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Pain. 2014 Nov;155(11):2408-17. doi: 10.1016/j.pain.2014.09.022. Epub 2014 Sep 22.

Longstanding complex regional pain syndrome is associated with activating autoantibodies against alpha-1a adrenoceptors.

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Institute of Translational Medicine, University of Liverpool, Liverpool L9 7AL, UK.
Neuroimmunology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DS, UK.
Department of Neurology, University of Giessen, Giessen, Germany.
Department of Neurology, University of Erlangen/Fuerth, Fuerth 90766, Germany.
Unit of Cardiac Physiology, University of Manchester, Manchester M13 9NT, UK.
Department of Rheumatology, Addenbrookes Hospital, Cambridge CB2 0QQ, UK.
Institute of Translational Medicine, University of Liverpool, Liverpool L9 7AL, UK; Department of Pain Medicine, Walton Centre NHS Foundation Trust, Liverpool L9 7LJ, UK. Electronic address:


Complex regional pain syndrome (CRPS) is a limb-confined posttraumatic pain syndrome with sympathetic features. The cause is unknown, but the results of a randomized crossover trial on low-dose intravenous immunoglobulins (IVIG) treatment point to a possible autoimmune mechanism. We tested purified serum immunoglobulin G (IgG) from patients with longstanding CRPS for evidence of antibodies interacting with autonomic receptors on adult primary cardiomyocytes, comparing with control IgG from healthy and diseased controls, and related the results to the clinical response to treatment with low-dose IVIG. We simultaneously recorded both single-cell contractions and intracellular calcium handling in an electrical field. Ten of 18 CRPS preparations and only 1/57 control preparations (P<0.0001) increased the sensitivity of the myocytes to the electric field, and this effect was abrogated by preincubation with α-1a receptor blockers. By contrast, effects on baseline calcium were blocked by preincubation with atropine. Interestingly, serum-IgG preparations from all 4 CRPS patients who had responded to low-dose IVIG with meaningful pain relief were effective in these assays, although 4/8 of the nonresponders were also active. To see if there were antibodies to the α-1a receptor, CRPS-IgG was applied to α-1a receptor-transfected rat-1 fibroblast cells. The CRPS serum IgG induced calcium flux, and fluorescence-activated cell sorting showed that there was serum IgG binding to the cells. The results suggest that patients with longstanding CRPS have serum antibodies to α-1a receptors, and that measurement of these antibodies may be useful in the diagnosis and management of the patients.


Adrenergic; Autoantibodies; CRPS; Complex regional pain syndrome; Pain

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