CRPS Bugle February 2013

Some recent papers published:

BMC Neurol. 2013 Feb 6;13:14. doi: 10.1186/1471-2377-13-14.

Morphological macrovascular alterations in complex regional pain syndrome type I demonstrated by increased intima-media thickness. click here

Derenthal N, Maecken T, Krumova E, Germing A, Maier C.


Department of Pain Medicine, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil GmbH, Ruhr University Bochum, Bochum, Germany.




Although intima-media thickness (IMT) was increased in several inflammatory diseases, studies investigating whether the inflammatory processes lead to macrovascular alteration with increased IMT in complex regional pain syndrome (CRPS) lack.


Using ultrasound (high-resolution B-mode), we compared bilaterally the IMT of the common carotid artery (CCA-IMT), the radial artery (RA-IMT), the brachial artery (BRA-IMT) and the quotient QRA/CCA, in CRPS type I (n=17), peripheral nerve injury (PNI, n=17) and pain-free controls (PFC, n=22, matched to CRPS by gender, age and traditional cardiovascular risk factors). Statistics: Spearman’s correlation, paired t-test, ANOVA (p<0.05).


Compared to PFC, RA-IMT were significantly increased in both patient groups bilaterally (mean±standard deviation, CRPS affected side vs. PFC dominant side: 0.32±0.08 mm vs. 0.19±0.08 mm, p<0.001; PNI affected side vs. PFC dominant side: 0.27±0.09 mm vs. 0.19±0.08 mm, p< 0.05; CRPS non-affected side vs. PFC non-dominant side: 0.30±0.10 mm vs. 0.19±0.09 mm, p<0.001; PNI non-affected side vs. PFC non-dominant side: 0.25±0.10 mm vs. 0.19±0.09 mm, p<0.05) and QRA/CCA (CRPS affected-side vs. PFC dominant side: 0.49±0.12 vs. 0.30±0.11, p<0.001; PNI affected side vs. PFC dominant side: 0.41±0.10 vs. 0.30±0.11, p<0.05; CRPS non-affected side vs. PFC non-dominant side: 0.43±0.19 vs. 0.30±0.13, p<0.001; PNI non-affected side vs. PFC non-dominant side: 0.39±0.14 vs. 0.30±0.13, p<0.05), and BRA-IMT – only on the affected side in CRPS (CRPS: 0.42±0.06 mm vs. PFC: 0.35±0.08 mm; p<0.05). In CRPS, QRA/CCA was significantly higher on the affected side compared to PNI (p<0.05). However, only CRPS displayed within-group side-to-side differences with a significantly increased RA-IMT and QRA/CCA on the affected side (p<0.05). The CCA-IMT was comparable between all groups and sides.


The increased IMT of peripheral arteries in CRPS suggests ongoing inflammatory process. Until now, only endothelial dysfunction has been reported. The presented morphological macrovascular alterations might explain the treatment resistance of some CRPS patients.


Clin J Pain. 2013 Jan 30. [Epub ahead of print]

Patients with Complex Regional Pain Syndrome Type 1: Fractal Dynamics of Heart Rate Variability and Baroreflex Evaluations. click here

Taneyama C, Yokota S, Goto H.


*Anesthesia and Pain Relief, Chishukai Taneyama Clinic, Shiojiri City, Nagano, Japan †Department of Anesthesiology, University of Kansas Medical Center, Kansas City, KS.


OBJECTIVE:: Patients with complex regional pain syndrome type 1 might have disturbed autonomic function and increased heart rate fractal dynamics with a resultant impaired baroreflex sensitivity (BRS). We hypothesized that these parameters of impaired cardiovascular regulation might improve with a reduction of pain intensity. METHODS:: Ten patients and 10 healthy volunteers entered the study. Power spectral analysis of heart rate (HR) variability was performed by the maximum entropy method. Ratios of low-frequency domain to high-frequency domain (LF/HF) and a fractal slope, the slope of a regression line of power spectral density (1/f), were calculated. BRS was assessed with a head-up tilt test. When the visual analogue scale scores decreased to ≦20 mm during treatments, those measurements were repeated. RESULTS:: LF/HF and steepness of fractal slope before treatments decreased significantly during treatments when visual analogue scale was ≦20 mm (2.23±0.68 to 1.30±0.45, P=0.005 and -1.90±0.35 to -1.16±0.14, P=0.00032, respectively). BRS before treatments was low (-0.28±0.27 bpm/mm Hg) as compared with BRS of volunteers but significantly improved to -0.62±0.48 bpm/mm Hg during treatments (P=0.032). CONCLUSIONS:: Increased LF/HF ratios likely indicate that patients had an imbalance of the autonomic nervous system. The increased fractal slope suggests that patients developed strong self-similarity of HR variability. The highly predictable HR variability leads to impaired hemodynamic homeostasis, resulting in decreased BRS. The impaired cardiovascular regulation improved with a reduction of pain. Thus, spectral analysis of HR variability may be useful objectively to follow complex regional pain syndrome type 1 patients, not only for pain management but also for the status of cardiovascular stability.


J Med Case Rep. 2011 Aug 4;5:349. doi: 10.1186/1752-1947-5-349.

Improvement of pain and regional osteoporotic changes in the foot and ankle by low-dose bisphosphonate therapy for complex regional pain syndrome type I: a case series. click here

Abe Y, Iba K, Takada J, Wada T, Yamashita T.


Department of Orthopedic Surgery, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.



Complex regional pain syndrome is characterized by pain, allodynia, hyperalgesia, edema, signs of vasomotor instability, movement disorders, joint stiffness, and regional osteopenia. It is recognized to be difficult to treat, despite various methods of treatment, including physiotherapy, calcitonin, corticosteroids, sympathetic blockade, and nonsteroidal anti-inflammatory drugs. Pathophysiologically, complex regional pain syndrome reveals enhanced regional bone resorption and high bone turnover, and so bisphosphonates, which have a potent inhibitory effect on bone resorption, were proposed for the treatment of complex regional pain syndrome.


A 48-year-old Japanese man with complex regional pain syndrome type I had severe right ankle pain with a visual analog scale score of 59 out of 100 regardless of treatment with physiotherapy and nonsteroidal anti-inflammatory drugs for five months. Radiographs showed marked regional osteoporotic changes and bone scintigraphy revealed a marked increase in radioactivity in his ankle. One month after the start of oral administration of risedronate (2.5 mg per day), his bone pain had fallen from a VAS score of 59 out of 100 to 18 out of 100. Bone scintigraphy at 12 months showed a marked reduction in radioactivity to a level comparable to that in his normal, left ankle. On the basis of these results, the treatment was discontinued at 15 months. At 32 months, our patient had almost no pain and radiographic findings revealed that the regional osteoporotic change had returned to normal.A second 48-year-old Japanese man with complex regional pain syndrome type I had severe right foot pain with a visual analog scale score of 83 out of 100 regardless of treatment with physiotherapy and nonsteroidal anti-inflammatory drugs for nine months. Radiographs showed regional osteoporotic change in his phalanges, metatarsals, and tarsals, and bone scintigraphy revealed a marked increase in radioactivity in his foot. One month after the start of oral administration of alendronate (35 mg per week), his bone pain had fallen from a visual analog scale score of 83 out of 100 to 30 out of 100 and, at nine months, was further reduced to 3 out of 100. The treatment was discontinued at 15 months because of successful pain reduction. At 30 months, our patient had no pain and the radiographic findings revealed marked improvement in regional osteoporotic changes.


We believe low-dose oral administration of bisphosphonate is worth considering for the treatment of idiopathic complex regional pain syndrome type I accompanied by regional osteoporotic change.


Exp Neurol. 2013 Jan 26. pii: S0014-4886(13)00030-7. doi: 10.1016/j.expneurol.2013.01.017. [Epub ahead of print]

Cutaneous noradrenaline measured by microdialysis in complex regional pain syndrome during whole-body cooling and heating. click here

Terkelsen AJ, Gierthmühlen J, Petersen LJ, Knudsen L, Christensen NJ, Kehr J, Yoshitake T, Madsen CS, Wasner G, Baron R, Jensen TS.


Danish Pain Research Center and Department of Neurology, Aarhus University Hospital, Aarhus, Denmark. Electronic address:


Complex regional pain syndrome (CRPS) is characterised by autonomic, sensory, and motor disturbances. The underlying mechanisms of the autonomic changes in CPRS are unknown. However, it has been postulated that sympathetic inhibition in the acute phase with locally reduced levels of noradrenaline is followed by an up-regulation of alpha-adrenoceptors in chronic CRPS leading to denervation supersensitivity to catecholamines. This exploratory study examined the effect of cutaneous sympathetic activation and inhibition on cutaneous noradrenaline release, vascular reactivity, and pain in CRPS patients and in healthy volunteers. Seven patients and nine controls completed whole-body cooling (sympathetic activation) and heating (sympathetic inhibition) induced by a whole-body thermal suit with simultaneous measurement of the skin temperature, skin blood flow, and release of dermal noradrenaline. CRPS pain and the perceived skin temperature were measured every 5min during thermal exposure, while noradrenaline was determined from cutaneous microdialysate collected every 20min throughout the study period. Cooling induced peripheral sympathetic activation in patients and controls with significant increases in dermal noradrenaline, vasoconstriction, and reduction in skin temperature. The main findings were that the noradrenaline response did not differ between patients and controls or between the CRPS hand and the contralateral unaffected hand, suggesting that the evoked noradrenaline release from the cutaneous sympathetic postganglionic fibres is preserved in chronic CRPS patients.


Pain. 2002 Jul;98(1-2):19-26.

Skin temperature side differences–a diagnostic tool for CRPS? click here

Wasner G, Schattschneider J, Baron R.


Klinik für Neurologie, Universitätsklinikum Kiel der Christian-Albrechts-Universität, Niemannsweg 147, 24105 Kiel, Germany.


Complex regional pain syndrome type I (CRPS I) is a chronic painful disease of one extremity that may develop as a disproportionate consequence of a trauma affecting the limbs without overt nerve injury. It is clinically characterized by sensory, motor and autonomic symptoms including vascular abnormalities. Previously, we have reported that pathophysiological alterations of the ongoing sympathetic activity play a crucial role in vasomotor disturbances (Brain 124 (2001) 587). As a companion article, the aim of this study was to evaluate the diagnostic value of skin temperature side differences in consideration of the spontaneous sympathetic vasoconstrictor activity. Twenty-five patients with CRPS I were studied. Fifteen patients with painful limbs of other origin and 20 healthy individuals served as controls. Controlled thermoregulation was performed to change cutaneous sympathetic vasoconstrictor activity by the use of a thermal suit: skin sympathetic vasoconstrictor neurones were activated by whole-body cooling and nerve activity was abolished by whole-body warming. Skin temperature at the affected and unaffected limbs (infra-red thermometry) was measured under resting conditions and continuously monitored during controlled modulation of sympathetic activity. The results showed only minor skin temperature asymmetries between both limbs under resting conditions in most CRPS patients. However, during controlled thermoregulation temperature differences between both sides increased dynamically and were most prominent at a high to medium level of vasoconstrictor activity. In both control groups, there were only minor side differences in temperature both in rest and during thermoregulatory changes of sympathetic activity. When comparing the diagnostic value of skin temperature asymmetries in CRPS I, sensitivity was only 32% under resting conditions, but increased up to 76% during controlled alteration of sympathetic activity. Specificity was 100% at rest and 93% at controlled thermoregulation. We concluded that the degree of unilateral vascular disturbances in CRPS I depends critically on spontaneous sympathetic activity. Taking this into consideration, skin temperature differences in the distal limbs are capable of reliably distinguishing CRPS I from other extremity pain syndromes with high sensitivity and specificity.


Pain Pract. 2013 Jan 21. doi: 10.1111/papr.12027. [Epub ahead of print]

Targeting Oxidative Injury and Cytokines’ Activity in the Treatment with Anti-Tumor Necrosis Factor-α Antibody for Complex Regional Pain Syndrome 1. click here

Miclescu AA, Nordquist L, Hysing EB, Butler S, Basu S, Lind AL, Gordh T.


Pain Clinic, Uppsala University Hospital, Uppsala, Sweden.


Cytokines and oxygen free radicals have been implicated in the potential pathogenic development of complex regional pain syndrome (CRPS). We aimed to analyze the relationship between clinical status, circulating levels of cytokines, and markers of oxidative damage during the treatment with anti-TNFα antibodies. The patient chosen for treatment had not had improvement through a number of conventional therapies and fulfilled the current diagnostic criteria for CRPS-1. We investigated the clinical variables before and after systemic administration of 1.4 mg/kg anti-TNFα antibody (infliximab), repeated after 1 month in a dose of 3 mg/kg. Blood samples were collected before and after anti-TNFα antibodies administration, and plasma was analyzed for 8-isoprostane-prostaglandin F2α (8-iso-PGF2α, a marker of oxidative injury) and cytokines (TNF-α, IL-4, IL-6, IL-7, IL-8, IL-10, IL-17A). Plasma concentrations of 8-iso-PGF2α were measured with radioimmunoassay (RIA), and the kinetics of cytokines were detected in plasma by antibody-based proximity ligation (PLA). Pathologically high levels of 8-iso-PGF2α were found in the patient. Immediately after each administration of infliximab, the levels of 8-iso-PGF2α decreased. Although the patient showed an improvement of the cutaneous dystrophic symptoms and diminished pain associated with these lesions, the levels of circulating TNFα increased after the administration of anti-TNFα antibodies. In a patient with CRPS-1 treated with anti-TNFα antibodies, we report increased levels of circulating TNFα and a temporary mitigation of oxidative stress as measured by plasma F(2) -isoprostane. This case report provides evidence 2 supporting the indication of monitoring the oxidative stress biomarkers during treatment with anti-TNFα antibodies in CRPS 1.


Neuroscience. 2013 Jan 3;234C:69-76. doi: 10.1016/j.neuroscience.2012.12.042. [Epub ahead of print]

High-intensity swimming exercise reduces neuropathic pain in an animal model of complex regional pain syndrome type I: Evidence for a role of the adenosinergic system. click here

Martins DF, Mazzardo-Martins L, Soldi F, Stramosk J, Piovezan AP, Santos AR.


Laboratório de Neurobiologia da Dor e Inflamação, Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário – Trindade, Florianópolis, SC, Brazil; Programa de Pós-Graduação em Neurociências, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário – Trindade, Florianópolis, SC, Brazil; Curso de Fisioterapia, Universidade do Sul de Santa Catarina, Campus Grande Florianópolis – Palhoça, SC, Brazil.


This study investigated the involvement of the adenosinergic system in antiallodynia induced by exercise in an animal model of complex regional pain syndrome type I (CRPS-I). Furthermore, we analyzed the role of the opioid receptors on exercise-induced analgesia. Ischemia/reperfusion (IR) mice, nonexercised and exercised, received intraperitoneal injections of caffeine (10mg/kg, a non selective adenosine receptor antagonist), 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) (0.1mg/kg, a selective adenosine A(1) receptor antagonist), ZM241385 (3mg/kg, a selective adenosine A(2A) receptor antagonist), adenosine deaminase inhibitor erythro-9-(2-hydroxy-3nonyl) adenine [(EHNA), 5mg/kg, an adenosine deaminase inhibitor] or naloxone (1mg/kg, a nonselective opioid receptor antagonist). The results showed that high-intensity swimming exercise reduced mechanical allodynia in an animal model of CRPS-I in mice. The antiallodynic effect caused by exercise was reversed by pretreatment with caffeine, naloxone, DPCPX but it was not modified by ZM241385 treatment. In addition, treatment with EHNA, which suppresses the breakdown of adenosine to inosine, enhanced the pain-relieving effects of the high-intensity swimming exercise. This is the first report demonstrating that repeated sessions of high-intensity swimming exercise attenuate mechanical allodynia in an animal model of CRPS-I and that the mechanism involves endogenous adenosine and adenosine A(1) receptors. This study supports the use of high-intensity exercise as an adjunct therapy for CRPS-I treatment.


For information about our clinics in London specialising in the treatment of CRPS, please visit our website here or call 07932 689081


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