Knowledge of abnormalities in the sleep process improves our understanding of fibromyalgia.

First described by William Balfour, a surgeon at the University of Edinburgh in 1816, fibromyalgia syndrome (FMS) is a chronic multisymptom illness characterized by widespread pain with the presence of discrete tender points symmetrically distributed over the body and associated with neuropsychological symptoms including fatigue, unrefreshing sleep, cognitive dysfunction, anxiety, and depression. It affects an estimated 3.7 million people in the United States and is seen primarily in middle-aged and geriatric women, about eight to nine times more than in men. Patients are typically Caucasian females as it is often not diagnosed in other races. It rarely affects the pediatric population.

Pathophysiology
Although the cause and pathophysiology of fibromyalgia are unknown, various physiologic alterations have been observed in patients with this syndrome. Many of those who suffer from FMS have post-traumatic stress disorder (PTSD) and psychological abnormalities and often have depression, anxiety, somatization, and hypochondrias. Psychological abnormality and psychosocial distress play an important role in the production and maintenance of fibromyalgia symptoms.

Knowledge of abnormalities in the sleep process improves our understanding of the disease and leads to better treatment of patients. More than 75% of patients with fibromyalgia experience a nonrestorative sleep pattern,¹ most likely due to intrusion of faster alpha waves during non-REM (NREM) sleep (stages 2, 3, and 4). Although alpha-wave intrusion has been reported in normal and dysthymic persons as well as those with postaccident pain, this alpha-wave NREM sleep may occur with increased frequency in patients with fibromyalgia.^2,3 Sleep efficiency is low with an increase in awakenings and NREM.¹ Disturbance of sleep physiology with an increase in periodic movements of the legs during sleep and the number of apneas was also seen in some studies, but only in selected patients. The sleep disturbances in FMS have also been related to growth hormone (GH) secretion, and lower levels of growth hormone-related peptide have been found in these patients. As most growth hormone is produced pulsatively, mainly during slow-wave sleep (SWS), which is NREM3+4, disturbances of this sleep stage may result in decreased secretion of growth hormone.⁴

In the mid 1980s, Swedish researchers theorized that the muscle pain of fibromyalgia is a result of tissue hypoxia because of the inability of the muscles to functionally use oxygen. Alterations in muscle, including reports of “moth-eaten” and “ragged-red” muscle fibers, local muscle hypoxia, reduced high-energy phosphate levels, and “rubber band” (also called “taut band”) structure, have been observed in patients with fibromyalgia.^5,6 Although “ragged-red” muscle fibers, local hypoxia, and reduced levels of high-energy phosphate are suggestive of abnormal muscle metabolism, phosphorus nuclear magnetic resonance imaging has not consistently revealed significant differences in muscle metabolic variables between patients and condition-matched controls. In spite of this, many researchers still believe there is substance to this theory. But in the absence of additional evidence, a possible role of impaired muscle metabolism or impaired blood flow seems unlikely.

Serotonin has been found to play an important role in the modulation of pain and stage 4 sleep.⁷ Serotonin is important in deep sleep and in central and peripheral pain mechanisms. Serum levels of serotonin and its dietary precursor tryptophan are classically low in FMS. Decreased levels of serotonin result in decreased SWS and increased somatic symptoms and perceived pain.^7,8 Findings on the relation between serotonin and fibromyalgia include decreased serum levels of serotonin and tryptophan and an increased density of serotonin receptors on circulating platelets in patients with fibromyalgia,⁹ as well as abnormal transport of serum tryptophan.¹⁰ Large doses of oral tryptophan, however, have not been found to affect sleep or intensity of pain in patients with fibromyalgia. Whether serotonin abnormalities are etiologically important in FMS or secondary to it is still unknown.

A significant amount of research has focused on the chemicals of the nervous system, which help regulate pain messages sent out by the brain. Evidence collected during the past several decades suggests a link between FMS abnormalities in the hypothalamus, the autonomic nervous system, and the hypothalamic-pituitary-adrenal (HPA) axis, which regulates production of certain hormones and the body’s response to stress, as likely in the underlying cause of fibromyalgia. Increased cerebrospinal fluid levels of substance P and decreased cerebrospinal levels of norepinephrine have been reported.^11,12 In addition, circadian rhythms of the autonomic nervous system may be blunted in patients with fibromyalgia, resulting in a constant level of sympathetic activity and diminished response to stressors.

The theory that some people with fibromyalgia have exceptionally high-intensity pain messages sent to the brain, along with a deficiency in pain inhibition, is supported by the research indicating abnormal levels of substance P and serotonin, and decreased brain blood flow.

The neuroendocrine theory of FMS analyzed the connection between sleep disorders and muscle damage. The research available so far indicates that about one third of fibromyalgia patients have a growth hormone deficiency. The cause of growth hormone deficiency in FMS patients is due to too much somatostatin (SMS), a regulating hormone released from the brain that inhibits growth hormone production. Researchers postulate that stress and disturbed sleep, leading to the increase of SMS, play a role in GH deficiency. GH deficiency may be linked to lack of proper muscle tissue repair and excessive muscle tissue microtrauma after exertion in fibromyalgia patients. Significantly low levels of serum IGF-I have been found in fibromyalgia patients, which is an indirect measure of GH deficiency.¹³

Some researchers suggested that the sex hormone estrogen is involved as FMS is more common in women than men; however, little correlation has been discovered. It also has been suggested that the lower levels of testosterone in women than in men are more likely involved since testosterone is involved in building muscle strength.

Studies have shown that abnormally low levels of the hormone cortisol may be associated with fibromyalgia. A research team from Massachusetts found that fibromyalgia patients paradoxically produced less cortisol in response to stress than do healthy people, possibly having to do with a defect in the HPA axis, which controls cortisol production.^14,15 This theory of cortisol deficiency occurring in the onset of fibromyalgia is doubtful, as giving patients cortisol steroid medications does not improve the condition.¹⁶

Biological and genetic factors have been studied in this area as well. The relationship between children and parents having either fibromyalgia or other pain-related problems has led some researchers to suggest a genetic cause. It is hoped that further studies will increase understanding about fibromyalgia and may suggest new ways to treat the disorder.

The autoimmune theory of FMS has been considered in the past too since it is often diagnosed in people with autoimmune diseases such as rheumatoid arthritis and lupus erythematosus.

Although adequate evidence supports a hypothesis of neurotransmitter abnormalities in the pathophysiology of fibromyalgia, the increasing number of theories reveals our little understanding of this disorder.

Clinical Presentation and Diagnosis
Fibromyalgia can be a difficult diagnosis when confounding factors such as concomitant illnesses and psychosocial abnormalities are prominent. There are no gold standard diagnostic tests available. It is a diagnosis of exclusion. The diagnosis is essentially made on a basis of the history and an absence of abnormal physical findings and laboratory tests. Polysomnographic evaluation is a helpful aid in reaching the diagnosis. These patients often come with generalized pain and a chief complaint of “pain all over my body” and weakness. Classically, they complain of lower back pain and aching stiffness of the trunk, hip, and shoulder girdles. The quality of the pain varies from burning to stiffness to soreness. Stiffness tends to improve over the course of the day; these patients are worse in the morning. Their pain experience is often worsened by stress, anxiety, cold, and damp weather, plus overexertion. Warmer climates often help these patients feel better. Other common features include irritable bowel syndrome, Raynaud syndrome-like symptoms, headaches, subjective swelling, nondermatomal paresthesia, psychological distress, and significant functional disability.

History should specifically focus on pain, fatigue, and sleep disturbances. History of pain should include location, intensity, daily pain, overall pain, pain at rest, and pain during movement. Focus on latency, nighttime awakenings, quality of sleep, total sleep time, daytime sleepy periods, and levels of daytime alertness while taking sleep history. And history of fatigue should include duration and timing of fatigue (end of day, overall fatigue, or morning fatigue).

Physical examination should stress tender spots (mechanical allodynia) and total number of tender points. Pain can be graded as per a visual analogue scale or none, mild, moderate, severe, to unbearable.

Diagnosis can be aided by polysomnographic evaluation to look for sleep latency, alpha intrusions, REM sleep percentage, SWS percentage, number of nighttime awakenings, total sleep time, sleep efficiency index, time to wake after sleep onset, and sleep fragmentation index.

The American College of Rheumatology has developed criteria for fibromyalgia that physicians can use in diagnosing this disease. These criteria include the presence of widespread pain (defined as pain in the left and right sides of the body as well as both above and below the waist) for at least 3 months. Axial skeletal pain, defined as pain in the cervical spine, anterior chest, thoracic spine, or low back, must also be present. In addition, the patient must report pain in at least 11 of 18 tender point sites (see Table 1) on digital palpation with an approximate force of 4 kg/cm.

These patients are diagnosed with meeting 11 of 18 classically defined tender points as shown in the table. There are nine pairs of tender points. Each pair has one point on each side of the body, for a total of 18 points.

Examination of the joints is often unremarkable, and there are no abnormal laboratory findings. It is a purely clinical diagnosis with a strong dependence on history and physical examination. Psychosocial distress and psychological abnormality occur frequently in fibromyalgia patients. Patterns of decreased levels of education and increased rates of divorce, obesity, and smoking have been noted in clinical and epidemiological studies. Fibromyalgia appears to be an increasingly important source of disability claims and payments; 25% of patients seen in rheumatology clinics have received disability payments.¹⁷

Treatment Options
Treatment success in fibromyalgia is often limited. Fewer than 50% of patients experience adequate symptom relief. Although no drugs are currently indicated specifically for the treatment of fibromyalgia, many agents have been studied, and active research into the therapeutic potential of several other agents is ongoing. Patients with established fibromyalgia, followed up for as long as 7 years, have markedly abnormal scores for pain, functional disability, fatigue, sleep disturbance, and psychological status, and these values do not change substantially over time.¹⁸ Half the patients are dissatisfied with their health, and 59% rate their health as fair or poor.¹⁸ Values at the first assessment are predictive of final values.¹⁸

Controlled studies have shown that amitriptyline, cyclobenzaprine, alprazolam, aerobic exercise, and other interventions are of benefit in treating FMS, but the percentage of patients responding to each alone is small. The beneficial effects of tricyclic antidepressants (TCAs) in the treatment of fibromyalgia are believed to be related to their ability to inhibit reuptake of serotonin and possibly norepinephrine. Serotonin modulates both pain and sleep, systems that seem to function abnormally in patients with fibromyalgia. Amitriptyline is the most widely prescribed pharmacologic agent for treatment of fibromyalgia and has been found to alleviate fibromyalgia symptoms. It is estimated, however, that only 25% to 30% of patients experience clinically significant improvement with amitriptyline.¹⁹ Venlafaxine, a nontricyclic antidepressant, significantly improved pain, fatigue, sleep quality, morning stiffness, depression, anxiety, and patient global assessment of fibromyalgia in a small, open-label clinical trial.²⁰

Selective serotonin reuptake inhibitors (SSRIs) were also investigated in fibromyalgia. It appears that the benefit of SSRIs in the treatment of fibromyalgia is related to their ability to relieve concomitant depression and sleep disorders rather than to any specific effect on pain. Adding a tricyclic antidepressant at bedtime (fluoxetine and amitriptyline) was found to alleviate fibromyalgia symptoms significantly more than either agent alone.²¹

Tramadol may be useful for treatment of fibromyalgia pain. In a study of 100 patients, significantly fewer tramadol recipients (27%) than placebo recipients (57%) withdrew from the study because of inadequate pain relief.²² Significant improvements in patient-reported pain scores and pain relief ratings were also demonstrated. Tramadol has been found to be as effective as acetaminophen with codeine in elderly patients with various chronic painful conditions, including fibromyalgia.²³

In a double-blind, randomized, placebo controlled crossover trial, sodium oxybate, a commercial form of gamma-hydroxybutyrate (GHB), effectively reduced the symptoms of pain and fatigue in patients with FMS, and dramatically reduced the sleep abnormalities (alpha intrusion and decreased slow-wave sleep) associated with nonrestorative sleep.²⁴ According to the authors, no other compound has been reported to reduce the alpha sleep abnormality. GHB is a naturally occurring metabolite of the human nervous system, with the highest concentration in the hypothalamus and basal ganglia.

Medications effective in the treatment of FMS appear to work mainly through an effect on deep sleep. They should be started at the lowest possible dose and increased every few days to a week to maximum relief of daytime FMS symptoms. The risks and benefits of each medication should be reviewed with the patient, especially elderly patients, as treatment success is very limited and medication side effects are significant. The potential for side effects due to anti-cholinergic and sedative properties of TCAs limits their use in older patients. SSRIs have been considered particularly safe for older patients to use because they do not cause orthostatic hypotension, arrhythmias, or marked sedation, which is true for TCAs. Tramadol can lower the seizure threshold. Both TCAs and tramadol may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. These side effects may be of medicolegal importance in patients treated with such medications. Long-acting opioid medications such as morphine sulfate should be considered as an alternative drug for patients with a high-risk profile. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. When switching from one medication to another, it is recommended to add the second medication while continuing the first to try to maintain sleep quality and avoid exacerbating FMS symptoms unless problems with the first medication preclude this approach.

Nonpharmacologic Treatment
Patients with fibromyalgia were significantly more likely to report current use of alternative therapies, particularly dietary modifications, chiropractic, or massage therapy. Various types of exercise, including aerobic dance, stationary cycling, and aerobic walking, three times a week, can reduce tender-point tenderness. Studies of biofeedback show that patients with fibromyalgia who received treatment experienced a significant decrease in the number of tender points, overall pain intensity, and morning stiffness compared with pretreatment assessment. A National Institutes of Health consensus statement on acupuncture concluded that in some situations, including fibromyalgia, “acupuncture may be useful as an adjunct treatment or an acceptable alternative or may be included in a comprehensive management program.”

A good evaluation helps to make a proper diagnosis, assess severity, recognize aggravating and relieving factors of symptoms, appraise psychological factors, evaluate relevant associated or concomitant conditions, document individualized problems in a given patient, and subsequently formulate proper and individualized management. Best therapeutic yield is possible by reassuring and explaining the nature of the illness to the patient, patient education, evaluation and eradication of mechanical stressors, symptomatic analgesic drug treatment, and individually tailored physical exercise programs.

Conclusion
Persons suffering with FMS often suffer from profound fatigue, cognitive difficulties, and sleep disturbances. Strong evidence exists for abnormal central pain processing; sensitized spinal cord neurons in the dorsal horn are responsible for augmented pain processing of nociceptive signals. FMS is receiving increasing attention as a therapeutic target. Aided by advances in molecular biology, researchers surmise that the future of a therapeutic breakthrough lies in correcting abnormal sensory processing and central sensitization as well as combating underlying neuroendocrine abnormalities. Goal-oriented treatment aimed at maintaining specific functions can be directed at helping a patient get restorative sleep, alleviating the somatic pains that ail the patient, keeping a person productive, and regulating schedules or using goal-oriented agreements made with the patient. Risks and benefits of the medication should be discussed with the patient because of their medicolegal implications.

Ksenia Kastanenka is a medical student at SUNY at Buffalo, North Campus, Neuropsychology Research; Naseer Masoodi, MD, is clinical assistant professor of medicine, Department of Clinical Services, Florida State University College of Medicine, Tallahassee, and medical director, Advent Christian Village Inc, Dowling Park, Fla; and Taj M. Jiva, MD, is a diplomate of the American Board of Sleep Medicine, and director of the Sleep Disorders Clinic, Orchard Park, NY.

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