Rheumatology 2001;40:1394–1397
`
`Treatment of reflex sympathetic dystrophy
`with pamidronate: 29 cases
`
`I. Kubalek, O. Fain, J. Paries, A. Kettaneh and M. Thomas
`Service de Me´decine Interne, Hoˆpital Jean Verdier, Assistance Publique—
`Hoˆpitaux de Paris, Universite´ Paris Nord, UPRES Recherche Clinique et
`The´rapeutique, Avenue du 14 Juillet, 93140 Bondy, France
`
`Abstract
`
`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 mguday 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.
`
`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
`impairment anduor debilitating pain w1– 4x.
`functional
`The classical medical treatments (calcitonin, physical
`treatment, sympathetic blockade, etc.) are not always
`effective and new therapies must be evaluated. Acceler-
`ated and enhanced bone resorption and turnover play
`a central pathophysiological role in RSD w5–10x. Bis-
`phosphonates were proposed in the treatment of RSD
`due to their action as potent osteoclast-blocking agents
`w9–14x. 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 contrib-
`ute to the pain and trophic changes observed in RSD w7x.
`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
`w11, 12, 14, 15x. The aims of our study were to evaluate
`the effectiveness of a standard dose of intravenous
`
`Submitted 6 June 2000; revised version accepted 14 June 2001.
`Correspondence to: O. Fain.
`
`pamidronate in the treatment of RSD, and to find
`factors predictive of response to treatment.
`
`Patients and methods
`
`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 w4x. All patients complained of
`pain associated with allodynia anduor 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 w2x. 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), calci-
`tonin, steroids and infiltrations was not authorized
`during the study. Twenty-nine cases of RSD were
`studied, comprising 10 men (34.5%) and 19 women
`the average age was 53.0 " 14.0 yr (range
`(65.5%);
`14 –81 yr), without
`significant difference between
`the sexes wmen 53.6 " 11.6 yr; women 52.6 " 12.4 yrx.
`
`1394
`
`ß 2001 British Society for Rheumatology
`
`

`

`Treatment of reflex sympathetic dystrophy with pamidronate
`
`1395
`
`the disease before treatment with
`The duration of
`pamidronate, was on average 41.89 " 38.90 weeks
`(range 2–163). For 20 patients wshoulder (16), knee (3)
`(1)x,
`and wrist
`the quantification of
`the reduction
`in amplitude was on average 45.258 " 15.08 (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 208 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 multi-
`variate analysis of categorical variables (functional
`improvement and disappearance of pain).
`
`TABLE 1. Characteristics of 29 patients treated with pamidronate
`
`Patient
`
`Sex
`
`Age (yr)
`
`Site
`
`Aetiology
`
`Disease duration
`(weeks)
`
`Treatment before
`pamidronate
`
`Pain on day 45
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`
`F
`M
`F
`M
`F
`F
`F
`F
`M
`M
`F
`F
`M
`F
`F
`F
`F
`F
`F
`F
`M
`M
`F
`F
`M
`M
`M
`F
`F
`
`34
`58
`48
`27
`48
`62
`68
`59
`46
`41
`40
`51
`53
`56
`68
`44
`53
`81
`71
`49
`59
`69
`51
`14
`56
`60
`68
`43
`61
`
`Shoulder
`Hand
`Shoulder
`Knee
`Shoulder
`Shoulder
`Foot
`Knee
`Shoulder
`Knee
`Foot
`Foot
`Knee
`Shoulder
`Foot
`Shoulder
`Foot
`Foot
`Shoulder
`Shoulder
`Shoulder
`Foot
`Foot
`Foot
`Shoulder
`Shoulder
`Shoulder + hand
`Shoulder
`Shoulder
`
`Trauma
`Trauma
`Cancer
`Trauma
`Diabetes
`Idiopathic
`Cancer
`Trauma
`Drugs
`Idiopathic
`Trauma
`Trauma
`Diabetes
`Diabetes
`Diabetes
`Stroke
`Trauma
`Diabetes
`Cancer
`Hyperthyroiditis
`Diabetes
`Diabetes
`Diabetes
`Trauma
`Diabetes
`Drugs
`Diabetes
`Drugs
`Trauma
`
`24
`52
`8
`52
`36
`32
`10
`163
`52
`2
`24
`24
`24
`24
`24
`40
`12
`38
`60
`52
`32
`108
`26
`12
`108
`12
`24
`20
`120
`
`C, I, N
`N
`C, I, N
`C, N
`C, N
`C, I, N
`N, S
`C
`C, N, I
`C, N
`N
`C, N, B, G
`C, N
`C, N, S
`N, I
`N
`C, N
`N
`N, S
`N
`C, N, I, S
`N
`C, N
`C, G
`C, N, I, B
`C, N, I
`C, I, N
`C, N
`C, N
`
`Yes
`No
`No
`Yes
`No
`No
`No
`No
`No
`No
`No
`No
`No
`No
`No
`No
`No
`No
`No
`No
`Yes
`Yes
`No
`No
`No
`No
`No
`No
`No
`
`C, calcitonin; N, non-steroidal anti-inflammatory drugs; S, steroids; I, infiltration; B, b- blockers; G, griseofulvin.
`
`TABLE 2. Characteristics of the 29 patients treated with pamidronate
`
`Localization
`
`Aetiology
`
`Previous treatment
`
`Shoulder
`Hand
`Knee
`Foot
`
`51.7%
`6.9%
`13.8%
`31%
`
`Stroke
`Diabetes
`Trauma
`Hyperthyroidism
`Drugs
`Cancer
`Idiopathic
`
`3.4%
`34.5%
`31%
`3.4%
`10.3%
`10.3%
`6.9%
`
`Calcitonin
`NSAID
`Steroids
`Griseofulvin
`b-blockers
`Infiltration
`Physical
`
`69%
`93.1%
`13.8%
`6.9%
`6.9%
`32%
`55.2%
`
`

`

`1396
`
`Results
`
`I. Kubalek et al.
`
`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 "
`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 "
`18.26 days, without significant difference between the
`(men 32 " 11 days, women 28 " 20 days;
`sexes
`P = 0.154). Functional
`improvement was
`faster
`in
`younger patients (r = 20.460; P = 0.0031). The aetio-
`logy of RSD varied according to age: trauma was more
`frequent in younger people (r = 20.459; 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
`
`TABLE 3. Clinical evolution after pamidronate treatment
`
`did not seem to be associated with faster functional
`improvement ( r = 20.285; P = 0.14) and the disap-
`pearance of pain was not significantly related to its
`localization ( r = 20.112; P = 0.58). Multivariate ana-
`lysis did not reveal any factor predictive of response to
`treatment. Side-effects were observed in 20.7% (n = 6)
`of cases wfever 20.7% (n = 6), shivers 17.2% (n = 5) and
`diarrhoea 10.7% (n = 3)x.
`
`Discussion
`
`The natural course of RSD is lengthy and varies from
`3 to 9 months w1–4x 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 dis-
`appearance 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,
`
`Pain disappearance
`on day 45
`
`Delay of pain
`disappearance (days)
`
`Functional improvement
`on day 45
`
`Delay of functional
`improvement (days)
`
`Sex
`Men
`Women
`Localization
`Upper limb
`Lower limb
`Aetiology
`Post-traumatic
`Other
`Total
`
`(%)
`
`66.7
`94.4
`
`85.7
`86.7
`
`77.8
`88.9
`86.2
`
`P
`
`NS
`
`NS
`
`NS
`
`(mean " S.D.)
`
`P
`
`(%)
`
`27.8 " 16
`17 " 12.1
`
`21 " 14.4
`19 " 14.9
`
`16.9 " 13.5
`21.3 " 16.7
`19.96 " 14.4
`
`NS
`
`NS
`
`NS
`
`50
`77.8
`
`64.3
`71.4
`
`77.8
`65
`70
`
`P
`
`NS
`
`NS
`
`NS
`
`(mean " S.D.)
`
`P
`
`32.5 " 11.3
`27.8 " 20.4
`
`29.5 " 21.6
`28.3 " 14.2
`
`16.9 " 9.7
`34.9 " 18.1
`28.9 " 18.3
`
`NS
`
`NS
`
`0.04
`
`TABLE 4. Treatment of reflex sympathetic dystrophy with bisphosphonates in the literature
`
`Number of
`patients
`
`Characteristics
`of RSD
`
`Characteristics
`of study
`
`Maillefert et al., 1995 w15x
`Cortet et al., 1997 w14x
`
`Adami et al., 1997 w17x
`
`Varenna et al., 2000 w18x
`
`11
`
`23
`
`20
`
`32
`
`Refractory
`
`Refractory
`
`Open
`
`Open
`
`10 naive +
`10 refractory
`
`Double-blind
`and open
`
`16 naive +
`16 refractory
`
`Randomized
`double-blind
`
`Bisphosphonate
`
`Pamidronate i.v.
`
`Dose
`30 mguday
`3 days
`Pamidronate i.v. Variable
`1 mgukguday
`1–3 days
`7.5 mguday
`3 days
`300 mguday
`10 days
`
`Alendronate i.v.
`
`Clodronate i.v.
`
`i.v., intravenous; CGA, clinical global assessment; BMD, Bone mineral density.
`
`Evaluation
`
`Criteria
`
`Day
`
`Positive
`response
`
`Pain
`
`Pain
`
`Pain,
`swelling,
`BMD
`Pain,
`CGA
`
`90
`
`30
`60
`90
`30
`
`55%
`
`58.8%
`41%
`38.8%
`62%
`
`40
`90
`180
`
`72%
`75%
`93.2%
`
`

`

`Treatment of reflex sympathetic dystrophy with pamidronate
`
`1397
`
`and an aetiological agent was usually found in only
`50–75% of the cases w14–16x. 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 satisfac-
`tory 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. w15x. Cortet et al.
`w14x have already demonstrated,
`in a series of 23
`patients, significant effectiveness of intravenous pami-
`dronate 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. w15x
`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
`w16x. Adami et al. w17x 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. w18x observed
`a significant decrease in pain and clinical global
`improvement in 15 patients treated with clodronate com-
`pared 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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`