Clinical phenotypes and classification algorithm for complex regional pain syndrome.

OBJECTIVE: We pursued the hypothesis that complex regional pain syndrome (CRPS) signs observed by neurologic examination display a structure allowing for alignment of patients to particular phenotype clusters. METHODS: Clinical examination data were obtained from 3 independent samples of 444, 391, and 202 patients with CRPS. The structure among CRPS signs was analyzed in sample 1 and validated with sample 2 using hierarchical clustering. For patients with CRPS in sample 3, an individual phenotype score was submitted to k-means clustering. Pain characteristics, quantitative sensory testing, and psychological data were tested in this sample as descriptors for phenotypes. RESULTS: A 2-cluster structure emerged in sample 1 and was replicated in sample 2. Cluster 1 comprised minor injury eliciting CRPS, motor signs, allodynia, and glove/stocking-like sensory deficits, resembling a CRPS phenotype most likely reflecting a CNS pathophysiology (the central phenotype). Cluster 2, which consisted of edema, skin color changes, skin temperature changes, sweating, and trophic changes, probably represents peripheral inflammation, the peripheral phenotype. In sample 3, individual phenotype scores were calculated as the sum of the mean values of signs from each cluster, where signs from cluster 1 were coded with 1 and from cluster 2 with -1. A k-means algorithm separated groups with 78, 36, and 88 members resembling the peripheral, central, and mixed phenotypes, respectively. The central phenotype was characterized by cold hyperalgesia at the affected limb. CONCLUSIONS: Statistically determined CRPS phenotypes may reflect major pathophysiologic mechanisms of peripheral inflammation and central reorganization.

CRPS: what's in a name? Taxonomy, epidemiology, neurologic, immune and autoimmune considerations.

This account of the condition now termed complex regional pain syndrome (CRPS) spans approximately 462 years since a description embodying similar clinical features was described by Ambroise Paré in 1557. While reviewing its historical origins, the text describes why it became necessary to change the taxonomies of two clinical syndromes with similar pathophysiologies to one which acknowledges this aspect but does not introduce any mechanistic overtones. Discussed at length is the role of the sympathetic component of the autonomic nervous system (ANS) and why its dysfunction has both directly and indirectly influenced our understanding of the inflammatory aspects of CRPS. As the following article will show, our knowledge has expanded in an exponential fashion to include musculoskeletal, immune, autoimmune, central and peripheral nervous system and ANS dysfunction, all of which increase the complexity of its clinical management. A burgeoning literature is beginning to shed light on the mechanistic aspects of these syndromes and the increasing evidence of a genetic influence on such factors as autoimmunity, and its importance is also discussed at length. An important aspect that has been missing from the diagnostic criteria is a measure of disease severity. The recent validation of a CRPS Severity Score is also included.

AAPT Diagnostic Criteria for Peripheral Neuropathic Pain: Focal and Segmental Disorders.

Peripheral neuropathic pain is among the most prevalent types of neuropathic pain. No comprehensive peripheral neuropathic pain classification system that incorporates contemporary clinical, diagnostic, biological, and psychological information exists. To address this need, this article covers the taxonomy for 4 focal or segmental peripheral neuropathic pain disorders, as part of the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership and the American Pain Society (APS) collaborative to develop a standardized, evidence-based taxonomy initiative: the ACTTION-APS Pain Taxonomy (AAPT). The disorders-postherpetic neuralgia, persistent posttraumatic neuropathic pain, complex regional pain disorder, and trigeminal neuralgia-were selected because of their clinical and clinical research relevance. The multidimensional features of the taxonomy are suitable for clinical trials and can also facilitate hypothesis-driven case-control and cohort epidemiologic studies. PERSPECTIVE: The AAPT peripheral neuropathic pain taxonomy subdivides the peripheral neuropathic pain disorders into those that are generalized and symmetric and those that are focal or segmental and asymmetric. In this article, we cover the focal and segmental disorders: postherpetic neuralgia, persistent posttraumatic neuropathic pain, complex regional pain disorder, and trigeminal neuralgia. The taxonomy is evidence-based and multidimensional, with the following dimensions: 1) core diagnostic criteria; 2) common features; 3) common medical and psychiatric comorbidities; 4) neurobiological, psychosocial, and functional consequences; and 5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors.

Complex regional pain syndrome: new concepts regarding diagnosis and treatment

Antecedentes: Los autores presentan una revisión crítica sobre el cuadro clínico, el diagnóstico, clasificación y tratamientodel síndrome de dolor regional complejo, discutiendo todos los métodos de tratamiento y haciendo hincapié en que la reabilitación debe ser empleada con el fin de obtener un mejor resultado. Aspecto psicológico debe ser discutido en el tratamiento y también se anima equipo multidisciplinario para participar en él.

Background: The authors presented a critical review about the clinical picture, diagnosis, classification and treatment ofcomplex regional pain syndrome, discussing all methods of treatment and emphasizing that the reabiltation must be employed in order to obtain a better result. Psychological aspect must be involved in the treatment and also multidisciplinary team is encouraged to take part on it.

Physiotherapy for pain and disability in adults with complex regional pain syndrome (CRPS) types I and II.

BACKGROUND: Complex regional pain syndrome (CRPS) is a painful and disabling condition that usually manifests in response to trauma or surgery. When it occurs, it is associated with significant pain and disability. It is thought to arise and persist as a consequence of a maladaptive pro-inflammatory response and disturbances in sympathetically-mediated vasomotor control, together with maladaptive peripheral and central neuronal plasticity. CRPS can be classified into two types: type I (CRPS I) in which a specific nerve lesion has not been identified, and type II (CRPS II) where there is an identifiable nerve lesion. Guidelines recommend the inclusion of a variety of physiotherapy interventions as part of the multimodal treatment of people with CRPS, although their effectiveness is not known. OBJECTIVES: To determine the effectiveness of physiotherapy interventions for treating the pain and disability associated with CRPS types I and II. SEARCH METHODS: We searched the following databases from inception up to 12 February 2015: CENTRAL (the Cochrane Library), MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS, PEDro, Web of Science, DARE and Health Technology Assessments, without language restrictions, for randomised controlled trials (RCTs) of physiotherapy interventions for treating pain and disability in people CRPS. We also searched additional online sources for unpublished trials and trials in progress. SELECTION CRITERIA: We included RCTs of physiotherapy interventions (including manual therapy, therapeutic exercise, electrotherapy, physiotherapist-administered education and cortically directed sensory-motor rehabilitation strategies) employed in either a stand-alone fashion or in combination, compared with placebo, no treatment, another intervention or usual care, or of varying physiotherapy interventions compared with each other in adults with CRPS I and II. Our primary outcomes of interest were patient-centred outcomes of pain intensity and functional disability. DATA COLLECTION AND ANALYSIS: Two review authors independently evaluated those studies identified through the electronic searches for eligibility and subsequently extracted all relevant data from the included RCTs. Two review authors independently performed 'Risk of bias' assessments and rated the quality of the body of evidence for the main outcomes using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: We included 18 RCTs (739 participants) that tested the effectiveness of a broad range of physiotherapy-based interventions. Overall, there was a paucity of high quality evidence concerning physiotherapy treatment for pain and disability in people with CRPS I. Most included trials were at 'high' risk of bias (15 trials) and the remainder were at 'unclear' risk of bias (three trials). The quality of the evidence was very low or low for all comparisons, according to the GRADE approach.We found very low quality evidence that graded motor imagery (GMI; two trials, 49 participants) may be useful for improving pain (0 to 100 VAS) (mean difference (MD) -21.00, 95% CI -31.17 to -10.83) and functional disability (11-point numerical rating scale) (MD 2.30, 95% CI 1.12 to 3.48), at long-term (six months) follow-up, in people with CRPS I compared to usual care plus physiotherapy; very low quality evidence that multimodal physiotherapy (one trial, 135 participants) may be useful for improving 'impairment' at long-term (12 month) follow-up compared to a minimal 'social work' intervention; and very low quality evidence that mirror therapy (two trials, 72 participants) provides clinically meaningful improvements in pain (0 to 10 VAS) (MD 3.4, 95% CI -4.71 to -2.09) and function (0 to 5 functional ability subscale of the Wolf Motor Function Test) (MD -2.3, 95% CI -2.88 to -1.72) at long-term (six month) follow-up in people with CRPS I post stroke compared to placebo (covered mirror).There was low to very low quality evidence that tactile discrimination training, stellate ganglion block via ultrasound and pulsed electromagnetic field therapy compared to placebo, and manual lymphatic drainage combined with and compared to either anti-inflammatories and physical therapy or exercise are not effective for treating pain in the short-term in people with CRPS I. Laser therapy may provide small clinically insignificant, short-term, improvements in pain compared to interferential current therapy in people with CRPS I.Adverse events were only rarely reported in the included trials. No trials including participants with CRPS II met the inclusion criteria of this review. AUTHORS' CONCLUSIONS: The best available data show that GMI and mirror therapy may provide clinically meaningful improvements in pain and function in people with CRPS I although the quality of the supporting evidence is very low. Evidence of the effectiveness of multimodal physiotherapy, electrotherapy and manual lymphatic drainage for treating people with CRPS types I and II is generally absent or unclear. Large scale, high quality RCTs are required to test the effectiveness of physiotherapy-based interventions for treating pain and disability of people with CRPS I and II. Implications for clinical practice and future research are considered.

The complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is the current consensus-derived name for a syndrome usually triggered by limb trauma. Required elements include prolonged, disproportionate distal-limb pain and microvascular dysregulation (e.g., edema or color changes) or altered sweating. CRPS-II (formerly "causalgia") describes patients with identified nerve injuries. CRPS-I (formerly "reflex sympathetic dystrophy") describes most patients who lack evidence of specific nerve injuries. Diagnosis is clinical and the pathophysiology involves combinations of small-fiber axonopathy, microvasculopathy, inflammation, and brain plasticity/sensitization. Females have much higher risk and workplace accidents are a well-recognized cause. Inflammation and dysimmunity, perhaps facilitated by injury to the blood-nerve barrier, may contribute. Most patients, particularly the young, recover gradually, but treatment can speed healing. Evidence of efficacy is strongest for rehabilitation therapies (e.g., graded-motor imagery), neuropathic pain medications, and electric stimulation of the spinal cord, injured nerve, or motor cortex. Investigational treatments include ketamine, botulinum toxin, immunoglobulins, and transcranial neuromodulation. Nonrecovering patients should be re-evaluated for neurosurgically treatable causal lesions (nerve entrapment, impingement, infections, or tumors) and treatable potentiating medical conditions, including polyneuropathy and circulatory insufficiency. Earlier impressions that CRPS represents malingering or psychosomatic illness have been replaced by evidence that CRPS is a rare complication of limb injury in biologically susceptible individuals.

Bimodal Modulation of Ipsilateral Spinal-Coeruleo-Spinal Pathway in CRPS: A Novel Model for Explaining Different Clinical Features of the Syndrome.

OBJECTIVE: The objective is to present a hypothesis to explain the sensory, autonomic, and motor disturbances associated with complex regional pain syndrome (CRPS) syndrome. METHODS: The author reviewed the available and relevant literature, which was supplemented with research on experimental animal models, with a focus on how they may translate into humans, particularly in areas about pathophysiologic mechanisms of CRPS. RESULTS: We propose that different CRPS subtypes may result from facilitative or inhibitory influences exerted by the spinal-coeruleo-spinal pathway in three sites at the spinal cord: the dorsal horn (DH), intermediolateral cell column (IML) and ventral horn (VH). A facilitatory influence over DH may have a pronociceptive effect that explains exacerbated pain, sensory disturbances, and spreading sensitization and neuroinflammation. Conversely, a facilitatory influence over preganglionic neurons located in IML cell column may increase sympathetic outflow with peripheral vasoconstriction, which leads to cold skin, ipsilateral limb ischaemia, and sympathetically maintained pain (SMP). For patients presenting with these symptoms, a descending inhibitory influence would be predicted to result in decreased sympathetic outflow and warm skin, as well as impairment of peripheral vasoconstrictor reflexes. Finally, a descending inhibitory influence over VH could explain muscle weakness and decreased active range of motion, while also facilitating motor reflexes, tremor and dystonia. CONCLUSIONS: The proposed model provides a mechanistically based diagnostic scheme for classifying and explaining the sensory, autonomic and motor disturbances associated with CRPS syndrome.

Complex regional pain syndrome of the upper limb: a review.

In this paper, we present some impressions and thoughts about CRPS which we found useful in our proceedings with CRPS patients. The clinical sub-types of the CRPS are presented and differences in their characteristics are discussed. The current pathophysiological concepts for CRPS are outlined. Diagnostic criteria are presented and critically discussed. Both classification and diagnosing have translation on research and clinical practice. Treatment modalities are provided, addressing separately acute/early and chronic forms of the syndrome. The "Szczecin" protocol of management of early CRPS is presented in details. Some information about prevention of the syndrome is given. We believe that the information presented may support doctors in resolving their diagnostic dilemmas associated with CRPS.

Short-term treatment with parecoxib for complex regional pain syndrome: a randomized, placebo-controlled double-blind trial.

BACKGROUND: Complex regional pain syndrome (CRPS) is characterized by signs and symptoms of peripheral inflammation, which leads to peripheral neural sensitization associated most frequently (in about 70%) with blunt pressure hyperalgesia. Therefore, we hypothesized that treatment of CRPS patients with a selective COX-2-inhibitor would alleviate the abnormally low pressure pain threshold (PPT) and reduce pain intensity and edema. METHODS: Twenty patients with CRPS type I (n = 16) and II of the upper limb and abnormally low PPT were double-blind randomised into 2 groups of 10 patients each to receive a 2-day intravenous treatment of either 80 mg parecoxib per day (group I) or placebo (NaCl 0.9%, group II). Standardized quantitative sensory testing (QST) using the DFNS protocol was performed before and after treatment. Pain intensity (NRS 0 - 10); circumferences of the fingers II, IV, and V (mm); PPT (kPa, thenar/hypothenar); and adverse events were recorded daily. STATISTICS: Wilcoxon-test, Mann-Whitney-U-test, Friedman-test, Fisher-test, significance level: P < 0.05. STUDY DESIGN: Proof of concept trial performed in randomized, placebo-controlled, double blind style . SETTING: Pain Management Center in Germany. RESULTS: There were no group differences in PTT or other QST parameters. After treatment, PPT decreased insignificantly in group I (median [range]; before: 224.0 [121.0 - 52937] kPa, afterwards: 186.4 [101.4 - 526.5] kPa) and increased insignificantly in group II (before: 207.6 [170.0 - 320.5] kPa; afterwards: 235.4 [163.5 - 349.9] kPa). Pain scores and finger circumferences remained unchanged in both groups. LIMITATIONS: Due to difficulty in recruitment the trial was closed after inclusion of 20 patients. CONCLUSION: In the present proof-of-concept trial, short-term treatment with the selective COX-2-inhibitor parecoxib influenced neither PPT nor edema or pain. COX-2 might be less important than previously assumed. However, the results are limited due to the small number of patients, short-term treatment, and focus on the PPT, which could have led to false negative results of the present study and covered the expected therapeutic effect.

Chronic, refractory CRPS involving 3 limbs: a case report.

We report the case of a 26-year-old woman with CRPS involving consecutively 3 extremities during 8 years. None of the treatments used was effective and each CRPS episode resulted in persistence and chronification of the disease. We suggest that this patient presents a specific subtype of the disease, called "chronic, refractory CRPS" which is extremely severe, disabling and resistant to treatment.

Children and adolescents with complex regional pain syndrome: more psychologically distressed than other children in pain?

BACKGROUND: Historically, in both adult and pediatric populations, a lack of knowledge regarding complex regional pain syndrome (CRPS) and absence of clear diagnostic criteria have contributed to the view that this is a primarily psychiatric condition. OBJECTIVE: To test the hypothesis that children with CRPS are more functionally disabled, have more pain and are more psychologically distressed than children with other pain conditions. METHODS: A total of 101 children evaluated in a tertiary care pediatric pain clinic who met the International Association for the Study of Pain consensus diagnostic criteria for CRPS participated in the present retrospective study. Comparison groups included 103 children with abdominal pain, 291 with headache and 119 with back pain. Children and parents completed self-report questionnaires assessing disability, somatization, pain coping, depression, anxiety and school attendance. RESULTS: Children with CRPS reported higher pain intensity and more recent onset of pain at the initial tertiary pain clinic evaluation compared with children with other chronic pain conditions. They reported greater functional disability and more somatic symptoms than children with headaches or back pain. Scores on measures of depression and anxiety were within normal limits and similar to those of children in other pain diagnostic groups. CONCLUSIONS: As a group, clinic-referred children with CRPS may be more functionally impaired and experience more somatic symptoms compared with children with other pain conditions. However, overall psychological functioning as assessed by self-report appears to be similar to that of children with other chronic pain diagnoses. Comprehensive assessment using a biopsychosocial framework is essential to understanding and appropriately treating children with symptoms of CRPS.

Complex regional pain syndrome: observations on diagnosis, treatment and definition of a new subgroup.

Several definitions and sets of diagnostic criteria of complex regional pain syndrome have been proposed, but to date none has been accepted completely. This article presents a specific subtype of the disease, called 'chronic, refractory complex regional pain syndrome' which is extremely severe, disabling and resistant to treatment. It also emphasizes difficulties with diagnosing complex regional pain syndrome because of its variable clinical presentation and diagnostic criteria being insufficiently precise. The necessity to distinguish between criteria for clinical use and for scientific purposes is suggested with a proposal of practical guideline for diagnosing acute complex regional pain syndrome. A review of treatments for complex regional pain syndrome is presented, with opinion on their effectiveness: good in an early stage, less well in chronic and generally poor in the chronic, refractory subtype.

Intramuscular botulinum toxin in complex regional pain syndrome: case series and literature review.

BACKGROUND: Pain associated with Complex Regional Pain Syndrome (CRPS) is frequently excruciating and intractable. The use of botulinum toxin for relief of CRPS-associated pain has not been well described. OBJECTIVES: To assess whether intramuscular botulinum toxin injections cause relief of pain caused by CRPS, and to assess the risks of this treatment. STUDY DESIGN: Retrospective chart review. SETTING: Outpatient clinic. METHODS: 37 patients with spasm/dystonia in the neck and/or upper limb girdle muscles. INTERVENTION: EMG-guided injection of Botulinum Toxin - A (BtxA), 10-20 units per muscle. Total dose used was 100 units in each patient. Local pain score was measured on an 11-point Likert scale, 4 weeks after BtxA injections. RESULTS: Mean pain score decreased by 43% (8.2 ± 0.8 to 4.5 ± 1.1, P < 0.001). 97% patients had significant pain relief. One patient had transient neck drop after the injections. LIMITATIONS: This is a retrospective study, it lacks a control group and hence the placebo effect cannot be eliminated. This study does not provide information on the efficacy of this treatment after 4 weeks. CONCLUSIONS: Intramuscular injection of botulinum toxin in the upper limb girdle muscles was beneficial for short term relief of pain caused by CRPS. The incidence of complications was low (2.7%).

Complex regional pain syndrome of the upper extremity.

The diagnosis and management of complex regional pain syndrome is often challenging. Early diagnosis and intervention improve outcomes in most patients; however, some patients will progress regardless of intervention. Multidisciplinary management facilitates care in complex cases. The onset of signs and symptoms may be obvious or insidious; temporal delay is a frequent occurrence. Difficulty sleeping, pain unresponsive to narcotics, swelling, stiffness, and hypersensitivity are harbingers of onset. Multimodal treatment with hand therapy, sympatholytic drugs, and stress loading may be augmented with anesthesia blocks. If the dystrophic symptoms are controllable by medications and a nociceptive focus or nerve derangement is correctable, surgery is an appropriate alternative. Chronic sequelae of contracture may also be addressed surgically in patients with controllable sympathetically maintained pain.

Complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is a challenging pain condition for doctors and patients, with a natural history characterized by chronicity and relapses that can result in significant disability. CRPS is difficult to diagnose and treat, and requires close follow-up to ensure that progress is being made. Early diagnosis and treatment are required to prevent a long-standing or permanent disability. Clinical features such as spontaneous pain, edema, hyperalgesia, temperature or sudomotor changes, motor function abnormality, and autonomic changes are the hallmark of this disease. The treatment of CRPS remains controversial, and includes medications, physical therapy, regional anesthesia, and neuromodulation.

Validity and reliability of the Arabic adapted version of the DN4 questionnaire (Douleur Neuropathique 4 Questions) for differential diagnosis of pain syndromes with a neuropathic or somatic component.

BACKGROUND: Verbal descriptors of pain can provide a basis for distinguishing neuropathic pain (NP) from pain of non-neuropathic origin. Much research has been undertaken to develop screening tools for this purpose. The DN4 questionnaire (NP in four questions), is one of theses tools, which was developed and validated in French in 2005. The purpose of this work is to provide an Arabic, culturally appropriate, reliable, and valid version of the DN4 interview questionnaire for the diagnosis of NP. METHODS: A study was conducted consisting of two phases. In the first phase, translation and cultural adaptation of the questionnaire into dialectal Arabic according to international guidelines was accomplished. The final version was reviewed by an expert panel, then tested on a group of 30 patients. The second phase was the validation of the translated version. The analysis of psychometric properties included reliability (internal consistency, inter-rater agreement) and validity (receiver operating characteristics curve analysis and determination of sensitivity, specificity, and positive and negative predictive values). RESULTS: A sample of 170 subjects (129 women, 75%; age: 49.5 ± 12.4 years), 94 (55.3%) with NP and 76 with non-neuropathic pain was enrolled. The questionnaire was reliable (Cronbach's alpha coefficient: 0.63, inter-rater agreement coefficient: 0.96 [0.94-0.97]) and valid for a cut-off value ≥3 points, which was the best value to discriminate between NP and NNP subjects. DISCUSSION: This study represents the second validation DN4 in a language different from the original after the Spanish adaptation. These results support the high discriminatory value of the DN4 questionnaire for identification of NP.

Objectification of the diagnostic criteria for CRPS.

The current diagnostic criteria for complex regional pain syndrome (CRPS), codified by the International Association for the Study of Pain's taxonomy committee, and newer statistically derived criteria (the "Budapest" criteria), are both deliberately based on bedside testing. Designing criteria that are accessible to any clinician, not requiring any special equipment or training, is very important for clinical diagnosis. However, that approach, albeit pragmatic, forces a very heavy reliance on the subjective (not only the subjective response of the patient, but the subjective impression of the clinician). This is very problematic scientifically and statistically. Fortunately, with some new technologies and new approaches to old technologies, significant improvements can be made not only in terms of quantification, but also in allowing significant objectification of the diagnostic data. We will initiate a discussion of some of these potentially useful approaches.