Vol. 21 No. 6 June 2001
Journal of Pain and Symptom Management
511
Review Article
Treatment of Reflex Sympathetic Dystrophy
(CRPS Type 1): A Research Synthesis of 21
Randomized Clinical Trials
Roberto S.G.M. Perez, MSc, PT, Gert Kwakkel, PhD, PT,
Wouter W.A. Zuurmond, MD, PhD, and Jaap J. de Lange, MD, PhD
Department of Anesthesiology (R.S.G.M.P., W.W.A.Z., J.J. de L.) and Department of Physical Therapy
(G.K.), Research Institute for Clinical and Fundamental Human Movement Sciences, University
Hospital Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Abstract
A blinded meta analysis was performed on randomized clinical trials (RCT) on the medicinal
treatment of reflex sympathetic dystrophy (complex regional pain syndrome type I) to assess the
methodological quality and quantify the analgesic effect of treatments by calculating
individual and summary effect sizes. The internal validity of 21 RCTs was investigated and
the quality weighted summary effect size was calculated using a fixed effect model (Glass ).
The methodological quality ranged from moderate to good (average 46%). Differences were
found between the trials in inclusion/exclusion criteria, treatment methods, duration of
treatments and trials, and measurement instruments. Statistical analysis was possible for four
subgroups; one evaluating the analgesic effects of sympathetic suppressors in general (n 12),
one subgroup concerning the analgesic effects of guanethidine (n 6), one investigating the
analgesic effect of intravenous regional sympathetic blocks (n 9), and one subgroup (n 5)
evaluating the analgesic effect of calcitonin. Except for the calcitonin subgroup (P 0.002),
the quality-weighted summary effect size of these subgroups were not significant. No significant
analgesic effect by sympathetic suppressing agents could be established. Calcitonin seems to
provide effective pain relief in reflex sympathetic dystrophy patients. The results of the present
study show that weighting methodological quality influences the magnitude of the effect sizes
of specific treatment methods. Future studies should control for methodological quality. J Pain
Symptom Manage 2001: 21:511–526 © U.S. Cancer Pain Relief Committee, 2001.
Key Words
Reflex sympathetic dystrophy, complex regional pain syndrome type 1, meta analysis,
randomized clinical trials, pain
Introduction
Reflex sympathetic dystrophy (RSD) is a syndrome characterized by diffuse pain, edema, re-
Address reprint requests to: Roberto Perez, MSc, PT, Department of Anesthesiology, P.O. Box 7057, 1007 MB
Amsterdam, The Netherlands.
Accepted for publication: August 17, 2000.
© U.S. Cancer Pain Relief Committee, 2001
Published by Elsevier, New York, New York
duced range of motion, and changes in temperature and skin color of the affected extremity.
These signs occur for the most part at the distal
part of the extremity (e.g., hands and feet), usually as a consequence of major or minor trauma.
The symptoms appear in an area disproportionate to the inciting event and are aggravated by
activity of the involved extremity.1–3 The incidence rate of RSD in The Netherlands is esti0885-3924/01/$–see front matter
PII S0885-3924(01)00282-2
512
Perez et al.
mated at 7500 patients per year. Approximately
20% of these patients remain disabled in performing normal activities of daily living (ADL)
activities (e.g., work, housekeeping, etc.).4,5
Despite general interest in RSD, clear understanding concerning this disorder is still lacking, resulting in several pathophysiological concepts and treatment methods. The role of the
sympathetic nervous system in RSD is a particular source of dispute among researchers.2,6–9
The uncertainty surrounding this disorder is
well reflected by the disparate nomenclature,
such as causalgia, Sudeck’s atrophy, post-traumatic
dystrophy, sympathetically-maintained pain, algodystrophy, etc. The English and Dutch literature
combined account for 93 different names for
what is presumed to be one illness.6 Making a
reliable diagnosis may be complicated by a lack
of uniform definition and classification of
RSD. This has led the International Association
for the Study of Pain (IASP) to advocate the
use of the term complex regional pain syndrome
(CRPS) instead of RSD. CRPS has been differentiated into CRPS type I (RSD) and CRPS
type II (causalgia, after nerve lesion).10,11
Between 1980 and early 1996 (February), 75
studies on CRPS type I can be found in the literature in which a broad variety of treatments
have been investigated. Only a few of those
studies applied random allocation of treatment
methods when comparing an experimental
treatment with a control treatment. Several
narrative reviews on the effectiveness of CRPS
type I treatments have been published.12,13
Kozin’s12 noted different approaches to diagnosis and treatment of CRPS type I , and
stressed the necessity of early diagnosis and
treatment. In this review, an explicit methodological screening was not described. Jadad et
al13 did assess the methodological quality of 7
randomized clinical trials (RCTs), and concluded that most trials showed major methodological deficiencies. However, they did not apply a rigid methodological framework to assess
systematically the internal and external statistical validity. An exception was made by
Kingery,14 who reviewed 22 controlled trials on
the treatment of CRPS type I following a methodological framework. The overall conclusions
were that CRPS type I trials tended to use fewer
subjects (compared to trials on peripheral neuropathic pain) and were less likely to use placebo controls or double-blinding, or perform
Vol. 21 No. 6 June 2001
statistical tests for differences in outcome measurements between groups. Kingery’s analysis
gave support for analgesia with corticosteroids
and limited support for analgesia through dimethylsulfoxide (DMSO), epidural clonidine
and intravenous regional blocks (IVRBs) with
bretylium and ketanserin. IVRBs with guanethidine and reserpine were ineffective, as seemed
droperidol and atropine IVRBs. According to
Kingery there was contradictory evidence for
the use of intranasal calcitonin and intravenous phentolamine.
As opposed to the review by Kingery, the
present research synthesis includes only articles which have applied random allocation of
treatment methods, and includes six additional RCTs. Furthermore, the RCTs were
blinded prior to reviewing and, as stressed by
Jenicek15 and Detsky et al,16 the methodological quality was incorporated in determining
the effect size of specific treatment methods.
Since the methodological quality of the trials
was a major confounder in Kingery’s study and
obstructed definite conclusions, is was hypothesized in the present study that weighing the
methodological quality on the summary effect
size may result in other conclusions concerning effectiveness of CRPS type I treatment.
The purpose of this study was: 1) to investigate the methodological quality of RCTs on
the medicinal treatment of CRPS type I using a
rigid methodological framework, and 2) to
quantify the effect of methodological quality
by performing quantitative analysis in which
the quality weighted effect sizes of individual
studies on amount of pain relief is estimated.
Subsequently, the individual effect sizes were
pooled into relevant subgroups on the basis of
treatment types in order to determine the summary effect size and perform sensitivity analysis
for analgesic effects of specific treatment
method. Finally, the studies with the best methodological scores are described.
Methods
Referring to the Medline and Cochrane databases over the period 1980 to 2000, supplemented with 22 journals in the field of pain,
anesthesiology, and general medicine from
January 2000 to May 2000, articles were collected with the following requirements:
Vol. 21 No. 6 June 2001
Treatment of Reflex Sympathetic Dystrophy (CRPS Type 1)
• The study had to be a randomized trueexperimental research written in the English, Dutch, German, or French language. Letters were excluded. The following MeSH-headings were used in the
search: randomized clinical trial, controlled
trial, double blind method, randomized trial,
prospective study, crossover trial.
• The patients included in the trials had to
be diagnosed with CRPS type I or one of
its synonyms (e.g., complex regional pain,
Sudeck’s atrophy, algodystrophy, posttraumatic dystrophy).
• The patients in the experimental group
had to be submitted to at least one medicinal treatment.
513
The item ‘study size’ was deleted from the list
since it would already be incorporated in the
statistical analysis. The list was used descriptively; items were scored if they were described
in the text or could be derived from tables and
figures.
The names of the authors, the titles of the
articles, and the names of the journals were
blinded. In order to assess the reliability of the
methodological criteria list, one non-blinded
article20 was scored independently by the researcher (R.P.) and a research assistant (C.B.).
No appreciable differences were found between both reviewers (Cohen’s Kappa 0.91).
The studies with a methodological score of
more than 50% of the total number of
points17–19 will be discussed more elaborately.
Methodological Assessment
In order to determine the methodological
quality, the studies were scored according to a
previously used methodological assessment list
(Table 1).17–20 The criteria were adapted to fit
to the specific research population. The items
‘gender,’ ‘localization of complaint’ and ‘illness duration’ were added to the item prognostic comparability. To the item ‘outcome measures’ were added ‘edema’ and ‘discoloration.’
Table 1
Scoring Criteria for Methodological Assessment of
Randomized Clinical Trials
Items
A:
B:
D:
E:
Selection and restriction
Treatment allocation
Prognostic comparability
Drop-outs
1. No drop-outs
2. Number of drop-outs given
3. Reasons for withdrawal given
4. Drop-outs not leading to bias
F: Loss to follow-up
1. No loss to follow-up
2. Less than 20% loss to follow-up
3. Less than 10% loss to follow-up
4. Follow-up not leading to bias
G: Interventions; experimental/control
H: Extra treatments
I: Blinding patients
J: Blinding of therapist
K: Blinding of observer
L: Outcome measures
M: Follow-up period
N: Side effects
O: Analysis and presentation of data
P*: In case of crossover; complete crossover and
sufficient washout period ( 4 weeks)
Maximum possible score
Weight
4
15
8
12
2
2
8
12
2
2
8
6
2
4
4
4
5
3
1
4
2
84/86*
Quantitative Analysis
The studies were analyzed by determining the
effect size Glass i,22 calculating the absolute difference between the means of experimental
and control treatment at the end of the treatment period, divided by the standard deviation
(SD) of the control group, using a Fixed Effects
model. Glass i was used because most studies
compared two groups, of which the difference
between their means and their control group
SDs were available. The difference in pain relief
between experimental and control treatment
was taken as the primary outcome measure in
this analysis. Preferably, outcomes based on VAS
scores were used if available. In studies which
applied other outcome measurements for pain,
the primary measure suggested by the authors
was used in the statistical analysis.
In order to prevent type II error (1), this
review was started from a best case scenario; if
two or more treatments were compared with a
control treatment, the best scoring experimental treatment was included into the quantitative analysis. In studies in which treatment averages were not reported or could not be
derived from figures or tables, the effect size
was calculated from F- and t-values.22 If appropriate data for quantitative analysis were not
present in the article, written permission for
additional data was requested from the authors
of these articles. In cases where no additional
information was obtained from the author, the
effect size was derived from significance levels,
assuming conservative values (i.e., P 0.5 if
not significant; P 0.005 if significant).
514
Perez et al.
Since Glass i tends to overestimate the population effect sizes in studies with small sample
sizes, a correction was made in order to obtain
the unbiased estimator u.22 For each study, a
weighting factor wi was estimated, assigning
larger weights to effect sizes from studies with
larger study samples and, thus, smaller variances. Subsequently, the methodological quality qi (the percentage of the maximum score
on the methodological quality list, ranging
from 0–1) for each study was calculated in the
effect size.23
The summary effect size Tu(q) was then established by averaging the individual effect sizes.
For each individual effect size and for the summary effect size, a 95% confidence interval was
obtained.23 The homogeneity test statistic Q
was determined to assess whether or not the set
of effect sizes shared a common effect size. If a
heterogeneity was found (which means that
the variance could not be explained by sampling error alone), a Random Effects model
was applied.23 The formulas for Tu(q) and Q are
given in Appendix A.
For all outcome variables, the significance
level () was set at 0.05.
Results
After Medline screening and research of individual journals, 22 RCTs3,13,21,24–42 were found
(see further Table 2) meeting the inclusion criteria. One article by Chiase et al.38 did not
make clear whether or not patients included in
the study had CRPS type I, since the aim of the
study was to assess if CRPS type I could be prevented in patients undergoing hand surgery.
This study was excluded from the analysis. One
of the studies3 was conducted by members of
our group and could therefore not be blinded.
In 10 RCTs, a crossover design was used,13,29–
33,35–37,42 and in 11 cases a parallel design was
used.3,24–28,34,39–41 In 14 RCTs, the treatments
were administered in a double-blind fashion,3,13,21,30–37,40–42 in 1 RCT only patients were
blinded29 and in 6 RCTs no blinding procedure
was applied.24–28,39 The sample sizes varied from
630 to 9527 patients. Nine studies investigated
the influence of regional intravenous sympathetic blocks in patients suffering from CRPS
type I, where guanethidine was the active substance in 6 studies.13,26,31,33,39,40 Other RCTs assessed the effects of calcitonin,21,25,27,28,34 cloni-
Vol. 21 No. 6 June 2001
dine,37 DMSO,3,29 griseofulvin (and phentonium),25,27 beta blockers,25,27 prednisone,24
bisphosphonate41 and lidocaine intravenously
(IV).42 Four studies25,27,31,33 evaluated three
different pharmacological substances, two
studies13,37 compared a high and a low dose of
medication with a control treatment, and one
study investigated the dose-effect relationship
(at multiple levels) of the active treatment.42
Pain was measured in twelve studies using a visual analogue scale (VAS).3,13,26,27,30–33,35,37,41,42
Sixteen RCTs reported positive results from
the experimental treatment(s), as compared to
the control treatment.3,21,24–26,28,29,32,35–37,39,41,42
In six studies, no difference was found between
experimental and control treatments.13,27,30,33,34,40
The methodological quality was expressed as
a percentage of the total score on the methodological quality list. Overall, the methodological quality of the RCTs (Table 3) ranged from
moderate to good, and the mean score was
46% (range 15–75). Five studies3,13,21,33,40
scored more than 50% of the total score.
Twelve studies gave little or no information
about the randomization procedure13,24–
29,33,35,36,39 and only two studies41,42 gave a clear
description about the registration of effect
measures. Furthermore, none of the studies
evaluated whether the blinding of therapists
was successful, and one study evaluated
whether blinding of patients and researchers
was successful.13 Nine studies failed to provide
sufficient statistical data.27,28,30,32,34,36–37,41,42 Cointerventions or the absence of co-interventions were described in six cases.21,24,28,29,31,39
Four studies presented a follow-up period.26,31,33,40 The washout period of the studies
with a crossover design was insufficient in nine
out of ten cases.13,29,31–33,35–37,42 Occurrence of
side effects was described in twelve studies.3,13,21,26,30–35,37,42
Due to the differences in treatment methods
(i.e., medication used) and outcome measures
between the studies, it was not relevant to calculate the summary effect size for all the RCTs
involved. It was, however, possible to establish
the effect sizes for four subgroups of the reviewed articles. In the first subgroup, the analgesic effects of one or more treatments which
influenced the sympathetic nervous system
were compared with the analgesic effects of a
control treatment. Twelve articles were found
having used a sympathetic suppresser.13,25–27,30–
19
95
24
21
6
12
16
21
40
Bonelli et al. 198326
Cherot et al. 198327
Gobelet et al. 198628
Goris et al. 198629
Kettler et al. 198830
Rocco et al. 198931
Hanna et al. 198932
Blanchard et al. 199033
Bickerstaff et al. 199134
23
55
198224
Sample
Size
Friez et al. 198225
Christensen et al.
Authors
Parallel, open
Parallel, open
Parallel, open
Design
1. IRSB 20 mg guanethidine (in 50 ml lidocaine 0.5%)
2. IRSB 1.25 mg reserpine (in 50 ml lidocaine 0.55)
3. Placebo (50 ml lidocaine 0.5%)
1. Intravenous 10/20 mg ketanserine
2. Placebo (?)
1. IRSB 20/30 mg guanethidine
2. IRSB 0.5/1 mg reserpine
3. Placebo (saline)
1. 400 IU intranasal calcitonin
2. Placebo (saline)
1. IRSB 2.5 mg droperidol (in 500 units heparin)
2. Placebo (500 units heparin)
1. DMSO 50%
2. Placebo (water)
1. Physical therapy 100 MRCu/d Calcitonin
2. Physical therapy
Parallel, double-blind
Crossover, double-blind
Crossover, double-blind
Crossover, double-blind
Crossover, double-blind
Crossover, single-blind
Parallel, open
1. Thyrocalcitonin 100 IU
Parallel, open
2. -Blocker 2–3 tablets
3. Griseofulvin 6 tablets Penthonium 45–60–90 drops per day.
1. Stellate ganglion block with 15 mg 0.5% bupivacaine
2. IRSB with 20 mg guanethidine
1. Griseofulvin 2–3 g per day
2. -Blockers up to bradycardy of 60 mn.
3. Calcitonin 160 IU
1. Prednisone 10 mg
2. Placebo (?)
Interventions
Results/Conclusions
Treatment of Reflex Sympathetic Dystrophy (CRPS Type 1)
(continued)
All 13 patients in the prednisone-treated group
showed more than 75% clinical improvement;
only two patients in the placebo group reported
improvement.
Delay in drug effect seems similar for the 3 drugs,
griseofulvin is associated with a greater failure
rate. -blocking agents and calcitonin gave
comparable results. -blocking agents appear to
obtain better results than other 2 treatments in
patients with a psychological component to their
disease.
IRSB with guanethidine gave better and longer
lasting pharmacological effects than stellate
ganglion block. Therapeutic effects of 4
guanethidine blocks were comparable to those of
8 stellate ganglion blocks.
No significant differences between the treatments.
The thyrocalcitonin group improved 53%, the
-blocker group 42.5% and in the griseofulvin penthionum group 53%.
Significant improvement in pain relief in the
calcitonin group after one week of treatment.
Both groups showed improvement on pain,
edema, ROM, ability to work and laboratory tests.
DMSO was the most effective treatment with regard
to improvement of ROM and overall
improvement.
Droperidol did not give pain relief better than
placebo, the study was terminated because of the
side effects of droperidol.
None of the patients experienced permanent pain
relief. No difference was found between
reserpine and guanethidine.
Ketanserine (and not placebo) provided significant
pain relief in patients with RSD.
Significant pain relief was found in all 3 groups at 30
min. There were no differences between the 3
groups.
No demonstrable effect on clinical or skeletal
progression of RSD. A small but significant
hypoglycemic response was demonstrated in the
calcitonin group.
Table 2
Randomized Clinical Trials, Designs, and Authors’ Results and Conclusions
Vol. 21 No. 6 June 2001
515
30
26
26
60
Glynn et al. 199336
Rauck et al. 199337
Geertzen et al. 199439
Ramamurthy et al. 199540
32
20
16
Zuurmond et al. 19963
Adami et al. 199741
Wallace et al. 200042
9
12
Hord et al. 199235
Jadad et al. 199513
66
Sample
Size
Gobelet et al. 199221
Authors
Parallel, double-blind
Crossover, double-blind
1. Lidocaine IV of 1, 2, and 3 g/ml plasma level
2. Dyphenhydramide (?) IV
Parallel, double-blind
1. DMSO 50% cream physical therapy
2. Placebo cream physical therapy
1. 7.5 mg alendronate IV
2. Placebo (?)
Crossover, double-blind
1. IRSB 10 mg guanethidine
2. IRSB 30 mg guanethidine
3. Placebo (saline)
Parallel, double-blind
Parallel, open
Crossover, double-blind
1. 300 g epidural clonidine
2. 700 g epidural clonidine
3. Placebo (saline)
1. IRSB Ismelin (?)
2. DMSO 50%,
1. 2, 3, or IRSB’s 2/4 ml guanethidine in 0.5% lidocaine
2. Placebo (?) in 0.5% lidocaine
Crossover, double-blind
Crossover, double-blind
Parallel, double-blind
Design
1. IRSB 0.6 mg atropine
2. Placebo (saline)
1. 100 IU intranasal calcitonin
2. Placebo (?)
1. IRSB 1.5 mg/kg bretylium in 0.5 lidocaine
2. Placebo (0.5 lidocaine)
Interventions
Table 2
Continued
Pain, ROM, and ability to work improved by
calcitonin administration.
Combination of bretylium and lidocaine is
significantly more effective than lidocaine.
Combination of both substances provided longer
pain relief and increase in temperature in
comparison with lidocaine.
Atropine provided more pain relief than placebo,
but the differences between the groups were not
significant.
Clonidine, not placebo, caused pain relief, sedation
and decreased blood pressure and heart rate
after bolus injection. Smaller dose of clonidine
provided the same effects but with less sedation.
No statistical differences between both groups;
overall results were better in the DMSO group.
Placebo treatment provided greater pain decrease
than guanethidine at 4 days. Long-term follow up
showed no difference in pain scores between
groups.
The experiment was prematurely stopped because
of the severity of adverse effects. No significant
difference was found between guanethidine and
placebo.
Application of the creams resulted in both groups
in an improvement of RSD and VAS scores.
Improvement of RSD score was significantly
better than in the placebo group.
Alendronate administration resulted in significant
diminution of spontaneous pain, tenderness and
swelling and improvement in ROM, opposed to
baseline and control treatment.
No effects of both interventions on cool, warm or
cold pain thresholds. Lidocaine caused
significant elevation of the hot pain thresholds, a
significant decreased response to stroking and
cool stimuli. At highest plasma level lidocaine
caused significant decrease in spontaneous pain
and pain reaction to cool stimuli.
Results/Conclusions
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Perez et al.
Vol. 21 No. 6 June 2001
Vol. 21 No. 6 June 2001
Treatment of Reflex Sympathetic Dystrophy (CRPS Type 1)
517
Table 3
Results of the Methodological Score of the Analyzed Randomized Clinical Trials
Items
A
B
D
E
F
G
H
I
J
K
L
M
N
O
Pa
Total
Points
→
RCT
↓
24
25
26
27
28
29
30
31
32
33
34
21
35
36
37
39
40
13
3
41
42
4
15
8
12
12
6
2
4
4
4
5
3
1
4
2
84/86a
4
2
4
2
10
10
12
4
2
1
4
1
1
5
15
15
15
10
15
15
5
5
15
1.5
2
4.5
3.33
3
4
5
5
4
4
5
3.5
5
6
4
4
5
6
2.5
3
4
2
4
4
4
4
2
2
2
4
2
4
3
2
4
4
3
4
5
6
5
4
6
5
3
6
2
6
a in
2
15
10
15
15
15
5
5
4
7
7
6
5
6
12
12
4
12
12
4
12
4
10
4
4
4
12
12
12
12
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
4
1
2
2
2
2
1
2
2
2
4
1
1
1
2.25
1.25
2.75
0.75
0.75
1.5
1.75
1
1.5
1.25
2.25
1.5
1.75
3
2.25
2.25
4.75
2.25
2
3
1
3
1
3
2
3
2
1
2
1
2
2
3
1
1
2
1
1
1
1
1
1
1
1
1
1
1
1
2
1
1
4
1
1
4
3
3
2
1
45%
29%
26%
15%
45%
43%
50%
48%
40%
51%
43%
75%
33%
40%
43%
23%
72%
56%
69%
49%
43%
case of crossover design.
33,35,36,39,40
Of these 12 articles, 425,31,36,39 studies
provided insufficient data for statistical analysis. Written permission for additional information was requested, but no additional information was sent. For these articles, a conservative
estimate of the P value was made. One article
compared two sympathetic suppressing agents,
and could therefore not be included in this
group.26 On the remaining 11 articles (with a
total of 342 patients) the above-mentioned statistical pooling strategy was applied, testing the
H0 hypothesis that there was no difference in
effectiveness between experimental and control treatment. The individual and summary effect sizes are displayed in Figure 1. The quality
weighted summary effect size Tuq1 for these 11
studies was 0.07 0.232 standard deviation
units (SDU), which is not significant (P 0.28). If the methodological quality was not incorporated, the summary effect size Tu1 for this
subgroup was not significant (0.131 0.215
SDU; P 0.11) either. The Q test was rejected
for both subgroups, indicating that this set of
effect sizes shared a common effect size.
Leaving out the four studies for which a conservative estimate of the P value was made did
not alter the quality weighted summary effect
size significantly (0.118 .339 SDU; P 0.25).
On the basis of the Q test, homogeneity was
found for this subset.
Three articles25,27,39 compared two active
substances in their studies. The summary effect
size as well as the Q test for the studies13,30–
33,36,40 that compared a sympathetic suppresser
with a placebo control were also not significant
and were slightly lower than the summary effect size for this subgroup as a whole (Tuq1 plac 0.05 0.277; P 0.36). Again, when leaving
out the articles for which a conservative estimate was made, the summary effect size remained homogeneous and not significant (Tuq 0.08 0.399; P 0.32).
A second subgroup contained six articles (n 147 patients) in which guanethidine was compared with a control treatment (see Figure
2).13,26,31,33,39,40 The summary effect size for this
subgroup with quality weighting Tuq2, as well as
the summary effect size without quality weighting Tu2, were not significant (respectively
0.03 0.339 SDU; P 0.45 and 0.01 0.277 SDU, P 0.47). The Q test was rejected,
indicating homogeneity for both effect sizes of
this subgroup. Deleting the studies for which a
conservative estimate of the P value was
518
Perez et al.
Vol. 21 No. 6 June 2001
Fig. 1. Individual and summary effect sizes for subgroup 1.13,25,27,29–33,35,36,39,40 Displayed are the effect sizes with
95% CI. Tuq1: subgroup 1, sympathetic suppressor versus control with quality weighting; Tu1: subgroup 1, sympathetic suppressor versus control without quality weighting; Tuq1plac: subgroup 1, sympathetic suppressor versus placebo with quality weighting.
made,31,39 decreased the summary effect size
slightly (0.06 0.358; P 0.36) but did not
alter the homogeneity of the subgroup.
Leaving out the studies which used an active
agent as a control26,39 did not change the quality
weighted summary effect size for the remaining
guanethidine-subset substantially (Tuq2 plac 0.03 0.371 SDU; P 0.44). Further reduction of this subset to the studies which could be
analyzed without a P-value estimate, decreased
the summary effect size slightly (Tuq 0.09 0.414; P 0.34). The latter subset consisted of
articles13,33,40 which scored more than 50% on
the methodological quality list. In both cases,
the Q statistic showed the placebo-controlled
guanethidine-subgroups to be homogeneous.
The third subgroup consisted of nine studies
(n 226 patients) in which the analgesic effect
of intravenous regional sympathetic blocks
(IRSBs) were compared with a control treatment
(see Figure 3).13,26,30,31,33,35,36,39,40 Two articles provided insufficient data for analysis,36,39 for which
a conservative estimate of the P-values was made.
The quality weighted summary effect size of this
subgroup Tuq3, as well as the unweighted summary effect size Tu3 were not significant (respectively 0.01 0.255 SDU; P 0.47 and 0.02 0.239 SDU; P 0.44). Both IRSB-subgroups were
homogeneous. Without studies for which the P
values were estimated, the quality weighted summary effect size for the IRSB-subset was higher,
but remained homogeneous and was not significant (Tuq 0.02 0.331; P 0.45).
Leaving out the studies without placebo
control26,39 did not change the quality
weighted summary effect size, which remained
not significant (Tuq3 plac 0.01 0.277; P 0.47). As in the other IRSB-subsets, the Q statistic was rejected, indicating that this set of effect
sizes shared a common effect size. Calculating
the placebo-controlled IRSB-effect size without
studies with estimated P values did not substantially alter the homogeneity and the effect size
of this subset (0.002 0.375; P 0.50).
A fourth subgroup contained five articles (n 280 patients) comparing the analgesic effect of
Vol. 21 No. 6 June 2001
Treatment of Reflex Sympathetic Dystrophy (CRPS Type 1)
519
Fig. 2. Individual and summary effect sizes for subgroup 2.13,26,31,33,38,39 Displayed are the effect sizes with 95% CI.
Tuq2: subgroup 2, guanethidine IRSB versus control with quality weighting; Tu2: subgroup 2, guanethidine IRSB
versus control without quality weighting; Tuq2plac: subgroup 2, guanethidine IRSB versus placebo with quality
weighting.
calcitonin treatment with a control treatment
(see Figure 4).21,25,27,28,34 Two articles provided
insufficient data for statistical analysis,25,34 for
these studies a conservative estimate of the P-values was made. The summary effect size with
quality weighting Tuq4, as well as the unweighted
summary effect size Tu4, were significant (respectively, 0.401 0.277 SDU; P 0.002 and
0.313 0.277 SDU; P 0.004). Leaving out
studies for which a conservative estimate of the
P-value was made, resulted in a higher and significant quality weighted summary effect size
(Tuq 0.588 0.187; p 0.001).
The summary effect size for calcitonin-articles with placebo control21,28,34 was slightly
higher, and remained significant (Tuq4 plac 0.444 0.362; P 0.005). When leaving out
the placebo-controlled studies with estimated
P-values, the effect size for the remaining two
studies21,28 was significant as well (0.644 0.438; P 0.002). The Q statistic for all subsets
in this calcitonin-subgroup was rejected, thus
showing the subsets to be homogeneous.
Description of the Best Articles
In a placebo-controlled study, Gobelet et al.
investigated the effects of three daily doses
(100 U/day) of intranasal calcitonin spray and
physical therapy on 66 CRPS type I patients,
randomly allocated into two balanced
groups.21 Inclusion criteria, administered treatments, data, and possible side effects were
clearly described. Interventions were evaluated
on pain, range of movement, edema, and
working capacity after 1, 3, and 8 weeks from
the onset of treatment. The placebo group as
well as the calcitonin group improved on pain
and mobility, but the calcitonin group improved significantly more on pain, mobility,
and ability to work after 8 weeks. Unfortunately, effects of co-interventions (such as physical therapy) were hardly described. In previous research by Gobelet et al., in which
comparable treatments were administered,
similar results were found.26
Rammamurthy et al. assessed in a doubleblind controlled study short- and long-term ef-
520
Perez et al.
Vol. 21 No. 6 June 2001
Fig. 3. Individual and summary effect sizes for subgroup 3.13,26,30,31,33,35,36,39,40 Displayed are the effect sizes with
95% CI. Tuq3: subgroup 3, IRSB versus control plus quality weighting; Tu3: subgroup 3, IRSB versus control without
quality weighting; Tuq3plac: subgroup 3, IRSB versus placebo with quality weighting.
fects of IRSBs with guanethidine in 60 patients
suffering from CRPS type I.40 A crossover design was used in which the patients received
blocks at 4-day intervals with either guanethidine or placebo in 0.5% lidocaine. Each patient was randomized to receive either 1, 2, or
4 blocks with guanethidine. Follow-up visits
were scheduled for 4 days, 1, 3, and 6 months
after the final block. At each visit, a global evaluation of CRPS type I impairments, a pain
questionnaire, range of movement, and bilateral skin temperatures were measured. Blood
count, blood chemistry, and urinalysis were
performed at the first screening and at each
follow-up visit. The authors found that four
days after the first block the placebo treatment
provided more pain relief than guanethidine.
Follow-up revealed that in 35% of the patients
significant pain relief was achieved. However,
no significant differences were found between
placebo and guanethidine.
In this study, the inclusion and exclusion criteria, the interventions, patient data, and statistical data were described well. As in Gobelet et
al., whether any side effects occurred was not
mentioned by the authors.21
Jadad et al. found similar effects when comparing IRSBs with saline and low (10 mg for
the arm and 20 mg for the leg) and high (30
mg for the affected extremity) doses of
guanethidine.13 Patients who had reported
pain relief after an open administration of
guanethidine were included in the doubleblind phase of the study. Of the initial 16 patients entering the study, 9 patients reported
sufficient pain relief to proceed with the double-blind phase in which the interventions
were administered in a crossover fashion. Pain
intensity and pain relief, duration of analgesia,
adverse effects, mood, and global rating of
treatment effectiveness were recorded. No significant differences were found between
guanethidine and placebo on any of the outcome measures. Patients reported less than
30% of the maximum possible relief after one
week. The trial was stopped prematurely because of the severity of the adverse effects.
In this study inclusion and exclusion criteria,
the experimental treatments, and blinding
procedures were adequately reported. The
washout period between administrations was
insufficient. Furthermore, baseline values were
Vol. 21 No. 6 June 2001
Treatment of Reflex Sympathetic Dystrophy (CRPS Type 1)
521
Fig. 4. Individual and summary effect sizes for subgroup 4.21,25,27,28,34 Displayed are the effect sizes with 95% CI.
Tuq4: subgroup 4, calcitonin versus control with quality weighting; Tu4: subgroup 4, calcitonin versus control without quality weighting; Tuq4plac: subgroup 4, calcitonin versus placebo with quality weighting.
not reported, making it difficult for the reader
to interpret the effects.
Blanchard et al. compared the effects of
IRSBs with guanethidine, reserpine, and saline. All three administrations provided significant pain relief 30 minutes after administration.33 No significant differences were found
between the interventions at 30 minutes and
24 hours after administration, and no longterm pain relief was found between the
groups. The guanethidine block caused significant decrease in blood pressure, but this did
not seem to be of any clinical importance according to the authors. Twenty-one patients
were studied. Patients who did not report significant pain relief after the first injection
were given one of the other agents. The allocation procedure, the prognostic comparability,
the follow-up procedure and the loss to followup were clearly described. It was however unclear whether any side effects had occurred,
and if any co-interventions had taken place.
Also the blinding and randomization procedures were not mentioned, and the crossover
was in some cases incomplete. There was insuf-
ficient data about the duration of the washout
period.
As in the studies by Rammamuthy et al. and
Jadad et al., the (presumed active) agents did
not bring about better effects than the placebo
treatment did. The authors claimed that the
amount of pain relief seen with the saline
blocks was more than should be expected from
a placebo, and suggest that this could be partially due to a mechanism of tourniquet-induced analgesia.
Zuurmond et al.3 studied the effects of
DMSO 50% in a fatty cream on 32 CRPS type I
patients in a placebo-controlled, double-blind
study. Patients with acute CRPS type I were included and judged according to strict and reproducible criteria and received DMSO 50%
(n 16) or placebo cream (n 15) and low
intensity physiotherapy for two months. VAS
scores and a global CRPS type I rating were
used to evaluate the effects of both treatments.
Application of creams resulted in both groups
having an improvement of the VAS and CRPS
type I scores, but improvement of the CRPS
type I score was significantly better in the
522
Perez et al.
DMSO group than in the placebo group. The
inclusion and exclusion criteria, the allocation
and blinding procedure, as well as the dropouts, were accurately registered. Unfortunately,
the blinding procedure was not evaluated,
which is problematic where—as in the case of
this study—the side effects differ distinctively
between placebo and the actual treatment.
Discussion
The analgesic effect of sympathetic suppressers, whether in general or applied by intravenous block, could not be confirmed by the statistical analysis performed this research
synthesis. The analgesic effectiveness was low
and just one of the studies evaluating the effect
of sympathetic suppressers reached a significant effect size.35 In accordance with Kingery’s
research, this study shows that guanethidine
IRSBs are not effective in reducing pain in
CRPS type I compared to a control of placebo
treatment. This result is further emphasized by
the fact that the summary effect size for best
scoring articles with regard to the methodological quality13,33,40 did not reach significance.
These findings do not mean that the sympathetic nervous system is not involved in the
pathophysiolology of CRPS type I, but rather
that the interventions aimed at reducing the
sympathetic activity analyzed in this study do
not seem to be effective in reducing pain. Recently, however, Harden et al. pointed out that
the serum norepinephrine level was significantly lower in the affected limb of CRPS type I
and causalgia patients than in the unaffected
limb, and serum epinephrine levels did not differ significantly from those in the unaffected
limb.43 Drummond et al. also found concentration of plasma noradrenaline to be lower in
the painful extremity.44 These findings do not
support the still widely held view that the autonomic disturbances in CRPS type I are due to
sympathetic overactivity. To establish whether
or not the sympathetic nervous system is involved in patients with CRPS type I, the phentolamine test is proposed.45–47 Blocking the
-adrenoreceptors by phentolamine prevents
excitation of nociceptive afferents by noradrenaline. If pain relief occurs after phentolamine administration, the sympathetic nervous
system is likely to be the cause of that pain.48
However, as Verdugo et al. pointed out in 77
Vol. 21 No. 6 June 2001
patients diagnosed with CRPS type I or causalgia, pharmacological manipulation of the
-adrenoreceptors by either an agonist (phenylephrine) or an antagonist (phentolamine)
does not affect neuropathic pains in these patients.48 It is clear that more research is necessary to establish the way in which the sympathetic nervous system is involved in CRPS type
I, and how the autonomic disturbances of
CRPS type I could be reduced.
Treatment with calcitonin does seem to be
effective in the treatment of pain in patients
with CRPS type I. Both the quality-weighted
and unweighted effect sizes were small but significant. This is in contradiction with Kingery’s
results, who concluded that the evidence for
the effects of calcitonin where contradictory. In
our study, the positive results stem largely from
the positive results of one article.21 Nevertheless, they suggest that calcitonin is an effective
treatment for CRPS type I. Several mechanisms
of action have been proposed in literature to
explain the antinociceptive properties of calcitonin, such as serotoninergic and cathecholaminergic mechanisms, Ca2 fluxes, protein
phosphorylation, endorphin production, cyclooxygenase inhibition and histamine inference.49 However, the analgesic mechanism of
calcitonin remains unclear. More research into
the specific effects of calcitonin on pain in general and CRPS type I should address this issue.
The results of the present review show the
influence of the methodological quality of the
articles on the overall outcome of specific
treatment methods. The latter is illustrated by
the differences in effect size calculations with
or without methodological quality. In the first
three subgroups, the summary effect sizes were
slightly higher when calculated without qualityweighting. This effect could be explained by
the fact that in these subgroups, studies with
less methodological quality (50% score or less)
tend to report on average higher effect sizes
(Tu 0.45), whereas studies with higher methodological quality (more than 50% score) report lower effect sizes (Tu 0.20). Similar findings have been reported by Kwakkel et al.50 and
Ottenbacher et al.51 in trials on the efficacy of
rehabilitation after stroke. In the fourth subgroup, however, weighting the methodological
quality leads to an increment of the summary
effect size. In this case the slightly positive result of the article by Gobelet et al.26 has been
Vol. 21 No. 6 June 2001
Treatment of Reflex Sympathetic Dystrophy (CRPS Type 1)
assigned a larger weight because of the high
score for methodological quality. Although the
differences between weighted and unweighted
calculations are small, they do indicate that effect size calculations based on studies without
prior methodological screening could lead to
an over- or underestimation of the actual effects of the treatment method under scrutiny.
These findings suggest that incorporating
the methodological quality of the trials in
meta-analytic procedures plays an important
role in determining the overall effects of specific treatment methods. Furthermore, the results of this study show that the methodological
quality of the reviewed articles could well be
improved. Every study description contained at
least some methodological flaws, of which inadequate randomization procedures, poorly
described effect measurements, unevaluated
or absent blinding procedures, lack of statistical data, absence of follow-up, insufficient
washout periods or incomplete crossover, and
lack of information about possible co-interventions or side effects were the most common. A
major problem for most studies was the lack of
statistical power due to heterogeneous patient
populations and the small sample sizes. Results
from a prospective study on 104 CRPS type I
patients in our pain clinic revealed an average
VAS score of 6.72 cm (SD 2.64). Using the standard formula,52 the sample size needed to detect a moderate difference between interventions of 2 points on the VAS with a power of
80% and set at 0.05 is 28 per group. (Calculations based on two randomly assigned parallel
groups. In case of a crossover study, where the
patient and control are the same person and
therefore tightly ‘matched’, this method provides a conservative estimate, in the sense that
the sample size is overestimated and the power
is underestimated.)
Only four of the articles21,27,36,40 used an appropriate sample size according to these calculations. The power of the remaining articles
ranged from 26% to 78%. Possibly, the small
power attributed to the lack of effect in some
studies.
It should be noted, however, that the methodological quality of the articles tended to improve
over the years. Linear regression analysis of the
quality scores of the evaluated articles showed a
significant relationship (P 0.03) between the
quality scores and the publishing date.
523
The results found in our study with regard to
the methodological quality are comparable
with those found by Jadad et al.13 As major
methodological deficiencies, they encountered
poorly defined diagnostic criteria, inadequate
washout periods, incomplete crossover, open
administration of treatment, no description of
technique, and a high proportion of withdrawals with no “intent to treat” analysis. Using the
same methodological quality score as in our
study, Kingery found that trials on CRPS type I
(n 22) scored significantly lower than trials
on peripheral neuropathic pain (n 50) (14).
According to Kingery, the CRPS type I trials
tended to use fewer subjects and trials were less
likely to use placebo controls, perform doubleblinding and use statistical tests for differences.
Both CRPS type I and peripheral neuropathic
pain trials failed to test for the accuracy of patient blinding, and long-term outcomes were
not evaluated. Kingery’s and Jadad’s findings
are in agreement with the results from our
study and emphasize the necessity for well designed randomized controlled trials.
These results show that conducting a randomized trial does not guarantee the validity of
the research. Research syntheses can be instrumental to the assessment of the internal validity
of a study.53 Research syntheses, however, are
not free from biases, such as selection bias and
publication bias. The selection bias is illustrated
by the differences between the number of articles analyzed in this study, and the reviews by
Jadad et al.13 and Kingery.14 Comparing the
number of articles found in these three studies
over the same time period (1980–1993), Jadad
et al. found seven RCTs, Kingery found 11
RCTs, and we found 15 RCTs, indicating the
importance of clear description of the search
strategy used in the meta analysis. Furthermore, publication bias could cause overestimation of the results of certain treatments. Hence,
negative results tend to be discarded, and in
some cases remain unpublished.54 Also, in this
study the number of positive reporting articles
exceeded the number in which negative outcomes were presented, but when taking the effect sizes on pain relief into account, negative
outcomes seem to prevail.
Another point of discussion is the assumptions made in this meta analysis concerning incomplete data, adopting a P-value of 0.5 (middle of the Gaussian curve) for not-significant
524
Perez et al.
results and 0.05 for reported significance. Although no strict guidelines for these imputations exist, they would provide us with lower
limit estimates of the effect size of individual
studies.22 Further analysis (see Results) revealed that these conservative estimates had no
substantial influence on the summary effect
sizes and the homogeneity statistics of the analyzed subsets. It should be noted, however, that
the results found in this research synthesis do
not cover the entire spectrum of effects of the
analyzed treatments. This study evaluated the
effectiveness of the treatments on pain relief.
Possibly effect sizes could differ if other outcome measures were to be analyzed. Furthermore, in this study, only RCTs were included,
because of the scientific strength of this type of
experimental design. Incorporating pre- and
quasi-experimental studies into the effect size
calculations could alter the magnitude of the
effect sizes found in this research.
Conclusions
A great diversity was found between studies
concerning the methodological quality, the designs used, the effect measures, and the treatment methods under scrutiny. Significant effect on pain relief by sympathetic suppressing
agents could not be established. Calcitonin
seems effective in reducing pain in CRPS type
I. The results of this study show that weighting
methodological quality results in either a decrement or increment of the effect size of specific treatment methods.
We suggest that the quality of research
should be improved. This is possible if every
study to be published is judged according to a
certain set of pre-defined methodological criteria, as was used in this study. Since no analgesic
effect of medication influencing the sympathetic nervous system could be established in
this research synthesis, using this therapeutic
approach in the treatment of pain in CRPS type
I is difficult to justify. More research into the effects of alternative treatments of CRPS type I as
well as more fundamental research could provide us with new insight into this illness.
Acknowledgments
This study was supported by a research grant
from the Dutch National Health Council (Col-
Vol. 21 No. 6 June 2001
lege voor Zorgverzekeringen), The Netherlands. The authors wish to thank Christa Boer
for her contribution in blinding and reviewing
the articles, and Silvio Perez for his grammar
corrections.
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Appendix A
Formula for calculating summary effect size
Tu(q) (23):
k
∑
Tu =
wi ti
i=1
----------------k
∑ w1
i=1
k
∑
T u(q) =
qi wi ti
i=1
---------------------k
∑ qi wi
49. Braga BC. Calcitonin and its antinociceptive activity: animal and human investigations 1975–1972.
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trials in stroke rehabilitation research. Arch Neurol
1993;50:37–44.
52. Kelsey JL, Thompson WD, Evans AS. Methods in
observational epidemiology. In: Kelsey JL, Thompson WD, Evans AS, eds. Methods in observational
epidemiology. New York: Oxford University Press,
1986, pp.259–289.
53. Cooper H, Hedges LV. Research synthesis as a
scientific enterprise. In: Cooper H, Hedges LV, eds.
The handbook of research synthesis. New York: Russel Sage Foundation, 1994, pp.3–19.
54. Bouter LM. Meta-analyse: controleerbaar en reproduceerbaar literatuuronderzoek als basis voor rationele beslissingen in de gezondheidszorg. The
Netherlands: Amsterdam University Press, 1994.
i=1
1
Where w i = ---- ,
vi
vi variance of ith study
qi quality weight of ith study
ti effect size of ith study
Formula for calculating homogeneity statistic Q (23):
k
Q =
∑
i=1
 w t 2
 ∑ i i
w i t i – ----------------------k
∑ wi
i=1
If Q exceeds the upper tail critical value of chisquare at k1 degrees of freedom, homogeneity has to be rejected for that particular summary effect size.