Fibromyalgia
Fibromyalgia is a chronic rheumatic pain syndrome of unknown cause, defined by widespread pain and tenderness and accompanied by fatigue, poor sleep, mood disturbance and impaired cognition. It is common and costly, hard to diagnose, and thought to involve a cycle of dysfunction across the central pain system, the stress response, the autonomic nervous system and muscle, and it is managed with a combination of exercise, education and drugs.
What fibromyalgia is
Fibromyalgia is a common, complex, multidimensional, nonarticular rheumatic disorder of unknown aetiology, characterised by chronic widespread pain together with consistent focal areas of tenderness known as tender points, stiffness, nonrestorative sleep, fatigue, frequent psychological comorbidities such as depression and anxiety, and impaired memory and cognition. It may be underdiagnosed and highly unpredictable in its course of progression, and it is distinguished from other pain disorders by its tender points, nonrestorative sleep, fatigue and frequent psychological comorbidities. It is a chronic, debilitating pain syndrome characterised by central sensitisation, widespread pain in peripheral tissues, psychological distress, fatigue and sleep disturbance.
Prevalence and risk
Prevalence in most nations is 2% to 7%, and it rises with age, peaking between 60 and 79 years. Fibromyalgia is about nine times more common in women than in men, and it may also affect children. In the United States the overall prevalence is about 2%, or 3.7 million people, which makes it the third most common rheumatic disorder after low back pain and osteoarthritis. It is highly heritable: the risk is approximately eightfold greater for first-degree relatives of an affected person than in the general population. The aetiology is multifactorial, with genetic, hormonal, neuroendocrine, environmental and behavioural elements interacting and depending on one another.
Burden and costs
Fibromyalgia is a major cause of morbidity, places a substantial economic burden on the health care system, and has a negative effect on quality of life. The economic burden falls on patients, their families, employers and payors, and alongside substantial direct medical costs the condition is associated with indirect costs from lost work productivity. In a United States insurance-database analysis of more than 60,000 people with fibromyalgia and age- and sex-matched controls, mean and median total health care costs were approximately three and five times higher respectively in the fibromyalgia group ($9,573 versus $3,291 and $4,247 versus $822, P < .001 for each). People with fibromyalgia had four times as many physician office and emergency department visits, were almost four times as likely to receive pain-related and non-pain-related prescription medications including antidepressants, and had significantly more comorbid psychiatric conditions. Almost half had health care encounters for symptoms other than chronic widespread pain: headache, abdominal pain, chest pain, fatigue and gastrointestinal symptoms.
Clinical picture
The condition has four main components: pain, fatigue, mood and function. Along with pain, morning stiffness and fatigue are present in over 73% of people with the condition, and up to an estimated 99% experience some problem with sleep. Nonrestorative sleep predicts increased pain and decreased physical functioning, and electroencephalographic examinations identify slow-wave sleep, the fourth and deepest stage, as the major component of sleep architecture affected. Cognitive impairment, often called fibrofog, and neuropsychiatric disturbances such as anxiety and depression are also important aspects of the clinical spectrum.
Its auxiliary features include skin tenderness, post-exertional pain, exercise intolerance, irritable bowel syndrome, overactive bladder syndrome or interstitial cystitis, tension and migraine headaches, dizziness, fluid retention, paraesthesias, restless leg syndrome and Raynaud's phenomenon.
Name and diagnosis
For several decades researchers tried to find the pathology in muscle tissue that was thought to be the major underlying cause of pain for most people with the condition. The condition was originally called fibrositis on the speculation that inflammation of muscle tissue was intrinsic to it, and was renamed fibromyalgia syndrome in the mid-1970s after research found that true inflammation in musculoskeletal or fibrous tissue was not the cause. In 1990 the American College of Rheumatology defined it by two main criteria: a history of widespread pain in an axial distribution (bilateral, upper and lower body, and the spine) present for three months or more, and excessive tenderness on palpation in at least 11 of 18 specified muscle-tendon points.
Comorbidities that closely mimic the clinical spectrum of fibromyalgia, and the overlap of its symptoms with other rheumatic conditions, make diagnosis challenging. Comorbidities such as chronic fatigue syndrome, myofascial pain syndrome, hypothyroidism, systemic lupus and other inflammatory rheumatic diseases can complicate the diagnosis, but unlike them fibromyalgia is not associated with abnormal radiographic or laboratory findings.
Pathophysiology
Although the pathophysiology is poorly understood, it involves a complex, cyclical interplay of dysfunction of the central pain modulatory system, the autonomic nervous system and the neuroendocrine network, leading to chronic widespread pain, nonrestorative sleep and cognitive dysfunction. As of 2011, abnormalities had been identified over the preceding decade at multiple levels of the peripheral, central and sympathetic nervous systems and in the hypothalamic-pituitary-adrenal stress-response system.
Central sensitisation
Central sensitisation and temporal summation are the two pivotal elements of the central pain modulatory dysfunction. Central sensitisation is enhanced excitability of neurons in the dorsal horn of the spinal cord, giving augmented spontaneous nerve activity and hyperactivity across multiple spinal segments through large- and small-calibre primary afferent fibres. A key contributor to that hyperactivity is temporal summation, or wind-up, in which the intensity of rapidly repeated noxious stimuli culminates in prolonged stimulation of the unmyelinated group C nociceptive fibres.
N-methyl D-aspartate (NMDA) receptors at the postsynaptic membrane of dorsal horn neurons may play an integral role in both. Glutamate activation of those receptors raises intracellular calcium and initiates second-messenger pathways that mediate amplified firing rates of nociceptive neurons, long-term potentiation (enduring enhancement of synaptic transmission after the initiating stimulus has ceased) and neuroplastic changes. Substance P and the release of nitric oxide through neuronal nitric oxide synthase can also modulate the receptors' responsiveness to glutamate.
Once central sensitisation is established, sensitivity to painful stimuli is exaggerated (hyperalgesia), the threshold for activating new noxious inputs is reduced (allodynia), and endogenous noxious inhibitory control is reduced, resulting in chronic widespread pain perceived as dull, aching or burning. This regional neuronal hyperactivity has been demonstrated by functional magnetic resonance imaging and single photon emission computed tomography in studies using noxious or heat stimuli. People with fibromyalgia may also have a global disturbance in somatosensory processing rather than an isolated abnormality in pain processing, shown as heightened responsiveness or a lower threshold to light, auditory, tactile, heat, cold, odour and pressure stimuli.
Because the pain is not associated with peripheral structural damage or inflammation, the underlying cause of the interference in pain processing remains unclear. Sensitisation of the central nociceptive system may result from a variety of sensory inputs: a physical insult producing traumatised tissue, inflammatory mediators and localised pain, or a psychological insult such as chronic stress. Altered pain processing in fibromyalgia has been demonstrated by brain imaging studies. Russell and colleagues found cerebrospinal fluid substance P threefold higher in people with fibromyalgia than in matched controls, and Harris and colleagues found elevated glutamate in the insula, at levels that predicted experimental pressure-evoked pain thresholds and clinical pain ratings. Nerve growth factor, which stimulates substance P production in small afferent unmyelinated neurons and interneurons, has also been found elevated in the cerebrospinal fluid of people with fibromyalgia.
Stress response and the hypothalamic-pituitary-adrenal axis
Fibromyalgia is considered a stress-associated syndrome because it often begins after acute or chronic stressors and its symptoms are often exacerbated during periods of physical or emotional stress. Some studies have found that the onset and exacerbation of symptoms correlate with periods of physical or emotional stress. Alongside central sensitisation, sensory inputs activate circuits of other systems involved in stress responses: the limbic system, the autonomic nervous system and the neuroendocrine system including the hypothalamic-pituitary-adrenal axis. No anatomic or structural pathology has been found in those systems, but dysregulation of the hypothalamic-pituitary-adrenal axis in fibromyalgia is characterised by a low integrated basal cortisol level measured by 24-hour urinary free cortisol, and by blunted cortisol secretion in response to stress-induced pituitary adrenocorticotrophic hormone release and to exercise. Abnormalities of related neuronal networks, particularly decreased serotonergic activity and an abnormal growth hormone axis, may also contribute to the neuroendocrine perturbations. The increased sensitivity to stressors and the altered pain processing contribute to the typical constellation of symptoms: physical and mental fatigue, negative mood, nonrestorative sleep, impaired memory and cognitive function, syncope, morning stiffness, Raynaud's phenomenon and intestinal irritability.
Autonomic dysfunction and muscle
Dysautonomia, or disturbed autonomic system activity, is another integral element of the clinical spectrum, and it manifests as hyperactive sympathetic and decreased parasympathetic activity. Chronic stimulation of the sympathetic nervous system's alpha-adrenergic receptors leads to receptor desensitisation, stress hyporesponsiveness and central hyperalgesia. Selective sympathetic blockade with guanethidine in people with fibromyalgia reduces pain and the number of tender points, and norepinephrine injections can restore these symptoms.
Enhanced peripheral sympathetic activity may lead, among other autonomic responses, to a generalised peripheral vasoconstriction that reduces blood flow to skeletal muscle. In this state a relatively mild challenge, such as stretching or light exercise, can evoke ischaemia of skeletal muscle, alter muscle metabolism and sensitise ergoreceptors. The decline in energy expenditure of skeletal muscle is indicated by biochemical markers such as low levels of phosphocreatine, resting ATP, phosphorylation potential, nitric oxide and total oxidative capacity, and the histopathological changes include a reduction in the number and size of skeletal muscle mitochondria along with muscle degeneration. These changes may underlie the reduced maximal exercise time and exertional fatigue experienced by people with fibromyalgia. Muscle ischaemia and altered metabolism activate nociceptors, resulting in a generalised sensitisation to pain within skeletal muscle and multifocal, spatially distributed allodynia and hyperalgesia. Changes in peripheral factors, especially intramuscular microcirculation and muscle metabolism, can therefore act as excitatory triggers for multifocal muscle pain and further sensitisation of the central pain-processing system. Activation of the central nociceptive system completes a reverberating feedback loop through these elements, in which a trigger such as tender points, tissue trauma, exercise or stress at any point can initiate and express the array of symptoms typical of fibromyalgia.
Management
Management is complicated by the unknown pathophysiology and by the overlap of symptoms with other chronic conditions such as chronic fatigue syndrome, myofascial pain and systemic lupus. The development of focused, mechanistically based treatments targeting the array of symptoms has been limited, in part because of the debate over whether fibromyalgia is a single entity or a constellation of symptoms. As of 2011, management integrated physical, psychosocial and behavioural factors in a multidisciplinary rehabilitation model that combines exercise, education and pharmacological treatment. The exercise includes cardiovascular training, strength training, flexibility training and aerobics such as cycle ergometry, walking, jogging and water-based activity, and the education includes stress management programmes, cognitive behavioural therapy, electromyography and heart rate variability biofeedback, meditation-based stress reduction, tai chi and yoga therapy. The European League Against Rheumatism and the American Pain Society recommended the rehabilitative model, but it was not a universally accepted treatment algorithm. The overall management is a multidisciplinary approach that integrates pharmacological and non-pharmacological therapies aiming to improve quality of life. It involves a multidisciplinary pharmacological, rehabilitative and cognitive-behavioural approach. As of 2011, an individually tailored, multidisciplinary, pharmacological, rehabilitative and cognitive-behavioural approach seemed the most effective.
Drug treatment
The goal of pharmacotherapy is primarily the alleviation of pain and the improvement of mood-related symptoms. Nonsteroidal anti-inflammatory drugs such as naproxen and ibuprofen, opioids such as tramadol, and corticosteroids such as prednisone are not consistently effective, because the symptoms are not caused by peripheral structural damage or inflammation. Sedative hypnotics such as temazepam, alprazolam and bromazepam, which modulate the benzodiazepine receptor complex on neuronal GABA-A receptors, have also given inconsistent relief.
Antidepressants are used to address many of the symptoms, among them duloxetine and milnacipran, selective serotonin reuptake inhibitors such as fluoxetine and paroxetine, and tricyclics such as amitriptyline and dothiepin. Their role rests on their potential to dampen pain signals by enhancing serotonin and norepinephrine activity in the descending inhibitory system that links the periaqueductal grey and the rostral ventromedial medulla with the spinal cord. Duloxetine has a balanced inhibitory profile of serotonin and norepinephrine reuptake, whereas milnacipran, like amitriptyline, preferentially inhibits norepinephrine reuptake and also weakly inhibits the NMDA receptor.
Inhibitors of voltage-activated presynaptic calcium channels that contain the alpha-2-delta-1 subunit block calcium influx into nociceptive nerve terminals and inhibit the release of glutamate and substance P, so attenuating the abnormal postsynaptic hyperexcitability of these neuronal networks. Ligands of the alpha-2-delta subunit, such as gabapentin and pregabalin, have use-dependent properties that let them significantly modulate sustained neuronal depolarisation or hyperexcitability while minimally altering physiological synaptic function.
The clinical efficacy and tolerability of the treatments, and their effect on quality of life, vary among people with fibromyalgia. As of 2011, three agents had US Food and Drug Administration approval for the indication: milnacipran (Savella), duloxetine (Cymbalta) and pregabalin (Lyrica). At that time sodium oxybate, a GABA receptor agonist and the sodium salt of the GABA precursor gamma-hydroxybutyrate, was a novel compound under clinical evaluation for the condition. Studies indicated that it significantly improves the major symptoms of fibromyalgia, namely pain, tenderness, sleep quality and fatigue, possibly by consolidating and improving the quality of deep sleep.