Lower levels of anti-inflammatory proteins may contribute to chronic widespread pain

Chronic widespread pain, a common medical condition, can be difficult to treat and is often associated with fatigue, poor sleep and depression. A connection between fibromayalgia (FM) and cytokines (proteins that act as messengers between cells) was suspected after cancer patients treated with the cytokine interleukin -2 developed FM-like symptoms. Since then, other studies have shown contradictory results. A new study published in the August 2006 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis) examined cytokine profiles in patients with chronic widespread pain and found that they had significantly lower levels of the anti-inflammatory cytokines IL-4 and IL-10.

Led by Nurcan Üçeyler of Julius-Maximilians University in Wurzburg, Germany, researchers analyzed cytokines in 40 patients with chronic widespread pain (26 of whom had FM), 40 controls and an additional group of 15 patients. The 40 pain patients had received intravenous immunoglobulin (IVIG) as a novel treatment for pain that was not responsive to standard therapy, while the additional 15 patients did not receive this treatment. Blood samples were analyzed for both pro-inflammatory and anti-inflammatory cytokines. In addition, patients were asked to rate their pain, fatigue, mood, cognitive function and sleep quality on a scale of 1 to 10.

Patients in the pain group did not differ in the expression of the pro-inflammatory cytokines IL-2, IL-8 and TNFα, but did have significantly lower levels of the anti-inflammatory cytokines IL-4 and IL-10 compared with the healthy control group. The 15 patients in the additional group showed similar findings, although the difference in IL-10 between this group and the controls was not statistically significant.

The authors point out that there may be several factors involved in the cause of low cytokine levels and how they might be linked to pain. Previous studies have shown that IL-10, administered as a protein or via gene transfer, reduces sensitivity to pain. Similarly, IL-4 has been shown to dull the pain response. "Signals arising through physiologic stimulation of the opioid receptor system may be reduced in patients with low IL-4 levels with subsequent increase in pain perception and the common relative opioid resistance seen in patients with chronic widespread pain," the authors note. In addition, genetic variations in different cytokine genes are associated with distinct diseases, such as the association between IL-4 gene variations and asthma, Crohn's disease, and chronic polyarthritis. "The low levels of IL-4 and IL-10 we observed in the patients with chronic widespread pain might therefore also be caused by genetic alterations either in the cytokine genes themselves or in regulatory elements, although other factors may be involved," the authors state.

The authors acknowledge that this study on 6 key cytokines does not exclude the possibility that other cytokines may play a role in chronic widespread pain. While they acknowledge that low levels of anti-inflammatory cytokines may be a consequence of chronic widespread pain and its treatment, they favor the hypothesis that these proteins actually play a role in the pathophysiology of chronic widespread pain. "Once confirmed and validated in further studies," they conclude, "cytokine expression patterns may eventually help in supporting the diagnosis of chronic widespread pain and in guiding the appropriate treatment approach."

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Article: "Reduced Levels of Antiinflammatory Cytokines in Patients With Chronic Widespread Pain," Nurcan Üçeyler, Regine Valenza, Michael Stock, Robert Schedel, Günter Sprotte, Claudia Sommer, Arthritis & Rheumatism, August 2006; (DOI: 10.1002/art.22026).


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