Is Physiotherapy Effective for Children With Complex Regional Pain Syndrome Type 1? Andrea E. Bialocerkowski, PhD* and Anne Daly, MManipTherw

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1 REVIEW ARTICLE Is Effective for Children With Complex Regional Pain Syndrome Type 1? Andrea E. Bialocerkowski, PhD* and Anne Daly, MManipTherw Objectives: This study synthesized current research evidence on the effectiveness of for the management of children complex regional pain syndrome type 1 (), to provide up-to-date treatment recommendations, and to identify areas that require further investigation. Methods: Nine electronic databases were searched for quantitative studies that evaluated the effect of on children with. The methodological quality of the studies was evaluated using the Critical Review Form. Data were extracted regarding the study design, participant characteristics, types of outcome measures used, and technique used and its effectiveness. Results: The search strategy identified 303 potential studies, of which 12 met the inclusion criteria (1 randomized controlled trial, 1 comparative study, 10 case series). The methodological quality of all studies was rated as poor to fair. The stand-alone value of could not be determined as was prescribed in conjunction with psychological and medical interventions. There is low volume and poor-to-fair quality evidence which suggests that prescribed with other interventions may lead to short-term improvement in the signs and symptoms of or functional ability in children with CRPS- 1, and the relapse rate may be moderately high. Discussion: High-quality studies are required in this area. These studies should evaluate a package of care (which includes ); they should investigate the effects of treatments that have proven effectiveness in adults with ; they should use psychometrically sound measures to evaluate outcome; and the nature of should be detailed in future publications to enable replication in the clinical setting. Key Words: complex regional pain syndrome,, systematic review (Clin J Pain 2012;28:81 91) Complex regional pain syndrome type 1 () is considered as a systemic disorder, which involves both the central and peripheral nervous systems. The diagnosis Received for publication August 18, 2010; revised March 20, 2011; accepted April 17, From the *School of Biomedical and Health Sciences, University of Western Sydney, Sydney; and wdepartment of, Austin Health, Melbourne, Australia. This study was funded in part by a New Research Project Development Grant, awarded to Andrea Bialocerkowski, from the School of Biomedical and Health Sciences, the University of Western Sydney, Penrith, Australia. The authors declare no conflict of interest. Reprints: Andrea E. Bialocerkowski, PhD, School of Biomedical and Health Sciences (Campbelltown Campus), Locked Bag, 1797, Penrith South DC 1797, Australia ( a.bialocerkowski@uws. edu.au). Copyright r 2011 by Lippincott Williams & Wilkins of is based on the presence of a range of signs and symptoms, such as pain, swelling, autonomic and motor disturbances, in the absence of peripheral nerve injury. These physical manifestations may differ depending on the chronicity of the disorder. 1 has an annual incidence rate of approximately 27 cases per 100,000 per year, which in Australia equates to more than 5500 new cases annually. 2 It occurs in both adults and children, usually after trauma to the limb, such as after a fracture, sprain, or surgery. 3,4 The demographic profile of adults and children is similar, in that more frequently affects white females compared with female individuals from other races and males. The is more frequently affected in children, whereas the upper limb is the region that is more commonly affected in adults. In addition, children have been as having higher recurrence rates, which may be as high as 50%, compared with adults. 2,5 tends to be difficult to treat because of its spectrum of symptoms and an incomplete understanding of its pathophysiology. 1 This condition often leads to significant disability that impacts on everyday activities. 6 is costly to treat, particularly in its chronic form, due to the lengthy rehabilitation period required to maximize function. Treatment in both children and adults is often multifaceted and may consist of various combinations of behavioral, psychological, pharmacological, interventional, complementary, and alternative therapies and physical therapies depending on the chronicity of the disorder. 2 In adults there is some evidence to support the use of pharmacological approaches in the management of CRPS (eg, anticonvulsants, sodium channel blockers, oral corticosteroids, calcium regulating drugs) 7,8 and also interventional therapies (eg, spinal cord stimulation, surgical sympathectomy). 9 is recommended in clinical guidelines as a treatment for both adults and children with There is good to very good quality level II evidence (from randomized controlled trials) that the technique graded motor imagery is effective in reducing pain in adults. 12 Although it is recommended that be prescribed to manage children with, it is not clear which techniques are the most effective in both acute and chronic. 9 This recommendation is based on a comprehensive review of the literature upto with the aim of developing a clinical guideline. 13 This guideline, although providing concise statements regarding treatment recommendations, lacks current research evidence in addition to detail regarding the methodological quality of the body of evidence. Therefore, previous publications provide little information regarding the limitations of existing evidence and specific areas that require further investigation. This review focuses on synthesizing the current research evidence on the Clin J Pain Volume 28, Number 1, January

2 Bialocerkowski and Daly Clin J Pain Volume 28, Number 1, January 2012 effectiveness of for the management of children so that up-to-date treatment recommendations can be made and areas that require further investigation are identified. MATERIALS AND METHODS The methodology used in this systematic review was identical to that used in our previous review on the effectiveness of for adults with. 12 Using the same approach will facilitate the development of a standardly framed body of knowledge on and, irrespective of the age of the patient. Search Strategy Electronic search strategies were developed to identify studies that the effect of for children and adolescents. Medline, CIHL, ISI Web of Science, EMBASE and Scopus databases, and 4 evidence-based practice resources [Cochrane Library (The Cochrane Collaboration, 2009), Turning Research into Practice Database (TRIP Database, 2009), Evidence Database (PEDro) (Centre for Evidence Based, 2007), and the Joanna Briggs Institute (complete site) (Joanna Briggs Institute, 2010)] were systematically searched using our earlier search strategy 12 for research evidence published in the last 2 decades (January 1987 to June 2010). The search strategy used various synonyms for (due to the change in terminology used to describe this condition over the last 2 decades 14 ) and multiple terms for (due to the range of techniques that could be used to treat children ). Key terms and subject headings were both used in the search strategy where appropriate, and searches were narrowed to retrieve evidence that specifically referred to children and adolescents where possible. The search strategy was first developed in Medline (Table 1) and subsequently tailored for each database. Secondary searching (reviewing the reference lists of included articles) was also undertaken. Selection Criteria Quantitative studies (ie, randomized controlled trials, comparative studies, cohort studies, and case series) were included in this review if they fulfilled all of the selection criteria. The study primarily included who were (1) classified as children or adolescents (ie, below 19 y of age), (2) diagnosed clinically with, and (3) where a intervention was evaluated or. was defined as the treatment of disorders with physical agents and methods, 15 such as manual therapy, electrotherapy, massage, and therapeutic exercise. A description of the technique used was needed to be provided for studies to be eligible for this review. Studies were also included in this review if they contained (1) a subgroup of who met the above selection and their data were analyzed and independent to the other subgroups of ; (2) (who were children receiving ) with varying diagnoses but where there was statistical evidence that that there was no difference in outcome variables between at baseline compared with with other diagnoses (eg, CRPS-2); or (3) Z85% of the sample who were and who met the selection criteria. No language limits were set. Studies were excluded from this review if TABLE 1. Search Strategy for the Medline Database 1. Complex regional pain syndromes (subject heading and key word) 2. CRPS (key word) 3. Reflex sympathetic dystrophy (key word) 4. RSD (subject heading and key word) 5. Algodystrophy (key word) 6. Shoulder hand syndrome (key word) 7. Sympathetic dystrophy (key word) 8. 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 9. Mirror therapy OR mirror visual therapy OR mirror visual feedback OR graded motor imagery OR motor imagery (key words) 10. Stress loading or scrub and carry (key words) 11. Electrotherapy OR TENS OR transcutaneous nerve stimulation OR ultrasound OR low frequency electrical cutaneous therapy (key words) 12. Manual therapy OR manipulative therapy OR manipulative (key words) 13. Exercise therapy OR therapeutic exercise (subject heading and key words) 14. Kinesiotherapy (key word) 15. Hydrotherapy (key word) 16. Aquatic therapy OR water exercise OR aquatic exercise OR aquatic therapy (key words) 17. Cryotherapy (key word) 18. Heat therapy (key word) 19. Electromagnatic fields (key word) 20. Biofeedback (subject heading and key word) 21. Exercise therapy OR physical therapy modalities OR physical therapy (speciality) (subject heading and key words) 22. or hand therapy or treatment (key words) 23.9OR10OR11OR12OR13OR14OR15OR15 OR 16 OR 16 OR 17 OR 18 OR 19 OR 20 OR 21 OR AND Child (subject heading and key word) 26. Adolesc (subject heading and key word) OR AND 27 they used a case study methodology (as this study design does not provide group data regarding the effect of an intervention). 16 Studies were also excluded if they were conference abstracts on the grounds that these provided insufficient information for data extraction. Study Selection The title and the abstracts of all identified articles were evaluated independently by 2 researchers to determine their eligibility. If this was unclear, the full text version of the study was reviewed to verify eligibility. A consensus method was used to resolve disagreements regarding inclusion. Data Extraction and Synthesis Evaluation of Methodological Quality To identify potential risks of bias, 2 researchers independently evaluated the methodological quality of the included studies by: (1) rating the study design according to the National Health and Medical Research Council (of Australia) Hierarchy of Evidence 17 ; (2) evaluating the quality of the studies using the 16 criteria from the Critical Review Form Quantitative Studies. 18 This critical appraisal tool can be used for all types of quantitative studies, which enhances comparison of study quality when different study designs have been used. Each item was scored as r 2011 Lippincott Williams & Wilkins

3 Clin J Pain Volume 28, Number 1, January 2012 for Children With CRPS point when the criterion was completely fulfilled. When items were not completely fulfilled, they scored 0. These scores were tallied to provide a total score, which ranged from 0 to 16, where 16 indicated excellent methodological quality. 19 Using our earlier methodological approach, quality scores were then divided into 5 arbitrary categories: poor (score, <8), fair (score=9 to 10), good (score=11 to 12), very good (score=13 to 14), and excellent (15 to 16). 12 This allowed broad word descriptors to be used to summarize methodology quality. Percentage agreements between the researchers were calculated for study design and quality. Discussion and consensus was used to resolve any disagreements. Data Extraction Two reviewers independently extracted the following data from the included studies: participant characteristics, intervention used, comparison treatment, the types and timing of outcome measurement, and the results of the study. Outcome variables and their measurement instruments were classified according to the World Health Organization International Classification of Functioning, Disability, and Health 20 as abnormalities of body function and structure; activity limitation and participation restriction. Additional variables, such as relapse rate, were classified as other. Again, discussion and consensus was used to resolve disagreements. Data Synthesis The extracted data were analyzed using descriptive statistics to summarize the study types and their methodological quality, the, the interventions, and outcome measures used. On the basis of the results by Daly and Bialocerkowski, 12 it was expected that there would be heterogeneity in, interventions, and outcomes in this study and consequently the data would be synthesized in a narrative format based on effect size. To determine the effect of the intervention on each outcome measure, the mean and 95% confidence interval for between-group differences was calculated for randomized controlled trials and comparative studies, based on the results provided in each of the primary studies. 21 In addition, the mean change between pretreatment and posttreatment (and 95% confidence intervals) was calculated for studies which employed a case series design. On the basis of research evidence, pain reduction of >20% irrespective of the measurement tool, was considered clinically worthwhile. 22,23 RESULTS The search strategy yielded 303 potentially relevant studies of which 70 full text articles were reviewed to determine their eligibility. Of these, 12 studies met the inclusion criteria and were included in this systematic review. 2,5,24 33 A subsample of children from the Lee et al 5 study also participated in the study by Meier et al. 30 As these studies have different aims and consequently have used different outcome measures and points of measurement, their results were separately in this systematic review. Methodological Quality of the Included Studies There was 100% agreement between the researchers regarding the study designs used in the included studies. This review consists of 1 level II study (randomized controlled trial), 5 1 level III study (comparative study), 30 and 10 level IV studies (case series) (Table 2). 2,24 29,31 33 There was 97% agreement between the researchers regarding the methodological quality of the included studies (based on the items contained in the Critical Review Form Quantitative Studies 18 ). Five disagreements occurred (from a total of 192 items), and all were resolved by discussion. All included studies had poor-to-fair methodological quality (median quality score=8.5, range=4 to 10). The most prevalent methodological limitations were: (1) no sample size justification (100%); (2) lack of reporting the reliability of outcome measures used (100%); (3) lack of reporting the validity of outcome measures used (92%); (4) no assessor blinding (92%); and (5) no informed consent (84%). Participant Characteristics in the Included Studies This systematic review is based on 12 studies. Ten studies included solely. 2,24,25,27 29,31 33 Participants CRPS-2 were included in 3 studies. Kachko et al 26 included a small number of children CRPS-2 (2 of a total 14 ). Thirty-six percent of Lee et al 5 and Meier et al 30 sample included children CRPS-2. However, there was no statistically significant difference at baseline between children or CRPS-2. In total, the included studies were conducted on 366 children. Twenty-two percent of children (n=82) were lost at follow-up. In general, the sample size of the included studies was small (median sample size=23, range=6 25 to children). The were relatively heterogeneous between studies, with respect to age (range, 5 to 21 y 2 ) and symptom duration (range, to mo). Most were female (n=299, 82%) and had confined to their (n=295, 81%). Six different diagnostic criteria were used across the 12 studies in this review (Table 2). Intervention In all included studies, was prescribed in various combinations with psychological and medical interventions (Table 2). 2,5,24 33 This often occurred without being randomized into treatment groups. Often there was a lack of criteria to justify treatment prescription decisions. Various psychological interventions were used, such as cognitive-behavioral therapy, 2,5,26,28,30 psychology, 24,32 counseling, 29 and psychiatry. 31 Medical interventions included those that were pharmacological (the use of simple analgesics and nonsteroidal anti-inflammatory drugs, 24,27 29,31 tricyclic antidepressants, 2,26,28 calcitonin, 24 biphosphonate pamidronate 24 ) and interventional (sympathetic blocks or infusions, 2,26,33 surgery 26,33 or sympathectomies 2 ). There were variable approaches to the prescription of between the studies. was delivered in both inpatient (hospital) or outpatient settings. Often this was not defined, 2,5,27,32,33 and analyses were often not conducted on treatment subgroups. The specific techniques were poorly described and often lacked information regarding the frequency, intensity, and duration of treatments. Exercise was the most frequently used technique. 2,5,25,27 30,32 Various types of exercise were r 2011 Lippincott Williams & Wilkins 83

4 Bialocerkowski and Daly Clin J Pain Volume 28, Number 1, January 2012 TABLE 2. Included Studies: Study Design, Participants, Interventions, Method of Outcome Measurement, Quality Score, and Main Findings Author Barbier et al 24 Brik et al 25 Kachko et al 26 Study Design (Hierarchy of Evidence) Participants Intervention prospective n=10 (9 female, 1 male) with a clinical diagnosis of Mean age: 11y (range: 5-16 y) Mean onset of symptoms to 3.3 mo (range: mo) CRPS: 90% n=6 (4 female, 2 male) by presence of Z2 neuropathic pain descriptors and 2 physical signs of autonomic dysfunction in an extremity Mean age: 12.3 y (range: 8-17 y) Mean onset of symptoms to 8.6 mo (range: 3-12 mo) CRPS: 83% lower limb n=14 (10 female, 4 male), 12 with, 2 with CRPS-2 diagnosed by using the Harden & Bruehl 10 criteria Mean age: 11.9±3.2 y (range: 7-16 y) Mean onset of symptoms to 24.5 wk (range: wk) CRPS: 57% Desensitization, heat, exercise, weight bearing)± calcitonin± biphosphonate pamidronate ±NSAIDS± psychologic treatment Inpatient and outpatient treatment: exercise, electrical stimulation, sensory stimulation, hydrotherapy, and psychological intervention. (4 times per week in a 2 h session) and home exercises twice daily and cognitivebehavioral therapy, drug treatment as required Outcome Measurement Quality Score Main Findings Functional scale (0-5), effects Median duration 6.3 y (range 2-11 y) Improved function, pain Discharge, 4-6 mo postdischarge Recovery (Full: complete resolution of signs and symptoms, resumption of age appropriate activity Partial: incomplete resolution of signs and symptoms, lowering of pain, resumption of age appropriate activities), time to recovery, relapse rate, time from recovery to relapse 3 86% of (n=6/7 children) responded well to 6 83% of (n=5/6 children) improved function and resolution of pain after 6 wk of and psychological intervention (range: 3-8 wk), which was maintained for 4-6 mo 8 79% of (n=11/14) fully recovered in 8 wk (range: 2-28 wk) with ±drug treatment and cognitivebehavioral therapy. Partial recovery was achieved in 15% (n=2/14). 29% of (4/14) a recurrence after a new traumatic event that fully recovered after 2.4±0.5 wk of (continued ) 84 r 2011 Lippincott Williams & Wilkins

5 Clin J Pain Volume 28, Number 1, January 2012 for Children With CRPS TABLE 2. (continued) Author Kesler et al 27 Lee et al 5 Low et al 28 Study Design (Hierarchy of Evidence) Participants Intervention Randomized controlled trial (II) n=10 (9 female, 1 male) based on severe pain, tenderness and autonomic dysfunction in the extremity Age range: 8-18 y CRPS: 50% n=28 (26 female, 2 male) 18 with, 10 with CRPS-2 (no significant difference in signs and symptoms at baseline) diagnosed using the Stanton-Hicks et al 34 criteria Mean age: 12.8±2.2 y CRPS: 100% n=20 (18 female, 2 male) by Harden et al 35 criteria Mean age of onset: 12.1 y girls; 8.9 y boys Mean time to 13.6 wk (range: 2 d-41 wk) CRPS: 85% TENS (1 h, 4 daily, at a comfortable intensity, over vascular supply to extremity), exercise±analgesics and antiinflammatory medications TENS, tactile desensitization, massage, contrast baths, and an individualized home exercise program and cognitivebehavioral therapy (1 week for 6 wk) Group A: 1 h/wk for 6 wk Group B: 3 h/wk for 6 wk Inpatient or outpatient : graded exercise program and hydrotherapy to increase muscle strength, joint motion and proprioception; massage and tactile desensitiza- Outcome Measurement Quality Score Main Findings 6 mo after recovery and drug therapy Resolution of symptoms, relapse rate Pain intensity and pain affect (VAS), allodynia (7 point ordinal scale), physical functioning (gait score, stair climbing score), recurrence of CRPS, participation in sports Pre treatment, 6 wk and 6-12 mo posttreatment Symptom resolution, relapse rate At symptom resolution and 3mo postsymptom resolution 4 70% of (n=7/10) complete resolution of CRPS after 2 mo of TENS and home exercises. 20% of (n=2/10) improvement. 30% of (n=3/10) relapsed after trauma 9 Function and pain improved significantly with and cognitivebehavioral therapy irrespective of the intensity of. There was a sustained benefit up to 12 mo posttreatment. 50% of (n=12/25) recurrent episodes of CRPS 12 mo after the commencement of treatment 8 78% of (n=14/18) full recovery in 25 wk (range=1-15 mo) with intensive ±cognitivebehavioral therapy and analgesia. Relapses occurred in 22% of (continued ) r 2011 Lippincott Williams & Wilkins 85

6 Bialocerkowski and Daly Clin J Pain Volume 28, Number 1, January 2012 TABLE 2. (continued) Author Maillard et al 29 Meier et al 30 Study Design (Hierarchy of Evidence) Participants Intervention tion±cognitive-behavioral therapy and analgesia Comparative study (III-3) n=23 (18 female, 5 male) with the Harden et al 35 criteria Median age at onset: 11.9 y ( y) Median age at 12.1 y ( y) CRPS: 83% n=20 (19 female, 1 male) from a sample of 28 children (18 with, 10 with CRPS- 2 diagnosed using the Stanton-Hicks et al 34 criteria. No significant difference in signs and symptoms at baseline for and CRPS-2 Mean age: 13.1±2.5 y Median duration of pain prior to study: 2mo CRPS: 100% Outpatient exercises to restore movement and function, desensitization OR Inpatient treatment consisting of <2 h of hydrotherapy and 2 h of daily and occupational therapy±drug therapy and counseling for 2 wk and then a home exercise program n=20 TENS, tactile desensitization, massage, contrast baths 1 h/wk for 6 wk and an individualized home exercise program and cognitivebehavioral therapy (1 week for 6 wk) n=39 health controls (24 female, 15 male, mean age: 11.7±2.7 y) n=21 children with postural orthostatic tachycardia syndrome (13 female, 8 male, mean age: 15.5±2.2 y, median Outcome Measurement Quality Score Main Findings (n=4/18) after 13 wk (range=7-52 wk) and resolved in 29 wk (range=16-27 wk) 9 78% of Time to recovery, relapse rate (n=18/23) fully recovered with intensive Not stated ±occupational therapy, drug therapy, and counseling after 25 wk (range=1-15 mo) of treatment Orthostatic symptom score, pain intensity (VAS), allodynia (VAS), dysesthesia, physical signs of CRPS including autonomic profile, functional score (0-5 scale) Pretreatment, 6 wk and 6 mo posttreatment 10 Autonomic symptoms, function and pain improved significantly with and cognitivebehavioral therapy, with sustained benefit up to 6mo posttreatment (P<0.01) (continued ) 86 r 2011 Lippincott Williams & Wilkins

7 Clin J Pain Volume 28, Number 1, January 2012 for Children With CRPS TABLE 2. (continued) Author Murray et al 31 Sherry et al 32 Wesdock et al 33 Study Design (Hierarchy of Evidence) Participants Intervention duration of symptoms: prospective n=46 (35 female, 11 male) with diagnosed by severe pain with at Z2 descriptors of neuropathic pain and physical signs of autonomic dysfunction Median age: 12y (range: y) Mean onset of symptoms to 23.6 wk (range: wk) CRPS: 65% n=103 (87 female, 16 male) using the Merskey & Bogduck 14 criteria Median age: 12.7 y (range: y) Median duration of symptoms: 2.0 mo (range: mo) CRPS: lower limb 81% n=36 (24 female, 12 male) clinically Mean age: 13.4 y (range: 8-19 y) CRPS: 83% 12 mo) Physiothera- py±n- SAIDS±psychiatry 5-6 h daily of aerobic exercise program focusing on function including hydrotherapy (eg, : jumping, running, stairs, weightbearing exercises, sports; upper limb: writing, carrying), desensitization using massage and contrast baths, and 45 mins 3 h of home exercises daily Exercise, electrotherapy (including TENS), cold, splinting, pressure, desensitization±counseling by physicians/ psycholo- gists±medica- Outcome Measurement Quality Score Main Findings Time to recovery, relapse rate 3-6 mo postresolution Pain intensity (numeric rating scale: 0-10), self-report and therapist-report of dysfunction 6-8 mo and >2 y after completion of exercise program Time to initial symptom resolution, number of recurrences, functional return to normal activities Resolution of 7 87% of (n=40/46) to recover in a median of 7 wk (range=1.140 wk). 27% of (11/46) relapsed 10 92% of (n=95/103) complete resolution of pain and full function with 14 d of aerobic exercise (range: 1-90 d). 42% of (43/103) no CRPS symptoms after on average 5 y and 3 mo follow-up (52% of were lost at follow-up) 8 47% of (n=15/32) that CRPS had resolved without recurrences after and other interventions after an (continued ) r 2011 Lippincott Williams & Wilkins 87

8 Bialocerkowski and Daly Clin J Pain Volume 28, Number 1, January 2012 TABLE 2. (continued) Author Wilder et al 2 Study Design (Hierarchy of Evidence) Participants Intervention tions±local injections± sympathetic blocks±manipulation under general anesthetic± surgery n=70 (59 female, 11 male) diagnosed based on the presence of Z2 neuropathic pain descriptors and 2 physical signs of autonomic dysfunction in an extremity Mean age: 12.5 y (range: 5-17 y) CRPS: 87% lower extremity Desensitization, heat, cold, motion exercises stretching, strengthening, physical conditioning±transcutaneous electrical nerve stimulation± cognitivebehavioral therapy±drug therapy±sympathetic blocks Outcome Measurement Quality Score Main Findings symptoms average of 3.1 mo. 25% of (n=8/32) recurrence of symptoms) Pain intensity (0-10 scale), function (0-5 scale), ability to perform in work, school or sports Median duration=3 y (range: 2-8 y) 10 69% of (n=44/64) that improved function indicates complex regional pain syndrome type 1; CRPS-2, complex regional pain syndrome type 2;, not applicable; NSAIDS, nonsteroidal anti-inflammatory drugs; TENS, transcutaneous electrical nerve stimulation; VAS, visual analogue scale. prescribed to facilitate motion, muscle strength, muscle length, proprioception, aerobic capacity, and weight bearing on the affected limb. Exercise in water, hydrotherapy, 25,28,29,32 and home exercise programs were also utilized. 26,28,29,32 Sensory desensitization, which was also prescribed in the majority of studies, 2,5,24,25,28,30,32,33 consisted of various combinations of massage of the affected extremity, the application of cold, heat, and contrast baths. Transcutaneous electrical nerve stimulation was also used for desensitization and for an analgesic effect. 2,5,27,30 However, insufficient information was provided to allow replication of this modality. Outcome Measurement There was variability in the outcome measures used to determine the effectiveness of for children. In 58% of the studies (n=7), outcome was based on the time for symptom resolution and the relapse rate. 5,24,26 29,31,33 Definitions of these variables were either absent or inconsistent across the included studies. For example, the term recovery was defined by 4 of the 7 investigators who evaluated this variable. It was defined as a favorable effect, 24 or the resumption of age appropriate activity. 26,29,31 The resolution of physical symptoms 29 and pain 26 was inconsistently used in these definitions. Moreover, the variables recurrence and relapse were evaluated by 8 investigators, 5,24,26 29,31,33 but were only defined by Low et al. 28 In the remaining studies, outcome was quantified in terms of impairments, activity limitations, and participation restrictions. Pain was the most frequently evaluated impairment variable, although characteristics of muscle, joints, skin, and gastrointestinal changes were also evaluated. 26,30 A range of pain dimensions were evaluated, such as intensity, 5,30,32 affect, 2,31 allodynia, 5,26,30 dysethesia, 30 hyperalgesia, 26 and hyperpathia. 30 Various activity limitations, such as gait, 5 stairs, 5 and general functioning 2,24,30 were evaluated in less than half the studies included in this review. A similar trend were apparent for the measurement of participation restrictions. 2,5,32,33 In addition, these variables were often evaluated using purpose-designed questionnaires with unknown psychometric properties. Outcomes were measured at various times with only 2 research groups evaluating before treatment, after the treatment (which was a standard duration), and after a standardized follow-up period. 5,30 In the remainder of the studies, data pertaining to the change in outcome variables from pretreatment to posttreatment were not provided. Effectiveness of Data gained from the included studies could not be pooled because of the heterogeneity of outcome measures. Moreover, effect sizes could not be calculated for the 88 r 2011 Lippincott Williams & Wilkins

9 Clin J Pain Volume 28, Number 1, January 2012 for Children With CRPS studies because of the lack of variables that were measured before and after the intervention, small sample sizes (medians were provided instead of means), and the lack of raw data in the publications. On the basis of the main findings of the included studies (Table 2), it seems that in combination with other interventions may lead to the short-term improvement in the signs and symptoms of or functional ability in children. This is based on the results of 10 studies, in which in total 269 children were to have improved after from a total of 323 children. 2,24 29,31 33 There is low-volume and poor-to-fair quality evidence which suggests that the relapse rate may be moderately high. This is based on the results of 6 studies, in which a total of 46 were to have relapsed after the cessation of from a total of 148 children. 5,26 28,32,33 DISCUSSION This systematic review synthesized the current research evidence regarding the effectiveness of interventions for the treatment of children with. It is possible that some relevant evidence may have been omitted from this systematic review. This is unlikely as a well-established search strategy was used, 12 in addition to secondary searching. Furthermore, our search strategy was comprehensive, as it yielded a greater number of included studies (up until 2005) compared with the review conducted by Perez et al. 9 In this study, the reviewers were not blinded to the source of the primary studies. However, the 2 reviewers independently provided almost identical methodological quality ratings for the included studies. Therefore, reviewer bias is unlikely. The main finding of this systematic review is that there is low-volume and poor-to-fair quality evidence on the effect of for children with. 36 Despite this, there is some consistency in the evidence which suggests that, in combination with other interventions, could assist in the resolution of the signs and symptoms of in children or increase their functional ability. In all studies, was prescribed in combination with various other interventions, such as psychological and medical treatments. On the basis of TABLE 3. Body of Evidence for the Effectiveness of for the Treatment of Evidence Technique Effect Population Level* Quality Reference Graded motor imagery+medical management pain management+medical management Electromagnetic field treatment Graded exposure in vivo program Four week interdisciplinary program Sensorimotor treatment program Mirror visual feedback +other therapies as required More effective than graded motor imagery or medical management alone More effective than occupational therapy or social work combined with medical management Offers no added benefit to calcitonin and exercise Reduced pain related fear and pain disability Adults with upper or low limb Adults with upper limb Adults with upper limb II Good very good Moseley II Good Oerlemans et al Severens et al 45 II Good Durmus et al 46 Adults IV Good De Jong et al 47 Increases function Adults IV Good Singh et al 48 Reduced pain and increased tactile discrimination Reduced the perception of pain in early and stiffness in intermediate Reduced the signs and symptoms of CRPS Adults IV Fair Pleger et al 49 Adults III Fair McCabe et al 50 Children IV Poor fair Barbier et al 24 Brik et al 25 Kacho et al 26 Kesler et al 27 Low et al 28 Maillard et al 29 Murray et al 31 Wesdock et al 33 Wilder 2 *Level of evidence according to the National Health and Medical Research Council (of Australia) guidelines. 17 indicates complex regional pain syndrome type 1. r 2011 Lippincott Williams & Wilkins 89

10 Bialocerkowski and Daly Clin J Pain Volume 28, Number 1, January 2012 current research evidence, it is not possible to draw conclusions regarding the effectiveness of as a stand-alone treatment. However, is frequently prescribed in conjunction with other interventions. Therefore, a goal of future studies should be to determine the effectiveness of a package of care, which includes. Moreover, consideration must be given to the treatment techniques used in this package based on the chronicity of. The trends identified in this review may have been influenced by the variable criteria that were used to define, as CRPS diagnostic criteria have changed over the last 30 years. 37 It is likely that across the included studies were not homogeneous and this may explain the variation in recovery and relapse rates between the primary studies. Moreover, there was a lack of consensus regarding the measurement tools used to evaluate outcome after for in children. Variable criteria were used to define recovery and relapse. Outcome variables were evaluated at different points in time, using various types of outcome measures. The psychometric properties of these outcome measures were insufficiently described. This means that it was not possible to determine the effect of measurement error on the results gained. These issues need to be considered when interpreting the published evidence, and when designing future pediatric studies. Other issues that should be considered in future pediatric studies are the study design selected and the quality of the methodology used in studies, which evaluate treatment effectiveness. The majority of studies in this systematic review were case series. This study design ranks low on the hierarchy of evidence due to the large magnitude of bias that it is likely to contain. 16 Case series are descriptive in nature, as they document the outcome of who are prescribed a similar treatment. They are, consequently, confounded by selection bias that limits statements of causality. Nevertheless, the results gained from high-quality case series can be used to generate hypotheses and to design future research studies using higher-order study designs. 38 An additional and concerning factor was that the methodological quality of all studies included in this review was poor to fair. This indicates that potentially there were uncontrolled or confounding variables that may have influenced the results. Moreover, the results of these studies have limited ability to generate future research hypotheses. The clinical impact of the findings of this systematic review is potentially limited. 36 Currently, there is a paucity of evidence regarding what constitutes for children and the most effective type of treatment in acute and chronic forms of. 9 Included studies also lacked information regarding how the treatment should be applied (eg, how to progress the treatment, treatment duration, treatment intensity). These details need to be provided in future research so that treatments with proven effectiveness can be replicated, where appropriate, in the clinical setting. Table 3 presents the body of evidence regarding the effectiveness of for individuals (both children and adults). It shows that there is a greater volume and higher methodological quality of evidence, which supports the use of for adults with compared with children. Specifically, there is good to very good quality level II evidence (from randomized controlled trials) that graded motor imagery is effective in reducing pain in adults with, irrespective of the outcome measure used. 12 This form of intervention, along with other techniques, (such as graded exposure, sensorimotor treatment, and mirror visual feedback) has not been evaluated in pediatric populations. This may be because of previously differences in presentation between adults and children. 51 The differences between adults and children with could be less than previously thought, and explained by different activity profiles and disability requirements required for referral to a tertiary pain management center between adults and children. 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