CHRONIC DISABLING DISEASES AND DISORDERS: THE CHALLENGES OF FIBROMYALGIA
The National Institute of Dental Research

 

The success of American health care over the last 50 years has profoundly reduced mortality. The science and knowledge transfer to health professionals and the public has been remarkable. People live longer than ever before in human history. We have evolved from an era of acute and dramatic diseases to the current era of chronic disabling diseases and disorders. Ironically, as we live longer, chronic diseases and disorders now account for 80 percent of all deaths and 80 percent of all morbidity. Moreover, the rate of increase in chronic disabling diseases and disorders such as periodontal diseases, chronic facial pain, temporomandibular diseases and disorders, diabetes, cerebrovascular strokes, coronary diseases, arthritis, osteoporosis and rheumatism continues to surpass the growth of acute diseases.

Chronic diseases require a different paradigm. Chronic and disabling diseases and disorders are complex and persist over very long periods of time. Most important, chronic disease requires that each of us make a critical distinction between disease and illness.

Disease in this sense is a biological phenomenon, which can be defined and understood in molecular and physiological terms. Much of biomedical research is motivated to discover the molecular basis of a disease--to define and understand the natural history, etiology and pathogenesis of the disease. For example, the discovery of insulin and the relationship between insulin and diabetes, amelogenin and ameloblastin and amelogenesis imperfecta, mutations in hemoglobin and the relationship with sickle cell anemia. Modern dentistry and medicine are accumulating an ever-increasing arsenal of molecular-based diagnostics and therapeutics for a large number of human diseases. Illness, in contrast, is not a biological process that has become abnormal, but rather a subjective set of issues that encompasses pain, discomfort and dysfunction and often interferes with social as well as physical functioning. Illness further involves fears, concerns and profound emotional dislocations produced by the disease state.

For the increasing number of patients with chronic and disabling diseases and disorders, health professionals need to develop a comprehensive understanding of the disease as well as the competence to manage the illness over the long term. This article focuses on the recently defined fibromyalgia syndrome to serve as an exemplar for the challenges of chronic diseases for today and tomorrow.

 

FIBROMYALGIA

A patient with symptoms of chronic facial muscle pain and/or aching is not unusual. Each of us in dentistry understands that a number of diseases and disorders are associated with the symptoms of pain--for example, tooth decay, diabetic neuropathy, amputation neuroma, trigeminal neuralgia, TMD, periapical abscess, osteoarthritis and progressive osteopenia. Facial pain can also be associated with periodontal disease, facial trauma, oral cancer and the pain and discomfort associated with xerostomia in Sjögren's syndrome. Consider the literally millions of American patients who have long-standing and widespread chronic facial and skeletal muscle pain, which is localized and diffuse and located bilaterally as well as above and below the waist. The pain is exquisitely sensitive to pressure in well-defined areas. These patients additionally may suffer from disturbed sleep, depression and chronic fatigue. Consider the differential diagnosis of a newly recognized medical syndrome called fibromyalgia and the attendant issues of illness.

In the mid-19th century European scientists described a seemingly exaggerated tenderness to palpation and called this condition by a number of terms, including spinal irritation and fibrositis. For a time it was deemed the cause of low back pain. By the early 1900s, this condition of tenderness was identified under the light microscope as inflamed areas of the fibrous tissue or fascia that surrounds the major muscles of the back. Utilization of more sophisticated microscopes and carefully designed research studies revealed that the nature of this pain may not be due to inflammation. With the lack of a definitive cause of the pain, the condition was identified as psychogenic rheumatism; it was considered not to be a legitimate condition but thought to be a neurotic or hysterical problem.

Significantly, in 1979 fibrositis again surfaced as a disease entity when Smythe and colleagues in Toronto published Fibrositis as a Disorder of Pain Modulation. They catalogued sleep EEG abnormalities, quantified and described pain tender points, and associated chronic fatigue with related systemic conditions. In the early 1980s, this syndrome was termed fibromyalgia, or FMS, from three Latin words: fibro (meaning fibrous tissue such as ligaments, tendons or fascia); my (meaning muscle tissue); and algia (denoting pain). FMS includes pain that emanates from tendons, ligaments, bursae and muscle tissue. The term syndrome is used rather than disease because disease implies that all people with a given disorder have essentially the same or similar symptoms that result from a common biological source. In FMS, the symptoms can vary from person to person and may include more generalized discomfort beyond the chronic and widespread craniofacial and skeletal muscular pain with specific tender points. Of course, in the absence of a definitive biological marker(s), it is reasonable to assume that FMS may describe more than one disease with closely related or shared symptoms.

 

 

 

IDENTIFYING THE CRITERIA

The genesis of FMS is interesting to consider. In 1987, the reproducibility of the abnormalities in FMS led the Journal of the American Medical Association to editorialize that FMS did exist. A national panel was formed to define FMS for statistical and epidemiological purposes; its recommendations were published and adopted by the American College of Rheumatology in 1990. As there are no specific or unique genes or protein markers for this syndrome yet, the following criteria to establish a diagnosis of FMS were recommended:

• a history of at least three months of widespread pain;
• the pain is evident by digital palpation (approximate force of 4 kilograms) in at least 11 of the 18 tender-point sites indicated in the figure.

An instrument called a dolorimeter, which distributes pressure evenly over a discrete point, is often used to more objectively gain data about each patient and each site of pain and discomfort. In addition, craniofacial/axial skeletal pain (cervical spine, anterior chest, thoracic spine and/or low back) must be present. The 18 tender points as shown in the figure are:

• occiput: bilateral, at the suboccipital muscle insertions;
• low cervical: bilateral, at anterior aspects of the intertransverse spaces at C5-C7;
• trapezius: bilateral, at the midpoint of the upper border;
• supraspinatus: bilateral, at origins above the scapula spine near the medial border;
• second rib: bilateral, at the second costochondral junctions;
• lateral epicondyle: bilateral, 2 centimeters distal to the epicondyles;
• gluteal: bilateral, in upper, outer quadrants of buttocks in the anterior fold of muscle;
• greater trochanter: bilateral, posterior to the trochanter prominence;
• knee: bilateral, at the medial fat pad proximal to the joint line.

The criteria indicate that the combination of widespread pain in all four quadrants of at least three months' duration and mild or greater tenderness at 11 of the 18 tender points was observed to be specific for more than 80 percent of the cases in delineating the presence of FMS. In the diagnosis of FMS, inclusion of chronic fatigue, sleep disturbance, paresthesias and anxiety has an accuracy of more than 60 percent and headache or irritable bowel syndrome an accuracy of more than 50 percent.

 

Until the pathophysiology of this entity is clarified, clinicians need to consider the possibility that patients with typical complaints but fewer tender points may still have similar processes affecting them as those affecting patients with classic FMS. As FMS can be found in association with a wide variety of conditions, the concomitant diagnosis of FMS may be obscured by an underlying entity such as TMD, chronic fatigue syndrome, irritable bowel syndrome and rheumatoid arthritis. Likewise, in new patients presenting with symptoms suggesting FMS, a search should be made for an underlying condition.

 

THE EPIDEMIOLOGY AND ETIOLOGY OF FMS

With the criteria set for the syndrome, surveys were conducted to determine its principle epidemiologic features. In the United States, 3 to 6 million people may be afflicted with FMS. In a recent study in Wichita, Kan., it was reported that the prevalence of FMS increased with age. It was 0.9 percent in the age group of 18 to 30 years, 5.6 percent in the age group of 50 to 59 years and 7.4 percent in the age group of 70 years and older. FMS is probably present in 2 percent of the general population as opposed to chronic widespread pain in 11 percent and chronic regional pain in 20 percent of the population. Eighty to 90 percent of those afflicted are women with a mean age in the early 50s. It is estimated that 15 to 20 percent of patients seen by rheumatologists have FMS. Surveys performed outside the United States frequently used different assumptions, but suggest that FMS is present worldwide, with a prevalence ranging from 0.5 to 12 percent.

In defining FMS, the overwhelming characteristic is long-standing pain at defined tender points. Full recovery can occur but is unusual. This soft-tissue pain can be described as deep aching, radiating, gnawing, shooting or burning. These sensations range from mild to severe and are felt deep within muscles, ligaments or tendons. Often a patient appears to suffer joint pain although this is usually associated with rheumatoid arthritis and suggests a connective-tissue disorder, autoimmunelike disease, neuromuscular dysfunctions, neuroendocrine disorders or several other candidates. Typically, the body aches with stiffness upon awakening; the aches may improve during the day and increase again toward the evening. Pain often increases with activity, cold, damp weather, anxiety and stress. Muscle spasm and cramping are more common at night, often awakening the patient.

The term trigger point is often incorrectly used in referring to a tender point. Tender points as found in FMS hurt only when pressed, while trigger points may be tender locally but also lead to referred pain that travels or spreads. Trigger points are used to identify myofascial pain syndrome, which results from specific injury or mechanical stress such as unaccustomed repetitive movement, and are limited to one region of the body. In FMS, patients appear to experience pain from noxious stimuli that is usually below one's pain threshold; the stimuli transmit this pain from the periphery to the central nervous system (nociception). Pain perception is normal but pain tolerance may be decreased as a result of perturbations in the central nociceptive mechanisms.

Several normal body chemicals are suspected of being responsible for this pain amplification, including substance P, serotonin, excitatory amino acids, and opiates and endorphins. Substance P is an inflammatory mediator involved in pain and inflammation, is believed to initiate nerve activity in the periphery, cause vasodilation, plasma extravation and hyperalgesia as well as the release of cytokines, endorphins and cellular enzymes. It has been reported to be significantly raised in the cerebrospinal fluid, or CSF, of patients with FMS. The decrease in serotonin levels in the spinal fluid has become the focus of research for several FMS groups. Serotonin is a neurotransmitter that inhibits transmission of pain in the spinal cord. It is derived from the amino acid L-trytophan, one of a group of excitatory amino acids decreased in amount in the spinal fluid of patients with FMS. Serotonin itself is difficult to measure but can be measured indirectly by the binding of isotopically labeled imipramine, a biochemical indicator of serotonin uptake in platelets (which contain most serotonin). This activity is increased in patients with FMS. Serotonin also interacts with opiates to decrease pain perception. In 1996, a class of opioids called kappa opioids was reported to relieve moderate-to-severe pain in women, and with little effect in men, suggesting a gender biological difference in pain perception. The involvement of serotonin and the effect of its decrease in FMS are the subject of controversy. Its role as well as that of a number of CSF molecules, if any, in FMS pain will await the results of future research.

 

CONDITIONS ASSOCIATED WITH FMS

A number of conditions are regularly reported to be associated with FMS or to mimic its symptoms. These include, among others, rheumatoid arthritis, hypothyroidism, cervical and low-back degenerative disease, Lyme disease, chronic fatigue syndrome, sleep disorders, depression and even HIV infection. Two other conditions that are of particular interest to those of us in dentistry include Sjögren's syndrome, or SS, and TMD. In the past few years, there have been a number of research articles addressing the relationship of these dental, oral and craniofacial conditions with FMS. FMS, SS, osteoarthritis, osteoporosis and TMD all suggest the importance to oral health professionals of gaining more knowledge and a much better understanding of gender biology in the context of chronic disabling diseases and disorders and accompanying illness.

 

 

 

Sjögren's syndrome. In several recent clinical studies, it was reported that approximately 50 percent of the patients with SS also had FMS. SS is an autoimmune exocrinopathy having features of both organ-specific and generalized immune disease. The main clinical features are those related to dryness of the mucous membranes, including dry mouth disease, or xerostomia. Other symptoms such as myalgia, arthralgias, fatigue and sleep disturbances have been reported. SS may occur alone, in association with other autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosis or in association with FMS and chronic fatigue syndrome. The presence of FMS and sleep disturbances is believed to be nonspecific.

 

TMD. The relationship between FMS and TMDs is a matter of interest and investigation. Both include chronic pain primarily affecting women, although TMD is reported in a younger population of women (20 to 40 years old) and appears to decrease in prevalence with age, whereas the prevalence of FMS (mean age, 40 years) increases with age. It has been reported that a small proportion of patients with TMD (18.4 percent) also has FMS, but that most individuals with FMS (75 percent) also have myofascial TMD. TMD is often considered to be a local or focal disease or disorder, whereas FMS is essentially a generalized syndrome with clinical signs and symptoms of pain in multiple craniofacial and skeletal regions. Patients with FMS further appear to have generally lower pain thresholds and more intense manifestations of pain, fatigue and sleep loss. A recent survey indicates that the features that best differentiate FMS from TMD are functional disability, reports of work disability and a general dissatisfaction with health.

 

TREATMENT FOR FMS

Treatments for FMS are in many instances palliative and often include patient education, physical therapy and counseling. There are many claims for the benefits of nutritional supplements but as yet no prospective, randomized and double-blinded clinical trials. At this time there is no special diet for patients with FMS, but several reports indicate that fish oil, magnesium/malic acid combinations or vitamins (particularly B12) may be effective. Stress reduction and developing improved coping mechanisms are suggested, often through counseling, hypnosis, electromyograms and biofeedback, fitness training, self-help group discussions and cognitive or behavioral therapy. Gradual exercise programs including swimming and walking, which is low impact, are suggested. Physical therapy in the form of gentle massage, strengthening exercises, electronic acupuncture and relaxation techniques is also being used and may prove to be helpful.

 

 

 

In general, a science-based knowledge of the natural history, etiology and pathophysiology of a disease often leads to reliable diagnostics and therapeutics. Unfortunately, such knowledge is not yet available for FMS and a number of other confounding chronic diseases and disorders. These chronic diseases require scientific inquiry. Therefore, a science-based pharmacological therapeutic approach to FMS will be possible when more scientific knowledge becomes available from future basic, translational and patient-oriented, and demonstration scientific research. Presently, there is a paucity of controlled clinical studies to analyze.

The antidepressants amitriptyline or cyclbenzaprine hydrochloride, in low doses, have been shown to be beneficial in decreasing depression, relaxing craniofacial and skeletal muscles, improving sleep and releasing endorphins. These drugs act by blocking norepi-nephrine and serotonin re-uptake inhibition. Of course, benefits are also accompanied by risks. Common side effects of these drugs include weight gain, palpitation and urinary retention. Benzodiazepines such as clonazepam also promote better sleep, relax craniofacial as well as skeletal muscles and help restless leg syndrome. These drugs can be used with the anti-depressants or with serotonin re-uptake inhibitors but they can also become addictive. Analgesic agents have only limited usefulness in FMS and it is best to avoid narcotics. Non-steroidal anti-inflammatory drugs, although often used in FMS, have not proven to be beneficial in clinical trials. Steroids do not appear to be helpful. Injecting tender points with steroids or local anesthetics such as lidocaine is considered controversial and could lead to a dependence on this method for the relief of symptoms.

Other therapeutic approaches being studied include s-adenosyl-methionine (an antidepressant with anti-inflammatory actions), capsaicin creams (which delete substance P but can be irritating), alprazolam to decrease panic reactions and sleep preparations such as zolpidem. Meanwhile, in the absence of a well-defined, science-based diagnosis and therapy for FMS, patients use so-called complementary or alternative medicine measures such as over-the-counter dietary, vitamin or herbal products, spiritual practices, homeopathy, reflexology, chiropractic strategies and massage.

 

WHAT CAUSES FMS?

Although the specific cause of FMS is not yet established, researchers have several theories about this syndrome. Some suggest that an initial injury or trauma that may affect the central nervous system may cause the syndrome. Others suggest that stress plays an important role in the initiation of FMS and certainly can affect its outcome. FMS may be associated with changes in craniofacial and skeletal muscle metabolism, such as decreased blood flow, causing chronic fatigue and decreased strength. Another hypothesis is that an infectious microbe, such as a virus in susceptible individuals, triggers FMS, but as yet no virus or other microbe (for example, bacteria, yeast or parasite) has been identified.

Several pilot studies suggest a possible familial segregation of FMS that is consistent with autosomal-dominant inheritance with possible female preponderance. In a recent study by Buskila involving 20 mothers with FMS and their 58 offspring aged 5 to 46 years, a high prevalence (that is, 16 offspring [28 percent]) were diagnosed with FMS. The data involve a very small number of individuals in an isolated community. However, these findings complement other published reports that also point to a possible genetic susceptibility to FMS that involves an autosomal-dominant gene(s), which is an expressed clinical phenotype that is gender dependent or modified. This putative genetic liability for a subset of women could be influenced by age, eventually resulting in a strong female preponderance in the older age group (in a general population of people 50 years of age and older with FMS, 80 percent are female). Large family studies including analyses of additional genetic markers are required to eventually define the genetics of this complex human syndrome.

Another fascinating option has surfaced from preliminary research studies seeking to understand a possible relationship between FMS and failed trans-criptional regulation by thyroid hormone. This hypothesis is attractive because it would explain the serotonin deficiency and other objective findings and symptoms of euthyroid (normal thyroid hormone levels) FMS. Virtually all of the signs and symptoms of FMS are mimicked by hypothyroidism. Included in the hypothesis is the premise that a mutant c-erbAb1 gene for the thyroid hormone receptor results in a low-affinity receptor that prevents normal thyroid hormone regulation of transcription. The result would be tissue-specific, hyperthyroidlike symptoms despite normal circulating thyroid hormone levels. This hypothesis is testable with current methodology and is currently being investigated.

Other scientific studies include those designed to investigate the regulation of the function of the adrenal gland, which produces the hormone cortisol. Cortisol is present in abnormally low levels in patients with FMS and can result in many of the same symptoms found with FMS. Researchers are also concentrating on how specific brain structures are involved in the painful symptoms of FMS. Magnetic resonance imaging and magnetic resonance spectroscopy are powerful tools that have become useful in evaluating craniofacial and skeletal muscle diseases and disorders, and these methods are being applied to research in FMS. Yet other scientific projects are being carried out using as a model a post-Lyme disease syndrome that resembles FMS.

 

CONCLUSION

We are entering a new era, an era dominated by chronic and disabling diseases and disorders rather than acute diseases. We clearly need to make a distinction between disease and illness when considering the millions of patients who present the confounding challenges of chronic diseases. Research studies indicate that 2 percent of the general adult population is afflicted with FMS; this represents almost 5 million people. At this time, there is not an understanding of the etiology and pathogenesis of this syndrome or a highly specific and sensitive diagnostic and therapeutic approach. This is an example of an area yet to be fully explored and understood.

Meanwhile, for those of us in the oral health profession, this discussion of FMS was intended to provide a useful prompt so that each of us can improve our understanding and management of the increasing number of patients who have diseases and illnesses associated with chronic facial pain and chronic fatigue.

 

Figure. Eighteen tender-point sites associated with fibromyalgia.A number of conditions are regularly reported to be associated with FMS or to mimic its symptoms.Treatments for FMS are in many instances palliative and often include patient education, physical therapy and counseling.