Daniel Clauw M.D.

Associate Professor of Medicine and Chief, Division of Rheumatology, Immunology, and Allergy

Georgetown University Medical Center

Approximately 10% of the U.S. population suffers from chronic pain throughout their entire body, and over 20% experiences chronic pain in one or more regions of their body [1,2]. The complaint of chronic pain will frequently lead a person to seek medical attention, and the health care provider they consult will typically begin by attempting to identify the source for their patient’s pain. This diagnostic work-up will usually include a history and physical examination, and may also consist of laboratory testing, imaging studies (e.g., X-rays, MRI’s), or other diagnostic testing. At the conclusion of this process, the health care provider usually will interpret all of this information, and the patient is given a diagnosis, and a "cause" for their pain.

Often, a "structural" abnormality is blamed for this chronic pain. Examples of such structural abnormalities include arthritis seen on a plain X-ray, or a bulging disc seen on an MRI. In many cases, the abnormalities that are identified on imaging studies are the true cause for pain, and if this is the case the patient may even benefit from surgery aimed at correcting the abnormality. However, innumerable research studies have shown that in virtually any type of chronic pain condition, there is a poor overall correlation between what is seen on X-ray’s or MRI’s, and how much pain an individual is experiencing [3,4]. For example, there are many people in the population who have arthritis on X-rays, and have no pain in these joints, and many more people who have pain in their joints, but have normal X-rays. This is even more true with MRIs, where up to half of the population may have findings such as bulging discs in their spine, but only a small percentage will have any pain associated with these abnormalities. And again, there are many people who have severe pain but no abnormalities shown by an MRI of this region of the body. The problem of a poor relationship between diagnostic tests and symptoms also holds true for blood tests such as anti-nuclear antibodies, where up to a third of healthy individuals may test positive. When the abnormality on the diagnostic test is not causing the symptom or illness that the person is experiencing, this is called a "false positive" test, and this occurs commonly in chronic pain conditions.

Another equally important problem in chronic regional or widespread pain is a variation a "false-negative" tests. A "false-negative" test refers to the situation where the individual has a negative test result, but nonetheless has the illness or condition that the study is supposed to test for. This is not exactly the situation that occurs in chronic pain, because unfortunately there are no "diagnostic tests" for most chronic pain conditions. However, a variation on this "false-negative" does occur frequently, when the individual presents to a health care provider with chronic regional or widespread pain, and the diagnostic testing which is performed all comes back normal or negative. In some cases this will lead the health care provider to tell the patient that they do not know precisely what is causing their pain (the preferred approach), but in other instances these negative tests will lead the health care provider to infer (or explicitly state) that the patient has a psychiatric cause for their pain.

The above problems are all too familiar to the patient with chronic pain. The solution to these problems is complex, but a few basic principles apply. The first is to acknowledge that we do not know the precise cause for most types of chronic pain, and instead define these syndromes on the location of the pain, and/or the accompanying symptoms. The second principle is that the focus in this setting should be on treatment, since we have some reasonably effective treatments for chronic pain, no matter where it is located in the body.

Chronic pain and fatigue syndromes. There are a number of overlapping syndromes characterized by chronic pain and/or fatigue. Several of these are systemic syndromes (i.e. involving several areas of the body) and include fibromyalgia and chronic fatigue syndrome. Others are regional or localized syndromes that are defined on the basis of involving one area of the body (e.g. TMJ/TMJ syndrome). Although these latter syndromes are defined by the particular area of the body that is involved, in reality many individuals who are found to have one of these localized syndromes will also have chronic pain in other areas of the body (or a past history of pain in other regions of the body). In addition, patients who are diagnosed with one of these regional conditions frequently suffer from not only pain, but also fatigue, sleep problems, memory problems, and a variety of other symptoms that are common to many of these syndrome. This is the reason that many investigators view systemic conditions such as fibromyalgia and chronic fatigue syndrome, as well as a number of organ-specific syndromes such as TMJ, headaches, and irritable bowel syndrome, as being one large group of illnesses that share common underlying mechanisms, as well as similar treatments [5,6]. The clinical features of fibromyalgia and chronic fatigue syndrome, as well as the overlap with organ-specific syndromes, are reviewed below.

Pain and Tender Points. Widespread pain and tenderness are the primary features of fibromyalgia. Although the 1990 American College of Rheumatology criteria require that this pain and tenderness are present in all four quadrants of the body, this is not always the case. There are many individuals who clearly have fibromyalgia whose pain involves only one side of the body, or only affects the upper or lower halves of the body. The pain in fibromyalgia tends to be both migratory (move from place to place) and to wax and wane over time. Stiffness in the morning or after remaining in one position for a prolonged period is common, and patients will frequently note that the pain is worsened by weather changes, physical activity, stress, and menstruation (in women). Although it is common for individuals to report swelling in the regions of pain (e.g., it is common to hear that rings no longer fit on their hands), there is typically no swelling detectable on a physical examination. Although chronic fatigue syndrome is not defined on the basis of tenderness, this illness is also characterized by pain in various location throughout the body, including the joints and muscles, throat, neck, and head.

A tender point is defined as a site where an individual complains of pain when nine pounds of pressure is applied. Although the presence of tender points on physical examination is the hallmark of fibromyalgia, it has recently become clear that there are problems with tender points. There have been several studies suggesting that individuals with fibromyalgia are more sensitive to pain throughout the body, not simply in areas recognized as tender points [7]. In fact, pain sensitivity may be increased in both internal organs and in muscles and joints in fibromyalgia, as has been noted in related conditions such as irritable bowel syndrome [9]. Also, the presence of some tender points is not abnormal, since many people who do not suffer from fibromyalgia will have a few tender points [10]. Finally, pain sensitivity is probably influenced by a number of factors besides age and gender, with aerobic fitness, and poor sleep and depression, probably having opposite effects [10,11]. Because there are so many variables that influence pain sensitivity, it becomes easier to understand why diagnostic criteria that utilize tenderness as the principal determinant will always have limited usefulness.

Fatigue. Most patients with fibromyalgia complain of fatigue, but this is not universally present and is not required for the diagnosis. In some individuals the fatigue can be severe and debilitating, whereas in others it is either not present or has been acclimated because of its chronicity. In chronic fatigue syndrome, fatigue is the defining symptom, meaning that all patients suffer from this complaint. In the general population, persons who have any type of chronic pain problem are also more likely to have chronic fatigue, which has led many to suspect that there may similar underlying causes for chronic pain and fatigue.

Because of early work by Moldofsky and colleagues, the fatigue in fibromyalgia, as well some of the other clinical symptoms, had been considered to be due to a disruption of deep sleep (stage III/IV) by alpha waves. However, there are many individuals with both fibromyalgia and chronic fatigue syndrome who have entirely normal sleep patterns [12]. At present, then, the role of sleep disturbances in the pathogenesis of fibromyalgia is unclear; poor sleep almost certainly makes fibromyalgia, chronic fatigue syndrome, and other related illnesses worse, and in some persons poor quality sleep may cause the illness.

Temporomandibular Joint Dysfunction. Patients with fibromyalgia have been demonstrated to have a higher than expected rate of TMJ, and patients with TMJ have been demonstrated to have a higher than expected rate of fibromyalgia [13]. It is likely that in many cases TMJ is occurring because of pain in the

entire region of the temporomandibular joint, and is associated with diffuse tenderness in the soft tissues in this region, and thus represents a localized form of fibromyalgia, or myofascial pain. Patients with TMJ also have a higher than expected rate of many other fibromyalgia and chronic fatigue syndrome symptoms, including fatigue as well as many of the other symptoms noted below.

Neurological symptoms. For some time it has been clear that individuals with fibromyalgia and chronic fatigue syndrome have a higher than normal incidence of both tension and migraine headaches. There are a number of other neurologic symptoms in these groups of patients, however, that are not as well recognized. Numbness or tingling, typically fleeting in nature and not following the distribution of a single nerve, is a very common complaint in fibromyalgia. In one series, 84% of individuals with fibromyalgia complained of these paresthesias [14]. Hearing, vision, and balance problems have also been noted, including a 70% incidence of decreased painful sound threshold, 40% with evidence of abnormal eye movements, and 27% with low frequency hearing loss [15,16]. Cognitive or memory complaints, especially difficulty with concentration and short-term memory, are also common. Despite these symptoms, standard neurological examinations as well as nerve conduction and imaging studies are normal in these individuals.

"Allergic" symptoms. Patients with fibromyalgia display a wide array of "allergic" symptoms ranging from adverse reactions to drugs and environmental stimuli (such that many fit criteria for "multiple chemical hypersensitivity syndrome") to a higher than expected incidence of rhinitis ("runny nose"), nasal congestion, and lower respiratory symptoms [17]. It is unlikely that there is a true allergic basis for most of these symptoms, but instead that they are due to "hypersensitivities" rather than true immune-mediated allergies.

Cardiac, pulmonary, gastrointestinal symptoms. Individuals with fibromyalgia have long been felt to suffer from a number of symptoms of "functional" disorders of visceral organs, including a high incidence of recurrent non-cardiac chest pain, heartburn, palpitations, and irritable bowel symptoms (IBS) such as alternating diarrhea and constipation, bloating, and abdominal pain. Scientific studies have also documented evidence of subtle dysfunction in many of these areas including a high incidence of echocardiographic (sonogram) evidence of mitral valve prolapse, evidence of abnormal muscle tone in the muscles of the esophagus, and evidence of positive tilt table tests, indicative of "neurally mediated hypotension." These studies suggest that there is a physiologic mechanism for these symptoms, and it is likely to be caused by abnormalities in the control of organs by the central nervous system.

Genitourinary. Individuals with fibromyalgia have a higher than expected incidence of painful menstrual periods, as well as having to urinate often and of feeling the urge to urinate [18]. There may also be an association with other genitourinary conditions such as interstitial cystitis and vulvar vestibulitis or vulvodynia (which are characterized by painful intercourse and sensitivity of the vaginal region).

Affective disorders. Individuals with both chronic fatigue syndrome and fibromyalgia have a higher than expected incidence of current (approximately 20%) and lifetime (50%) major depression, as well as other psychiatric disorders. There is considerable controversy regarding the relationship between these psychiatric conditions and the concurrent physical symptoms. Some feel that this is primarily a psychiatric condition, and that the symptoms experienced are the result of somatization, but most feel that the psychiatric problems some patients with these illnesses experience occur largely as a consequence of the chronic pain, fatigue, and disability that accompanies these conditions.

Summary: Although it is tempting to view pain as a response to inflammation or damage to an organ or tissue, in many patients with chronic pain no such cause can be identified. There are a group of systemic syndromes such as fibromyalgia and chronic fatigue syndrome that are characterized by chronic pain in various locations in the body as well as fatigue, and other syndromes (e.g. TMJ) that are characterized by chronic pain in one region of the body. However, there is overlap between these systemic and regional syndromes. Persons who have diffuse pain also frequently have regional pain syndromes and thus qualify for diagnoses such as TMJ, and persons with diagnoses such as TMJ are more likely to also have chronic pain in other regions of their body, or throughout their entire body. In all of these conditions, it is likely that dysfunction in the nervous system is responsible for pain, instead of the pain being due to damage or inflammation in the painful region. Because of the recognition that we are dealing with a group of overlapping conditions, current research is focusing on how and why an individual experiences pain in the absence of tissue damage. This research is likely to lead to more effective treatments for this spectrum of illness.

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