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Complex regional pain syndrome: Which treatments show promise?
- Treatments for CRPS type 1 supported by evidence of efficacy and little likelihood for harm are: topical DMSO cream (B), IV bisphosphonates (A) and limited courses of oral corticosteroids (B). Despite some contradictory evidence, physical therapy and calcitonin (intranasal or intramuscular) are likely to benefit patients with CRPS type 1 (B).
- Due to modest benefits and the invasiveness of the therapies, epidural clonidine injection, intravenous regional sympathetic block with bretylium and spinal cord stimulation should be offered only after careful counseling (B).
- Therapies to avoid due to lack of efficacy, lack of evidence, or a high likelihood of adverse outcomes are IV regional sympathetic blocks with anything but bretylium, sympathetic ganglion blocks with local anesthetics, systemic IV sympathetic inhibition, acupuncture, and sympathectomy (B).
In last issue of the Journal of Family Practice, we discussed diagnosis of CRPS type 1 (“Complex regional pain syndrome underdiagnosed,” 2005; 54: 524–532). Once other conditions have been ruled out, a primary care practitioner can diagnose CRPS type 1 right in the office using clinical findings and the patient’s report of symptoms. Similarly, primary care practitioners can provide most of the best treatments for CRPS type 1. In fact, evidence indicates that no benefit has been proven from more invasive treatments such as sympathectomy which continue to be included in recommendations by experts.1
Evidence for intervention less than compelling
A review of the literature on treating CRPS type 1 raises a question: is there any evidence that treatment makes a difference in outcomes that matter to patients, such as returning to work, regaining functionality of the affected limb, or resolution of pain? The large discrepancy between the high rates of CRPS type 1 documented in prospective studies of post-traumatic patients and the low rates of diagnosis of CRPS type 1 in actual practice suggests that most cases of CRPS type 1 resolve without being diagnosed and treated. This is not proven because, unfortunately, the natural history of persons diagnosed in the first 9 weeks after injury is not known.2
Are there benefits to early treatment?
From the clinician’s perspective, persons diagnosed with CRPS type 1 early appear more likely to respond to treatment. There is an “oft-quoted contention that results of early treatment will be better than those when the pain is treated late.”2 Yet, the great majority of these patients may have improved just as readily without treatment. For the few cases of undiagnosed CRPS type 1 that will persist to become chronic and treatment resistant, it is unknown whether early treatment would have been preventive2 or how clinicians could distinguish these cases early enough to target them for treatment.
Intriguing but limited data exist for using preventive therapies in all at-risk patients. One prospective cohort study documented a lower rate of CRPS type 1 in stroke patients who underwent early inpatient rehabilitation, compared with patients in earlier studies who rarely received early rehabilitation. This finding indirectly suggests a possible preventive effect of physical/occupational therapy (LOE: 3, cross-study comparison).3 Luckily, early inpatient rehabilitation in stroke patients has become the standard of care, which may prevent many cases of CRPS type 1 as a side effect.
It also appears that injury to a newly hemiplegic arm may contribute to the shoulder-hand syndrome; a study that alerted patients and care-takers to the risk of injury reduced the rate of shoulder hand syndrome from 27 to 8% (LOE: 2, lowerquality RCT).4 Among post-traumatic patients with wrist fracture, a double-blind randomized placebo controlled trial (n=115) of vitamin C 500 mg tabs initiated upon diagnosis of fracture and continued for 50 days resulted in a marked decrease of CRPS type 1 from 22% in the placebo group to 7% in the vitamin C group (relative risk=0.17) (LOE: 1, high-quality RCT).5 These results have not been tested in subsequent trials, however.
Guideline recommendations: Physical and psychological therapy, pain management
Many treatments for CRPS have been tried and are summarized without a systematic or evidence-based approach to the literature in a consensus statement released in 2002 by an interdisciplinary expert panel (LOE: 3, consensus guideline).1 These guidelines suggest rapid initiation of multidisciplinary treatment with advancement to higher levels of intervention if no benefit from initial therapy occurs in 2 weeks. Simultaneous physical rehabilitation, psychological therapy, and pain management are recommended.
Rehabilitation through physical therapy and occupational therapy starts with desensitization and stress loading, progresses to increasing flexibility with gentle active range of motion and stretching, and eventually to normalization of use.
Psychological therapy starts with teaching patients that 1) pain sensations in CRPS type 1 do not indicate tissue damage, and 2) reactivation of the affected limb is important. With persistent symptoms, clinical psychological assessment is recommended, eventually followed by cognitive behavioral therapy.
Pain management starts with oral or topical medications typically used for other neuropathic pain conditions (eg, amitriptyline (Elavil), gabapentin (Neurontin), opioids, and nonsteroidal antidepressants). The guideline also recommends steroids, calcitonin, and alpha-1 adrenoceptor antagonists (terazosin [Hytrin] or phenoxybenzamine [Dibenzylene]). With persistent symptoms, intravenous regional sympathetic blocks (IRSBs) and somatic nerve blocks are recommended. According to the guideline, treatment for resistant cases may progress to epidural catheters for sympathetic blockade, spinal cord stimulation, intrathecal baclofen (Lioresal), or sympathectomy.1
Reviews of medication trials show minimal effectiveness
Meta-analyses and systematic reviews of the literature reveal that many of the treatments recommended in the guidelines are minimally if at all effective, or have been inadequately researched.6-12 This is particularly so concerning invasive therapies such as sympathetic ganglion block,13 sympathectomy,12 and spinal cord stimulation9,10 that introduce the possibility of adverse effects. Yet, evidence is equally sparse for common pain therapies in CRPS type 1, such as nonsteroidal anti-inflammatory drugs, antidepressants, opiates, or antiseizure medications.
Systematic review and meta-analysis of medication trials for CRPS only partially agree.6-8,11 A 1999 systematic review concluded that oral corticosteroids demonstrated a consistent and long-term analgesic effect in CRPS.6 This review identified only limited data to suggest an analgesic effect from topical dimethylsulfoxide (DMSO), epidural clonidine and IRSB with ketanserin (not available in the US), and bretylium. The review concluded there was contradictory evidence of an analgesic effect from calcitonin or intravenous phentolamine and most likely no effect, and evidence against the effectiveness of guanethidine and reserpine IRSBs, and droperidol and atropine IRSBs.6
A 1995 systematic review of IRSBs concluded as well that overall there was no effect on pain, but a single RCT of each bretylium and ketanserin showed an analgesic effect.8 In a systematic review focused on upper extremity post-stroke CRPS (also known as shoulder-hand syndrome), 1 RCT was identified, and indicated that corticosteroids had an analgesic effect.11 High-quality evidence for the use of intramuscular calcitonin was lacking.11
Calcitonin may be one exception. A systematic review of medical treatment for CRPS type 1 identified 21 randomized trials, enough to undertake a statistical analysis of the analgesic effect of 4 types of treatment: sympathetic suppressors, guanethidine, intravenous regional blocks, and calcitonin.7 Of the 4, only calcitonin appeared to have a significant beneficial effect on pain.7
IV bisphosphonates show promise. More recently, intravenous bisphosphonates have demonstrated clinical and analgesic benefits in 2 small but high-quality RCTs.14,15 Strikingly, short-term therapy of 3 to 10 days of IV alendronate (Fosamax) or clodronate (Bonefos) without adverse effects resulted in significant overall improvements for the duration of the 2 trials, 4 weeks14 and 180 days.15
Nonpharmacologic treatments
Nonmedical treatments that have been studied include spinal cord stimulation, physical therapy, occupational therapy, and acupuncture. Spinal cord stimulation demonstrated a modest long-term (2-year) reduction in pain and improvement in health related quality of life in 1 RCT,16 but with no improvement in patient functioning and a 34% rate of adverse occurrences.9 Similarly, physical therapy and occupational therapy have been studied only in 1 large RCT (n=135).
Treatment with physical therapy did decrease pain compared with occupational therapy and control therapy,17 but revealed no improvement in active range of motion with physical or occupational therapy compared with control therapy.17 Furthermore, physical therapy led only to uncertain diminishment of impairment when data were analyzed in 2 different ways, 1 of which showed a benefit of physical and occupational therapy over control treatment,18 1 of which did not.19
Acupuncture demonstrated no improvement over sham treatment.20
Applying the evidence: Medical treatment
Choose any of the therapies least likely to do harm and supported by evidence of efficacy: topical 50% DMSO cream (SOR: B), intravenous bisphosphonates (SOR: A), or limited courses of oral corticosteroids (SOR: B). Despite some contradictory findings in the literature,6,17,18 other studies demonstrate that physical therapy18,19 and calcitonin7 reduce pain, and neither is likely to cause harm (SOR: B).
Epidural clonidine injection,6 IRSB with bretylium,6-8 and spinal cord stimulation9,16 have demonstrated some efficacy, but due to the invasiveness of the treatments and the modest benefits, patients should be counseled carefully before initiating these therapies (SOR: B) (TABLE 1).
Therapies to avoid. Therapies to avoid due to lack of evidence, lack of efficacy, or likelihood of adverse outcomes include IV regional blocks with everything but bretylium,6-8 sympathetic ganglion blocks with local anesthetics (very short duration of analgesia),13 systemic intravenous sympathetic inhibition,6 acupuncture,20 and sympathectomy (SOR: B).12
TABLE 1
Effectiveness of treatments for CRPS type 1
| TREATMENT | STUDY TYPE | STUDY QUALITY | EFFECT* |
|---|---|---|---|
| DMSO | SR6 | 2 – small RCT (n=32)21 | (+): Analgesia during therapy |
| Bisphosphonates | RCTs14,15 | 1 – multiple RCTs (n=32)15 and (n=20)14 | (+): Long-term (4 weeks14 to 180 days15) overall clinical improvement with significant analgesia |
| Corticosteroids | 2 SRs6,11 | 2 – 2 small RCTs, 1 in post-traumatic CRPS type 1 (n=23)22 and 1 (poor-quality) in shoulder-hand syndrome (n=36)3 | (+): 75% clinical improvement to 12 wk in CRPS type 1;22 and resolution of symptoms in shoulder-hand syndrome3 |
| Clonidine | SR6 | 2 – small RCT (n=26)23 | (+): Temporary analgesia |
| Spinal cord stimulation | SR9-11 | 2 – multiple SRs based on 1 RCT (n=36)16 | (+): Modest long-term (2-y)16 analgesic effect, improved health-related quality of life, no improvement in patient functioning and 34% rate of adverse occurrences9 |
| Physical therapy and occupational therapy | RCT17-19 | 1 – RCT (n=135) | (+/–): Contradictory analyses using different methods of measuring impairment, 1 showing no advantage of PT or OT over control,17 the other showing improvement with both.18 Significant improvement in pain at 1 y with PT over OT and control, no significant improvement in active ROM.19 |
| Calcitonin | SR6,7 | 1 – multiple RCTs24-26 | (+/–): Contradictory results – 1 SR indicating a significant analgesic effect7 the other suggesting no analgesic effect6 |
| IRSBs (bretylium, ketanserin, guanethidine, reserpine, droperidol, or atropine) | SR6-8 | 1 and 2 – Good-quality RCTs | (+/–): When collectively analyzed, no overall positive of guanethidine, otherwise effect.7,8 When evaluated by particular medication, small or poor quality RCTs limited evidence for analgesia with bretylium and ketanserin (not available in the US),6,8 and no analgesia with guanethidine, reserpine, droperidol and atropine6 |
| Sympathetic ganglion blocks (lidocaine/bupivacaine) | RCT13 | 2 – small RCT (n=7) | (+/–): Short-term analgesia with longer duration of pain control in treatment group (3.5 days) vs placebo (1 day) |
| Sympathectomy (chemical or surgical) | SR12 | 2 – SR based on poor-quality evidence, no placebo controlled RCTs | (+/–): No evidence of effectiveness, high rates (>10%) of adverse effects including worse pain, new neuropathic pain and pathological body sweating |
| Acupuncture (30 min 5x/wk for 3 wk | RCT20 | 2 – small RCT (n=14) | (–): Immediate and long-term (6-mo) clinical improvement and analgesia in sham/acupuncture treatment groups |
| Sympathetic inhibition | SR6 | 1 & 2 – variable-quality RCTs27-29 | (+/–): Contradictory results, with the best-designed study showing only a 9% short-term relief of pain28 |
| DOSAGES: DMSO: 50% cream applied 5x/d for at least 2 mo.21 | |||
| Bisphosphonates: IV alendronate 7.5 mg once daily for 3 days14 or intravenous clodronate 300 mg once daily for 10 days.15 | |||
| Calcitonin: intranasal 400 IU once daily26 or 100 IU 3 times daily27 or intramuscular 100 IU once daily for 3 weeks.28 | |||
| Corticosteroids: prednisone 10 mg 3 times daily until remission, max. up to 12 weeks,22 or prednisolone 32 mg daily for 2 wk with a 2-wk taper.4 | |||
| Clonidine: 300 μg epidural injection.23 | |||
| Sympathetic inhibition: IV phentolamine.27-29 | |||
| *Effect: (+) = positive, (+/–) = contradictory results or poor quality evidence, (–) = no effect. | |||
| SR, systematic review; MA, meta-analysis; RCT, randomized controlled trial; DMSO, dimethylsulfoxide; PT, physical therapy; OT, occupational therapy; ROM, range of motion. | |||
Acknowledgments
The authors would like to express their appreciation to Cheryl Mongillo, Peggy Lardear, and Brian Pellini for their assistance in preparing the manuscript, Dolores Moran and Diane Wolfe for their assistance in finding articles, and to Roger Rodrigue, MD for reviewing the manuscript. Funding for this project was provided by a grant from the Delaware Department of Health and Social Services, Division of Public Health.
CORRESPONDING AUTHOR
Anna Quisel, MD, c/o Cheryl Mongillo, Family Medicine Center, 1401 Foulk Road, Wilmington, DE 19803. E-mail: DrQuisel@comcast.net
1. Stanton-Hicks MD, Burton AW, Bruehl SP, et al. An updated interdisciplinary clinical pathway for CRPS: Report of an expert panel. Pain Practice 2002;2:1-16.
2. Commentary on RSD focus article Bandolier 2002. Available at:www.jr2.ox.ac.uk/bandolier/booth/painpag/wisdom/RSD.html.
3. Petchkrua W, Weiss DJ, Patel RR. Reassessment of the incidence of complex regional pain syndrome type 1 following stroke. Neurorehabil Neural Repair 2000;14:59-63.
4. Braus DF, Krauss JK, Strobel J. The shoulder-hand syndrome after stroke: a prospective clinical trial. Ann Neurol 1994;36:728-733.
5. Zollinger PE, Tuienebreijer WE, Kreis RW, Breederveld RS. Effect of vitamin C on frequency of reflex sympathetic dystrophy in wrist fractures: a randomised trial. Lancet 1999;354:2025-2028.
6. Kingery WS. A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes. Pain 1997;73:123-139.
7. Perez RS, Kwakkel G, Zuurmond WW, de Lange JJ. Treatment of reflex sympathetic dystrophy (CRPS type 1). a research synthesis of 21 randomized clinical trials. J Pain Symptom Manage 2001;21:511-526.
8. Jadad AR, Carroll D, Glynn CJ, McQuay HJ. Intravenous regional sympathetic blockade for pain relief in reflex sympathetic dystrophy: a systematic review and a randomized, double-blind crossover study. J Pain Symptom Manage 1995;10:13-20.
9. Turner JA, Loeser JD, Deyo RA, Sanders SB. Spinal cord stimulation for patients with failed back surgery syndrome or complex regional pain syndrome: a systematic review of effectiveness and complications. Pain 2004;108:137-147.
10. Grabow TS, Tella PK, Raja SN. Spinal cord stimulation for complex regional pain syndrome: an evidencebased medicine review of the literature. Clin J Pain 2003;19:371-383.
11. Geurts AC, Visschers BA, van Limbeek J, et al. Systematic review of aetiology and treatment of post-stroke hand oedma and shoulder-hand syndrome. Scan J Rehabil Med 2000;32:4-10.
12. Mailis A, Furlan A. Sympathectomy for neuropathic pain. Cochrane Database Syst Rev 2003;2.-
13. Price DD, Long S, Wilsey B, Rafii A. Analysis of peak magnitude and duration of analgesia produced by local anesthetics injected into sympathetic ganglia of complex regional pain syndrome patients. Clin J Pain 1998;14:216-226.
14. Adami S, Fossaluzza V, Gatti D, et al. Bisphosphonate therapy of reflex sympathetic dystrophy syndrome. Ann Rheum Dis 1997;56:201-204.
15. Varenna M, Zucchi F, Ghiringhelli D, et al. Intravenous clodronate in the treatment of reflex sympathetic dystrophy syndrome. A randomized double blind, placebo controlled study. J Rheumatol 2000;27:1477-1483.
16. Kemler MA, De Vet HC, Barendse GA, Van Den Wildenberg FA, Van Kleef M. The effect of spinal cord stimulation in patients with chronic reflex sympathetic dystrophy: two years’ follow-up of the randomized controlled trial. Ann Neurol 2004;55:13-18.
17. Oerlemans HM, Goris JA, de Boo T, Oostendorp RA. Do physical therapy and occupational therapy reduce the impairment percentage in reflex sympathetic dystrophy? Am J Phys Med Rehabil 1999;78:533-539.
18. Oerlemans HM, Oostendorp RA, de Boo T, van der Laan L, Severens JL, Goris JA. Adjuvant physical therapy versus occupational therapy in patients with reflex sympathetic dystrophy/complex regional pain syndrome type I. Arch Phys Med Rehabil 2000;81:49-56.
19. Oerlemans HM, Oostendorp RA, de Boo T, Goris RJ. Pain and reduced mobility in complex regional pain syndrome I: outcome of a prospective randomised controlled clinical trial of adjuvant physical therapy versus occupational therapy. Pain 1999;83:77-83.
20. Korpan MI, Dezu Y, Schneider B, Leitha T, Fialka-Moser V. Acupuncture in the treatment of posttraumatic pain syndrome. Acta Orthop Belg 1999;65:197-201.
21. Zuurmond WW, Langendijk PN, Bezemer PD, Brink HE, de Lange JJ, van loenen AC. Treatment of acute reflex sympathetic dystrophy with DMSO 50% in a fatty cream. Acta Anaesthesiol Scand 1996;40:364-367.
22. Christensen K, Jensen EM, Noer I. The reflex dystrophy syndrome response to treatment with systemic corticosteroids. Acta Chirurgica Scandinavica 1982;148:653-655.
23. Rauck RL, Eisenach JC, Jackson K, Young LD, Southern J. Epidural clonidine treatment for refractory reflex sympathetic dystrophy. Anesthesiology 1993;79:1163-1169.
24. Bickerstaff DR, Kanis JA. The use of nasal calcitonin in the treatment of post-traumatic algodystrophy. Br J Rheumatol 1991;30:291-294.
25. Gobelet C, Waldburger M, Meier JL. The effect of adding calcitonin to physical treatment on reflex sympathetic dystrophy. Pain 1992;48:171-175.
26. Gobelet C, Meier J, Schaffner W, et al. Calcitonin and reflex sympathetic dystrophy syndrome. Clin Rheumatol 1986;5:382-388.
27. Raja AN, Treed RD, Davis KD, Campbell JN. Systematic alpha-adrenergic blockade with phentolamine: a diagnostic test for sympathetically maintained pain. Anesthesiol 1991;74:691-698.
28. Verdugo RJ, Ochoa JL. Sympathetically maintained pain. I. Phentolamine block questions the concept. Neurology 1994;44:1003-1010.
29. Verdugo RJ, Campero M, Ochoa JL. Phentolamine sympathetic block in painful polyneuropathies. II. Further questioning of the concept of “sympathetically maintained pain.” Neurology 1994;44:1010-1014.
- Treatments for CRPS type 1 supported by evidence of efficacy and little likelihood for harm are: topical DMSO cream (B), IV bisphosphonates (A) and limited courses of oral corticosteroids (B). Despite some contradictory evidence, physical therapy and calcitonin (intranasal or intramuscular) are likely to benefit patients with CRPS type 1 (B).
- Due to modest benefits and the invasiveness of the therapies, epidural clonidine injection, intravenous regional sympathetic block with bretylium and spinal cord stimulation should be offered only after careful counseling (B).
- Therapies to avoid due to lack of efficacy, lack of evidence, or a high likelihood of adverse outcomes are IV regional sympathetic blocks with anything but bretylium, sympathetic ganglion blocks with local anesthetics, systemic IV sympathetic inhibition, acupuncture, and sympathectomy (B).
In last issue of the Journal of Family Practice, we discussed diagnosis of CRPS type 1 (“Complex regional pain syndrome underdiagnosed,” 2005; 54: 524–532). Once other conditions have been ruled out, a primary care practitioner can diagnose CRPS type 1 right in the office using clinical findings and the patient’s report of symptoms. Similarly, primary care practitioners can provide most of the best treatments for CRPS type 1. In fact, evidence indicates that no benefit has been proven from more invasive treatments such as sympathectomy which continue to be included in recommendations by experts.1
Evidence for intervention less than compelling
A review of the literature on treating CRPS type 1 raises a question: is there any evidence that treatment makes a difference in outcomes that matter to patients, such as returning to work, regaining functionality of the affected limb, or resolution of pain? The large discrepancy between the high rates of CRPS type 1 documented in prospective studies of post-traumatic patients and the low rates of diagnosis of CRPS type 1 in actual practice suggests that most cases of CRPS type 1 resolve without being diagnosed and treated. This is not proven because, unfortunately, the natural history of persons diagnosed in the first 9 weeks after injury is not known.2
Are there benefits to early treatment?
From the clinician’s perspective, persons diagnosed with CRPS type 1 early appear more likely to respond to treatment. There is an “oft-quoted contention that results of early treatment will be better than those when the pain is treated late.”2 Yet, the great majority of these patients may have improved just as readily without treatment. For the few cases of undiagnosed CRPS type 1 that will persist to become chronic and treatment resistant, it is unknown whether early treatment would have been preventive2 or how clinicians could distinguish these cases early enough to target them for treatment.
Intriguing but limited data exist for using preventive therapies in all at-risk patients. One prospective cohort study documented a lower rate of CRPS type 1 in stroke patients who underwent early inpatient rehabilitation, compared with patients in earlier studies who rarely received early rehabilitation. This finding indirectly suggests a possible preventive effect of physical/occupational therapy (LOE: 3, cross-study comparison).3 Luckily, early inpatient rehabilitation in stroke patients has become the standard of care, which may prevent many cases of CRPS type 1 as a side effect.
It also appears that injury to a newly hemiplegic arm may contribute to the shoulder-hand syndrome; a study that alerted patients and care-takers to the risk of injury reduced the rate of shoulder hand syndrome from 27 to 8% (LOE: 2, lowerquality RCT).4 Among post-traumatic patients with wrist fracture, a double-blind randomized placebo controlled trial (n=115) of vitamin C 500 mg tabs initiated upon diagnosis of fracture and continued for 50 days resulted in a marked decrease of CRPS type 1 from 22% in the placebo group to 7% in the vitamin C group (relative risk=0.17) (LOE: 1, high-quality RCT).5 These results have not been tested in subsequent trials, however.
Guideline recommendations: Physical and psychological therapy, pain management
Many treatments for CRPS have been tried and are summarized without a systematic or evidence-based approach to the literature in a consensus statement released in 2002 by an interdisciplinary expert panel (LOE: 3, consensus guideline).1 These guidelines suggest rapid initiation of multidisciplinary treatment with advancement to higher levels of intervention if no benefit from initial therapy occurs in 2 weeks. Simultaneous physical rehabilitation, psychological therapy, and pain management are recommended.
Rehabilitation through physical therapy and occupational therapy starts with desensitization and stress loading, progresses to increasing flexibility with gentle active range of motion and stretching, and eventually to normalization of use.
Psychological therapy starts with teaching patients that 1) pain sensations in CRPS type 1 do not indicate tissue damage, and 2) reactivation of the affected limb is important. With persistent symptoms, clinical psychological assessment is recommended, eventually followed by cognitive behavioral therapy.
Pain management starts with oral or topical medications typically used for other neuropathic pain conditions (eg, amitriptyline (Elavil), gabapentin (Neurontin), opioids, and nonsteroidal antidepressants). The guideline also recommends steroids, calcitonin, and alpha-1 adrenoceptor antagonists (terazosin [Hytrin] or phenoxybenzamine [Dibenzylene]). With persistent symptoms, intravenous regional sympathetic blocks (IRSBs) and somatic nerve blocks are recommended. According to the guideline, treatment for resistant cases may progress to epidural catheters for sympathetic blockade, spinal cord stimulation, intrathecal baclofen (Lioresal), or sympathectomy.1
Reviews of medication trials show minimal effectiveness
Meta-analyses and systematic reviews of the literature reveal that many of the treatments recommended in the guidelines are minimally if at all effective, or have been inadequately researched.6-12 This is particularly so concerning invasive therapies such as sympathetic ganglion block,13 sympathectomy,12 and spinal cord stimulation9,10 that introduce the possibility of adverse effects. Yet, evidence is equally sparse for common pain therapies in CRPS type 1, such as nonsteroidal anti-inflammatory drugs, antidepressants, opiates, or antiseizure medications.
Systematic review and meta-analysis of medication trials for CRPS only partially agree.6-8,11 A 1999 systematic review concluded that oral corticosteroids demonstrated a consistent and long-term analgesic effect in CRPS.6 This review identified only limited data to suggest an analgesic effect from topical dimethylsulfoxide (DMSO), epidural clonidine and IRSB with ketanserin (not available in the US), and bretylium. The review concluded there was contradictory evidence of an analgesic effect from calcitonin or intravenous phentolamine and most likely no effect, and evidence against the effectiveness of guanethidine and reserpine IRSBs, and droperidol and atropine IRSBs.6
A 1995 systematic review of IRSBs concluded as well that overall there was no effect on pain, but a single RCT of each bretylium and ketanserin showed an analgesic effect.8 In a systematic review focused on upper extremity post-stroke CRPS (also known as shoulder-hand syndrome), 1 RCT was identified, and indicated that corticosteroids had an analgesic effect.11 High-quality evidence for the use of intramuscular calcitonin was lacking.11
Calcitonin may be one exception. A systematic review of medical treatment for CRPS type 1 identified 21 randomized trials, enough to undertake a statistical analysis of the analgesic effect of 4 types of treatment: sympathetic suppressors, guanethidine, intravenous regional blocks, and calcitonin.7 Of the 4, only calcitonin appeared to have a significant beneficial effect on pain.7
IV bisphosphonates show promise. More recently, intravenous bisphosphonates have demonstrated clinical and analgesic benefits in 2 small but high-quality RCTs.14,15 Strikingly, short-term therapy of 3 to 10 days of IV alendronate (Fosamax) or clodronate (Bonefos) without adverse effects resulted in significant overall improvements for the duration of the 2 trials, 4 weeks14 and 180 days.15
Nonpharmacologic treatments
Nonmedical treatments that have been studied include spinal cord stimulation, physical therapy, occupational therapy, and acupuncture. Spinal cord stimulation demonstrated a modest long-term (2-year) reduction in pain and improvement in health related quality of life in 1 RCT,16 but with no improvement in patient functioning and a 34% rate of adverse occurrences.9 Similarly, physical therapy and occupational therapy have been studied only in 1 large RCT (n=135).
Treatment with physical therapy did decrease pain compared with occupational therapy and control therapy,17 but revealed no improvement in active range of motion with physical or occupational therapy compared with control therapy.17 Furthermore, physical therapy led only to uncertain diminishment of impairment when data were analyzed in 2 different ways, 1 of which showed a benefit of physical and occupational therapy over control treatment,18 1 of which did not.19
Acupuncture demonstrated no improvement over sham treatment.20
Applying the evidence: Medical treatment
Choose any of the therapies least likely to do harm and supported by evidence of efficacy: topical 50% DMSO cream (SOR: B), intravenous bisphosphonates (SOR: A), or limited courses of oral corticosteroids (SOR: B). Despite some contradictory findings in the literature,6,17,18 other studies demonstrate that physical therapy18,19 and calcitonin7 reduce pain, and neither is likely to cause harm (SOR: B).
Epidural clonidine injection,6 IRSB with bretylium,6-8 and spinal cord stimulation9,16 have demonstrated some efficacy, but due to the invasiveness of the treatments and the modest benefits, patients should be counseled carefully before initiating these therapies (SOR: B) (TABLE 1).
Therapies to avoid. Therapies to avoid due to lack of evidence, lack of efficacy, or likelihood of adverse outcomes include IV regional blocks with everything but bretylium,6-8 sympathetic ganglion blocks with local anesthetics (very short duration of analgesia),13 systemic intravenous sympathetic inhibition,6 acupuncture,20 and sympathectomy (SOR: B).12
TABLE 1
Effectiveness of treatments for CRPS type 1
| TREATMENT | STUDY TYPE | STUDY QUALITY | EFFECT* |
|---|---|---|---|
| DMSO | SR6 | 2 – small RCT (n=32)21 | (+): Analgesia during therapy |
| Bisphosphonates | RCTs14,15 | 1 – multiple RCTs (n=32)15 and (n=20)14 | (+): Long-term (4 weeks14 to 180 days15) overall clinical improvement with significant analgesia |
| Corticosteroids | 2 SRs6,11 | 2 – 2 small RCTs, 1 in post-traumatic CRPS type 1 (n=23)22 and 1 (poor-quality) in shoulder-hand syndrome (n=36)3 | (+): 75% clinical improvement to 12 wk in CRPS type 1;22 and resolution of symptoms in shoulder-hand syndrome3 |
| Clonidine | SR6 | 2 – small RCT (n=26)23 | (+): Temporary analgesia |
| Spinal cord stimulation | SR9-11 | 2 – multiple SRs based on 1 RCT (n=36)16 | (+): Modest long-term (2-y)16 analgesic effect, improved health-related quality of life, no improvement in patient functioning and 34% rate of adverse occurrences9 |
| Physical therapy and occupational therapy | RCT17-19 | 1 – RCT (n=135) | (+/–): Contradictory analyses using different methods of measuring impairment, 1 showing no advantage of PT or OT over control,17 the other showing improvement with both.18 Significant improvement in pain at 1 y with PT over OT and control, no significant improvement in active ROM.19 |
| Calcitonin | SR6,7 | 1 – multiple RCTs24-26 | (+/–): Contradictory results – 1 SR indicating a significant analgesic effect7 the other suggesting no analgesic effect6 |
| IRSBs (bretylium, ketanserin, guanethidine, reserpine, droperidol, or atropine) | SR6-8 | 1 and 2 – Good-quality RCTs | (+/–): When collectively analyzed, no overall positive of guanethidine, otherwise effect.7,8 When evaluated by particular medication, small or poor quality RCTs limited evidence for analgesia with bretylium and ketanserin (not available in the US),6,8 and no analgesia with guanethidine, reserpine, droperidol and atropine6 |
| Sympathetic ganglion blocks (lidocaine/bupivacaine) | RCT13 | 2 – small RCT (n=7) | (+/–): Short-term analgesia with longer duration of pain control in treatment group (3.5 days) vs placebo (1 day) |
| Sympathectomy (chemical or surgical) | SR12 | 2 – SR based on poor-quality evidence, no placebo controlled RCTs | (+/–): No evidence of effectiveness, high rates (>10%) of adverse effects including worse pain, new neuropathic pain and pathological body sweating |
| Acupuncture (30 min 5x/wk for 3 wk | RCT20 | 2 – small RCT (n=14) | (–): Immediate and long-term (6-mo) clinical improvement and analgesia in sham/acupuncture treatment groups |
| Sympathetic inhibition | SR6 | 1 & 2 – variable-quality RCTs27-29 | (+/–): Contradictory results, with the best-designed study showing only a 9% short-term relief of pain28 |
| DOSAGES: DMSO: 50% cream applied 5x/d for at least 2 mo.21 | |||
| Bisphosphonates: IV alendronate 7.5 mg once daily for 3 days14 or intravenous clodronate 300 mg once daily for 10 days.15 | |||
| Calcitonin: intranasal 400 IU once daily26 or 100 IU 3 times daily27 or intramuscular 100 IU once daily for 3 weeks.28 | |||
| Corticosteroids: prednisone 10 mg 3 times daily until remission, max. up to 12 weeks,22 or prednisolone 32 mg daily for 2 wk with a 2-wk taper.4 | |||
| Clonidine: 300 μg epidural injection.23 | |||
| Sympathetic inhibition: IV phentolamine.27-29 | |||
| *Effect: (+) = positive, (+/–) = contradictory results or poor quality evidence, (–) = no effect. | |||
| SR, systematic review; MA, meta-analysis; RCT, randomized controlled trial; DMSO, dimethylsulfoxide; PT, physical therapy; OT, occupational therapy; ROM, range of motion. | |||
Acknowledgments
The authors would like to express their appreciation to Cheryl Mongillo, Peggy Lardear, and Brian Pellini for their assistance in preparing the manuscript, Dolores Moran and Diane Wolfe for their assistance in finding articles, and to Roger Rodrigue, MD for reviewing the manuscript. Funding for this project was provided by a grant from the Delaware Department of Health and Social Services, Division of Public Health.
CORRESPONDING AUTHOR
Anna Quisel, MD, c/o Cheryl Mongillo, Family Medicine Center, 1401 Foulk Road, Wilmington, DE 19803. E-mail: DrQuisel@comcast.net
- Treatments for CRPS type 1 supported by evidence of efficacy and little likelihood for harm are: topical DMSO cream (B), IV bisphosphonates (A) and limited courses of oral corticosteroids (B). Despite some contradictory evidence, physical therapy and calcitonin (intranasal or intramuscular) are likely to benefit patients with CRPS type 1 (B).
- Due to modest benefits and the invasiveness of the therapies, epidural clonidine injection, intravenous regional sympathetic block with bretylium and spinal cord stimulation should be offered only after careful counseling (B).
- Therapies to avoid due to lack of efficacy, lack of evidence, or a high likelihood of adverse outcomes are IV regional sympathetic blocks with anything but bretylium, sympathetic ganglion blocks with local anesthetics, systemic IV sympathetic inhibition, acupuncture, and sympathectomy (B).
In last issue of the Journal of Family Practice, we discussed diagnosis of CRPS type 1 (“Complex regional pain syndrome underdiagnosed,” 2005; 54: 524–532). Once other conditions have been ruled out, a primary care practitioner can diagnose CRPS type 1 right in the office using clinical findings and the patient’s report of symptoms. Similarly, primary care practitioners can provide most of the best treatments for CRPS type 1. In fact, evidence indicates that no benefit has been proven from more invasive treatments such as sympathectomy which continue to be included in recommendations by experts.1
Evidence for intervention less than compelling
A review of the literature on treating CRPS type 1 raises a question: is there any evidence that treatment makes a difference in outcomes that matter to patients, such as returning to work, regaining functionality of the affected limb, or resolution of pain? The large discrepancy between the high rates of CRPS type 1 documented in prospective studies of post-traumatic patients and the low rates of diagnosis of CRPS type 1 in actual practice suggests that most cases of CRPS type 1 resolve without being diagnosed and treated. This is not proven because, unfortunately, the natural history of persons diagnosed in the first 9 weeks after injury is not known.2
Are there benefits to early treatment?
From the clinician’s perspective, persons diagnosed with CRPS type 1 early appear more likely to respond to treatment. There is an “oft-quoted contention that results of early treatment will be better than those when the pain is treated late.”2 Yet, the great majority of these patients may have improved just as readily without treatment. For the few cases of undiagnosed CRPS type 1 that will persist to become chronic and treatment resistant, it is unknown whether early treatment would have been preventive2 or how clinicians could distinguish these cases early enough to target them for treatment.
Intriguing but limited data exist for using preventive therapies in all at-risk patients. One prospective cohort study documented a lower rate of CRPS type 1 in stroke patients who underwent early inpatient rehabilitation, compared with patients in earlier studies who rarely received early rehabilitation. This finding indirectly suggests a possible preventive effect of physical/occupational therapy (LOE: 3, cross-study comparison).3 Luckily, early inpatient rehabilitation in stroke patients has become the standard of care, which may prevent many cases of CRPS type 1 as a side effect.
It also appears that injury to a newly hemiplegic arm may contribute to the shoulder-hand syndrome; a study that alerted patients and care-takers to the risk of injury reduced the rate of shoulder hand syndrome from 27 to 8% (LOE: 2, lowerquality RCT).4 Among post-traumatic patients with wrist fracture, a double-blind randomized placebo controlled trial (n=115) of vitamin C 500 mg tabs initiated upon diagnosis of fracture and continued for 50 days resulted in a marked decrease of CRPS type 1 from 22% in the placebo group to 7% in the vitamin C group (relative risk=0.17) (LOE: 1, high-quality RCT).5 These results have not been tested in subsequent trials, however.
Guideline recommendations: Physical and psychological therapy, pain management
Many treatments for CRPS have been tried and are summarized without a systematic or evidence-based approach to the literature in a consensus statement released in 2002 by an interdisciplinary expert panel (LOE: 3, consensus guideline).1 These guidelines suggest rapid initiation of multidisciplinary treatment with advancement to higher levels of intervention if no benefit from initial therapy occurs in 2 weeks. Simultaneous physical rehabilitation, psychological therapy, and pain management are recommended.
Rehabilitation through physical therapy and occupational therapy starts with desensitization and stress loading, progresses to increasing flexibility with gentle active range of motion and stretching, and eventually to normalization of use.
Psychological therapy starts with teaching patients that 1) pain sensations in CRPS type 1 do not indicate tissue damage, and 2) reactivation of the affected limb is important. With persistent symptoms, clinical psychological assessment is recommended, eventually followed by cognitive behavioral therapy.
Pain management starts with oral or topical medications typically used for other neuropathic pain conditions (eg, amitriptyline (Elavil), gabapentin (Neurontin), opioids, and nonsteroidal antidepressants). The guideline also recommends steroids, calcitonin, and alpha-1 adrenoceptor antagonists (terazosin [Hytrin] or phenoxybenzamine [Dibenzylene]). With persistent symptoms, intravenous regional sympathetic blocks (IRSBs) and somatic nerve blocks are recommended. According to the guideline, treatment for resistant cases may progress to epidural catheters for sympathetic blockade, spinal cord stimulation, intrathecal baclofen (Lioresal), or sympathectomy.1
Reviews of medication trials show minimal effectiveness
Meta-analyses and systematic reviews of the literature reveal that many of the treatments recommended in the guidelines are minimally if at all effective, or have been inadequately researched.6-12 This is particularly so concerning invasive therapies such as sympathetic ganglion block,13 sympathectomy,12 and spinal cord stimulation9,10 that introduce the possibility of adverse effects. Yet, evidence is equally sparse for common pain therapies in CRPS type 1, such as nonsteroidal anti-inflammatory drugs, antidepressants, opiates, or antiseizure medications.
Systematic review and meta-analysis of medication trials for CRPS only partially agree.6-8,11 A 1999 systematic review concluded that oral corticosteroids demonstrated a consistent and long-term analgesic effect in CRPS.6 This review identified only limited data to suggest an analgesic effect from topical dimethylsulfoxide (DMSO), epidural clonidine and IRSB with ketanserin (not available in the US), and bretylium. The review concluded there was contradictory evidence of an analgesic effect from calcitonin or intravenous phentolamine and most likely no effect, and evidence against the effectiveness of guanethidine and reserpine IRSBs, and droperidol and atropine IRSBs.6
A 1995 systematic review of IRSBs concluded as well that overall there was no effect on pain, but a single RCT of each bretylium and ketanserin showed an analgesic effect.8 In a systematic review focused on upper extremity post-stroke CRPS (also known as shoulder-hand syndrome), 1 RCT was identified, and indicated that corticosteroids had an analgesic effect.11 High-quality evidence for the use of intramuscular calcitonin was lacking.11
Calcitonin may be one exception. A systematic review of medical treatment for CRPS type 1 identified 21 randomized trials, enough to undertake a statistical analysis of the analgesic effect of 4 types of treatment: sympathetic suppressors, guanethidine, intravenous regional blocks, and calcitonin.7 Of the 4, only calcitonin appeared to have a significant beneficial effect on pain.7
IV bisphosphonates show promise. More recently, intravenous bisphosphonates have demonstrated clinical and analgesic benefits in 2 small but high-quality RCTs.14,15 Strikingly, short-term therapy of 3 to 10 days of IV alendronate (Fosamax) or clodronate (Bonefos) without adverse effects resulted in significant overall improvements for the duration of the 2 trials, 4 weeks14 and 180 days.15
Nonpharmacologic treatments
Nonmedical treatments that have been studied include spinal cord stimulation, physical therapy, occupational therapy, and acupuncture. Spinal cord stimulation demonstrated a modest long-term (2-year) reduction in pain and improvement in health related quality of life in 1 RCT,16 but with no improvement in patient functioning and a 34% rate of adverse occurrences.9 Similarly, physical therapy and occupational therapy have been studied only in 1 large RCT (n=135).
Treatment with physical therapy did decrease pain compared with occupational therapy and control therapy,17 but revealed no improvement in active range of motion with physical or occupational therapy compared with control therapy.17 Furthermore, physical therapy led only to uncertain diminishment of impairment when data were analyzed in 2 different ways, 1 of which showed a benefit of physical and occupational therapy over control treatment,18 1 of which did not.19
Acupuncture demonstrated no improvement over sham treatment.20
Applying the evidence: Medical treatment
Choose any of the therapies least likely to do harm and supported by evidence of efficacy: topical 50% DMSO cream (SOR: B), intravenous bisphosphonates (SOR: A), or limited courses of oral corticosteroids (SOR: B). Despite some contradictory findings in the literature,6,17,18 other studies demonstrate that physical therapy18,19 and calcitonin7 reduce pain, and neither is likely to cause harm (SOR: B).
Epidural clonidine injection,6 IRSB with bretylium,6-8 and spinal cord stimulation9,16 have demonstrated some efficacy, but due to the invasiveness of the treatments and the modest benefits, patients should be counseled carefully before initiating these therapies (SOR: B) (TABLE 1).
Therapies to avoid. Therapies to avoid due to lack of evidence, lack of efficacy, or likelihood of adverse outcomes include IV regional blocks with everything but bretylium,6-8 sympathetic ganglion blocks with local anesthetics (very short duration of analgesia),13 systemic intravenous sympathetic inhibition,6 acupuncture,20 and sympathectomy (SOR: B).12
TABLE 1
Effectiveness of treatments for CRPS type 1
| TREATMENT | STUDY TYPE | STUDY QUALITY | EFFECT* |
|---|---|---|---|
| DMSO | SR6 | 2 – small RCT (n=32)21 | (+): Analgesia during therapy |
| Bisphosphonates | RCTs14,15 | 1 – multiple RCTs (n=32)15 and (n=20)14 | (+): Long-term (4 weeks14 to 180 days15) overall clinical improvement with significant analgesia |
| Corticosteroids | 2 SRs6,11 | 2 – 2 small RCTs, 1 in post-traumatic CRPS type 1 (n=23)22 and 1 (poor-quality) in shoulder-hand syndrome (n=36)3 | (+): 75% clinical improvement to 12 wk in CRPS type 1;22 and resolution of symptoms in shoulder-hand syndrome3 |
| Clonidine | SR6 | 2 – small RCT (n=26)23 | (+): Temporary analgesia |
| Spinal cord stimulation | SR9-11 | 2 – multiple SRs based on 1 RCT (n=36)16 | (+): Modest long-term (2-y)16 analgesic effect, improved health-related quality of life, no improvement in patient functioning and 34% rate of adverse occurrences9 |
| Physical therapy and occupational therapy | RCT17-19 | 1 – RCT (n=135) | (+/–): Contradictory analyses using different methods of measuring impairment, 1 showing no advantage of PT or OT over control,17 the other showing improvement with both.18 Significant improvement in pain at 1 y with PT over OT and control, no significant improvement in active ROM.19 |
| Calcitonin | SR6,7 | 1 – multiple RCTs24-26 | (+/–): Contradictory results – 1 SR indicating a significant analgesic effect7 the other suggesting no analgesic effect6 |
| IRSBs (bretylium, ketanserin, guanethidine, reserpine, droperidol, or atropine) | SR6-8 | 1 and 2 – Good-quality RCTs | (+/–): When collectively analyzed, no overall positive of guanethidine, otherwise effect.7,8 When evaluated by particular medication, small or poor quality RCTs limited evidence for analgesia with bretylium and ketanserin (not available in the US),6,8 and no analgesia with guanethidine, reserpine, droperidol and atropine6 |
| Sympathetic ganglion blocks (lidocaine/bupivacaine) | RCT13 | 2 – small RCT (n=7) | (+/–): Short-term analgesia with longer duration of pain control in treatment group (3.5 days) vs placebo (1 day) |
| Sympathectomy (chemical or surgical) | SR12 | 2 – SR based on poor-quality evidence, no placebo controlled RCTs | (+/–): No evidence of effectiveness, high rates (>10%) of adverse effects including worse pain, new neuropathic pain and pathological body sweating |
| Acupuncture (30 min 5x/wk for 3 wk | RCT20 | 2 – small RCT (n=14) | (–): Immediate and long-term (6-mo) clinical improvement and analgesia in sham/acupuncture treatment groups |
| Sympathetic inhibition | SR6 | 1 & 2 – variable-quality RCTs27-29 | (+/–): Contradictory results, with the best-designed study showing only a 9% short-term relief of pain28 |
| DOSAGES: DMSO: 50% cream applied 5x/d for at least 2 mo.21 | |||
| Bisphosphonates: IV alendronate 7.5 mg once daily for 3 days14 or intravenous clodronate 300 mg once daily for 10 days.15 | |||
| Calcitonin: intranasal 400 IU once daily26 or 100 IU 3 times daily27 or intramuscular 100 IU once daily for 3 weeks.28 | |||
| Corticosteroids: prednisone 10 mg 3 times daily until remission, max. up to 12 weeks,22 or prednisolone 32 mg daily for 2 wk with a 2-wk taper.4 | |||
| Clonidine: 300 μg epidural injection.23 | |||
| Sympathetic inhibition: IV phentolamine.27-29 | |||
| *Effect: (+) = positive, (+/–) = contradictory results or poor quality evidence, (–) = no effect. | |||
| SR, systematic review; MA, meta-analysis; RCT, randomized controlled trial; DMSO, dimethylsulfoxide; PT, physical therapy; OT, occupational therapy; ROM, range of motion. | |||
Acknowledgments
The authors would like to express their appreciation to Cheryl Mongillo, Peggy Lardear, and Brian Pellini for their assistance in preparing the manuscript, Dolores Moran and Diane Wolfe for their assistance in finding articles, and to Roger Rodrigue, MD for reviewing the manuscript. Funding for this project was provided by a grant from the Delaware Department of Health and Social Services, Division of Public Health.
CORRESPONDING AUTHOR
Anna Quisel, MD, c/o Cheryl Mongillo, Family Medicine Center, 1401 Foulk Road, Wilmington, DE 19803. E-mail: DrQuisel@comcast.net
1. Stanton-Hicks MD, Burton AW, Bruehl SP, et al. An updated interdisciplinary clinical pathway for CRPS: Report of an expert panel. Pain Practice 2002;2:1-16.
2. Commentary on RSD focus article Bandolier 2002. Available at:www.jr2.ox.ac.uk/bandolier/booth/painpag/wisdom/RSD.html.
3. Petchkrua W, Weiss DJ, Patel RR. Reassessment of the incidence of complex regional pain syndrome type 1 following stroke. Neurorehabil Neural Repair 2000;14:59-63.
4. Braus DF, Krauss JK, Strobel J. The shoulder-hand syndrome after stroke: a prospective clinical trial. Ann Neurol 1994;36:728-733.
5. Zollinger PE, Tuienebreijer WE, Kreis RW, Breederveld RS. Effect of vitamin C on frequency of reflex sympathetic dystrophy in wrist fractures: a randomised trial. Lancet 1999;354:2025-2028.
6. Kingery WS. A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes. Pain 1997;73:123-139.
7. Perez RS, Kwakkel G, Zuurmond WW, de Lange JJ. Treatment of reflex sympathetic dystrophy (CRPS type 1). a research synthesis of 21 randomized clinical trials. J Pain Symptom Manage 2001;21:511-526.
8. Jadad AR, Carroll D, Glynn CJ, McQuay HJ. Intravenous regional sympathetic blockade for pain relief in reflex sympathetic dystrophy: a systematic review and a randomized, double-blind crossover study. J Pain Symptom Manage 1995;10:13-20.
9. Turner JA, Loeser JD, Deyo RA, Sanders SB. Spinal cord stimulation for patients with failed back surgery syndrome or complex regional pain syndrome: a systematic review of effectiveness and complications. Pain 2004;108:137-147.
10. Grabow TS, Tella PK, Raja SN. Spinal cord stimulation for complex regional pain syndrome: an evidencebased medicine review of the literature. Clin J Pain 2003;19:371-383.
11. Geurts AC, Visschers BA, van Limbeek J, et al. Systematic review of aetiology and treatment of post-stroke hand oedma and shoulder-hand syndrome. Scan J Rehabil Med 2000;32:4-10.
12. Mailis A, Furlan A. Sympathectomy for neuropathic pain. Cochrane Database Syst Rev 2003;2.-
13. Price DD, Long S, Wilsey B, Rafii A. Analysis of peak magnitude and duration of analgesia produced by local anesthetics injected into sympathetic ganglia of complex regional pain syndrome patients. Clin J Pain 1998;14:216-226.
14. Adami S, Fossaluzza V, Gatti D, et al. Bisphosphonate therapy of reflex sympathetic dystrophy syndrome. Ann Rheum Dis 1997;56:201-204.
15. Varenna M, Zucchi F, Ghiringhelli D, et al. Intravenous clodronate in the treatment of reflex sympathetic dystrophy syndrome. A randomized double blind, placebo controlled study. J Rheumatol 2000;27:1477-1483.
16. Kemler MA, De Vet HC, Barendse GA, Van Den Wildenberg FA, Van Kleef M. The effect of spinal cord stimulation in patients with chronic reflex sympathetic dystrophy: two years’ follow-up of the randomized controlled trial. Ann Neurol 2004;55:13-18.
17. Oerlemans HM, Goris JA, de Boo T, Oostendorp RA. Do physical therapy and occupational therapy reduce the impairment percentage in reflex sympathetic dystrophy? Am J Phys Med Rehabil 1999;78:533-539.
18. Oerlemans HM, Oostendorp RA, de Boo T, van der Laan L, Severens JL, Goris JA. Adjuvant physical therapy versus occupational therapy in patients with reflex sympathetic dystrophy/complex regional pain syndrome type I. Arch Phys Med Rehabil 2000;81:49-56.
19. Oerlemans HM, Oostendorp RA, de Boo T, Goris RJ. Pain and reduced mobility in complex regional pain syndrome I: outcome of a prospective randomised controlled clinical trial of adjuvant physical therapy versus occupational therapy. Pain 1999;83:77-83.
20. Korpan MI, Dezu Y, Schneider B, Leitha T, Fialka-Moser V. Acupuncture in the treatment of posttraumatic pain syndrome. Acta Orthop Belg 1999;65:197-201.
21. Zuurmond WW, Langendijk PN, Bezemer PD, Brink HE, de Lange JJ, van loenen AC. Treatment of acute reflex sympathetic dystrophy with DMSO 50% in a fatty cream. Acta Anaesthesiol Scand 1996;40:364-367.
22. Christensen K, Jensen EM, Noer I. The reflex dystrophy syndrome response to treatment with systemic corticosteroids. Acta Chirurgica Scandinavica 1982;148:653-655.
23. Rauck RL, Eisenach JC, Jackson K, Young LD, Southern J. Epidural clonidine treatment for refractory reflex sympathetic dystrophy. Anesthesiology 1993;79:1163-1169.
24. Bickerstaff DR, Kanis JA. The use of nasal calcitonin in the treatment of post-traumatic algodystrophy. Br J Rheumatol 1991;30:291-294.
25. Gobelet C, Waldburger M, Meier JL. The effect of adding calcitonin to physical treatment on reflex sympathetic dystrophy. Pain 1992;48:171-175.
26. Gobelet C, Meier J, Schaffner W, et al. Calcitonin and reflex sympathetic dystrophy syndrome. Clin Rheumatol 1986;5:382-388.
27. Raja AN, Treed RD, Davis KD, Campbell JN. Systematic alpha-adrenergic blockade with phentolamine: a diagnostic test for sympathetically maintained pain. Anesthesiol 1991;74:691-698.
28. Verdugo RJ, Ochoa JL. Sympathetically maintained pain. I. Phentolamine block questions the concept. Neurology 1994;44:1003-1010.
29. Verdugo RJ, Campero M, Ochoa JL. Phentolamine sympathetic block in painful polyneuropathies. II. Further questioning of the concept of “sympathetically maintained pain.” Neurology 1994;44:1010-1014.
1. Stanton-Hicks MD, Burton AW, Bruehl SP, et al. An updated interdisciplinary clinical pathway for CRPS: Report of an expert panel. Pain Practice 2002;2:1-16.
2. Commentary on RSD focus article Bandolier 2002. Available at:www.jr2.ox.ac.uk/bandolier/booth/painpag/wisdom/RSD.html.
3. Petchkrua W, Weiss DJ, Patel RR. Reassessment of the incidence of complex regional pain syndrome type 1 following stroke. Neurorehabil Neural Repair 2000;14:59-63.
4. Braus DF, Krauss JK, Strobel J. The shoulder-hand syndrome after stroke: a prospective clinical trial. Ann Neurol 1994;36:728-733.
5. Zollinger PE, Tuienebreijer WE, Kreis RW, Breederveld RS. Effect of vitamin C on frequency of reflex sympathetic dystrophy in wrist fractures: a randomised trial. Lancet 1999;354:2025-2028.
6. Kingery WS. A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes. Pain 1997;73:123-139.
7. Perez RS, Kwakkel G, Zuurmond WW, de Lange JJ. Treatment of reflex sympathetic dystrophy (CRPS type 1). a research synthesis of 21 randomized clinical trials. J Pain Symptom Manage 2001;21:511-526.
8. Jadad AR, Carroll D, Glynn CJ, McQuay HJ. Intravenous regional sympathetic blockade for pain relief in reflex sympathetic dystrophy: a systematic review and a randomized, double-blind crossover study. J Pain Symptom Manage 1995;10:13-20.
9. Turner JA, Loeser JD, Deyo RA, Sanders SB. Spinal cord stimulation for patients with failed back surgery syndrome or complex regional pain syndrome: a systematic review of effectiveness and complications. Pain 2004;108:137-147.
10. Grabow TS, Tella PK, Raja SN. Spinal cord stimulation for complex regional pain syndrome: an evidencebased medicine review of the literature. Clin J Pain 2003;19:371-383.
11. Geurts AC, Visschers BA, van Limbeek J, et al. Systematic review of aetiology and treatment of post-stroke hand oedma and shoulder-hand syndrome. Scan J Rehabil Med 2000;32:4-10.
12. Mailis A, Furlan A. Sympathectomy for neuropathic pain. Cochrane Database Syst Rev 2003;2.-
13. Price DD, Long S, Wilsey B, Rafii A. Analysis of peak magnitude and duration of analgesia produced by local anesthetics injected into sympathetic ganglia of complex regional pain syndrome patients. Clin J Pain 1998;14:216-226.
14. Adami S, Fossaluzza V, Gatti D, et al. Bisphosphonate therapy of reflex sympathetic dystrophy syndrome. Ann Rheum Dis 1997;56:201-204.
15. Varenna M, Zucchi F, Ghiringhelli D, et al. Intravenous clodronate in the treatment of reflex sympathetic dystrophy syndrome. A randomized double blind, placebo controlled study. J Rheumatol 2000;27:1477-1483.
16. Kemler MA, De Vet HC, Barendse GA, Van Den Wildenberg FA, Van Kleef M. The effect of spinal cord stimulation in patients with chronic reflex sympathetic dystrophy: two years’ follow-up of the randomized controlled trial. Ann Neurol 2004;55:13-18.
17. Oerlemans HM, Goris JA, de Boo T, Oostendorp RA. Do physical therapy and occupational therapy reduce the impairment percentage in reflex sympathetic dystrophy? Am J Phys Med Rehabil 1999;78:533-539.
18. Oerlemans HM, Oostendorp RA, de Boo T, van der Laan L, Severens JL, Goris JA. Adjuvant physical therapy versus occupational therapy in patients with reflex sympathetic dystrophy/complex regional pain syndrome type I. Arch Phys Med Rehabil 2000;81:49-56.
19. Oerlemans HM, Oostendorp RA, de Boo T, Goris RJ. Pain and reduced mobility in complex regional pain syndrome I: outcome of a prospective randomised controlled clinical trial of adjuvant physical therapy versus occupational therapy. Pain 1999;83:77-83.
20. Korpan MI, Dezu Y, Schneider B, Leitha T, Fialka-Moser V. Acupuncture in the treatment of posttraumatic pain syndrome. Acta Orthop Belg 1999;65:197-201.
21. Zuurmond WW, Langendijk PN, Bezemer PD, Brink HE, de Lange JJ, van loenen AC. Treatment of acute reflex sympathetic dystrophy with DMSO 50% in a fatty cream. Acta Anaesthesiol Scand 1996;40:364-367.
22. Christensen K, Jensen EM, Noer I. The reflex dystrophy syndrome response to treatment with systemic corticosteroids. Acta Chirurgica Scandinavica 1982;148:653-655.
23. Rauck RL, Eisenach JC, Jackson K, Young LD, Southern J. Epidural clonidine treatment for refractory reflex sympathetic dystrophy. Anesthesiology 1993;79:1163-1169.
24. Bickerstaff DR, Kanis JA. The use of nasal calcitonin in the treatment of post-traumatic algodystrophy. Br J Rheumatol 1991;30:291-294.
25. Gobelet C, Waldburger M, Meier JL. The effect of adding calcitonin to physical treatment on reflex sympathetic dystrophy. Pain 1992;48:171-175.
26. Gobelet C, Meier J, Schaffner W, et al. Calcitonin and reflex sympathetic dystrophy syndrome. Clin Rheumatol 1986;5:382-388.
27. Raja AN, Treed RD, Davis KD, Campbell JN. Systematic alpha-adrenergic blockade with phentolamine: a diagnostic test for sympathetically maintained pain. Anesthesiol 1991;74:691-698.
28. Verdugo RJ, Ochoa JL. Sympathetically maintained pain. I. Phentolamine block questions the concept. Neurology 1994;44:1003-1010.
29. Verdugo RJ, Campero M, Ochoa JL. Phentolamine sympathetic block in painful polyneuropathies. II. Further questioning of the concept of “sympathetically maintained pain.” Neurology 1994;44:1010-1014.
Complex regional pain syndrome underdiagnosed
- Complex regional pain syndrome (CRPS) type 1 may be diagnosed by history and physical exam with no further testing (B). Several different diagnostic criteria have undergone validity testing: the 1993 IASP criteria, Bruehl’s criteria, and Veldman’s criteria; there is no compelling reason to recommend 1 set of criteria over the others (C).
- Some cases of CRPS type 1 may be preventable. Some cases of CRPS type 1 in post-stroke upper extremity hemiplegia (also known as shoulder-hand syndrome) may be prevented by early inpatient rehabilitation (C) and avoidance of shoulder trauma to the affected arm (B). Some cases of post-fracture CRPS type 1 may be prevented with 500 mg vitamin C daily started upon diagnosis of fracture and continued through healing (B).
Do you have a patient recovering from a limb fracture who is complaining of pain and tenderness long after most patients with a similar injury would be symptom free? The problem may be an under-recognized one—complex regional pain syndrome (CRPS) type 1, also known as reflex sympathetic dystrophy. The problem is also encountered in immobilized limbs of post-stroke patients.
Persons with persistent post-traumatic pain eventually diagnosed with CRPS type 1 often undergo unnecessary testing resulting in inappropriate or delayed treatment.1
Signs and symptoms typical of CRPS type 1 can also occur transiently with a normally recovering immobilized limb,2,3 so diagnosis of CRPS type 1 is based on increasing severity and duration of signs and symptoms (level of evidence [LOE]: 3; consensus guidelines)4:
- pain
- hyperalgesia/allodynia (pain or exaggerated response resulting from a normally painless or only slightly painful stimulus)
- joint stiffness
- swelling
- autonomic abnormalities (often sweating and temperature differences compared with the unaffected limb).
Diagnosis: Watch recovery course over first 9 weeks
Clinicians face a number of challenges in diagnosing CRPS type 1. No psychological or personality traits appear to predispose to CRPS type 1 (LOE: 2, lower-quality literature review).5 Fracture types and severity of injury among persons who develop CRPS type 1 are not significantly different from persons who recover normally (LOE: 2, case control studies).6,7 The key is to remain alert to deviation from the normal course of recovery.
Studies have shown that 9 weeks post injury, persons with persistent pain, tenderness, swelling, joint stiffness (fingers and wrist), and sweating or temperature changes in the injured limb may have CRPS type 1 (LOE: 2, case series and case control studies).6,8 In a prospective case series (n=109), no new cases of CRPS type 1 developed beyond 9 weeks (LOE: 2, case series).8
Diagnostic criteria: No consensus
No one test identifies all persons with CRPS type 1. There is no objective gold standard for diagnosis.9 Instead, researchers and clinicians must rely on clinically derived diagnostic criteria. Unfortunately, despite the development of diagnostic criteria by the IASP in 1994 (TABLE 1),4 experts have not reached consensus on the best method of diagnosis, and several different sets of diagnostic criteria are used.7,10
Initial IASP criteria.Of these, the 1994 IASP consensus-based diagnostic criteria appear to be most widely used in the litera- ture. These criteria were intended as a starting point, requiring validation through future clinical research.4,11 In further studies using controls with neuropathic conditions, IASP criteria have demonstrated low specificity (TABLE 2 ).11,12
The diagnosis of CRPS type I is often missed,1,29,30so it is likely that the diagnosis rate per population of 0.02% reported in a recent population based study is an underestimate of the actual prevalence.31 After distal radial fracture, rates of CRPS type I have varied widely in reports, from 0.9% 32 to 15% 33 to 28%.34 After tibial shaft fracture, Sarangi et al 35 reported that 30% of persons developed CRPS type I.
In cases of post-stroke hemiplegia, CRPS type I has been reported in the paralyzed arm at rates between 25% 36 and 40%.37 However, in a more recent study among stroke patients in the US who underwent early inpatient rehabilitation, Petchkrua et al reported a lower incidence of about 2%.38 Impairment can be severe among persons with persistent CRPS type 1. A prospective study revealed that activities of daily living were significantly impaired in 62% of persons with chronic CRPS type 1.39
Criteria refinements.Derived from 1 of these studies, Bruehl’s criteria were subsequently developed to improve the IASP criteria (TABLE 1).11Several other sets of diagnostic criteria exist, but only Veldman’s criteria ( TABLE 1),13 which have been adopted as the standard in the Netherlands, have undergone further study.14 Studies of Bruehl’s and IASP criteria have measured specificity and sensitivity, and along with Veldman’s criteria, interobserver reliability (TABLE 2 ).11,12,14,15 However, these numbers must be interpreted with care due to the absence of an objective and independent gold standard.
The absence of an objective gold standard does not mean CRPS type 1 is not a “real” disorder.12 In developing diagnostic criteria for CRPS, the IASP turned to models developed for other conditions without objectively measurable findings: the International Headache Society (IHS) classification and the Diagnostic and Statistical Manual of Mental Disorders (DSM). These descriptive systems are based largely on history and self-reported symptoms rather than on clinical signs and laboratory tests. The accuracy of these types of diagnostic criteria is refined over time, through repeated, controlled validation studies using the best means available.11
Specificity of criteria. Specificity has been tested using controls with neuro-pathic conditions.11,12 In these studies, nonblinded clinicians applied CRPS type 1 diagnostic criteria, except the exclusion criterion, to patients who had either CRPS type 1 or neuropathic pain from other causes. Many persons with peripheral neuropathy met criteria for CRPS type 1. However, as stated in the IASP criteria, the diagnosis of CRPS type 1 is not considered until common causes of neuropathic pain and post-traumatic limb pain have been excluded.4 As long as the primary care provider considers and rules out other causes of pain, the clinically relevant specificity of these criteria is likely much higher.
Sensitivity of criteria varies.The sensitivity in these studies is based on a non-independent reference standard. Patients with CRPS type 1 were chosen for these studies using clinical criteria, and these criteria were reapplied by study clinicians to determine sensitivity.11,12 This method does not allow any determination of whether cases of CRPS type 1 might be missed by the criteria. Sensitivity measured in this way more closely resembles interobserver reliability—the likelihood that different clinicians using the same diagnostic criteria will reach the same diagnosis— and it appears quite good, especially for IASP criteria, in these 2 studies.11,12
However, when interobserver reliability has been directly studied, albeit in small studies of 3 and 6 observers, only Veldman’s criteria achieve good reliability; IASP and Bruehl’s criteria appear unreliable ( TABLE 3).15,16 However, IASP and Bruehl’s criteria do fall within the range of reliability of other clinical assessments including medical fitness for a job and shoulder disorders.15
TABLE 1
Diagnostic criteria for CRPS type 1*
| NAME | CRITERIA |
|---|---|
| IASP 1994 consensus criteria4 | Criteria 2, 3 and 4 are necessary for a diagnosis of CRPS type 1.10
|
| Bruehl’s criteria: IASP-family11 |
|
| Veldman’s criteria13 |
|
| *IASP definition of CRSP 1: A variety of painful conditions following injury which appears regionally having a distal predominance of abnormal findings, exceeding in both magnitude and duration the expected clinical course of the inciting event and often resulting in significant impairment of motor function, and showing variable progression over time. (All 3 criteria sets use this definition.) | |
TABLE 2
Accuracy of diagnostic criteria for CRPS type 1
| CRITERIA TESTED | STUDY OF ACCURACY | STUDY QUALITY | CONTROL GROUP | SN | SP | LR+ | LR- | PV+ | PV- |
|---|---|---|---|---|---|---|---|---|---|
| IASP | Bruehl et al, 199911 | 3 (non-indep. ref. standard | Patients with diabetic neuropathy, polyneuropathy, postherpetic neuralgia, and radiculopathy | 98% | 36% | 1.5 | 0.1 | 0.21 | 0.99 |
| IASP | Galer et al, 199812 | 3 (non-indep. ref. standard) | Patients with diabetic neuropathy | 100% | 55% | 2.2 | 0 | 0.28 | 1.0 |
| Bruehl’s | Bruehl et al, 199911 | 3 (non-indep. ref. standard) | Patients with diabetic neuropathy, polyneuropathy, postherpetic neuralgia and radiculopathy | 70% | 94% | 12 | 0.3 | 0.67 | 0.94 |
| Sn, sensitivity; Sp, specificity; LR+, positive likelihood ratio; LR-, negative likelihood ratio; PV+, positive predictive value (probability of disease given a positive test); PV-, negative predictive value (probability of disease given a negative test). PV+ and PV- assume baseline likelihood of disease of 15%. | |||||||||
TABLE 3
Interobserver reliability of diagnostic criteria for CRPS type 1
| DIAGNOSTIC CRITERIA TESTED | STUDY QUALITY | STUDY SIZE | INTEROBSERVER RELIABILITY |
|---|---|---|---|
| IASP15 | 2 (small cohort study) | 6 diagnosticians | Poor |
| Bruehl’s15 | 2 (small cohort study) | 6 diagnosticians | Borderline moderate |
| Veldman’s16 | 2 (small cohort study) | 3 diagnosticians | Good |
Factors undermining objective evaluation
Despite clinically based diagnostic criteria, researchers and physicians continue to use office, laboratory, and radiographic tests to diagnose CRPS type 1,1,10 perhaps in an attempt to provide a more objective basis for the diagnosis. However, the evaluation of these methods has been plagued by difficulties.
First, because current clinical diagnostic criteria are not yet optimized or even standardized in the literature, there is no gold standard by which to measure the accuracy of these tests.
Second, patients in different studies have been diagnosed with CRPS type 1 by varying criteria.
Third, CRPS type 1 presents differently in different people, and symptoms and signs vary over time in the same person. As a result, the sets of diagnostic criteria have been designed with various clinical findings, and CRPS patients may meet only a few at any one time.
For example, if a group of CRPS type 1 patients were tested for sweating abnormalities, only 24% at best might be expected to test positive (see TABLE 4 for representative frequency of symptoms and signs),17 resulting in an apparent sensitivity of 24% for sweating abnormalities. This is why it is important for clinicians to consider patients’ report of typical signs even when these signs are not present on exam when making a diagnosis of CRPS type 1.
TABLE 4
Frequency of symptoms and clinically observed signs in CRPS type 1
| Variables | SIGNS (%) | Symptoms (%) |
|---|---|---|
| Allodynia | 74 | — |
| Decreased range of motion | 70 | 80 |
| Color changes | 66 | 87 |
| Hyperalgesia | 63 | — |
| Temperature asymmetry | 56 | 79 |
| Edema | 56 | 80 |
| Weakness | 56 | 75 |
| Sweating changes | 24 | 53 |
| Skin changes | 20 | 24 |
| Dystonia | 14 | 20 |
| Nail changes | 9 | 21 |
| Hair changes | 9 | 19 |
| Tremor | 9 | 24 |
| Hyperesthesia | — | 65 |
| “Burning” pain | — | 81 |
| By exam or report in patients meeting IASP criteria for CRPS, adapted from Harden et al, 1999.17 | ||
Diagnostic instrumentation adds little
Some investigators have tried using instruments to measure the clinically apparent signs included in diagnostic criteria— volumetry to measure edema, thermometry to measure skin temperature differences, and resting sweat output (RSO) to measure sweating.
Confounding nature of CRPS 1. The value of these tests is limited by factors such as the duration of CRPS type 1, time of day, relaxation of the subject, ambient temperature, body temperature, and exact placement of the measuring device,18,19 so it is not clear that objective measurement is practical or adds precision. In fact, in a study comparing testing to clinical diagnosis, instrumentation added little to the overall accuracy of diagnosing CRPS type 1 (LOE: 2, prospective cohort study).14
Sympathetic nerve block unhelpful. Other investigators have focused on testing to improve or replace clinical diagnostic criteria. Although at one time a response to sympathetic block was considered diagnostic for CRPS type 1,4 subsequent studies have demonstrated there is a significant placebo response to sympathetic block, that many persons with CRPS type 1 do not respond, and that some persons with other neuropathic pain conditions do respond. A negative or positive response to sympathetic block cannot rule CRPS type 1 in or out (LOE: 2, systematic reviews with only a few high-quality studies).20-22
Radiographic findings add nothing. Bone scanning (scintigraphy) and radiography have been used frequently in the diagnosis of CRPS type 1. Although 3phase scintigraphy looking for different uptake of radioisotope between affected and unaffected limbs has been touted as an objective and definitive test for CRPS type 1,23 this method also suffers from the subjective interpretation of the radiologist and poor interobserver reliability.24 Researchers disagree on whether the typical appearance on scintigraphy is periarticular cuffing 25,26 or diffuse uptake of radioisotope,27 and about whether delayed phase scintigraphy is adequate 26 or whether 3-phase scintigraphy is necessary.27
To make the interpretation of these scans more objective, quantitative analysis of bone scans has been undertaken; however, subjective interpretation was required to decide where to measure the uptake and what degree of difference between affected and unaffected limbs was considered positive for CRPS type 1.27
In 1 study, without mention of whether the radiologist was blinded but using an appropriate post-traumatic control group, sensitivity of 80% and specificity of 80% were reported (LOE: 2, casecontrol design).27 In a cohort of persons with upper extremity pain, also without mention of blinding, sensitivity of 73% and specificity of 86% were reported (LOE: 2, cohort design).25 Using normal controls, not a clinically relevant comparison, sensitivity of 97% and specificity of 86% using bone scans have been reported (LOE: 2, case control design).26
Despite the reasonable sensitivity and specificity of the bone scans in these studies, clinical assessment was used as the gold standard for diagnosis and the bone scans did not add any degree of accuracy to that clinical assessment. Based on these studies, clinicians using a bone scan to rule in or rule out CRPS type 1 instead of using a clinical assessment risk missing up to 27% of cases and over-diagnosing 20% of cases.
Older literature suggested that osteopenia/porosis demonstrated on plain radiography or dual energy x-ray absorptiometry (DEXA) scanning was important for the diagnosis of CRPS type 1, but more recent studies have revealed sensitivity for plain radiography as low as 23% (LOE: 2, exploratory cohort study with good reference standards)13 and for DEXA a sensitivity of 76% (LOE: 2, case-control design).28 No studies were identified that used a control group post-trauma, so an adequate assessment of specificity has not been made.
Applying the evidence in practice
CRPS type 1 is often relegated to specialists. But, in fact, no special equipment or testing is required for the diagnosis of CRPS type 1, and the best treatments appear to be non-invasive and completely within the realm of family medicine.
With more attention to deviations from the normal course of recovery from trauma, the family physician will begin to recognize more cases of CRPS type 1 and can have full confidence that the treatments prescribed and monitored are in fact the treatments of choice.
Preventing CRPS 1
For persons with hemiplegia, and of course early inpatient rehabilitation of post-stroke patients with upper extremity hemiplegia. Give 500 mg of vitamin C daily to post-fracture patients in the hope of preventing CRPS type 1 (SOR: B).
Researchers have been unable to identify the underlying pathophysiology for CRPS type 1, perhaps in part because patients with different pathophysiologies may present with similar clinical findings.9 Recent discovery of an HLA linkage suggests that there may be a genetic predisposition to CRPS type 1.40
By definition, in CRPS type 1 no major nerve damage can be detected, but there may be damage to nerve fibers too small to detect on electromyograph. Research suggests that injured peripheral C-fibers and A-delta pain fibers immediately flood the central nervous system (CNS) with neurochemicals via the dorsal root ganglion and central pain projecting neurons of the CNS. The CNS is pathologically altered and sends signals to the injured area that serve to maintain the clinical signs and symptoms of CRPS type 1: peripheral pain and sensory changes, local sympathetic changes in blood vessels and sweat glands, and local motor changes.9 Abnormal sympathetic activity can be clearly demonstrated, but there is no evidence to suggest that this is the cause of CRSP type 1.41
Base evaluation on history and physical exam
More often, the family physician will be in the position of evaluating persistent post-traumatic pain. Given the absence of compelling evidence in the literature, rely on your experience to guide the work up.
To diagnose CRPS type 1, first rule out other diseases (FIGURE).4 The frequency with which other conditions occur in persons at risk for CRPS type 1 is not known because the research concerning CRPS type 1 has been undertaken in specialty care clinics; primary care physicians had already done the work of excluding many other disorders.
Physical diagnosis. The differential diagnosis for limb pain is extensive and includes fracture non-union, tendonitis, diabetic neuropathy,4 osteomyelitis or cellulitis,13 polyneuropathy, radiculopathy,11 phlebothrombosis,13 and Raynaud’s disease.13 Physical exam will reveal signs of infection, focal tenderness consistent with tendonitis, erythema suggestive of cellulitis, a distribution of pain following a nerve suggestive of radiculopathy or carpal tunnel syndrome, or the stocking-glove distribution diabetic neuropathy.
Auxiliary testing. Limited testing may be helpful. Plain radiography or bone scanning may identify a poorly healed fracture or other bony lesions. A white blood cell count and inflammatory markers may identify infection or autoimmune disorders.
Using the diagnostic criteria. Once other disorders have been ruled out, evidence does support the diagnosis of CRPS type 1 based on history and physical exam without further testing (SOR: B). In the absence of clear evidence supporting 1 set of criteria over the others, clinicians may use IASP, Bruehl’s, or Veldman’s clinical criteria for diagnosis (SOR: C). While the IASP criteria are nonspecific and possibly not as reproducible as Bruehl’s or Veldman’s criteria, they are cited more widely the literature including treatment trials. The criteria (FIGURE) can also be combined to encompass their complementary aspects (SOR: C, this author’s opinion).
CRPS has historically been described as comprising 2 distinct subtypes: type 1, also known as reflex sympathetic dystrophy, in which nerve damage is not detectable, and type 2, also known as causalgia, in which nerve damage can be detected by electromyograph (EMG) but pain is not confined to the distribution of that nerve.4 However, the clinical relevance of distinguishing the 2 types of CRPS has not been proven. Although the mechanism of pain is hypothesized to be different, thus far the 2 syndromes appear to be clinically similar (LOE: 2, case-control study).11 Many, but not all, recent articles on treatment of CRPS combine types 1 and 2 in their subject populations. Yet, because CRPS types 1 and 2 have not yet been officially merged and because some researchers continue to make the distinction in studies, this paper will focus on CRPS type 1.
The nature of, diagnostic criteria for, and even the naming of CRPS have been controversial. In 1995 the International Association for the Study of Pain (IASP) recommended abandoning the commonly used term reflex sympathetic dystrophy because: 1) the existence of a “reflex” is questionable, 2) “sympathetic” or autonomic changes may not be causative, and 3) “dystrophy” is rare.4 Despite this recommendation, a review of the literature 5 years later revealed that the terms reflex sympathetic dystrophy and causalgia are still commonly used, along with algodystrophy, shoulder-hand syndrome, Sudeck’s atrophy, and transient osteoporosis.42
ACKNOWLEDGMENTS
The authors would like to express their appreciation to Cheryl Mongillo, Peggy Lardear, and Brian Pellini for their assistance in preparing the manuscript, Dolores Moran and Diane Wolfe for their assistance in finding articles, and to Roger Rodrigue, MD for reviewing the manuscript. Funding for this project was provided by a grant from the Delaware Department of Health and Social Services, Division of Public Health.
CORRESPONDING AUTHOR
Anna Quisel, MD, Anna Quisel, MD, c/o Cheryl Mongillo, Family Medicine Center, 1401 Foulk Road, Wilmington, DE 19803. E-mail: bretandanna@comcast.net.
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16. Perez RS, Burm PE, Zuurmond WW, et al. Interrater reliability of diagnosing complex regional pain syndrome type I. Acta Anaesthesiologica Scandinavica 2002;46:447-450.
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18. Wasner G, Schattschneider J, Baron R. Skin temperature side differences—a diagnostic tool for CRPS? Pain 2002;98:19-26.
19. Sandroni P, Low PA, Ferrer T, Opfer-Gehrking TL, Willner CL, Wilson PR. Complex regional pain syndrome I (CRPS I): prospective study and laboratory evaluation. Clin J Pain 1998;14:282-289.
20. Kingery WS. A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes. Pain 1997;73:123-139.
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22. Cepeda MS, Lau J, Carr DB. Defining the therapeutic role of local anesthetic sympathetic blockade in complex regional pain syndrome: a narrative and systematic review. Clin J Pain 2002;18:216-233.
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- Complex regional pain syndrome (CRPS) type 1 may be diagnosed by history and physical exam with no further testing (B). Several different diagnostic criteria have undergone validity testing: the 1993 IASP criteria, Bruehl’s criteria, and Veldman’s criteria; there is no compelling reason to recommend 1 set of criteria over the others (C).
- Some cases of CRPS type 1 may be preventable. Some cases of CRPS type 1 in post-stroke upper extremity hemiplegia (also known as shoulder-hand syndrome) may be prevented by early inpatient rehabilitation (C) and avoidance of shoulder trauma to the affected arm (B). Some cases of post-fracture CRPS type 1 may be prevented with 500 mg vitamin C daily started upon diagnosis of fracture and continued through healing (B).
Do you have a patient recovering from a limb fracture who is complaining of pain and tenderness long after most patients with a similar injury would be symptom free? The problem may be an under-recognized one—complex regional pain syndrome (CRPS) type 1, also known as reflex sympathetic dystrophy. The problem is also encountered in immobilized limbs of post-stroke patients.
Persons with persistent post-traumatic pain eventually diagnosed with CRPS type 1 often undergo unnecessary testing resulting in inappropriate or delayed treatment.1
Signs and symptoms typical of CRPS type 1 can also occur transiently with a normally recovering immobilized limb,2,3 so diagnosis of CRPS type 1 is based on increasing severity and duration of signs and symptoms (level of evidence [LOE]: 3; consensus guidelines)4:
- pain
- hyperalgesia/allodynia (pain or exaggerated response resulting from a normally painless or only slightly painful stimulus)
- joint stiffness
- swelling
- autonomic abnormalities (often sweating and temperature differences compared with the unaffected limb).
Diagnosis: Watch recovery course over first 9 weeks
Clinicians face a number of challenges in diagnosing CRPS type 1. No psychological or personality traits appear to predispose to CRPS type 1 (LOE: 2, lower-quality literature review).5 Fracture types and severity of injury among persons who develop CRPS type 1 are not significantly different from persons who recover normally (LOE: 2, case control studies).6,7 The key is to remain alert to deviation from the normal course of recovery.
Studies have shown that 9 weeks post injury, persons with persistent pain, tenderness, swelling, joint stiffness (fingers and wrist), and sweating or temperature changes in the injured limb may have CRPS type 1 (LOE: 2, case series and case control studies).6,8 In a prospective case series (n=109), no new cases of CRPS type 1 developed beyond 9 weeks (LOE: 2, case series).8
Diagnostic criteria: No consensus
No one test identifies all persons with CRPS type 1. There is no objective gold standard for diagnosis.9 Instead, researchers and clinicians must rely on clinically derived diagnostic criteria. Unfortunately, despite the development of diagnostic criteria by the IASP in 1994 (TABLE 1),4 experts have not reached consensus on the best method of diagnosis, and several different sets of diagnostic criteria are used.7,10
Initial IASP criteria.Of these, the 1994 IASP consensus-based diagnostic criteria appear to be most widely used in the litera- ture. These criteria were intended as a starting point, requiring validation through future clinical research.4,11 In further studies using controls with neuropathic conditions, IASP criteria have demonstrated low specificity (TABLE 2 ).11,12
The diagnosis of CRPS type I is often missed,1,29,30so it is likely that the diagnosis rate per population of 0.02% reported in a recent population based study is an underestimate of the actual prevalence.31 After distal radial fracture, rates of CRPS type I have varied widely in reports, from 0.9% 32 to 15% 33 to 28%.34 After tibial shaft fracture, Sarangi et al 35 reported that 30% of persons developed CRPS type I.
In cases of post-stroke hemiplegia, CRPS type I has been reported in the paralyzed arm at rates between 25% 36 and 40%.37 However, in a more recent study among stroke patients in the US who underwent early inpatient rehabilitation, Petchkrua et al reported a lower incidence of about 2%.38 Impairment can be severe among persons with persistent CRPS type 1. A prospective study revealed that activities of daily living were significantly impaired in 62% of persons with chronic CRPS type 1.39
Criteria refinements.Derived from 1 of these studies, Bruehl’s criteria were subsequently developed to improve the IASP criteria (TABLE 1).11Several other sets of diagnostic criteria exist, but only Veldman’s criteria ( TABLE 1),13 which have been adopted as the standard in the Netherlands, have undergone further study.14 Studies of Bruehl’s and IASP criteria have measured specificity and sensitivity, and along with Veldman’s criteria, interobserver reliability (TABLE 2 ).11,12,14,15 However, these numbers must be interpreted with care due to the absence of an objective and independent gold standard.
The absence of an objective gold standard does not mean CRPS type 1 is not a “real” disorder.12 In developing diagnostic criteria for CRPS, the IASP turned to models developed for other conditions without objectively measurable findings: the International Headache Society (IHS) classification and the Diagnostic and Statistical Manual of Mental Disorders (DSM). These descriptive systems are based largely on history and self-reported symptoms rather than on clinical signs and laboratory tests. The accuracy of these types of diagnostic criteria is refined over time, through repeated, controlled validation studies using the best means available.11
Specificity of criteria. Specificity has been tested using controls with neuro-pathic conditions.11,12 In these studies, nonblinded clinicians applied CRPS type 1 diagnostic criteria, except the exclusion criterion, to patients who had either CRPS type 1 or neuropathic pain from other causes. Many persons with peripheral neuropathy met criteria for CRPS type 1. However, as stated in the IASP criteria, the diagnosis of CRPS type 1 is not considered until common causes of neuropathic pain and post-traumatic limb pain have been excluded.4 As long as the primary care provider considers and rules out other causes of pain, the clinically relevant specificity of these criteria is likely much higher.
Sensitivity of criteria varies.The sensitivity in these studies is based on a non-independent reference standard. Patients with CRPS type 1 were chosen for these studies using clinical criteria, and these criteria were reapplied by study clinicians to determine sensitivity.11,12 This method does not allow any determination of whether cases of CRPS type 1 might be missed by the criteria. Sensitivity measured in this way more closely resembles interobserver reliability—the likelihood that different clinicians using the same diagnostic criteria will reach the same diagnosis— and it appears quite good, especially for IASP criteria, in these 2 studies.11,12
However, when interobserver reliability has been directly studied, albeit in small studies of 3 and 6 observers, only Veldman’s criteria achieve good reliability; IASP and Bruehl’s criteria appear unreliable ( TABLE 3).15,16 However, IASP and Bruehl’s criteria do fall within the range of reliability of other clinical assessments including medical fitness for a job and shoulder disorders.15
TABLE 1
Diagnostic criteria for CRPS type 1*
| NAME | CRITERIA |
|---|---|
| IASP 1994 consensus criteria4 | Criteria 2, 3 and 4 are necessary for a diagnosis of CRPS type 1.10
|
| Bruehl’s criteria: IASP-family11 |
|
| Veldman’s criteria13 |
|
| *IASP definition of CRSP 1: A variety of painful conditions following injury which appears regionally having a distal predominance of abnormal findings, exceeding in both magnitude and duration the expected clinical course of the inciting event and often resulting in significant impairment of motor function, and showing variable progression over time. (All 3 criteria sets use this definition.) | |
TABLE 2
Accuracy of diagnostic criteria for CRPS type 1
| CRITERIA TESTED | STUDY OF ACCURACY | STUDY QUALITY | CONTROL GROUP | SN | SP | LR+ | LR- | PV+ | PV- |
|---|---|---|---|---|---|---|---|---|---|
| IASP | Bruehl et al, 199911 | 3 (non-indep. ref. standard | Patients with diabetic neuropathy, polyneuropathy, postherpetic neuralgia, and radiculopathy | 98% | 36% | 1.5 | 0.1 | 0.21 | 0.99 |
| IASP | Galer et al, 199812 | 3 (non-indep. ref. standard) | Patients with diabetic neuropathy | 100% | 55% | 2.2 | 0 | 0.28 | 1.0 |
| Bruehl’s | Bruehl et al, 199911 | 3 (non-indep. ref. standard) | Patients with diabetic neuropathy, polyneuropathy, postherpetic neuralgia and radiculopathy | 70% | 94% | 12 | 0.3 | 0.67 | 0.94 |
| Sn, sensitivity; Sp, specificity; LR+, positive likelihood ratio; LR-, negative likelihood ratio; PV+, positive predictive value (probability of disease given a positive test); PV-, negative predictive value (probability of disease given a negative test). PV+ and PV- assume baseline likelihood of disease of 15%. | |||||||||
TABLE 3
Interobserver reliability of diagnostic criteria for CRPS type 1
| DIAGNOSTIC CRITERIA TESTED | STUDY QUALITY | STUDY SIZE | INTEROBSERVER RELIABILITY |
|---|---|---|---|
| IASP15 | 2 (small cohort study) | 6 diagnosticians | Poor |
| Bruehl’s15 | 2 (small cohort study) | 6 diagnosticians | Borderline moderate |
| Veldman’s16 | 2 (small cohort study) | 3 diagnosticians | Good |
Factors undermining objective evaluation
Despite clinically based diagnostic criteria, researchers and physicians continue to use office, laboratory, and radiographic tests to diagnose CRPS type 1,1,10 perhaps in an attempt to provide a more objective basis for the diagnosis. However, the evaluation of these methods has been plagued by difficulties.
First, because current clinical diagnostic criteria are not yet optimized or even standardized in the literature, there is no gold standard by which to measure the accuracy of these tests.
Second, patients in different studies have been diagnosed with CRPS type 1 by varying criteria.
Third, CRPS type 1 presents differently in different people, and symptoms and signs vary over time in the same person. As a result, the sets of diagnostic criteria have been designed with various clinical findings, and CRPS patients may meet only a few at any one time.
For example, if a group of CRPS type 1 patients were tested for sweating abnormalities, only 24% at best might be expected to test positive (see TABLE 4 for representative frequency of symptoms and signs),17 resulting in an apparent sensitivity of 24% for sweating abnormalities. This is why it is important for clinicians to consider patients’ report of typical signs even when these signs are not present on exam when making a diagnosis of CRPS type 1.
TABLE 4
Frequency of symptoms and clinically observed signs in CRPS type 1
| Variables | SIGNS (%) | Symptoms (%) |
|---|---|---|
| Allodynia | 74 | — |
| Decreased range of motion | 70 | 80 |
| Color changes | 66 | 87 |
| Hyperalgesia | 63 | — |
| Temperature asymmetry | 56 | 79 |
| Edema | 56 | 80 |
| Weakness | 56 | 75 |
| Sweating changes | 24 | 53 |
| Skin changes | 20 | 24 |
| Dystonia | 14 | 20 |
| Nail changes | 9 | 21 |
| Hair changes | 9 | 19 |
| Tremor | 9 | 24 |
| Hyperesthesia | — | 65 |
| “Burning” pain | — | 81 |
| By exam or report in patients meeting IASP criteria for CRPS, adapted from Harden et al, 1999.17 | ||
Diagnostic instrumentation adds little
Some investigators have tried using instruments to measure the clinically apparent signs included in diagnostic criteria— volumetry to measure edema, thermometry to measure skin temperature differences, and resting sweat output (RSO) to measure sweating.
Confounding nature of CRPS 1. The value of these tests is limited by factors such as the duration of CRPS type 1, time of day, relaxation of the subject, ambient temperature, body temperature, and exact placement of the measuring device,18,19 so it is not clear that objective measurement is practical or adds precision. In fact, in a study comparing testing to clinical diagnosis, instrumentation added little to the overall accuracy of diagnosing CRPS type 1 (LOE: 2, prospective cohort study).14
Sympathetic nerve block unhelpful. Other investigators have focused on testing to improve or replace clinical diagnostic criteria. Although at one time a response to sympathetic block was considered diagnostic for CRPS type 1,4 subsequent studies have demonstrated there is a significant placebo response to sympathetic block, that many persons with CRPS type 1 do not respond, and that some persons with other neuropathic pain conditions do respond. A negative or positive response to sympathetic block cannot rule CRPS type 1 in or out (LOE: 2, systematic reviews with only a few high-quality studies).20-22
Radiographic findings add nothing. Bone scanning (scintigraphy) and radiography have been used frequently in the diagnosis of CRPS type 1. Although 3phase scintigraphy looking for different uptake of radioisotope between affected and unaffected limbs has been touted as an objective and definitive test for CRPS type 1,23 this method also suffers from the subjective interpretation of the radiologist and poor interobserver reliability.24 Researchers disagree on whether the typical appearance on scintigraphy is periarticular cuffing 25,26 or diffuse uptake of radioisotope,27 and about whether delayed phase scintigraphy is adequate 26 or whether 3-phase scintigraphy is necessary.27
To make the interpretation of these scans more objective, quantitative analysis of bone scans has been undertaken; however, subjective interpretation was required to decide where to measure the uptake and what degree of difference between affected and unaffected limbs was considered positive for CRPS type 1.27
In 1 study, without mention of whether the radiologist was blinded but using an appropriate post-traumatic control group, sensitivity of 80% and specificity of 80% were reported (LOE: 2, casecontrol design).27 In a cohort of persons with upper extremity pain, also without mention of blinding, sensitivity of 73% and specificity of 86% were reported (LOE: 2, cohort design).25 Using normal controls, not a clinically relevant comparison, sensitivity of 97% and specificity of 86% using bone scans have been reported (LOE: 2, case control design).26
Despite the reasonable sensitivity and specificity of the bone scans in these studies, clinical assessment was used as the gold standard for diagnosis and the bone scans did not add any degree of accuracy to that clinical assessment. Based on these studies, clinicians using a bone scan to rule in or rule out CRPS type 1 instead of using a clinical assessment risk missing up to 27% of cases and over-diagnosing 20% of cases.
Older literature suggested that osteopenia/porosis demonstrated on plain radiography or dual energy x-ray absorptiometry (DEXA) scanning was important for the diagnosis of CRPS type 1, but more recent studies have revealed sensitivity for plain radiography as low as 23% (LOE: 2, exploratory cohort study with good reference standards)13 and for DEXA a sensitivity of 76% (LOE: 2, case-control design).28 No studies were identified that used a control group post-trauma, so an adequate assessment of specificity has not been made.
Applying the evidence in practice
CRPS type 1 is often relegated to specialists. But, in fact, no special equipment or testing is required for the diagnosis of CRPS type 1, and the best treatments appear to be non-invasive and completely within the realm of family medicine.
With more attention to deviations from the normal course of recovery from trauma, the family physician will begin to recognize more cases of CRPS type 1 and can have full confidence that the treatments prescribed and monitored are in fact the treatments of choice.
Preventing CRPS 1
For persons with hemiplegia, and of course early inpatient rehabilitation of post-stroke patients with upper extremity hemiplegia. Give 500 mg of vitamin C daily to post-fracture patients in the hope of preventing CRPS type 1 (SOR: B).
Researchers have been unable to identify the underlying pathophysiology for CRPS type 1, perhaps in part because patients with different pathophysiologies may present with similar clinical findings.9 Recent discovery of an HLA linkage suggests that there may be a genetic predisposition to CRPS type 1.40
By definition, in CRPS type 1 no major nerve damage can be detected, but there may be damage to nerve fibers too small to detect on electromyograph. Research suggests that injured peripheral C-fibers and A-delta pain fibers immediately flood the central nervous system (CNS) with neurochemicals via the dorsal root ganglion and central pain projecting neurons of the CNS. The CNS is pathologically altered and sends signals to the injured area that serve to maintain the clinical signs and symptoms of CRPS type 1: peripheral pain and sensory changes, local sympathetic changes in blood vessels and sweat glands, and local motor changes.9 Abnormal sympathetic activity can be clearly demonstrated, but there is no evidence to suggest that this is the cause of CRSP type 1.41
Base evaluation on history and physical exam
More often, the family physician will be in the position of evaluating persistent post-traumatic pain. Given the absence of compelling evidence in the literature, rely on your experience to guide the work up.
To diagnose CRPS type 1, first rule out other diseases (FIGURE).4 The frequency with which other conditions occur in persons at risk for CRPS type 1 is not known because the research concerning CRPS type 1 has been undertaken in specialty care clinics; primary care physicians had already done the work of excluding many other disorders.
Physical diagnosis. The differential diagnosis for limb pain is extensive and includes fracture non-union, tendonitis, diabetic neuropathy,4 osteomyelitis or cellulitis,13 polyneuropathy, radiculopathy,11 phlebothrombosis,13 and Raynaud’s disease.13 Physical exam will reveal signs of infection, focal tenderness consistent with tendonitis, erythema suggestive of cellulitis, a distribution of pain following a nerve suggestive of radiculopathy or carpal tunnel syndrome, or the stocking-glove distribution diabetic neuropathy.
Auxiliary testing. Limited testing may be helpful. Plain radiography or bone scanning may identify a poorly healed fracture or other bony lesions. A white blood cell count and inflammatory markers may identify infection or autoimmune disorders.
Using the diagnostic criteria. Once other disorders have been ruled out, evidence does support the diagnosis of CRPS type 1 based on history and physical exam without further testing (SOR: B). In the absence of clear evidence supporting 1 set of criteria over the others, clinicians may use IASP, Bruehl’s, or Veldman’s clinical criteria for diagnosis (SOR: C). While the IASP criteria are nonspecific and possibly not as reproducible as Bruehl’s or Veldman’s criteria, they are cited more widely the literature including treatment trials. The criteria (FIGURE) can also be combined to encompass their complementary aspects (SOR: C, this author’s opinion).
CRPS has historically been described as comprising 2 distinct subtypes: type 1, also known as reflex sympathetic dystrophy, in which nerve damage is not detectable, and type 2, also known as causalgia, in which nerve damage can be detected by electromyograph (EMG) but pain is not confined to the distribution of that nerve.4 However, the clinical relevance of distinguishing the 2 types of CRPS has not been proven. Although the mechanism of pain is hypothesized to be different, thus far the 2 syndromes appear to be clinically similar (LOE: 2, case-control study).11 Many, but not all, recent articles on treatment of CRPS combine types 1 and 2 in their subject populations. Yet, because CRPS types 1 and 2 have not yet been officially merged and because some researchers continue to make the distinction in studies, this paper will focus on CRPS type 1.
The nature of, diagnostic criteria for, and even the naming of CRPS have been controversial. In 1995 the International Association for the Study of Pain (IASP) recommended abandoning the commonly used term reflex sympathetic dystrophy because: 1) the existence of a “reflex” is questionable, 2) “sympathetic” or autonomic changes may not be causative, and 3) “dystrophy” is rare.4 Despite this recommendation, a review of the literature 5 years later revealed that the terms reflex sympathetic dystrophy and causalgia are still commonly used, along with algodystrophy, shoulder-hand syndrome, Sudeck’s atrophy, and transient osteoporosis.42
ACKNOWLEDGMENTS
The authors would like to express their appreciation to Cheryl Mongillo, Peggy Lardear, and Brian Pellini for their assistance in preparing the manuscript, Dolores Moran and Diane Wolfe for their assistance in finding articles, and to Roger Rodrigue, MD for reviewing the manuscript. Funding for this project was provided by a grant from the Delaware Department of Health and Social Services, Division of Public Health.
CORRESPONDING AUTHOR
Anna Quisel, MD, Anna Quisel, MD, c/o Cheryl Mongillo, Family Medicine Center, 1401 Foulk Road, Wilmington, DE 19803. E-mail: bretandanna@comcast.net.
- Complex regional pain syndrome (CRPS) type 1 may be diagnosed by history and physical exam with no further testing (B). Several different diagnostic criteria have undergone validity testing: the 1993 IASP criteria, Bruehl’s criteria, and Veldman’s criteria; there is no compelling reason to recommend 1 set of criteria over the others (C).
- Some cases of CRPS type 1 may be preventable. Some cases of CRPS type 1 in post-stroke upper extremity hemiplegia (also known as shoulder-hand syndrome) may be prevented by early inpatient rehabilitation (C) and avoidance of shoulder trauma to the affected arm (B). Some cases of post-fracture CRPS type 1 may be prevented with 500 mg vitamin C daily started upon diagnosis of fracture and continued through healing (B).
Do you have a patient recovering from a limb fracture who is complaining of pain and tenderness long after most patients with a similar injury would be symptom free? The problem may be an under-recognized one—complex regional pain syndrome (CRPS) type 1, also known as reflex sympathetic dystrophy. The problem is also encountered in immobilized limbs of post-stroke patients.
Persons with persistent post-traumatic pain eventually diagnosed with CRPS type 1 often undergo unnecessary testing resulting in inappropriate or delayed treatment.1
Signs and symptoms typical of CRPS type 1 can also occur transiently with a normally recovering immobilized limb,2,3 so diagnosis of CRPS type 1 is based on increasing severity and duration of signs and symptoms (level of evidence [LOE]: 3; consensus guidelines)4:
- pain
- hyperalgesia/allodynia (pain or exaggerated response resulting from a normally painless or only slightly painful stimulus)
- joint stiffness
- swelling
- autonomic abnormalities (often sweating and temperature differences compared with the unaffected limb).
Diagnosis: Watch recovery course over first 9 weeks
Clinicians face a number of challenges in diagnosing CRPS type 1. No psychological or personality traits appear to predispose to CRPS type 1 (LOE: 2, lower-quality literature review).5 Fracture types and severity of injury among persons who develop CRPS type 1 are not significantly different from persons who recover normally (LOE: 2, case control studies).6,7 The key is to remain alert to deviation from the normal course of recovery.
Studies have shown that 9 weeks post injury, persons with persistent pain, tenderness, swelling, joint stiffness (fingers and wrist), and sweating or temperature changes in the injured limb may have CRPS type 1 (LOE: 2, case series and case control studies).6,8 In a prospective case series (n=109), no new cases of CRPS type 1 developed beyond 9 weeks (LOE: 2, case series).8
Diagnostic criteria: No consensus
No one test identifies all persons with CRPS type 1. There is no objective gold standard for diagnosis.9 Instead, researchers and clinicians must rely on clinically derived diagnostic criteria. Unfortunately, despite the development of diagnostic criteria by the IASP in 1994 (TABLE 1),4 experts have not reached consensus on the best method of diagnosis, and several different sets of diagnostic criteria are used.7,10
Initial IASP criteria.Of these, the 1994 IASP consensus-based diagnostic criteria appear to be most widely used in the litera- ture. These criteria were intended as a starting point, requiring validation through future clinical research.4,11 In further studies using controls with neuropathic conditions, IASP criteria have demonstrated low specificity (TABLE 2 ).11,12
The diagnosis of CRPS type I is often missed,1,29,30so it is likely that the diagnosis rate per population of 0.02% reported in a recent population based study is an underestimate of the actual prevalence.31 After distal radial fracture, rates of CRPS type I have varied widely in reports, from 0.9% 32 to 15% 33 to 28%.34 After tibial shaft fracture, Sarangi et al 35 reported that 30% of persons developed CRPS type I.
In cases of post-stroke hemiplegia, CRPS type I has been reported in the paralyzed arm at rates between 25% 36 and 40%.37 However, in a more recent study among stroke patients in the US who underwent early inpatient rehabilitation, Petchkrua et al reported a lower incidence of about 2%.38 Impairment can be severe among persons with persistent CRPS type 1. A prospective study revealed that activities of daily living were significantly impaired in 62% of persons with chronic CRPS type 1.39
Criteria refinements.Derived from 1 of these studies, Bruehl’s criteria were subsequently developed to improve the IASP criteria (TABLE 1).11Several other sets of diagnostic criteria exist, but only Veldman’s criteria ( TABLE 1),13 which have been adopted as the standard in the Netherlands, have undergone further study.14 Studies of Bruehl’s and IASP criteria have measured specificity and sensitivity, and along with Veldman’s criteria, interobserver reliability (TABLE 2 ).11,12,14,15 However, these numbers must be interpreted with care due to the absence of an objective and independent gold standard.
The absence of an objective gold standard does not mean CRPS type 1 is not a “real” disorder.12 In developing diagnostic criteria for CRPS, the IASP turned to models developed for other conditions without objectively measurable findings: the International Headache Society (IHS) classification and the Diagnostic and Statistical Manual of Mental Disorders (DSM). These descriptive systems are based largely on history and self-reported symptoms rather than on clinical signs and laboratory tests. The accuracy of these types of diagnostic criteria is refined over time, through repeated, controlled validation studies using the best means available.11
Specificity of criteria. Specificity has been tested using controls with neuro-pathic conditions.11,12 In these studies, nonblinded clinicians applied CRPS type 1 diagnostic criteria, except the exclusion criterion, to patients who had either CRPS type 1 or neuropathic pain from other causes. Many persons with peripheral neuropathy met criteria for CRPS type 1. However, as stated in the IASP criteria, the diagnosis of CRPS type 1 is not considered until common causes of neuropathic pain and post-traumatic limb pain have been excluded.4 As long as the primary care provider considers and rules out other causes of pain, the clinically relevant specificity of these criteria is likely much higher.
Sensitivity of criteria varies.The sensitivity in these studies is based on a non-independent reference standard. Patients with CRPS type 1 were chosen for these studies using clinical criteria, and these criteria were reapplied by study clinicians to determine sensitivity.11,12 This method does not allow any determination of whether cases of CRPS type 1 might be missed by the criteria. Sensitivity measured in this way more closely resembles interobserver reliability—the likelihood that different clinicians using the same diagnostic criteria will reach the same diagnosis— and it appears quite good, especially for IASP criteria, in these 2 studies.11,12
However, when interobserver reliability has been directly studied, albeit in small studies of 3 and 6 observers, only Veldman’s criteria achieve good reliability; IASP and Bruehl’s criteria appear unreliable ( TABLE 3).15,16 However, IASP and Bruehl’s criteria do fall within the range of reliability of other clinical assessments including medical fitness for a job and shoulder disorders.15
TABLE 1
Diagnostic criteria for CRPS type 1*
| NAME | CRITERIA |
|---|---|
| IASP 1994 consensus criteria4 | Criteria 2, 3 and 4 are necessary for a diagnosis of CRPS type 1.10
|
| Bruehl’s criteria: IASP-family11 |
|
| Veldman’s criteria13 |
|
| *IASP definition of CRSP 1: A variety of painful conditions following injury which appears regionally having a distal predominance of abnormal findings, exceeding in both magnitude and duration the expected clinical course of the inciting event and often resulting in significant impairment of motor function, and showing variable progression over time. (All 3 criteria sets use this definition.) | |
TABLE 2
Accuracy of diagnostic criteria for CRPS type 1
| CRITERIA TESTED | STUDY OF ACCURACY | STUDY QUALITY | CONTROL GROUP | SN | SP | LR+ | LR- | PV+ | PV- |
|---|---|---|---|---|---|---|---|---|---|
| IASP | Bruehl et al, 199911 | 3 (non-indep. ref. standard | Patients with diabetic neuropathy, polyneuropathy, postherpetic neuralgia, and radiculopathy | 98% | 36% | 1.5 | 0.1 | 0.21 | 0.99 |
| IASP | Galer et al, 199812 | 3 (non-indep. ref. standard) | Patients with diabetic neuropathy | 100% | 55% | 2.2 | 0 | 0.28 | 1.0 |
| Bruehl’s | Bruehl et al, 199911 | 3 (non-indep. ref. standard) | Patients with diabetic neuropathy, polyneuropathy, postherpetic neuralgia and radiculopathy | 70% | 94% | 12 | 0.3 | 0.67 | 0.94 |
| Sn, sensitivity; Sp, specificity; LR+, positive likelihood ratio; LR-, negative likelihood ratio; PV+, positive predictive value (probability of disease given a positive test); PV-, negative predictive value (probability of disease given a negative test). PV+ and PV- assume baseline likelihood of disease of 15%. | |||||||||
TABLE 3
Interobserver reliability of diagnostic criteria for CRPS type 1
| DIAGNOSTIC CRITERIA TESTED | STUDY QUALITY | STUDY SIZE | INTEROBSERVER RELIABILITY |
|---|---|---|---|
| IASP15 | 2 (small cohort study) | 6 diagnosticians | Poor |
| Bruehl’s15 | 2 (small cohort study) | 6 diagnosticians | Borderline moderate |
| Veldman’s16 | 2 (small cohort study) | 3 diagnosticians | Good |
Factors undermining objective evaluation
Despite clinically based diagnostic criteria, researchers and physicians continue to use office, laboratory, and radiographic tests to diagnose CRPS type 1,1,10 perhaps in an attempt to provide a more objective basis for the diagnosis. However, the evaluation of these methods has been plagued by difficulties.
First, because current clinical diagnostic criteria are not yet optimized or even standardized in the literature, there is no gold standard by which to measure the accuracy of these tests.
Second, patients in different studies have been diagnosed with CRPS type 1 by varying criteria.
Third, CRPS type 1 presents differently in different people, and symptoms and signs vary over time in the same person. As a result, the sets of diagnostic criteria have been designed with various clinical findings, and CRPS patients may meet only a few at any one time.
For example, if a group of CRPS type 1 patients were tested for sweating abnormalities, only 24% at best might be expected to test positive (see TABLE 4 for representative frequency of symptoms and signs),17 resulting in an apparent sensitivity of 24% for sweating abnormalities. This is why it is important for clinicians to consider patients’ report of typical signs even when these signs are not present on exam when making a diagnosis of CRPS type 1.
TABLE 4
Frequency of symptoms and clinically observed signs in CRPS type 1
| Variables | SIGNS (%) | Symptoms (%) |
|---|---|---|
| Allodynia | 74 | — |
| Decreased range of motion | 70 | 80 |
| Color changes | 66 | 87 |
| Hyperalgesia | 63 | — |
| Temperature asymmetry | 56 | 79 |
| Edema | 56 | 80 |
| Weakness | 56 | 75 |
| Sweating changes | 24 | 53 |
| Skin changes | 20 | 24 |
| Dystonia | 14 | 20 |
| Nail changes | 9 | 21 |
| Hair changes | 9 | 19 |
| Tremor | 9 | 24 |
| Hyperesthesia | — | 65 |
| “Burning” pain | — | 81 |
| By exam or report in patients meeting IASP criteria for CRPS, adapted from Harden et al, 1999.17 | ||
Diagnostic instrumentation adds little
Some investigators have tried using instruments to measure the clinically apparent signs included in diagnostic criteria— volumetry to measure edema, thermometry to measure skin temperature differences, and resting sweat output (RSO) to measure sweating.
Confounding nature of CRPS 1. The value of these tests is limited by factors such as the duration of CRPS type 1, time of day, relaxation of the subject, ambient temperature, body temperature, and exact placement of the measuring device,18,19 so it is not clear that objective measurement is practical or adds precision. In fact, in a study comparing testing to clinical diagnosis, instrumentation added little to the overall accuracy of diagnosing CRPS type 1 (LOE: 2, prospective cohort study).14
Sympathetic nerve block unhelpful. Other investigators have focused on testing to improve or replace clinical diagnostic criteria. Although at one time a response to sympathetic block was considered diagnostic for CRPS type 1,4 subsequent studies have demonstrated there is a significant placebo response to sympathetic block, that many persons with CRPS type 1 do not respond, and that some persons with other neuropathic pain conditions do respond. A negative or positive response to sympathetic block cannot rule CRPS type 1 in or out (LOE: 2, systematic reviews with only a few high-quality studies).20-22
Radiographic findings add nothing. Bone scanning (scintigraphy) and radiography have been used frequently in the diagnosis of CRPS type 1. Although 3phase scintigraphy looking for different uptake of radioisotope between affected and unaffected limbs has been touted as an objective and definitive test for CRPS type 1,23 this method also suffers from the subjective interpretation of the radiologist and poor interobserver reliability.24 Researchers disagree on whether the typical appearance on scintigraphy is periarticular cuffing 25,26 or diffuse uptake of radioisotope,27 and about whether delayed phase scintigraphy is adequate 26 or whether 3-phase scintigraphy is necessary.27
To make the interpretation of these scans more objective, quantitative analysis of bone scans has been undertaken; however, subjective interpretation was required to decide where to measure the uptake and what degree of difference between affected and unaffected limbs was considered positive for CRPS type 1.27
In 1 study, without mention of whether the radiologist was blinded but using an appropriate post-traumatic control group, sensitivity of 80% and specificity of 80% were reported (LOE: 2, casecontrol design).27 In a cohort of persons with upper extremity pain, also without mention of blinding, sensitivity of 73% and specificity of 86% were reported (LOE: 2, cohort design).25 Using normal controls, not a clinically relevant comparison, sensitivity of 97% and specificity of 86% using bone scans have been reported (LOE: 2, case control design).26
Despite the reasonable sensitivity and specificity of the bone scans in these studies, clinical assessment was used as the gold standard for diagnosis and the bone scans did not add any degree of accuracy to that clinical assessment. Based on these studies, clinicians using a bone scan to rule in or rule out CRPS type 1 instead of using a clinical assessment risk missing up to 27% of cases and over-diagnosing 20% of cases.
Older literature suggested that osteopenia/porosis demonstrated on plain radiography or dual energy x-ray absorptiometry (DEXA) scanning was important for the diagnosis of CRPS type 1, but more recent studies have revealed sensitivity for plain radiography as low as 23% (LOE: 2, exploratory cohort study with good reference standards)13 and for DEXA a sensitivity of 76% (LOE: 2, case-control design).28 No studies were identified that used a control group post-trauma, so an adequate assessment of specificity has not been made.
Applying the evidence in practice
CRPS type 1 is often relegated to specialists. But, in fact, no special equipment or testing is required for the diagnosis of CRPS type 1, and the best treatments appear to be non-invasive and completely within the realm of family medicine.
With more attention to deviations from the normal course of recovery from trauma, the family physician will begin to recognize more cases of CRPS type 1 and can have full confidence that the treatments prescribed and monitored are in fact the treatments of choice.
Preventing CRPS 1
For persons with hemiplegia, and of course early inpatient rehabilitation of post-stroke patients with upper extremity hemiplegia. Give 500 mg of vitamin C daily to post-fracture patients in the hope of preventing CRPS type 1 (SOR: B).
Researchers have been unable to identify the underlying pathophysiology for CRPS type 1, perhaps in part because patients with different pathophysiologies may present with similar clinical findings.9 Recent discovery of an HLA linkage suggests that there may be a genetic predisposition to CRPS type 1.40
By definition, in CRPS type 1 no major nerve damage can be detected, but there may be damage to nerve fibers too small to detect on electromyograph. Research suggests that injured peripheral C-fibers and A-delta pain fibers immediately flood the central nervous system (CNS) with neurochemicals via the dorsal root ganglion and central pain projecting neurons of the CNS. The CNS is pathologically altered and sends signals to the injured area that serve to maintain the clinical signs and symptoms of CRPS type 1: peripheral pain and sensory changes, local sympathetic changes in blood vessels and sweat glands, and local motor changes.9 Abnormal sympathetic activity can be clearly demonstrated, but there is no evidence to suggest that this is the cause of CRSP type 1.41
Base evaluation on history and physical exam
More often, the family physician will be in the position of evaluating persistent post-traumatic pain. Given the absence of compelling evidence in the literature, rely on your experience to guide the work up.
To diagnose CRPS type 1, first rule out other diseases (FIGURE).4 The frequency with which other conditions occur in persons at risk for CRPS type 1 is not known because the research concerning CRPS type 1 has been undertaken in specialty care clinics; primary care physicians had already done the work of excluding many other disorders.
Physical diagnosis. The differential diagnosis for limb pain is extensive and includes fracture non-union, tendonitis, diabetic neuropathy,4 osteomyelitis or cellulitis,13 polyneuropathy, radiculopathy,11 phlebothrombosis,13 and Raynaud’s disease.13 Physical exam will reveal signs of infection, focal tenderness consistent with tendonitis, erythema suggestive of cellulitis, a distribution of pain following a nerve suggestive of radiculopathy or carpal tunnel syndrome, or the stocking-glove distribution diabetic neuropathy.
Auxiliary testing. Limited testing may be helpful. Plain radiography or bone scanning may identify a poorly healed fracture or other bony lesions. A white blood cell count and inflammatory markers may identify infection or autoimmune disorders.
Using the diagnostic criteria. Once other disorders have been ruled out, evidence does support the diagnosis of CRPS type 1 based on history and physical exam without further testing (SOR: B). In the absence of clear evidence supporting 1 set of criteria over the others, clinicians may use IASP, Bruehl’s, or Veldman’s clinical criteria for diagnosis (SOR: C). While the IASP criteria are nonspecific and possibly not as reproducible as Bruehl’s or Veldman’s criteria, they are cited more widely the literature including treatment trials. The criteria (FIGURE) can also be combined to encompass their complementary aspects (SOR: C, this author’s opinion).
CRPS has historically been described as comprising 2 distinct subtypes: type 1, also known as reflex sympathetic dystrophy, in which nerve damage is not detectable, and type 2, also known as causalgia, in which nerve damage can be detected by electromyograph (EMG) but pain is not confined to the distribution of that nerve.4 However, the clinical relevance of distinguishing the 2 types of CRPS has not been proven. Although the mechanism of pain is hypothesized to be different, thus far the 2 syndromes appear to be clinically similar (LOE: 2, case-control study).11 Many, but not all, recent articles on treatment of CRPS combine types 1 and 2 in their subject populations. Yet, because CRPS types 1 and 2 have not yet been officially merged and because some researchers continue to make the distinction in studies, this paper will focus on CRPS type 1.
The nature of, diagnostic criteria for, and even the naming of CRPS have been controversial. In 1995 the International Association for the Study of Pain (IASP) recommended abandoning the commonly used term reflex sympathetic dystrophy because: 1) the existence of a “reflex” is questionable, 2) “sympathetic” or autonomic changes may not be causative, and 3) “dystrophy” is rare.4 Despite this recommendation, a review of the literature 5 years later revealed that the terms reflex sympathetic dystrophy and causalgia are still commonly used, along with algodystrophy, shoulder-hand syndrome, Sudeck’s atrophy, and transient osteoporosis.42
ACKNOWLEDGMENTS
The authors would like to express their appreciation to Cheryl Mongillo, Peggy Lardear, and Brian Pellini for their assistance in preparing the manuscript, Dolores Moran and Diane Wolfe for their assistance in finding articles, and to Roger Rodrigue, MD for reviewing the manuscript. Funding for this project was provided by a grant from the Delaware Department of Health and Social Services, Division of Public Health.
CORRESPONDING AUTHOR
Anna Quisel, MD, Anna Quisel, MD, c/o Cheryl Mongillo, Family Medicine Center, 1401 Foulk Road, Wilmington, DE 19803. E-mail: bretandanna@comcast.net.
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2. Birklein F, Kunzel W, Sieweke N. Despite clinical similarities there are significant differences between acute limb trauma and complex regional pain syndrome I (CRPS I). Pain 2001;93:165-171.
3. Schurmann M, Gradl G, Andress HJ, Furst H, Schildberg FW. Assessment of peripheral sympathetic nervous function for diagnosing early posttraumatic complex regional pain syndrome type I. Pain 1999;80:149-159.
4. Stanton-Hicks M, Janig W, Hassenbusch S, Haddox JD, Boas R, Wilson P. Reflex sympathetic dystrophy: changing concepts and taxonomy. Pain 1995;63:127-133.
5. Lynch ME. Psychological aspects of reflex sympathetic dystrophy: a review of the adult and paediatric literature. Pain 1992;49:337-347.
6. Field J, Atkins R. Algodystrophy is an early complication of Colles’ fracture: What are the implications. J Hand Surg Br 1997;22B(2):178-182.
7. Reinders MF, Geertzen JH, Dijkstra PU. Complex regional pain syndrome type I: use of the International Association for the Study of Pain diagnostic criteria defined in 1994. Clin J Pain 2002;18:207-215.
8. Atkins R, Duckworth T, Kanis JA. Algodystrophy following Colles’ fracture. J Hand Surg Br 1989;14:161-164.
9. Baron R, Fields HL, Janig W, Kitt C, Levine JD. National Institutes of Health Workshop: reflex sympathetic dystrophy/complex regional pain syndromes— state-of-the-science. Anesth Analg 2002;95:1812-1816.
10. van de Beek WJ, Schwartzman RJ, van Nes SI, Delhaas EM, van Hilten JJ. Diagnostic criteria used in studies of reflex sympathetic dystrophy. Neurology 2002;58:522-526.
11. Bruehl S, Harden RN, Galer BS, et al. External validation of IASP diagnostic criteria for Complex Regional Pain Syndrome and proposed research diagnostic criteria. International Association for the Study of Pain. Pain 1999;81:147-154.
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14. Oerlemans HM, Oostendorp RA, de Boo T, Perez RS, Goris RJ. Signs and symptoms in complex regional pain syndrome type I/reflex sympathetic dystrophy: judgment of the physician versus objective measurement. Clin J Pain 1999;15:224-232.
15. van de Vusse AC, Stomp-van den Berg SG, de Vet HC, Weber WE. Interobserver reliability of diagnosis in patients with complex regional pain syndrome. Eur J Pain 2003;7:259-265.
16. Perez RS, Burm PE, Zuurmond WW, et al. Interrater reliability of diagnosing complex regional pain syndrome type I. Acta Anaesthesiologica Scandinavica 2002;46:447-450.
17. Harden RN, Bruehl S, Galer BS, et al. Complex regional pain syndrome: are the IASP diagnostic criteria valid and sufficiently comprehensive? Pain 1999;83:211-219.
18. Wasner G, Schattschneider J, Baron R. Skin temperature side differences—a diagnostic tool for CRPS? Pain 2002;98:19-26.
19. Sandroni P, Low PA, Ferrer T, Opfer-Gehrking TL, Willner CL, Wilson PR. Complex regional pain syndrome I (CRPS I): prospective study and laboratory evaluation. Clin J Pain 1998;14:282-289.
20. Kingery WS. A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes. Pain 1997;73:123-139.
21. Perez RS, Kwakkel G, Zuurmond WW, de Lange JJ. Treatment of reflex sympathetic dystrophy (CRPS type 1). a research synthesis of 21 randomized clinical trials. J Pain Symptom Manage 2001;21:511-526.
22. Cepeda MS, Lau J, Carr DB. Defining the therapeutic role of local anesthetic sympathetic blockade in complex regional pain syndrome: a narrative and systematic review. Clin J Pain 2002;18:216-233.
23. Demangeat JL, Constantinesco A, Brunot B, Foucher G, Farcot JM. Three-phase bone scanning in reflex sympathetic dystrophy of the hand. J Nucl Med 1988;29:26-32.
24. Lee GW, Weeks PM. The role of bone scintigraphy in diagnosing reflex sympathetic dystrophy [comment]. J Hand Surg Amer 1995;20:458-463.
25. Schiepers C, Bormans I, De Roo M. Three-phase bone scan and dynamic vascular scintigraphy in algoneurodystrophy of the upper extremity. Acta Orthop Belg 1998;64:322-327.
26. Todorovic-Tirnanic M, Obradovic V, Han R, et al. Diagnostic approach to reflex sympathetic dystrophy after fracture: radiography or bone scintigraphy? Eur J Nuclear Med 1995;22:1187-1193.
27. Zyluk A. The usefulness of quantitative evaluation of three-phase scintigraphy in the diagnosis of posttraumatic reflex sympathetic dystrophy. J Hand Surg 1999;24:16-21.
28. Chapurlat RD, Duboeuf FP, Liens D, Meunier PJ. Dual energy x-ray absorptiometry in patients with low limb reflex sympathetic dystrophy syndrome. J Rheumatol 1996;23:1557-1559.
29. Murray CS, Cohen A, Perkins T, Davidson JE, Sills JA. Morbidity in reflex sympathetic dystrophy. Arch Dis Child 2000;82:231-233.
30. Wesdock KA, Stanton RP, Singsen BH. Reflex sympathetic dystrophy in children. A physical therapy approach. Arthritis Care Res 1991;4:32-38.
31. Sandroni P, Benrud-Larson LM, McClelland RL, Low PA. Complex regional pain syndrome type I: incidence and prevalence in Olmsted county, a population-based study. Pain 2003;103:199-207.
32. Hove LM. Nerve entrapment and reflex sympathetic dystrophy after fractures of the distal radius. Scan J. Plast Resconstr Surg Hand Surg 1995;29:53-58.
33. Schurmann M, Gradl G, Zaspel J, Kayser M, Lohr P, Andress HJ. Peripheral sympathetic function as a predictor of complex regional pain syndrome type I (CRPS I) in patients with radial fracture. Auton Neurosci 2000;86:127-134.
34. Bickerstaff DR, Kanis JA. Algodystrophy: an underrecognized complication of minor trauma. Br J Rheumatol 1994;33:240-248.
35. Sarangi PP, Ward AJ, Smith EJ, Staddon GE, Atkins RM. Algodystrophy and osteoporosis after tibial fractures. J Bone Joint Surg Br 1993;75:450-452.
36. Greyson ND, Tepperman PS. Three-phase bone studies in hemiplegia with reflex sympathetic dystrophy and the effect of disuse. J Nucl Med 1984;25:423-429.
37. Wang YL, Tsau JC, Huang MH, Lee BH, Li CH. Reflex sympathetic dystrophy syndrome in stroke patients with hemiplegia-three phase bone scintigraphy and clinical characteristics. Kaohsiung J Med Sci 1998;14:40-47.
38. Petchkrua W, Weiss DJ, Patel RR. Reassessment of the incidence of complex regional pain syndrome type 1 following stroke. Neurorehabil Neural Repair 2000;14:59-63.
39. Geertzen JH, Dijkstra PU, van Sonderen EL, Groothoff JW, ten Duis HJ, Eisma WH. Relationship between impairments, disability and handicap in reflex sympathetic dystrophy patients: a long-term follow up study. Clin Rehabil 1998;12:402-412.
40. van de Beek WJ, Roep BO, van der Slik AR, Giphart MJ, van Hilten BJ. Susceptibility loci for complex regional pain syndrome. Pain 2003;103:93-97.
41. Commentary on RSD focus article Bandolier 2002. Available at: www.jr2.ox.ac.uk/bandolier/booth/ painpag/wisdom/RSD.html. Accessed on May 17, 2005.
42. Alvarez-Lario B, Aretxabala-Alcibar I, Alegre-Lopez J, Alonso-Valdivielso JL. Acceptance of the different denominations for reflex sympathetic dystrophy. Ann Rheum Dis 2001;60:77-79.
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23. Demangeat JL, Constantinesco A, Brunot B, Foucher G, Farcot JM. Three-phase bone scanning in reflex sympathetic dystrophy of the hand. J Nucl Med 1988;29:26-32.
24. Lee GW, Weeks PM. The role of bone scintigraphy in diagnosing reflex sympathetic dystrophy [comment]. J Hand Surg Amer 1995;20:458-463.
25. Schiepers C, Bormans I, De Roo M. Three-phase bone scan and dynamic vascular scintigraphy in algoneurodystrophy of the upper extremity. Acta Orthop Belg 1998;64:322-327.
26. Todorovic-Tirnanic M, Obradovic V, Han R, et al. Diagnostic approach to reflex sympathetic dystrophy after fracture: radiography or bone scintigraphy? Eur J Nuclear Med 1995;22:1187-1193.
27. Zyluk A. The usefulness of quantitative evaluation of three-phase scintigraphy in the diagnosis of posttraumatic reflex sympathetic dystrophy. J Hand Surg 1999;24:16-21.
28. Chapurlat RD, Duboeuf FP, Liens D, Meunier PJ. Dual energy x-ray absorptiometry in patients with low limb reflex sympathetic dystrophy syndrome. J Rheumatol 1996;23:1557-1559.
29. Murray CS, Cohen A, Perkins T, Davidson JE, Sills JA. Morbidity in reflex sympathetic dystrophy. Arch Dis Child 2000;82:231-233.
30. Wesdock KA, Stanton RP, Singsen BH. Reflex sympathetic dystrophy in children. A physical therapy approach. Arthritis Care Res 1991;4:32-38.
31. Sandroni P, Benrud-Larson LM, McClelland RL, Low PA. Complex regional pain syndrome type I: incidence and prevalence in Olmsted county, a population-based study. Pain 2003;103:199-207.
32. Hove LM. Nerve entrapment and reflex sympathetic dystrophy after fractures of the distal radius. Scan J. Plast Resconstr Surg Hand Surg 1995;29:53-58.
33. Schurmann M, Gradl G, Zaspel J, Kayser M, Lohr P, Andress HJ. Peripheral sympathetic function as a predictor of complex regional pain syndrome type I (CRPS I) in patients with radial fracture. Auton Neurosci 2000;86:127-134.
34. Bickerstaff DR, Kanis JA. Algodystrophy: an underrecognized complication of minor trauma. Br J Rheumatol 1994;33:240-248.
35. Sarangi PP, Ward AJ, Smith EJ, Staddon GE, Atkins RM. Algodystrophy and osteoporosis after tibial fractures. J Bone Joint Surg Br 1993;75:450-452.
36. Greyson ND, Tepperman PS. Three-phase bone studies in hemiplegia with reflex sympathetic dystrophy and the effect of disuse. J Nucl Med 1984;25:423-429.
37. Wang YL, Tsau JC, Huang MH, Lee BH, Li CH. Reflex sympathetic dystrophy syndrome in stroke patients with hemiplegia-three phase bone scintigraphy and clinical characteristics. Kaohsiung J Med Sci 1998;14:40-47.
38. Petchkrua W, Weiss DJ, Patel RR. Reassessment of the incidence of complex regional pain syndrome type 1 following stroke. Neurorehabil Neural Repair 2000;14:59-63.
39. Geertzen JH, Dijkstra PU, van Sonderen EL, Groothoff JW, ten Duis HJ, Eisma WH. Relationship between impairments, disability and handicap in reflex sympathetic dystrophy patients: a long-term follow up study. Clin Rehabil 1998;12:402-412.
40. van de Beek WJ, Roep BO, van der Slik AR, Giphart MJ, van Hilten BJ. Susceptibility loci for complex regional pain syndrome. Pain 2003;103:93-97.
41. Commentary on RSD focus article Bandolier 2002. Available at: www.jr2.ox.ac.uk/bandolier/booth/ painpag/wisdom/RSD.html. Accessed on May 17, 2005.
42. Alvarez-Lario B, Aretxabala-Alcibar I, Alegre-Lopez J, Alonso-Valdivielso JL. Acceptance of the different denominations for reflex sympathetic dystrophy. Ann Rheum Dis 2001;60:77-79.