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• administer methionine, vitamin B12 (both inexpensive and with a good safety profile) and
possibly folic or folinic acid to patients repeatedly exposed to N 2O. The doses that may
prevent the complications of exposure to N 2O have not been established; and
• monitor for clinical signs and symptoms of neuropathy on a regular basis.
Methoxyflurane
Methoxyflurane is a volatile anaesthetic agent with analgesic properties. It was first marketed
in 1962 and later withdrawn from sale in 2001. The FDA withdrew the drug because of the risk
of nephrotoxicity and hepatotoxicity and stated that it would not consider reintroduction into
the market until new clinical trials were undertaken (FDA‐Penthrane, 2005). Methoxyflurane is
also not licensed in the United Kingdom. Although no longer used as an anaesthetic, methoxy‐
flurane has been reintroduced into the health‐care market in Australia and New Zealand for
use as an analgesic, and is available as a self‐administered ‘Penthrox®’ inhaler, which
dispenses 0.2% to 0.4% methoxyflurane (Medical Devices International, 2009).
Methoxyflurane was first described for obstetric analgesia in 1966 (Bodley et al, 1966 Level IV)
and then used as an analgesic for burns dressings (Packer & Titel, 1969 Level IV; Calverley, 1972
Level IV; Firn, 1972 Level IV; Marshall & Ozorio, 1972 Level IV).
There are few studies examining the effectiveness of methoxyflurane as an analgesic for
painful procedures. A review of its use as an analgesic in prehospital and emergency care
CHAPTER 4 settings found a total of 48 relevant papers although all but one (an abstract only) were
observational studies; however, this limited data would suggest that it is effective (Grindlay &
Babl, 2009). For example, use of the Penthrox® inhaler in children reduced pain associated with
extremity injuries (Babl et al, 2006 Level IV) but did not provide adequate analgesia for
subsequent fracture manipulation (Babl et al, 2007 Level IV). It also provided effective pain relief
for adult patients in the prehospital setting (Buntine et al, 2007 Level IV). Side effects included
hallucinations, vomiting, confusion and dizziness, and sedation/drowsiness was common
(26%) in children (Babl et al, 2006 Level IV; Buntine et al, 2007 Level IV).
Methoxyflurane causes a dose‐dependent renal toxicity and, as noted above, renal failure was
a key reason behind the withdrawal of the drug from use. Use of an analgesic device delivering
higher concentrations of methoxyflurane was reported to have led to two fatalities from renal
toxicity (Toomath & Morrison, 1987). However, the amount of methoxyflurane delivered using
the Penthrox® inhaler is said to be significantly less than the dose that has been associated
with subclinical nephrotoxicity (Grindlay & Babl, 2009).
Key messages
1. Nitrous oxide has some analgesic efficacy and is safe during labour (U) (Level I).
2. Nitrous oxide is an effective analgesic agent in a variety of other acute pain situations (U)
(Level II).
3. Methoxyflurane, in low concentrations, may be an effective analgesia in the hospital and
prehospital setting (N) (Level IV).
82 Acute Pain Management: Scientific Evidence
