Robert Bennett MD
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
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
Pain or physical discomfort
Joint pain or aching
Lack of energy or fatigue
Lack of energy
Difficulty falling asleep
Difficulty with moving
Having to push yourself to accomplish things
Problems setting goals and completing tasks
Tenderness to touch
Feeling hands are swollen
Limitations in normal daily activities
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
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.
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.
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
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”;
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.
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.
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.
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.
patients usually report disturbed sleep QUOTE "(Moldofsky et al
1975)" ADDIN REFMAN
ÿ\11\05‘\19\01\00\00\00\16(Moldofsky et al
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
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.
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
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?”
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
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
technology may provide some explanation for these deficits. For
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.
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.
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
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.
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.
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
glossodynia 32.8%, dysphagia 37.3%
Blurred vision, that cannot be corrected by prescription lenses,
is also a common complaint (author’s experience).
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.
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.
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.
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.
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
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.
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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