Osteoarthritis (OA) of the hip and knee is a common chronic pain condition, the impact of which will continue to increase as the population ages. OA is typically diagnosed when an individual presents for medical attention with pain in the hip or knee and a radiograph is obtained that documents degenerative changes consistent with OA. Pain in OA has been classically attributed to joint damage, and nearly all therapies have been aimed at treating or curing the pain derived from this “organ,” including exercise, topical analgesics, oral nonsteroidal antiinflammatory drugs (NSAIDs) and opioids, direct injections, and eventually joint replacement. Clearly, the limited or short-term efficacy of most available therapies (1) and the observation that even replacing the joint does not always cure the pain (2) suggest that factors other than joint pathology must be partially responsible for the pain and dysfunction experienced by patients with chronic OA pain. If damage to the cartilage and bone is the “disease” called OA, then the magnitude of damage to or inflammation in one or both of these structures should predict clinical symptoms. However, population-based studies suggest that there is a significant disparity between the degree of peripheral damage noted on radiographs and the pain and functional limitations that patients with this condition experience. The most dramatic evidence of this is that 30–60% of individuals with moderate to severe radiographic changes of OA are completely asymptomatic, and 10% of individuals with moderate to severe knee pain have normal radiographs (3,4). Not surprisingly, the disparity between radiographic features and symptoms has led investigators to explore the notion that psychological factors are responsible for this discordance. Again, these studies have suggested that psychological factors such as anxiety and depression do account for some of this variance in pain and other symptoms, but to only a small degree (5,6). In this issue of Arthritis & Rheumatism, van Meurs and colleagues explore a new line of research in hip OA that suggests that some of the variance between pain and peripheral damage can be accounted for by a gene involved in modulating pain sensitivity, as well as several other traits. They showed that in a large OA database in which there was the typical poor overall relationship between radiographic changes and pain levels, individuals with the 158Met variant of COMT had an almost 3-fold higher risk (P 0.02) of hip pain as compared with carriers of the Val/Val genotype. As noted by van Meurs et al, this effect was fully driven by the female carriers. Female carriers of the 158Val allele were 4.9-fold more likely to have pain (95% confidence interval 1.6–14.8, P 0.005), while radiographic damage to the hip was present in both genotype groups. Although this effect is very strong, it is not surprising to those involved in the study of pain. Pain is ultimately experienced in the brain, not in the peripheral tissues, and the function of pain processing systems throughout the body markedly influences who has pain and how much pain an individual experiences. Just as we know that there is tremendous variability in pain sensitivity between strains of rodents, there similarly is great variability in pain sensitivity among humans (7). In the past decade, there has been an explosion of knowledge regarding the genetics of pain. Within the past few years alone, we have learned that genes such as those responsible for catechol-O-methyltranferase (COMT), GTP cyclohydrolase 1 (GCH1), and the voltage-gated sodium channel Nav1.9 exert significant control in human pain perception (8–11). Because of this, many investigators involved in the study of pain now believe that chronic pain is itself a disease, and the location of the body Daniel J. Clauw, MD: University of Michigan, Ann Arbor; James Witter, MD, PhD: National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland. Dr. Clauw has received consulting fees, speaking fees, and/or honoraria from Wyeth and UCB (less than $10,000 each) and from Eli Lilly, Forest, Cypress Biosciences, and Pfizer (more than $10,000 each). Address correspondence and reprint requests to Daniel J. Clauw, MD, Professor of Anesthesiology and Medicine, University of Michigan, 24 Frank Lloyd Wright Drive, PO Box 385, Ann Arbor MI 48106. E-mail: dclauw@umich.edu. Submitted for publication November 14, 2008; accepted November 17, 2008.
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Jul 6, 2010
G D Iannetti + 1
Open Access