A complex regional pain syndrome (CRPS)—multiple system dysfunction, severe and often chronic pain, and disability—can be triggered by a minor injury, a fact that has fascinated scientists and perplexed clinicians for decades. However, substantial advances across several medical disciplines have recently improved our understanding of CRPS. Compelling evidence implicates biological pathways that underlie aberrant infl ammation, vasomotor dysfunction, and maladaptive neuroplasticity in the clinical features of CRPS. Collectively, the evidence points to CRPS being a multifactorial disorder that is associated with an aberrant host response to tissue injury. Variation in susceptibility to perturbed regulation of any of the underlying biological pathways probably accounts for the clinical heterogeneity of CRPS.

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Clinical features and pathophysiology of complex regional pain syndrome

The neuro-immune balance in neuropathic pain: involvement of inflammatory immune cells, immune-like glial cells and cytokines.

Fibromyalgia syndrome is a clinically well-characterized chronic pain condition of high socio-economic impact Although the pathophysiology is still unclear, there is increasing evidence for nervous system dysfunction in patients with fibromyalgia syndrome In this case-control study we investigated function and morphology of small nerve fibres in 25 patients with fibromyalgia syndrome Patients underwent comprehensive neurological and neurophysiological assessment We examined small fibre function by quantitative sensory testing and pain-related evoked potentials, and quantified intraepidermal nerve fibre density and regenerating intraepidermal nerve fibres in skin punch biopsies of the lower leg and upper thigh The results were compared with data from 10 patients with monopolar depression without pain and with healthy control subjects matched for age and gender Neurological and standard neurophysiological examination was normal in all patients, excluding large fibre polyneuropathy Patients with fibromyalgia syndrome had increased scores in neuropathic pain questionnaires compared with patients with depression and with control subjects (P < 0001 each) Compared with control subjects, patients with fibromyalgia syndrome but not patients with depression had impaired small fibre function with increased cold and warm detection thresholds in quantitative sensory testing (P < 0001) Investigation of pain-related evoked potentials revealed increased N1 latencies upon stimulation at the feet (P < 0001) and reduced amplitudes of pain-related evoked potentials upon stimulation of face, hands and feet (P < 0001) in patients with fibromyalgia syndrome compared to patients with depression and to control subjects, indicating abnormalities of small fibres or their central afferents In skin biopsies total (P < 0001) and regenerating intraepidermal nerve fibres (P < 001) at the lower leg and upper thigh were reduced in patients with fibromyalgia syndrome compared with control subjects Accordingly, a reduction in dermal unmyelinated nerve fibre bundles was found in skin samples of patients with fibromyalgia syndrome compared with patients with depression and with healthy control subjects, whereas myelinated nerve fibres were spared All three methods used support the concept of impaired small fibre function in patients with fibromyalgia syndrome, pointing towards a neuropathic nature of pain in fibromyalgia syndrome

Small fibre pathology in patients with fibromyalgia syndrome

Complex regional pain syndrome (CRPS) may develop after limb trauma and is characterized by pain, sensory-motor and autonomic symptoms. Most important for the understanding of the pathophysiology of CRPS are recent results of neurophysiological research. Major mechanism for CRPS symptoms, which might be present subsequently or in parallel during the course of CRPS, are trauma-related cytokine release, exaggerated neurogenic inflammation, sympathetically maintained pain and cortical reorganisation in response to chronic pain (neuroplasticity). The recognition of these mechanisms in individual CRPS patients is the prerequisite for a mechanism-oriented treatment.

Complex regional pain syndrome

Peripheral nerve injuries and diseases often lead to pain persisting beyond the resolution of damage, indicating an active disease-promoting process, which may result in chronic pain. This is regarded as a maladaptive mechanism resulting from neuroinflammation that originally serves to promote regeneration and healing. Knowledge on these physiological and pathophysiological processes has accumulated over the last few decades and has started to yield potential therapeutic targets. Key players are macrophages, T-lymphocytes, cytokines, and chemokines. In the spinal cord and brain, microglia and astrocytes are involved. Recently, data have been emerging on the regulation of these players. MicroRNAs and other noncoding RNAs have been discussed as potential master switches that may link nerve injury, pain, and inflammation. Clinical disorders most intensely studied in the context of neuroinflammation and pain are the complex regional pain syndrome, polyneuropathies, postherpetic neuralgia, and the fibromyalgia syndrome, in which recently a neuropathic component has been described. Research from several groups has shown an important role of both proinflammatory and anti-inflammatory cytokines in neuropathic and other chronic pain states in humans. There is ample evidence of an analgesic action of anti-inflammatory cytokines in animal models. The interplay of anti-inflammatory cytokines and the nociceptive system provides possibilities and challenges concerning treatment strategies based on this concept.

Inflammation in the pathophysiology of neuropathic pain.

Complex regional pain syndromes (CRPS) are characterized by persistent and severe pain after trauma or surgery. Neuro-immune alterations are assumed to play a pathophysiological role. Here we set out to investigate whether patients with CRPS have altered systemic pro- and anti-inflammatory cytokine profiles compared to controls on mRNA and protein level. We studied blood cytokine mRNA and protein levels of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF), interleukin-2 (IL-2) and IL-8 and the anti-inflammatory cytokines IL-4, IL-10, and transforming growth factor-beta1 (TGF beta 1) in 40 prospectively recruited patients with CRPS I, two patients with CRPS II, and 34 controls. Quantitative real-time PCR and enzyme linked immunosorbent assay were used. Additionally, the patients underwent quantitative sensory testing and were assessed with the McGill pain questionnaire and the Hospital anxiety and depression scale. Patients with CRPS had higher blood TNF and IL-2 mRNA levels (p=0.005; p=0.04) and lower IL-8 mRNA levels (p<0.001) than controls. The mRNA for the anti-inflammatory cytokines IL-4 and IL-10 was reduced in the patient group (p=0.004; p=0.006), whereas TGF beta 1 mRNA levels did not differ between groups. These results were paralleled by serum protein levels, except for TGF beta 1, which was reduced in patients with CRPS, and for IL-8, which gave similar protein values in both groups. Sensory testing showed a predominant loss of small fiber-related modalities in the patient group. The shift towards a pro-inflammatory cytokine profile in patients with CRPS suggests a potential pathogenic role in the generation of pain.

Differential expression patterns of cytokines in complex regional pain syndrome

Posttraumatic TNF-alpha signaling may be one of the factors responsible for pain and hyperalgesia in complex regional pain syndromes (CRPS). In order to further specify the role of TNF-alpha we investigated tissue (skin) and serum concentrations in three different patient groups: patients with osteoarthritis and planned surgery, with acute traumatic upper limb bone fracture waiting for surgery, and with CRPS I. Thirty patients (10 in each group) were recruited. Mean CRPS duration was 36.1 ± 8.1 weeks (range 8- 90 weeks). Skin punch biopsies were taken at the beginning of the surgery in osteoarthritis and fracture patients and from the affected side in CRPS patients. Blood samples were taken before the respective procedures. Skin and serum TNF-alpha levels were quantified by ELISA. Compared to patients with osteoarthritis, skin TNF-alpha was significantly elevated in CRPS (p<0.001) and fracture patients (p<0.04). Skin TNF-alpha in CRPS patients was higher than in patients with acute bone fracture (p<0.02). In contrast, serum TNF-alpha values were the same in osteoarthritis and CRPS, and lower in fracture patients (p<0.03). Our results indicate a local but not systemic increase of TNF-alpha in CRPS patients. This increase persists for months after limb trauma and may offer the opportunity for targeted treatment.

TNF-alpha in CRPS and ‘normal’ trauma – Significant differences between tissue and serum

Objective: To investigate clinical differences in warm and cold complex regional pain syndrome (CRPS) phenotypes. Background: CRPS represents inhomogeneous chronic pain conditions; approximately 70% patients with CRPS have “warm” affected limbs and 30% have “cold” affected limbs. Methods: We examined 50 patients with “cold” and “warm” CRPS (n 25 in each group). Both groups were matched regarding age, sex, affected limb, duration of CRPS, and CRPS I and II to assure comparability. Detailed medical history and neurologic status were assessed. Moreover, quantitative sensory testing (QST) was performed on the affected ipsilateral and clinically unaffected contralateral limbs. Results: Compared with patients who had warm CRPS, patients who had cold CRPS more often reported a history of serious life events (p 0.05) and chronic pain disorders (p 0.05). In cold CRPS, the incidence of CRPS-related dystonia was increased (p 0.05), and cold-induced pain had a higher prevalence (p 0.01). Furthermore, QST revealed a predominant sensory loss in patients with cold CRPS (p 0.05). In contrast, patients with warm CRPS were characterized by mechanical hyperalgesia (p 0.05) in the QST of affected limbs. Conclusion: Our results indicate that warm and cold complex regional pain syndromes (CRPS) are associated with different clinical findings, beyond skin temperature changes. This might have implications for the understanding of CRPS pathophysiology. Neurology ® 2009;72:505–512

https://rsds.org/wp-content/uploads/2015/02/Eberle_Neurology_2009.pdf

Warm and cold complex regional pain syndromes: differences beyond skin temperature?

Objective: Complex regional pain syndrome (CRPS) is a chronic pain condition characterized by sensory, motor, and autonomic symptoms. It develops after limb trauma and may be associated with relevant psychiatric comorbidity. As there is evidence for central pathophysiology which might be related to an altered opioidergic neurotransmission, we investigated the cerebral opioid receptor status under resting conditions in this patient population. Methods: In this case-control study, 10 patients with CRPS and 10 age- and gender-matched healthy subjects underwent a PET scan using the subtype-nonselective opioidergic radioligand [ 18 F]fluoroethyl-diprenorphine. As a surrogate for regional cerebral opioid receptor availability, the opioid receptor binding potential (OR-BP) was assessed by means of the modified Logan plot with reference region input for categorical group comparison and correlation with clinical data in the patient group. Results: Patients with CRPS showed reduced OR-BP in contralateral amygdala and parahippocampal gyri and increased OR-BP in contralateral prefrontal cortical areas. When OR-BP in the midcingulate cortex and the ipsilateral temporal cortex was low, the McGill pain rating index was high. In general, when anxiety and depression scales were high, contralateral temporal OR-BP was high as well. In addition, the anxiety scale decreased with increasing OR-BP in the contralateral parahippocampal cortex. Conclusions: These results demonstrate altered central opioidergic neurotransmission in CRPS. The correlation of regional opioid receptor availability to measures of pain, anxiety, and depression underlines the clinical importance of these findings.

Central opioidergic neurotransmission in complex regional pain syndrome

Stress tasks are used to induce sympathetic nervous system (SNS) arousal. However, the efficacy and the patterns of SNS activation have not been systematically compared between different tasks. Therefore, we analyzed SNS activation during the following stress tasks: Presentation of negative, positive, and - as a control - neutral affective pictures, Color-Word interference test (CWT), mental arithmetic under time limit, singing a song aloud, and giving a spontaneous talk. We examined 11 healthy subjects and recorded the following SNS parameters: Activation of emotional sweating by quantitative sudometry, skin vasoconstriction by laser-Doppler flowmetry, heart rate by ECG, blood pressure by determination of pulse wave transit time (PWTT), and electromyographic (EMG) activity of the trapezius muscle. Moreover, subjective stress ratings were acquired for each task using a visual analog scale. All tasks were felt significantly stressful when compared to viewing neutral pictures. However, SNS activation was not reliable: Affective pictures did not induce a significant SNS response; singing, giving a talk and mental arithmetic selectively increased heart rate and emotional sweating. Only the CWT globally activated the SNS. Regarding all tasks, induction of emotional sweating, increase of heart rate and blood pressure significantly correlated with subjective stress ratings, in contrast to EMG and skin vasoconstriction.Our results show that the activation of the SNS widely varies depending on the stress task. Different stress tasks differently activate the SNS, which is an important finding when considering sympathetic reactions - in clinical situations and in research.

/pdf/patterns-of-sympathetic-responses-induced-by-different-3fhniunlws.pdf

Patterns of sympathetic responses induced by different stress tasks.

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