Reumatismo, 2008; 60: Supplemento 1: 36-49
La sindrome fibromialgica (FM) è una condizione di frequente riscontro nella pratica clinica caratterizzata da dolo-
re muscoloscheletrico cronico e diffuso, sensazione di tensione e/o di rigidità muscolare e articolare, affatticabilità,
disturbi del sonno, alterazioni del tono dell’umore e dolore alla digitopressione di almeno 11/18 tender points (TPs).
Fino ad oggi, non disponiamo né di esami strumentali né di marcatori specifici per effettuare la diagnosi di FM; in-
fatti, la maggior parte degli esami attualmente disponibili sono utili solo ai fini di ricerca. La maggior parte delle dia-
gnosi differenziali può essere effettuata mediante un accurato esame clinico e anamnestico. Se consideriamo il possi-
bile overlap tra la FM ed altre malattie, il medico curante dovrebbe sottoporre tutti i pazienti con sospetta FM a ra-
diografia del torace ed ecografia dell’addome, oltre ad un accurato esame obiettivo. La risonanza magnetica funzio-
nale ha messo in evidenza diverse alterazioni sovraspinali nei pazienti affetti da FM, una condizione clinica a pato-
genesi sconosciuta. Nei pazienti affetti da FM sono diversi i trattamenti utilizzati, ma valutarne il loro effetto è diffi-
cile poiché questa sindrome presenta molteplici aspetti. Al fine di identificare un “core outcome domains”, l’iniziati-
va dell’ IMMPACT e il workshop OMERACT ha convocato un meeting per sviluppare le raccomandazioni utili per i
trials clinici sul dolore cronico.
Reumatismo, 2008; 60: Supplemento 1: 36-49
The evaluation of the fibromyalgia patients
La valutazione del paziente fibromialgico
F. Atzeni1, F. Salaffi2, L. Bazzichi3, R.H. Gracely4, R. Carignola5, R. Torta6, R. Gorla7, A. Marsico8,
F. Ceccherelli9, M. Cazzola10, D. Buskila11, M. Spath12, M. Di Franco13, G. Biasi14, G. Cassisi15,
S. Stisi16, R. Casale17, L. Altomonte18, G. Arioli19, A. Alciati20, G. Leardini21, F. Marinangeli22,
M.A. Giamberardino23, P. Sarzi-Puttini1(Italian Fibromyalgia Network)
1Rheumatology Unit, L. Sacco University Hospital, Milan, Italy; 2Department of Rheumatology, Polytechnic University of the Marche
Region, Ancona, Italy; 3Department of Internal Medicine, Division of Rheumatology, S. Chiara Hospital, University of Pisa, Italy;
4Department of Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA; 5Department of Neuroscience, University
of Turin, A.S.O. San Giovanni Battista of Turin, Turin, Italy; 6Department of Neuroscience, University of Turin, A.S.O. San Giovanni
Battista of Turin, Turin, Italy; 7Rheumatology and Clinical Immunology, Spedali Civili and University of Brescia, Italy; 8Rheumatology
Unit, Hospital of Taranto, Taranto, Italy; 9IOV (Veneto Cancer Institute), IRCCS, Department of Pharmacology and Anesthesiology,
University of Padua, Italy; 10Unit of Rehabilitative Medicine “Hospital of Circolo”, Saronno (VA), Italy; 11Department of Medicine H,
Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University, Beer Sheva, Israel; 12Friedrich-Baur-Institute,
University of Munich, Munich, Germany; 13Chair of Rheumatology, University la Sapienza Rome, Rome, Italy; 14Unit of Rheumatology,
University of Siena, Siena, Italy; 15Rheumatology Branch, Specialist Outpatients’ Department, Belluno, Italy; 16Rheumatology Unit,
“G.Rummo” Hospital, Benevento, Italy; 17Department of Clinical Neurophysiology and Pain Rehabilitation Unit, Foundation Salvatore
Maugeri, IRCCS, Scientific Institute of Montescano, Montescano (PV), Italy; 18UOC of Rheumatology Hospital S. Eugenio, Rome, Italy;
19Division of Rehabilitative Medicine and Rheumatology, General Hospital of Pieve di Coriano (Mantua), Italy;
20Department of Psychiatry, L. Sacco University Hospital, Milan, Italy; 21Rheumatology Unit, SS Giovanni e Paolo Hospital, Venice,
Venice, Italy; 22Department of Anesthesiology and Pain Medicine, L'Aquila University, L’Aquila, Italy;
23Ce.S.I. “G. D’Annunzio” Foundation, Department of Medicine and Science of Aging, “G. D’Annunzio”, University of Chieti, Italy
Competing interests: none declared
Fabiola Atzeni, MD, PhD
L. Sacco Hospital, Milan, Italy
acterized by musculoskeletal pain, chronic dif-
fuse tension and/or stiffness from joints and mus-
ibromyalgia (FM) is a rheumatic disease char-
cles, easy fatigue, sleep and emotional disturbances,
and pressure pain sensitivity in at least 11 of 18 ten-
der points (TP) (1, 2). This disease has an incidence
of 2% in the general population, but it is found more
often in middle-aged women (3.4%) (3, 4). The
etiopathogenesis of FM has not been clarified yet.
FM patients have a dysregulation of pain neuro-
transmitters and neurohormone-mediated associa-
tion with irregularities in the physiology of sleep.
The American College of Rheumatology (ACR)
The evaluation of the fibromyalgia patients
ward general evaluation of all patients with sus-
pected FM. An individualized, multidisciplinary
range of treatments should be employed to treat
the various symptoms that patients experience. Al-
though some of these therapies have been tested in
randomized controlled trials (RCT), there has been
little standardization in the approach to these trials
and in the outcome measures used. Evaluating ther-
apeutic effects in FM patients is difficult because
of the many facets of the syndrome. To address the
identification of core outcome domains, the Initia-
tive on Methods, Measurement, and Pain Assess-
ment in Clinical Trials (IMMPACT) (8) and Out-
come Measures in Rheumatoid Arthritis Clinical
Trials (OMERACT) (9) workshop convened a
meeting to develop consensus recommendations
for chronic pain clinical trials.
LABORATORY AND INSTRUMENTAL
EVALUATIONS IN PATIENTS WITH FM
In clinical studies and observational research stud-
ies, FM is usually diagnosed by application of the
ACR criteria (1). Moreover, diagnosis is made by a
combination of patient history, physical examina-
tion, laboratory evaluations and exclusion of other
causes for symptoms attributed to FM (10, 11).
BIOMARKERS IN FM
Compared to healthy subjects or patients with oth-
er diseases, FM patients present with high an-
tipolymer antibodies (APA) (12) and antiserotonin
antibody (13) values, with contrasting results in
the Italian population. The APA positivity in a re-
cent work appears to be less than that evidenced in
the USA, and it appears to correlate with the sever-
ity of the disease; this result could be due to a dif-
ferent ethnic origin of the populations studied. Oth-
er antibodies (antiganglioside and antiphospho-
lipids) were identified in FM patients compared to
healthy subjects, but the sensitivity and specificity
was not clear. Patients with FM have a higher fre-
quency of anti-thyroid antibodies, and their values
seem to be correlated with the presence of certain
symptoms (14). Recent studies have shown higher
hyaluronic acid values in FM patients compared to
healthy controls, but this data has not been con-
firmed (15, 16). Alterations of branched-chain
amino acids (valine, leucine, isoleucine), pheny-
criteria diagnostic criteria for FM are based upon
chronic widespread pain and tenderness in 11 of 18
defined muscular sites (1). Recent evidence sug-
gests that the tenderness component of FM is not
confined to these sites; rather, it is present through-
out the body, including non-muscular sites such as
the thumb. The widespread nature of spontaneous
pain in FM implicates general mechanisms that may
involve spinal or supraspinal modulation of normal
peripheral input, or effector mechanisms that alter
pain sensitivity at the periphery. These mechanisms
are likely observed at supraspinal sites. Functional
neuroimaging of the brain has opened a window in-
to the supraspinal processes in health and disease
(5). With a few exceptions, these methods infer
neural activity in the brain by changes in regional
cerebral blood flow (rCBF). This inference is based
on the principle that localized brain activity signals
a discreet increase in rCBF to meet the metabolic
demands of this increase in neural activity. The in-
crease in rCBF occurs after a hemodynamic delay
of a few seconds and is closely coupled to the mag-
nitude and duration of the activity. Most function-
al imaging methods are based on the evaluation of
the time course of changes in rCBF throughout the
The absence of anatomopathological lesions and
biohumoral abnormalities, demonstrated with clas-
sical instrumental methods, has led to considerable
difficulties in diagnosis. The diagnostic criteria fre-
quently overlap with those of other diseases; in
fact, some patients with chronic fatigue syndrome
(CFS) meet the criteria for FM, and an FM-like
framework may be present even in non-rheumatic
For example, patients with hypothyroidism show
musculoskeletal pain that is similar FM. The diag-
nosis based on the ACR criteria, therefore, must be
accompanied by the exclusion of diseases that have
symptoms, but not causes, in common with FM as
evidenced by the evaluation of markers and hu-
moral scans (miositis, rheumatic polmyalgia,
spondyloarthritis, etc.) (7). Often, FM is comorbid
with other diseases that act as confounding and ag-
gravating factors (Sjögren, systemic lupus eriythe-
matosus (SLE), rheumtoid arthritis (RA), thyroid
disease). There are no instrumental tests to con-
firm the diagnosis of FM; and many differential di-
agnoses may be excluded by an extensive clinical
examination and patient history. Considering the
overlap of FM with other medical conditions, treat-
ing physicians should be vigilant: chest-X-rays and
abdominal ultrasonography are the first steps to-
F. Atzeni et al.
lalanine (17), and collagen cross links, and partic-
ularly, a reduction in the ratio of pyridinoline to de-
oxypyridinoline as well as decreased levels of hy-
droxipyroline (18) were also found. Neopterin has
been suggested as an inflammation marker, which
has an inversely proportional relationship with L-
tryptophan availability. Other studies showed low
serum levels of 5-HT in FM patients compared to
both healthy controls and patients with rheumatic
diseases such as RA. These studies provide indirect
evidence supporting the alteration of 5-HT metab-
olism in FM subjects. In a recent study, FM patients
exhibited a tendency to have lower serotonin lev-
els than patients with RA and healthy controls; but
the variation of serotonin levels within the disease
groups is too broad to differentiate FM from other
conditions, especially depression (19). There is al-
so evidence to suggest that FM patients may have
alterations in the expression of 5-HT transporters
due to a transcriptional polymorphism in the region
that could lead to an increase of the same tran-
scriptional region (20). Another study has sug-
gested that an alteration of the growth hormone
(GH), an indirect modulator of the immune system
that interacts with the hormonal system, seems to
protect the body from the immunosuppressive ef-
fects of glucocorticoids during stress (21) and
favours IGF1-mediated muscle repair. Altered
serum cortisol and melatonin levels were found;
these hormone secretions are closely associated
with the circadian rhythms. The study also found
alterations of 5-HT, somatomedin C, calcitonin
gene-related peptide, calcitonin and cholecys-
tokinin which are possible indicators of FM wide-
spread pain (22). Studies conducted on FM patients
showed an increase in plasma levels of IL-6 and IL-
8 compared to healthy controls, an increased pro-
duction of IL-1 and TNF-alpha, and a reduced pro-
duction of IL-2 and IFN-alpha, which highlights an
immune activation and a down-regulation of the
HPA. A study showed an increase in plasma IL-10,
IL-8 and TNF-alpha in FM patients independent of
the presence of psychiatric comorbidity; this sup-
ports the hypothesis of an activation of the immune
system (23). Abnormal levels of ACTH, 5-HT,
IGF-1 and FT4 were found, which suggests an al-
teration of the endocrine system in this disease
(14). The role of free radicals in FM is controver-
sial, as this could suggest that FM is also an ox-
idative disorder; studies have shown high levels of
malondialdehyde, markers of oxidative damage,
and low levels of superoxide dismutase, an intra-
cellular antioxidant (24) in FM.
The stress factor is probably crucial in this condi-
tion and alterations of the urinary corticotropin-re-
leasing factor (CRF)-L1, catecholamine, cortisol,
with the haplotypes of catecholamine COMT gene
(25) were recently found; as in the serum, cross-
links of collagen, a reduction in the ratio of pyridi-
noline to deoxypyridinoline and decreased levels of
hydroxyproline (18) were found in the urine.
In FM subjects, substance P levels increase in cere-
brospinal fluid and this event leads to the release
of IL-6. Substance P induces the production of IL-
8, a pro-inflammatory cytokine, which stimulates
the passage of neutrophils through the vascular
walls. Altered levels of serotonin and increased
corticotropin-releasing hormone (CRH) and a pool
of proteins (alpha-1-macroglobulina, keratin 16,
orosomucoide, amyloid precursors etc.) were also
found in the cerebrospinal fluid of FM patients
(26). Among FM patients, pain, but not fatigue,
was associated with the concentration of CRF in
the cerebrospinal fluid (27).
These data support the hypothesis that abnor-
malities in the stress response are associated with
FM pain. In FM subjects, a reduction of glial cell-
derived neurotophic factor was also found (28);
this result could be related to the role of this neu-
rotophic factor in preventing and reversing ab-
normalities that develop in chronic pain condi-
Somatostatin levels appear to be reduced in the
cerebrospinal fluid of FM patients and significant-
ly correlated with reduced levels of neurotophic
Alterations of the immune cells have been studied
in FM patients, highlighting an abnormal lympho-
cyte and cytokine (IL-6-8-10 TNF-alpha) response
related to FM. Specifically, the number of T lym-
phocytes and the immunoglobulin M level appear
to be altered, and the number of natural killer cells
appears to be reduced. In FM patients, reduced ac-
tivation of T lymphocytes was also found. The cell
receptors, especially the peripheral benzodiazepine
receptor (PBR), the 5-HT receptors and the 5-HT
re-uptake system were altered. Studies conducted
on platelets have shown a reduced receptor densi-
ty and functionality of 5-HT and its carrier, which
were identified by lower 5-HT re-uptake rate from
the synaptic cleft (29). Other research has shown
The evaluation of the fibromyalgia patients
an up-regulation of PBR, also related to the sever-
ity of illness (30). In the platelets of FM patients
increased intracellular concentrations of calcium
and magnesium ions and decreased ATP levels
were also found. In a recent study (31), a compar-
ison was made between FM patients, subjects with
complex regional pain syndrome (CRPS) and
healthy controls regarding the influence of pain on
subpopulations, lymphocyte number, and the ratio
of Th1 to Th2 cytokine in T lymphocytes. The lym-
phocyte number did not differ between groups, but
there was a significant reduction of cytotoxic CD8+
lymphocytes in FM and CRPS patients.
In skin biopsies an increase of activated mast cells
has been observed (25). It appears that muscle tis-
sue does not exhibit alterations at the cellular lev-
el; and while the data appear inconsistent, inflam-
matory infiltrates have not been found. The skin of
FM patients shows unusual patterns of unmyeli-
nated nerve fibers as well as Schwann cells; if these
results are replicated in a larger study, these ab-
normalities may contribute to the lower pain thresh-
old of FM subjects (32).
Studies that employ existing or innovative testing
devices or methodologies are usually negative, and
these testing methodologies are not recommended
for purposes of screening or diagnosis (33); how-
ever, imaging tests can be used to exclude con-
comitant illnesses that could resemble FM.
The following overview of comorbidities highlights
the need for improved instruments for accurate as-
sessment of FM. Environmental factors can influ-
ence both the development of FM and a number of
“stressors” that are temporally correlated with the
onset of the syndrome, including trauma, infec-
tions (e.g., hepatitis C virus, HIV, and Lyme dis-
ease), emotional stress, catastrophic events (e.g.,
war), autoimmune diseases and other pain condi-
tions (34, 35). FM has been reported to coexist in
25% of patients with RA, 30% of patients with
SLE and 50% of patients with Sjogren’s syndrome
The most common rheumatic diseases that could
overlap and be confused with FM are: osteoarthri-
tis (OA), RA, ankylosing spondylitis (AS),
polymyalgia rheumatica (PMR), SLE, Sjogren’s
syndrome, osteomalacia, polymyositis.
OA is observed most often in people over age 50
(most of them are asymptomatic); OA, together
with FM, is among the most prevalent (7%)
rheumatic syndromes in clinical practice (39). OA
can be confused with FM because it causes arthral-
gias of the whole body and could be associated
with significant limitation of activity. It has a clear
predilection for certain joints, in particular, the first
carpometacarpal joints, cervical and lumbar spine,
hips, knees and metatarsophalangeal joints (40).
Radiographically, OA has classic changes that in-
clude osteophyte formation, joint space narrowing,
subchondral sclerosis, and subchondral cysts (41).
It may seem reasonable to study the painful region
on radiograph, but radiographs are not necessarily
correlated with clinical symptoms and must be in-
terpreted correctly in the clinical context.
RA is an inflammatory arthritis; the patients pre-
sent with inflammatory symptoms. The historical
evaluation and the physical examination are fun-
damental to determine, for example, if real syn-
ovitis is present. The radiographic manifestations
of RA have been well described (marginal erosions,
joint space narrowing, joint destruction), and dis-
ease-specific alterations that can be seen during the
clinic visit (e.g., soft tissue swelling, deformities,
subluxations) could be partially found on radi-
ographs. In fact, it takes months or years to devel-
op these alterations, which emphasizes the impor-
tance of developing new instrumental assessments
that will facilitate early diagnosis of RA. Magnet-
ic resonance imaging (MRI) is the gold standard for
confirming the diagnosis of RA, but is too expen-
sive for normal management. Muscoloskeletal ul-
trasonography is easy to perform, can be repeated
without X-ray exposure risks for patient, and rep-
resents the best compromise between cost and re-
sult (42-44). The ultrasonography evaluation of the
patient could help the clinician to identify the ele-
ments for RA or FM diagnosis.
AS usually begins with an insidious onset of chron-
ic inflammatory back pain symptoms in adoles-
cence or early adulthood (45). AS can be easily
mistaken for FM, because both diseases occur in
young patients who may have constitutional symp-
toms such as malaise, fatigue and impaired sleep
(45). The hallmark of AS is sacroiliitis as identi-
fied radiographically via conventional pelvic X-
ray, although this condition may not be evident in
the early stages of the illness (46). Sacroiliitis does
not occur in FM, though, so its presence is funda-
mental in distinguishing AS from FM. Recent re-
ports indicate that the role of MRI has become
F. Atzeni et al.
clearer and it may be a better tool for early identi-
fication of these patients (47).
PMR is characterized by widespread pain and pro-
found morning stiffness. Patient’s historical fac-
tors (age, distribution of pain and stiffness) and
laboratory tests can help to distinguish FM from
PMR. The response to prednisone therapy is dra-
matic in PMR (24 to 48 hours), whereas no re-
sponse is present in FM. Instrumental tests are not
helpful to diagnose both diseases.
FM could mimic SLE as demographic and clinical
features overlap: young women, fatigue, dermato-
logical involvement, arthralgias (48, 49). Howev-
er, organ system involvement such as malar rash
and photosensitivity, fever, serositis, haematologi-
cal alterations, and neurological signs typically oc-
cur in SLE whereas these elements are not present
in FM (50). Conventional X-rays, ultrasonography,
computed tomography, MRI help clinicians to di-
agnose SLE and to distinguish SLE from FM.
Fatigue and generalized arthralgias are common for
Sjogren’s syndrome and FM. The fundamental clin-
ical features of Sjogren’s syndrome are dry eyes
and dry mouth. In FM mucosal dryness is related
to sympathetic hyperactivity (51). Sjogren’s syn-
drome is also characterized by damage to the eye
epithelium whereas no damage is evident in patients
with FM. Rose bengal and/or fluorescein dyes are
used by oculists to identify this hallmark feature. In
recent years, salivary gland ultrasonography be-
came a simple and noninvasive test for the detection
of gland involvement in Sjogren’s syndrome; color
doppler sonography can also increase diagnostic
accuracy (52). Both methods are important to dif-
ferentiate Sjogren’s syndrome from FM.
The radiographic evidence of osteopenia with pseu-
dofractures distinguishes osteomalacia from FM
(24). Bone density in FM patients is comparable to
healthy controls (53).
Profound proximal muscle weakness with mild
pain is typical of polymyositis. The muscle biopsy
is the gold standard in the diagnosis of this in-
flammatory myopathy. The histological features of
polymyositis include variability in muscle fiber
size, scattered necrotic and regenerating fibers and
endomysial inflammation with invasion of non-
necrotic muscle fibers (54). Use of electromyogra-
phy increases spontaneous and insertional activity
with fibrillation potential, complex repetitive dis-
charges, positive sharp waves, small polyphasic
motor unit potentials and early recruitment (54).
Muscle biopsy and electromyography are normal
in FM patients.
Nonrheumatic syndromes that could overlap and be
confused with FM include thyroid dysfunction and
hepatitis B and C virus infection.
Thyroid dysfunction. Hypo- and hyperthyroidism
are characterized by profound fatigue and muscle
weakness. Anxiety may be presented in hyperthy-
There are significant similarities between the clin-
ical findings in FM and the symptoms of thyroid
dysfunction (55). Many studies report that a con-
siderable proportion of FM patients has problems
in the production or utilization of thyroid hormones
(56); therefore, signs of thyroid dysfunction must
be investigated in FM patients. When clinically in-
dicated, thyroid function tests may be performed.
Gland ultrasonography can be helpful, but the in-
strumental results are not necessarily indicative of
disease as thyroid tissue abnormalities can be pre-
sent in healthy subjects, too.
Hepatitis B and C virus (HBV/HCV) infection. Pa-
tients with HCV infection may frequently present
some rheumatologic manifestations such as FM
(57). Diffuse musculoskeletal pain is present in ap-
proximately half of HB antibody positive patients
and approximately 25% of HB antigen positive pa-
tients present with FM syndrome (58). Hepatic ul-
trasonography indicates liver alterations and is an
important test for differentiating FM from hepati-
tis B or C infections.
Generalized pain is a feature of many malignant
diseases, including multiple myeloma, and
metastatic breast, lung and prostatic cancer (59).
Usually FM does not predict cancer, but an in-
creased risk of breast cancer was found among
those female patients that did not satisfy the ACR
criteria for FM (60). Clinicians must be vigilant of
those patients that develop any symptoms of breast
malignancy and thoroughly screen using proce-
dures such as mammography.
The tilt table test is another useful tool to study or-
thostatic intolerance and syncope. The method is
based on the physiological changes that occur af-
ter adopting an upright posture with pooling of ap-
proximately 700 ml blood in the lower parts of the
body. In normal circumstances, the autonomic ner-
vous system quickly compensates for this relative
volume loss by increasing vascular tone and cardiac
output. This mechanism serves to prevent hy-
potension and inadequate cerebral perfusion. Tilt
table testing examines this response in a controlled
The evaluation of the fibromyalgia patients
With passive orthostasis, additional stress is exert-
ed on the sympathetic nervous system by blocking
the influence of muscle contraction that could in-
crease venous return. Subjects are supine for 30
minutes in the first step. The subject is then tilted
upright for 30-45 minutes at an angle of 60-80°.
Pharmacological stimulation with isoproterenol is
sometimes used as an additional step. The normal
responses to tilting consist of an increase in heart
rate of 10-15 beats per minute, an elevation of di-
astolic blood pressure of about 10 mmHg, and lit-
tle change in systolic pressure. There are two types
of abnormal responses. One response is orthostat-
ic hypotension, defined as a reduction of systolic
blood pressure of at least 20 mmHg or a reduction
of diastolic blood pressure of at least 10 mmHg.
This hypotension may induce syncope (61). The
other type of abnormal response is postural ortho-
static tachycardia, which consists of a sustained in-
crease in heart rate of at least 30 beats per minute
or a sustained pulse rate of 120 beats per minute.
Tilt table testing has been used mostly to study
syncope in patients with no evidence of structural
heart disease. Furlan et al. (62) showed that, while
recumbent, patients with FM seemed to experience
a global increase of central cardiovascular sympa-
thetic activity and a blunted enhancement of sym-
pathetic activity. A blunted enhancement of sym-
pathetic modulation to the vessels and impaired
cardiac vagal withdrawal characterized their auto-
nomic profiles during gravitational stress and may
have accounted for the excessive rate of syncope
they experienced upon standing.
Patients with FM often complain of poor sleep
quality. Polysomnography (PSG) is a recording of
sleep stages and architecture that is used to inves-
tigate underlying pathology, including sleep apnea.
Sarzi-Puttini et al. (63) reported that FM patients
complaining of daytime hypersomnolence had a
higher number of TPs, a greater score of subjective
pain and more fatigue than FM patients with no
daytime hypersomnolence. Moreover, hypersom-
nolent patients slept significantly less efficiently,
had a lower proportion of stages 3 and 4 sleep, and
had twice as many arousals per hour of sleep com-
pared to patients with no hypersomnolence. Rizzi
et al. (64) reported that FM patients experience an
increased cyclic alternating pattern (CAP) rate,
which indicates poorer quality of sleep. Further,
these data are strongly correlated with severity of
The first studies that used functional neuroimaging
to evaluate brain processing in fibromyalgia pa-
tients used the method of single photon emission
computed tomography (SPECT). SPECT quanti-
fies regional cerebral blood flow (rCBF) by de-
tecting the distribution of a radioactive tracer that
is infused before the scan. Mountz et al. (65) eval-
uated baseline levels of rCBF in ten patients with
FM and in seven healthy control subjects. After the
tracer infusion the participants sat quietly for the
duration of the 32-minute SPECT scan. This
method produced images with a resolution of about
8.5 mm in predefined regions of interest (ROI) cor-
responding to the right and left thalamus and right
and left head of the caudate nucleus. Patients, rel-
ative to controls, had lower rCBF in both the right
and left thalamus and in both the right and left cau-
date nucleus. Kwiatek et al. (66) subsequently per-
formed a similar study using SPECT in 17 patients
with FM and in 22 healthy control subjects and
found decreased rCBF in the right thalamus but no
decreases in either the left thalamus or in the cau-
date nuclei of FM patients. Additional activations
were found in the inferior pontine tegementum and
near the right lentiform nucleus of patients. The
consistent finding of reduced baseline rCBF in the
right thalamus was replicated by Cohen-Gadol et
al. (67) and has been observed in patients with pain
associated with traumatic peripheral neuropathy
(68) and metastatic breast cancer (69).
During the time of these initial SPECT studies in
FM, functional magnetic resonance imaging (fM-
RI) methods were being developed to assess brain
activity with greater temporal and spatial resolution
than either SPECT or positron emission tomogra-
phy (PET). The commonly used fMRI method of
blood oxygen level dependent (BOLD) imaging
has the further advantage of not requiring the in-
fusion of a radioactive tracer. The first study to ap-
ply fMRI to the evaluation of FM evaluated brain
responses to painful blunt pressure applied to the
thumb (6). This study assessed the pressure pain
sensitivity in patients and control subjects before
and during the fMRI experiments. For each of 16
FM and 16 control participants, this study deter-
mined pressures that evoked pain described as near
“slightly intense” on a calibrated pain scale (6, 70).
The comparison of the effects of these subjective-
ly equal evoked pain sensations (produced by ap-
proximately half the pressure in the fibromyalgia
patients) defined the equal pain contrast. The
F. Atzeni et al.
healthy control subjects received an additional scan
in which they received the same low pressures that
were delivered to the patients (equal pressure con-
trast). These pressures provoke ratings of “slight-
ly intense” pain by the FM patients, and ratings of
“not painful” or “faintly painful” by the control
subjects. Pressures were applied to the thumbnail
by a 1-cm diameter hard rubber probe attached to
a hydraulic cylinder. The thumb site was chosen for
its dense innervation and its large representation in
the primary somatosensory cortex. The thumb was
also chosen to test the concept that tenderness in
FM is not due to muscle sensitivity or confined to
muscles at specific tender point sites, but rather, it
is a property of deep tissue and is found through-
out the body in these patients.
The patients underwent an fMRI scan during which
30 seconds of painful pressure (e.g., 2 kg) was al-
ternated with 30 seconds of non-painful pressure
(e.g., 0.5 kg) for the duration of the 10–minute
scan. Control participants underwent the same type
of scan whereby painful pressure alternated with
nonpainful pressure (equal pain control), and an
additional scan in which the painful pressure was
reduced to the values delivered to the patients
(equal pressure control). All participants also re-
ceived a conventional anatomical MRI of the head
to facilitate localization of the fMRI-derived brain
activity. During the anatomical session complete
functional images of the entire brain and cerebel-
lum were obtained every 5 seconds, with a resolu-
tion of 3 mm in all three dimensions. These data
were processed by standard methods (6), and the
result is a statistical volume, or map, of each sub-
ject’s brain that represents the statistical results of
the difference between painful and nonpainful pres-
sure. To perform group analyses, each of these vol-
umes was converted to standard coordinates and
presented as group activity for each group or as a
statistical difference between groups. The results
show that a similar experience of pain (the equal
pain contrast), which was produced using about
half the amount of pressure in patients compared
to controls, was associated with similar activations
in a number of brain regions that are usually acti-
vated in pain imaging experiments. These include
contralateral primary (SI) and secondary (SII) so-
matosensory cortex, insular cortex and inferior
parietal lobule. In this case the brain response ap-
pears to be consistent with the verbal reports of the
subjects. A second analysis evaluated the effects of
the equal pressure contrast by identifying regions
in which the same pressure produced greater effects
in one of the groups. The relatively low pressure of
2 kg evoked significantly greater activity in a num-
ber of brain regions in FM patients, including both
regions found in the first analysis and additional re-
gions such as anterior cingulate cortex.
This result with painful pressure has been found
with painful heat as well. Cook et al. (5) adminis-
tered similarly painful, 10-second heat stimuli to
the left hand of nine female FM patients and nine
female healthy controls. The reduced heat tolerat-
ed by patients (mean 47.4°C) compared to controls
(48.3 °C) resulted in no significant differences in
brain activation. This study also showed evidence
of increased activity in the contralateral insular cor-
tex of patients.
Additional studies have characterized regions that
show graded responses to stimulus intensity and re-
gions that appear to show a binary response to
painful stimulation, i.e., turning on at some thresh-
old level of stimulation (71). Both patients and con-
trols have shown graded responses to stimulus pres-
sure in regions that are involved in processing the
sensory-discriminative dimension of pain sensa-
tion, including contralateral (right) thalamus, and
primary (SI) and secondary (SII) somatosensory
These initial studies explored the effects of the
amount of painful stimulation on the pattern and
magnitude of brain responses. A large body of ev-
idence indicates that pain perception and behavior
are much more complex and influenced by a num-
ber of variables such as mood and cognition. An
additional group of studies have begun to investi-
gate this complexity by using fMRI to evaluate the
modulation of evoked pain by mood or cognitive
variables that have been shown to influence pain
and pain behavior.
Depression is a significant factor in the expression
of pain and response to treatment. Giesecke, et al.
(72) evaluated the effects of depression on brain re-
sponse to pressure pain in FM. Thirty FM patients
and 7 control participants received fMRI scans dur-
ing alternating pressure and no pressure stimulation
using methods similar to the initial fMRI study de-
scribed above by Gracely, et al. (6). However, in-
stead of comparing two groups, the first analysis
compared three groups: 7 age- and gender-matched
control subjects, 7 FM patients diagnosed with ma-
jor depressive disorder, and 7 matched fibromyal-
gia patients without major depressive disorder.
Equally painful stimuli, produced by significantly
lower stimulus pressures in the FM patients, re-
sulted in similar activations in all three groups.
The evaluation of the fibromyalgia patients
These activations were in regions implicated in pro-
cessing the sensory-discriminative dimension of
pain, including contralateral SI and SII. The pa-
tients with major depressive disorder showed ad-
ditional activations in bilateral amygdala and in a
specific region of the contralateral anterior insula.
A second analysis examined the influence of de-
pression using a correlational method in all 30 FM
patients in which the level of pain-induced brain ac-
tivation for each subject was correlated with the
symptoms of depression, as measured by the Cen-
ter for Epidemiological Studies Depression Scale
(CES-D). No associations between depression and
pressure pain sensitivity were found in brain re-
gions associated with processing the sensory dis-
criminative dimensions of pain. CES-D scores,
however, were significantly associated with pain-
evoked activity in brain regions implicated in pro-
cessing the motivational-affective dimensions of
the pain experience, specifically the contralateral
anterior insula and bilateral amygdale, the same
regions identified in the between groups analysis.
These results suggest that depression modulates
pain-evoked activity in structures involved in pro-
cessing affective characteristics of pain experience.
Similar correlation analyses have been applied to
the cognitive variable of catastrophizing, which is
emerging as a significant variable predicting pain
chronicity and poor treatment response (73). Since
this cognitive style has been linked to depression,
the analysis controlled for depression statistically.
The results correlating catastrophizing with pain-
evoked activity in each subject found significant as-
sociations in brain regions related to the anticipa-
tion of (contralateral medial frontal cortex, ipsilat-
eral cerebellum) and attention to (contralateral an-
terior cingulate gyrus, bilateral dorsolateral pre-
frontal cortex) pain, and to both emotional (ipsi-
lateral claustrum, interconnected to the amygdala)
and motor (contralateral lentiform nuclei) re-
sponses (74). These results suggest that the effects
of negative cognitions are mediated through a num-
ber of separate mechanisms. Successful treatment
may involve identification of the relevant and most
The field of brain neuroimaging continues to ad-
vance at a fast pace, and both old and new meth-
ods have been applied to the evaluation of FM. In
an application of the older method of structural
MRI, Kuchinad, et al. (75) have found that the size
of specific brain regions is significantly reduced in
patients with FM. A PET study of opioid receptors
showed significant differences in endogenous opi-
oid activity in FM (76), and the neuroimaging
method of magnetic resonance spectroscopy
(MRS) showed differences in the concentrations
of metabolites related to neural activity in the in-
sula (Harris, unpublished observations). Newer fM-
RI methods such as arterial spin labeling (ASL)
have indentified insular mechanisms in patients that
are related to increased activity at rest in the ab-
sence of painful stimulation and differences in the
interconnections of the pain network at rest. A re-
cent multi-center European trial has found that long
term treatment with milnacipran results in changes
in pain-evoked brain activity not observed with
A range of treatments are employed to treat the
various symptom facets of FM. Although some of
these therapies have been tested in randomized
controlled trials (RCT), there has been little stan-
dardization of an approach to trials or of the out-
come measures used, and evaluating therapeutic
effects on widely varying symptoms is difficult. To
address the identification of core outcome domains,
the Initiative on Methods, Measurement, and Pain
Assessment in Clinical Trials (IMMPACT) (9) and
Outcome Measures in Rheumatoid Arthritis Clin-
ical Trials (OMERACT) (8) workshop convened a
meeting to develop consensus recommendations
for chronic pain clinical trials. The consensus of
these groups has been that key outcomes should in-
clude pain, physical functioning, emotional func-
tioning, patient global ratings of satisfaction,
health-related quality of life, and adverse events
Chronic generalized pain is a core feature of FM
(77, 78). A number of tools are available for the as-
sessment of pain, including the visual analogue
scale, the daily pain diary, and the McGill Pain
Questionnaire (MPQ). Important issues that may
influence assessment of pain in patients with FM
include recall bias, use of paper versus electronic
diaries to assess pain experiences, and pain scaling
methods (79). The standard visual analogue scale
is a 10 cm scale with a border on each end. The left
end may be anchored by a numeric (i.e., “0”) and/or
verbal (e.g., “No pain at all”) indicator. The right
end may be anchored by a numeric (e.g., “10”)
F. Atzeni et al.
and/or verbal (e.g., “Pain as bad as it could be”) in-
dicator. There are occasional distortions through
photocopying and printing, but adjustments can be
made so that the highest score is 10. Huskisson et
al. (80) also suggested that an alternative descrip-
tive pain relief scale based on the indications “com-
plete relief” “moderate relief,” “slight relief” and
“no pain relief” was possible, but this would be
much less sensitive than the visual analogue scale.
A number of studies have established that data from
self-report visual analogue scales are reproducible.
With the development of optical scanning technolo-
gy for the automated computer entry of scores, visual
analogue scales can be presented in a format of 11
small boxes or circles for patients to assess their pain
from 0-10 (or 100) (81). Although formal direct com-
parative studies have not been performed to analyze
the results of automated optical scanning, this scal-
ing format appears to have criterion validity.
The visual analogue pain scale has proven to be a
great advance in the assessment of pain. A daily di-
ary has been used to assess the impact of pain in
patients with FM and has been reported to be use-
ful for demonstrating the manner in which pain in-
fluences activities of daily living in these individ-
uals. The MPQ can provide detailed information on
the characteristics of pain in FM (82). It includes
78 pain adjectives that are divided into 4 major cat-
egories (sensory, affective, evaluative, and miscel-
laneous sensory) (82, 83). This index takes 10 to
15 minutes to complete. Tender point assessment
is a demonstrably useful part of the official ACR
criteria for the diagnosis of FM. However, TPs are
not unique to the syndrome. Tenderness is wide-
spread in patients with FM rather than being con-
fined to specific anatomic regions, and these indi-
viduals may also demonstrate more hypersensitiv-
ity to heat, cold, and electrical stimulation. Some
methods of assessing tenderness (e.g., dolorimetry)
may demonstrate increased pain sensitivity in pa-
tients with FM more objectively than palpation and
are relatively independent of biasing factors or pa-
tient distress. In addition to tender point count, as-
sessment of tender point intensity or score has been
developed as an assessment tool. For example, the
FM Intensity Score (FIS) is obtained by averaging
the pain intensity scores (on a 0-10 scale) for the
18 sites assessed in the Manual Tender Point Sur-
Psychological and behavioural assessment
Psychological evaluation of the patient can provide
useful information about the psychological and be-
havioural features that may influence their pain and
dysfunction and, conversely, provide a sense of the
impact of pain, fatigue, and other symptoms on their
psychological health (85, 86). It is often presumed
that patients with greater psychological impairment
and/or psychiatric pathology may be more sympto-
matic or resistant to improvement with therapeutic
intervention. However, this assumption may be true
only in some cases. Both in clinical practice and in
drug trials, it is important to diagnose and effec-
tively treat concomitant depression, anxiety, bipo-
lar states, and especially, suicidal tendencies. In ad-
dition to a careful history, a number of screening
tools are available for both clinical and research
purposes, including the Multidimensional Pain In-
ventory, the Pain Behaviour Scale, the Dartmouth
Pain Questionnaire, the Coping Strategies Ques-
tionnaire, the Ways of Coping Scale and the Illness
Behaviour Questionnaire (79, 85).
Fatigue is one of the core features of FM, and its
measurement is important in both research and
clinical settings. A variety of measures exist and
have proven useful in measuring fatigue in other
rheumatic diseases, such as RA and AS (87). These
include the Multidimensional Fatigue Index, which
measures various types of fatigue including phys-
ical and emotional (87); the Functional Assessment
of Chronic Illness Therapy (FACIT) system, which
has been validated in a number of disease states and
may be customized to certain disease indications
(88); And the Fatigue Severity Scale, which was
originally developed for multiple sclerosis and lu-
pus fatigue assessment (89). The advantage of such
tools is their ability to explore the multiple dimen-
sions of fatigue. More simple, single-question fa-
tigue assessments are embedded within such com-
posite instruments as the FM Impact Questionnaire
Multiple dimensions of sleep quality have been as-
sessed in FM trials, including quantity, quality, ease
of falling asleep, frequency of waking, and feeling
refreshed upon awakening. Sleep quality can be
assessed on a 100 mm linear scale with “sleep is
no problem” at one extreme and “sleep is a major
problem” at the other extreme. Similar scales can
be used to rate number of awakenings, and “rest-
edness” on awakening in the morning. The Med-
ical Outcome Study (MOS) sleep scale is an ex-
ample of an instrument used in an FM trial.
The evaluation of the fibromyalgia patients
Quality of life and functional assessment
Measurement of global sense of well being, qual-
ity of life, and functional capacity in multiple di-
mensions (physical, vocational, social, emotional)
is a key area of assessment and is considered es-
sential by regulatory agencies when contemplat-
ing approval of medications for chronic pain states
(90, 91). Assessment with the MOS Short Form-
36 (SF-36) Health Survey (SF-36) has shown that
patients with FM have reduced physical function-
ing, physical role functioning, body pain, general
health, vitality, and social functioning compared to
The SF-36 is a generic instrument with scores that
are based on responses to individual questions,
which are summarized in eight scales (bodily pain,
physical functioning, general health perception,
role function - physical aspect, role function - emo-
tional aspect, vitality, social functioning, and men-
tal health), each of which measures a health con-
cept (92). These scales, weighed according to nor-
mative data, are scored from 0 to 100, with higher
scores reflecting a better quality of life. The SF-36
has been validated for use in Italy, and it can be
completed within 15 min by most people. The Not-
tingham Health Profile (NHP) is intended for pri-
mary health care to provide a brief indication of a
patient’s perceived emotional, social and physical
health problems (93).
The questionnaire consisted of two parts, but only
part I is now used: it contains 38 yes/no items that
can be grouped into 6 domains (physical mobility,
pain, sleep, social isolation, emotional reactions, and
energy level) with each question weighted for sever-
ity. The sum of all weighted values in a given do-
main represents a continuum between 0 (best health)
and 100 (worst health). The FM Impact Question-
naire (FIQ) is an assessment instrument designed to
measure the components of health status that are be-
lieved to be most affected by FM patients. It is com-
posed of 20 items and is used to measure FM patient
status, progress and outcomes (93, 94). The FIQ is
a brief, self-administered instrument that takes ap-
proximately 5 minutes to complete (90, 91).
It is not known whether improvement in pain inten-
sity alone should define response to treatment in FM,
given that the syndrome is characterized by multiple
and varying symptoms. In an attempt to develop a
multi-component criterion for response to treatment
in FM patients, Simms, et al. (95) proposed that a
meaningful response to treatment should be consid-
ered to have been achieved if patients met 4 of the 6
following criteria: 50% reduction in pain, sleep, fa-
tigue, patient global assessment, or physician global
assessment; and an increase of 1 kg in mean total
myalgic score. Application of these criteria in a trial
that compared amitriptyline, cyclobenzaprine, and
placebo in patients with FM indicated that about one-
third of patients had at least short-term responses to
active treatment. These authors attempted to improve
the definition for a response to FM therapy by test-
ing criteria using a known, effective treatment as a
gold standard (96).
A set of preliminary criteria was developed using
data from a placebo-controlled clinical trial of
amitriptyline versus naproxen. The outcome mea-
sures with the highest sensitivity in discriminating
between patients receiving amitriptyline versus
placebo or naproxen were change in physician
global assessment, change in tender point score,
and patient sleep assessment.
This analysis resulted in the response criteria com-
posed of physician global assessment, patient-as-
sessed sleep score, and tender point score. More re-
cently, Dunk,l et al. (97) proposed preliminary cri-
teria for identifying responders in FM clinical tri-
als that were based on a study of magnetic therapy
in patients with this disease (Table I). These pre-
liminary criteria identified responders with a sen-
sitivity of 70.5% and specificity of 87.5%; howev-
er, these criteria have not been validated in other
At present, there are no specific markers for FM;
in fact, many of the existing factors are significant
Table I - Proposed preliminary response criteria for fibromyalgia.
Improvement in at least 3 of the 4 measures; and at least 3 of
the post-treatment scores must satisfy the respective cutoffs:
1. FIQ score <5 (range 0 = no impact to 80 = maximum im-
2. Pain intensity rating <5 (11 point numeric rating scale; 0 =
no pain, 10 = very severe pain)
3. Tender point count <14 (4 kg/cm2pressure is applied with
a dolorimeter and the patient rates pain from 0 [no pain] to
10 [worst pain ever experienced]; positive tender point de-
fined as pain intensity at >2)
4. Total tender point pain intensity score <85 (sum of pain in-
tensity scores for the 18 ACR defined sites; range 0 to
FIQ: Fibromyalgia Impact Questionnaire. ACR: American College of Rheumato-
F. Atzeni et al.
for study purposes only. The presence of these fac-
tors, however, helps researchers and clinicians to
understand the pathogenetic mechanisms and to
identify patient subgroups. Some of these factors
could be used as indices of disease severity. The
current literature is engaged in identifying and sug-
gesting serological alterations or instrumental in-
vestigations as new, specific markers of FM; but it
is necessary to identify precise biomarkers of dis-
ease in accordance with the criteria of feasibility
and reproducibility for diagnostic and therapeutic
purposes. Unfortunately, the symptoms of FM are
not specific and there are no instrumental diagnos-
tic tests for FM. Many differential diagnoses may
be excluded via extensive clinical examination and
patient history, and considering the overlap of FM
with other medical conditions, treating physicians
should be vigilant: chest-X-rays and abdominal ul-
trasonography are the first steps of general evalu-
ation for all patients with suspected FM. Functional
neuroimaging methods have revealed a large num-
ber of supraspinal effects in FM, a disorder medi-
ated by mechanisms that are essentially unknown.
The goal of future studies will be to assess whether
these findings are associated with the mechanisms
that initiate and maintain this disorder, or whether
they represent supraspinal consequences of these
unknown mechanisms. Evaluating therapeutic ef-
fects in FM is difficult because of the many facets
of the syndrome. To address the identification of
core outcome domains, the IMMPACT and
OMERACT workshops are working to develop
consensus recommendations for chronic pain clin-
Fibromyalgia (FM) is a rheumatic disease characterized by musculoskeletal pain, chronic diffuse tension and/or stiff-
ness in joints and muscles, easy fatigue, sleep and emotional disturbances, and pressure pain sensitivity in at least 11
of 18 tender points. At present, there are no instrumental tests or specific diagnostic markers for FM; in fact, many of
the existing indicators are significant for research purposes only. Many differential diagnoses may be excluded by an
extensive clinical examination and patient history. Considering overlap of FM with other medical conditions, the treat-
ing physicians should be vigilant: chest-X-rays and abdominal ultrasonography are the first steps of general evalua-
tion for all the patients with suspected FM. Functional neuroimaging methods have revealed a large number of
supraspinal effects in FM, a disorder mediated by mechanisms that are essentially unknown. Many treatments are used
in FM patients, but evaluating their therapeutic effects in FM is difficult because the syndrome is so multifaceted. To
address the identification of core outcome domains, the Initiative on IMMPACT and OMERACT workshop convened
a meeting to develop consensus recommendations for chronic pain clinical trials.
Key words - Biomarkers, functional magnetic resonance, clinimetric approaches, polysomnography, tilting test.
Parole chiave - Biomarkers, risonanza magnetica funzionale, clinimetria, polisonnografia, tilting test.
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