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administration of vitamin B12 +/‐ methionine (Wu et al, 2007; Meyers & Judge, 2008; Singer et al,
2008) although this is not always the case.
In monkeys exposed continuously to N 2O, SACD is prevented by a diet supplemented with
methionine (Scott et al, 1981) and in cultured human fibroblasts, a methionine‐rich media
diminished the rate of MS activation (Christensen & Ueland, 1993). Despite the lack of any good
data assessing efficacy in humans, and even though the bone marrow changes are usually
reversible, it may be reasonable to give patients repeatedly exposed to N 2O, vitamin B12 and
folic or folinic acid supplements (Weimann, 2003).
Another consequence of N 2O‐induced inactivation of MS is elevation of plasma homocysteine
(a known risk factor for coronary artery and cerebrovascular disease), the levels of which rise
after anaesthesia using N 2O (Badner et al, 1998 Level II; Myles, Chan, Leslie et al, 2008 Level II; Nagele
et al, 2008 Level III‐3). Patients who are homozygous for polymorphisms in the gene encoding
the enzyme that is an antecedent to MS are at a higher risk of developing abnormal plasma
homocysteine concentrations after N 2O anaesthesia (Nagele et al, 2008 Level III‐3). A subset
analysis of data from a large trial of 2050 patients — the ENIGMA trial (Myles et al, 2007) —
found a relationship between increased plasma homocysteine levels and all major
postoperative complications (Myles, Chan, Leslie et al, 2008 Level II) as well as marked
impairment of endothelial function (Myles, Chan, Kaye et al, 2008 Level II). However, the ENIGMA
study looked at patients who were undergoing major surgery that lasted for 2 hours or longer
and were given N 2O in a concentration of 70% (compared with a nitrous‐free anaesthetic), and
not at N 2O used as an analgesic agent in a non‐operative setting. The significance of this in
respect to N 2O use in this group of patients is unknown. CHAPTER 4
Methionine given preoperatively to patients undergoing N 2O anaesthesia improved the rate of
recovery of MS and prevented the prolonged postoperative rise in plasma homocysteine
concentrations (Christensen et al, 1994 Level IV). Preoperative administration of oral B vitamins
(folate, B6 and B12) also prevent the postoperative increase in homocysteine following N 2O
anaesthesia (Badner et al, 2001 Level II).
The information about the complications of N 2O comes from case reports only. There are no
controlled studies that evaluate the safety of repeated intermittent exposure to N 2O in
humans and no data to guide the appropriate maximum duration or number of times a patient
can safely be exposed to N 2O. Nevertheless, the severity of the potential problems requires
highlighting. The suggestions for the use of N 2O outlined below are extrapolations only from
the information above.

Suggestions for the use of nitrous oxide as an analgesic
When N 2O is to be used repeatedly for painful short procedures, it may be reasonable to:
• exclude patients with a known vitamin B12 deficiency;
• screen patients at risk of B12 deficiency by examination of the blood picture and serum
B12 concentrations before using N 2O;
• exclude asymptomatic patients with macrocytic anaemia or hypersegmentation of
neutrophils until it is established that vitamin B12 or folate deficiency is not the cause;
• exclude females who may be in the early stages of pregnancy, although this will depend on
the relative harm of any alternative methods;
• limit exposure to N 2O to the briefest possible time — restricting the duration of exposure
may require strict supervision and limited access to the gas;

Acute pain management: scientific evidence 81