Fibromyalgia
Fibromyalgia (new lat., fibro-, fibrous tissue, Gk. myo-, muscle, Gk. algos-, pain), meaning muscle and connective tissue pain (also referred to as FM or FMS), is a disorder classified by the presence of chronic widespread pain and a heightened and painful response to gentle touch (tactile allodynia).[1] Other core features of the disorder include debilitating fatigue, sleep disturbance, and joint stiffness. In addition, persons affected by the disorder frequently experience a range of other symptoms that involve multiple body systems, including difficulty with swallowing,[2] functional bowel and bladder abnormalities,[3] difficulty breathing,[4] diffuse sensations of numbness and tingling (non-dermatomal paresthesia),[5] abnormal motor activity (i.e. nocturnal myoclonus, sleep bruxism),[6] and cognitive dysfunction.[7
] An increased prevalence of affective and anxiety-related symptoms is also well known.[8] While the criteria for such an entity have not yet been thoroughly developed, the recognition that fibromyalgia involves more than just pain has led to the frequent use of the term "fibromyalgia syndrome".[9] Not all affected persons experience all the symptoms associated with the greater syndrome.
Fibromyalgia is considered a controversial diagnosis, with some authors contending that the disorder is a ‘non-disease’, due in part to a lack of abnormalities on physical examination, objective laboratory tests or medical imaging studies to confirm the diagnosis.[10] While historically considered either a musculoskeletal disease or neuropsychiatric condition, evidence from research conducted in the last three decades has revealed abnormalities within the central nervous system affecting brain regions that may be linked both to clinical symptoms and research phenomena.[11] Although there is as yet no generally accepted cure for fibromyalgia, there are treatments that have been demonstrated by controlled clinical trials to be effective in reducing symptoms, including medications, patient education, exercise, and behavioral interventions.[12]
Contents
* 1 Signs and symptoms
* 2 Causation hypotheses
o 2.1 Genetic predisposition
o 2.2 Stress-induced pathophysiology
o 2.3 Consequence of sleep disturbance
o 2.4 Central dopamine dysfunction (hypodopaminergia)
o 2.5 Abnormal serotonin metabolism
o 2.6 Deficient human growth hormone (HGH) secretion
o 2.7 Psychological factors
o 2.8 Other hypotheses
* 3 Pathophysiology
o 3.1 Sleep disturbances
o 3.2 Poly-modal sensitivity
o 3.3 Neuroendocrine disruption
o 3.4 Sympathetic hyperactivity
o 3.5 Cerebrospinal fluid abnormalities
o 3.6 Brain imaging studies
* 4 Diagnosis
* 5 Treatment
o 5.1 Pharmaceutical
+ 5.1.1 Analgesics
+ 5.1.2 Antidepressants
+ 5.1.3 Anti-seizure medication
+ 5.1.4 Dopamine agonists
+ 5.1.5 Insomnia
o 5.2 Investigational medications
o 5.3 Physical treatments
o 5.4 Psychological/behavioural therapies
* 6 Prognosis
* 7 Epidemiology
* 8 History
* 9 Controversies
* 10 See also
* 11 References
* 12 External links
Signs and symptoms
Common signs and symptoms of fibromyalgia.[13]
The defining symptoms of fibromyalgia are chronic, widespread pain and painful response to touch (allodynia). Other symptoms can include moderate to severe fatigue, needle-like tingling of the skin, muscle aches, prolonged muscle spasms, weakness in the limbs, nerve pain, functional bowel disturbances,[14] and chronic sleep disturbances.[15] Sleep disturbances may be related to a phenomenon called alpha-delta sleep, a condition in which deep sleep (associated with delta waves) is frequently interrupted by bursts of alpha waves, which normally occur during wakefulness. Slow-wave sleep is often dramatically reduced.[citation needed]
Many patients experience cognitive dysfunction[16] (known as "brain fog" or "fibrofog"), which may be characterized by impaired concentration,[17] problems with short[17][18] and long-term memory, short-term memory consolidation,[18] impaired speed of performance,[17][18] inability to multi-task, cognitive overload,[17][18] diminished attention span, anxiety, and depressive symptoms.[18] "Brain fog" may be directly related to the sleep disturbances experienced by sufferers of fibromyalgia.[citation needed]
Other symptoms often attributed to fibromyalgia that may possibly be due to a comorbid disorder include myofascial pain syndrome also referred to as Chronic Myofascial Pain, diffuse non-dermatomal paresthesias, functional bowel disturbances and irritable bowel syndrome (possibly linked to lower levels of ghrelin,[19] genitourinary symptoms and interstitial cystitis, dermatological disorders, headaches, myoclonic twitches, and symptomatic hypoglycemia. Although fibromyalgia is classified based on the presence of chronic widespread pain, pain may also be localized in areas such as the shoulders, neck, low back, hips, or other areas. Many sufferers also experience varying degrees of facial pain and have high rates of comorbid temporomandibular joint disorder.
Eye problems such as eye pain, sensitivity to light, blurred vision, and fluctuating visual clarity, can also be a symptom of the condition.[20] As a consequence of this, sufferers who wear glasses or contact lenses may have to change their lens prescription frequently.
Symptoms can have a slow onset, and many patients have mild symptoms beginning in childhood, that are often misdiagnosed as growing pains.[citation needed] Symptoms are often aggravated by unrelated illness or changes in the weather.[citation needed]They can become more or less tolerable throughout daily or yearly cycles; however, many people with fibromyalgia find that, at least some of the time, the condition prevents them from performing normal activities such as driving a car or walking up stairs. The disorder does not cause inflammation as is characteristic of rheumatoid arthritis, although some non-steroidal anti-inflammatory drugs may temporarily reduce pain symptoms in some patients. Their use, however, is limited, and often of little to no value in pain management.[21]
An epidemiology study consisting of an internet-based survey of 2,596 people with fibromyalgia[22] reported that the most frequently cited factors perceived to worsen fibromyalgia symptoms were emotional distress (83%), weather changes (80%), sleeping problems (79%), strenuous activity (70%), mental stress (68%), worrying (60%), car travel (57%), family conflicts (52%), physical injuries (50%) and physical inactivity (50%). Other factors included infections, allergies, lack of emotional support, perfectionism, side effects of medications, and chemical exposures.
Causation hypotheses
The cause of fibromyalgia is currently unknown. However, several hypotheses have been developed:
Genetic predisposition
There is evidence that genetic factors may play a role in the development of fibromyalgia. For example, there is a high aggregation of fibromyalgia in families.[23][24] The mode of inheritance is currently unknown, but it is most probably polygenic.[25] Research has demonstrated that fibromyalgia is associated with polymorphisms of genes in the serotoninergic,[26] dopaminergic[27] and catecholaminergic systems.[28] However, these polymorphisms are not specific for fibromyalgia and are associated with a variety of allied disorders (e.g. chronic fatigue syndrome,[29] irritable bowel syndrome[30]) and with depression.[31]
Stress-induced pathophysiology
Studies have shown that stress is a significant precipitating factor in the development of fibromyalgia.[32] Accordingly, it has been proposed that fibromyalgia may result from stress-induced changes in the function and integrity of the hippocampus.[33] This proposition was based in part on the observation that preclinical studies in non-human primates have shown that exposure to psychosocial duress results in material changes to the very tissues of the brain, including atrophic and metabolic changes in the hippocampal complex.[34][35] Evidence in support of this hypothesis have been generated by two studies that employed single-voxel magnetic resonance spectroscopy (1H-MRS) to demonstrate metabolic abnormalities within the hippocampal complex in patients with fibromyalgia with significant correlations between hippocampal metabolic abnormalities and severity of clinical symptoms.[36][37]
Other authors have proposed that, because exposure to stressful conditions can alter the function of the hypothalamic-pituitary-adrenal (HPA) axis, the development of fibromyalgia may stem from stress-induced disruption of the HPA axis.[38] This proposition is supported in part by the observation from a prospective epidemiology study which found that variations in HPA function characterized by high levels of circulating cortisol following dexamethasone suppression testing, low levels of morning salivary cortisol and high levels of evening salivary cortisol are all associated with the development of chronic widespread pain.[39]
Consequence of sleep disturbance
Electroencephalography (EEG) studies have shown that people with fibromyalgia lack slow-wave sleep and that circumstances that interfere with stage four sleep (pain, depression, serotonin deficiency, certain medications or anxiety) may cause or worsen the condition.[40] According to the sleep disturbance hypothesis, an event such as trauma or illness causes sleep disturbance and possibly initial chronic pain that may initiate the disorder. The hypothesis supposes that stage four sleep is critical to the function of the nervous system, as it is during that stage that certain neurochemical processes in the body 'reset.' In particular, pain causes the release of the neuropeptide substance P in the spinal cord which has the effect of amplifying pain and causing nerves near the initiating ones to become more sensitive to pain. Under normal circumstances, areas around a wound become more sensitive to pain but if pain becomes chronic and body-wide this process can run out of control. The sleep disturbance hypothesis holds that deep sleep is critical to reset the substance P mechanism and prevent this out-of-control effect, and that an ongoing lack of sleep for any reason could become a source for the condition.
Central dopamine dysfunction (hypodopaminergia)
The 'dopamine hypothesis of fibromyalgia’ proposes that the central abnormality responsible for symptoms associated with fibromyalgia is a disruption of normal dopamine-related neurotransmission. Dopamine is a catecholamine neurotransmitter perhaps best known for its role in the pathology of schizophrenia, Parkinson's disease and addiction. There is also strong evidence for a role of dopamine in restless leg syndrome,[41] which is a condition found frequently in patients with fibromyalgia.[42] In addition, dopamine plays a critical role in pain perception and natural analgesia. Accordingly, musculoskeletal pain complaints are common among patients with Parkinson's disease,[43] which is characterized by drastic reductions in dopamine owing to neurodegeneration of dopamine-producing neurons, while patients with schizophrenia, which is thought to be due (in part) to hyperactivity of dopamine-producing neurons, have been shown to be relatively insensitive to pain.[44][45] Patients with restless leg syndrome have also been demonstrated to have an increased sensitivity to pain to static mechanical stimulation.[46]
As noted above, fibromyalgia has been commonly referred to as a "stress-related disorder" due to its frequent onset and worsening of symptoms in the context of stressful events.[47][48] Hence, it was proposed that fibromyalgia may represent a condition characterized by low levels of central dopamine that likely results from a combination of genetic factors and exposure to environmental stressors, including psychosocial distress, physical trauma, systemic viral infections or inflammatory disorders (e.g. rheumatoid arthritis, systemic lupus erythematosus).[49] This conclusion was based on three key observations; fibromyalgia is associated with stress, chronic exposure to stress results in a disruption of dopamine-related neurotransmission[50] and dopamine plays a critical role in modulating pain perception and central analgesia in such areas as the basal ganglia[51] including the nucleus accumbens,[52] insular cortex,[53] anterior cingulate cortex,[54] thalamus,[55] periaqueductal gray[56] and spinal cord.[57][58]
In support of the dopamine hypothesis of fibromyalgia, a reduction in dopamine synthesis has been reported by a study that used positron emission tomography (PET) and demonstrated a reduction in dopamine synthesis among fibromyalgia patients in several brain regions in which dopamine plays a role in inhibiting pain perception, including the mesencephalon, thalamus, insular cortex and anterior cingulate cortex.[59] A subsequent PET study demonstrated that, whereas healthy individuals release dopamine into the caudate nucleus and putamen during a tonic experimental pain stimulus (i.e. hypertonic saline infusion into a muscle bed),[60] fibromyalgia patients fail to release dopamine in response to pain and, in some cases, actually have a reduction in dopamine levels during painful stimulation.[61] Moreover, a substantial subset of fibromyalgia patients respond well in controlled trials to pramipexole, a dopamine agonist that selectively stimulates dopamine D2/D3 receptors and is used to treat both Parkinson's disease and restless leg syndrome.[62]
Abnormal serotonin metabolism
Serotonin is a neurotransmitter that is known to play a role in regulating sleep patterns, mood, feelings of well-being, concentration and descending inhibition of pain. Accordingly, it has been hypothesized that the pathophysiology underlying the symptoms of fibromyalgia may be a dysregulation of serotonin metabolism, which (it was proposed) may explain in part many of the symptoms associated with the disorder.[63] This hypothesis is supported by the observation of decreased serotonin metabolites in patient plasma[64] and cerebrospinal fluid.[65] However, selective serotonin reuptake inhibitors (SSRIs) have met with limited success in alleviating the symptoms of the disorder, while drugs with activity as mixed serotonin-norepinephrine reuptake inhibitors (SNRIs) have been more successful.[66] Accordingly, duloxetine (Cymbalta), a SNRI originally used to treat depression and painful diabetic neuropathy, has been demonstrated by controlled trials to relieve symptoms of some patients. It should be noted, however, that the relevance of dysregulated serotonin metabolism to the pathophysiology is a matter of debate.[67] Complicating the analysis, one of the more effective types of medication for the treatment of the disorder (i.e. serotonin 5-HT3 antagonists) actually block some of the effects of serotonin.[68]
Deficient human growth hormone (HGH) secretion
An alternate hypothesis suggests that stress-induced problems in the hypothalamus may lead to reduced sleep and reduced production of human growth hormone (HGH) during slow-wave sleep. People with fibromyalgia tend to produce inadequate levels of HGH.[citation needed] Most patients with fibromyalgia with low IGF-I levels failed to secrete HGH after stimulation with clonidine and l-dopa.[citation needed] This view is supported by the fact that those hormones under the direct or indirect control of HGH, including IGF-1, cortisol, leptin and neuropeptide Y are abnormal in people with fibromyalgia,[69] In addition, treatment with exogenous HGH or growth hormone secretagogue reduces fibromyalgia related pain and restores slow wave sleep[70][71][72][73] though there is disagreement about the proposition.[74]
Psychological factors
There is strong evidence that major depression is associated with fibromyalgia, although the nature of the association is controversial. A comprehensive review into the relationship between fibromyalgia and major depressive disorder (MDD) found substantial similarities in neuroendocrine abnormalities, psychological characteristics, physical symptoms and treatments between fibromyalgia and MDD, but currently available findings do not support the assumption that MDD and fibromyalgia refer to the same underlying construct or can be seen as subsidiaries of one disease concept.[75] Indeed, the sensation of pain has at least two dimensions: a sensory dimension which processes the magnitude of the pain, and an affective-motivational dimension which processes the unpleasantness. Accordingly, a study that employed functional magnetic resonance imaging to evaluate brain responses to experimental pain among fibromyalgia patients found that depressive symptoms were associated with the magnitude of clinically-induced pain response specifically in areas of the brain that participate in affective pain processing, but not in areas involved in sensory processing which indicate that the amplification of the sensory dimension of pain in fibromyalgia occurs independently of mood or emotional processes.[76]
An alternative hypothesis regarding the development of fibromyalgia in relationship to psychological conflict proposes that the disorder may be a psychosomatic illness as described by John E. Sarno's writing related to "tension myositis syndrome," in which chronic pain is proposed to be a psychic diathesis of the mind's subconscious strategy of distracting painful or dangerous emotions. Education, attitude change, and in some cases, psychotherapy are proposed as treatments.[77]
Other hypotheses
Other hypotheses have been proposed related to various toxins from the patient's environment,[78][79] viral causes such as the Epstein-Barr Virus,[80] an aberrant immune response to intestinal bacteria,[81] and erosion of the protective chemical coating around sensory nerves.[82] Still another hypothesis regarding the cause of fibromyalgia symptoms proposes that affected individuals suffer from vasomotor dysregulation resulting in sluggish or improper vascular flow.[83]
Pathophysiology
Sleep disturbances
The first objective findings associated with the disorder were reported in 1975 by Moldofsky and colleagues who reported the presence of anomalous alpha wave activity (typically associated with arousal states) on sleep electroencephalogram (EEG) during non-rapid-eye-movement sleep.[63] In fact, by disrupting stage IV sleep consistently in young, healthy subjects Moldofsky was able to reproduce a significant increase in muscle tenderness similar to that experienced by fibromyalgia but which resolved when the subjects were able to resume their normal sleep patterns.[84] Since that time a variety of other EEG sleep abnormalities have also been reported in subgroups of fibromyalgia patients.[85]
Poly-modal sensitivity
Results from studies examining responses to experimental stimulation have shown that fibromyalgia patients display sensitivity to pressure, heat, cold, electrical and chemical stimulation.[86] Experiments examining pain regulatory systems have shown that fibromyalgia patients also display a dysregulation of diffuse noxious inhibitory control,[87] an exaggerated wind-up in response to repetitive stimulation,[88] and an absence of exercise-induced analgesic response.[89] Together these results point to dysregulation of the nociceptive system at the central level.
Neuroendocrine disruption
Patients with fibromyalgia have been demonstrated to have a disruption of normal neuroendocrine function, characterized by mild hypocortisolemia,[90] hyperreactivity of pituitary adrenocorticotropin hormone release in response to challenge, and glucocorticoid feedback resistance.[91] A progressive reduction of serum growth hormone levels has also been documented—at baseline in a minority of patients, while most demonstrate reduced secretion in response to exercise or pharmacological challenge.[92] Other abnormalities include reduced responsivity of thyrotropin and thyroid hormones to thyroid-releasing hormone,[93] a mild elevation of prolactin levels with disinhibition of prolactin release in response to challenge[94] and hyposecretion of adrenal androgens.[95] These changes might be attributed to the effects of chronic stress, which, after being perceived and processed by the central nervous system, activates hypothalamic corticotrophin-releasing hormone neurons. Thus, the multiple neuroendocrine changes evident in fibromyalgia have been proposed to stem from chronic overactivity of corticotropin-releasing hormone releasing neurons, resulting in a disruption of normal function of the pituitary-adrenal axis and an increased stimulation of hypothalamic somatostatin secretion, which, in turn, inhibits the secretion of a multiplicity of other hormones.[96]
Sympathetic hyperactivity
Functional analysis of the autonomic system in patients with fibromyalgia has demonstrated disturbed activity characterized by hyperactivity of the sympathetic nervous system at baseline[97] with reduced sympathoadrenal reactivity in response to a variety of stressors including physical exertion and mental stress.[98][99] Fibromyalgia patients demonstrate lower heart rate variability, an index of sympathetic/parasympathetic balance, indicating sustained sympathetic hyperactivity, especially at night.[100] In addition, plasma levels of neuropeptide Y, which is co-localized with norepinephrine in the sympathetic nervous system, have been reported as low in patients with fibromyalgia,[101] while circulating levels of epinephrine and norepinephrine have been variously reported as low, normal and high.[102][103] Administration of interleukin-6, a cytokine capable of stimulating the release of hypothalamic corticotropin-releasing hormone which in turn stimulates activity within the sympathetic nervous system, results in a dramatic increase in circulating norepinephrine levels and a significantly greater increase in heart rate over baseline in fibromyalgia patients as compared to healthy controls.[104]
Cerebrospinal fluid abnormalities
The most reproduced laboratory finding in patients with fibromyalgia is an elevation in cerebrospinal fluid levels of substance P, a putative nociceptive neurotransmitter.[105][106][107] Metabolites for the monoamine neurotransmitters serotonin, norepinephrine, and dopamine—all of which play a role in natural analgesia—have been shown to be lower,[108] while concentrations of endogenous opioids (i.e., endorphins and enkephalins) appear to be higher.[109] The mean concentration of nerve growth factor, a substance known to participate in structural and functional plasticity of nociceptive pathways within the dorsal root ganglia and spinal cord, is elevated.[110] There is also evidence for increased excitatory amino acid release within cerebrospinal fluid, with a correlation demonstrated between levels for metabolites of glutamate and nitric oxide and clinical indices of pain.[111]
Brain imaging studies
Evidence of abnormal brain involvement in fibromyalgia has been provided via functional neuroimaging. The first findings reported were decreased blood flow within the thalamus and elements of the basal ganglia and mid-brain (i.e., pontine nucleus).[112][113] Differential activation in response to painful stimulation has also been demonstrated.[114][115] Brain centers showing hyperactivation in response to noxious stimulation include such pain-related brain centers as the primary and secondary somatosensory cortex, anterior cingulate cortex and insular cortex, while relative hypoactivation at subjectively equal pain levels appears to occur within the thalamus and basal ganglia. Patients also exhibit neural activation in brain regions associated with pain perception in response to nonpainful stimuli in such areas as the prefrontal, supplemental motor, insular, and cingulate cortices. Evidence of hippocampal disruption indicated by reduced brain metabolite ratios has been demonstrated by studies using single-voxel magnetic resonance spectroscopy (1H-MRS).[36][37] A significant negative correlation was demonstrated between abnormal metabolite ratios and a validated index of the clinical severity (i.e. the Fibromyalgia Impact Questionnaire).[116] Correlations between clinical pain severity and concentrations of the excitatory amino acid neurotransmitter glutamate within the insular cortex have also been demonstrated using 1H-MRS.[117] An acceleration of normal age-related brain atrophy has been demonstrated using voxel-based morphometry (VBM) with areas of reduced gray matter located in the cingulate cortex, insula and parahippocampal gyrus.[118] Studies utilizing positron emission tomography have demonstrated reduced dopamine synthesis in the brainstem and elements of the limbic cortex.[119] A significant negative correlation between pain severity and dopamine synthesis was demonstrated within the insular cortex. A subsequent study demonstrated gross disruption of dopaminergic reactivity in response to a tonic pain stimulus within the basal ganglia with a significant positive correlation between the defining feature of the disorder (i.e. tender point index) and dopamine D2 receptor binding potential specifically in the right putamen.[120] Finally, reduced availability of mu-opioid receptors in the ventral striatum/nucleus accumbens and cingulate cortex has been demonstrated, with a significant negative correlation between affective pain levels and receptor availability in the nucleus accumbens.[121]
Diagnosis
The location of the nine paired tender points that comprise the 1990 American College of Rheumatology criteria for fibromyalgia.
There is still debate over what should be considered essential diagnostic criteria. The difficulty with diagnosing fibromyalgia is that, in most cases, laboratory testing appears normal and that many of the symptoms mimic those of other rheumatic conditions such as arthritis or osteoporosis. In general, most doctors diagnose patients with a process called differential diagnosis, which means that doctors consider all of the possible things that might be wrong with the patient based on the patient's symptoms, gender, age, geographic location, medical history and other factors. They then narrow down the diagnosis to the most likely one. The most widely accepted set of classification criteria for research purposes was elaborated in 1990 by the Multicenter Criteria Committee of the the American College of Rheumatology. These criteria, which are known informally as "the ACR 1990," define fibromyalgia according to the presence of the following criteria:
* A history of widespread pain lasting more than three months—affecting all four quadrants of the body, i.e., both sides, and above and below the waist.
* Tender points—there are 18 designated possible tender or trigger points (although a person with the disorder may feel pain in other areas as well). During diagnosis, four kilograms-force (39 newtons) of force is exerted at each of the 18 points; the patient must feel pain at 11 or more of these points for fibromyalgia to be considered.[122] Four kilograms of force is about the amount of pressure required to blanch the thumbnail when applying pressure.
This set of criteria was developed by the American College of Rheumatology as a means of classifying an individual as having fibromyalgia for both clinical and research purposes. While these criteria for classification of patients were originally established as inclusion criteria for research purposes and were not intended for clinical diagnosis, they have become the de facto diagnostic criteria in the clinical setting. It should be noted that the number of tender points that may be active at any one time may vary with time and circumstance.
Treatment
As with many other syndromes, there is no universally accepted cure for fibromyalgia, and treatment is typically aimed at symptom management. Developments in the understanding of the pathophysiology of the disorder have led to improvements in treatment, which include prescription medication, behavioral intervention, exercise, and alternative and complementary medicine. Indeed, integrated treatment plans that incorporate medication, patient education, aerobic exercise and cognitive-behavioral therapy have been shown to be effective in alleviating pain and other fibromyalgia-related symptoms.[12] In 2005, the American Pain Society produced the first comprehensive guidelines for patient evaluation and management.[123] More recently, the European League Against Rheumatism (EULAR) issued updated treatment guidelines.[124]
Pharmaceutical
Analgesics
A number of analgesics are used to treat the pain symptoms resulting from fibromyalgia, including nonsteroidal anti-inflammatory drugs (NSAID) and COX-2 inhibitors.[citation needed]
Antidepressants
There is growing evidence that fibromyalgia symptoms are associated with the abnormal processing of pain in the central nervous system.[125] Dysfunction of serotonin and norepinephrine in the pain-inhibitory pathways is thought to contribute to chronic pain[citation needed], and antidepressants which increase the activity of these neurotransmitters may alleviate the pain symptoms.
A study published in JAMA on January 14 of 2009 underlined and supported the increasing body of research that antidepressants as a group are helpful in treating pain, depression, fatigue, sleep disturbances, and quality of life in individuals suffering from fibromyalgia.[126]
Tricyclic antidepressants continue to be widely prescribed for fibromyalgia, although their efficacy in treating fibromyalgic symptoms appears to be limited, with the largest improvement being in sleep quality. Tricyclics also have many side-effects due to interaction with adrenergic, cholinergic or histaminergic receptors, and sodium channels.
Recent meta-analyses show that selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs) have the greatest benefit in reducing pain, with SNRIs having the most significant benefit.[citation needed] Additionally, SSRIs and SNRIs do not have the side-effects that are associated with tricyclics. A pooled meta-analysis of multiple medications showed that SSRIs had a significant symptomatic benefit that was moderate for sleep, overall well being, and pain severity[citation needed], and mild for fatigue and number of tender points[citation needed]. The results were mixed, showing that the SSRIs that had dual effects on norepinephrine and serotonin had the greatest benefit in pain reduction.
Recent research has focused on SNRIs, such as duloxetine. Although no meta-analyses are available, two placebo-controlled clinical trials have shown that duloxetine results in a significant reduction in pain compared to placebo. It was also found that the reduction in pain was independent of both comorbid depression and of any reduction in depression or anxiety. It should be noted, however, that in the first study the pain reduction was only found in women, not men, and the second study only looked at women. More research needs to be done to determine whether duloxetine has any pain reducing effect for men.[127]
Anti-seizure medication
Anti-seizure drugs are also sometimes used, such as gabapentin (Neurontin)[128] and pregabalin (Lyrica). Gabapentin is not approved or labeled for use in treatment of neuropathic pain or fibromyalgia. Pregabalin, originally labeled for the treatment of nerve pain suffered by diabetics, has been cleared by the US Food and Drug Administration for treatment of fibromyalgia.[129] A randomized controlled trial of pregabalin 450 mg/day found that 6 patients is the number needed to treat for one patient to have a 50% reduction in pain.[130]
Dopamine agonists
Dopamine agonists (e.g. pramipexole (Mirapex) and ropinirole(ReQuip) have been studied for use in the treatment of fibromyalgia with good results.[62] A trial of transdermal rotigotine is currently ongoing.[131]
Insomnia
As fibromyalgia sufferers often have insomnia, and insomnia is also believed to increase fibromyalgia pain, they should consider Zolpidem/Ambien CR or Zaleplon (insomnia medications seeming least disruptive to normal sleep architecture).[132] Some studies suggest these may be taken 7 to 10 days without the dependencies of other insomnia medications. If taken for longer periods then tapering of the medications are recommended to prevent the rebound of insomnia. [133]
Investigational medications
Milnacipran, a serotonin-norepinephrine reuptake inhibitor (SNRI), until recently, was only available in parts of Europe where it has been safely prescribed for other disorders. On May 22, 2007, a Phase III study demonstrated statistically significant therapeutic effects of Milnacipran as a treatment of fibromyalgia syndrome and in January 2009, the FDA approved the use of Milnacipran for chronic pain related to fibromyalgia, lupus and neuropathy.
Dextromethorphan is an over-the-counter cough medicine with activity as an NMDA receptor antagonist. It has been used in the research setting to investigate the nature of fibromyalgia pain;[134][135] however, there are no controlled trials of safety or efficacy in clinical use.
A study comprising a 3-month open trial of oral∆9-tetrahydrocannabinol(THC) in nine fibromyalgia patients reported a significant reduction in daily recorded pain and electronically induced pain in the 4 subjects who completed the study.[136] A subsequent controlled trial to evaluate the potential benefits of nabilone (a synthetic cannabinoid) in pain management and quality of life improvement in 40 patients with fibromyalgia reported significant decreases in comparison to baseline in the visual analog scale for pain (-29%), Fibromyalgia Impact Questionnaire score (-18%) and anxiety (-28%) following four weeks of therapy. No statistically significant differences were observed in any of the outcome measures in the placebo group. Patients receiving nabilone experienced more side effects, which included drowsiness (7/15), dry mouth (5/15), vertigo (4/15), and ataxia (3/15).[137] Previous clinical and preclinical trials have shown that both naturally occurring and endogenous cannabinoids hold analgesic qualities,[138] particularly in the treatment of cancer pain and neuropathic pain,[139][140] both of which are poorly treated by conventional opioids. As a result, some experts have suggested that cannabinoid agonists would be applicable for the treatment of chronic pain conditions unresponsive to opioid analgesics, and they propose that the disorder may be associated with an underlying clinical deficiency of the endocannabinoid system.[141]
Among the more controversial therapies involves the use of guaifenesin; called St. Amand's protocol or the guaifenesin protocol[142] the efficacy of guaifenesin in treating fibromyalgia has not been proven in properly designed research studies. Indeed, a controlled study conducted by researchers at Oregon Health Science University in Portland failed to demonstrate any benefits from this treatment,[143] and the lead researcher has suggested that the anecdotally reported benefits were due to placebo suggestion.[144] The results of the study have since been contested by Dr St. Amand, who was a co-author of the original research report.[145]
Physical treatments
Studies have found exercise improves fitness and sleep and may reduce pain and fatigue in some people with fibromyalgia.[146] Many patients find temporary relief by applying heat to painful areas. Those with access to physical therapy, massage, or acupuncture may find them beneficial.[147] Most patients find exercise, even low intensity exercise to be extremely helpful.[148] Osteopathic manipulative therapy can also temporarily relieve pain due to fibromyalgia.[149]
Psychological/behavioural therapies
Cognitive behavioural therapy has been shown to alleviate fibromyalgic symptoms, although it is not curative. The greatest benefit occurs when CBT is used along with exercise.[12][150] Self-management techniques such as pacing and stress management may also be helpful for some patients.[citation needed] Because the nature of fibromyalgia is not well understood, some physicians believe that it may be psychosomatic or psychogenic.[151] Accordingly, some doctors have claimed to have successfully treated fibromyalgia when a psychological cause is accepted.[152]
Prognosis
Although neither degenerative nor fatal, the chronic pain of fibromyalgia is pervasive and persistent. Most fibromyalgia patients report that their symptoms do not change over time. An evaluation of 332 consecutive new fibromyalgia patients found that, out of 15 factors, pain levels, self-assessed inability to work, psychological distress, pending litigation, helplessness, level of education, and coping ability had a significant and independent association with symptom severity and function.[153] Of those diagnosed with fibromyalgia, 10% to 30% report being work-impaired, and patients often need accommodations to fully participate in their education or remain active in their careers.[citation needed]
Epidemiology
Fibromyalgia is seen in about 2% of the general population[154] and affects more females than males, with a ratio of 9:1 by ACR criteria.[155] It is most commonly diagnosed in individuals between the ages of 20 and 50, though onset can occur in childhood.
[edit] History
Fibromyalgia has been studied since the early 1800s and referred to by a variety of former names, including muscular rheumatism and fibrositis.[156] The term fibromyalgia was coined in 1976 to more accurately describe the symptoms, from the Latin fibra (fiber)[157] and the Greek words myo (muscle)[158] and algos (pain).[159]
Dr. Muhammad B. Yunus, considered the father of the modern view of fibromyalgia, published the first clinical, controlled study of the characteristics of fibromyalgia syndrome in 1981.[160][161] Yunus' work validated the known symptoms and tender points that characterise the condition, and proposed data-based criteria for diagnosis. In 1984, Yunus proposed the interconnection between fibromyalgia syndrome and other similar conditions, and in 1986 demonstrated the effectiveness of serotonergic and norepinephric drugs.[162] Yunus later emphasized the "biopsychosocial perspective" of fibromyalgia, which synthesized the contributions of genes, personal and medical history, stress, posttraumatic and mood disorders, coping skills, self-efficacy of pain management and social support towards the functioning and dysfunctioning of the central nervous system in relation to pain and fatigue.[160][161]
Fibromyalgia was recognized by the American Medical Association as an illness and a cause of disability in 1987.[citation needed] In an article the same year, the Journal of the American Medical Association also called the disorder fibromyalgia.[163] The American College of Rheumatology (ACR) published criteria for fibromyalgia in 1990 and developed neurohormonal mechanisms with central sensitization in the 1990s.[162]
[edit] Controversies
Several controversial issues exist with regard to fibromyalgia that range from questions regarding the validity of the disorder as a clinical entity, to issues regarding primary pathophysiology and the potential existence of fibromyalgia sub-types. Dr. Frederick Wolfe, the lead author of the 1990 paper that first defined the classification criteria for fibromyalgia, has been since quoted as saying he has become cynical and discouraged about the diagnosis and that he now considers the condition a physical response to stress, depression, and economic and social anxiety.[164] Opponents of the fibromyalgia concept argue that fibromyalgia represents a ‘non-disease’ and that giving it a label simply legitimizes patients' sickness behavior.[10]
In contrast, findings from the London Fibromyalgia Epidemiology Study, which comprised a 36 month prospective, within-group comparison of 100 individuals identified as having fibromyalgia (72 of whom were newly diagnosed with the disorder), demonstrated that although physical functioning decreased slightly over time, there was also a statistically significant improvement in satisfaction with health, and newly diagnosed fibromyalgia cases reported fewer symptoms and major symptoms over the long term. No other differences in clinical status or health service use occurred over time.[165] The authors of the study concluded that the ‘fibromyalgia label’ does not have a meaningful adverse affect on clinical outcome over the long term. It is however possible that these results can be accounted for by Regression toward the mean.
The validity of fibromyalgia as a unique clinical entity is also a matter of some contention among researchers in the field. Contradictory findings from clinical research, compounded by differences in psychological and autonomic profiles among affected individuals, have been interpreted by different groups to indicate the existence of fibromyalgia sub-types.[166][167] There is also considerable overlap between fibromyalgia and other clinical disorders, which are frequently referred to collectively as "functional somatic syndromes" (e.g. irritable bowel syndrome, chronic fatigue syndrome).[168] Others have proposed that the clinical phenomena that fall under the label ‘fibromyalgia syndrome' might actually comprise several clinical entities, ranging from mild, idiopathic inflammatory processes in some individuals, to somatoform disorders resulting from neuropsychiatric processes in others, with probable overlaps in between.[166]
There is no clear-cut cause for trigeminal neuralgia (TN). Some say that TN is caused by trauma to the nerve as it passes from the skull to the muscles and tissue of the face. This trauma compresses the nerve, causing the nerve cell to shed its protective and conductive coating. Others believe the cause of TN is a biochemical change in the nerve tissue. Recently, it has been proposed that an abnormal blood vessel compresses the nerve as it exits from the brain. In all cases, an excessive amount of activity from a damaged nerve causes the painful attacks.
The term hydrocephalus is derived from two words: "hydro" meaning water, and "cephalus" referring to the head.
Hydrocephalus can be treated in a variety of ways. The problem area may be treated directly (by removing the cause of CSF obstruction), or indirectly (by diverting the fluid to somewhere else; typically to another body cavity). Indirect treatment is performed by implanting a device known as a shunt to divert the excess CSF away from the brain. The body cavity in which the CSF is diverted is usually the peritoneal cavity (the area surrounding the abdominal organs).
