CRPS and inflammation

Following from Luke’s outline of his work, here are some other pieces of research looking at inflammation and CRPS

Inflammation

 

 

 

 

 

 

J Pain. 2012 Jan;13(1):10-20. Epub 2011 Dec 14.

Changes in plasma cytokines and their soluble receptors in complex regional pain syndrome.

Department of Neurology, Drexel University College of Medicine, Philadelphia, Pennsylvania.

Complex Regional Pain Syndrome (CRPS) is a chronic and often disabling pain disorder. There is evidence demonstrating that neurogenic inflammation and activation of the immune system play a significant role in the pathophysiology of CRPS. This study evaluated the plasma levels of cytokines, chemokines, and their soluble receptors in 148 subjects afflicted with CRPS and in 60 gender- and age-matched healthy controls. Significant changes in plasma cytokines, chemokines, and their soluble receptors were found in subjects with CRPS as compared with healthy controls. For most analytes, these changes resulted from a distinct subset of the CRPS subjects. When the plasma data from the CRPS subjects was subjected to cluster analysis, it revealed 2 clusters within the CRPS population. The category identified as most important for cluster separation by the clustering algorithm was TNFα. Cluster 1 consisted of 64% of CRPS subjects and demonstrated analyte values similar to the healthy control individuals. Cluster 2 consisted of 36% of the CRPS subjects and demonstrated significantly elevated levels of most analytes and in addition, it showed that the increased plasma analyte levels in this cluster were correlated with disease duration and severity. PERSPECTIVE: The identification of biomarkers that define disease subgroups can be of great value in the design of specific therapies and of great benefit to the design of clinical trials. It may also aid in advancing our understanding of the mechanisms involved in the pathophysiology of CRPS, which may lead to novel treatments for this very severe condition.

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Pain Med. 2011 Dec;12(12):1784-807. doi: 10.1111/j.1526-4637.2011.01273.x. Epub 2011 Nov 14.

Implications of a Local Overproduction of Tumor Necrosis Factor-α in Complex Regional Pain Syndrome.

School of Psychology, Murdoch University, Perth, Western Australia, Australia.

Objective.   To review the implications of a local overproduction of tumor necrosis factor-α for the pathogenesis and treatment of complex regional pain syndrome. Background.  Elevated local production of tumor necrosis factor-α contributes to prolonged inflammation in the early stages of complex regional pain syndrome. Consequences could include hypoxia and necrosis of local tissues. Methods.  We conducted a review of articles published since 2000 on tumor necrosis factor-α in complex regional pain syndrome. Results.  We propose that exaggerated local inflammation, subsequent inhibition of N-type calcium channel currents in sympathetic vasoconstrictor neurons and reduced sympathetic neurotransmitter release from perivascular terminals disrupt sympathetic cutaneous vasoconstrictor activity in complex regional pain syndrome. The resultant microvascular disturbance could exacerbate inflammation in the affected limb. In addition, an underactive cholinergic anti-inflammatory pathway might lead to overproduction of tumor necrosis factor-α. The results of large, randomized controlled treatment studies that test the efficacy of selective anti-tumor necrosis factor-α drugs in complex regional pain syndrome are not yet available. However, numerous small-scale studies and case reports indicate that anti-inflammatory drug treatments that directly or indirectly target tumor necrosis factor-α ameliorate pain and other symptoms in some cases. Conclusions.  An exaggerated inflammatory cytokine cascade may contribute to sensory and autonomic disturbances in complex regional pain syndrome. Further investigation of anti-tumor necrosis factor-α therapy as a cost-effective treatment option for this devastating disease is required. Whether increased activity in the cholinergic anti-inflammatory pathway provides therapeutic benefits for complex regional pain syndrome also warrants further investigation.

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Handchir Mikrochir Plast Chir. 2010 Feb;42(1):8-14. Epub 2010 Mar 4.

Current concepts in pathophysiology of CRPS I.

[Article in German]

Knowledge about the pathophysiology underlying the complex regional pain syndrome (CRPS) has increased over the last years. Classically, CRPS has been considered to be mainly driven by sympathetic dysfunction with sympathetically maintained pain being its major pathogenetic mechanism. Currently, the disease is understood as result of a complex interplay between altered somatosensory, motor, autonomic and inflammatory systems. Peripheral and central sensitization is a common feature in CRPS as in other neuropathic pain syndromes. One important mechanism is the sensitization of spinal dorsal horn cells via activation of postsynaptic NMDA-receptors by chronic C-fiber input. Differential activity of endogenous pain modulating systems may play a pivotal role in the development of CRPS, too. Neuronal plasticity of the somatosensory cortex accounts for central sensory signs. Also the motor system is subject to central adaptive changes in patients with CRPS. Calcitonin-gene related peptide (CGRP) and substance P mediate neurogenic inflammation. Additionally other proinflammatory cytokines involved in the inflammatory response in CRPS have been identified. In terms of the sympathetic nervous system, recent evidence rather points to a sensitization of adrenergic receptors than to increased efferent sympathetic activity. Particularly the expression of alpha (1)-adrenoceptors on nociceptive C-fibers may play a major role. These pathophysiological ideas do not exclude each other. In fact they complement one another. The variety of the involved systems may explain the versatile clinical picture of CRPS.

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Neurosci Lett. 2008 Jun 6;437(3):199-202. Epub 2008 Mar 30.

Neuropeptides, neurogenic inflammation and complex regional pain syndrome (CRPS).

This review explains symptoms and nature of neuropeptide signaling and its importance for clinical symptoms of CRPS. Neurogenic inflammation regularly accompanies excitation of primary afferent nociceptors. It has two major components-plasma extravasation and vasodilatation. The most important mediators are the calcitonin gene-related peptide (CGRP) and substance P (SP). After peripheral trauma immune reaction (e.g. cytokines) and the attempts of the tissue to regenerate (e.g. growth factors) sensitize nociceptors and amplify neurogenic inflammation. This cascade of events has been demonstrated in rat models of CRPS. Clinical findings in these animals strongly resemble clinical findings in CRPS, and can be prevented by anti-cytokine and anti-neuropeptide treatment. In CRPS patients, there is meanwhile also plenty of evidence that neurogenic inflammation contributes to clinical presentation. Increased cytokine production was demonstrated, as well as facilitated neurogenic inflammation. Very recently even “non-inflammatory” signs of CRPS (hyperhidrosis, cold skin) have been linked to neuropeptide signaling. Surprisingly, there was even moderately increased neurogenic inflammation in unaffected body regions. This favors the possibility that CRPS patients share genetic similarities. The future search for genetic commonalities will help us to further unravel the “mystery” CRPS.

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Neurosci Lett. 2004 Apr 15;359(3):163-6.

Facilitated neurogenic inflammation in unaffected limbs of patients with complex regional pain syndrome.

Pain, edema, increased skin temperature, reddening and trophic changes characterize complex regional pain syndrome (CRPS). Recently, we have been able to show facilitated neurogenic inflammation on the affected limb. In the current study unaffected limbs were examined after resolution of the CRPS symptoms to assess possible generalized changes predisposing to CRPS. In 12 patients and in 12 healthy volunteers dermal microdialysis in combination with electrical C-fiber stimulation was employed to induce neuropeptide release. Dialysate protein concentration and axon reflex vasodilation were measured. Neither in patients nor in controls did electrical stimulation lead to protein extravasation, while axon reflex vasodilation was significantly enhanced even on the patients’ unaffected limbs (P < 0.05). Our results support the hypothesis that facilitated neurogenic inflammation is a predisposing factor for CRPS. The lack of protein extravasation indicates that an initiating trauma is necessary to induce neuropeptide up-regulation in primary afferents.

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Neurology. 2001 Dec 26;57(12):2179-84.

The important role of neuropeptides in complex regional pain syndrome.

Source

Neurologische Klinik, Friedrich-Alexander-Universität Erlangen, Germany. birklein@neurologie.klinik.uni-mainz.de

Abstract

OBJECTIVE:

To test the contribution of neurogenic inflammation and neuropeptide release to the pathophysiology of complex regional pain syndrome (CRPS).

BACKGROUND:

CRPS is characterized by edema and increased skin temperature, sympathetic dysfunction and pain, or hyperalgesia. This investigation was prompted by a recent study by the authors that suggested a facilitated neurogenic inflammation in CRPS.

METHODS:

In addition to physical examination, calcitonin gene-related peptide (CGRP) serum concentrations were measured using a radioimmunoassay (RIA) for human CGRP in 19 patients with acute CRPS, on the affected and unaffected sides (n = 13), before and 9 months after therapy (n = 9). In addition, an age- and sex-matched group of 16 healthy controls was investigated.

RESULTS:

In blood from the cubital vein, CGRP levels in patients with CRPS (122.2 +/- 14.6 pmol/L) were increased (controls 83.8 +/- 6.7 pmol/L, p < 0.03). There was no difference between the affected and unaffected sides. There was, however, a reduction of serum CGRP after therapy (acute disease: 141.2 +/- 18.5 pmol/L, after therapy 106.7 +/- 11.3 pmol/L, p < 0.005); absolute CGRP levels then no longer differed from controls. Increased serum CGRP was correlated to the incidence of nerve lesions (p < 0.02) and hyperhidrosis (p < 0.04). There was no correlation to other clinical symptoms, duration of CRPS, or pain. However, normalization of CGRP after therapy was accompanied by clinical improvement of local inflammatory signs, but not by pain reduction.

CONCLUSIONS:Increased systemic CGRP levels in patients with acute CRPS suggest neurogenic inflammation as a pathophysiologic mechanism contributing to vasodilation, edema, and increased sweating. However, pain and hyperalgesia, in particular in chronic stages, were independent of increased neuropeptide concentration.

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A brief commentary

There are many studies that identify inflammatory involvement in CRPS. Inflammation can be a pain mechanism that underpins part of the experience alongside the other signs and symptoms. Several mechanisms of pain can co-exist, often neuropathic pain concurrent with inflammatory pain. The ‘feel’ can differ, however it surmounts to the overall encounter of the condition. This is the reason why different medication can be prescribed, to tackle the mechanisms identified in the assessment.

The brain always wants to know about inflammation. When the nervous system has been sensitised, it only needs the slightest stimulus to trigger an amplified and prolonged response. This response is protective of the affected area, however, this can be vigorous in CRPS, including other features such as altered movement and sympathetic activity.

We must think about the presence of inflammation and how to best manage this period in terms of movement, exercise and rest. ‘Active rest’ is a self-care tool that should be employed during an inflammatory flare-up. This is NOT bed rest. Active rest means maintaining a level of activity that is tolerable and not at an intensity or volume that provokes further flaring or impedes recovery. A subsequent blog will address active rest.

** Please note that this information does not replace the assessment and treatment of a qualified health professional. If you have concerns about your condition, you are advice to seek the advice of your doctor or physiotherapist.

London CRPS Clinic @ Specialist Pain Physio

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