Bilateral deficiency of Meissner corpuscles and papillary microvessels in patients with acute complex regional pain syndrome.

ABSTRACT: Complex regional pain syndrome (CRPS) presents postinjury with disproportionate pain and neuropathic, autonomic, motor symptoms, and skin texture affection. However, the origin of these multiplex changes is unclear. Skin biopsies offer a window to analyze the somatosensory and vascular system as well as skin trophicity with their protecting barriers. In previous studies, barrier-protective exosomal microRNAs were altered in CRPS. We here postulated that tissue architecture and barrier proteins are already altered at the beginning of CRPS. We analyzed ipsilateral and contralateral skin biopsies of 20 fully phenotyped early CRPS patients compared with 20 age- and sex-matched healthy controls. We established several automated unbiased methods to comprehensively analyze microvessels and somatosensory receptors as well as barrier proteins, including claudin-1, claudin-5, and claudin-19. Meissner corpuscles in the skin were bilaterally reduced in acute CRPS patients with some of them lacking these completely. The number of Merkel cells and the intraepidermal nerve fiber density were not different between the groups. Dermal papillary microvessels were bilaterally less abundant in CRPS, especially in patients with allodynia. Barrier proteins in keratinocytes, perineurium of dermal nerves, Schwann cells, and papillary microvessels were not affected in early CRPS. Bilateral changes in the tissue architecture in early CRPS might indicate a predisposition for CRPS that manifests after injury. Further studies should evaluate whether these changes might be used to identify risk patients for CRPS after trauma and as biomarkers for outcome.

Transient immune activation without loss of intraepidermal innervation and associated Schwann cells in patients with complex regional pain syndrome.

BACKGROUND: Complex regional pain syndrome (CRPS) develops after injury and is characterized by disproportionate pain, oedema, and functional loss. CRPS has clinical signs of neuropathy as well as neurogenic inflammation. Here, we asked whether skin biopsies could be used to differentiate the contribution of these two systems to ultimately guide therapy. To this end, the cutaneous sensory system including nerve fibres and the recently described nociceptive Schwann cells as well as the cutaneous immune system were analysed. METHODS: We systematically deep-phenotyped CRPS patients and immunolabelled glabrous skin biopsies from the affected ipsilateral and non-affected contralateral finger of 19 acute (< 12 months) and 6 chronic (> 12 months after trauma) CRPS patients as well as 25 sex- and age-matched healthy controls (HC). Murine foot pads harvested one week after sham or chronic constriction injury were immunolabelled to assess intraepidermal Schwann cells. RESULTS: Intraepidermal Schwann cells were detected in human skin of the finger-but their density was much lower compared to mice. Acute and chronic CRPS patients suffered from moderate to severe CRPS symptoms and corresponding pain. Most patients had CRPS type I in the warm category. Their cutaneous neuroglial complex was completely unaffected despite sensory plus signs, e.g. allodynia and hyperalgesia. Cutaneous innate sentinel immune cells, e.g. mast cells and Langerhans cells, infiltrated or proliferated ipsilaterally independently of each other-but only in acute CRPS. No additional adaptive immune cells, e.g. T cells and plasma cells, infiltrated the skin. CONCLUSIONS: Diagnostic skin punch biopsies could be used to diagnose individual pathophysiology in a very heterogenous disease like acute CRPS to guide tailored treatment in the future. Since numbers of inflammatory cells and pain did not necessarily correlate, more in-depth analysis of individual patients is necessary.

Disturbed insular functional connectivity and its clinical implication in patients with complex regional pain syndrome.

BACKGROUND: Complex regional pain syndrome (CRPS) is characterized by continued amplification of pain intensity. Given the pivotal roles of the insula in the perception and interpretation of pain, we examined insular functional connectivity and its associations with clinical characteristics in patients with CRPS. METHODS: Twenty-one patients with CRPS and 49 healthy controls underwent resting-state functional magnetic resonance imaging. The seed-to-seed functional connectivity analysis was performed for the bilateral insulae and cognitive control regions including the dorsal anterior cingulate cortex (dACC) and bilateral dorsolateral prefrontal cortex (DLPFC) between the two groups. Correlations between altered functional connectivity and clinical characteristics were assessed in CRPS patients. RESULTS: CRPS patients exhibited lower functional connectivity within the bilateral anterior insulae, between the insular and cognitive control regions (the bilateral anterior/posterior insulae-dACC; the right posterior insula-left DLPFC), as compared with healthy controls at false discovery rate-corrected p < 0.05. In CRPS patients, pain severity was associated negatively with the left-right anterior insular functional connectivity (r = -0.49, p = 0.03), yet positively with the left anterior insula-dACC functional connectivity (r = 0.51, p = 0.02). CONCLUSIONS: CRPS patients showed lower functional connectivity both within the bilateral anterior insulae and between the insular and cognitive control regions. The current findings may suggest pivotal roles of the insula in dysfunctional pain processing of CRPS patients.

The role of the bone in complex regional pain syndrome 1-A systematic review.

OBJECTIVE: The aim of this systematic review was to appraise and analyse the knowledge on bone-related biochemical and histological biomarkers in complex regional pain syndrome 1 (CRPS 1). DATABASE: A total of 7 studies were included in the analysis (biochemical analyses n = 3, animal study n = 1, histological examination n = 3). RESULTS: Two studies were classified as having a low risk of bias and five studies with a moderate risk of bias. Biochemical analysis indicated an increased bone turnover with increased bone resorption (elevated urinary levels of deoxypyridinoline) and bone formation (increased serum levels of calcitonin, osteoprotegerin and alkaline phosphatase). The animal study reported an increased signalling of proinflammatory tumour necrosis factor 4 weeks postfracture, which did, however, not contribute to local bone loss. Histological examination from biopsies revealed thinning and resorption of cortical bone, rarefication and reduction in trabecular bone and vascular modification in the bone marrow in acute CRPS 1, and replacement of the bone marrow by dystrophic vessels in chronic CRPS 1. CONCLUSION: The limited data reviewed revealed certain potential bone-related biomarkers in CRPS. Biomarkers hold the potential to identify patients who may benefit from treatments that influence bone turnover. Thus, this review identifies important areas for future research in CRPS1 patients.

Discovery of novel targets in a complex regional pain syndrome mouse model by transcriptomics: TNF and JAK-STAT pathways.

Complex Regional Pain Syndrome (CRPS) represents severe chronic pain, hypersensitivity, and inflammation induced by sensory-immune-vascular interactions after a small injury. Since the therapy is unsatisfactory, there is a great need to identify novel drug targets. Unbiased transcriptomic analysis of the dorsal root ganglia (DRG) was performed in a passive transfer-trauma mouse model, and the predicted pathways were confirmed by pharmacological interventions. In the unilateral L3-5 DRGs 125 genes were differentially expressed in response to plantar incision and injecting IgG of CRPS patients. These are related to inflammatory and immune responses, cytokines, chemokines and neuropeptides. Pathway analysis revealed the involvement of Tumor Necrosis Factor (TNF) and Janus kinase (JAK-STAT) signaling. The relevance of these pathways was proven by abolished CRPS IgG-induced hyperalgesia and reduced microglia and astrocyte markers in pain-associated central nervous system regions after treatment with the soluble TNF alpha receptor etanercept or JAK inhibitor tofacitinib. These results provide the first evidence for CRPS-related neuroinflammation and abnormal cytokine signaling at the level of the primary sensory neurons in a translational mouse model and suggest that etanercept and tofacitinib might have drug repositioning potentials for CRPS-related pain.

Senso-Immunologic Prospects for Complex Regional Pain Syndrome Treatment.

Complex regional pain syndrome (CRPS) is a chronic pain syndrome that occurs in tissue injuries as the result of surgery, trauma, or ischemia. The clinical features of this severely painful condition include redness and swelling of the affected skin. Intriguingly, it was recently suggested that transient receptor potential ankyrin 1 (TRPA1) is involved in chronic post-ischemia pain, a CRPS model. TRPA1 is a non-selective cation channel expressed in calcitonin gene-related peptide (CGRP)-positive primary nociceptors that becomes highly activated in ischemic conditions, leading to the generation of pain. In this review, we summarize the history of TRPA1 and its involvement in pain sensation, inflammation, and CRPS. Furthermore, bone atrophy is also thought to be a characteristic clinical sign of CRPS. The altered bone microstructure of CRPS patients is thought to be caused by aggravated bone resorption via enhanced osteoclast differentiation and activation. Although TRPA1 could be a target for pain treatment in CRPS patients, we also discuss the paradoxical situation in this review. Nociceptor activation decreases the risk of bone destruction via CGRP secretion from free nerve endings. Thus, TRPA1 inhibition could cause severe bone atrophy. However, the suitable therapeutic strategy is controversial because the pathologic mechanisms of bone atrophy in CRPS are unclear. Therefore, we propose focusing on the remission of abnormal bone turnover observed in CRPS using a recently developed concept: senso-immunology.

Prefrontal White Matter Abnormalities Associated With Pain Catastrophizing in Patients With Complex Regional Pain Syndrome.

OBJECTIVE: To investigate altered prefrontal white matter integrity in complex regional pain syndrome (CRPS) and its relation with the degree of pain catastrophizing. DESIGN: Cross-sectional study. SETTING: University hospital. PARTICIPANTS: Twenty-one CRPS patients and 49 patients without CRPS (N=70). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The fractional anisotropy values within the prefrontal regions reflecting the structural integrity of white matter were measured in CRPS patients and patients without CRPS using diffusion tensor imaging. The degree of pain catastrophizing was also evaluated in CRPS patients. RESULTS: The structural integrity of the prefrontal white matter was lower in CRPS patients than in patients without CRPS (P=.03). In addition, lower structural integrity in the prefrontal cortex was correlated with a higher degree of pain catastrophizing among CRPS patients (r= -0.54, P=.01). CONCLUSIONS: Our findings suggest that pain catastrophizing, which is frequently reported in patients with CRPS, may be associated with the dysfunction of the prefrontal white matter.

Rol de la densitometría ósea como herramienta diagnóstica y de control en el síndrome de dolor regional complejo: reporte de un caso / Role of bone densitometry as a diagnostic and monitoring tool in complex regional pain syndrome: report of a case

El síndrome de dolor regional complejo (SDRC) es una patología poco frecuente, caracterizada por dolor crónico y cambios locales del sitio afectado. Ocurre en forma posterior a un traumatismo, o, menos frecuentemente, sin desencadenante claro. El diagnóstico se realiza de forma clínica, evaluando la presencia de hallazgos típicos detallados en los criterios de Budapest, como el dolor continuo y desproporcionado, y síntomas y signos típicos, como edema, asimetría térmica y disminución del rango de movilidad. Los estudios por imágenes, así como la radiografía, la resonancia magnética o el centellograma óseo de 3 fases, también brindan información valiosa, sobre todo en los casos que se presentan con más dudas, y para realizar diagnóstico diferencial de otras patologías. En este sentido, la medición de la densidad mineral ósea por absorciometría dual de rayos X (DXA) se presenta también como herramienta de utilidad, no solo en la fase diagnóstica, al evidenciar la mayor desmineralización del miembro afectado, sino también en la evaluación de la respuesta terapéutica a bifosfonatos. Presentamos el caso de una paciente con SDRC del miembro inferior, donde la densitometría ósea resultó de gran utilidad en su manejo clínico. (AU)

Complex regional pain syndrome (CRPS) is a rare pathology, characterized by chronic pain and local changes of the affected site. It occurs after trauma or, less frequently, without a clear trigger. The diagnosis is made clinically, evaluating the presence of typical findings detailed in the Budapest criteria, such as continuous and disproportionate pain, and typical signs and symptoms, like edema, thermal asymmetry, and decreased range of motion. Imaging studies, such as radiography, magnetic resonance imaging, or 3-phase bone scintigraphy also provide valuable information, especially in cases that present with more doubts, and to make a differential diagnosis with other pathologies. In this regard, the measurement of bone mineral density by dual X-ray absorptiometry (DXA) is also a useful tool, not only in the diagnostic phase, by showing the greater demineralization of the affected limb, but also in the evaluation of the therapeutic response to bisphosphonates. We present the case of a patient with CRPS of the lower limb, where bone densitometry was very useful in her clinical management. (AU)

Anti-Allodynic Effects of Polydeoxyribonucleotide in an Animal Model of Neuropathic Pain and Complex Regional Pain Syndrome.

BACKGROUND: Spinal nerve ligation (SNL) model is one of the representative models of the neuropathic pain model. Neuropathic pain in a chronic post-ischemic pain (CPIP) mimics the symptoms of complex regional pain syndrome (CRPS). The administration of polydeoxyribonucleotide (PDRN), which has regenerative and anti-inflammatory effects, has been studied and is used in clinical practice treating various diseases. However, the analgesic effect of PDRN in a neuropathic pain or CRPS model remains unknown. METHODS: PDRN (3.3, 10, and 20 mg/kg) was administered into the subcutaneous (SC) layer of the hind paws of SNL and CPIP models. Mechanical anti-allodynic effects were then investigated using the von Frey test. In the immunohistochemical examination, dorsal root ganglia (DRG) and the spinal cord were harvested and examined for the expression of glial fibrillary acidic protein (GFAP) after the 20 mg PDRN injection. RESULTS: Mechanical allodynia was significantly alleviated by administration of PDRN in SNL and CPIP mice at all of the time point. As the dose of PDRN increased, the effect was greater. The 20 mg PDRN injection was found to have the most effective anti-allodynic effect. The increased expression of GFAP in DRG and the spinal cord of SNL and CPIP model decreased following the administration of PDRN than vehicle. CONCLUSION: SC administration of PDRN results in the attenuation of allodynia and activation of astrocytes in neuropathic pain or CRPS models. We propose that PDRN can have significant potential advantages in neuropathic pain treatment.

Comparative Study of Chronic Postischemic Pain Models in Mice: O-Ring Versus Tie Method.

BACKGROUND: The success rate for the production of animal models of chronic postischemia pain (CPIP) using an O-ring has yet to be improved in the study of complex regional pain syndrome-type I (CRPS-I), and producing a CPIP model is challenging, especially for mice. OBJECTIVES: We devised a new CPIP model with a higher success rate that induces ischemia for 3 hours by tying the hind limbs of mice with a rubber band, followed by reperfusion. STUDY DESIGN: A randomized, controlled animal trial. METHODS: Twenty-two male C57BL/6 mice were divided into a sham (n = 6), a ring (n = 8), and a tie group (n = 8). Anesthesia was induced using isoflurane. A precut O-ring was mounted on the upper left ankle in the sham group. A tight-fitting O-ring and a push-pull gauge manometer were mounted at the same location in the ring and tie groups, respectively. Reperfusion was induced 3 hours later. The thickness and circumference of the hind paws were measured before ischemia induction. Measurements were repeated 10 days after reperfusion. Mechanical allodynia was measured with a von Frey filament until 12 weeks after reperfusion. RESULTS: The new tie model required 5 additional days until the onset of allodynia compared with the existing CPIP O-ring model. However, the successful induction rate of CPIP was higher in the tie group than in the ring group, and allodynia was maintained for over 30 days in the tie group. The ring and tie groups exhibited significantly high levels of tumor necrosis factor-alpha than those in the sham group. LIMITATIONS: First, we did not evaluate hyperalgesia, cold or heat allodynia. Second, we did not measure blood levels of inflammatory or antiinflammatory cytokines, and research on oxidative stress biomarkers such as isoprostane, 8-hydroxy-2'-deoxyguanosine (a marker of DNA oxidative damage), and malondialdehyde was not performed. CONCLUSIONS: The new CPIP tie model has a higher rate of successful induction than existing O-ring models for mice, with longer duration of mechanical allodynia. The model may reduce the number of animals sacrificed in CRPS-I research and could be useful for studying long-term effects of drugs. KEY WORDS: CPIP, mouse, O-ring, rubber band, reperfusion, allodynia, hyperalgesia.

Early Treatment With Metformin in a Mice Model of Complex Regional Pain Syndrome Reduces Pain and Edema.

BACKGROUND: Metformin, an adenosine monophosphate (AMP)-activated protein kinase activator, as well as a common drug for type 2 diabetes, has previously been shown to decrease mechanical allodynia in mice with neuropathic pain. The objective of this study is to determine if treatment with metformin during the first 3 weeks after fracture would produce a long-term decrease in mechanical allodynia and improve a complex behavioral task (burrowing) in a mouse tibia fracture model with signs of complex regional pain syndrome. METHODS: Mice were allocated into distal tibia fracture or nonfracture groups (n = 12 per group). The fracture was stabilized with intramedullary pinning and external casting for 21 days. Animals were then randomized into 4 groups (n = 6 per group): (1) fracture, metformin treated, (2) fracture, saline treated, (3) nonfracture, metformin treated, and (4) nonfracture, saline treated. Mice received daily intraperitoneal injections of metformin 200 mg/kg or saline between days 14 and 21. After cast removal, von Frey force withdrawal (every 3 days) and burrowing (every 7 days) were tested between 25 and 56 days. Paw width was measured for 14 days after cast removal. AMP-activated protein kinase downregulation at 4 weeks after tibia fracture in the dorsal root ganglia was examined by immunohistochemistry for changes in the AMP-activated protein kinase pathway. RESULTS: Metformin injections elevated von Frey thresholds (reduced mechanical allodynia) in complex regional pain syndrome mice versus saline-treated fracture mice between days 25 and 56 (difference of mean area under the curve, 42.5 g·d; 95% CI of the difference, 21.0-63.9; P < .001). Metformin also reversed burrowing deficits compared to saline-treated tibial fracture mice (difference of mean area under the curve, 546 g·d; 95% CI of the difference, 68-1024; P < .022). Paw width (edema) was reduced in metformin-treated fracture mice. After tibia fracture, AMP-activated protein kinase was downregulated in dorsal root ganglia neurons, and mechanistic target of rapamycin, ribosomal S6 protein, and eukaryotic initiation factor 2α were upregulated. CONCLUSIONS: The important finding of this study was that early treatment with metformin reduces mechanical allodynia in a complex regional pain syndrome model in mice. Our findings suggest that AMP-activated protein kinase activators may be a viable therapeutic target for the treatment of pain associated with complex regional pain syndrome.

Complex regional pain syndrome as a paraneoplastic disorder associated with metatypical basal cell carcinoma.

Metatypical basal cell carcinoma (MTBCC) is a rare form of tumor, which associates the clinical and histopathological (HP) characteristics of both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), with a 5% chance for the development of metastases. The reference diagnosis remains the HP confirmation from the lesional tissue. The current report illustrates the case of a 74-year-old patient, diagnosed with MTBCC consequently to the biopsy from the clinically malignant lesion with HP and immunohistochemical examination, currently in clinical remission following surgical treatment. The musculoskeletal symptoms represent the patient's admission reason to the Clinic of Rheumatology, where he was diagnosed with paraneoplastic type I complex regional pain syndrome (CRPS-I). The onset was six weeks prior with intense pain in the upper limb, burning sensation and nondermatomal distribution, exacerbated by lowering the position of the upper limb. The clinical evaluation revealed vasomotor disorders: color changes on the skin of the upper limb, venous turgescence on the back of the hands, and local increased temperature. Also, there were evident sudomotor modifications with hyperspiration and fluffy edema. The presence of clinical manifestations associated with the HP confirmation of MTBCC and the information provided by the imaging tests regarding the evaluation of tumor extension advocates for the diagnosis of paraneoplastic CRPS, consequently to both the primary tumor and the pulmonary metastasis. Diagnosis of CRPS-I is generally established on the basis of clinical criteria after excluding other conditions that may explain the degree of pain and the existing dysfunction. The therapist should be aware of the clinical manifestation of CRPS, as early recognition and aggressive treatment often leads to the best response.

Expansion and activation of distinct central memory T lymphocyte subsets in complex regional pain syndrome.

BACKGROUND: Complex regional pain syndrome (CRPS) is a debilitating condition where trauma to a limb results in devastating persistent pain that is disproportionate to the initial injury. The pathophysiology of CRPS remains unknown; however, accumulating evidence suggests it is an immunoneurological disorder, especially in light of evidence of auto-antibodies in ~ 30% of patients. Despite this, a systematic assessment of all circulating leukocyte populations in CRPS has never been performed. METHODS: We characterised 14 participants as meeting the Budapest clinical criteria for CRPS and assessed their pain ratings and psychological state using a series of questionnaires. Next, we performed immunophenotyping on blood samples from the 14 CRPS participants as well as 14 healthy pain-free controls using mass cytometry. Using a panel of 38 phenotypic and activation markers, we characterised the numbers and intracellular activation status of all major leukocyte populations using manual gating strategies and unsupervised cluster analysis. RESULTS: We have shown expansion and activation of several distinct populations of central memory T lymphocytes in CRPS. The number of central memory CD8+ T cells was increased 2.15-fold; furthermore, this cell group had increased phosphorylation of NFkB and STAT1 compared to controls. Regarding central memory CD4+ T lymphocytes, the number of Th1 and Treg cells was increased 4.98-fold and 2.18-fold respectively, with increased phosphorylation of NFkB in both populations. We also found decreased numbers of CD1c+ myeloid dendritic cells, although with increased p38 phosphorylation. These changes could indicate dendritic cell tissue trafficking, as well as their involvement in lymphocyte activation. CONCLUSIONS: These findings represent the first mass cytometry immunophenotyping study in any chronic pain state and provide preliminary evidence of an antigen-mediated T lymphocyte response in CRPS. In particular, the presence of increased numbers of long-lived central memory CD4+ and CD8+ T lymphocytes with increased activation of pro-inflammatory signalling pathways may indicate ongoing inflammation and cellular damage in CRPS.

Sex matters in complex regional pain syndrome.

BACKGROUND: Complex regional pain syndrome (CRPS) is much more prevalent in women than men but potential differences in clinical phenotype have not been thoroughly explored to date. Differences in the clinical presentation between sexes may point at new avenues for a more tailored management approach of CRPS. We therefore explored if in CRPS, the patient's sex is associated with differences in clinical and psychological characteristics. METHODS: In this cross-sectional study of 698 CRPS patients (599 females) fulfilling the Budapest clinical or research criteria, CRPS signs and symptoms, CRPS severity, pain (average pain intensity in the previous week and McGill pain rating index), pain coping (Pain Coping Inventory), physical limitations (Radboud Skills Questionnaire (upper limb), Walking and Rising questionnaire (lower limb)), anxiety and depression (Hospital Anxiety and Depression scale) and kinesiophobia (Tampa scale for kinesiophobia) were evaluated. RESULTS: Male CRPS patients used more often extreme words to describe the affective qualities of pain, used more passive pain coping strategies, and were more likely to suffer from depression and kinesiophobia. CONCLUSION: Sex-related differences are present in CRPS, but the effect is generally small and mainly concerns psychological functioning. A greater awareness of sex-specific factors in the management of CRPS may contribute to achieving better outcomes. SIGNIFICANCE: What is known? Nonsex-specific clinical data of CRPS patients. What is new? Male CRPS patients used more often extreme words to describe the affective qualities of pain, used more passive pain coping strategies, and were more likely to suffer from depression and kinesiophobia.

Bone microstructure is significantly altered in CRPS-affected distal tibiae as detected by HR-pQCT: a retrospective cross-sectional study.

In the course of complex regional pain syndrome (CRPS), local osteopenia in the subchondral/subcortical areas of the affected limb represents a central manifestation. Mechanistic aspects of CRPS-associated pathologies remain unclear, and knowledge about bone morphology in CRPS-affected areas is rare. The aim of this study was to assess trabecular and cortical bone microstructure in patients with CRPS of the distal tibiae. We retrospectively analysed 14 women diagnosed with unilateral CRPS type I of the lower limb whose affected and unaffected distal tibiae were examined by high-resolution peripheral quantitative computed tomography (HR-pQCT). Laboratory tests included serum levels of calcium, phosphate, 25-hydroxyvitamin D, bone alkaline phosphatase, parathyroid hormone, osteocalcin and urinary levels of deoxypyridinoline (DPD). Bone mineral density was measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and both proximal femurs. Average urinary DPD levels, a biochemical marker of bone resorption, were elevated in the examined patient cohort (7.1 ± 1.9 nmol/mmol, reference 3.0-7.0 nmol/mmol). According to HR-pQCT, CRPS-affected distal tibiae showed significantly lower values of cortical BMD and cortical thickness compared to the unaffected contralateral side. Also, bone volume relative to total volume was significantly lower. Trabecular number and trabecular thickness tended to be lower in the affected tibiae. CRPS is associated with significant alterations in bone microstructure of the affected tibiae. Increased bone resorption seems to play a crucial role within a multifactorial process of CRPS-mediated bone atrophy. HR-pQCT could possibly serve as a diagnostic tool in specific CRPS therapy.

Successful treatment of complex regional pain syndrome with topical ambroxol: a case series.

AIM: The secretolytic drug ambroxol may be useful for the treatment of neuropathic pain due to its multiple modes of action. We hypothesized that ambroxol may be a treatment option for complex regional pain syndrome (CRPS). METHODS: Additional to standard therapy, eight CRPS-patients with symptoms of less than 12 months were treated with topical 20% ambroxol cream. Clinical courses were assessed using detailed anamnesis and clinical examination. RESULTS: Following treatment we found a reduction of spontaneous pain (6 patients), pain on movement (6 patients), edema (seven patients), allodynia (six patients), hyperalgesia (seven patients), reduction of skin reddening (four patients), improvement of motor dysfunction (six patients) and improvement of skin temperature (four patients). CONCLUSION: Topical treatment with ambroxol cream may ameliorate symptoms of CRPS.

Dermal nerve fibre and mast cell density, and proximity of mast cells to nerve fibres in the skin of patients with complex regional pain syndrome.

An interaction between cutaneous nerves and mast cells may contribute to pain in complex regional pain syndrome (CRPS). To explore this, we investigated the density of dermal nerve fibres, and the density and proximity of mast cells to nerve fibres, in skin biopsies obtained from the affected and unaffected limbs of 57 patients with CRPS and 28 site-matched healthy controls. The percentage of the dermis stained by the pan-neuronal marker protein gene-product 9.5 was lower in the affected limb of patients than in controls (0.12 ± 0.01% vs 0.22 ± 0.04%, P < 0.05), indicating a reduction in dermal nerve fibre density. This parameter did not correlate with CRPS duration. However, it was lower in the affected than unaffected limb of patients with warm CRPS. Dermal mast cell numbers were similar in patients and controls, but the percentage of mast cells less than 5 µm from nerve fibres was significantly lower in the affected and unaffected limbs of patients than in controls (16.8 ± 1.7%, 16.5 ± 1.7%, and 31.4 ± 2.3% respectively, P < 0.05). We confirm previous findings of a mild neuropathy in CRPS. Our findings suggest that this either develops very early after injury or precedes CRPS onset. Loss of dermal nerve fibres in CRPS might result in loss of chemotactic signals, thus halting mast cell migration toward surviving nerve fibres. Failure of normal nerve fibre-mast cell interactions could contribute to the pathophysiology of CRPS.

Neuropeptide regulation of adaptive immunity in the tibia fracture model of complex regional pain syndrome.

BACKGROUND: Both dysfunctional neuropeptide signaling and immune system activation are characteristic of complex regional pain syndrome (CRPS). Unknown is whether substance P (SP) or calcitonin gene-related peptide (CGRP) support autoantibody production and, consequently, nociceptive sensitization. METHODS: These experiments involved the use of a well-characterized tibia fracture model of CRPS. Mice deficient in SP expression (Tac1-/-) and CGRP signaling (RAMP1-/-) were used to probe the neuropeptide dependence of post-fracture sensitization and antibody production. The deposition of IgM in the spinal cord, sciatic nerves, and skin was followed using Western blotting, as was expression of the CRPS-related autoantigen cytokeratin 16 (Krt16). Passive serum transfer to B-cell-deficient muMT mice was used to assess the production of functional autoantibodies in CRPS model mice. The use of immunohistochemistry allowed us to assess neuropeptide-containing fiber distribution and Langerhans cell abundance in mouse and human CRPS patient skin, while Langerhans cell-deficient mice were used to assess the functional contributions of these cells. RESULTS: Functional SP and CGRP signaling were required both for the full development of nociceptive sensitization after fracture and the deposition of IgM in skin and neural tissues. Furthermore, the passive transfer of serum from wildtype but not neuropeptide-deficient mice to fractured muMT mice caused enhanced allodynia and postural unweighting. Langerhans cells were increased in number in the skin of fracture mice and CRPS patients, and those increases in mice were reduced in neuropeptide signaling-deficient animals. Unexpectedly, Langerhans cell-deficient mice showed normal nociceptive sensitization after fracture. However, the increased expression of Krt16 after tibia fracture was not seen in neuropeptide-deficient mice. CONCLUSIONS: Collectively, these data support the hypothesis that neuropeptide signaling in the fracture limb of mice is required for autoantigenic IgM production and nociceptive sensitization. The mechanism may be related to neuropeptide-supported autoantigen expression.