Inflammation in complex regional pain syndrome: a systematic review and meta-analysis

Abstract

Objectives: We conducted a systematic review of the literature with meta-analysis to determine whether complex regional pain syndrome (CRPS) is associated with a specific inflammatory profile and whether this is dependent on the duration of the condition.

Methods: Comprehensive searches of the literature using MEDLINE, Embase, Scopus, Web of Science, and reference lists from published reviews identified articles that measured inflammatory factors in CRPS. Two independent investigators screened titles and abstracts, and performed data extraction and risk of bias assessments. Studies were subgrouped by medium (blood, blister fluid, and CSF) and duration (acute and chronic CRPS). Where possible, meta-analyses of inflammatory factor concentrations were performed and pooled effect sizes were calculated using random-effects models.

Results: Twenty-two studies were included in the systematic review and 15 in the meta-analysis. In acute CRPS, the concentrations of interleukin (IL)-8 and soluble tumor necrosis factor receptors I (sTNF-RI) and II (sTNF-RII) were significantly increased in blood. In chronic CRPS, significant increases were found in 1) TNFα, bradykinin, sIL-1RI, IL-1Ra, IL-2, sIL-2Ra, IL-4, IL-7, interferon-γ, monocyte chemoattractant protein-1 (MCP-1), and sRAGE (soluble receptor for advanced glycation end products) in blood; 2) IL-1Ra, MCP-1, MIP-1β, and IL-6 in blister fluid; and 3) IL-1β and IL-6 in CSF. Chronic CRPS was also associated with significantly decreased 1) substance P, sE-selectin, sL-selectin, sP-selectin, and sGP130 in blood; and 2) soluble intercellular adhesion molecule-1 (sICAM-1) in CSF. Most studies failed to meet 3 or more of our quality criteria.

Conclusion: CRPS is associated with the presence of a proinflammatory state in the blood, blister fluid, and CSF. Different inflammatory profiles were found for acute and chronic cases.

Figure 1. Flow diagram of study selection

CRPS = complex regional pain syndrome.

Figure 2. Forest plot of inflammatory factor effect sizes for blood samples from acute complex regional pain syndrome cases compared with healthy controls

Each study effect size (standardized mean difference) and weight is indicated by an open box and its 95% confidence interval (CI) are indicated by a horizontal line. The filled diamonds represent the overall effect size and CIs for each factor. Statistically significant outcomes are indicated by an asterisk. CGRP = calcitonin gene-relaxed peptide; ET-1 = endothelin-1; IL = interleukin; SP = substance P; sTNF-R = soluble tumor necrosis factor receptor.

Figure 3. Forest plot of inflammatory factor effect sizes for blood samples from chronic complex regional pain syndrome cases compared with healthy controls

Each study effect size (standardized mean difference) and weight is indicated by an open box and its 95% confidence intervals (CIs) are indicated by a horizontal line. The filled diamonds represent the overall effect size and CIs for each factor. Statistically significant outcomes are indicated by an asterisk. CGRP = calcitonin gene-relaxed peptide; ET-1 = endothelin-1; GP = glycoprotein; IFN = interferon; IL = interleukin; MCP-1 = monocyte chemoattractant protein-1; NPY = neuropeptide Y; SP = substance P; sRAGE = soluble receptor for advanced glycation end products; sTNF-R = soluble tumor necrosis factor receptor.

Figure 4. Forest plot of inflammatory factor effect sizes for suction blister fluid samples from chronic complex regional pain syndrome (CRPS) cases (CRPS-affected compared with the unaffected arm)

Each study effect size (standardized mean difference) and weight is indicated by an open box and its 95% confidence intervals (CIs) are indicated by a horizontal line. The filled diamonds represent the overall effect size and CIs for each factor. Statistically significant outcomes are indicated by an asterisk. IL = interleukin; IP-10 = interferon-inducible protein-10; MCP-1 = monocyte chemoattractant protein-1; MIP-1β = macrophage inflammatory protein 1 beta; TNF = tumor necrosis factor.

Figure 5. Forest plot of inflammatory factor effect sizes for CSF samples from chronic complex regional pain syndrome (CRPS) cases (CRPS cases compared with controls)

Each study effect size (standardized mean difference) and weight is indicated by an open box and its 95% confidence intervals (CIs) are indicated by a horizontal line. The filled diamonds represent the overall effect size and CIs for each factor. Statistically significant outcomes are indicated by an asterisk. IL = interleukin; IP-10 = interferon-inducible protein-10; MCP-1 = monocyte chemoattractant protein-1; MIP-1β = macrophage inflammatory protein 1 beta; NO = nitric oxide; sICAM-1 = soluble intercellular adhesion molecule-1; TNF = tumor necrosis factor.