A Review of Physiological Measurements Among Patients Diagnosed With Complex Regional Pain Syndrome

The combination of disproportionate pain intensity and limb disuse is often diagnosed as complex regional pain syndrome (CRPS), a label that may imply a specific measurable pathophysiology. In a review of studies of pathophysiology associated with diagnosis of CRPS, we asked, "How often are studies based on comparisons of diagnosed limbs and either undiagnosed limbs or healthy controls, and how many different research groups have addressed specific measures?"

We searched PubMed, Embase, and Cochrane using keyword terms to identify studies of CRPS pathophysiology. Peer-reviewed experiments measuring pathophysiology in ≥10 people diagnosed with CRPS were included. Pilot searches demonstrated sufficient attempts to measure pathophysiology, and a structured review was deemed feasible. A formal search yielded 1,207 studies. Fifty studies from each database (150 in total) were audited revealing no eligible studies, confirming that initial screening captured the relevant evidence.

Thirty-seven studies measured different aspects of pathophysiology: molecular concentrations (serum cytokines, induced blister fluid and CSF cytokines, and serum autoantibodies, protease, and CGRP), neuropathophysiology in skin biopsy (fiber degeneration and nerve fiber density), cell type (mast cells/keratinocytes, monocytes, and T lymphocytes), metabolism (skin lactate, tissue oxygenation, and protein extravasation), and others (serum OPG, amino acids/antioxidants/B-endorphin, alpha-1 adrenoceptors, and MMP) among 1,340 people diagnosed with complex regional pain syndrome and 960 control subjects. Ten studies compared measurements between diagnosed and undiagnosed limbs and eight reported a difference. Thirty-four studies compared measurements between people diagnosed and not diagnosed with CRPS and 30 reported a difference.

To date, the measured physiological differences between limbs diagnosed with CRPS and other limbs are compatible with known consequences of limb disuse and are somewhat inconsistent. While experiments continue to search for treatable pathophysiology, CRPS can be accurately and usefully associated with universal and treatable aspects of human illness behavior such as kinesiophobia and worst-case thinking.