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al, 2007 Level III‐2), and laceration repair (Burton et al, 1998 Level II; Luhmann et al, 2006 Level II). It
has been reported to provide analgesia for the pain associated with fracture manipulation in
children (Gregory & Sullivan, 1996 Level III‐1; Evans et al, 1995 Level III‐1), although its efficacy as an
analgesic during very painful procedures may be limited (Babl et al, 2008 Level IV).
In the experimental setting, a study measuring changes in detection and pain thresholds to
electrical tooth stimulation, reported the development of acute and chronic tolerance in
response to single and repeated administration of N 2O (38% or 35%) for 30 minutes (Ramsay
et al, 2005 Level II). The significance of this finding in the clinical setting is unknown.
N 2O diffuses more rapidly than nitrogen and can expand enclosed air‐containing spaces within
the body. Its use is therefore contraindicated in the presence of a pneumothorax, obstruction
of middle ear and sinus cavities, recent vitreoretinal surgery, pneumocephalus, bowel
obstruction and gas embolism (Shaw & Morgan, 1998).
Toxicity
N 2O oxidises the cobalt ion of cobalamin (vitamin B12) preventing it from acting as a coenzyme
for methionine synthetase (MS); MS also requires 5‐methyltetrahydrofolate as a coenzyme
(Sanders et al, 2008). MS is required for the synthesis of deoxyribonucleic acid (DNA) and
ribonucleic acid (RNA), and therefore the production of rapidly dividing tissues such as bone
marrow and GI mucosa, as well as the synthesis of myelin (Sanders et al, 2008).
CHAPTER 4 Bone marrow and neurological complications have been reported in patients exposed to N 2O.
The risk may be greater in critically ill patients with increased metabolic demands or poor
nutrition (Amos et al, 1982 Level IV).
N 2O‐induced bone marrow toxicity leading to megaloblastic anaemia is usually progressive but
reversible. The bone marrow changes are almost completely prevented by administration of
folinic acid (Amos et al, 1982).
Neurotoxicity associated with N 2O use is rare but can be rapid and may be irreversible.
Patients deficient in vitamin B12, including those with a subclinical deficiency (ie without an
associated anaemia), may develop a severe and progressive myeloneuropathy even after brief
exposure to N 2O. There are many examples of such case reports (Schilling, 1986; Holloway &
Alberico, 1990; Flippo & Holder, 1993; Kinsella & Green, 1995; Nestor & Stark, 1996; Rosener & Dichgans,
1996; Sesso et al, 1999; Marie et al, 2000; Waters et al, 2005; Cartner et al, 2007; Wu et al, 2007; Meyers
& Judge, 2008; Singer et al, 2008; Somyreddy & Kothari, 2008). Those at risk of vitamin B12
deficiency include some vegetarians (in particular vegans), the newborn of vegetarian
mothers, patients with GI pathology, elderly people or patients taking PPIs and H2 blockers,
and alcoholics (Schilling, 1986; Rosener & Dichgans, 1996; Nilsson‐Ehle, 1998; Schenk et al, 1999;
Carmel, 2000; McNeely et al, 2000; Sanders et al, 2008). In individuals who are not vitamin B12
deficient, larger quantities or more prolonged use of N 2O seems to be required before
neurotoxicity is seen. Examples have been reported in those abusing the drug (Sanders
et al, 2008).
The neuropathy appears to be the result of decreased methionine and subsequent defective
myelin formation. The clinical and radiological (magnetic resonance imaging [MRI]) picture is
that of a vitamin B12 deficiency where subacute combined degeneration (SACD) of the spinal
cord causes numbness, tingling, paresthesiae, ataxia and spasticity (Weimann, 2003).
Involvement of peripheral, autonomic and central nervous systems may also lead to
incontinence, diplopia, confusion or impaired cognitive function (Weimann, 2003). In patients
with pernicious anaemia, SACD usually responds well to treatment with vitamin B12, although
it may take many months and response to treatment may be incomplete (Toh et al, 1997).
Patients with SACD related to N 2O exposure may sometimes show improvement after

80 Acute Pain Management: Scientific Evidence