Summer 2010 - The British Pain Society

CHANGING PRACTICE
Does Vitamin C have a
role in the prevention of
Complex Regional Pain
Syndrome?
Dr Michael J.E. Neil
Ninewells Hospital Dundee
mneil@nhs.net
Complex regional pain syndrome
(CRPS) is an important and
commonly encountered neuropathic
condition in the pain clinic. CRPS
has a significant associated morbidity
and is characterised by spontaneous
pain, hypersensitivity, sudomotor
dysfunction and functional loss. It
can be triggered by potentially any
stimulus but is most frequently seen
following fracture, dislocation or
surgery.
The pathophysiology of CRPS is
complex and no one intervention
has been shown to have consistent
and reliable efficacy in its
management. In this regard, there
has been a lot of work undertaken in
recent years aimed at preventing the
syndrome developing. Studies have
examined many different therapies
but unfortunately most have
involved only small patient numbers
with largely inconclusive results.
However, there is some good quality
evidence to suggest that vitamin C
may have a significant role to play
in attenuating the development of
CRPS.
Vitamin C is a simple water
soluble sugar-like molecule that is
an essential dietary component.
Humans are unable to synthesise
vitamin C due to a deficiency
in the enzyme L-gulonolactone
oxidase required in the last stage
of its synthesis. The recommended
adult daily intake of vitamin C is
75-90mg per day 1 and is relatively
easily achieved as vitamin C is
found in plentiful supply in fruit and
vegetables. Historically however,
deficiency of vitamin C, popularly
known as scurvy, carried a significant
mortality on long sea-faring voyages
and even during land based
conflicts as recently as world war
one. Clinical characteristics include
fatigue, myalgia and arthralgia
in minor deficiency progressing
to neuropathy, haemorrhage
and convulsions in severe cases.
Although it is rare to see frank
vitamin C deficiency in modern
practice, some evidence suggests
that up to 30% of the population in
North America may have sub-clinical
deficiency 1 .
Vitamin C is involved in a number of
important physiological processes.
Vitamin C is well known as an antioxidant
that aids in the elimination
of reactive oxygen species such
as hydroxyl ions. This is important
for the protection of capillary
endothelium and in decreasing
vascular permeability. Victims of
polytrauma and severe sepsis,
conditions that exert a very high
oxidative stress on the body, have
been found to have extremely low
or absent levels of vitamin C in their
plasma at an early stage following
their injury 2 . Vitamin C is also a
co-factor in at least eight different
enzyme processes including collagen
hydroxylation, norepinephrine
synthesis, tyrosine metabolism and
amidation of peptide hormones.
Furthermore, animal studies indicate
that vitamin C may have an effect on
the glutaminergic system, of which
the NMDA receptor plays a key role,
leading to an anti-nociceptive effect 3 .
The pathophysiology of CRPS
involves a number of components
including a neuroendocrine,
inflammatory and sympathetic
response. Increased free radical
expression has been found to be a
feature of CRPS and is associated
with altered micro-angiopathic
circulation and lipid membrane
oxidation 4 . With other studies
demonstrating the utility of vitamin
C in decreasing membrane
permeability and scavenging of
free radicals 5 , there does therefore
appear to be a rationale for its use in
this condition.
Evaluation of therapeutic
interventions in pain medicine are
often hampered by a paucity of
good quality evidence from clinical
studies. Vitamin C is a rare exception
to this in that there have been three
good quality randomised controlled
trials examining the use of Vitamin
C in the prevention of CRPS 6,7,8 .
The first of these was published by
Zollinger et al in 1999 with a second
study by the same group in 2007.
This later study was a double blind
randomised-controlled, multi-centre
study looking at the incidence of
CRPS in patients following wrist
fracture. Patients were randomised
to receive a placebo or 200, 500 or
1500mg of vitamin C starting from
the day of fracture for 50 days. 427
patients were enrolled in the study
with a total of 317 randomised to
receive vitamin C and 99 to receive
placebo.
The results of the trial were clinically
and statistically significant. Using
the International Association for
the study of Pain (IASP) criteria for
establishing the presence of CRPS,
they found a total incidence of CRPS
in the vitamin C group of 2.4% (8
of 317 patients) and 10.1% (10 of 99
patients) in the placebo group (p
value 0.002). Examining differences
between the vitamin C treatment
groups revealed a prevalence of
CRPS of 4.2% in the 200mg group
and 1.8% and 1.7% in the 500mg
and 1500mg group respectively. This
gave a number needed to treat of 12
for the 500mg dose of Vitamin C.
The most recent study to examine
the role of vitamin C in preventing
CRPS was conducted by Besse et al
and looked at patients undergoing
elective foot and ankle surgery.
This study involved 392 patients
divided between two groups. The
first enrolled 177 patients having
elective foot or ankle surgery over
a one-year period and were given
standard treatment. The second
group were enrolled the following
year and consisted of 215 patients
given 1g of vitamin C from the
first post-operative day for 45
days. Results were again significant
revealing that patients in Group 1
had a prevalence of CRPS of 9.6%
(18 patients) while those in Group
2 showed a prevalence of 1.7% (4
cases) with a p value of 0.0001.
Although the results of these studies
are persuasive there are a number
of potential sources of error. Firstly,
criticism of the later study could
be directed at the fact that follow
up was by case note review and
not clinical examination. This raises
questions of sensitivity of screening
to pick up CRPS and does not
include information on pain scoring
and sensory testing that would
have been helpful. The latter study
also did not consider peri-operative
anaesthetic management to identify
if, for example, a regional technique
5 4
PAI N N E W S S U M M E R 2010