Clinical Features of Fibromyalgia

Robert Bennett MD 

SYNOPSIS

Since the American College of Rheumatology Classification Criteria for Fibromyalgia were published in 1990.  there have been an ever increasing number of research articles and reviews. The major clinical manifestations of fibromyalgia have not changed, but their prevalence, association, relative importance to the patient and scientific underpinnings are increasingly better understood. This review provides an update on fibromyalgia symptomatology.

CLINICAL MANIFESTATIONS OF FIBROMYALGIA

The basic clinical manifestations of fibromyalgia (FM), in terms of pain, fatigue, dysfunctional, sleep and tenderness, were described by Smythe in 1977 ¹²⁸ and elaborated by Yunus in 1981 ¹⁵² The 1990 American College of Rheumatology Fibromyalgia Classification paper listed many other symptoms that were commonly reported by FM patients (paresthesias, anxiety, headaches, irritable bowel, urinary urgency, sicca symptoms, noise and cold intolerance, dysmenorrhea, depression, low back pain, neck pain, Raynaud’s phenomenon and weather effects) ¹⁵¹.  An internet survey conducted by the National Fibromyalgia Association (NFA) on 2,569 people with diagnosed fibromyalgia reported the rank order of symptoms as: morning stiffness, fatigue, non restorative sleep, pain, forgetfulness, poor concentration, difficulty falling asleep, muscle spasms, anxiety and depression.¹⁶ and reported the rank order of symptom intensity (Table 1). A similar questionnaire from the German Fibromyalgia Association (DFV) was mailed to 3,996 patients and was completed by 699 patients; the rank order of the most frequent symptoms was: muscle pain, morning stiffness, non-restorative sleep, poor concentration, lack of energy, low productivity and forgetfulness ⁶³. Since that time many of these symptoms have been subject to further study of outcome measures in rheumatology clinical trials and the patients’ perspective has been more rigorously evaluated process as part of the OMERACT (Outcome Measures in Rheumatology Clinical Trials) process ^28;98;99. These manifestations of FM are now described in more detail:

Pain

 The core symptom of FM, according to the 1990 ACR classification criteria is chronic widespread pain ¹⁵¹.  FM patients usually describe their pain as arising from muscle and joints ⁶³, however the majority of FM patients also have tender skin ^92;128.  Fibromyalgia pain typically waxes and wanes in intensity; flares are associated with unaccustomed exertion, prolonged inactivity, soft tissue injuries, surgery, poor sleep, cold exposure, long car trips and psychological stressors.  Many FM patients describe increased pain with cold damp weather, in particular low pressure fronts ¹⁶; ¹³²; ⁵⁶. FM pain is predominantly axial in distribution; but pain in the hands and feet is not uncommon and may lead to a misdiagnosis of “early” rheumatoid arthritis ¹¹⁷.  Staud has surmised that “peripheral factors account for most of the variance of overall clinical FM pain, suggesting that the input of pain by the peripheral tissues is clinically relevant ¹²⁹.”Many patients describe a feeling of swelling in their soft tissues; this is often localized to the area of joints - leading to self-diagnosis of arthritis and often referral to a rheumatologist. Martinez-Lavin has reported that many FM symptoms are similar to those experienced by patients with neuropathic pain syndromes ⁹²; these “neuropathic” symptoms mainly refer to changes in skin sensation.   Fibromyalgia pain and stiffness typically have a diurnal variation, with a nadir during the hours of about 11.00 am to 3.00 pm¹⁰².  Fibromyalgia often occurs in the setting of other pain states/syndromes, such as rheumatoid arthritis (~ 20%)¹⁴⁹, systemic lupus erythematosus (~25%)²³, osteoarthritis (~35%) ^147;151 etc. There has been a profusion of sophisticated psycho-neurophysiological and imaging studies indicating that FM pain is a result of disordered sensory processing ⁸⁹.

Fatigue

Fatigue is one of the most common symptoms encountered in patients seeking medical care, with a prevalence of 24% in one report ⁷⁶. The association of fatigue and pain has a long history and was a prominent feature in the diagnosis of neurasthenia of the late nineteenth century ^10;29;141.The differential diagnosis of fatigue includes many medical illnesses, but a well defined diagnosis is only found in about 5% of fatigued patients presenting in primary care ⁷⁷.  The OMERACT 8 patient Delphi rated fatigue as the third most important symptom after 2 pain related items; it was endorsed by 96% of participants ⁹⁸ . In the NFA and German surveys it was rated as the second most troublesome symptom (Table 1). The Fibromyalgia Impact Questionnaire (FIQ ) has a question of “How tired have you been”  with anchors of No tiredness and Very tired on a 0-10 VAS scale; it is often used a surrogate measure of fatigue.  However, exactly what is meant by “fatigue” needs to be considered . Sleepiness and fatigue are interrelated, but distinct phenomena; that are often reported in the context of medical disorders,  psychiatric disorders and  primary sleep disorders. Sleepiness and fatigue usually have different implications in terms of diagnosis and treatment; however,  they are often used interchangeably, or merged under the more general lay term of 'feeling tired'. Most FM patients describe their fatigue as a weariness of mind and body that impairs their productivity and enjoyment of life.

A careful analysis is required in the evaluation of the fatigued patient in order to determine the possible cause of the symptoms and the patient’s reaction to being fatigued. Wessely conceptualized 4 components of fatigue: behavior (effects of fatigue), feeling (subjective experience), mechanisms, and context (e. g. environment, attitudes) ¹⁴². He stresses that even when a discrete cause for fatigue is identified, such as chronic infection or multiple sclerosis, social, behavioral, and psychological variables are important in the comprehensive evaluation of a patient’s fatigue. Arnold has emphasized the wide-range of symptoms that can masquerade as “fatigue”; she divides fatigue into 3 major domains:  1. Physical (e.g., reduced activity, low energy, tiredness, decreased physical endurance, increased effort with physical tasks and with overcoming inactivity, general weakness, heaviness, slowness or sluggishness,nonrestorative sleep, and sleepiness); 2. Cognitive (e.g., decreased concentration, decreased attention, decreased mental endurance, and slowed thinking); and 3. Emotional dimensions (e.g., decreased motivation or initiative, decreased interest, feeling overwhelmed, feeling bored, aversion to effort, and feeling low) ⁶.

In FM patients, the 2 most obvious contributors to fatigue are depression and non-restorative sleep. However, although antidepressant therapy often results in a modest improvement in fatigue scales they are seldom curative of this symptom ^5;33;100.  Furthermore, improvements in non-restorative sleep do not necessarily translate into absence of fatigue. In the 2009 sodium oxybate study the overall improvement of sleep was about 30% (Jenkins sleep questionnaire) and tiredness (FIQ) was reduced by about  25%¹²².

Chronic pain itself appears to have a fatiguing effect ^1;44. This is probably the result of comorbidities such as insomnia, deconditioning and depression. However, there is increasing interest in the notion that the fatigue/pain association may be a direct result of chronic pain modulating the release of inflammatory cytokines from pain activated astrocytes and microglia within the brain with the induction of a “sickness syndrome” ^{145 88}. The effective management of fatigue is clearly a major problem in the comprehensive treatment of FM patients and a refined understanding of the meaning of this symptom, as per OMERACT methodology, should provide useful new insights. 

Stiffness

Stiffness is a prominent complaint in many musculoskeletal disorders. Patients in the NFA online survey rated morning stiffness as their most troublesome symptom, German FM patients rated it as their fourth most important symptom (table 1).  In the OMERACT 8 Delphi stiffness was reported by 91% of participants and was rated the sixth most important symptom ⁹⁸. The combination of stiffness with the common FM complaint of joint pain raises questions about a diagnosis of an early inflammatory arthritis; hence the often requested interest of many patients Stiffness is an item of the FIQ ²¹, and thus an indication of its relevance can be found in the many studies that have used the FIQ ¹³. There have not been any physiologic studies of stiffness in FM.  Muscle stiffness is a combination of the intrinsic properties of muscle tissue, mainly non elastic connective tissue, and the resting muscle tone.  There is an increase in this non-elastic tissue with aging ¹⁴⁶ and muscle tissue displays thixotropic properties (i.e. it stiffens with increasing rest and vice versa) ⁷⁸;this may be relevant to the benefits of exercise in FM. On the other hand, exercise induced muscle damage increases muscle stiffness  ⁹⁷ thus the need for restraint in the prescription of vigorous exercise in FM patients⁶⁷. Muscle stiffness maybe a prominent early symptom of several disorders; for instance stiffness is a feature of severe hypothyroidism (Hoffman’s syndrome)³⁸ and is often an early symptom of Parkinson’s disease ³⁷. It is quite evident that a greater understanding of stiffness in FM patients should yield important clues as to clinically relevant changes in muscle composition, muscle tone and deconditioning.

Disordered sleep

Fibromyalgia patients usually report disturbed sleep  QUOTE "(Moldofsky et al 1975)"  ADDIN REFMAN ÿ\11\05‘\19\01\00\00\00\16(Moldofsky et al 1975)\00\16\00(C:\5CProgram Files\5CWinRM9\5CRM Databases\5CFMS\03\00\041306,Moldofsky, Scarisbrick, et al. 1975 1306 /id\00,\00 ^58;103.  While they often have problems with sleep initiation and maintenance, the most notable feature is still feeling tired on awakening. This is usually referred to as “non-restorative sleep”(NRS) and typically causes greater daytime impairment than difficulty initiating or maintaining sleep ^{106 104}. There is no definitive classification of NRS; Stone has suggested this definition: “a report of persistently feeling un-refreshed upon awakening in the presence of normal sleep duration, occurring in the absence of a sleep disorder”.¹³¹. This is partly captured in the FIQ question on sleep: “how have you felt when you get up in the morning”?  Awoke well rested / Awoke very tired. NRS has been associated with certain EEG changes. In the 1970s alpha intrusion into the delta rhythm of non-REM sleep was initially described in psychiatric patients ⁶⁰ and shortly thereafter Moldofsky described a similar abnormality in “fibrositis” patients ¹⁰⁵. It is now apparent that alpha-delta sleep is not always found in FM patients and does not always correlate with the symptom of NRS ⁸⁶. More recently other abnormal EEG patterns have been found in FM patients:Rizzi reported that a cyclic alternating pattern of sleep correlated with FM symptoms¹¹⁹, and Roizenblatt reported that alpha intrusion had several different patterns, with a phasic pattern correlating most closely with FM symptoms Roizenblatt, 2001 6241 /id]. Landis reported that female FM patients had fewer spindles during NREM stage 2 sleep and a lower spindle time per epoch of NREM stage 2 sleep ⁷⁹.

In the clinical evaluation of disturbed sleep in FM patients, the most important issue is the determination as to whether a patient has a primary sleep disorder. By far the most common is restless leg syndrome (RLS) which is associated with periodic limb movement disorder in most cases ⁸⁷.  A 2008 study found a 64% prevalence of RLS in 3302 women with fibromyalgia and noted that these patients experienced more sleep disturbances and pronounced daytime sleepiness ¹³⁰. The history and response to a dopamine agonist are so typical that a formal sleep study is often unnecessary to diagnose RLS unless a comorbid sleep apnea is suspected. However, it is suggested that patients with RLS have a ferritin level, as there is a relationship of RLS with iron deficiency ⁴. This iron deficiency seems similar to the iron deficiency of chronic disease and is often unresponsive to oral iron supplements. Interestingly patients with RLS have been reported to have low levels of iron in the substantia nigra and putamen ³; neuropathological studies have led to the notion that RLS may be a functional disorder resulting from impaired iron acquisition by the neuromelanin cells. ³¹.  There are no large studies of sleep apnea prevalence in FM; one study of 50 people attending a sleep clinic found the prevalence of  FM was 10 times higher in subjects with sleep apnea/hypopnea compared to the reported prevalence of FM in the general population ⁴⁷. Upper-airway resistance syndrome (UARS) is increasingly being diagnosed in patients with dysfunctional sleep; this diagnosis will be missed unless additional channels are incorporated into the plysomnography testing ⁹. UARS was found in 26 out of 28 female FM patients attending a sleep clinic; only 1 patient had obstructive sleep apnea, continuous positive airways pressure CPAP resulted in an improvement in functional symptoms ranging from 23% to 47% ⁵⁰. If these results were confirmed in a larger sample, there would be a good rationale for including polysomnography in the routine evaluation of FM patients.

Tenderness

FM patients typically complain that they are more sensitive to touch, and experience pain on relatively minor contact (Table 1). Skin roll tenderness (from inter-scapular area) was incorporated into an early diagnostic definition of FM ¹²⁸. Some 95% of FM patients endorsed the Leeds neuropathic pain question, “Does your pain make the affected skin abnormally sensitive to touch?” ⁹².  Superficial pressure pain thresholds using von Frey hairs were found to be less in FM than healthy controls, as were deep pressure pain thresholds and tourniquet test tolerance ²⁴. Another feature of some FM patients that suggests cutaneous sensitization is dermatographia. This is the reactive hyperemia increased local blood flow and edema that occur on mechanical or chemical stimulation of the skin. It results from the local release of histamine from mast cells and the antidromic release of substance P, neurokinin A, and calcitonin gene-related peptide (CGRP) from the peripheral endings ¹²⁴. Dermatographia was one of the 6 clinical features used in FM diagnosis in the 1976 paper reporting on non-REM sleep changes in patients with the “fibrositis syndrome” ¹⁰⁵. Littlejohn subsequently reported that FM patients had an exaggerated skin flare response to both mechanical and chemical (capsaicin) stimulation and a positive correlation between the size of the flare and the number of tender points ⁸³.. It was suggested that the exaggerated skin response reflected increased activity of polymodal nociceptors of afferent nerves and that this may play a role in FM related skin tenderness. These observations were largely forgotten until Salemi found that the skin biopsies of about 30% of FM patients had demonstrable amounts of messenger RNA coding for IL-1ßb, IL-6 and TNF-a, whereas no cytokine coding mRNA was found in skin biopsies from healthy controls ¹²³. It was surmised that this finding was a result of neurogenic inflammation. Supportive of this explanation was the earlier finding of dermal deposits of IgG and increased numbers of mast cells in FM compared to controls ⁴². Interestingly there is one report of experimental slow wave sleep disruption being related to an exaggerated skin response as well as a reduced pain threshold ⁸². Whether these findings are of primary relevance or a FM related epiphenomenon is always an issue in such research; the author is of the opinion that skin tenderness is a currently neglected area of FM research which may be of relevance to the initiation and maintenance of central sensitization ¹².

Cognitive dysfunction

Difficulties with memory, concentration and dual tasking are a major problem, according to self-reports, of many fibromyalgia patients ^{110 49}. On 3 self rating surveys (see Table 1), dyscognition was the fifth most distressing symptom.  Patients commonly describe difficulties with short-term memory, concentration, logical analysis and motivation. This decrease in cognitive performance and been estimated to be equivalent to 20 years of aging ¹¹⁰. Defects have been described in terms of working memory, episodic memory and verbal fluency.  Short-term memory problems have been linked to a disproportionate interference from distraction influences ⁸¹ . Some investigators have noted that cognitive defects in FM maybe a result of associated fatigue, pain and depression ^{133 52} and others have failed to find significant defects using automated neuropsychological assessment ¹⁴⁰.

Newer imaging technology may provide some explanation for these deficits. For instance  a proton magnetic resonance spectroscopy (1H-MRS) study showed lower levels of N-acetylaspartate (NAA) in the hippocampus of FM patients ⁴¹. The hippocampus is important in the formation of new memories and thus its dysfunction may be implicated in short term memory loss.¹¹¹.  There are several recent studies reporting a reduction in hippocampal volume in chronically stressed individuals ^72;94;136.  Using the relatively new technique of magnetic resonance diffusion-tensor imaging and MR imaging of voxel-based morphometry, defects in neuronal circuitry were noted in FM patients along with decreases in gray matter volume in the post central gyri, amygdalae, hippocampi, superior frontal gyri, and anterior cingulate gyri ⁸⁵. Luerding has reported that cognitive deficits in non-verbal working memory were positively correlated with grey matter values in the left dorsolateral prefrontal cortex, whereas working memory was positively correlated with grey matter values in the supplementary motor cortex ⁸⁴. The definitive etiology of these changes are not known, but contemporary notions suggest that increased neuronal apoptosis resulting from chronic stress ⁹⁵ and epigenetic changes in glucocorticoid receptors resulting from childhood adversity ⁹⁶ are possible explanations. This symptom domain will be the subject of increased attention by OMERACT with special reference to evaluation of targeted therapies. 

Dysthesias

FM patients commonly report numbness and tingling in the extremities without any obvious cause coming to light on further testing. In some patients this may be due to restless legs syndrome and in others an early peripheral neuropathy. Symptoms mimicking a neurological disorder were first reported some 20 years ago ¹²⁶. More recently Martinez-Lavin has postulated that fibromyalgia is a neuropathic pain syndrome ⁹¹ and that dysthetic sensations are evidence for this notion. In order to test this hypothesis the Leeds neuropathic pain questionnaire was given to 20 FM patient and 20 RA patients ⁹². ⁹². Sensory symptoms were more common in the FM cohort: dysesthetic (% v 30%), evoked (95%  v 35%), paroxysmal (90% v 15%), and thermal (90% v 20%).  Another explanations for the experience of these neurological sounding symptoms is a conflict between sensory-motor central nervous processing ⁹³ and central sensitization syndrome ¹⁵⁴. 

Poor Balance

Poor balance is increasingly being recognized as a manifestation of fibromyalgia. In the NFA survey balance problems were reported by 45% of participants ¹⁶. Jones studied 32 FM patients and 32 controls as regards number of falls, confidence about balance and a clinical evaluation of physiological dysfunctions (stability limits, anticipatory postural adjustments, reactive postural responses, sensory orientation and stability in gait) relating to balancing ⁶⁸. Over a 6 month period FM patients had 37 falls compared to 6 falls in the controls. FM patients lacked confidence in their ability to do specific tasks with an increased fear of falling compared to controls. The reasons for this imbalance in FM is unclear at this time, issues that may be relevant include: poor proprioception, vestibular dysfunction, disturbed spatio-visual orientation, lower limb weakness, concentration/distraction deficits and orthostatic hypotension.

Raynaud’s Phenomenon

FM patients often complain of being cold in situations where others are not; this is often associated with changes in the color of their fingers. Symptoms suggestive of primary Raynaud’s have been reported in FM patients for the last 25 years, with a prevalence ranging from 8.8% to 53.3% ^39;137;155. One study of nail-fold capillaroscopy in FM did not find any of the morphological changes that have been described in connective tissue disorders, but did note sluggish circulation in those patients with Raynaud’s ⁴⁵. Bennett reported on quantitative evaluation of cold induced vasospasm in 29 FM patients using the Nielsen test; 41% had an abnormal test and 38% had elevated levels of platelet alpha 2-adrenergic receptors. There was a positive correlation between the percentage of change in finger systolic pressure on cooling (Nielsen test) and the number of alpha 2-adrenergic receptors. Digital photoplethysmography did not reveal any changes suggestive of organic disease in the digital vessels ¹⁵. Thermo-sensory testing has uniformly found a reduced threshold for cold induced pain ^18;24;65. The relationship of cold intolerance and Raynaud’s phenomenon to the dyautonomia of FM and reduced perfusion of muscle is an area warranting further research ^{40 69}.

Oral and ocular symptoms

Dry mouth is a common complaint of FM patients with estimates ranging from 18% to 71%^39;53. In some cases this may be a result of side effects from tricyclic antidepressants ⁷¹, coexistent hepatitis C infection ¹¹⁶ or dysautonomia ⁷³; but in the majority of cases no obvious cause can be found ⁵³.  However, FM does appear to have a common association with Sjogren’s syndrome, with a 22% prevalence in one study ¹⁰⁸ and is often the only diagnosis that can be made in patients with keratoconjunctivitis sicca¹¹⁵. On the other hand a diagnosis of biopsy proven Sjogren’s syndrome was only found in 7% of 72 FM patients ²⁰. In a study of 67 FM patients a high prevalence of oral symptoms were recorded xerostomia 70.9%, glossodynia 32.8%, dysphagia 37.3% and  dysgeusia 34.2% ¹¹⁸. Blurred vision, that cannot be corrected by prescription lenses, is also a common complaint (author’s experience).

Impaired Function

Most FM patients report some limitations of function. The item 1 of the FIQ consists of 11 questions relating to function with an average value of between 40 and 50 (on a 0-100 VAS scale) in several recent pharmaceutical studies ^17;100.

Difficulty with moving and low productivity are prominent complaints (See table 1). An analysis of the NFA survey data found that over 25% of female FM patients self reported difficulties in taking care of personal needs and the majority reported problems with light housework and negotiating one flight of stairs ⁶⁶. The average FM patient in this sample was assessed as having less functional ability than the typical woman in her 80s. In general reduced function was associated with higher levels of pain, fatigue, depression, balance problems, irritable bladder, restless legs and muscle spasms.  FM patients’ reports of reduced functioning have been correlated to reduced activity on electronic ambulatory monitoring ⁷⁴. There is some evidence that depression plays a role in reduced daytime activity ⁷⁵. Problems with physical function and cognitive defects may result in difficulties in sustained employment ^46;120;139. ¹⁴⁴.

Sexuality

It is not surprising that chronic pain and fatigue have an adverse effect on sexuality. This is an area of clinical manifestations that has only recently been explored Ryan, 2008 15797 /id].  Orellana gave the Changes in Sexual Functioning Questionnaire to 31 FM patients along with 20 healthy controls and 26 patients with rheumatoid arthritis ¹⁰⁷. Sexual dysfunction was more frequent among FM patients (97%) and RA patients (84%) compared to controls. There was a major correlation of sexual dysfunction with intensity of depression. A similar association with depression was reported by Aydin ⁸. On the other hand a study using The Female Sexual Function Index (FSFI) compared sexual dysfunction in 40 patients with FM only, 27 with FM plus major depression and 33 healthy controls found no association with depression ¹³⁵. One prevalence study of vulvodynia reported that FM patients have an increased odds ratio of 3.84 for having this problem Arnold, 2006 15634 /id]. Pelvic pain syndrome is also common according to one study of FM patients ⁶⁴; its relationship to endometriosis in FM patients needs further study.

Headaches

Headaches were prominently ranked in the NFA and DFV surveys, but not in the OMERACT Delphi (table 1).  The prevalence of International Headache Society diagnoses in one study of FM patients was: migraine without aura – 20%, migraine with aura – 23%, tension alone 24%, combined tension and migraine – 22%, post traumatic – 5% and probable analgesic overuse syndrome – 8% lone (n=15 with aura, n=17 without aura), tension-type alone (n=18), combined migraine and tension-type (n=16), post-traumatic (n=4), and probable analgesic overuse headache (n=6) ⁹⁰. It was reported that FM/migraine patients have more disabling headaches and have higher CSF glutamate levels than migraine alone ¹¹²; it was postulated that chronic migraine patients with fibromyalgia suffer from a more severe central sensitization process. Others have also opined that migraine, daily chronic headache and fibromyalgia are an expression of abnormal pain processing ²⁵. Questions regarding headache should be part of the comprehensive evaluation of all FM patients.

Psychological distress

Self reported depression is a common symptom in FM patients (table 1). As FM was once considered to be a psychiatric diagnosis there have been numerous studies evaluating the psychological profiles of FM patients. For instance early studies noted elevations of certain scales on the Minnesota Multiphasic Personality Inventory (MMPI), especially the hypochondriasis, hysteria and depression scales ². Smythe noted that any chronic pain patient would give positive answers on the MMPI to questions relating to pain and somatic symptoms ¹²⁷, and concluded that there was a 40% bias of labeling a chronic pain patient as being "neurotic". There is a general consensus that depression, anxiety disorders and PTSD are common in FM patients ²². Arnold has reported the odds ratios for psychiatric diagnoses in individuals with fibromyalgia versus individuals with rheumatoid arthritis are: bipolar disorder: 153, major depressive disorder: 2.7,  any anxiety disorder: 6.7 any eating disorder: 2.4 , and any substance use disorder: 3.3 ⁷.  Contrary to popular misconceptions, personality disorders are not especially common in the FM population, Thieme found a prevalence of 8.7% ¹³⁴and Fietta 7%⁴³. The coexistence of anxiety and depression with FM generally has a negative influence on the expression of FM symptoms and functionality, but this association can be quite variable ⁴⁸.

Associated disorders

In addition to the numerous clinical manifestations of FM described here, many FM patients have an associated clinical syndrome such as irritable bowel, overactive bladder, restless legs, multiple chemical sensitivity, chronic fatigue syndrome, vulvodynia etc. These syndromes are described in more detail in the accompanying chapter by Dr. Clauw. The association of these disorders with FM and between themselves is now considered to be a manifestation of widespread central sensitization and is increasingly being referred to as “central sensitivity syndromes” ¹⁵⁴.

CONCLUSIONS

Over the past 28 years since the publication of the 1990 ACR Classification Criteria for Fibromyalgia, there has been an impressive advancement in our understanding of FM symptoms and their psycho-neurological underpinnings in terms of central sensitization and genetic influences. However, the roles of peripheral pain states, sleep disorders, psychopathology and cytokines in initiating and perpetuating disordered sensory processing are less clear.  

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