PRIMER

Fibromyalgia
Winfried Huser1,2, Jacob Ablin3, Mary-Ann Fitzcharles4, Geoffrey Littlejohn5,
JuanV.Luciano6, Chie Usui7 and Brian Walitt8
Abstract | Fibromyalgia is a common illness characterized by chronic widespread pain, sleep problems
(including unrefreshing sleep), physical exhaustion and cognitive difficulties. The definition, pathogenesis
and treatment are controversial, and some even contest the existence of this disorder. In 1990, the
American College of Rheumatology (ACR) defined classification criteria that required multiple tender
points (areas of tenderness occurring in muscles and muscletendon junctions) and chronic widespread
pain. In 2010, the ACR preliminary diagnostic criteria excluded tender points, allowed less extensive pain
and placed reliance on patient-reported somatic symptoms and cognitive difficulties. Fibromyalgia occurs
in all populations worldwide, and symptom prevalence ranges between 2% and 4% in the general
population. The prevalence of people who are actually diagnosed with fibromyalgia (administrative
prevalence) is much lower. A model of fibromyalgia pathogenesis has been suggested in which biological
and psychosocial variables interact to influence the predisposition, triggering and aggravation of a chronic
disease, but the details are unclear. Diagnosis requires the history of a typical cluster of symptoms and the
exclusion of a somatic disease that sufficiently explains the symptoms by medical examination. Current
evidence-based guidelines emphasize the value of multimodal treatments, which encompass both
nonpharmacological and selected pharmacological treatments tailored to individual symptoms, including
pain, fatigue, sleep problems and mood problems. For an illustrated summary of this Primer, visit:
http://go.nature.com/LIBdDX

Fibromyalgia is a common but contested illness1. Its defi
nition has changed over the years2. In 1990, fibromyalgia
was defined by the American College of Rheumatology
(ACR) classification criteria as requiring multiple tender
points (assessed during physical examination) and
chronic widespread pain3. In 1994, the tenth revision
of the International Classification of Diseases (ICD10)
listed fibromyalgia under diseases of the musculo
skeletal system and connective tissue (REF.4). The intent
of the 2010 ACR preliminary diagnostic criteria was
toeliminate the tender point examination (TPE) andto
address important symptoms through which fibro
myalgia was identified and characterized in clinical
settings, such as patient-reported somatic symptoms
and cognitive difficulties5. Chronic widespread pain,
Correspondence to W.H.
sleep problems or unrefreshing sleep, physical exhaus
e-mail: whaeuser@
klinikum-saarbruecken.de
tion and cognitive difficulties are the key symptoms of
Department of Internal fibromyalgia. Most patients diagnosed with fibromyalgia
Medicine 1, report a wide range of additional somatic and psycho
KlinikumSaarbrcken, logical symptoms6. Co-morbid illnesses such as func
Winterberg 1,
D-66119Saarbrcken,
tional somatic syndromes (for example, irritable bowel
Germany. syndrome (IBS))7, anxiety and depressive disorders8
and rheumatic diseases9 are often noted in people with
Article number: 15022
doi:10.1038/nrdp.2015.22
fibromyalgia. Depending on the number and sever
Published online ity of symptoms and the degree of dysfunction, mild,
13 August 2015 moderate and severe forms of fibromyalgia can be
differentiated, either by clinical criteria10 or by scores of
symptom questionnaires11,12.
The diagnostic label fibromyalgia is contested by
many clinicians. Psychiatrists and psychologists pre
fer to diagnose patients who exhibit fibromyalgia-like
symptoms with somatoform disorders (somatoform
pain disorder or somatization disorder)13 (BOX1). As
many consider fibromyalgia to be a rheumatic disease,
they argue that there is a risk of neglecting psychosocial
factors that contribute to the onset and course of symp
toms13,14. Primary care physicians use the diagnostic
label chronic widespread pain (REF.15). Those who use
the diagnostic label fibromyalgia such as some rep
resentatives of rheumatology, psychosomatic medicine
and pain medicine classify fibromyalgia as a central
sensitization syndrome16,17, a psychosomatic disorder 14
or a neuropathic pain syndrome18. Some authors view
fibromyalgia as a continuation of mass psychocultural
movements (for example, neurasthenia)1.
In the past 30years, the number of publications
on fibromyalgia has grown considerably. This surge
of studies might be explained by a shared interest of
patient self-help organizations, clinicians, researchers
and the pharmaceutical industry to promote awareness
of fibromyalgia, to understand its pathophysiology
and to improve therapy 2. Indeed, social forces such as

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PRIMER
Author addresses
1
Department of Internal Medicine 1, Klinikum Saarbrcken, Winterberg 1,
D-66119Saarbrcken, Germany.
2
Department Psychosomatic Medicine and Psychotherapy, Technische Universitt
Mnchen, Ismaninger Street 22, 81675 Mnchen, Germany.
3
Institute of Rheumatology, Tel Aviv Sourasky Medical Center and Sackler School
ofMedicine, Tel Aviv University, Tel Aviv, Israel.
4
McGill University Health Center, Montreal, Quebec, Canada.
5
Departments of Rheumatology and Medicine, Monash Health and Monash University,
Clayton, Australia.
6
Teaching, Research and Innovation Unit, Parc Sanitari Sant Joan de Du,
SantBoideLlobregat, Barcelona, Spain.
7
Department of Psychiatry, Juntendo University School of Medicine, Tokyo, Japan.
8
National Center for Complementary and Integrative Health, and National Institute
ofNursing Research, National Institutes of Health, Bethesda, Maryland, USA.
patient and professional organizations, pharmaceutical
companies, and legal and academic communities have
a role in defining the context of fibromyalgia2. The goals
of such forces might be legitimation of symptoms and
sickness for patients, influence for academics, economic
gain for pharmaceutical companies and legalinterests2.
In this Primer, we review the current understanding
including controversies regarding the diagnosis,
pathogenesis and management of fibromyalgia.
Epidemiology
Chronic widespread pain is difficult to accurately measure
and study. It often has a poorly defined onset and can
be episodic1,10. Most epidemiological studies have used
either the 1990 ACR classification2 or the modified 2010
ACR diagnostic criteria (the socalled survey or research
criteria)4,19, or slightly different approaches (TABLE1).
Fibromyalgia is a common disorder, which occurs in
all populations worldwide. In general, the prevalence of
patients with symptoms that meet diagnostic criteria has
been between 2% and 4% in moststudies20.
Box 1 | Alternative diagnostic labels
Somatoform pain disorder according to International Classification of
Diseases (10th revision)*
Severe, excruciating pain for >6months;
No sufficient evidence obtained from adequately conducted somatic testing to
explain the symptoms;
Occurs in conjunction with emotional conflicts or psychosocial problems that are
important causal factors owing to their severity; and
Exclusion of:
Psychogenic pain during the course of a depressive disorder or schizophrenia
Pain due to known or psychophysiological mechanisms, such as muscle tension pain
ormigraine.
Somatization disorder according to International Classification of Diseases
(10th revision)*
At least 2years of multiple and variable physical symptoms for which no adequate
physical explanation has been found;
Persistent refusal to accept the advice or reassurance of several doctors that there
isno physical explanation for the symptoms; and
Some degree of impairment of social and family functioning that is attributable
to the nature of the symptoms and resulting behaviour.
*See REF. 4.
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2015 Macmillan Publishers Limited. All rights reserved
Identification of the true incidence of fibromyalgia
is problematic. A study interrogated a USbased large
insurance claims database for new fibromyalgia cases
and found that the age-adjusted (to the US population)
rate for new fibromyalgia was 6.88 cases per 1,000
person years for men and 11.28 cases per 1,000 person
years for women21.
The prevalence of people diagnosed with fibro
myalgia (administrative prevalence) is probably lower
than the 24% prevalence reported in epidemiologi
cal population studies. In a Japanese study, only 2.5%
of the individuals meeting the diagnostic criteria were
reported to be diagnosed with fibromyalgia22. A US
study found an age-adjusted and sex-adjusted preva
lence of people diagnosed with fibromyalgia by clinical
criteria to be 1.1%23 and of potential fibromyalgia, diag
nosed by the modified 2010 ACR diagnostic criteria19,
to be 6.4%24. The 1year prevalence of people with fibro
myalgia defined by at least one billing case with the code
for fibromyalgia of a German health insurance company
with 7 million insured individuals was 0.3%25. The same
study showed the prevalence ratio of women to men was
12:1; most insured individuals were between 50years
and 60years of age25. When the 1990 ACR criteria are
used for clinical surveys, women are more frequently
diagnosed with the disorder. Using these criteria, the
women to men ratio has ranged from 8:1 to 30:1 in
patients who were studied in clinical institutions and
surveys2628. However, with criteria that do not use TPE,
the sex ratio can be close to equal. The sex ratio has
ranged from 4:1 to 1:1 in studies that were conducted
in the general population using the research criteria
forfibromyalgia22,24,29,30.
Most patients studied in clinical institutions and sur
veys are middle aged (4060years)2628. In general popu
lation studies, the prevalence of people with fibromyalgia
increases with age30,31.
Mechanisms/pathophysiology
Fibromyalgia is a complex syndrome, which incorpor
ates a wide range of symptoms and functional alterations
in many systems, but the involvement of the central
nervous system (CNS) is a key element. Thus, it is a
major challenge to clarify which of the many described
alterations are pathogenetic and which simply represent
epiphenomena. This mission is further complicated by
the many potential triggering factors and co-morbidities
for fibromyalgia, such as stressors, infection, depression,
anxiety, trauma, inactivity and obesity (see below).
In the current literature, pain centralization repre
sents the most prominent pathophysiological hypoth
esis; here, we focus on this scientific idea, but also
briefly explore alternative hypotheses and highlight
controversies about the pathophysiology of fibromyalgia.
Genetics
Current research strongly supports genetic under
pinnings in the development of fibromyalgia, as in most
other chronic pain conditions32. First-degree relatives of
patients with fibromyalgia show an eightfold greater risk
of developing the syndrome33, and family members have
 PRIMER

more tender points than controls and are at increased
risk of having other functional disorders (disorders
that affect body function but not structure), including
IBS, temporomandibular disorder, headache and other
regional pain syndromes34. This familial coaggregation
is assumed to represent an overlap between clinical
syndromes that are characterized by pain centraliza
tion and shared features such as pain, fatigue, cognitive
difficulties and affective symptoms.
The genetic basis for these functional disorders has
been underscored by twin studies, which have dem
onstrated that different functional somatic syndromes
coaggregate and genetic factors contribute up to half the
risk of developing them35,36. Several polymorphisms have
been identified as specific markers of this genetic risk.
Many of these specific markers are related to metabolism
and breakdown of neurotransmitters that are involved
in pain modulation: polymorphisms in the genes

Table 1 | Prevalence of fibromyalgia in the general population (modified and expanded)

Country Case definition n Age Overall Female Male Refs
(years) prevalence prevalence prevalence
(%) (%) (%)
Africa
Tunisia LFESSQ 1,000 15 9.3 N.R. N.R. 161
Americas
Brazil COPCORD 3,038 16 2.5 3.9 0.1 162
Canada 1990 ACR criteria 3,395 16 3.3 4.9 1.6 163
Canada Self-reported 131,535 12 1.1 1.8 0.3 164
United States 1990 ACR criteria 3,006 18 2.2 3.4 0.5 30
United States Modified 2010 ACR criteria 830 21 6.4 7.7 4.9 24
Asia
Bangladesh COPCORD 5,211 15 3.6 6.2 0.9 165
China 1990 ACR criteria 1,467 N.R. 0.8 N.R. N.R. 166
Israel LFESSQ and 1990 ACR criteria 1,019 18 2 2.8 1.1 167
Japan Modified 2010 ACR criteria 20,407 20 2.1 N.R. N.R. 22
Malaysia COPCORD 2,594 15 0.9 1.5 0.2 168
Pakistan COPCORD 1,997 15 2.1 N.R. N.R. 169
Thailand Modified 2010 ACR criteria 1,000 N.R. 0.6 N.R. N.R. 170
Turkey 1990 ACR criteria 600 N.R. 8.8 12.5 5.1 171
Europe
Denmark 1990 ACR criteria 1,219 18 0.7 N.R. N.R. 172
France LFESSQ and 1990 ACR criteria 1,014 15 1.4 2 0.7 173
France LFESSQ and 1990 ACR criteria 3,081 18 1.6 N.R. N.R. 174
Finland Yunus 7,217 30 0.8 1 0.5 175
Germany LFESSQ and 1990 ACR criteria 1,002 15 3.2 3.9 2.5 176
Germany Modified 2010 ACR criteria 2,445 14 2.1 2.4 1.8 29
Greece 1990 ACR criteria 8,740 19 0.4 N.R. N.R. 177
Italy 1990 ACR criteria 2,155 18 2.2 N.R. N.R. 178
Italy LFESSQ and 1990 ACR criteria 1,002 15 3.7 5.5 1.6 176
Portugal LFESSQ and 1990 ACR criteria 500 15 3.6 5.2 1.8 176
Scotland 1990 ACR criteria 1,604 18 1.7 N.R.* N.R.* 31
2010 ACR preliminary criteria 1.2 N.R.* N.R.*
Modified 2010 ACR criteria 5.4 N.R.* N.R.*
Spain LFESSQ and 1990 ACR criteria 1,001 15 2.3 3.3 1.3 176
Spain 1990 ACR criteria 2,192 20 2.4 4.2 0.2 179
Sweden 1990 ACR criteria 2,425 20 1.3 2.4 0 180
ACR, American College of Rheumatology; COPCORD, Community Oriented Program for Control of Rheumatic Diseases;
LFESSQ,London Fibromyalgia Epidemiology Study Screening Questionnaire; N.R., not reported. *Women to men ratio of 13.7, 4.8
and 2.3 for the 1990 ACR, the 2010 ACR preliminary and the modified 2010 ACR criteria, respectively. Adapted with permission
from REF.20, Springer.

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PRIMER

encoding catechol-Omethyltransferase, the dopamine
type 4 receptor, the serotonin 5hydroxytryptamine 2A
receptor and the serotonin transporters have been impli
cated37. Data from both genome-wide association studies
and copy number variant analyses have recently been
incorporated into our understanding of fibromyalgia
genetics38,39. Nonetheless, the risk attributable to these
genetic markers seems modest, with odds ratios (ORs)
ranging between 1.5 and 5.4 (REF.32).
To date, replicable genes of large effect size have not
been found40. Similar to other complex conditions, a
large element of missing heritability remains to be
explained through other pathways41. It is likely that the
final CNS set point for pain processing is determined by
a large number of separate genetic markers that interact
with lifetime events and behaviours.
Stressors and environmental factors
Various infections have been linked to fibromyalgia.
Infections with EpsteinBarr virus or parvovirus,
brucellosis and Lyme disease are often cited, although any
prolonged febrile disorder, particularly if accompanied
by protracted bed rest, might act as a trigger 42. Physical
Nociception-
Hypothalamus inhibiting
neurons
Pain Transmission of the
pain signal to the brain
Nociception-
facilitating
neurons
Cortex Thalamus
trauma, particularly affecting the spine, has also
frequently been described to trigger fibromyalgia43.
However, in many patients, no specific trigger can be
identified and the importance of particular infections
and physical traumas in the aetiology of fibromyalgia
has been contested44,45.
Fibromyalgia is much more common in individuals
who have chronic pain that is attributable to peripheral
pain generators. Thus, patients with inflammatory joint
diseases, such as rheumatoid arthritis or ankylosing
spondyloarthritis46 as well as joint hyperlaxity 47, often
develop typical fibromyalgia symptoms. Clinicians treat
ing these patients must differentiate between peripheral
and central aspects of pain, and treat both accordingly.
Fibromyalgia has also been associated with a variety
of psychological stressors, including childhood trauma
and abuse48, daily life hassles49, exposure to war, cata
strophic events and persecution50. These links have led
to extensive research into the human stress system,
which has revealed alterations in the hypothalamic
pituitaryadrenal axis and the sympathetic nervous
system in patients with fibromyalgia and related condi
tions51. A recent review has reported decreased heart rate
variability, sympathetic overactivity and a blunted auto
nomic response to stress in patients with fibromyalgia52.
However, these findings are only noted in a subset of
patients and are partly related to comorbidities, such as
deconditioning and early-life trauma52. The causal direc
tion of the relationship between fibromyalgia andauto
nomic dysfunction and whether treatment and
improvement of any of these abnormalities is associated
with amelioration of symptoms is notknown.

Hypothalamus Understanding pain centralization

Input Modulation
Activation of peripheral pain receptors (nociceptors;
FIG.1) by noxious stimuli generates signals that travel
to the dorsal horn of the spinal cord via the dorsal root
Ascending Descending
Dorsal root input modulation ganglion. From the dorsal horn, the signals are carried
ganglion along the ascending pain pathway or the spinothalamic
Dorsal horn Activation of the CNS tract to the thalamus and the cortex. Pain can be con
at the spinal cord trolled by pain-inhibiting and pain-facilitating neurons.
Descending signals originating in supraspinal centres
can modulate activity in the dorsal horn by controlling
Spinothalamic tract
spinal pain transmission.
Pain centralization has emerged as a prominent
Peripheral
nerve hypothesis for the pathogenesis of fibromyalgia. This
Transmission
term simply means that the CNS has the leading role
Joint in the augmentation or amplification of pain, and in
Trauma the development of other comorbid symptoms (such
as disturbed sleep, fatigue, memory and depressed
Skin mood). There are two broad groups of individuals with
Peripheral
nociceptors Activation of the centralized pain53. The first (which has previously been
peripheral nervous system referred to as primary fibromyalgia) are individuals
with no identifiable ongoing nociceptive input that
Figure 1 | Pain processing and its modulation. Activation of peripheral pain
Nature Reviews | Disease Primers could account for pain, such as damage or inflammation.
receptors (also called nociceptors) by noxious stimuli generates signals that travel
These individuals often develop regional pain conditions
tothedorsal horn of the spinal cord via the dorsal root ganglion. From the dorsal horn,
thesignals are carried along the ascending pain pathway or the spinothalamic tract (including headache, temporomandibular disorder, IBS,
tothe thalamus and the cortex. Pain can be controlled by nociception-inhibiting and dysmenorrhea and interstitial cystitis) as well as other
nociception-facilitating neurons. Descending signals originating in the supraspinal somatic and psychological symptoms (including fatigue,
centres can modulate activity in the dorsal horn by controlling spinal pain transmission. anxiety and depression) early in life. Over time, pain
CNS, central nervous system. Figure from REF.160, Nature Publishing Group. becomes widespread and recognized as fibromyalgia.

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 PRIMER

CNS hyper-responsiveness and dysregulation

for pain and sensory

Genetic set point

processing
Diuse hyperalgesia, allodynia and
sensory hyper-responsiveness
Altered functional
connectivity
CNS neuroplasticity
Modications by and reorganization
the environment

Neurotransmitter Altered HPA axis

imbalance and autonomic function
Stressors, trauma and infection
Cognitive and behavioural Hypo-
responses to pain thalamus
Psychological co-morbidities
Glutamate,
substance P Pituitary
and NGF gland
Contributory peripheral factors
Ongoing peripheral nociceptive input
from co-morbidities Adrenal
Inactivity and deconditioning gland
Obesity (causing slight Serotonin,
increase in the levels of noradrenaline
pro-inammatory cytokines)? and GABA

Figure 2 | Potential pathophysiological processes in fibromyalgia. Sensitization of the central

Nature nervous| Disease
Reviews system (CNS)
Primers
has been suggested as one of the main pathophysiological changes underlying fibromyalgia16. The genetic set point for
sensory (including pain) regulation can be modified by psychological factors, such as anxiety, depression and
catastrophizing and biopsychosocial stress (for example, trauma, childhood adversities, major life events or infections).
Peripheral factors, such as ongoing nociceptive input produced by co-morbidities, can also affect pathogenesis. In the
CNS, several changes can be noted, including neurotransmitter imbalances, altered functional connectivity and changes
in the hypothalamicpituitaryadrenal (HPA) axis, which influence the autonomic system. Red arrows represent stressors.
GABA, aminobutyric acid; NGF, nerve growth factor.

The second category of fibromyalgia or centralized
pain occurs as a co-morbidity in individuals with a
disease that has identifiable ongoing nociceptive input
(such as osteoarthritis, autoimmune disorders and sickle
cell disease)53. We do not yet know if these are the same
or different conditions. It is possible that primary fibro
myalgia is a top-down process, whereas the second cat
egory is a bottomup process. Centralization of pain can
be driven by ongoing peripheral nociceptive input, as
evidenced by total knee replacements in osteoarthritis54;
however, this evidence seems to be less-robust in the set
ting of osteoarthritis with concomitant fibromyalgia55.
Although interventions to reduce nociceptive input
have not been shown to dramatically alter the long-term
course of fibromyalgia56, physicians should identify and
treat peripheral pain generators when possible.
Several mechanisms have been described and
incorporated into the concept of centralized pain,
including mechanisms acting at the spinal level as well
as interactions and altered connectivity between pain
and non-pain-related brain areas. At the spinal level,
central sensitization encompasses active amplification
of sensory stimulation, which enhances pain response to
noxious stimuli, and recruitment of normally sublimi
nal low-threshold sensory inputs, which can then acti
vate the pain circuit57. One such mechanism is temporal
summation of second pain, which results from repetitive
stimulation of peripheral Cfibres and reflects a dorsal
horn neuron summation mechanism (also known as
windup)58. Patients with fibromyalgia have demonstrated
increased windup and temporal summation59, although
conflicting results have been reported recently 60 (FIG.2).
Another closely related mechanism involves reduc
tion in the capacity of the CNS to achieve descending
pain modulation. This effect termed conditioned pain
modulation (CPM) is attenuated in many patients with
fibromyalgia61. Interestingly, positive expectations of pain
relief can achieve effective analgesia, despite not altering
spinal hyperexcitability and impairing the recruitment of
CPM62. This finding implies that higher cortical areas can
compensate for deficient inhibitorycontrol62.
CPM is mediated by both descending opioidergic and
serotonergicnoradrenergic pathways. Although both
inhibitory systems could theoretically be involved in the
attenuation of CPM in fibromyalgia, decreased activity of
serotonergicnoradrenergic pathways is probably at fault.
For example, in the cerebrospinal fluid, the levels of the
main noradrenaline metabolites63, such as 3methoxy
4hydroxyphenethylene, and the serum levels of sero
tonin, tryptophan and 5hydroxyindoleacetic acid
(5HIAA)64 are lower in patients with fibromyalgia than
in healthy controls. Serotoninnoradrenaline reuptake
inhibitors (SNRIs) have been shown to reach a mini
mal clinically important difference in trials for treating
chronic pain and fibromyalgia65. It is unclear whether
this effect is the direct result of restoring CPM by increas
ing the concentrations of these two neurotransmitters in
the cerebrospinal fluid, but the finding that patients with

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PRIMER
chronic neuropathic pain and decreased CPM preferen
tially respond to duloxetine (an SNRI) compared with
patients with a normal modulation pattern of efficient
CPM strongly supports this mechanism66. Many cen
trally acting drugs show favourable responses in more
than one domain; patients with reduced pain are likely
to have improvements in other symptoms that are driven
by the same neurotransmitter abnormalities.
In fibromyalgia, there is decreased opioid receptor
binding in the pain-processing areas of the brain67, which
implies increased baseline endogenous opioidergic activ
ity 68. This finding might be related to the induction of
socalled opioid-induced hyperalgesia, a clinical phenom
enon attributed to the opioid-induced Toll-like receptor 4
(TLR4)-mediated activation of glial cells69. Such activa
tion concurs with the clinical experience, which shows
that exogenous opiates are generally ineffective (and
overused) for managing chronic pain associated with
fibromyalgia, whereas low-dose naltrexone, an opioid
antagonist, has shown modestbenefit70.
Glutamate levels in the cerebrospinal fluid are
increased in fibromyalgia71, and proton magnetic reso
nance spectroscopy has demonstrated increased insu
lar glutamate levels, which change in correlation with
clinical and experimental pain72. In addition, treating
fibromyalgia pharmacologically with pregabalin, an
anticonvulsant drug that reduces the release of several
neurotransmitters, was associated with decreased insu
lar glutamatergic activity, which correlated with both
neuroimaging and clinical responses73. These results, as
well as a recent study suggesting efficacy of memantine,
which acts on the glutamatergic system as an Nmethyl-
daspartate (NMDA) receptor antagonist 74, indicate
that glutamate might be an important agent of pain
centralization in fibromyalgia.
Nerve growth factor and substance P are additional
pro-nociceptive neurotransmitters that are increased
in fibromyalgia75,76. Cerebrospinal fluid levels of nerve
growth factor, in particular, have been shown to be
increased in primary but not in secondary fibro
myalgia75, which supports the distinction between
topdown and bottomup mechanisms (FIG.2).
Neuroimaging abnormalities
In a functional MRI (fMRI) study, a lower pressure stim
ulus was required to produce similar central somato
sensory cortical activation in people with fibromyalgia
than was required for the same level of activation in the
brains of healthy controls77. This and subsequent stud
ies78 have provided objective evidence of an increased
CNS set point for experimental pain in fibromyalgia.
Comorbid psychological factors, such as catastro
phizing or depression, which are present in a subset of
patients, can amplify these abnormalities, and this can be
seen in neuroimaging studies with increases in activity in
limbic regions in individuals with these co-morbidities78.
Resting-state connectivity analysis is a more-recent
advance that has been helpful in studying CNS activ
ity in fibromyalgia. Increased connectivity between the
default mode network and insula was related to sponta
neous pain intensity 79,80 as well as decreased connectivity
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2015 Macmillan Publishers Limited. All rights reserved
between pain-inhibitory areas81. Thus, fibromyalgia is
associated with objective signs of altered connectivity,
which might serve as both a biomarker and a tool to
direct rational treatment development.
Proton magnetic resonance spectroscopy has shown
increased glutamate activity and decreased insular
levels of aminobutyric acid (GABA)82. The assump
tion that GABA plays a pathophysiological part is sup
ported by the fact that GABA agonists, for example,
hydroxybutyrate and even low amounts of alcohol83,
can lead to symptomatic improvements in some patients
with fibromyalgia.
Emerging pathophysiological abnormalities
Although fibromyalgia has historically evolved from
being considered an inflammatory to a non-inflamma
tory syndrome, recent intriguing evidence points to the
possibility that subtle immunological and inflammatory
factors might have a role. Glial cells have been implicated
in maintaining central sensitization and seem to partici
pate in causing chronic pain, through the production of
various chemokines and cytokines84, such as IL6 and
IL8, which have increased levels in the sera of patients
with fibromyalgia85.
Interesting findings have recently been reported
regarding peripheral nervous system abnormalities.
Quantitative sensory testing, pain-related evoked poten
tials and punch biopsy of the skin have demonstrated
impaired small nerve fibre function and reduced small
fibre density in patients with fibromyalgia86. Thus,
central and peripheral factors might interact in the
development of chronicpain.
Alternative hypotheses
Understanding the pathogenesis of fibromyalgia is
an ongoing project 87. As classification and diagnostic
criteria continue to evolve, technological advances in
neuroimaging, genetics and immunology provide novel
tools for understanding the neurological basis of pain
centralization. Determining cause and effect regarding
the association between diverse clinical symptoms and
neurophysiological imaging data remains challenging.
Furthermore, the pathophysiological mechanisms dis
cussed above are disputed considered unproven or
are over-interpreted by some researchers.
Proponents of pain centralization describe the pri
mary pathophysiological issue of fibromyalgia as the pain
volume control system being set too high87. However,
considerable current research suggests that periph
eral pain generators play a small part and that the CNS
component is largely independent of peripheralinput.
If peripheral signalling is not essential to the experi
ence of fibromyalgia pain, it is unclear how the patho
physiology can be best described as pain augmentation
or pain amplification. Thus, findings of CNS alterations
that are used to support the idea of pain centralization
also support other CNS-based hypotheses, including
the consequences of personality traits (such as pain
catastrophizing), sympathetic nervous system dysfunc
tion88, theevolutionary stress response89, pain memory 90
andthe activation of homeostatic neural programmes.
 PRIMER

These alternative ideas might also provide impor By the late 1980s, different criteria sets for fibromyalgia
tant insights into why painful experiences are largely had emerged94. However, no clear agreement was made
independent from peripheral input in fibromyalgia91. between clinicians on which tender point sites should be
Although there is much evidence of physiological examined, how they should be examined or how many
differences between people with fibromyalgia and those sites had to be tender for a positive examination. Similarly,
without, the physical phenomena themselves poorly no rules were established on how to assess the symptoms.
correlate with symptom severity and are neither nec Both in the clinic and in the research setting, the reliability
essary nor sufficient to cause or sustain fibromyalgia60. and validity of the available criteria was not tested95.
Multiple neurological mechanisms regulate pain, but
there is no evidence that any of these processes, or The 1990 ACR criteria. A group of rheumatologists of the
their interdependent coordination, cause fibromyalgia. ACR with expertise in fibromyalgia compared patients
These altered mechanisms found in patients with fibro with fibromyalgia diagnosed by their individual cri
myalgia are not unique to fibromyalgia and may reflect teria with age-matched and sex-matched controls (who
predisposing factors, contributing endophenotypes had local pain syndromes or (potential) inflammatory
orepiphenomena. rheumatic diseases). The ACR committee found that the
presence of widespread pain combined with atleast 11
Diagnosis, screening and prevention out of 18 tender points best separated patients with fibro
No confirmatory blood tests (biomarkers), imaging myalgia from controls3. Some combinations of symptoms
or histological analysis are available for fibromyalgia. (for example, fatigue and cognitive problems) were not
However, for the initial assessment of a patient with evaluated because the committee did not recognize the
chronic widespread pain, national (Canadian, German importance of these symptoms at the time of the study.
and Israeli) guidelines have proposed diagnostic work- The panel suggested that the presence of 11 out of 18
ups, including obtaining a history of pharmacological tender points and the simultaneous presence of chronic
drug use, complete medical assessment and some labora widespread pain for at 3months should be the classi
tory tests (including complete blood count, Creactive fication criteria for fibromyalgia (TABLE2). Patients with
protein levels, serum calcium levels, creatine phospho primary and secondary (that is, concomitant to an inflam
kinase levels and thyroid-stimulating hormone levels10,92) matory rheumatic disease) did not significantly differ in
to screen for medical conditions that can mimic fibro any studyvariable3.
myalgia symptoms. Particular concerns are widespread Although initially intended for research purposes,
metastatic cancer and statin-induced muscle pain10,92. these criteria were soon widely used for clinical diagno
In addition, the diagnosis of other medical conditions sis, particularly among rheumatologists, as well as in basic
that contribute to widespread pain is important for the science and in clinical studies95. Indeed, numerous con
management of the patient, because for example cerns were raised on the reliability and validity of the TPE
severe osteoarthritis of the knee as a cause of knee pain when used for the diagnosis of fibromyalgia in the clinical
would require treatment strategies other than those setting, which eventually led to the recommendation to
forfibromyalgia. stop their use in the clinic96. In support of this recom
A diagnosis of fibromyalgia is currently made based mendation, a standardized TPE protocol was developed97.
on the history of fibromyalgia-like symptoms and the However, this protocol was almost never used by rheuma
exclusion of another somatic condition that sufficiently tologists in clinical practice, and was used only in a few
explains the symptoms10. However, the criteria for clinical and basic science studies. Furthermore, the TPE
fibromyalgia have undergone numerous revisions since was shown to be influenced by the interaction between
firstreported. the patient and examiner and was highly correlated
with distress98. The TPE was a poor marker ofchange in
Diagnostic criteria clinical studies and the reliability and validity of the TPE
Pre-ACR diagnostic criteria. Illnesses characterized outside the context of fibromyalgia-specialized rheuma
by chronic widespread pain and chronic fatigue were tology settings was never tested. Moreover, fibromyal
identified as early as the nineteenth century. Sporadic gia is not a disorder that is exclusively diagnosed and
descriptions of fibromyalgia-like symptoms were avail treated by rheumatologists. Patients are also diagnosed
able throughout the literature in the 1960s2. The mod and treated by general practitioners, pain specialists or
ern construct of fibromyalgia arose in 1977 from an mental health specialists the TPE is largely ignored
article by Smythe and Moldofsky 93 with contributions in these settings. Indeed, increased tenderness, or hyper
to the understanding of fibrositis syndrome. They algesia or allodynia, to pressure stimuli in patients with
proposed clinical criteria based on what they saw as fibromyalgia had been replicated by standardized experi
key features of fibrositis syndrome: unrefreshing sleep mental procedures; its relevance and specificity for the
and tender points. Tender points were defined as pre- diagnosis of fibromyalgia had been questioned99.
specifiedpoints on the body that were particularly sensi
tive to pressure in individuals with the syndrome. The 2010 ACR preliminary diagnostic criteria. The 2010
presence of widespread aching for longer than 3months ACR preliminary diagnostic criteria5 (TABLE2) addressed
and disturbed sleep with morning fatigue and stiffness numerous problems with the 1990 ACR criteria. First, the
were also required in these criteria. Decreased pain 2010 ACR preliminary criteria eliminated the TPE, which
threshold was measured by a count of tenderpoints. was replaced by the Widespread Pain Index (WPI). The

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PRIMER

Table 2 | The 1990, 2010 preliminary and modified 2010 ACR criteria for fibromyalgia
Criteria Diagnostic items Comments Refs
1990 ACR Widespread pain (bilateral, above Tender points can be found at the spine, shoulders, ribs, 3
criteria and below the waist and axial) hips and knees and often at the sites of insertions of
Pain in 11 out of 18 tender points ligaments, muscles and tendons
(on palpation with a force of ~4kg)
2010 ACR Widespread pain and substantial Pain is scored by the physician according to the number 5
preliminary somatic symptoms of affected areas (total score: 019), andsymptom
criteria Symptoms present for 3months severity ranges from no problem (0) to severe
No other disorder that could symptoms(3) in four domains (fatigue, unrefreshing
explain the pain sleep, cognitive and somatic symptoms; total score:
012). Total score: 031
Modified 2010 Modified version of the 2010 Widespread Pain Index is scored by the patient 19
ACR criteria ACR preliminary criteria according to the number of affected areas (total score:
(research (entirelyself-reported assessment 019). The symptom severity score is modified to include
or survey of symptoms) headaches, pain or cramps in the lower abdomen and
criteria) depression (total score: 012). Total score: 031
ACR, American College of Rheumatology.

WPI is a 019 count of the number of body regions that
are reported as painful or sensitive to pressure (tender)
by the patient. Second, the criteria assessed on a 03
severity scale a series of symptoms that were defined
as additional key symptoms of fibromyalgia: fatigue,
unrefreshing sleep, cognitive problems and the extent
of somatic symptom reporting. The items were com
bined into a 012point Symptom Severity (SS) Scale.
Last, theWPI and SS Scale could be combined5. In addi
tion,the diagnostic criteria require that the patient has
had symptoms present at a similar level for 3months
and the patient does not have another disorder that
would otherwise sufficiently explain thepain5.
Modified 2010 ACR diagnostic criteria (research or
survey criteria). The assessment of the modified 2010
ACR diagnostic criteria in the clinical setting was at
least as time consuming as the 1990 ACR classifica
tion criteria. The WPI and SS Scale items require a
detailed and thoughtful interview of the patient.
Symptom assessment by physicians is inherently sub
jective. The Fibromyalgia Survey Questionnaire (FSQ;
also known as the Fibromyalgia Symptom Scale andthe
Polysymptomatic Distress Scale) was developed for
theself-reported (that is, by the patients) assessment
ofthe key symptoms of fibromyalgia in survey research
and in settings where the use of interviews to evaluate
the number of pain sites and extent of somatic symptom
intensity would bedifficult.
The FSQ substituted the assessment of the extent of
somatic symptom intensity completed by physicians
with a questionnaire assessing the number of pain sites
and somatic symptom severity completed by the patient.
Patients who satisfy the research criteria (a diagnosis of
fibromyalgia in a research context) meet the following
conditions: the patient has a WPI of 7 out of 19 pain
sites and an SS score of 5 out of 12, or a WPI of between
3 and 6 pain sites and an SS score of 9. The symptoms
should be present for at least 3months19.
Given that the WPI and SS Scale comprise the FSQ,
this questionnaire can be used to assist medical diag
nosis. However, the interpretation and assessment of
the validity of the questionnaire must be determined
bythephysician. Self-diagnosis of fibromyalgia based
only on the FSQ is strongly discouraged95,100. The combi
nation of the continuous scale WPI and SS score (that is,
the Fibromyalgia Symptom Scale) enables the assessment
of the symptom burden in patients instead of classifying
patients as fibromyalgia positive or negative100.
Clinical implications of different criteria
The concordance rates of the 1990 ACR, 2010 ACR
preliminary and modified 2010 ACR diagnostic criteria
in validation studies conducted in clinical samples in
Canada101, Germany 102, Japan103 and Spain104 were high.
The use of the 2010 ACR preliminary and modified 2010
ACR criteria will probably lead to a higher prevalence
in men, because the bias towards diagnosis in women
bythe 1990 ACR classification criteria was eliminated by
the new diagnostic criteria in the general population,
more positive tender points can be detected in women
than inmen95.
Challenges of the diagnosis
Many patients report a long delay of the first diagnosis
of fibromyalgia105. Potential reasons are as follows: some
physicians might not recognize that some people with
chronic pain would satisfy fibromyalgia criteria; other
doctors do not use the diagnostic label of fibromyal
gia because they disagree with the concept of fibro
myalgia;and some physicians think that the diagnosis
will be harmful to the patient and/or health care sys
tem. However, making a valid diagnosis of fibromyal
gia and properly explaining it to the patient can often
decrease the patients anxiety, reduce unnecessary fur
ther investigations of symptoms and provide a rational
framework to apply interventions such as exercise, which
is knownto be useful for this disorder 10.
Inaccuracy, mostly observed to be overdiagnosis,
by referring physicians has been reported by rheuma
tology centres106,107. Data from the US National Health
Interview Survey has shown that 75% of individuals who
reported a physicians diagnosis of fibromyalgia did not
satisfy fibromyalgia research criteria108.

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CNS neurostimulation Decreased descending
serotonin and noradrenaline
activity (for example, tricyclic
antidepressants, SNRIs
(duloxetine and milnacipran)
and tramadol)
Cognitivebehavioural
therapy, stress reduction
and meditative movement Decreased -hydroxybutyrate
treatment (for example, GABA,
gabapentinoids, memantine
and low amounts of alcohol*)
Exercise and rehabilitation Identify and treat peripheral
nociceptive input
Non-pharmacological treatments
Pharmacological treatments
Both pharmocological and
non-pharmacological treatments
Figure 3 | Potential therapies for fibromyalgia. Both non-pharmacological (such
Nature Reviews | Disease Primers
ascognitivebehavioural therapy and exercise) and pharmacological treatment (such as
gabapentinoid anticonvulsants and antidepressants) options are available for
fibromyalgia16. CNS, central nervous system; GABA, aminobutyric acid; SNRI,
serotoninnoradrenaline reuptake inhibitor. *Plausible treatment. Could be treated
both ways depending on the co-morbidity.
Screening
Fibromyalgia criteria can highlight the somatic and
psychological symptom burden in patients with lower
back pain, rheumatoid arthritis, headache and other pain
syndromes109. Thus, it is useful to screen patients with
chronic pain for fibromyalgia using theFSQ.
Risk factors
A biopsychosocial model of factors that predispose, trig
ger and perpetuate fibromyalgia symptoms has been
suggested44. Potential predisposing factors are genes37,
lifestyle factors (such as obesity and physical inactivity)110,
low socioeconomic status111, psychological and physical
stress112 and sleep disturbances113. Physical andsexual
abuse in childhood and adolescence48 and somatic dis
eases (such as rheumatoid arthritis111) often precede
the development of fibromyalgia symptoms. However,
fibromyalgia is observed among individuals who do not
demonstrate any of these risk factors.
Prevention
Most clinically relevant and potentially modifi
able risk factors for fibromyalgia currently fall into
the psychological and sociocultural areas, such as the
promotion of a healthy lifestyle and the reduction of
childhoodmaltreatment.
Management
As pathogenetic mechanisms in fibromyalgia are
increasingly understood, treatments begin to move from
empirical to more rational approaches (FIG.3). Current
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PRIMER
challenges in the management of fibromyalgia are due to
heterogeneity in clinical presentation and multiplicity of
core symptoms, which makes fibromyalgia a prototypic
example of the dictum one size does not fit all. Targeting
core symptoms (including pain, fatigue, unrefreshing
sleep and mood disorders) is a good starting point, but
it needs to be understood that individual treatments sel
dom address all symptoms. Particularly challenging to
treat are fatigue and difficulties with cognition, which are
commonly aggravated by adverse effects of pharmacologi
cal treatments but do not have any specific medical inter
vention. Treatment recommendations should be guided
by the evidence-based literature while still being aware of
clinical experience and patient preferences. This creates
a tension between the published evidence and clini
cal practice. Although the medical community tends to
look to pharmaceutical preparations, drug treatments for
symptom relief in fibromyalgia tend to only offer a modest
effect on average114. As only three drugs (duloxetine and
milnacipran (SNRIs), and pregabalin (an anticonvulsant))
are approved for fibromyalgia in various countries world
wide, but none in Europe, most pharmacological treat
ments remain off-label114. In addition, the drug doses that
are actually taken by patients are often considerably lower
than those reported in clinical trials, attrition in medica
tion use is common and some medications that are pre
ferred by patients27,28 are untested or not recommended
by current guidelines92.
General treatment principles
In the past decade, guidelines for the management of
fibromyalgia have been reported by groups in Europe,
North America and the Middle East 92. The essence of
all current guidelines, supported by a recent network
meta-analysis115, is to emphasize the value of multimodal
treatments that encompass both non-pharmacological
and selected pharmacological treatments tailored to the
individual. In line with the heterogeneity of symptoms,
no single treatment is effective for all patients. In addi
tion, owing to the scant resources available in the pub
lic health sector worldwide, it is commendable to apply
cost-effectiveness evaluations alongside treatment trials
to inform policy makers about the treatment choices that
generate maximum benefits for patients and society.
Non-pharmacological management
Recent guidelines strongly recommend patient educa
tion to emphasize validity of symptoms, importance of
self-management techniques, recommendation to remain
working and expectation for normal life expectancy. Non-
pharmacological strategies that promote self-efficacy,
physical activity and good health-related behaviours
should be recommended for all patients92 (TABLE3).
There is less evidence for the effect of many non-
pharmacological strategies than for drug treatments for
methodological reasons. Cognitivebehavioural thera
pies show sustained benefit for pain, mood and function,
and some third-generation psychological therapies such
as acceptance and commitment therapy and mindfulness-
based stress reduction are promising but need further
study 116119. Moreover, cognitivebehavioural therapies
PRIMER

have recently shown evidence of cost effectiveness com Pharmacological management

pared with drugs recommended by the US FDA, but these All drug treatments must balance efficacy and adverse
are often not readily available for patients owing to both effects, especially on those that affect cognition and
accessibility and cost120. Accordingly, non-pharmacological fatigue. Drug treatments must be reevaluated to ensure
treatments have the potential to offer a broader range of the need for continuation and should be prescribed
symptom relief and benefits to generalhealth. inthe lowest effective dose, which is often lower than the
Aerobic exercise, cognitivebehavioural therapies and doses reported for clinical trials, and ideally for a limited
multicomponent therapy, which incorporate at least one time. Patients with fibromyalgia use on average at least
educational or psychological therapy and one exercise two classes of medications, with some even prescribed
therapy, offer an advantage over treatment as usual or five or more classes25,27,28.
waiting list control121. Water-based exercise or meditative Pain is traditionally treated with simple analgesics,
activities that include movement such as Tai Chi can be NSAIDs or opioid medications. However, NSAIDs lack
attractive options for those who begin an exercise routine superiority compared with placebo for fibromyalgia
and for those who are overweight or deconditioned122,123. symptoms, and are associated with considerable adverse
Participation in a regular community-based exercise pro effects124. We can speculate that patients and rheumatolo
gramme is accessible to most people, is affordable and gists assume that fibromyalgia is a rheumatic disease and
promotes contact with others in a social milieu that might that the standard pain relief in rheumatic diseaseis an
deemphasize the sick-person role that contributes to the NSAID. Another explanation is that patients take NSAIDs
medicalization of patients. The choice of physical activ because of co-morbid osteoarthritis28. Tramadol, a weak
ity should be guided by patient preference to maintain -opioid receptor agonist with serotoninnoradrenaline-
compliance. Treatments that entirely depend on inter enhancing activity, has shown a modest effect on pain,
action with a health care professional should be limited but no changes in health-related quality of life (HRQOL),
to discourage the impression of passive dependency and was associated with an adverse effect profile similar
on health care. Some non-pharmacological treatments to other opioid agents124. With increasing concerns related
with large effect sizes, such as balneotherapy (water to adverse effects and negative impact on outcome, the
therapy) and magnetic cerebral stimulation, might not use of strong opioids is discouraged in fibromyalgia124,125.
be available to most patients and require further study Ifused in selected patients, treatment should begin with a
beforerecommendation116,122,123. weakeropioidagonists, such as tramadol, before stronger
opioids, which include morphine, hydromorphone and
oxycodone, are considered92. Nevertheless, 2550% of
Table 3 | Comparison of treatment recommendations of three guidelines all patients with fibromyalgia receive an opioid, with
Intervention Canada Germany Israel tramadol being prescribed for over 25% of patients125.
(level of evidence/ (level of evidence/ (level of evidence/ Antidepressants and anticonvulsants are the best-
strength of strength of strength of studied pharmacological treatment in fibromyalgia,
recommendation) recommendation) recommendation) with fewer studies of other drug classes, such as cannabi
Aerobic exercise Ia/A Ia/A Ia/A noids, dopamine agonists and hypnotics114. The absence
Amitriptyline Ia/A Ia/B Ia/A of studies for many drug categories can be explained by
Anticonvulsants Ia/A Ia/C Ia/A
the requirement for investigator-driven studies ofagents
(gabapentin and that are currently available for the treatment of other con
pregabalin) ditions, often without patent restrictions and, therefore,
Balneotherapy No comment Ia/B Ia/C with less incentive for the involvement of the pharma
ceutical industry. Antidepressant medications have been
Cognitive Ia/A Ia/A* Ia/A
behavioural the cornerstone of recommended pharmacological treat
therapy ments; these drugs increase serotonin and noradrenaline
levels and show effects on pain that are mainly independ
Multicomponent Ia/A Ia/A Ia/A
therapy ent of the effects on mood. A recent systematic review
provides support for the effect of pregabalin126, dulox
SNRIs (duloxetine Ia/A Ia/B or C Ia/A
and milnacipran) etine and milnacipran65. As these drugs have different
modes of action, combination therapy should be investi
SSRIs Ia/A Ia/C Neither positive gated in future research. Antidepressant medications are
nor negative
recommendation believed to act primarily by influencing the descending
pain modulatory system via molecules such as sero
Tramadol IIa/C No comment IIa/B
tonin and noradrenaline65. Cyclobenzaprine, which
The level of evidence according to the Canadian guideline in the order of the strength of is structurally analogous to tricyclic antidepressants,
recommendation93,106,107. Comparison of treatment recommendations of three guidelines from
REF.92. Ia: systematic review with meta-analysis of randomized controlled trials. IIa: one has sleep-promoting effects in low doses127. Low-dose
well-conducted randomized controlled trial. A: strong recommendation the intervention amitriptyline, a tricyclic antidepressant, has shown a
should be offered to most of the patients. B: recommendation the intervention can be offered
to the majority of patients. The intervention cannot be offered to a substantial minority of
favourable effect size for pain relief, sleep disturbance
patients. C: open recommendation the intervention can be offered to a minority of patients. and fatigue, but its use is limited by anticholinergic and
SNRI, serotoninnoradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor. antihistamine adverse effects, as well as the development
*Ifcombined with exercise. B in cases with a co-morbid depressive or generalized anxiety
disorder and C in cases without co-morbid depressive or generalized anxiety disorder. In cases of tachyphylaxis (adecrease in the effect after repeated
of only one randomized controlled trial with positive results, no recommendation was given. administration)127. Owing to the adverse effect profile of

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Table 4 | Health-related quality of life in large fibromyalgia studies
HRQOL measure Scale range n Score in fibromyalgia (SD) Refs
QALY 01* 2,575 0.56 (0.09) 138
EuroQol5D 01 2,733 0.61 (0.22) 140
SF36 PCS 0100 2,733 31.9 (9.6) 141
8,186 31.8 (8.8) 144
2,098 34.0 (7.3) 181
SF36 MCS 0100 2,733 41.9 (12.5) 140
8,186 41.6 (12.2) 144
2,098 37.3 (11.2) 181
HAQ 03 1,555 1.3 (0.6) 142
8,186 1.1 (0.6) 144
HAQ, Health Assessment Questionnaire; HRQOL, health-related quality of life; MCS, Mental
Component Summary; PCS, Physical Component Summary; QALY, quality-adjusted life year;
SF36, Short Form36 Health Survey. *0 represents death, 1 represents perfect health.
tricyclic antidepressants, other antidepressants includ
ing selective serotonin reuptake inhibitors (SSRIs) and
SNRIs have been studied. In a systematic review of 26
studies of amitriptyline, SSRIs and SNRIs, all agents, with
the exception of citalopram, showed a positive effect on
pain, with also some effect on fatigue, depression, sleep
and improved quality of life128. Subsequent studies have
reported that the effect size for pain reduction was most
evident for tricyclic antidepressants, with SSRIs and
SNRIs showing a smaller effect on pain and, in general,
a lesser effect on other core symptoms115,124. Overall,
severe adverse events related to antidepressants, espe
cially SNRIs, are rare, but 20% of patients discontinue
treatment owing to intolerance65.
Anticonvulsant medications dampen neuronal excit
ability both peripherally and centrally. Gabapentinoids
(second-generation anticonvulsants) have shown effi
cacy in the treatment of fibromyalgia, although with
small and clinically meaningful effect size126. Pregabalin
has shown to lead to a slight reduction of pain and sleep
problems but has limited effects on fatigue, depression,
anxiety and quality of life126. In clinical practice, lower
doses compared with clinical trials are used owing to
adverse effects of drowsiness, weight gain and oedema129.
Only a minority of patients report substantial benefits;
most will have moderate benefits. Studies as well as post-
marketing data65,124,126 indicate that there are few seri
ous adverse effects or drug interactions, but substantial
adverse effects lead to discontinuation of treatment or
failure to achieve optimaldoses.
Other drug categories that could be used in fibro
myalgia include cannabinoids, dopaminergic agents,
naltrexone, tranquilizers and 5hydroxytryptamine3
receptor antagonists. As herbal cannabinoid use is
controversial, the pharmaceutical preparation nabilone
might have some effect on pain and improved sleep130,131.
The dopaminergic agent pramipexole was associated
with improvement in pain in a small study, but its use
was tempered by gastrointestinal adverse effects132.
Memantine has shown efficacy for pain relief with a
number needed to treat of approximately six patients74.
In a single small study, the opioid antagonist naltrexone
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PRIMER
was superior to placebo for its effect on pain but not
for fatigue and sleep70. Agents that promote sleep in
fibromyalgia include zopiclone 133, low-dose cyclo
benzaprine127 and quetiapine134. Agents that have been
primarily used as anti-emetic drugs (against vomiting
and nausea) are the 5hydroxytryptamine3 recep
tor antagonists, with some preliminary evidence for
effect in fibromyalgia135. Sodium oxybate, which affects
hydroxybutyric acid receptors held promise for the
management of symptoms in fibromyalgia, but general
concerns about public safety have precluded approval by
licensing bodiesworldwide136.
As the efficacy of monotherapy is limited and most
patients use drug combinations, well-designed clinical
trials that explore drug combinations selected on the
basis of potential additive or synergistic effects should
be performed137.
Quality of life
As described above, fibromyalgia is defined as a col
lection of severe pain and physical and psychological
symptoms in the absence of an attributable pathological
cause4. This defines fibromyalgia as a state of diminished
HRQOL, which represents an inherent tautology. Unlike
with other diseases, inferences about fibromyalgia caus
ing reductions in HRQOL must be made cautiously, as
fibromyalgia cannot be both a cause and itseffect.
The amount of diminishment in HRQOL that fibro
myalgia represents is a vigorously studied and debated
topic. Many different scales have been used to estimate
how much diminishment in HRQOL fibromyalgia
represents in the clinical setting (TABLE4).
One way to consider the HRQOL burden of fibro
myalgia is to compare it to other diseases, using tools such
as the quality-adjusted life year (QALY) and the EuroQol
(EQ5D) scores. Both of these instruments score perfect
health as 1 and death as 0, which enables comparison
across diseases. In fibromyalgia, QALY scores have been
estimated to be 0.56 (REF.138) and EQ5D scores range
between 0.44 and 0.61 (REFS139,140). These scores tend
to be lower (more compromising of HRQOL) than the
scores generally seen with other rheumatic, somatic and
psychological disorders, such as inflammatory arthri
tis (0.66), lower back pain (0.630.79), gout (0.77),
osteoarthritis (0.70), IBS (0.66), migraine (0.81), meno
pause (0.73), depression (0.73) and neurotic disorders
(0.74)140,141. The reduction of HRQOL in fibromyalgia
approaches what is seen in blindness or low vision (0.69)
and renal failure (0.65)141. The experience of illness in
fibromyalgia seems to be comparably worse than most
other disorders.
The HRQOL burden of fibromyalgia can also be
considered from a population viewpoint. This has been
measured using HRQOL instruments that are normal
ized to the population, particularly the Short Form36
Health Survey (SF36). The SF36 scores the HRQOL of
the population mean as 50, with increments of 10 corres
ponding to a standard deviation from the population
mean. As shown in TABLE4, SF36 scores for the physical
component in patients with fibromyalgia range between
1.5 and 2 standard deviations below the population
PRIMER
mean (the bottom 510%), whereas scores for the mental
component are generally one standard deviation lower
(the bottom 33%). Those who experience fibromyalgia
report feeling considerably worse than a large majority
of the general population.
For patients with fibromyalgia, the experience of
low levels of HRQOL is stable over time. Although
both pharmacological and non-pharmacological
treatments have been shown to lead to modest ben
efits inHRQOL65,114,117, prospective population stud
ies show that HRQOL levels are generally stable and
far below population norms in fibromyalgia regardless
of therapy 142,143. However, this stability is somewhat
artificial. Symptom fluctuation is part of the expected
course of fibromyalgia. Meaningful improvements in
symptoms, typically defined as 2530% improve
ment in symptom measurements (such as the Visual
Analogue Scale for pain or the Fibromyalgia Impact
Questionnaire)144 have been shown to occur in 25% of
people with fibromyalgia. Conversely, symptom severity
worsened in 36% of individuals with fibromyalgia in the
same prospective study 142. Fibromyalgia seems to have
little effect on overall mortality, except for increases in
accidental deaths and suicide compared with the gen
eral population. The standardized mortality OR com
pared with the US general population was increased for
suicide(OR:3.31;95%CI:2.155.11) and for accidental
deaths (OR: 1.45; 95% CI: 1.022.06)145,146. The low level
of HRQOL associated with fibromyalgia has an impor
tant impact on health care use and disablement. Direct
and indirect health care costs of patients with fibromyal
gia are higher than those of matched peers and similar to
what is seen in other chronic diseases146150. Furthermore,
the rates of work disablement and receipt of disability
pensions are high in fibromyalgia149151, even when
compared with other chronic pain disorders13.
Although the aforementioned HRQOL estimates
describe fibromyalgia severity, they cannot be consid
ered immutable. Recently, it has been demonstrated that
fibromyalgia symptoms exist on a continuum of levels of
somatic and psychological symptom burden in popula
tions29. Moderate amounts of somatic and psychological
symptom burden that fall below what is calculated for
fibromyalgia occur in a sizable proportion of people29,152.
Furthermore, it has been shown that fibromyalgia symp
toms wax and wane considerably in diagnosed individuals
over time, enough that 44% of patients with fibromyalgia
did not fulfil the severity criteria of fibromyalgia at some
point during prospective observations142. Such observa
tions support a view of fibromyalgia as the severe tail-end
of a spectrum of symptoms that everyone experiences in
ever-shifting amounts, emphasizing the arbitrariness of
selecting a cut-off point for fibromyalgia95,153. These new
ideas are already influencing the academic discussion of
fibromyalgia. Ultimately, the level of symptom severity
that is considered to be fibromyalgia is governed by con
sensus and is susceptible to redefinition based on shifting
ideas in academic medicine. Thus, the decline in HRQOL
that fibromyalgia represents today might change over
time, with potential ramifications on diagnosis, health
care use, social benefits andentitlements154.
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Outlook
There is still much that is unknown and contested in
fibromyalgia. To some of the authors of this Primer,
fibromyalgia represents a disease or a discrete dysfunc
tion of human physiological processes. This perspective
is based on the interpretation of a wide array of physio
logical differences between individuals withfibro
myalgia symptoms and healthy people. To others,
fibromyalgia is simply a name given to the end of the
spectrum of frequently occurring and broadly defined
symptoms. This spectrum (called polysymptomatic dis
tress by some and fibromyalgia symptoms by others) can
be clearly demonstrated in epidemiological studies29,152
and ranges from a minor to a major medical problem.
The scientific search for answers to what fibromyalgia
is will hopefully provide greater insights into deeper
issues of what it means to be human. To fully understand
fibromyalgia will require an understanding of the seem
ingly dualistic biology that creates sensation and aware
ness, how our bodies, individual life events, personal
history and memories and society shape our sensory
experiences, and the potential and limitations of human
agency to change how our bodies feel. Despite its clinical
severity and obvious impact on the lives of the afflicted,
it remains possible that fibromyalgia is the result of the
essential, unknown principles that govern consciousness
and interoception rather than being caused by a particular
physiological dysfunction or a discrete medicaldisease91.
Clear answers to the question of the nature of fibro
myalgia will require scientific strategies that consider
the wide range of factors that potentially predispose
individuals to develop fibromyalgia and perpetuate the
symptoms. One such strategy that addresses complex
and polygenic psychological syndromes is the Research
Domain Criteria (RDoC) project at the US National
Institute of Mental Health (NIMH)153. This ambitious
project aims to create a framework for incorporating
genetics, neuroscience and behavioural science find
ings into the research classification of mental disorders.
Future research might adopt similar methodology to
better define the complex and interactional physiology
of fibromyalgia. Such an approach would also enable
exploration of concepts that do not fit gracefully into
the current pathophysiological hypotheses for fibro
myalgia, such as dysfunction of the stress response
system, circadian rhythm abnormalities, endocrine or
paracrine phenomena, inflammation and the effects of
environmental modulators (such as smoking, diet, physi
cal activity and adiposity). These research efforts could
also be applied across the full spectrum of somatic and
psychological symptom burden and in the setting of
other concomitant illnesses and diseases. When applied
to patients, this approach has the potential to address
concerns about the arbitrariness of the fibromyalgia
diagnosis. Symptomatic patients could be identified
in a matrix that incorporates all relevant data, without
requiring the need for a particular diagnostic label, and
treatment could by tailored accordingly. If successful, this
approach could bring an end to the fibromyalgia wars by
providing unbiased insight into the biological nature of
fibromyalgia. The meaning and importance of biological
 PRIMER

data in fibromyalgia will become clearer with time, but
our understanding and management will be improved if
we follow the science rather than guess at the meaning
of the science.
Until the answer to what fibromyalgia is avails itself,
physicians will be pressed to provide guidance about what
it means to have fibromyalgia symptoms and what can be
done to palliate them. It is essential to aid patients and
society in understanding that, despite its ambiguity, the
experience of fibromyalgia is common in both modern
and historic societies, is not caused by conscious choice
or desire to deceive and is not a neurological destiny
that is outside a persons ability to influence. Underlying
all consensus statements about treatment is the need for
physicians to educate and orient patients about their
problem, strengthen self-efficacy and personal respon
sibility for their care and habits, and provide treatments
to help patients manage both the daytoday variations of
their symptoms and the chronic issues that have the least
potential to causeharm.
Despite best intentions and the desire to advocate for
their patients, it is imperative for physicians to under
stand the potential harms and benefits of a fibromyalgia
diagnosis and the role of the physician in diagnosing
more people with fibromyalgia155. The objectives of
health economics are to limit overdiagnosis and mis
diagnosis, educate the health care community to curtail
excessive investigations and medicalization of patients
and to carefully contribute to the evidence-based evalu
ation of the concept of disability owing to fibromyalgia
in the developedworld.
Current studies demonstrate the difficulties of long-
term fibromyalgia care. Positive outcomes obtained
during non-pharmacological treatment are often lost in
the first 12months following the end of the interven
tion119,121. Poor patient adherence and engagement with
aftercare tasks in psychological treatments are problematic
and a challenge for clinicians and researchers. Clinical
trials of pharmaceutical agents frequently demonstrate
the ability to induce minimally important clinical differ
ences in pain at 3months of use8,65,115,128, but drug treat
ments have not been shown to be particularly effective or
maintained for extended periods of time when studied in
more general populations142. The development of treat
ments that benefit patients over their lifetime remains a
major challenge.
Physicians are continuing to innovate to respond to
these clinical challenges. New ways are being developed
to keep patients engaged with non-pharmacological
treatments. Mobile-based therapeutic approaches have
been recommended to improve access to evidence-
based, continued and integrated care156,157. Preliminary
evidence of the effectiveness of Internet-based cognitive
behavioural therapies and virtual reality suggests that
such approaches have promise158,159. Improving recogni
tion of specific risk factors that predispose to fibromyal
gia, as well as early clinical identification, might enable
behavioural andpharmacological intervention to reduce
severity and chronicity of symptoms. A readily available,
reliable and cost-effective biomarker or clinical tool for
use in making diagnoses and in measuring symptom
severity could have enormous clinical use. However, all
efforts to objectively quantify subjective symptoms have
fallen short to date. In the absence of such a test, the strat
egy of subgrouping patients on clinical characteristics and
directing treatments accordingly seems reasonable. The
development of tests and clinical tools to better predict
an individuals treatment response and drug tolerability
is an active area of pharmacological research.
What the future has in store for fibromyalgia is uncer
tain. However, it is clear that many people will continue to
experience severe and clinically invisible pain and aver
sive symptoms and that their plight cannot be ignored by
medicine, science or society.

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Acknowledgements
D. Clauw provided useful discussions and contributions to the
writing and editing process but chose not to be credited with
authorship. This manuscript was supported (in part) by the
Intramural Research Program of the US NIH, National Center
for Complementary and Integrative Health (NCCIH) and
Miguel Servet research contract awarded by the Institute of
Health Carlos III (CP14/00087; ISCIII, Madrid,Spain).
Author contributions
Introduction (W.H.); Epidemiology (W.H. and C.U.);
Mechanisms/pathophysiology (J.A. and B.W.); Diagnosis,
screening and prevention (G.L. and W.H); Management
(M.-A.F. and J.V.L.); Quality of life (B.W. and G.L); Outlook
(allauthors); overview of Primer (W.H.).
Competing interests
B.W., J.V.L. and C.U. declare no competing interests. J.A. has
received research funding and participated in educational
activity sponsored by Pfizer. M.-A.F. has received consulting
fees, speaking fees and/or honoraria from BioVale, Janssen,
Eli Lilly, Pfizer, Purdue and Valeant. W.H. received one
consulting fee from Daiichi Sankyo and honoraria for
educational lectures by Abbott, MSD, Sharp & Dohme and
Pfizer. G.L. has been involved in clinical trials for Pfizer
and EliLilly at Monash Health and received consulting and/
or speaking fees from Pfizer, Eli Lilly, Mundipharma,
Grnenthal, bioCSL and Pierre Fabre Medicament Australia.