In a randomized, placebo-controlled trial described in this issue of Arthritis & Rheumatism, Fregni and colleagues studied the effect of transcranial direct current stimulation (tDCS) on pain and quality of life in patients with fibromyalgia (1). These investigators observed that this noninvasive approach was safe and effective for the short-term treatment of fibromyalgiaassociated pain. The study also highlights the rapid movement toward neuromodulatory treatment of chronic pain, which requires a paradigm shift in how we think of chronic pain and its management. The use of various procedures to treat pain is certainly nothing new. For centuries, many procedures have been performed to ameliorate the “source” of pain and typically have been aimed at eliminating peripheral inflammation or repairing peripheral tissue. Some of these procedures work well (e.g., hip replacement surgery), while others have widespread use even though they have not been shown to be efficacious when formally tested in randomized controlled trials. For example, recent systematic reviews revealed only limited evidence, if any, for the long-term therapeutic benefits (compared with placebo) of facet joint injections, extracorporeal shock wave therapy for lateral elbow pain, or corticosteroid injections for shoulder capsulitis, rotator cuff tendonitis, and lateral epicondylitis (2–5). Moreover, procedures aimed at stabilizing or fusing vertebrae or joints have shown limited success in treating pain, and only in highly selected patients (6,7). The failure of peripherally directed procedures to treat many types of pain is consonant with our current understanding that not all chronic pain is attributable to peripheral damage or inflammation, as measured, for instance, radiographically. In patients with osteoarthritis, there is little relationship between the degree of joint space narrowing and the degree of pain (8). In the setting of low back pain, structural abnormalities on magnetic resonance imaging and discography have only a weak association with back pain episodes and no association with disability or future medical care (9). In fact, in nearly any disease there is a poor relationship between an individual patient’s level of pain and the extent or degree of peripheral damage or inflammation that can be documented on objective testing. We are beginning to understand why such discrepancies may occur. In addition to peripheral or nociceptive pain due to damage or inflammation, there are (at least) 2 other mechanistically distinct types of chronic pain, and these may coexist with peripheral pain (10). Neuropathic pain is a non-nociceptive chronic pain that has been recognized and understood for some time. Although neuropathic pain is usually attributed to damage and subsequent irritability of peripheral nerves, central changes in pain processing constitute a second type of chronic pain in patients with this condition (11). A third type of chronic pain is caused by disturbances in the central processing of pain, alone rather than in association with identifiable peripheral input or nerve damage. Such conditions have sometimes been included in the category of neuropathic pain, but they have fundamental differences from neuropathic pain and are often termed “central” pain syndromes. Such syndromes include fibromyalgia, irritable bowel syndrome, temporomandibular joint disorder, and idiopathic low back pain (12). The hallmark of these conditions is the evidence of pain amplification occurring in Michael C. Hsu, MD, Daniel J. Clauw, MD: University of Michigan Medical School, Ann Arbor. Address correspondence and reprint requests to Daniel J. Clauw, MD, University of Michigan Chronic Pain and Fatigue Research Center, 24 Frank Lloyd Wright Drive, PO Box 385, Ann Arbor, MI 48106. E-mail: dclauw@med.umich.edu. Submitted for publication August 31, 2006; accepted in revised form September 6, 2006. Arthritis & Rheumatism