Rheumatology 2001; 40: 1394-1397
© 2001 British Society for Rheumatology
Treatment of reflex sympathetic dystrophy with pamidronate: 29 cases
I. Kubalek,
O. Fain,
J. Paries,
A. Kettaneh and
M. Thomas
Service de Médecine Interne, Hôpital Jean Verdier, Assistance Publique—Hôpitaux de Paris, Université Paris Nord, UPRES Recherche Clinique et Thérapeutique, Avenue du 14 Juillet, 93140 Bondy, France
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Abstract
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Objective. To evaluate the efficacy of treatment with pamidronate
in reflex sympathetic dystrophy (RSD) refractory to previous
treatment.
Methods. We studied the response (disappearance of pain and functional improvement) to pamidronate (60 mg/day for 3 days) in 29 patients with RSD refractory to previous treatment for at least 14 days.
Results. On day 45, complete pain disappearance was observed in 86.2% of patients and functional improvement in 70%. The mean delay until the pain disappeared was 20±14 days and the delay until functional improvement was observed was 29±18 days. The mean delay of functional improvement was shorter in patients with post-traumatic RSD. Multivariate analysis did not reveal any factor predictive of response to treatment. Six (20.7%) patients suffered from side-effects (fever, diarrhoea).
Conclusion. Pamidronate appeared to be effective in the treatment of refractory RSD; however, these results need to be confirmed by a controlled placebo study.
KEY WORDS: Pamidronate, Bisphosphonates, Reflex sympathetic dystrophy, Algodystrophy, Complex regional pain syndrome (CRPS) type I.
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Introduction
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Reflex sympathetic dystrophy (RSD), also called complex regional
pain syndrome type I, is a lengthy and painful affection with
a protracted course and chronic sequelae in 20–40% of
patients, represented by functional impairment and/or debilitating
pain [
1–
4]. The classical medical treatments (calcitonin,
physical treatment, sympathetic blockade, etc.) are not always
effective and new therapies must be evaluated. Accelerated and
enhanced bone resorption and turnover play a central pathophysiological
role in RSD [
5–
10]. Bisphosphonates were proposed in the
treatment of RSD due to their action as potent osteoclast-blocking
agents [
9–
14]. Another property of bisphosphonates is
the ability to inhibit afferent nerve fibres, from whose endings
various neuropeptides are released following disease and trauma;
these neuropeptides may contribute to the pain and trophic changes
observed in RSD [
7]. Pamidronate, a second-generation bisphosphonate,
has shown efficacy in diverse pathological situations (hypercalcaemia,
bone metastasis, Paget's disease) and also appears to be effective
at various doses in RSD [
11,
12,
14,
15]. The aims of our study
were to evaluate the effectiveness of a standard dose of intravenous
pamidronate in the treatment of RSD, and to find factors predictive
of response to treatment.
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Patients and methods
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We included all patients affected by RSD who were seen at our
consultations or hospitalized in our Department of Internal
Medicine between 1 January 1993 and 30 June 1999. All patients
were treated with pamidronate, with their verbal consent, after
failure of classical medical treatment for at least 14 days.
Diagnosis of RSD was based on Doury's criteria [
4]. All patients
complained of pain associated with allodynia and/or hyperpathia,
tenderness and reduced range of motion, symptoms in an area
much larger than the primary injury, and symptoms aggravated
by physical activity of the affected extremity [
2]. Swelling
and changed skin temperature and skin colour were not always
present, especially in the shoulder. All patients had a bone
scintigraph suggestive of reflex sympathetic dystrophy. The
use of non-steroidal anti-inflammatory drugs (NSAID), calcitonin,
steroids and infiltrations was not authorized during the study.
Twenty-nine cases of RSD were studied, comprising 10 men (34.5%)
and 19 women (65.5%); the average age was 53.0±14.0 yr
(range 14–81 yr), without significant difference between
the sexes [men 53.6±11.6 yr; women 52.6±12.4 yr].
The duration of the disease before treatment with pamidronate,
was on average 41.89±38.90 weeks (range 2–163).
For 20 patients [shoulder (16), knee (3) and wrist (1)], the
quantification of the reduction in amplitude was on average
45.25°±15.0° (range 30–70). The RSD was
localized in the upper limb in 58.6% of cases, and in the lower
limb in 41.4% (Tables 1
and 2
). A secondary aetiology was found
in 93.2% of patients (
n=27) (Tables 1
and 2
). The treatments
carried out before the use of pamidronate are mentioned in Tables
1
and 2
. Pamidronate was administered intravenously in 500 ml
of glucose 5% over 4 h with a daily dose of 60 mg over a period
of 3 consecutive days (a cumulative dose of 180 mg). The treatment
was evaluated on days 15 and 45 after the beginning of pamidronate
treatment. The treatment was considered to be effective if the
pain disappeared completely (stopping of analgesics). The functional
improvement was judged to be favourable if the increase in range
of movement was more than 20° compared with the range of
movement prior to treatment. The measurements of the delay in
pain disappearance and the delay in functional improvement were
analysed as continuous variables. Side-effects of pamidronate
were noted.
We performed the statistical analysis using SPSS. All
P values
were two-sided, with a value of <0.05 considered to be statistically
significant. The tests used in the univariate analysis were
the Wilcoxon non-parametric test for comparison of averages,
the Fisher exact test for comparison of percentages and the
Pearson non-parametric test for correlations between variables.
Logistic regression was used for multivariate analysis of categorical
variables (functional improvement and disappearance of pain).
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Results
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On day 15 after the beginning of the treatment, total pain disappearance
was obtained in 17 patients (58.6%) and functional improvement
was observed in nine cases (45% of 20). On the 45th day after
the beginning of the treatment, total disappearance of pain
was obtained in 25 patients (86.2%) and functional improvement
was obtained in 14 out of 20 patients (70%) (Table 3
). The mean
delay before pain disappearance was 19.96±&!hairsp;14.4
days, without significant difference between the sexes (men
15±0 days, women 10±4.3 days;
P=0.079). The mean
delay until functional improvement was 28.95±&!hairsp;18.26
days, without significant difference between the sexes (men
32±11 days, women 28±20 days;
P=0.154). Functional
improvement was faster in younger patients (
=-0.460;
P=0.0031).
The aetiology of RSD varied according to age: trauma was more
frequent in younger people (
=-0.459;
P=0.012). The mean delay
until functional improvement was shorter in patients with post-traumatic
RSD (16.9±9.7 days) than in the other patients (34.5±18.4
days;
P=0.04). No correlation was found between age and disappearance
of pain. Localization in the lower limb did not seem to be associated
with faster functional improvement (
=-0.285;
P=0.14) and the
disappearance of pain was not significantly related to its localization
(
=-0.112;
P=0.58). Multivariate analysis did not reveal any
factor predictive of response to treatment. Side-effects were
observed in 20.7% (
n=6) of cases [fever 20.7% (
n=6), shivers
17.2% (
n=5) and diarrhoea 10.7% (
n=3)].
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Discussion
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The natural course of RSD is lengthy and varies from 3 to 9
months [
1–
4] with chronic sequelae in about 30% of cases.
This study, although imperfect because of the absence of a control
group, gives objective evidence for the effectiveness of pamidronate
in the treatment of RSD, as regards both pain disappearance
and functional improvement. This series is comparable to published
studies of the treatment of RSD with bisphosphonates (Table
4
) as regards the age and sex ratio of the patients and the
duration of the RSD. In contrast to the cases reported in other
publications, 93.2% of the cases of RSD were secondary, and
an aetiological agent was usually found in only 50–75%
of the cases [
14–
16]. This is probably due to the fact
that patients were seen in a department of internal medicine.
Our study only considered cases of refractory RSD, and is the
only one that has taken into account the total disappearance
of pain and improvement in the range of movement. It provides
evidence of a satisfactory response on day 45 (86.2% for pain
and 70% for functional improvement). As in our series, no factor
predictive of response to pamidronate was found in the study
(11 patients) of Maillefert
et al. [
15]. Cortet
et al. [
14]
have already demonstrated, in a series of 23 patients, significant
effectiveness of intravenous pamidronate on pain, expressed
as a reduction in the scores of pain scales on the 30th, 60th
and 90th days after the beginning of the treatment; however,
pamidronate was given in variable doses (60–180 mg). Maillefert
et al. [
15] noted an improvement in six of 11 cases with a dose
of 30 mg of intravenous pamidronate per day for 3 days (a cumulative
dose of 90 mg), expressed as a significant pain reduction on
day 90. A recent article on the pooled data of these two studies
is similar in its conclusions [
16]. Adami
et al. [
17] reported,
in an open, controlled factorial trial
vs placebo, a very significant
reduction in pain and local oedema in 62% of patients treated
with intravenous alendronate at a daily dose of 7.5 mg on 3
non-consecutive days (days 0, 15 and 30). They also noted an
increase in bone mass 6 weeks after the beginning of the treatment.
Varenna
et al. [
18] observed a significant decrease in pain
and clinical global improvement in 15 patients treated with
clodronate compared with the placebo group (17 patients). Pamidronate
appeared to be effective and well tolerated in the treatment
of refractory RSD. However, a randomized, double-blind, controlled
placebo study is necessary to confirm this. Use of pamidronate
as the first-intention treatment for RSD can be proposed. However,
there are two limiting factors: the cost of pamidronate and
the need for intravenous administration.
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Notes
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Correspondence to: O. Fain.
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Submitted 6 June 2000;
Accepted 14 June 2001
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Abstract
Introduction