RHEUMATOLOGY
`
`Original article
`
`Rheumatology 2013;52:534–542
`doi:10.1093/rheumatology/kes312
`Advance Access publication 30 November 2012
`
`Treatment of complex regional pain syndrome type I
`with neridronate: a randomized, double-blind,
`placebo-controlled study
`
`Massimo Varenna1, Silvano Adami2, Maurizio Rossini2, Davide Gatti2,
`Luca Idolazzi2, Francesca Zucchi1, Nazzarena Malavolta3 and Luigi Sinigaglia1
`
`Abstract
`
`Objective. Complex regional pain syndrome type I (CRPS-I) is a severely disabling pain syndrome for
`which no definite treatment has been established. The aim of this multi-centre, randomized, double-blind
`placebo-controlled trial was to test the efficacy of the amino-bisphosphonate neridronate in patients with
`CRP-I.
`
`Methods. Eighty-two patients with CRP-I at either hand or foot were randomly assigned to i.v. infusion of
`100 mg neridronate given four times over 10 days or placebo. After 50 days the former placebo patients
`were given open label the same regimen of neridronate.
`
`Results. Within the first 20 days, visual analogue scale (VAS) score decreased significantly more in the
`neridronate group. In the following 20 days, VAS remained unchanged in the placebo group and further
`decreased in the active group by 46.5 mm (95% CI 52.5, 40.5) vs 22.6 mm (95% CI 28.8, 16.3) for
`placebo group (P < 0.0001). Significant improvements vs placebo were observed also for a number of
`other indices of pain and quality of life. During the open-extension phase in the formerly placebo group the
`results of treatment were superimposable on those seen during the blind phase in the active group. A year
`later none of the patients was referring symptoms linked to CRPS-I.
`
`Conclusion. In patients with acute CRPS-I, four i.v. infusions of neridronate 100 mg are associated with
`clinically relevant and persistent benefits. These results provide conclusive evidence that the use of
`bisphosphonates, at appropriate doses, is the treatment of choice for CRPS-I.
`
`Trial registration: EU Clinical Trials Register, https://www.clinicaltrialsregister.eu/, 2007-003372-18.
`
`Key words: complex regional pain syndrome type I, neridronate, randomized clinical trial, bisphosphonates,
`algodystrophic syndrome.
`
`Introduction
`
`Complex regional pain syndrome type I (CRPS-I) is a se-
`verely disabling pain syndrome characterized by sensory
`and vasomotor disturbance, oedema and functional
`im-
`pairment
`[1]
`that
`in most cases develop following a
`trauma or surgery [2]. No specific test is currently available
`
`1Rheumatology Unit, Ospedale G. Pini, Milan, 2Rheumatology Unit,
`Department of Medicine, University of Verona, Verona and
`3Rheumatology Unit, Ospedale Malpighi, Bologna, Italy.
`Submitted 7 May 2012; revised version accepted 1 October 2012.
`
`Correspondence to: Silvano Adami, Rheumatology Unit, Policlinico GB
`Rossi, Piazzale Scuro, 37121 Verona, Italy.
`E-mail: silvano.adami@univr.it
`
`to diagnose CRPS-I and the recently updated Budapest
`Criteria are widely accepted to make a clinical diagnosis
`due to their sensitivity and specificity [3, 4]. To date, the
`treatment of CRPS-I remains a medical challenge and no
`definite treatment has been established. A number of
`therapeutic approaches have been proposed with varying
`success. The limited number of randomized controlled
`trials [5], the heterogeneity of the proposed treatments
`and the methodological limitations in terms of homogen-
`eity and size of the study samples preclude any definitive
`conclusion about the efficacy of these different thera-
`peutic modalities [6]. Among pharmacological treatments,
`bisphosphonates appear to offer clear benefits as docu-
`mented by the results of four randomized controlled trials,
`
`SCIENCE
`CLINICAL
`
`! The Author 2012. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
`
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`all of them showing positive results in controlling pain,
`oedema and functional impairment [7]. However, none of
`these trials provided sufficient data to make the use of
`a bisphosphonate formally indicated for the treatment
`of CRPS-I.
`Neridronate is an amino-bisphosphonate structurally
`similar to alendronate and pamidronate, differing only in
`the number of methyl groups of the side chain: five for
`neridronate, three for alendronate and two for pamidro-
`nate. It has been shown to be effective and then regis-
`tered for the treatment of Paget’s disease of bone and
`osteogenesis imperfecta [8, 9]. In this study we evaluated
`the efficacy of neridronate administered by i.v. infusion
`in patients with CRPS-I by a prospective, double-blind,
`placebo-controlled study.
`
`Methods
`
`Patients
`
`Patients were included over 20 months from the outpa-
`tient services of six Italian rheumatology centres. All pa-
`tients included in the study fulfilled the Budapest criteria
`for research purposes [3]. Only patients with involvement
`of the hands or feet were included. Additional
`inclusion
`criteria were age of at least 18 years, disease duration
`no longer than 4 months, spontaneous pain intensity in
`the affected limb of at least 50 mm on a visual analogue
`scale (VAS) ranging from 0 (no pain) to 100 mm (maximal
`pain) [10]. In all patients, a three-phase bone scintigraphy
`was obtained before study entry and an abnormal uptake
`of the bone-seeking agent in both early and late phases
`[11] was an indispensable prerequisite for being included
`in the study. Women of childbearing potential were
`required to have a negative pregnancy test before enter-
`ing the study. Exclusion criteria were hepatic, renal, endo-
`crine, haematological, cardiac, pulmonary or neurological
`diseases or routine laboratory abnormalities and prior
`treatment with bisphosphonates. The study complied
`with the amended Declaration of Helsinki and was
`approved by each local ethics committee (Comitato
`Etico, Ospedale G. Pini, Milan; Comitato Etico
`Provinciale, Ospedale Regionale, Lecce; Comitato Etico,
`Ospedale O Molinette, Torino; Comitato Etico, Ospedale
`Forlanini,
`Roma;
`Comitato
`Etico Ospedale
`S
`Orsola-Malpighi, Bologna). All patients gave written in-
`formed consent to participate in the study.
`
`Study design
`
`A centrally computer-generated table of random numbers
`was used for the treatment assignment. Patients were
`treated with either neridronate (Abiogen Pharma, Pisa,
`Italy) 100 mg/8 ml i.v. ampoules or placebo with an iden-
`tical appearance in a 1:1 ratio. Both neridronate and pla-
`cebo were diluted in a 500 ml saline isotonic solution and
`infused in the morning over 2 h.
`Neither patients nor investigators knew whether assign-
`ment would be to the placebo or neridronate group. The
`treatment was administered every third day four times,
`starting from day 1 (first infusion) and ending on day 10
`
`Treatment of CRPS-I with neridronate
`
`(fourth infusion). After 40 days from the first infusion, the
`last blind assessment of clinical results was immediately
`sent to the coordinating centre. The results were reviewed
`and locked and eventually the codes were unblinded. The
`patients who had been receiving neridonate exited the
`study, while 10 days after the last assessment, those
`who had been on placebo were given neridronate follow-
`ing the same regimen (four 100-mg infusions over
`10 days) and a follow-up obtained at 40 days.
`
`Measures
`
`Outcome measures were assessed before randomization
`and before the first infusion (day 1). Further assessments
`were obtained at the end of treatment (day 10) and after
`20 and 40 days. During the open phase the same proced-
`ure was repeated in the former control patients switched
`to neridronate treatment. The primary efficacy measure
`was the comparative changes in the VAS 40 days after
`the first infusion of neridronate in the double-blind phase
`of the study. A decrease from the baseline value of at least
`50% was considered clinically significant and qualified the
`patient as a responder [12].
`trials
`By analysing the data from previous clinical
`[13, 14] it was decided not to assess sweating (present
`only in a minority of the patients) and to assess changes in
`joint volume or local oedema only by scores (0 = none,
`1 = mild, 2 = moderate, 3 = severe) based on observations
`like the ability to normally wear socks, shoes or gloves.
`Additional clinical assessment included (i) pain evoked
`by passive motion (ankle for foot involvement and wrist
`and finger joints for hand involvement) rated as 0 = none,
`1 = mild, 2 = moderate, 3 = severe;
`(ii) allodynia (pain to
`light stroking with a small brush) and hyperalgesia (pain
`evoked by a pinprick at the affected site but not at the
`unaffected side), both rated as a dichotomous variable
`(present/absent); (iii) McGill Pain Questionnaire and 36-
`Item Short Form Health Survey (SF-36) questionnaire to
`assess functional status; (iv) a count of the number of
`NSAID or paracetamol tablets taken weekly.
`These outcome parameters, together with the treatment
`outcomes after
`the open-label
`treatment, were con-
`sidered as secondary end points. In each participating
`centre the clinical evaluation was independently per-
`formed by two investigators; in case of discordance, as-
`sessment was repeated by a third investigator.
`In order to verify the long-term treatment efficacy, all
`patients were asked to participate in one or
`two
`follow-up visits a few months after the completion of
`the controlled study. This was considered a separate
`study and might include a control of bone scintigraphy
`or MRI.
`
`Adverse events
`
`All patients were informed about a possible acute-phase
`reaction (polyarthralgia and/or fever) [15] occurring after
`i.v. amino-bisphosphonate administration. Physicians at
`the study sites reported adverse events (AEs) and serious
`adverse events that were coded as preferred terms in the
`Medical Dictionary for Regulatory Activities (MedDRA)
`
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`TABLE 1 Demographic and clinical characteristics of
`patients with CRPS-I treated with neridronate or placebo
`
`Characteristic
`
`Neridronate
`(n = 41)
`
`Placebo
`(n = 41)
`
`P
`value
`
`58.2 (12.7)
`
`16/25
`4.7 (4.1)
`
`Age, mean (S.D.),
`years
`Gender, M/F, n
`Disease duration,
`mean (S.D.),
`weeks
`Precipitating event, n (%)
`Fracture
`11 (26.8)
`Trauma
`10 (24.4)
`Surgery
`5 (12.2)
`Unknown
`15 (36.6)
`Site, n (%)
`Upper limb
`Lower limb
`
`8 (19.5)
`33 (80.5)
`
`57.0 (10.3)
`
`13/28
`5.0 (4.6)
`
`17 (41.4)
`7 (17.1)
`4 (9.8)
`13 (31.7)
`
`12 (29.3)
`29 (70.7)
`
`0.6
`
`0.6
`0.7
`
`0.2
`0.5
`0.9
`0.8
`
`0.4
`
`Massimo Varenna et al.
`
`a
`judgement,
`investigator
`to
`system. According
`drug-related AE was defined as definitely, probably or
`possibly related to study treatment. A non-drug-related
`AE was defined as unlikely or not related.
`
`Statistical analysis
`
`Sample size calculation was performed assuming a
`two-tailed probability of
`type I error equal
`to 0.05.
`The planned total sample size of 80 subjects, rando-
`mized in a 1:1 ratio for neridronate and placebo,
`achieves a 90% power to detect a proportion of 50%
`of patients in the neridronate group showing 550%
`VAS score reduction when a 35% difference is ex-
`pected vs placebo.
`The statistical analysis was carried out according to
`the intention-to-treat principle, including all randomized
`patients who received at least one dose of the study medi-
`cation. Baseline characteristics were compared with the
`use of Student’s t-test
`for quantitative variables and
`Fisher’s exact test for binary ones. VAS score changes
`were evaluated using an analysis of covariance
`(ANCOVA) model
`for
`repeated measures using the
`change from baseline as the dependent variable; treat-
`ment, visit, centre and the treatment-by-visit interaction
`as factors and baseline as covariates. Differences be-
`tween treatments were reported as least-square mean
`estimates together with associated two-sided 95% confi-
`dence limits. The proportion of responders (VAS reduc-
`tion 5 50%) as well as dichotomous variables (allodynia
`and hyperalgesia) were compared with Fisher’s exact test
`while results were reported as risk difference together with
`associated two-sided 95% confidence limits. The results
`of the McGill Pain Questionnaire and SF-36 questionnaire
`were analysed using repeated-measure analysis of var-
`iance (ANOVA) models. The comparison of clinical
`parameters evaluated by means of rating scales were per-
`formed using the Wilcoxon rank sum test. Multivariate
`regression analysis was performed to assess the potential
`influence of baseline variables on treatment effect [site of
`disease: (upper/lower limb), disease duration and precipi-
`tating event
`(none/trauma, surgery)]. The statistical
`analysis was performed using SAS (version 9.2; SAS
`Institute, Cary, NC, USA). Significance was taken at
`two-tailed P < 0.05.
`
`Results
`
`Between January 2008 and May 2010, 84 patients were
`screened and 82 were recruited from six Italian rheuma-
`tology units from Milan, Verona, Bologna, Lecce, Rome
`and Turin. Most patients (71) were coming from the two
`centres operating in a hospital devoted to bone and
`joint
`diseases:
`Hospital G.
`Pini
`(Milan)
`and
`Orthopaedic Rehabilitation of Valeggio (Verona).
`In
`these centres,
`the patients were almost
`invariably
`referred to the rheumatology centres immediately at
`the onset of the symptoms. One screening failure was
`due to previous bisphosphonate treatment for osteopor-
`osis and one to refusal to participate in a randomization
`including a placebo arm. No other exclusion criteria
`
`were applied. Participating patients were randomized
`to treatment or placebo in two equal
`(n = 41) groups.
`The two groups were well balanced for demographic
`and clinical characteristics (Table 1).
`The flow chart illustrating the disposition of patients is
`presented in Fig. 1. Six patients dropped out during the
`double-blind phase: one patient in the neridronate group
`and five in the placebo group; the main reasons were
`consent withdrawal
`(three patients in the placebo
`group), AE occurrence (one patient in each arm) and
`lack of efficacy for one placebo-treated patient. One of
`these patients in the placebo group did not have any
`post-baseline assessment available for a primary efficacy
`measure. Seventy-six patients, 40 (98%) and 36 (88%) in
`the neridronate group and placebo group, respectively,
`completed the double-blind phase. Among the 36 com-
`pleters of the placebo group who started the open phase,
`34 completed the extension study: one patient dropped
`out for AE and the other for consent withdrawal.
`
`Efficacy in double-blind phase
`
`The time course of VAS score is shown in Fig. 2. At study
`entry (day 1)
`the neridronate-treated group and the
`placebo-treated group had similar VAS score [mean (S.D.)
`71.6 (11.8) and 70.4 (8.3), respectively; P = 0.59]. Within the
`first 20 days of follow-up the pain score decreased in both
`groups, but a significant
`treatment-by-visit
`interaction
`(P < 0.0001) was observed, with the difference becoming
`significant at day 20 (P = 0.043). During the following 20
`days no further improvements were observed in the pla-
`cebo group, while VAS values continued to decrease lin-
`early in the neridronate group. At
`the end of
`the
`double-blind phase, estimates for changes from baseline
`were 47.0 mm (95% CI 53.7, 40.3) for the neridronate
`group and 22.6 mm (95% CI 29.5, 15.6) for the pla-
`cebo group, with
`a
`highly
`significant difference
`(P < 0.0001). A 5 50% VAS score decrease was obtained
`in 30 neridronate-treated patients (73.2%) vs 13 controls
`
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`Treatment of CRPS-I with neridronate
`
`FIG. 1 Flow chart illustrating the study protocol and the disposition of patients.
`
`Screened patients
`84
`
`Screening failures
`2
`
`Neridronate
`41
`
`Randomized patients
`82
`
`Placebo
`41
`
`Drop-outs
`1 (AE)
`
`Completed visit at day 40
`40
`
`Completed visit at day 40
`36
`Neridronate open
`
`Drop-outs
`5
`1 (AE)
`3 Consent withdrawal
`1 Lack of efficacy
`
`Drop-outs
`2
`1 (AE)
`1 Consent withdrawal
`
`Completed visit at day 40
`34
`
`FIG. 2 Double-blind phase.
`
`VAS, mean (S.D.)
`
`80
`
`60
`
`40
`
`20
`
`P=0.043
`
`P< 0.0001
`
`Placebo
`Neridronate
`
`1
`
`10
`
`20
`
`Day
`
`30
`
`40
`
`VAS trends from baseline to day 40 in patients with CRPS-I treated with neridronate or placebo.
`
`(32.5%), with a 40.7% (95% CI 20.8%, 60.5%; P = 0.0003)
`treatment difference. For the McGill Pain Questionnaire
`significant differences between groups for sensory items
`(5.47; 95% CI 8.28, 2.65; P = 0.0002) and affective
`items (2.45; 95% CI 3.40, 1.51; P < 0.0001) were
`observed at day 40.
`
`The results of the SF-36 questionnaire showed at day
`40 significant differences for all items except for role limi-
`tations due to emotional problems, vitality and general
`health (Table 2).
`Oedema and pain evoked by passive motion signifi-
`cantly improved in the neridronate group compared
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`

`Massimo Varenna et al.
`
`TABLE 2 SF-36: treatment difference estimates from baseline to day 40 in patients with CRPS-I
`treated with neridronate or placebo
`
`Difference between neridronate and placebo
`
`Domains and components
`
`Estimate
`
`95% CI
`
`P value
`
`Physical functioning
`Role limitations due to physical health
`Role limitations due to emotional problems
`Energy/fatigue (vitality)
`Emotional well-being (mental health)
`Social functioning
`Pain
`General health
`Physical component scale
`Mental component scale
`
`13.2
`19.1
`13.3
`3.5
`13.6
`9.9
`9.8
`1.2
`3.7
`4.9
`
`4.7, 21.8
`4.3, 33.9
`2.9, 29.5
`3.1, 10.2
`6.7, 20.5
`0.5, 19.3
`2.1, 17.4
`4.6, 7.1
`0.9, 6.5
`1.2, 8.6
`
`0.003
`0.012
`0.107
`0.295
`0.0002
`0.039
`0.013
`0.683
`0.009
`0.010
`
`Data are expressed as least-square mean estimates with associated 95% confidence interval.
`
`with the placebo group. At day 40, the oedema score fell
`from a baseline value of 1.66 to 0.53 in the neridronate
`group in comparison with a decrease from 1.63 to 1.11 in
`the placebo group (P = 0.0009). Pain at passive motion fell
`from 2.32 to 0.78 in the neridronate group and from 2.18
`to 1.70 in the placebo group (P < 0.0001 for between-
`group changes).
`At baseline, allodynia was detected in 25 patients in the
`neridronate group and in 26 patients in the placebo group.
`At day 40, allodynia was present in 6 neridronate-treated
`patients and in 18 placebo patients, a 34% difference (95%
`CI 53,14; P = 0.0027). Hyperalgesia was present at
`baseline in 31 patients in the neridronate group and in 34
`in the placebo group. At day 40, hyperalgesia was detected
`in 5 patients in the neridronate group and in 22 patients in
`the placebo group, with a 47% difference (95% CI 66,
`28; P < 0.0001). At study entry, 68 patients were taking
`either NSAIDs or paracetamol. All patients on neridronate
`and 45% on placebo discontinued the symptomatic drugs
`within 2 weeks (results not shown). In multivariate regres-
`sion analysis, neither baseline variables except treatment
`assignment nor the occurrence of the acute-phase reaction
`appeared to influence outcome measures.
`
`Open-extension phase
`
`The results of the open-extension phase in the patients
`previously receiving placebo are listed in Table 3. The
`mean (S.D.) VAS value decreased from 55.4 (24.2) at the
`start of the infusion course to 13.9 (15.8) 40 days later
`(P < 0.0001), with a trend similar to that observed in the
`neridronate group during the double-blind phase (Fig. 3).
`In 28 of the patients (82.3%) VAS score decreased by
`>50%. Neridronate treatment also improved the pain
`rating index of the McGill Pain Questionnaire (P < 0.0001
`for both sensory and affective items). The oedema score
`fell to zero in 32 patients (94.1%) and pain at passive
`motion significantly improved (P < 0.0001) and fell
`to
`zero in 20 patients (58.8%). Allodynia and hyperalgesia
`disappeared in all patients. Functional assessment
`
`(SF-36) improved significantly for all domains except for
`the mental component scale.
`At an investigator global assessment, the disease was
`considered resolved in all patients, with the remaining
`symptoms (pain or stiffness) not attributed to CRPS-I. At
`the last visit only two patients were still taking NSAIDs for
`problems unrelated to CRPS-I.
`Seventy-eight of the patients agreed to participate in
`the long-term follow-up. In all patients the clinical
`im-
`provements achieved at the end of the study remained
`unchanged or improved further. A bone scintigraphy con-
`trol was obtained in 36 of the patients and a complete
`normalization of the abnormal uptake was reported. In
`12 patients the disappearance of localized bone oedema
`was observed at an RMI control.
`
`Safety evaluation
`
`Twenty-one patients in the neridronate group and 12 pa-
`tients in the placebo group complained of at least one AE
`during the double-blind phase. Reports of drug-related
`AEs concerned musculoskeletal disorders (mainly polyar-
`thralgia) graded as mild to moderate, with an incidence
`of 12 patients (29.3%)
`for neridronate and 5 patients
`(12.2%) for placebo. Fever was reported by nine patients
`(21.9%) for neridronate and one patient (2.4%) for pla-
`cebo. Fever never exceeded 38C and disappeared
`within 3 days after
`the first
`infusion in all patients.
`Fourteen patients (38.9%) out of the 36 participating in
`the open-phase treatment
`reported drug-related AEs
`(polyarthralgia and/or fever with the same features as in
`the double-blind phase). No serious drug-related AEs
`were reported during the study.
`
`Discussion
`
`This randomized controlled study provides evidence that
`a course of i.v. neridronate reduces pain intensity and im-
`proves clinical signs and functional status in patients with
`CRPS-I at either the hand or foot. The age distribution,
`male-to-female ratio and prevalence of precipitating
`
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`Treatment of CRPS-I with neridronate
`
`TABLE 3 Changes in VAS and proportion of responders during the open-label extension phase of the study in patients
`with CRPS-I treated with neridronate
`
`Assessments
`
`Start of open phase (n = 36)
`
`Day 40 (n = 34)
`
`P value
`
`Pain assessment
`Pain assessed on VAS (mm), mean (S.D.)
`Responders (pain decrease > 50%), n (%)
`Other clinical signs and symptoms
`Oedema (presentc), n (%)
`Pain at motion (presentc), n (%)
`Allodynia (present), n (%)
`Hyperalgesia (present), n (%)
`SF-36
`Physical functioning, mean (S.D.)
`Role limitations due to physical health, mean (S.D.)
`Role limitations due to emotional problems, mean (S.D.)
`Energy/fatigue (vitality), mean (S.D.)
`Emotional well-being (mental health), mean (S.D.)
`Social functioning, mean (S.D.)
`Pain, mean (S.D.)
`General health, mean (S.D.)
`Physical component scale, mean (S.D.)
`Mental component scale, mean (S.D.)
`McGill Pain Questionnaire
`Sensory items, mean (S.D.)
`Affective items, mean (S.D.)
`
`55.4 (24.2)
`12 (33.3)a
`
`29 (80.6)
`34 (94.4)
`19 (52.8)
`22 (61.1)
`
`52.6 (29.7)
`38.2 (44.9)
`51.9 (44.7)
`50.1 (22.5)
`54.9 (20.6)
`52.8 (26.6)
`36.9 (15.8)
`45.4 (18.4)
`35.5 (9.0)
`42.5 (11.1)
`
`11.5 (6.7)
`3.8 (3.4)
`
`13.9 (15.8)
`28 (82.3)b
`
`2 (5.9)
`14 (41.2)
`0 (0.0)
`0 (0.0)
`
`71.5 (19.3)
`58.8 (43.5)
`68.6 (39.3)
`58.7 (14.5)
`63.6 (16.2)
`69.5 (20.9)
`61.4 (21.8)
`54.1 (17.0)
`43.3 (9.0)
`46.2 (9.0)
`
`3.8 (4.1)
`1.0 (1.3)
`
`<0.0001
`0.0015
`
`<0.0001
`<0.0001
`<0.0001
`<0.0001
`
`<0.0001
`0.0073
`0.043
`0.024
`0.011
`0.0001
`<0.0001
`0.006
`<0.0001
`0.121
`
`<0.0001
`<0.0001
`
`aIn comparison with baseline values. bIn comparison with start of the open phase. cOf any degree (mild, moderate or severe).
`
`FIG. 3 VAS values at the end of the follow-up period of the double-blind phase (day 10) and after the treatment course
`with i.v. neridronate in patients with CRPS-I.
`
`VAS, mean (S.D.)
`
`Wash out
`
`Neridronate
`100 mg µ 4
`
`80
`
`60
`
`40
`
`20
`
` P=0.0001
`
`P< 0.0001
`
`Neridronate
`
`–10
`
`1
`
`10
`
`20
`
`30
`
`40
`
`Day
`
`events in the study population was similar to that reported
`in the largest epidemiological survey carried out in the
`Netherlands [2], suggesting a lack of referral bias.
`In this study, most patients were recruited at a very
`early stage of
`the disease. This was made possible
`
`by the operating conditions of the main rheumatology
`centres, sited in orthopaedic hospitals. The inclusion of pa-
`tients with an early diagnosis is likely to better simulate the
`operating condition when i.v. bisphosphonate will be for-
`mally registered for the treatment of CRPS-I.
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`Massimo Varenna et al.
`
`Of interest is the remarkable reduction in pain intensity
`observed in patients treated with placebo and reported
`also by others [16]. This further emphasizes the need for
`well-randomized, double-blind studies while testing new
`therapies for CRPS-I. However, in this study the placebo
`effect was limited to the first 3 weeks of observation, with
`a clear diverging of the two arms during the following
`weeks. In patients who experienced an acute-phase re-
`action, possibly revealing the treatment they were given,
`the response rate was similar. We could not identify other
`baseline factors influencing the outcome measures to ner-
`idronate treatment as well as the high positive response
`rate we observed. The previously reported difference in
`clinical
`improvement between hand and foot CRPS-I
`using ibandronate was probably due to the small sample
`size of that study [17].
`For registrative purposes the primary end point of this
`study was subjective pain but the evidence of efficacy is
`supported also by objective assessments obtained 7–14
`months later, such as the observation of the absence of
`bone oedema at the RMI examination (12 patients) and
`normalization of abnormal uptake at the bone scintigraphy
`in 36 patients. Remarkable also is the observation that in
`all patients interviewed months after completion of the
`study, the signs and symptoms of the disease did not
`relapse and they actually improved.
`Positive results have also been reported in four rando-
`mized clinical trials using a single i.v. infusion of 7.5 mg
`alendronate [13], i.v. clodronate (300 mg for 10 days) [14],
`i.v. pamidronate (60 mg once) [18] and 40 mg daily oral
`alendronate for 12–16 weeks [19]. However, none of
`these studies provided conclusive evidence of efficacy
`mainly because of their limited size, with 10–20 treated
`patients per study.
`A comparative analysis of the results is made difficult by
`the variety of drugs used and bio-equivalent doses.
`However, while designing the present study, in order to
`identify the most appropriate dose we had to rely on the
`analysis of previous studies and on previous open-label
`data accumulated in two of the centres participating in
`the study. By assuming a potency ratio of 1:10:10:40 for
`clodronate, neridronate, pamidronate and alendronate,
`respectively, and a 0.7% intestinal absorption rate for
`oral alendronate [20], the cumulative neridronate equiva-
`lent doses in the four previous studies were 900 mg [13],
`300 mg [14], 60 mg [18] and 76 mg [19]. In the studies with
`i.v. alendronate [13] and clodronate [14], bio-equivalent
`doses of bisphosphonates close to those used in this
`study (400 mg neridronate) were used and a complete
`remission of disease was reported in most patients,
`even though a long-term follow-up was not available. In
`the study with oral alendronate [19], a single treatment
`course with oral alendronate was not associated with
`the full resolution of the symptoms and signs of the dis-
`ease in most patients, and in the few patients who had a
`second treatment course further subjective and objective
`improvements were obtained. In the study with pamidro-
`nate [18], with the smallest bio-equivalent doses, the
`treatment was associated with only a partial remission
`
`of the symptoms. This analysis of previous studies per-
`mitted a rough estimate that the dose of i.v. neridronate to
`be tested in a phase 3 trial had to be somewhat higher
`than the 200 mg dose registered for the treatment of
`Paget’s disease of bone [8]. Smaller doses (200 and 300
`mg i.v. neridronate) had been previously tested in 37
`patients with CRPS-1 in two of the centres participating
`in this study [21]. In 20 of 37 patients, complete remission
`could not be obtained and symptoms partially relapsed
`within 1–3 months. These preliminary results and the ana-
`lysis of previous clinical trials with bisphosphonates pro-
`vided the rational for selecting the dose of 100 mg i.v.
`neridronate given four times over 10 days. It appears rea-
`sonable to assume that other bisphosphonates should
`be associated with comparable results, provided that
`equivalent i.v. doses are used. Our results suggest that
`for the treatment of CRPS-I the dose of bisphosphonate
`associated with long-term remission of the disease is
`somewhat higher
`than that generally recommended
`for the treatment of moderate Paget’s disease. Thus, in
`countries where neridronate is not available, the dose
`of pamidronate that should be recommended for the
`treatment of CRPS-I is an i.v. dose of 90 mg given four
`times over 4–10 days.
`The mechanism of action responsible for the brilliant
`results observed with bisphosphonates for the treatment
`of CRPS-I
`remains conjectural, mainly because the
`exact pathophysiology of the disease is still unknown.
`The most obvious action of bisphosphonate in bone is
`its capacity to inactivate osteoclast formation and activ-
`ity [22], and high levels of markers of bone resorption at
`baseline have been observed to be predictive of a posi-
`tive response to bisphosphonate therapy [14]. Local
`high bone turnover translates in the MRI
`findings of
`bone marrow oedema seen in CRPS-I [2, 23] and pos-
`sibly in the generation and maintenance of chronic pain
`[19].
`Intriguing also is our observation that
`treatment
`with bisphosphonates is associated with permanent re-
`mission of the disease. CRPS-I tends to spontaneously
`clear over several months in most cases; the longer the
`disease duration, the higher the risk of suffering per-
`manent rigidity and loss of function [2]. It is therefore
`conceivable that bisphosphonates, by suppressing lo-
`cally increased bone turnover, switch off an unknown
`vicious circle responsible for the maintenance of high
`bone turnover. This favours the acceleration of the heal-
`ing process, with positive results on the clinical sequels
`of the disease.
`A possible limitation of our study is the inclusion only of
`patients with a disease duration no longer than 4 months,
`since the general opinion is that the longer the disease
`duration, the worse the treatment outcome [24].
`In addition to the action of bisphosphonates on local
`bone turnover, an alternative mechanism of action might
`include a direct effect of locally accumulated drug [25] on
`metabolic aspects linked with inflammation and pain.
`These include decreased local lactate concentration and
`acidosis [26], since low pH is a recognized factor that in-
`duces the local release of peptides related with plasma
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`extravasation, swelling, hyperhidrosis and pain [27, 28].
`Bisphosphonates might also locally affect macrophage
`activities [29] involved in the expression of nerve growth
`factor, probably associated with the onset of neurogenic
`inflammation [30].
`In conclusion,
`this
`randomized,
`placebo-controlled trial has shown significant, clinically
`relevant and persistent benefit to patients with acute
`CRPS-I following an i.v. neridronate course, providing in
`our opinion conclusive evidence that the use of bispho-
`sphonate, at appropriate doses, is the treatment of choice
`for CRPS-I.
`
`Rheumatology key messages
`
`. No treatments are available for CRPS-I, a disabling
`pain syndrome.
`. i.v.
`infusion of the bisphosphonate neridronate is
`associated with CRPS-I persistent remission.
`. Bisphosphonates should be considered the first
`choice of treatment for CRPS-I.
`
`Acknowledgements
`
`This trial was sponsored by Abiogen Pharma, SpA, Pisa,
`Italy. Additional investigators and significant contributors
`in the study were M. Muratore (Ospedale, Lecce, Italy),
`E. Fusaro (O Molinette, Torino) and G. Minisola
`(Ospedale Forlanini, Roma).
`
`Funding: This work was supported by Abiogen Pharma,
`SpA, Pisa, Italy.
`
`Disclosure statement: The authors have declared no
`conflicts of interest