Complex regional pain syndromeBMJ 2015; 351 doi: https://doi.org/10.1136/bmj.h2730 (Published 29 July 2015) Cite this as: BMJ 2015;351:h2730
All rapid responses
We have read the response from Dr. Bruehl dated August 20, 2015. Dr. Bruehl agreed that CRPS is a diagnosis of exclusion.
He stated that “Anyone who has seen the sometimes dramatic objective changes in CRPS patients without identifiable nerve injury (CRPS-I), such as severe unilateral edema, skin temperature and color changes, allodynia, and dystonia, will have difficulty believing that this condition is entirely a social construction or that it is not truly a distinct pain syndrome”. These physical exam findings can be present in numerous commonly encountered and clinically explainable medical conditions.
Dr. Bruehl further stated “Based on these criticisms, the authors conclude that painful peripheral neuropathy with dysautonomia, due to better understood mechanisms, is a more appropriate diagnostic classification for what is now called CRPS (although diagnostic criteria that should be used to make this alternative diagnosis are not stated)”.
The following abbreviated response to Dr. Bruehl’s comment should assist physicians with the differential diagnosis and evaluation of patients with painful peripheral neuropathy/dysautonomia (PPND). These address physical issues only.
History and Symptoms:
The initial evaluation of an individual with limb pain and dysautonomia should begin with an extensive history including the date and mechanism of the onset of the complaints, the anatomic distribution, and a description of the manifestation of those complaints (Table 1). Documentation of limb involvement and distribution in each limb. Symmetry in some of these conditions is common, asymmetry can occur and is a far more logical explanation than “spreading” of an ill-defined syndrome.1-4.
Historic risk factors associated with the development of painful limb are noted (Table 2). The most common causes to consider regarding painful limb is provided (Table 3). Pathologic peripheral nerve processes may present as separate or mixed abnormalities. Complaints may be symmetric or asymmetric, and may involve single or multiple limbs 5, 6. A family history of neuropathy should be obtained. 7
Diabetes is a common cause of PPND, potentially producing mixed sensory, motor, and autonomic symptoms. Diabetes with variable controls has been associated with significant multisystem autonomic neuropathy and rheumatic complaints8. Impaired glucose tolerance has been associated with PPND9-13. Multi-system involvement may be indicative of autonomic diabetic dysautonomia 3,4,14-17.
Hypothyroidism has been associated with peripheral neuropathy. Thyroid function should be evaluated in patient with PPND 18,19.
Chronic viral conditions such as Hepatitis B and C, HIV, Herpes, Epstein-Barr, and cytomegalovirus can lead to PPND 20-28.The etiology is unclear.
Nutritional and Metabolic:
Obesity can be associated with nutritional deficiencies. Obese individuals have been reported to have vitamin D, iron, B12, folate deficiencies and anemia 29, 30. Gastric bypass surgery is well recognized to cause both acutely and remotely multivitamin and nutritional deficiencies (vitamins B complex, D, E, A, copper, zinc and selenium) secondary to malabsorption 31-35. Critical absorption portions of the stomach and duodenum (Roux-en-Y) may be removed from exposure to ingested food 29,31,36-37. Post-surgery, patients may discontinue chronic follow-up and nutritional supplementation leading to malnutrition and PPND 31,37-41.
PPND is well recognized in metabolic syndrome (obesity, diabetes, hypertension, and hyperlipidemia) 42.
Medications such as amiodarone, allopurinol, anti-virals, colchicine, phenytoin and statins have been associated with PPND (Table 3) 23,43-47.
Chronic renal and hepatic failure with associated co-morbidities can result in PPND due to circulating toxins 22.48,49. Mononeuritis or polyneuritis multiplex with PPND can be associated with diabetes, vasculitis, rheumatoid arthritis, lupus, sarcoidosis, amyloidosis, cryoglobulinemia, and various infectious etiologies (e.g. leprosy, Lyme disease, HIV, hepatitis B and C) 10, 50-58.
Rheumatologic conditions can produce asymmetric PPND. Such conditions include lupus, rheumatoid arthritis, Raynaud’s, mixed connective tissue disease, Sjögren’s syndrome, and scleroderma 50,53,56,57. Vasculitis has also been reported to result in PPND 58,59.
Cancer has been associated with the occurrence of PPND. This can occur with local, distant metastasis or with paraneoplastic syndrome. Symptoms may be due to neuronal autoantibodies, chemotherapeutic agents or both 60.
Inflammatory bowel disease (celiac, Crohn's and ulcerative colitis) has been associated with PPND occurring in up to 30% of this population61-63.
Exposures to various ingested and/or environmental toxins including alcohol, metals (lead, arsenic, mercury and thallium), organic solvents, and insecticides are recognized neurotoxins which can lead to PPND 64-69.
Chronic alcoholism is a common cause PPND. Alcoholism can produce a mixed sensory/motor/autonomic neuropathy in up to 66 % of individuals with this condition. A “mixed” appearance may be due to direct toxic effects of alcohol, metabolites and nutritional deficiencies 5,70-72.
Examination of an Individual with a Painful Limb:
Examination of the extremities should include descriptions of the skin turgor, appearance, lesions, temperature, hair growth pattern, nail appearance, posttraumatic/ postsurgical scars, and tattoos. Circumferential, symmetric measurements in at least two locations in each extremity (to address atrophy or edema) and a thorough neurologic exam including distribution of altered perception to fine touch or painful stimulus (to determine if the distribution is anatomic i.e. nerve root distribution, or reflective of toxic/metabolic or a non-physical abnormality) should be documented 17,18,73.
Laboratory Evaluation and Diagnostic Studies:
Initial diagnostic studies of an individual with PPND should include a complete blood count, chemistry profile including calcium, phosphorus, renal, electrolytes, fasting blood sugar, Hg A1C, liver function, gamma glutamyl transferase, thyroid panel, erythrocyte sedimentation rate and urinalysis.
If there has been a history of obesity, gastric bypass, major GI surgery, or inflammatory bowel disease, then levels of vitamins and trace minerals should be obtained as all have been linked to PPND. These levels should be tested even if the patient is taking supplements. Absorption may be diminished due to surgery, underlying malabsorption conditions and/or inflammatory bowel disease.
If there remains a suspicion of neurologic abnormalities despite unsuccessful electrodiagnostics, a skin biopsy looking for small fiber neuropathy (SFN) may be warranted as this form of pathology will not be detected by standard electromyography and nerve conduction studies 74-76.
A psychiatric evaluation is often warranted if aberrant disuse is noted.
Due to the complexity of the differential diagnoses, a three-tiered approach to the patient with PPND is suggested. (Table 4).
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Competing interests: No competing interests
We have read with great interest the Complex Regional Pain Syndrome review article 1.
As clinicians and researchers working with young people with CRPS we would like to emphasise the importance of recognising and treating this condition early in children and adolescents.
While complex regional pain syndrome (CRPS) is a well-established condition in adults, its occurrence in children was doubted for a long time. CRPS in children and adolescents is still underdiagnosed; the diagnosis more often than not is delayed and preceded by lengthy and repeated immobilisations of the affected limb resulting in increased pain levels and functional disability.
Paediatric CRPS type I develops more commonly in girls of white ethnicity, with the incidence rising around puberty. This condition often arises after minor trauma and there is a marked preponderance of lower extremity cases (versus upper extremity in adults). CPRS type II (indicating the likelihood of a specific nerve injury causing the symptoms) has been reported to occur in equal numbers in boys and girls.
Early recognition and multidisciplinary management are critical in improving outcome and preventing resistant CRPS, but even children with delayed diagnosis can still have complete functional restoration. Recurrence rates in the same or other locations appear higher than in adults (described in up to 30%), but response to reinitiation of treatment seems to be effective.
All paediatric chronic pain and therefore CRPS is assessed and managed with the biopsychosocial model in mind 2. The treatment concept is comprised of pain management and psychological therapy mainly cognitive behavioural therapy (CBT) and intensive physical therapy; physical therapy having the major impact in the case of CRPS 3. Clinical judgment dictates the extent of medication or interventional therapy added to the multimodal treatment to facilitate rehabilitation but in light of the lack of therapeutic evidence, greater restraint in the use of medications and invasive procedures is exercised compared to adults.
Clinical data is corroborated by neuroimaging studies. Indicatively, Erpelding and colleagues 4 demonstrated gray matter (GM) and functional connectivity (FC) changes in young patients following intensive interdisciplinary psychophysical pain treatment. Twenty-three patients (13 females, 9 males; average age ± SD = 13.3 ± 2.5 years) underderwent interdisciplinary paediatric pain rehabilitative treatment comprising intensive physical, occupational, and psychological therapy (8 h/day, 5 days/week for 3–4 weeks). Following treatment, patients had increased GM in the dlPFC, thalamus, basal ganglia, amygdala, and hippocampus, and enhanced FC between the dlPFC and the periaqueductal gray, two regions involved in descending pain modulation.
Becerra and colleagues 5 evaluated brain changes in well-characterized children and adolescents with CRPS by measuring resting state networks before and after a brief (median=3 weeks) intensive physical and psychological treatment program, and compared them to matched healthy controls. Differences in intrinsic brain networks were observed in children with CRPS compared to controls before treatment (disease state) with the most prominent differences in the fronto-parietal, salience, default mode, central executive, and sensorimotor networks. Following treatment, behavioural measures demonstrated a reduction of symptoms and improvement of pain intensity and motor functioning. Correlation of network connectivities with spontaneous pain measures pre- and post-treatment indicated concurrent reductions in connectivity in salience, central executive, default mode and sensorimotor networks.
Although, less clear cut evidence has been reported 6 these results show a rapid alteration in global brain networks with treatment and suggest that the typically higher chances of recovery that children with CRPS have are likely due to enhanced brain plasticity processes during childhood and adolescence 4 .
This research adds weight to the importance of early recognition and intensive interdisciplinary rehabilitation in young people with CRPS; allowing them to fully recover and re-engage in normal developmental activities.
1. Bruehl S. Complex regional pain syndrome. BMJ (Clinical research ed) 2015;351:h2730.
2. Rajapakse D, Liossi C, Howard RF. Presentation and management of chronic pain. Archives of disease in childhood 2014;99(5):474-80.
3. Katholi BR, Daghstani SS, Banez GA, et al. Noninvasive treatments for pediatric complex regional pain syndrome: a focused review. PM & R : the journal of injury, function, and rehabilitation 2014;6(10):926-33.
4. Erpelding N, Simons L, Lebel A, et al. Rapid treatment-induced brain changes in pediatric CRPS. Brain structure & function 2014.
5. Becerra L, Sava S, Simons LE, et al. Intrinsic brain networks normalize with treatment in pediatric complex regional pain syndrome. NeuroImage Clinical 2014;6:347-69.
6. Linnman C, Becerra L, Lebel A, et al. Transient and persistent pain induced connectivity alterations in pediatric complex regional pain syndrome. PloS one 2013;8(3):e57205.
Competing interests: No competing interests
The comments made by Dr. Ring and Dr. Randolph both question the existence of CRPS as a diagnostic entity. Dr. Ring argues that CRPS should be considered a social construction until a definitive pathophysiology is identified, that the CRPS label does more harm than good, and that the condition is best managed by using cognitive behavioral therapy and empathy to address the disproportionate pain. This opinion seems to have some parallels to arguments made in the early 1960’s that mental illness is a construction created by psychiatrists(1).
Dr. Randolph and colleagues argue that the pathophysiology of CRPS is speculative, note limitations in how the current CRPS diagnostic criteria were validated, and comment on the dearth of high quality randomized controlled intervention trials. Based on these criticisms, the authors conclude that painful peripheral neuropathy with dysautonomia, due to better understood mechanisms, is a more appropriate diagnostic classification for what is now called CRPS (although diagnostic criteria that should be used to make this alternative diagnosis are not stated). Their comments regarding differential diagnosis do make an important point. CRPS is explicitly a diagnosis of exclusion (per Criterion 4)(2) and the diagnosis should not be used for patients shown to have defined non-CRPS conditions that can better account for the CRPS-like symptoms.
Dr. Randolph and colleagues seem to be arguing that only patients with known neuropathic pathophysiology who display pain with autonomic abnormalities should receive a diagnosis, that is, only patients with CRPS-II should be considered as having a diagnosable pain condition. This subtype of CRPS reflects approximately 10% or less of CRPS patients(3,4). The remainder are currently diagnosed as having CRPS-I, a condition that one group of prominent pain researchers has concluded is not a neuropathic condition(5), thus the majority of current CRPS patients would not appear to qualify for the painful neuropathy classification described above. Clearly, patients diagnosed with CRPS-I are experiencing something more than a social construction characterized by disproportionate pain. While psychological pain management can be quite helpful in managing CRPS just as it is for other types of chronic pain, it does not logically follow that CRPS is therefore a psychological disorder. Anyone who has seen the sometimes dramatic objective changes in CRPS patients without identifiable nerve injury (CRPS-I), such as severe unilateral edema, skin temperature and color changes, allodynia, and dystonia, will have difficulty believing that this condition is entirely a social construction or that it is not truly a distinct pain syndrome. The key question is how to interpret these other features that co-occur with disproportionate pain in CRPS patients.
The arguments made by both Dr. Ring and Dr. Randolph are based in large part on the absence of a known, definitive pathophysiology for CRPS at the present time. This situation is not unique to CRPS, but rather is identical to the situation for headache disorders (including well-accepted conditions such as migraine and tension-type headache) and for all psychiatric disorders (e.g., major depression, post-traumatic stress disorder, schizophrenia). Headache disorders, psychiatric disorders, CRPS, musculoskeletal chronic low back pain, and indeed most chronic pain conditions are syndromes, that is, collections of clinical signs and symptoms that are observed to co-occur and that define each condition(6). While validation of diagnostic criteria in the absolute sense is not possible when there is no definitive pathophysiology, there are accepted approaches for providing evidence for construct validity of such diagnostic entities, including statistical pattern-recognition techniques that are not dependent on clinical assumptions(7,8). It is also possible to test relative validity of diagnostic criteria with regards to some existing reference standard, such as previously accepted consensus-based criteria, an approach applied both in development of the Diagnostic and Statistical Manual of Mental Disorders-IV(9) and in developing the Budapest criteria for CRPS(2). The issue of differential diagnosis raised by Dr. Randolph and colleagues, specifically CRPS vs. painful peripheral neuropathy with dysautonomia, highlights the importance of how decision rules in diagnostic criteria are worded (i.e., the nature and number of clinical features required to receive the diagnosis). These rules set the boundaries around a diagnostic category and determine how homogenous the clinical phenotype will be, and they can have important implications. For example, what clinical features of painful peripheral neuropathy with dysautonomia and how many of these must be present for this condition to be sufficiently distinct from its prototypical presentation to be considered a different syndrome entirely, such as CRPS-II. Unfortunately, these are complex issues without clear-cut answers.
A final point to be highlighted is that diagnostic classifications and criteria, even if they cannot be proven valid in an absolute sense, serve an important heuristic function(10). They provide a consistent means for defining research samples for purposes of increasing knowledge about pathophysiological mechanisms and for identifying effective treatments. Taking Dr. Ring’s arguments to an extreme, all psychiatric disorders and headache conditions might also be considered only social constructions that should be broken down into their component measurable behaviors and remain unlabeled as distinct disorders. The problems with this conceptualization are obvious For CRPS, a nihilistic approach that denies existence of a syndrome observed and reported consistently in the medical literature for well over 100 years simply because the mechanisms are not yet fully understood seems likely to lead to clinical chaos and serve as a barrier to advancing research regarding pathophysiological mechanisms of and treatments for this condition.
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Competing interests: CRPS clinical trial design consultant for Thar Pharmaceuticals, Eli Lilly, and Grunenthal.
This review omits consideration of the possibility that Complex Regional Pain Syndrome might be a social construction: an illness that exists only because we behave as if it exists. A case can be made that this construction has done more harm than good.
There is no way to objectively verify or falsify the diagnosis of CRPS. Some would argue that the diagnostic criteria are always internally inconsistent (1). For instance, if you fracture your distal radius and don’t move your fingers the first three IASP criteria will be met, but the fourth makes the diagnosis of CRPS unnecessary and inaccurate. The experts of the human mind (psychologists and psychiatrists) do well addressing measureable and treatable aspects of human illness behavior such as catastrophic thinking and kinesiophobia, not to mention inadequate analytical (Kahneman Type 2) thinking. We should follow their lead.
It seems preferable to use a descriptive term (disproportionate pain and disability) and avoid more specific labels until and only if the as yet elusive pathophysiological process is objectively identified. Empathy and methods based on cognitive behavioral therapy are sufficient for me to adequately treat disproportionate pain and disability. I have not made the diagnosis of CRPS in 15 years of hand surgery practice at a referral center.
1. Ring D, Barth R, Barsky A. Evidence-based medicine: disproportionate pain and
disability. J Hand Surg Am. 2010 Aug;35(8):1345-7. doi:10.1016/j.jhsa.2010.06.007. PubMed PMID: 20684932.
Competing interests: No competing interests
We have read with interest the recent State of the Art Review on Complex regional pain syndrome (CRPS) authored by Stephen Bruehl MD.
As clinicians and clinical researchers, we have grave concerns regarding the article discussion of incidence, pathophysiology, diagnosis and treatment of CRPS.
Our concerns include a clinical diagnosis of CRPS reported with “sensitivity of 0.99 and specificity of 0.68”. The original study “Validation of propose diagnostic criteria (the “Budapest criteria”) for Complex Regional Pain Syndrome” published in 2010 includes 113 CRPS Type I and 47 non-CRPS neuropathic pain patients. It appears that CRPS Type I patients are analyzed with the small proportion of CRPS Type II (13%) patients. This is inaccurate as CRPS Type I and CRPS Type II patients are different clinically.1
There is no gold standard test to confirm the true positive patient with CRPS. Therefore, it is not possible to calculate sensitivity. Additionally, no raw data was provided to reproduce the reported sensitivity and specificity. The analysis assumed 70% and 50% CRPS prevalence. The assumption for this high prevalence of CRPS to calculate positive and negative predictive value is not supported.2, 3
Differential diagnoses and testing are not discussed even when diagnostic criteria are “based solely on clinical signs and symptoms…objective tests are not needed for diagnosis and is directly related to the lack of definitive pathophysiological mechanisms”. The differential diagnosis for painful limb or painful peripheral neuropathy is lengthy and should be addressed. Since CRPS is a diagnosis of exclusion, a differential diagnostic process would seem mandated. The absence of such a discussion raises concerns regarding validity of a diagnostic conclusion, especially given the common nature of those conditions which should be considered.
Treatments are being promulgated even when there is “little support from high quality RCTs for many of the most common treatment approaches to CRPS”. Multidisciplinary care has no randomized controlled trials. Sympathetic ganglion blockade has been shown to be “ineffective”. Most importantly, most of these studies did not explain how the diagnosis of CRPS was established.
Various interventions including opioids, antidepressants, anti-convulsants, sympathetic blocks “have no supporting evidence” secondary to lack of RCTs or negative trials. The current recommendations state treatment of “CRPS must be guided by the collective experience of other clinicians”. The author correctly stated “it should be emphasized that clinical acceptance as part of the standard care does not necessarily imply efficacy”.
In summary, physicians are treating patients with a diagnosis which cannot be confirmed, incidence is estimated, pathophysiology is speculative, treatments are ineffective, experimental, lack supporting evidence for efficacy, absence of sufficient high quality evidence, and at best has “some evidence for efficacy”.
Painful peripheral neuropathy with dysautonomia is pathophysiologically explainable, is scientifically based, and responds to appropriate intervention once the diagnosis is objectively established.
“No human investigation can claim to be scientific if it does not pass the test of mathematical proof”. Leonardo da Vinci
1. Harden RN, Bruehl S, Perez R, Birklein F, Marinus J, Maihofner C.Validation of propose diagnostic criteria (the “Budapest criteria”) for complex regional pain syndrome. Pain. 2010;150: 268–274.
2. de Mos M, de Bruijn AG, Huygen FJ, Dieleman JP, Stricker BH, Sturkenboom MC. The incidence of complex regional pain syndrome: a population based study. Pain.2007;129:12-20.
3. Sandroni P, Benrud-Larson LM, McClelland RL, Low PA. Complex regional pain syndrome type 1: incidence and prevalence in Olmsted County, a population based study. Pain. 2003;103:199-207.
4. Chowdhury D, Patel N. Approach to a case of autonomic peripheral neuropathy. J Assoc Physicians India. 2006;54:727-732.
5. Freeman R. Autonomic peripheral neuropathy. Lancet . 2005;365(9466):1259-1270.
6. Grantz M, Huan MC. Unusual peripheral neuropathies. part I: Extrinsic causes. Semin Neurol. 2010;30(4):387-395.
7. Azhary H, Farooq MU, Bhanushali M, Majid A, Kassab MY. Peripheral neuropathy: Differential diagnosis and management. Am Fam Physician. 2010;81(7):887-892.
Competing interests: No competing interests
There is a dearth of high-quality evidence to guide the treatment of Complex Regional Pain Syndrome (CRPS). Given the lack of proven benefit associated with pharmacological and invasive interventions, management of CRPS patients should – as Bruehl argues – focus on physical and rehabilitative therapy. Mirror therapy (MT) and graded motor imagery programmes (GMIP) are two specific modalities of physical therapy which are especially promising options for managing CRPS. However, due to methodological constraints, it may be difficult to acquire better data in support of their use.
Case reports [2,3] and a limited number of controlled trials [4-6] suggest that these non-invasive modalities have a modest but significant benefit in CRPS, particularly in the acute phase. The only direct evidence suggests that mirror therapy is more effective than graded motor imagery in a population of post-stroke CRPS patients .
This evidence base is lacking for a few reasons. First, the small numbers of available patients mean that all of these studies are under-powered to detect subtle effects. Second, it is difficult to blind patients to the therapy they are receiving. Third, it is difficult to overcome the ‘novelty effect’ – the placebo effect that the patient enjoys when they start a new treatment for the first time. Another profound problem is that is difficult to convince patients to adhere to a strict MT/GMIP protocol if they do not respond well initially, as these programmes are time-consuming. This problem makes it almost impossible to detect long-term benefits of MT/GMIP in CRPS patients. Intuitively it seems unlikely that, if CRPS is underscored by maladaptive plastic changes in the CNS, these changes will be reversed by MT/GMIP quicker than they were established. Long-standing, chronic maladaptation is unlikely to respond to acute therapy. Rehabilitation with MT is unlikely to be successful unless it is performed for at least as long as the patient has suffered with the disease. For this reason, we think it will be probably difficult to demonstrate the efficacy of MT/GMIP in chronic CRPS patients.
It is a laudable goal to look for evidence-based treatments for CRPS. But it is difficult to get robust randomised controlled trial data on mirror therapy and graded motor imagery. Given their apparent efficacy and non-invasiveness, these modalities should be considered a first-line treatment for acute CRPS.
1. BMJ 2015;351:h2730
2. Al Sayegh, S. et al. MT for Complex Regional Pain Syndrome (CRPS)—A literature
review and an illustrative case report. Scandinavian Journal of Pain 4, 200-207 (2013).
3. Karmarkar, A. & Lieberman, I. Mirror box therapy for complex regional pain syndrome. Anaesthesia 61, 412-413 (2006).
4. McCabe, C. S. et al. A controlled pilot study of the utility of mirror visual feedback in the treatment of complex regional pain syndrome (type 1).Rheumatology (Oxford) 42, 97-101 (2003).
5. Moseley, G. Graded motor imagery is effective for long-standing complex regional pain syndrome: a randomised controlled trial. Pain 108, 192-198 (2004).
6. Moseley, G. L. Graded motor imagery for pathologic pain: a randomized controlled trial. Neurology 67, 2129-2134 (2006).
7. Cacchio, A., De Blasis, E., Necozione, S., Orio, F. d. & Santilli, V. MT for chronic complex regional pain syndrome type 1 and stroke. N. Engl. J. Med. 361, 634-636 (2009).
Competing interests: No competing interests