotoxicity in patients when
administered at anaesthetic doses,(2-4) and this is acknowledged by the manufacturer in the
product information.(5) However, methoxyflurane is no longer approved for anaesthesia in humans.
When used as an anaesthetic the drug had a prolonged induction time and was also associated with
protracted somnolence following the procedure, and these features along with the risk of
nephrotoxicity and hepatotoxicity led to the use of alternative agents.(6)
The dose required to achieve analgesia is considerably lower than the dose required to produce
anaesthesia, and the few case reports of renal failure or hepatitis following the use of the drug at
analgesic doses have involved prolonged administration or frequent use of the drug. None of these
cases occurred in a paramedic practice setting.(7-10)
Wright fails to reference a large Australian study that used data linking to investigate the odds of
heart disease, renal disease, hepatic disease, diabetes or cancer among patients receiving
paramedic-initiated methoxyflurane analgesia compared with a matched group that did not receive
this drug. The study failed to identify “any increase in the risk of disease occurrence or death with
the use of Methoxyflurane to that of a similarly comparable group.”(11) This is inconsistent with the
unsupported claim that methoxyflurane administered as an analgesic in paramedic practice is
associated with patient harm.
Wright also unconditionally states that frequent exposure to methoxyflurane poses a health risk to
paramedics, and cites a paper published in the Journal of the American Dental Association in 1980 to
support this claim.(12) In this study Cohen and colleagues conducted a survey to study self-reported
health problems among dentists and dental assistants who were exposed to anaesthetic gases
compared with those who used other forms of anaesthesia in the dental clinic (non-exposed control
group). The authors reported statistically significant increases in the reported rates of spontaneous
abortion among female dental assistants and wives of dentists among the group who were regularly
exposed to anaesthetic gases. The most common gas used was nitrous oxide, with only 18.7% of
dentists reporting the use of halogenated anaesthetics such as halothane in addition to nitrous oxide.
It should be noted that use of methoxyflurane was not reported in this study.(12) The study design
and methods used by Cohen and colleagues to report the outcomes of interest cannot control for
variables that may also be associated with the health problems reported.(13) These methodological
limitations and the fact that methoxyflurane was not described in this study should preclude the use
of this data to develop the recommendations made by Wright in the conclusion of his report.
Further evidence to support the claim that methoxyflurane represents an occupational hazard to
paramedics is based on extrapolation of patient dosing recommendations contained in the product
information to claim comparable exposure limits for paramedics. This fails to recognise that the
patient dose is many times higher than the ambient levels in the ambulance. The facts are further
embellished by the claim that the respiratory excretion of methoxyflurane is synonymous with the
fraction of inspired methoxyflurane measured in paramedics in the ambulance. This misrepresents
basic physiological and pharmacological principles.
The safety and efficacy of any therapeutic interventions are central to the care provided by
paramedics to individuals in the community. Likewise, paramedic safety and the management of
environmental hazards is a fundamental component of practice. It is important that studies are
undertaken to address any knowledge gaps in these areas. However, it is also vital that data is
reported accurately and objectively to inform practice.
Bill Lord
Associate Professor, Paramedic Science
University of the Sunshine Coast
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Fisher JD, Brown SN, Cooke M, Walker A, Moore F, Crispin P. UK Ambulance Services Clinical
Practice Guidelines 2013: Class Publishing; 2013.
Cousins MJ, Mazze RI. Methoxyflurane nephrotoxicity: A study of dose response in man.
JAMA. 1973;225(13):1611-6.
Cousins MJ, Mazze RI, Kosek JC, Hitt BA, Love FV. The etiology of methoxyflurane
nephrotoxicity. J Pharmacol Exp Ther. 1974;190(3):530-41.
Mazze RI, Trudell JR, Cousins MJ. Methoxyflurane metabolism and renal dysfunction: clinical
correlation in man. Anesthesiology. 1971 Sep;35(3):247-52.
Medical Developments International Pty Ltd. Product information: methoxyflurane
(Penthrox) Springvale, VIC: MDI; 2013 [updated 4 April 2013; cited 2014 3 Jan]. 7:[Available
from: http://www.medicaldev.com/wp/wp-content/uploads/2013/07/Penthrox-PI_v7.pdf.
Ball C, Westhorpe RN. Methoxyflurane: then and now. Anaesth Intensive Care.
2007;35(2):161.
Delia JE, Maxson WS, Breen JL. Methoxyflurane hepatitis: two cases following obstetric
analgesia. Int J Gynaecol Obstet. 1983;21(1):89-93.
Okuno T, Takeda M, Horishi M, Okanoue T, Takino T. Hepatitis due to repeated inhalation of
methoxyflurane in subanaesthetic concentrations. Can Anaesth Soc J. 1985;32(1):53-5.
English.
Toomath R, Morrison R. Renal failure following methoxyflurane analgesia. NZ Med J.
1987;100(836):707-8.
O’Rourke KM, McMaster S, Lust KM. A case of hepatitis attributable to repeated exposure to
methoxyflurane during its use for procedural analgesia. MJA. 2011;194(8):423-4.
11.
12.
13.
Jacobs I. Health effects of patients given methoxyflurane in the pre-hospital setting: a data
linkage study. Open Emerg Med J. 2010;3:7-13.
Cohen EN, Gift HC, Brown BW, Greenfield W, Wu ML, Jones TW, et al. Occupational disease
in dentistry and chronic exposure to trace anesthetic gases. JADA. 1980;101(1):21-31.
Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an
emerging consensus on rating quality of evidence and strength of recommendations. BMJ.
2008;336(7650):924-6.