Treatment of Reflex Sympathetic Dystrophy Randomized Clinical Trials
Transcription
Treatment of Reflex Sympathetic Dystrophy Randomized Clinical Trials
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 516 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. References 1. Reflex Sympathetic Dystrophy Guideline Panel. Recommendations for the approach of reflex sympathetic dystrophy patients. Clinical practice guideline. The national project on quality assurance of invasive anaesthesiological pain control. 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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.