Commentary on RSD focus article
Beginning
Whenever two or three pain doctors are gathered together
there is a high
probability that the conversation will drift to reflex
sympathetic dystrophy
(RSD). I think the reasons are that we all see RSD patients,
that there is a
tantalising link between our needle therapies and improvement,
and that in
the absence of evidence opinion holds sway - ideal fertile
ground for
conversation.
Tanelian's focus article highlights some of the areas
of ignorance:
what causes RSD?
what is the natural history?
how best should it be managed?
This paper will take these three points briefly and then
explore the wider
ramifications of how we should approach clinical research
into this and other
pain conditions, pursuing Tanelian's digression into
placebo.
WHAT CAUSES RSD?
The IASP definition of "continuous pain in an extremity
after trauma which
may include fracture but does not involve a major nerve,
associated with
sympathetic hyperactivity" together with its rider is
a succinct and
thoughtful description of the problem. The presence of
sympathetic
hyperactivity can be demonstrated with greater or lesser
ease. The problem is
that the presence of sympathetic hyperactivity has been
taken to mean that
sympathetic hyperactivity causes RSD. This is akin to
saying that it is dark
outside and the street lights are on, therefore the street
lights have caused
the darkness. As a buttress to the argument that sympathetic
hyperactivity
causes RSD it is argued that sympathetic blockade cures
RSD, therefore
sympathetic hyperactivity must have caused the RSD. This
is a false syllogism
because, as Tanelian points out, the evidence that sympathetic
blocks cure
RSD is far from strong. Patients may improve after treatment
which includes
sympathetic blockade, which is splendid, but there is
no proof that it is the
sympathetic block rather than a change from disuse to
use of the limb which
has effected the change.
The answer to the question "what causes RSD?" is that
we do not know. Why
don't all patients with a Colles' fracture develop RSD?,
or why, if all
patients have an injury response which could go on to
develop into RSD, do
only some patients present with the syndrome? There is
an obvious analogy to
pains which persist after surgery. A proportion (?1%)
of patients develop
pain after herniorrhaphy. As with RSD we do not know
what is different about these particular herniorrhaphy patients, and why
they go on to develop
persistent pain when their peers do not.
WHAT IS THE NATURAL HISTORY?
Once more the answer is that we do not know. Tanelian
quotes Subbarao and
Stilwell' audit [Subbarao and Stilwell, 1981] that, fourteen
months after
their last treatment, two-thirds of 125 RSD cases had
retired, were
officially disabled or did not return to the same job.
This was despite the
physicians reporting 51% as having excellent or good
response 2.5 months
after treatment. It suggests strongly that benefit of
the treatment did not
always persist and that this is not always a self-limiting
disorder.
Tanelian discusses the oft-quoted contention that results
of early treatment
will be better than those when the pain is treated late.
If there is an
element of self-limitation in RSD (the one-third of the
125 cases who had not
retired or had to change their jobs), then early treatment
may claim as cures
those who would have improved anyhow. The unknown is
the extent to which
early treatment could cure those who would otherwise
have had pain of long
duration. The Subbarao and Stilwell audit does not help
to answer this
question.
Our ignorance of the natural history means that any comparison
of treatment
intervention must be organised, for instance by stratified
randomisation, so
that duration of the syndrome among the patients in each
treatment group is
balanced. Testing a magical new cure on 'early' RSD patients
and comparing it
with standard treatment on long-standing RSD patients
might well give a
misleading answer.
HOW BEST SHOULD RSD BE MANAGED?
One way to approach this question is to turn it around
and ask what
constitutes a good clinical result, for the patient and
for us. The simple
answer is that function of the limb returns to normal,
and that pain
disappears. There is a catch here - which is the most
important outcome,
restoration of function or disappearance of the pain?,
or are both equally
important? For the design of future treatment comparisons
we need to plan the
outcome measures more carefully, to allow for the fact
that we may get
different answers for function and for pain.
Tanelian's focus article provides a huge number of studies
of treatments for
RSD in Table 1. It is not clear whether or not he has
looked at the full deck
of cards ("I have reviewed the majority of studies cited
in Medline"). He
cites reasonable criteria for study validity, five out
of the six quantitative diagnosis of RSD, cross-over design, randomisation,
prospective,
double-blind and placebo-controlled. He does not tell
us how many of the
studies in Table 1 meet these criteria, although we could
work it out for
ourselves. Most importantly there is no qualitative or
quantitative attempt
to pull this data together and to give us a clinically
useful conclusion.
Instead he chickens out, and says "Having reviewed the
literature, I agree
with the conclusion Betcher reached in 1953 ... "(that)
sympathetic blockade
is a beneficial means to reduce pain and thereby allow
patients to conduct
physical therapy, and resolve their manifestations of
RSD".
The process pundits would argue that this is not a valid
systematic review
[Mulrow, 1987]. We are not told how hard the author pushed
to obtain his
citations, or his search strategy or whether or not he
pursued citations in
the reference sections of the articles he identified.
There is no judgement
presented of the quality standards of the articles identified.
He has
included non-randomised studies in the Table despite
his mention in the text
of the fact that non-randomised studies can lead to overestimation
of
therapeutic effect of up to 40% [Schultz et al, 1995].
If this reads like
harsh criticism it is only because I really want to know
the answer, and what
shines through is that we do not have the randomised
studies we need to
provide such an answer. My concern is that by quoting
the non-randomised
studies we perpetuate the current state of ignorance.
Only by admitting that
ignorance can we move forward, declare a research agenda
and set about the
design and execution of the studies required to fulfil
the agenda.
The way forward
What we really want to provide is interventions which
break the cycle of
inability to use the limb. We can (to an extent) help
with the pain, but we
want to reverse the disuse if possible. If needle interventions
,such as
sympathetic blocks, from intravenous regional to stellate
to lumbar
sympathetic, can achieve this aim then that is marvellous.
What remains
unclear is whether sustained reversal is possible, in
which patients if not
all can this be achieved, and what it takes to achieve
the reversal. This is
very close to Tanelian's quote from Betcher "sympathetic
blockade is a
beneficial means to reduce pain and thereby allow patients
to conduct
physical therapy".
We do need to be sure that our blocks do not make things
worse. We need the
simplest and safest procedure to achieve our goal. If
local anaesthetic can
achieve the facilitation of physical therapy then we
should be using local
anaesthetic rather than neurolytics, because local anaesthetic
is safer. If
more sustained block is required would local anaesthetic
infusion be more
sensible than neurolytics?
DESIGN OF STUDIES
Studies in this field, as in others, need to be randomised
to minimise
selection bias. Ideally they should be double-blind,
although this may be
logistically difficult to organise for needle interventions.
They need to be
of adequate size to have the power to tell us that a
negative result is a
true negative. This would be buttressed by including
in the design an active
control known to work in the condition, so that we would
know that the
investigators could distinguish that active control from
either the test
treatment or a negative control (placebo). Unfortunately
in RSD, as in many
other conditions, there is no clear candidate as standard
treatment to act as
an active control.
The outcome measures need to include function as well
as pain. Ideally they
should include a dichotomous clinically intelligible
component, like the
time-honoured "Is your pain half gone?". Follow-up needs
to be at least a
year, judging from the data which Tanelian quotes.
None of this is easy. Tanelian helpfully includes Table
2 and text to
indicate that the numbers of patients required to answer
these questions are
substantial. Such calculations require making a guess
at the placebo
response. A core problem here is that we do not know
the natural history.
Some of these patients will get better despite the treatment.
Tanelian quotes
a conservative estimate of the placebo response as 35%,
while saying that
many studies report rates which are higher.
As part of a series of systematic reviews on neuropathic
pain treatment
[McQuay et al, in press] we have used L'Abbé plots
to try to pin down the
variability in trial results due to just this phenomenon
of 'success' (pain
relief) in the control groups [L'Abbé and Detsky,
1987]. Each trial is a
point on the scatter plot, using the success rate with
the intervention under
test (Experimental Event Rate, EER; y axis) and the success
rate in the
control group (Control Event Rate, CER; x axis). The
point for a trial in
which the test treatment proves better than the control
will be in the upper
left of the graph, between the y axis and the line of
equality. If test is no
better than control then the point will fall on the line
of equality.
The Figure shows results from trials of both antidepressants
and
anticonvulsants in diabetic neuropathy [McQuay et al,
in press]. The most
important feature to notice when thinking about future
RSD studies is that
the CER, the event rate in control groups, varies enormously,
even when
trials are showing similar levels of efficacy in the
EER. This means that
calculating sample size from a fixed CER of say 35% may
grossly underestimate the numbers required.
GETTING A GRIP
Few of us sees enough RSD patients each year to mount
studies of adequate
size which will complete within our working lifetimes.
The way forward has to
be multi-centre studies which follow the design feature
outlined by Tanelian
and above, perhaps organised under the aegis of APS.
Which question should we tackle first?
References
L'Abbé KA, Detsky AS. Meta-analysis in clinical
research. Ann Intern Med
1987; 107:224-33.
McQuay H, Nye BA, Carroll D, Wiffen PJ, Tramèr
M, Moore RA. A systematic
review of antidepressants in neuropathic pain. Pain (in
press)
McQuay H, Carroll D, Jadad AR, Wiffen P, Moore A. Anticonvulsant
drugs for
management of pain: a systematic review. British Medical
Journal 1995;
311:1047-52.
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