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`PA I N M E D I C I N E
`Volume 5 • Number 3 • 2004
`
`Efficacy of Pamidronate in Complex Regional Pain Syndrome
`Type I
`
`John N. Robinson, FAFMM, MMed (Pain),* Jenny Sandom, RN, PGDipHealSci,* and
`Peter T. Chapman, MD, FRACP†
`*Pain Management Centre, Burwood Hospital, Christchurch, New Zealand; †Department of Rheumatology, Christchurch
`Hospital, Christchurch, New Zealand
`
`A B S T R A C T
`
`Objectives. Complex regional pain syndrome (CRPS), formerly known as reflex sympathetic dys-
`trophy (RSD), is a painful, disabling disorder for which treatment is difficult. The aim of this study
`was to determine the efficacy of pamidronate in a double-blind randomized placebo-controlled trial.
`
`Methods. Patients referred to our regional multidisciplinary pain management center who fulfilled
`the International Association for the Study of Pain criteria for CRPS Type I were enrolled in the
`study over a 2-year period. Patients were administered, intravenously, either pamidronate, 60 mg
`as a single dose, or normal saline. Patients’ pain scores, global assessment of disease severity scores,
`and functional assessment (SF-36) scores were documented at baseline and at 1 and 3 months.
`
`Results. Twenty-seven patients (18 female, 9 male; average age 45 years) were recruited, of whom
`14 received pamidronate and 13 received placebo. Overall improvements in pain score, patient’s
`global assessment of disease severity score, and physical function (SF-36) score were noted in the
`pamidronate group at 3 months, and improvements in role physical (SF-36) score were noted at 1
`and 3 months. There was variability in pamidronate response among individuals.
`
`Conclusions. Pamidronate may be a useful treatment option in the management of patients with
`CRPS Type I. Although treatment response was variable, the majority of patients improved. Early
`administration in tandem with other treatment measures is recommended.
`
`Key Words. CRPS; Therapy; Pamidronate; Bisphosphonate
`
`Introduction
`
`Complex regional pain syndrome (CRPS), for-
`
`merly known as reflex sympathetic dystrophy
`(RSD), is a painful debilitating disorder usually
`affecting a peripheral limb and may follow a rela-
`tively minor injury [1]. CRPS Type I has a broad
`etiology, occurring after an initiating noxious
`event or a cause of immobilization. CRPS Type II
`follows a nerve injury [2,3]. The hallmarks of these
`conditions include continuing pain, allodynia,
`or hyperalgesia disproportionate to the inciting
`event, evidence at some time of edema, abnormal
`
`Reprint requests to: John Robinson, FAFMM MMed (Pain),
`Pain Management Centre, Burwood Hospital, Chris-
`tchurch, New Zealand. Tel: 03 3836831; Fax: 03 3100516;
`E-mail: jon.r@xtra.co.nz.
`
`sudomotor activity, and the exclusion of other
`conditions that would otherwise account for the
`degree of pain and dysfunction.
`Treatments to date have included analgesics
`(both systemic and topical), a variety of neuro-
`pathic agents, physiotherapy, sympathetic and
`other regional nerve blocks, acupuncture, trans-
`cutaneous electrical nerve
`stimulation, and
`psychotherapy—all with mixed and generally
`unfavorable results [4–6]. More invasive therapies,
`including spinal cord stimulation, have shown
`promise [7]; however, such therapies are expen-
`sive, require significant expertise, and are limited
`to highly selected patients in tertiary care centers.
`In recent years, bisphosphonates have been pro-
`moted as potential therapeutic agents, with several
`studies reporting positive results [8–11]. Bisphos-
`
`© American Academy of Pain Medicine 1526-2375/04/$15.00/276 276–280
`
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`Pamidronate in CRPS Type I
`
`phonates are potent antiosteoclastic agents, and it
`has been postulated that osteoclast hyperactivity is
`the dominant mechanism involved in the localized
`osteoporosis seen in CRPS [9]. Furthermore,
`bisphosphonates have been reported as having
`significant analgesic efficacy in a number of
`bone-related pathologies, including Paget’s disease
`[12], metastatic cancer [13], myeloma [13], acute
`vertebral fracture [14], and refractory rheumatic
`conditions [15], suggesting additional analgesic
`mechanisms [16].
`We report our experience on the efficacy of
`intravenous (IV) pamidronate in a randomized,
`double-blinded, placebo-controlled trial
`in a
`cohort of CRPS Type I patients.
`
`Methods
`Patients referred to our regional multidisciplinary
`pain management center who fulfilled the inter-
`national Association for the Study of Pain (IASP)
`criteria for CRPS Type I [3] were enrolled in the
`study over a 2-year period (Jan 1998–Jan 2000).
`Patients were randomized to receive either IV
`pamidronate (pamidronate disodium, disodium
`amonohydroxypropylidine bisphosphonate), 60
`mg as a single infusion (treatment group), or
`placebo (normal saline infusion, control group).
`Pain scores (visual analog scale [VAS]), patient’s
`global assessment of disease severity scores, and
`functional assessment (SF-36) scores were docu-
`mented at baseline and at 1 and 3 months. Back-
`ground analgesia continued throughout the study,
`and doses were held stable throughout the 3-
`month treatment period. Analgesics used included
`paracetamol
`(4g/day),
`codeine
`phosphate
`(120–180mg/day, as monotherapy and in combi-
`nation with paracetamol), and paracetamol
`(325mg)/dextropropoxyphene (50mg) combina-
`tion (maximum 8 per day). Both the patients and
`the investigators were blinded until completion
`of the study. The study was approved by the Can-
`terbury Ethics Committee.
`
`Statistical Analysis
`Changes in pain scores and patient’s global assess-
`ment of disease severity scores were analyzed
`using the nonparametric Mann-Whitney test.
`Functional assessment (SF-36) data were analyzed
`by repeated-measures analysis of variance, with
`time and allocated group as factors. The appro-
`priateness of a parametric analysis of this data was
`confirmed by visual inspection of residual plots
`from the analyses.
`
`277
`
`Results
`A total of 40 consecutive patients over the 2-year
`study period, who met the IASP criteria for CRPS
`Type I, were approached to participate, of whom 27
`were enrolled. The main reason for refusal was
`concern over randomization to the placebo arm.
`These patients tended to be younger and employed.
`Of the 27 recruited patients, 13 were random-
`ized to the placebo arm (control group) and 14
`received pamidronate (treatment group). The
`mean age of participants was 45 years (range:
`30–60 years), with 9 males and 18 females. A lower
`limb was affected in 13 cases, and an upper limb
`was affected in 14 cases. Disease duration ranged
`from 3 months to 6 years (average: 21.6 months).
`There were no significant differences in age, sex,
`or duration of treatment between the two groups.
`All patients completed the 3-month study.
`The overall pain score was significantly lower
`(P = 0.043, Figure 1A) and the percent change in
`VAS pain score was significantly greater (P =
`0.048, Figure 1B) in the treatment group at the 3-
`month assessment period than in the placebo
`group. There was an overall improvement at 3
`months in the patient’s global assessment of
`disease severity score in the treatment group that
`was not seen in the control group (Table 1). No
`significant differences in pain score or in global
`assessment of disease severity score were seen,
`however, between the two groups at 1 month.
`Regarding
`functional assessment
`(SF-36),
`patients in the treatment group had significantly
`higher scores than those in the placebo group in
`physical function at 3 months (P = 0.047) and in
`role physical at 1 and at 3 months (P = 0.008 and
`P = 0.04, respectively). There were no differences
`in other functional indices between the two groups.
`There was no correlation between analgesic use
`(type, dose, frequency) and treatment response.
`In the assessment of individual responses within
`the treatment group, there was substantial vari-
`ability, ranging from marked to minimal clinical
`improvement. The pamidronate therapy was well
`tolerated. Five patients in the treatment group
`and two in the control group experienced minor
`influenza-type symptoms, and two patients in the
`treatment group experienced mild infusion site
`reactions (erythema and discomfort). All symp-
`toms resolved within 6–48 hours.
`
`Discussion
`CRPS Type I, formerly known as RSD, is a
`challenging condition both in diagnosis and
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`Robinson et al.
`
`interquartile values
`
`range
`
`(median)
`
`D
`*
`D
`VAS (1 month)
`P = 0.043
`- -~ - - - -~ -~D
`VAS (3 months)
`CONTROL
`TREATMENT
` GROUP
` GROUP
`
`VAS (pretreatment)
`
`10
`
`8
`
`6
`
`4
`
`2
`
`0
`
`278
`
`A
`
`VAS PAIN SCORE
`
`B
`
`% CHANGE
`IN VAS PAIN
`SCORE
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`-20
`
`-40
`
`-60
`
`T
`
`1 =z:_ I 22 I
`
`- - D
`*P = 0.048
`D
`
`0-1 month
`
`0-3 months
`
`CONTROL
`GROUP
`
`TREATMENT
`GROUP
`
`Figure 1 A) Boxplot comparing
`change in VAS pain score between
`control and
`treatment groups. B)
`Boxplot comparing percentage (%)
`change in VAS pain score between
`control and treatment groups.
`
`management. The revised IASP criteria [3] are
`broad and reflect the heterogeneous nature of the
`condition. The mechanisms of pain in CRPS are
`complex and poorly understood, with a number of
`models promoted; it is likely that both peripheral
`and central mechanisms operate in the evolution
`of CRPS [17]. Most authorities agree that early
`
`Table 1 Patient’s global assessment of disease severity
`
`Pretreatment
`
`1 month
`
`3 months
`
`Control Group
`Median
`Interquartile range
`Treatment Group
`Median
`Interquartile range
`P value
`
`5.8
`(4.1–7.8)
`
`7.6
`(5.4–9.3)
`0.11
`
`4.6
`(4.0–7.6)
`
`6.9
`(5.0–8.4)
`0.23
`
`5.3
`(4.0–7.0)
`
`5.3
`(4.5–8.0)
`0.026
`
`Patients were asked to rate the severity of their condition on an arbitrary scale
`(0–10; 0 = no disease activity, 10 = maximal disease activity) at pretreatment
`and at 1 and 3 months posttreatment.
`
`recognition and treatment are integral to success-
`ful management.
`There have been a multitude of proposed treat-
`ments for CRPS Type I, with few achieving con-
`sistently positive results when assessed in a
`randomized, double-blinded, placebo-controlled
`setting [4–6]. Such studies are limited to relatively
`small numbers of patients due to the low incidence
`and poor recognition of this condition.
`Notwithstanding this, our small treatment
`cohort experienced significant benefits from a
`single 60-mg pamidronate infusion, which were
`not seen a control cohort treated with a sham
`infusion, in a randomized double-blind setting.
`This effect was sustained at 3 months. Modest
`improvements were noted in a number of patients
`at the first assessment (1 month), but these did not
`reach statistical significance in the group as a
`whole except in functional status (role physical,
`SF-36). Background therapy was kept to a
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`Pamidronate in CRPS Type I
`
`minimum, with only standard analgesics allowed.
`Additional therapies (physiotherapy/reactivation
`exercises, cognitive-behavioral approaches) were
`withheld during the course of the study. This, and
`concern regarding the placebo arm, was the main
`reason potential patients (13/40) declined to par-
`ticipate. We considered whether this might
`affect the generalizability of our results; however,
`these patients tended to be younger and employed,
`and the majority responded to subsequent pa-
`midronate infusion(s) given outside the trial
`setting.
`Another potential weakness of the study was
`that the treatment group had greater pain and
`disease activity scores at baseline than the control
`group. Patients were randomly assigned prior to
`their baseline assessments, and thus, were not
`matched according to pain severity. There was
`significant variability in the response within the
`treatment group; however, it showed an overall
`improvement that was not seen in the control
`group, whose indices did not change substantially.
`We do not believe the different baseline levels
`invalidate our findings; however, larger future
`studies are recommended.
`Our results are consistent with other published
`studies [8–11] demonstrating the potential benefit
`of bisphosphonate therapy. There are, however,
`some differences in the magnitude and consistency
`of response, particularly in comparison with the
`Varenna et al. study [11], which found dramatic
`and uniform responses following intravenous clo-
`dronate in their treatment group. The reasons for
`this are speculative but may include their study
`cohort having substantially shorter disease dura-
`tion and further efficacy with repeated treatments.
`There may also be differences in efficacy among
`different bisphosphonate drugs.
`Despite our positive findings, we would be cau-
`tious in promoting this treatment as a panacea
`for CRPS patients; we noted substantial inter-
`individual variation in response in our treatment
`group, ranging from dramatic to minimal benefit.
`We did not identify any standout predictors for a
`positive response in our treatment cohort.
`These findings are consistent with our more
`recent clinical experience, where we have found
`modest benefit in the majority of patients with a
`sustained response in those receiving repetitive
`treatments. Ideally, such treatment should be
`combined with physical therapy and a coordinated
`cognitive-behavioral approach, particularly
`in
`those more severely affected. Pamidronate infu-
`sions are well tolerated and easy to administer;
`
`279
`
`several patients reported minor infusion site reac-
`tions and mild flu-like symptoms that settled
`within 6–24 hours.
`The mechanism of analgesic effect of bisphos-
`phonates remains speculative. They are potent
`inhibitors of osteoclastic activity; they may also
`play a role in modifying inflammatory cytokines
`(e.g., interleukin-1) and other systemic factors
`(e.g., prostaglandin E2) involved in sensitizing
`painful nociceptors and low-threshold mechanor-
`eceptors [18,19]. If, as proposed, peripheral mech-
`anisms predominate in the early phase of the
`illness, with central mechanisms dominating in
`later phases [17], early treatment with pamidro-
`nate would appear optimal. Despite this theoreti-
`cal consideration, several of our patients with
`established disease of several years duration res-
`ponded to pamidronate, perhaps reflecting the
`heterogeneity of this condition. Our policy is
`to trial it in most patients regardless of disease
`duration, but we recommend early diagnosis and
`treatment.
`A number of therapeutic questions remain
`including: which (if any) bisphosphonate is the
`superior agent, what are the optimal dosing regi-
`mens, what is the efficacy of repeated treatments,
`what is the characterization of treatment respon-
`ders, and what is the optimal integration of
`bisphosphonate therapy with other treatment
`approaches?
`In summary, our study has shown significant
`benefit to a cohort of patients with CRPS Type I
`following a single 60-mg pamidronate infusion,
`demonstrating superior pain relief and functional
`outcome versus placebo at 3 months. However, we
`believe these results should be interpreted with
`caution in view of the relatively low number of
`patients studied and the heterogeneity of response.
`Further larger controlled studies are needed to
`validate these findings. Our current practice is to
`give the majority of our CRPS patients a trial of
`pamidronate therapy and to continue if they
`respond positively.
`This study adds to a growing body of evidence
`suggesting a role for bisphosphonates in this diffi-
`cult and potentially debilitating condition.
`
`Acknowledgments
`
`We would like to thank Alison Middlemiss, RN, for
`her assistance with the study, Nick Kendall and Chris
`Frampton for statistical advice, and Sue Banks for her
`secretarial assistance.
`
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`
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