Introduction We hypothesized that patients with complex regional pain syndrome (CRPS) would describe a more negative pain phenotype including higher pain severity, more neuropathic pain descriptors, more centralized pain symptoms, poorer physical function, and more affective distress when compared with patients with neuropathic pain of the extremities not meeting CRPS criteria.
Materials and methods This was a retrospective cross-sectional study conducted at a tertiary pain center. The sample included 212 patients who met Budapest Criteria for CRPS and 175 patients with neuropathic pain of the extremities who did not meet criteria. All patients completed a packet of questionnaires before their initial visit containing validated outcome measures assessing pain severity, pain interference, physical functioning, depression, anxiety, and catastrophizing.
Results Patients with CRPS reported higher physical disability (p=0.022) and more neuropathic pain symptoms (p=0.002) than patients not meeting CRPS criteria, but the groups did not otherwise differ significantly. There were no significant differences in pain severity or affective distress, despite power analyses suggesting the ability to detect small to medium effect sizes (d=0.29; w=0.14). Subanalyses of differences in neuropathic pain symptoms revealed that patients with CRPS, compared with patients not meeting CRPS criteria, were more likely to report pain with light touch (p=0.003), sudden pain attacks (p=0.003), pain with cold or heat (p=0.002), sensation of numbness (p=0.042), and pain with slight pressure (p=0.018).
Discussion Counter to our hypothesis, the present study suggests that patients with CRPS do not have a worse clinical phenotype compared with patients not meeting CRPS criteria, with the exception of higher physical disability and more neuropathic pain symptoms. This corresponds to recent evidence that patients with CRPS are similar to other patient populations with chronic pain.
- neuropathic pain
- physical function
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Complex regional pain syndrome (CRPS) is a chronic pain condition characterized by regional pain that is disproportionate to the typical course of pain after an inciting event, often related to minor trauma or surgery. It most commonly affects the upper or lower extremities, and in some patients, initial symptoms may spread to other parts of the body.1 CRPS is associated with classic neuropathic pain characteristics, such as intense burning pain, allodynia, and hyperalgesia. Unlike traditional neuropathic pain, however, patients with CRPS often have local edema and autonomic features, such as changes to skin color, temperature, or sweating in the affected region. Patients may also have trophic changes (to hair, nails, or skin) and/or motor dysfunction (such as weakness, decreased range of motion, or tremor).2
The pathophysiology of CRPS is multifactorial, involving both peripheral and central nervous system (CNS) mechanisms. Potential contributors include peripheral and central sensitization, inflammatory and immune changes, autonomic changes and sympatho-afferent coupling, and genetic and psychological factors.3 While psychological factors may play a role in the development of CRPS, studies have demonstrated that patients who develop CRPS do not differ psychologically from other patients with chronic pain, and that psychological factors are not the only contributors in the development of CRPS.4 Interestingly, CRPS can develop in very young children, long before major psychological disorders can be attributed to the pathophysiology. A number of studies have found, however, that major depression and other axis I psychiatric disorders are common in patients with CRPS, with prevalence estimates ranging from 24% to 49%.5–7 Furthermore, some data suggest that anxiety, depression, and other psychological factors have a stronger impact on pain and disability in patients with CRPS than in other chronic pain states.8–10
To our knowledge, no study has compared patients with CRPS with patients with neuropathic pain not meeting criteria for CRPS. In this study, we hypothesized that patients meeting Budapest Criteria for CRPS would describe a more negative pain phenotype including higher pain severity, more neuropathic pain descriptors, more centralized pain symptoms, poorer physical function, and more affective distress when compared with patients with neuropathic pain of the extremities not meeting CRPS criteria. Comparing CRPS and neuropathic pain will further our understanding of a complex and often misunderstood patient population. Patients with CRPS often describe their pain using classic peripheral neuropathic pain descriptors, yet we know that CRPS pathophysiology involves the CNS. Patients with unilateral CRPS symptoms can have bilateral sympathetic nervous system changes and many patients with CRPS process noxious, tactile, and thermal stimuli abnormally. Our study may help improve our understanding of CRPS and ultimately inform our therapeutic approach to patients with this condition.
Materials and methods
This is a single-center, retrospective cross-sectional study conducted at a large tertiary pain center. Informed consent was waived due to the survey being used in the context of clinical care. All patients completed a packet of questionnaires before their initial visit containing validated outcome measures assessing pain quality and severity, physical functioning, depression, anxiety, and catastrophizing. The questionnaire data were then entered into the Assessment of Pain Outcomes Longitudinal Electronic Data Capture system.11
The study population included patients who were seen at the University of Michigan Back and Pain Center for their initial visit between January 2010 and September 2015 and were evaluated for CRPS or neuropathic pain. Two hundred and twelve patients met Budapest Criteria for CRPS and 175 patients had neuropathic pain of the extremities but did not meet CRPS criteria (figure 1). We collected medical billing data from the date of each patient’s initial visit from the health system billing system, and patients were identified as having CRPS based on the International Classification of Diseases, Ninth Revision (ICD-9) code of CRPS on their initial patient visit. All charts were reviewed to ensure that patients had a diagnosis of CRPS. The ICD-9 codes used for patients with neuropathic pain of the extremities included the following as a primary diagnosis: 354.9—mononeuritis of upper limb, unspecified; 354.8—other mononeuritis of upper limb; 355.8—mononeuritis of lower limb, unspecified; 355.79—other mononeuritis of lower limb, and others (online supplementary appendix 1). We reviewed their charts and included patients who had signs and symptoms of neuropathic pain in an extremity and did not meet Budapest Criteria for CRPS (figure 1),1 and we excluded patients who did not have neuropathic pain in an extremity as well as those previously diagnosed with CRPS (online supplementary appendix 2). Patients who met Budapest Criteria were included in the CRPS cohort, even if they did not have an ICD-9 code for CRPS. Given that this is a retrospective review of patients seeking clinical care, the clinical criteria for CRPS were used.1
The Brief Pain Inventory (BPI) was used to assess the severity of overall body pain and the degree to which it interferes with the patient’s daily activities and various aspects of life. The BPI Severity subscale consists of four items, each measured on an 11-point Likert-type scale ranging from 0 (no pain) to 10 (worst pain imaginable). The BPI Interference subscale consists of seven items, each measured on an 11-point Likert-type scale ranging from 0 (does not interfere) to 10 (completely interferes).12
Centralized pain symptoms
We used the 2011 Fibromyalgia Survey Criteria as a surrogate of centralized pain. The fibromyalgia score consists of an assessment of widespread pain in 19 possible body areas using the Michigan Body Map (0–19 points)13 as well as the Symptom Severity Index,14 which assesses the severity and duration of various symptoms such as fatigue, trouble thinking, and headaches for a possible score of 0–12. The Michigan Body Map and Symptom Severity Index scores were summed to provide the fibromyalgia score, which ranges from 0 to 31. The fibromyalgia score was treated as a continuous variable; a fibromyalgia score ≥13 separated criteria-positive from criteria-negative patients.
Neuropathic pain descriptors
The painDETECT Questionnaire is a nine-item measure used to identify neuropathic components of pain. The first seven items are measured on a 6-point scale ranging from 0 (never) to 5 (very strongly) and evaluate the graduation of pain. The eighth item is a picture selected by the patient based on the pain course pattern; scoring ranges from −1 to +1. The final item determines whether radiating pain is present and scoring is either +2 (for yes) or 0 (for no).15
The Oswestry Disability Index is a 10-item measure used to assess how pain impacts the patient’s ability to engage in daily activities, including personal care, lifting, walking, sleeping, travel, and so on. Each item is measured on a 6-point scale ranging from 0 (no disability) to 5 (most severe disability).16
Anxiety and depression
The Hospital Anxiety and Depression Scale (HADS) is used to measure psychological distress in various clinical settings. It consists of the HADS Anxiety and HADS Depression subscales. Each subscale consists of seven items, and each item is measured on a 4-point ordinal scale ranging from 0 to 3.17
The Coping Strategies Questionnaire Catastrophizing subscale is used to evaluate whether a patient has the tendency to describe the pain experience in exaggerated terms and feel helpless about it compared with the average person. It consists of four items, each measured with a 7-point scale ranging from 0 (never think that) to 6 (always think that).18
We used χ2 and t-tests to evaluate univariate phenotypic differences between patients with CRPS and those not meeting CRPS criteria.
A post hoc power analysis revealed that we had 80% power to detect a small to medium effect size for t-tests (d=0.29) and small effect sizes for omnibus contingency analyses (n=387; w=0.14). For example, we had power to detect a mean difference of 0.29 points on the 11-point BPI pain severity scale. Studies have shown a clinically meaningful difference to be greater than 30% or 2 points on an 11-point Likert scale for pain severity19 or a 10% difference for other measures including physical function and affect.20 Thus, the study was adequately powered to detect clinically meaningful differences between the two groups had they been present.
We identified 212 patients with CRPS and 175 patients with neuropathic pain of the extremities not meeting CRPS criteria (figure 1). Patients with CRPS and those not meeting criteria did not differ significantly in terms of age, gender, race, marital status, or education level.
There were no significant differences in pain severity, pain interference, depression, anxiety, or catastrophizing between patients with CRPS and patients not meeting criteria. In terms of centralized pain symptoms, patients with CRPS reported a higher average fibromyalgia score (10.4 vs 10.0), although the difference was not statistically significant. See table 1.
Patients with CRPS reported higher physical disability (p=0.022) and more neuropathic pain symptoms on the painDETECT Questionnaire (p=0.002) compared with patients not meeting criteria. Sub-analyses of differences in neuropathic pain symptoms revealed that CRPS patients were more likely than those not meeting criteria to report pain with light touch (p=0.003), sudden pain attacks (p=0.003), pain with cold or heat (p=0.002), sensation of numbness (p=0.042), and pain with slight pressure (p=0.018). See table 2.
In this study, we found that patients with CRPS described more neuropathic pain and reported higher disability than patients with neuropathic pain of the extremities who did not meet CRPS criteria. Otherwise, patients with CRPS did not have a worse pain phenotype compared with patients with neuropathic pain of the extremities not meeting criteria, contrary to our a priori hypothesis. The two groups did not differ significantly in pain severity, pain interference, depression, anxiety, or catastrophizing.
Patients with CRPS described more neuropathic pain
The primary difference found between patients with CRPS and those not meeting criteria was more neuropathic pain in the CRPS group. Using the PainDETECT, a well-validated measure of neuropathic pain, patients with CRPS were significantly more likely to report pain with light touch, pain with cold or heat, pain with slight pressure, sensation of numbness, and sudden pain attacks than those not meeting criteria. Indeed, current understanding of the pathophysiology of CRPS supports these findings. Peripheral nervous system mechanisms are involved in CRPS, similar to neuropathic pain, but CNS mechanisms are also involved.3 Evidence for CNS involvement includes the fact that patients with CRPS process noxious, tactile, and thermal stimuli abnormally and that patients with unilateral CRPS symptoms can have bilateral sympathetic nervous system changes. Central sensitization occurs when continuous input from noxious stimuli, including nerve injury or tissue damage, results in enhanced excitability of nociceptive pathways in the spinal cord.21 This is mediated by the release of various neuropeptides, including substance P, bradykinin, and glutamate.21 22 Central sensitization produces exaggerated responses to painful stimuli, resulting in hyperalgesia. It also produces nociceptive responses to stimuli that are normally non-painful, including light touch, cold, heat, and pressure.21
Brain plasticity is another factor that can account for the differences between CRPS and neuropathic pain. Neuroimaging studies have demonstrated a consistent brain alteration in patients with CRPS: the reorganization of somatotopic maps. The part of the somatosensory cortex representing the CRPS-affected limb decreases in size compared with part representing the contralateral limb.23–27 A few studies have shown that these changes can return to baseline after CRPS is successfully treated.25 27 The pain intensity and degree of hyperalgesia experienced by a patient with CRPS correlate significantly with the extent of somatic reorganization.24 Patients with CRPS with somatic reorganization exhibit various sensory deficits, including impaired two-point tactile discrimination.26 The finding in this study that patients with CRPS were more likely to report numbness may be accounted for by somatotopic reorganization. More broadly, the fact that patients with CRPS characterized their pain as neuropathic to a higher degree than those not meeting criteria has clinical relevance. These results indicate that clinicians should specifically address neuropathic pain in their therapeutic approach to CRPS.
The diagnosis and treatment of CRPS remains a clinical conundrum for many providers. Diagnostic criteria are imperfect; for example, the clinical Budapest Criteria have a sensitivity and specificity of 85% and 69%, respectively.1 Additionally, our understanding of the pathophysiology of CRPS remains incomplete. While CRPS most often presents in the distal extremities in a stocking glove distribution, human anatomy is not organized this way in the periphery or in the spinal cord. Only at the level of the brain does this organizational pattern hold up. It is well known that many patients with CRPS suffer from strong affective components of pain and psychological distress. Yet many of the targets for therapy are aimed at the periphery and spinal levels. The homunculus and cerebral organization may ultimately be involved in CRPS, yet patients generally describe CRPS using classic peripheral neuropathic descriptors. Clearly further research is warranted.
Patients with CRPS have long been considered to suffer from higher levels of affective distress than other patients with chronic pain,8–10 possibly due to the relapsing and remitting nature of CRPS and because it can be very debilitating. A number of studies have investigated this, with varying conclusions. Bruehl et al 10 found no difference between patients with CRPS and patients with low back pain and limb pain in terms of depression but did find differences in phobic anxiety and somatization. DeGood et al 28 found that patients with CRPS did not report higher levels of anxiety and depression compared with patients with LBP and headache. Finally, a systematic review found no relationship between various psychological factors and the development and maintenance of CRPS and suggested that patients with CRPS do not differ psychologically from other patients with chronic pain.4
Despite the long-held perception that CRPS is much more severe than other chronic pain conditions, these data and other recent studies suggest that patients with CRPS report similar symptoms in some of the most important domains assessed in chronic pain. Moreover, these data demonstrate that for patients with symptoms not meeting criteria for CRPS, but showing some of the same features, the pain and psychological functioning may be similar. Hence, those not meeting criteria should in many cases be treated similarly to address the pain and affective distress often reported.
Strengths and limitations
The strengths of this study include the analysis of a patient population that is large, heterogeneous, and actively seeking treatment at an outpatient pain center, as well as the use of a robust set of validated patient-reported outcome measures. The study also has several limitations. First, the patient population was derived from a single tertiary pain center, which may limit generalizability to other populations. Tertiary pain centers tend to provide care for patients with more severe chronic pain, and this population may not reflect the characteristics of all patients with these conditions. Second, these data are cross sectional and thus do not allow for causal assessment of the development of a certain pain phenotype secondary to a given pain condition. Third, some patients with neuropathic pain may have had CRPS but might not have been evaluated for CRPS, and thus were misclassified. Also, some patients with CRPS may have presented late in the time course when their symptoms had resolved, and thus were misclassified as having neuropathic pain. Fourth, this study was a retrospective chart review. The clinical data used to classify patients were collected in the past and in the context of patient care. Limitations of chart review include missing data which can reduce the power of the study, inaccurate or incomplete documentation of the clinical encounter, variation in the quality of information recorded by clinical providers, and difficulty interpreting information in the chart.
Patients with CRPS reported higher disability and more neuropathic pain symptoms than patients with neuropathic pain of the extremities who did not meet CRPS criteria; however, the two groups did not otherwise differ significantly. There were no significant differences in pain severity, pain interference, or affective distress. This study lends further understanding to a complex and often misunderstood population of patients. Clinicians should appreciate that patients with CRPS do not necessarily have a more negative pain phenotype compared with patients with other chronic pain conditions. More studies are needed to better characterize and advance our understanding of CRPS.
The authors thank the research staff, medical assistants, nurses, pain faculty, residents, fellows, and administrative staff at the University of Michigan Back and Pain Center who are vital for the collection of these data and success of this effort.
Contributors OA and SM had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: CMB, GG. Acquisition, analysis, or interpretation of data: OA, BZ, SM, JP. Drafting of the manuscript: OA, JP. Critical revision of the manuscript for important intellectual content: CMB, PH, GG. Statistical analysis: SM, JP. Administrative, technical, or material support: SM, CMB, GG. Study supervision: SM, CMB.
Funding This study was supported by the Department of Anesthesiology at the University of Michigan. CMB receives research funding from the National Institutes of Health (R01 DA042859-05; R01 HD088712-05; R01 NR017096-05; K23 DA038718-04; R01 DA038261-05; P50 AR070600-05 CORT), the Michigan Department of Health and Human Services, and UM Michigan Genomics Initiative.
Disclaimer Heron Therapeutics and Recro Pharma are not associated with the content or preparation of this manuscript. This study represents the authors’ own work and does not represent the views of the funding entities.
Competing interests CMB serves as a consultant to Heron Therapeutics and Recro Pharma, and has a patent for peripheral perineural dexmedetomidine. The other authors (OA, GG, PH, SM, JP, and BZ) have no disclosures.
Patient consent for publication Not required.
Ethics approval This study was approved by the University of Michigan Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request.