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.

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.

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.

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.