Pain sensitivity and pain reactivity in osteoarthritis

Pain, stress and inflammation are intricately interrelated (1). Among patients with systemic inflammatory diseases, such as rheumatoid arthritis (RA), the stress response is altered (2). RA patients not taking anti-TNF agents have significantly greater stress-induced increases in TNF-α production compared to controls and RA patients taking anti-TNF agents (3). Similarly, RA patients exhibit increases in serum IL-6 after mental stress associated with anticipation of surgery (4) and increases in serum CRP after mental stress from paced auditory serial addition (5); however, no changes in CRP or IL-6 were noted among osteoarthritis (OA) patients in these studies. The association between stress and inflammation in chronic pain syndromes with low levels of systemic inflammation, such as OA, is not clear. To our knowledge, the two studies cited above are the only two that have assessed the inflammatory stress response in OA. These studies suggest that the inflammatory response to stress may not be as robust among OA patients compared to RA patients (4, 5), but neither study compared the stress response between OA patients and healthy controls. It is not clear whether other stressors (e.g., painful stimuli) may be more effective inducers of the inflammatory response. The potential role of pain as a stressor that enhances the inflammatory response is intriguing because this relationship could be a critical link in the cycle of pain and inflammation that perpetuates chronic painful conditions. Although the effect of acute experimental pain as a stressor in healthy individuals is well-documented (6–8), the data suggesting that pain induces an inflammatory response are limited. A few studies have shown that experimental pain stimuli induce elevations in serum IL-6 among healthy individuals, chronic low back pain patients and RA and juvenile RA patients (9). Our group also recently reported an increase in serum TNF-α among RA patients in response to acute experimental pain stimuli (10). Although these studies have been small and these data are not conclusive, they suggest that the relationship between pain and inflammation should be studied further. In this study, we used psychophysical tests to assess experimental pain sensitivity in 26 knee OA patients and 33 participants from the general population. We examined whether OA patients are more sensitive to experimental pain stimuli than healthy controls and whether the inflammatory response to pain is altered in OA patients compared to controls. These questions were asked because previous studies have shown that OA is a disease involving both peripheral and low-grade systemic inflammation, and inflammation may be associated with central pain processing. Human genetic studies have identified inflammation-relevant genotypes (e.g. polymorphisms in genes encoding IL-1 receptor antagonist) as potential risk factors for OA pain severity (11), and animal studies have shown that peripheral application of inflammatory cytokines induces hyperalgesia (12–14). Little, however, is known about the association between deficits in central pain processing and systemic inflammation (15). We hypothesize that OA patients are: 1) more sensitive to pain in a widespread distribution, indicative of deficits in central pain processing and 2) have an increased systemic inflammatory response to painful stimuli. Previous studies have established that OA patients have lower pain thresholds than healthy controls (16–18), and we recently reported that RA patients have elevated TNF-alpha levels in response to pain (10). If OA patients also have a heightened systemic inflammatory response to pain, then this study may provide a crucial link in the cycle of chronic pain and inflammation, suggesting a model in which peripheral inflammation leads to deficits in central pain processing and widespread pain sensitivity. This, in turn, may lead to an enhanced systemic inflammatory response that may reinforce central pain processing deficits, leading to a cycle of chronic pain and inflammation.