Computer Monitor, like mac with blank screen. OVERVIEWDIAGNOSISTREATMENTFM DVDsSTUDY SIGN-UP FIQR self-test
       Pain explainedMyofascial painHaving SurgeryYour weightLupus in FMSjögren's
       Herbal medsGrowth hormonePregnancyMindfulnessFM DisabilityFM literature
                                                             PPT Slides    Frida Kahlo            

 

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:

 

OMERACT 7 patient Delphi

NFA Survey

DFV Survey

Pain or physical discomfort

Morning stiffness

Pain

Joint pain or aching

Fatigue

Fatigue

Lack of energy or fatigue

Non-restorative sleep

Non-restorative sleep

Poor sleep

Pain

Morning stiffness

Fibro-fog

Forgetfulness

Poor concentration

Stiffness

Poor concentration

Lack of energy

Disorganized thinking

Difficulty falling asleep

Low productivity

Difficulty with moving

Muscle spasms

Forgetfulness

Having to push yourself to accomplish things

Anxiety

Irritability

Problems setting goals and completing tasks

Depression

Weather sensitivity

Tenderness to touch

Headaches

Feeling hands are swollen

Depression

Anger

Dizziness

Limitations in normal daily activities

Restless legs

Headaches

Poor memory

Abdominal pain

Visual disturbances


Table 1: A comparison of the major patient perceived manifestations of fibromyalgia as reported in 3 surveys: The OMERACT patient Delphi [Mease, 2008 15494 /id], the National Fibromyalgia Association internet survey [Bennett, 2007 15113 /id] and the German Fibromyalgia Association postal survey [Hauser, 2007 15352 /id].
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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.  

          References  

      1.   Aaron LA, Herrell R, Ashton S, Belcourt M, Schmaling K, Goldberg J et al. Comorbid clinical conditions in chronic fatigue: a co-twin control study. J Gen Intern Med 2001;16(1):24-31.

      2.   Ahles TA, Yunus MB, Gaulier B, Riley SD, Masi AT. The use of contemporary MMPI norms in the study of chronic pain patients. Pain 1986;24159-163.

      3.   Allen RP, Barker PB, Wehrl F, Song HK, Earley CJ. MRI measurement of brain iron in patients with restless legs syndrome. Neurology 2001;56(2):263-265.

      4.   Allen RP, Earley CJ. Restless legs syndrome: a review of clinical and pathophysiologic features. J Clin Neurophysiol 2001;18(2):128-147.

      5.   Arnold LM. Duloxetine and other antidepressants in the treatment of patients with fibromyalgia. Pain Med 2007;8 Suppl 2:S63-S74.

      6.   Arnold LM. Understanding fatigue in major depressive disorder and other medical disorders. Psychosomatics 2008;49(3):185-190.

      7.   Arnold LM, Hudson JI, Keck PE, Auchenbach MB, Javaras KN, Hess EV. Comorbidity of Fibromyalgia and Psychiatric Disorders. J Clin Psychiatry 2006;67(8):1219-1225.

      8.   Aydin G, Basar MM, Keles I, Ergun G, Orkun S, Batislam E. Relationship between sexual dysfunction and psychiatric status in premenopausal women with fibromyalgia. Urology 2006;67(1):156-161.

      9.   Bao G, Guilleminault C. Upper airway resistance syndrome--one decade later. Curr Opin Pulm Med 2004;10(6):461-467.

     10.   Beard GM. Neurasthenia, or nervous exhaustion. Boston Medical and Surgical Journal 1869;3217-221.

     11.   Bennett R. The concurrence of lupus and fibromyalgia: implications for diagnosis and management. Lupus 1997;6(6):494-499.

     12.   Bennett R. Fibromyalgia: present to future. Curr Rheumatol Rep 2005;7(5):371-376.

     13.   Bennett R. The Fibromyalgia Impact Questionnaire (FIQ): a review of its development, current version, operating characteristics and uses. Clin Exp Rheumatol 2005;23(5 Suppl 39):S154-S162.

     14.   Bennett RM. Emerging concepts in the neurobiology of chronic pain: evidence of abnormal sensory processing in fibromyalgia. Mayo Clin Proc 1999;74(4):385-398.

     15.   Bennett RM, Clark SR, Campbell SM, Ingram SB, Burckhardt CS, Nelson DL et al. Symptoms of Raynaud's syndrome in patients with fibromyalgia. A study utilizing the Nielsen test, digital photoplethysmography, and measurements of platelet alpha 2-adrenergic receptors. Arth Rheum 1991;34264-269.

     16.   Bennett RM, Jones J, Turk DC, Russell IJ, Matallana L. An internet survey of 2,596 people with fibromyalgia. BMC Musculoskelet Disord 2007;8:27.27.

     17.   Bennett RM, Kamin M, Karim R, Rosenthal N. Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: a double-blind, randomized, placebo-controlled study. Am J Med 2003;114(7):537-545.

     18.   Berglund B, Harju EL, Kosek E, Lindblom U. Quantitative and qualitative perceptual analysis of cold dysesthesia and hyperalgesia in fibromyalgia. Pain 2002;96(1-2):177-187.

     19.   Bliddal H, nneskiold-Samsoe B. Chronic widespread pain in the spectrum of rheumatological diseases. Best Pract Res Clin Rheumatol 2007;21(3):391-402.

     20.   Bonafede RP, Downey DC, Bennett RM. An association of fibromyalgia with primary Sjogren's syndrome: a prospective study of 72 patients. J Rheumatol 1995;22133-136.

     21.   Burckhardt CS, Clark SR, Bennett RM. The fibromyalgia impact questionnaire: development and validation. J Rheumatol 1991;18728-733.

     22.   Buskila D, Cohen H. Comorbidity of fibromyalgia and psychiatric disorders. Curr Pain Headache Rep 2007;11(5):333-338.

     23.   Buskila D, Press J, Abu-Shakra M. Fibromyalgia in systemic lupus erythematosus: prevalence and clinical implications. Clin Rev Allergy Immunol 2003;25(1):25-28.

     24.   Carli G, Suman AL, Biasi G, Marcolongo R. Reactivity to superficial and deep stimuli in patients with chronic musculoskeletal pain. Pain 2002;100(3):259-269.

     25.   Centonze V, Bassi A, Cassiano MA, Munno I, Dalfino L, Causarano V. Migraine, daily chronic headache and fibromyalgia in the same patient: an evolutive "continuum" of non organic chronic pain? About 100 clinical cases. Neurol Sci 2004;25 Suppl 3:S291-2.S291-S292.

     26.   Chesterton LS, Barlas P, Foster NE, Baxter GD, Wright CC. Gender differences in pressure pain threshold in healthy humans. Pain 2003;101(3):259-266.

     27.   Chiu YH, Silman AJ, MacFarlane GJ, Ray D, Gupta A, Dickens C et al. Poor sleep and depression are independently associated with a reduced pain threshold. Results of a population based study. Pain 2005;115(3):316-321.

     28.   Choy EH, Arnold LM, Clauw DJ, Crofford LA, Glass JM, Simon LS et al. Content and criterion validity of the preliminary core dataset for clinical trials in fibromyalgia syndrome. J Rheumatol. (in press). 2009.

     29.   Clauw DJ. The pathogenesis of chronic pain and fatigue syndromes, with special reference to fibromyalgia. Med Hypotheses 1995;44369-378.

     30.   Clauw DJ. Elusive syndromes: treating the biologic basis of fibromyalgia and related syndromes. Cleve Clin J Med 2001;68(10):830, 832-830, 834.

     31.   Connor JR, Boyer PJ, Menzies SL, Dellinger B, Allen RP, Ondo WG et al. Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology 2003;61(3):304-309.

     32.   Coster L, Kendall S, Gerdle B, Henriksson C, Henriksson KG, Bengtsson A. Chronic widespread musculoskeletal pain - a comparison of those who meet criteria for fibromyalgia and those who do not. Eur J Pain 2008;12(5):600-610.

     33.   Crofford LJ, Rowbotham MC, Mease PJ, Russell IJ, Dworkin RH, Corbin AE et al. Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2005;52(4):1264-1273.

     34.   Croft P, Burt J, Schollum J, Thomas E, Macfarlane G, Silman A. More pain, more tender points: is fibromyalgia just one end of a continuous spectrum? Ann Rheum Dis 1996;55482-485.

     35.   Croft P, Schollum J, Silman A. Population study of tender point counts and pain as evidence of fibromyalgia. BMJ 1994;309(6956):696-699.

     36.   Dadabhoy D, Crofford LJ, Spaeth M, Russell IJ, Clauw DJ. Biology and therapy of fibromyalgia. Evidence-based biomarkers for fibromyalgia syndrome. Arthritis Res Ther 2008;10(4):211.

     37.   de Lau LM, Koudstaal PJ, Hofman A, Breteler MM. Subjective complaints precede Parkinson disease: the rotterdam study. Arch Neurol 2006;63(3):362-365.

     38.   Deepak S, Harikrishnan, Jayakumar B. Hypothyroidism presenting as Hoffman's syndrome. J Indian Med Assoc 2004;102(1):41-42.

     39.   Dinerman H, Goldenberg DL, Felson DT. A prospective evaluation of 118 patients with the fibromyalgia syndrome: prevalence of Raynaud's phenomenon, sicca symptoms, ANA, low complement, and Ig deposition at the dermal-epidermal junction. J Rheumatol 1986;13368-373.

     40.   Elvin A, Siosteen AK, Nilsson A, Kosek E. Decreased muscle blood flow in fibromyalgia patients during standardised muscle exercise: a contrast media enhanced colour Doppler study. Eur J Pain 2006;10(2):137-144.

     41.   Emad Y, Ragab Y, Zeinhom F, El-Khouly G, bou-Zeid A, Rasker JJ. Hippocampus Dysfunction May Explain Symptoms of Fibromyalgia Syndrome. A Study with Single-Voxel Magnetic Resonance Spectroscopy. J Rheumatol 2008;35(7):1371-1377.

     42.   Enestrom S, Bengtsson A, Frodin T. Dermal IgG deposits and increase of mast cells in patients with fibromyalgia--relevant findings or epiphenomena? Scand J Rheumatol 1997;26(4):308-313.

     43.   Fietta P, Fietta P, Manganelli P. Fibromyalgia and psychiatric disorders. Acta Biomed 2007;78(2):88-95.

     44.   Fishbain DA, Lewis J, Cole B, Cutler B, Smets E, Rosomoff H et al. Multidisciplinary pain facility treatment outcome for pain-associated fatigue. Pain Med 2005;6(4):299-304.

     45.   Frodin T, Bengtsson A, Skogh M. Nail fold capillaroscopy findings in patients with primary fibromyalgia. Clin Rheumatol 1988;7384-388.

     46.   Gerdle B, Bjork J, Coster L, Henriksson K, Henriksson C, Bengtsson A. Prevalence of widespread pain and associations with work status: a population study. BMC Musculoskelet Disord 2008;9102.

     47.   Germanowicz D, Lumertz MS, Martinez D, Margarites AF. Sleep disordered breathing concomitant with fibromyalgia syndrome. J Bras Pneumol 2006;32(4):333-338.

     48.   Giesecke T, Williams DA, Harris RE, Cupps TR, Tian X, Tian TX et al. Subgrouping of fibromyalgia patients on the basis of pressure-pain thresholds and psychological factors. Arthritis Rheum 2003;48(10):2916-2922.

     49.   Glass JM. Fibromyalgia and cognition. J Clin Psychiatry 2008;69 Suppl 220-24.

     50.   Gold AR, Dipalo F, Gold MS, Broderick J. Inspiratory airflow dynamics during sleep in women with fibromyalgia. Sleep 2004;27(3):459-466.

     51.   Gracely RH. A pain psychologist's view of tenderness in fibromyalgia. J Rheumatol 2007;34(5):912-913.

     52.   Grisart J, Van der LM, Masquelier E. Controlled processes and automaticity in memory functioning in fibromyalgia patients: relation with emotional distress and hypervigilance. J Clin Exp Neuropsychol 2002;24(8):994-1009.

     53.   Gunaydin I, Terhorst T, Eckstein A, Daikeler T, Kanz L, Kotter I. Assessment of keratoconjunctivitis sicca in patients with fibromyalgia: results of a prospective study. Rheumatol Int 1999;19(1-2):7-9.

     54.   Gupta A, McBeth J, MacFarlane GJ, Morriss R, Dickens C, Ray D et al. Pressure pain thresholds and tender point counts as predictors of new chronic widespread pain in somatising subjects. Ann Rheum Dis 2007;66(4):517-521.

     55.   Hadler NM. A critical reappraisal of the fibrositis concept. Am J Med 1986;8126-30.

     56.   Hagglund KJ, Deuser WE, Buckelew SP, Hewett J, Kay DR. Weather, beliefs about weather, and disease severity among patients with fibromyalgia. Arthritis Care Res 1994;7(3):130-135.

     57.   Harden RN, Revivo G, Song S, Nampiaparampil D, Golden G, Kirincic M et al. A critical analysis of the tender points in fibromyalgia. Pain Med 2007;8(2):147-156.

     58.   Harding SM. Sleep in fibromyalgia patients: subjective and objective findings. Am J Med Sci 1998;315(6):367-376.

     59.   Harth M, Nielson WR. The fibromyalgia tender points: use them or lose them? A brief review of the controversy. J Rheumatol 2007;34(5):914-922.

     60.   Hauri P, Hawkins DR.  Alpha-delta sleep. Electroencephalogr Clin Neurophysiol 1973;34233-237.

     61.   Hauser W, Akritidou I, Felde E, Klauenberg S, Maier C, Hoffmann A et al. Steps towards a symptom-based diagnosis of fibromyalgia syndrome. Symptom profiles of patients from different clinical settings. Z Rheumatol 2008;67(6):511-515.

     62.   Hauser W, Zimmer C, Felde E, Kollner V. What are the key symptoms of fibromyalgia? : Results of a survey of the German Fibromyalgia Association.. Schmerz 2007;. 22(2):176-83

     63.   Hauser W, Zimmer C, Felde E, Kollner V. What are the key symptoms of fibromyalgia? Results of a survey of the German Fibromyalgia Association. Schmerz 2008;22(2):176-183.

     64.   Hughes L. Physical and psychological variables that influence pain in patients with fibromyalgia. Orthop Nurs 2006;25(2):112-119.

     65.   Hurtig IM, Raak RI, Kendall SA, Gerdle B, Wahren LK. Quantitative sensory testing in fibromyalgia patients and in healthy subjects: identification of subgroups. Clin J Pain 2001;17(4):316-322.

     66.   Jones J, Rutledge DN, Jones KD, Matallana L, Rooks DS. Self-assessed physical function levels of women with fibromyalgia: a national survey. Womens Health Issues 2008;18(5):406-412.

     67.   Jones KD, Clark SR. Individualizing the exercise prescription for persons with fibromyalgia. Rheum Dis Clin North Am 2002;28(2):419-36.

     68.   Jones KD, Horak FB, Winters-Stone K, Irvine JM, Bennett RM. Fibromyalgia is associated with impaired balance and falls. J Clin Rheumatol 2009;15(1):16-21.

     69.   Katz DL, Greene L, Ali A, Faridi Z. The pain of fibromyalgia syndrome is due to muscle hypoperfusion induced by regional vasomotor dysregulation. Med Hypotheses 2007;69(3):517-525.

     70.   Katz RS, Wolfe F, Michaud K. Fibromyalgia diagnosis: a comparison of clinical, survey, and American College of Rheumatology criteria. Arthritis Rheum 2006;54(1):169-176.

     71.   Keene JJ, Jr., Galasko GT, Land MF. Antidepressant use in psychiatry and medicine: importance for dental practice. J Am Dent Assoc 2003;134(1):71-79.

     72.   Kim JJ, Diamond DM. The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci 2002;3(6):453-462.

     73.   Klein CM, Vernino S, Lennon VA, Sandroni P, Fealey RD, Benrud-Larson L et al. The spectrum of autoimmune autonomic neuropathies. Ann Neurol 2003;53(6):752-758.

     74.   Kop WJ, Lyden A, Berlin AA, Ambrose K, Olsen C, Gracely RH et al. Ambulatory monitoring of physical activity and symptoms in fibromyalgia and chronic fatigue syndrome. Arthritis Rheum 2005;52(1):296-303.

     75.   Korszun A, Young EA, Engleberg NC, Brucksch CB, Greden JF, Crofford LA. Use of actigraphy for monitoring sleep and activity levels in patients with fibromyalgia and depression. J Psychosom Res 2002;52(6):439-443.

     76.   Kroenke K, Price RK. Symptoms in the community. Prevalence, classification, and psychiatric comorbidity. Arch Intern Med 1993;153(21):2474-2480.

     77.   Kroenke K, Wood DR, Mangelsdorff D, Meier NJ, Powell JB. Chronic fatigue in primary care:  prevalence, patient characteristics, and outcome. JAMA 1988;260929-934.

     78.   Lakie M, Robson LG. Thixotropy: stiffness recovery rate in relaxed frog muscle. Q J Exp Physiol 1988;73(2):237-239.

     79.   Landis CA, Lentz MJ, Rothermel J, Buchwald D, Shaver JL. Decreased sleep spindles and spindle activity in midlife women with fibromyalgia and pain. Sleep 2004;27(4):741-750.

     80.   Laursen BS, Bajaj P, Olesen AS, Delmar C, rendt-Nielsen L. Health related quality of life and quantitative pain measurement in females with chronic non-malignant pain. Eur J Pain 2005;9(3):267-275.

     81.   Leavitt F, Katz RS. Distraction as a key determinant of impaired memory in patients with fibromyalgia. J Rheumatol 2006;33(1):127-132.

     82.   Lentz MJ, Landis CA, Rothermel J, Shaver JL. Effects of selective slow wave sleep disruption on musculoskeletal pain and fatigue in middle aged women. J Rheumatol 1999;26(7):1586-1592.

     83.   Littlejohn GO, Weinstein C, Helme RD. Increased neurogenic inflammation in fibrositis syndrome. J Rheumatol 1987;141022-1025.

     84.   Luerding R, Weigand T, Bogdahn U, Schmidt-Wilcke T. Working memory performance is correlated with local brain morphology in the medial frontal and anterior cingulate cortex in fibromyalgia patients: structural correlates of pain-cognition interaction. Brain 2008;131(Pt 12):3222-3231.

     85.   Lutz J, Jager L, de QD, Krauseneck T, Padberg F, Wichnalek M et al. White and gray matter abnormalities in the brain of patients with fibromyalgia: A diffusion-tensor and volumetric imaging study. Arthritis Rheum 2008;58(12):3960-3969.

     86.   Mahowald ML, Mahowald MW. Nighttime sleep and daytime functioning (sleepiness and fatigue) in less well-defined chronic rheumatic diseases with particular reference to the 'alpha-delta NREM sleep anomaly'. Sleep Med 2000;1(3):195-207.

     87.   Mahowald MW. Restless Leg Syndrome and Periodic Limb Movements of Sleep. Curr Treat Options Neurol 2003;5(3):251-260.

     88.   Maier SF, Watkins LR. Cytokines for psychologists: implications of bidirectional immune-to- brain communication for understanding behavior, mood, and cognition. Psychol Rev 1998;105(1):83-107.

     89.   Marchand S. The physiology of pain mechanisms: from the periphery to the brain. Rheum Dis Clin North Am 2008;34(2):285-309.

     90.   Marcus DA, Bernstein C, Rudy TE. Fibromyalgia and headache: an epidemiological study supporting migraine as part of the fibromyalgia syndrome. Clin Rheumatol 2005;.

     91.   Martinez-Lavin M. Fibromyalgia as a sympathetically maintained pain syndrome. Curr Pain Headache Rep 2004;8(5):385-389.

     92.   Martinez-Lavin M, Lopez S, Medina M, Nava A. Use of the Leeds assessment of neuropathic symptoms and signs questionnaire in patients with fibromyalgia. Semin Arthritis Rheum 2003;32(6):407-411.

     93.   McCabe CS, Cohen H, Blake DR. Somaesthetic disturbances in fibromyalgia are exaggerated by sensory motor conflict: implications for chronicity of the disease? Rheumatology (Oxford) 2007;46(10):1587-1592.

     94.   McEwen BS. Plasticity of the hippocampus: adaptation to chronic stress and allostatic load. Ann N Y Acad Sci 2001;933:265-77.265-277.

     95.   McEwen BS. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev 2007;87(3):873-904.

     96.   McGowan PO, Sasaki A, D'Alessio AC, Dymov S, Labonte B, Szyf M et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 2009;12(3):342-348.

     97.   McHugh MP, Connolly DA, Eston RG, Kremenic IJ, Nicholas SJ, Gleim GW. The role of passive muscle stiffness in symptoms of exercise-induced muscle damage. Am J Sports Med 1999;27(5):594-599.

     98.   Mease P, Arnold LM, Bennett R, Boonen A, Buskila D, Carville S et al. Fibromyalgia syndrome. J Rheumatol 2007;34(6):1415-1425.

     99.   Mease PJ, Arnold LM, Crofford LJ, Williams DA, Russell IJ, Humphrey L et al. Identifying the clinical domains of fibromyalgia: Contributions from clinician and patient delphi exercises. Arthritis Rheum 2008;59(7):952-960.

   100.   Mease PJ, Russell IJ, Arnold LM, Florian H, Young JP, Jr., Martin SA et al. A Randomized, Double-blind, Placebo-Controlled, Phase III Trial of Pregabalin in the Treatment of Patients with Fibromyalgia. J Rheumatol 2008;35(3):502-514.

   101.   Middleton GD, McFarlin JE, Lipsky PE. The prevalence and clinical impact of fibromyalgia in systemic lupus erythematosus. Arthritis Rheum 1994;371181-1188.

   102.   Moldofsky H. Chronobiological influences on fibromyalgia syndrome: theoretical and therapeutic implications. Baillieres Clin Rheumatol 1994;8801-810.

   103.   Moldofsky H. The significance of the sleeping-waking brain for the understanding of widespread musculoskeletal pain and fatigue in fibromyalgia syndrome and allied syndromes. Joint Bone Spine 2008;.

   104.   Moldofsky H. The significance, assessment, and management of nonrestorative sleep in fibromyalgia syndrome. CNS Spectr 2008;13(3 Suppl 5):22-26.

   105.   Moldofsky H, Scarisbrick P, England R, Smythe H. Musculosketal symptoms and non-REM sleep disturbance in patients with "fibrositis syndrome" and healthy subjects. Psychosom Med 1975;37341-351.

   106.   Ohayon MM. Prevalence and correlates of nonrestorative sleep complaints. Arch Intern Med 2005;165(1):35-41.

   107.   Orellana C, Casado E, Masip M, Galisteo C, Gratacos J, Larrosa M. Sexual dysfunction in fibromyalgia patients. Clin Exp Rheumatol 2008;26(4):663-666.

   108.   Ostuni P, Botsios C, Sfriso P, Punzi L, Chieco-Bianchi F, Semerano L et al. Fibromyalgia in Italian patients with primary Sjogren's syndrome. Joint Bone Spine 2002;69(1):51-57.

   109.   Pamuk ON, Yethornil AY, Cakir N. Factors That Affect the Number of Tender Points in Fibromyalgia and Chronic Widespread Pain Patients Who Did not Meet the ACR 1990 Criteria for Fibromyalgia: Are Tender Points a Reflection of Neuropathic Pain? Semin Arthritis Rheum 2006;.

   110.   Park DC, Glass JM, Minear M, Crofford LJ. Cognitive function in fibromyalgia patients. Arthritis Rheum 2001;44(9):2125-2133.

   111.   Parkin AJ. Human memory: the hippocampus is the key. Curr Biol 1996;6(12):1583-1585.

   112.   Peres MF, Zukerman E, Senne Soares CA, Alonso EO, Santos BF, Faulhaber MH. Cerebrospinal fluid glutamate levels in chronic migraine. Cephalalgia 2004;24(9):735-739.

   113.   Petzke F, Khine A, Williams D, Groner K, Clauw DJ, Gracely RH. Dolorimetry performed at 3 paired tender points highly predicts overall tenderness. J Rheumatol 2001;28(11):2568-2569.

   114.   Price DD, Staud R. Neurobiology of fibromyalgia syndrome. J Rheumatol Suppl 2005;75:22-8.22-28.

   115.   Price EJ, Venables PJ. Dry eyes and mouth syndrome--a subgroup of patients presenting with sicca symptoms. Rheumatology (Oxford) 2002;41(4):416-422.

   116.   Ramos-Casals M, Munoz S, Zeron PB. Hepatitis C virus and Sjogren's syndrome: trigger or mimic? Rheum Dis Clin North Am 2008;34(4):869-84, vii.

   117.   Reilly PA, Littlejohn GO. Peripheral arthralgic presentation of fibrositis/fibromyalgia syndrome. J Rheumatol 1992;19281-283.

   118.   Rhodus NL, Fricton J, Carlson P, Messner R. Oral symptoms associated with fibromyalgia syndrome. J Rheumatol 2003;30(8):1841-1845.

   119.   Rizzi M, Sarzi-Puttini P, Atzeni F, Capsoni F, Andreoli A, Pecis M et al. Cyclic alternating pattern: a new marker of sleep alteration in patients with fibromyalgia? J Rheumatol 2004;31(6):1193-1199.

   120.   Robinson RL, Birnbaum HG, Morley MA, Sisitsky T, Greenberg PE, Claxton AJ. Economic cost and epidemiological characteristics of patients with fibromyalgia claims. J Rheumatol 2003;30(6):1318-1325.

   121.   Rohrbeck J, Jordan K, Croft P. The frequency and characteristics of chronic widespread pain in general practice: a case-control study. Br J Gen Pract 2007;57(535):109-115.

   122.   Russell IJ, Perkins AT, Michalek JE. Sodium oxybate relieves pain and improves function in fibromyalgia syndrome: A randomized, double-blind, placebo-controlled, multicenter clinical trial. Arthritis Rheum 2009;60(1):299-309.

   123.   Salemi S, Rethage J, Wollina U, Michel BA, Gay RE, Gay S et al. Detection of Interleukin 1beta (IL-1beta), IL-6, and Tumor Necrosis Factor-alpha in Skin of Patients with Fibromyalgia. J Rheumatol 2003;30(1):146-150.

   124.   Sann H, Pierau FK. Efferent functions of C-fiber nociceptors. Z Rheumatol 1998;57 Suppl 2:8-138-13.

   125.   Schlesinger N. Clues to pathogenesis of fibromyalgia in patients with sickle cell disease. J Rheumatol 2004;31(3):598-600.

   126.   Simms RW, Goldenberg DL. Symptoms mimicking neurologic disorders in fibromyalgia syndrome. J Rheumatol 1988;151271-1273.

   127.   Smythe HA. Problems with the MMPI. J Rheumatol 1984;11417-418.

   128.   Smythe HA, Moldofsky H. Two contributions to understanding of the "fibrositis" syndrome. Bull Rheum Dis 1977;28928-931.

   129.   Staud R, Vierck CJ, Robinson ME, Price DD. Overall fibromyalgia pain is predicted by ratings of local pain and pain-related negative affect--possible role of peripheral tissues. Rheumatology (Oxford) 2006;45(11):1409-1415.

   130.   Stehlik R, Arvidsson L, Ulfberg J. Restless Legs Syndrome Is Common among Female Patients with Fibromyalgia. Eur Neurol 2008;61(2):107-111.

   131.   Stone KC, Taylor DJ, McCrae CS, Kalsekar A, Lichstein KL. Nonrestorative sleep. Sleep Med Rev 2008;12(4):275-288.

   132.   Strusberg I, Mendelberg RC, Serra HA, Strusberg AM. Influence of weather conditions on rheumatic pain. J Rheumatol 2002;29(2):335-338.

   133.   Suhr JA. Neuropsychological impairment in fibromyalgia. Relation to depression, fatigue, and pain. J Psychosom Res 2003;55(4):321-329.

   134.   Thieme K, Turk DC, Flor H. Comorbid depression and anxiety in fibromyalgia syndrome: relationship to somatic and psychosocial variables. Psychosom Med 2004;66(6):837-844.

   135.   Tikiz C, Muezzinoglu T, Pirildar T, Taskn EO, Frat A, Tuzun C. Sexual dysfunction in female subjects with fibromyalgia. J Urol 2005;174(2):620-623.

   136.   Tischler L, Brand SR, Stavitsky K, Labinsky E, Newmark R, Grossman R et al. The relationship between hippocampal volume and declarative memory in a population of combat veterans with and without PTSD. Ann N Y Acad Sci 2006;1071:405-9.405-409.

   137.   Vaeroy H, Helle R, Forre O, Kass E, Terenius L. Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: new features for diagnosis. Pain 1988;3221-26.

   138.   Vargas A, Vargas A, Hernandez-Paz R, Sanchez-Huerta JM, Romero-Ramirez R, mezcua-Guerra L et al. Sphygmomanometry-evoked allodynia-a simple bedside test indicative of fibromyalgia: a multicenter developmental study. J Clin Rheumatol 2006;12(6):272-274.

   139.   Verbunt JA, Pernot DH, Smeets RJ. Disability and quality of life in patients with fibromyalgia. Health Qual Life Outcomes 2008;6:8.8.

   140.   Walitt B, Roebuck-Spencer T, Bleiberg J, Foster G, Weinstein A. Automated neuropsychiatric measurements of information processing in fibromyalgia. Rheumatol Int 2008;28(6):561-566.

   141.   Wessely S. Old wine in new bottles: neurasthenia and 'ME'. Psychol Med 1990;2035-53.

   142.   Wessely S. Chronic fatigue: symptom and syndrome. Ann Intern Med 2001;134(9 Pt 2):838-843.

   143.   White KP, Nielson WR, Harth M, Ostbye T, Speechley M. Chronic widespread musculoskeletal pain with or without fibromyalgia: psychological distress in a representative community adult sample. J Rheumatol 2002;29(3):588-594.

   144.   White LA, Birnbaum HG, Kaltenboeck A, Tang J, Mallett D, Robinson RL. Employees with fibromyalgia: medical comorbidity, healthcare costs, and work loss. J Occup Environ Med 2008;50(1):13-24.

   145.   Wieseler-Frank J, Maier SF, Watkins LR. Central proinflammatory cytokines and pain enhancement. Neurosignals 2005;14(4):166-174.

   146.   Wolfarth S, Lorenc-Koci E, Schulze G, Ossowska K, Kaminska A, Coper H. Age-related muscle stiffness: predominance of non-reflex factors. Neuroscience 1997;79(2):617-628.

   147.   Wolfe F, Cathey MA. Prevalence of primary and secondary fibrositis. J Rheumatol 1983;10965-968.

   148.   Wolfe F, Cathey MA. Prevalence of primary and secondary fibrositis. J Rheumatol 1983;10(6):965-968.

   149.   Wolfe F, Michaud K. Severe Rheumatoid Arthritis (RA), Worse Outcomes, Comorbid Illness, and Sociodemographic Disadvantage Characterize RA Patients with Fibromyalgia. J Rheumatol 2004;31(4):695-700.

   150.   Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 1990;33(2):160-172.

   151.   Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia: Report of the Multicenter Criteria Committee. Arth Rheum 1990;33160-172.

   152.   Yunus M, Masi AT, Calabro JJ, Miller KA, Feigenbaum SL. Primary fibromyalgia (fibrositis): clinical study of 50 patients  with matched normal controls. Semin Arthritis Rheum 1981;11151-171.

   153.   Yunus MB. Fibromyalgia and overlapping disorders: the unifying concept of central sensitivity syndromes. Semin Arthritis Rheum 2007;36(6):339-356.

   154.   Yunus MB. Central Sensitivity Syndromes: A New Paradigm and Group Nosology for Fibromyalgia and Overlapping Conditions, and the Related Issue of Disease versus Illness. Semin.Arthritis Rheum. 37(6), 339-352. 1-11-2008.

   155.   Yunus MB, Hussey FX, Aldag JC. Antinuclear antibodies and connective disease features in fibromyalgia syndrome: a controlled study. J Rheumatol 1993;201557-1560.

 

                                      About us    Donations  Disclaimer