REVIEWS

­ ibromyalgia: an update on clinical

F
characteristics, aetiopathogenesis
and treatment
Piercarlo Sarzi-Puttini   1 ✉, Valeria Giorgi   1, Daniela Marotto   2 and Fabiola Atzeni3
Abstract | Fibromyalgia is characterized by chronic widespread pain, fatigue, sleep disturbances
and functional symptoms. The etiopathogenesis, diagnostic criteria and classification criteria of
fibromyalgia are still debated and, consequently, so are the strategies for treating this condition.
Fibromyalgia is the third most frequent musculoskeletal condition, and its prevalence increases
with age. However, although diagnosis has improved with the evolution of more accurate diag­
nostic criteria, a considerable proportion of physicians still fail to recognize the syndrome.
Many factors contribute to the development of fibromyalgia in a unique manner: genetic pre­
disposition, personal experiences, emotional–cognitive factors, the mind–body relationship and
a biopsychological ability to cope with stress. The multiple components of the pathogenesis
and maintenance of the condition necessitate a multi-modal treatment approach. Individually
tailored treatment is an important consideration, with the increasing recognition that different
fibromyalgia subgroups exist with different clinical characteristics. Consequently, although an
evidence-based approach to fibromyalgia management is always desirable, the approach of
physicians is inevitably empirical, and must have the aim of creating a strong alliance with the
patient and formulating shared, realistic treatment goals.

Biopsychosocial model
of medicine
An interdisciplinary model
commonly used in the field of
chronic pain that incorporates
the interactions among bio­
logical factors (such as physio-
pathological factors), psychoso-
cial factors (that is, emotional
factors, such as distress or fear)
and behavioural factors.
1
Rheumatology Unit, ASST
Fatebenefratelli-Sacco, Luigi
Sacco University Hospital,
Milan, Italy.
2
Rheumatology Unit, ATS
Sardegna, Paolo Dettori
Hospital, Tempio Pausania,
Italy.
3
Rheumatology Unit,
Department of Internal and
Experimental Medicine,
University of Messina,
Messina, Italy.
✉e-mail: piercarlo.
sarziputtini@gmail.com
https://doi.org/10.1038/
s41584-020-00506-w
Fibromyalgia or fibromyalgia syndrome is one of the
most common causes of chronic widespread pain
(CWP), but, although pain is its main and distinguish-
ing feature, fibromyalgia is characterized by a complex
polysymptomatology that also comprises fatigue, sleep
disturbances and functional symptoms (that is, medical
symptoms not explained by structural or pathologically
defined causes). Fibromyalgia is quite a common con-
dition in the general population1,2; however, no consist-
ently effective treatments are yet available owing to a
lack of consensus regarding fibromyalgia diagnostic
and classification criteria and, especially, regarding
fibromyalgia aetiopathogenesis. Indeed, fibromyal-
gia has proven to be a mysterious syndrome and is an
interesting condition as far as philosophy of medicine
is concerned, because it falls outside the mechanistic
definition of disease3.
In this Review, we provide a comprehensive, critical
overview on the burden, diagnosis and treatment of
fibromyalgia, considering the latest research, guidelines
and clinical experience. We describe clinical aspects of
this syndrome, including the different diagnostic crite-
ria developed over time. We also bring together various
hypotheses of fibromyalgia aetiopathogenesis, keeping
in mind the biopsychosocial model of medicine and the
complex mind–body relationship. In particular, we
herein hypothesize that chronic pain and fibromyalgia
might rise both from a bottom-up (body periphery to
central nervous system) and a top-down (central nerv-
ous system to body periphery) mechanism, so that a
psychological pathogenic process (for example, trauma
or stress) can coexist with, but is not necessary for, a
physical pathogenic process (for example, an inflam-
matory or degenerative process). Finally, we discuss
fibromyalgia treatment, delving into the most effective
and the latest, most promising treatment strategies,
keeping in mind the importance of an individualized,
patient-centred perspective. We try to provide a novel
and practical management workflow for physicians,
based on clinical expertise and the latest EULAR criteria
for managing fibromyalgia4, to be used in their everyday
clinical practice.
Epidemiology
The reported prevalence of fibromyalgia varies depend-
ing on the diagnostic criteria used to define this condi-
tion. Studies using the 1990 ACR criteria have recorded
prevalence rates that range from 0.4% (Greece) to 8.8%
(Turkey), with a mean estimated global prevalence of
2.7%. The average worldwide female to male ratio for

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Key points
• Fibromyalgia is a fairly common syndrome in the general population, reaching a
prevalence of 2–3% worldwide.
• The complex polysymptomatology of fibromyalgia comprises not only chronic
widespread pain, fatigue and sleep alterations but also autonomic disturbances,
cognitive dysfunction, hypersensitivity to external stimuli, somatic symptoms and
psychiatric disorders.
• Owing to the subjectivity of the symptoms and the lack of biomarkers, diagnosis is
exquisitely clinical, and diagnostic criteria are constantly evolving; early diagnosis
and prevention are still elusive goals.
• Fibromyalgia severity and progression or improvement can be evaluated by means
of a plethora of composite tests.
• Fibromyalgia pathogenesis is not fully understood; hypotheses state that genetic
predisposition, stressful life events, peripheral (inflammatory) and central
(cognitive–emotional) mechanisms interplay to create pain dysperception owing
to neuromorphological modifications (‘nociplastic pain’).
• Treatment should be multimodal and built on four pillars (patient education; fitness;
pharmacotherapy; and psychotherapy); the approach should be individualized,
symptom-based and stepwise, establishing shared goals with the patient.
fibromyalgia is 3:1 (ref.1). One study of five European
countries (France, Portugal, Spain, Germany and Italy)5
estimated a general population prevalence of 4.7%.
However, these prevalence rates might vary by as much
as four times when considering subsequent criteria
sets2. Examples of the prevalence of fibromyalgia esti-
mated by different studies for various countries1,5–16 are
shown in Fig. 1.
Fibromyalgia is the third most common musculo-
skeletal condition in terms of prevalence, after lumbar
pain and osteoarthritis17. Prevalence is proportional to
the age of the population, peaking at 50–60 years old11.
However, these prevalence estimates might be inaccu-
rate: discrepancies exist between administrative data
(that is, rates reported by patients) and epidemiological
data (that is, data based on a diagnosis made by the phy-
sician)18, as a substantial proportion of physicians still
fail to recognize the syndrome.
The generally poor quality of life of patients with
fibromyalgia is reflected by the massive health-care costs
of patients, who frequently seek medical attention. The
annual number of consultations required is almost dou-
ble that of healthy individuals19, and total health-care
Paraesthesia costs are estimated to be three times higher for patients
A qualitative alteration of
the sensitivity of the skin
with fibromyalgia than for other individuals, as assessed
(which can be an abnormal by comparing costs among patients with those of a ran-
sensation of pricking, tingling dom population sample20. Indirect societal costs are also
and numbness). high, mainly because of lost working productivity21,22: one
study showed that 24.3% of the patients involved in the
Fibro-fog
A symptom of fibromyalgia
study stopped working 5 years after fibromyalgia onset23.
involving an inability to think
clearly or difficulties in Clinical features and diagnosis
concentrating. The symptoms of fibromyalgia
Raynaud phenomenon
Fibromyalgia is a complex, chronic pain condition that
A condition that causes primarily (but not only) involves the musculoskeletal
decreased blood flow to system. Unlike other rheumatic diseases, fibromyalgia
the extremities (such as the does not manifest by means of visible clinical signs: a
fingers, toes, ears and nose)
physical examination only reveals greater sensitivity
due to vasospasm; such
spasms occur in response to
to pressure at some specific points (‘tender points’),
cold, stress or emotional although these regions tend to be more tender than other
upset. regions in most individuals, regardless of whether they
have fibromyalgia24. Fibromyalgia symptomatology is
summarized in Fig. 2. In this section, we provide a brief
description of each symptom.
Cardinal features. In fibromyalgia, pain can affect the
whole body from head to toe. Patients with fibromyal-
gia use a plethora of pain descriptors, and their pain is
often described as being similar to neuropathic pain25:
20–30% of patients report paraesthesia in the limbs,
hands or trunk, which is commonly described as a tin-
gling sensation or pins-and-needles26. The type, location
and severity of pain depends on a number of modulating
factors, the most important of which are working activ-
ities, comorbidities (such as obesity27) and variations in
temperature28,29. Physical or mental stress is also a known
factor associated with worsening pain22,30.
The other two most frequent symptoms of fibromyal-
gia are fatigue and sleep disturbances31–33. Fatigue might
be physical or mental. The degree of fatigue varies widely
from mild tiredness to a state of exhaustion similar to
that experienced during viral diseases such as influenza.
Sleeping problems include any type of insomnia or fre-
quent awakenings. Non-restorative sleep is especially
preponderant and, even if the quality and duration of
sleep is normal, patients with fibromyalgia often report
the feeling of not having had enough rest31,32.
Other common features. Cognitive dysfunction (espe-
cially ‘fibro-fog’) and memory deficits are among the
more severe symptoms of patients with fibromyalgia33.
Depression, anxiety, pain or sleeping problems can all
have a negative effect on cognitive symptoms, but they
do not entirely explain all the cognitive symptoms of
patients with fibromyalgia34.
Patients with fibromyalgia often complain about
many other clinical symptoms involving almost all
organs and systems, the severity of which varies from
patient to patient and within each patient during the
syndrome course35. Idiopathic, regional pain syndromes
are particularly common. Headache with or without a
history of migraine is very frequent, and the reverse
is also true, with fibromyalgia being frequent among
individuals who have episodic migraines36. Dyspepsia,
abdominal pain and alternating constipation and diar-
rhoea are also common symptoms, and might be part of
a full-blown irritable bowel syndrome37. Many patients
experience genitourinary disorders (such as urinary
urgency in the absence of urinary tract infections38,
dysmenorrhoea or vulvar vestibulitis, which leads to
difficulties in sexual intercourse39). Another frequent
symptom is stiffness33,40, although morning stiffness does
not usually exceed 60 min.
Autonomic disturbances manifest in all body areas
and correlate with the severity of the condition41,42.
Patients can report a subjective feeling of dry mouth
(xerostomia) and eyes (xerophthalmia), blurred vision
and photophobia, and Raynaud phenomenon 43. Over
30% of patients develop lower limb discomfort and a
need to move their legs continuously (restless legs syn-
drome)44–46. Patients with fibromyalgia often report a
feeling of instability or staggering as well, especially after
standing upright for prolonged periods47.
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Canada 3.3%

Denmark 0.7%

France, Italy,
Germany, Spain, Japan 2.1%
Portugal 2.9–4.7%

Italy 3.6%
USA 6.4% Turkey 8.8%

Hong Kong 0.8%

Lebanon 1%

Tunisia 9.3% Israel 2–2.6%

Brazil 2.5%

Criteria and/or questionnaire Country or region Study Total prevalence (%)

1990 ACR Hong Kong Scudds et al. (2006)13 0.8

Denmark Prescott et al. (1993)15 0.7

Italy Salaffi et al. (2005) 16
3.6
Turkey Turhanoglu et al. (2008)8 8.8
The 2010 ACR criteria Japan Nakamura et al. (2014) 7
2.1
USA Vincent et al. (2013)12 6.4
LFESSQ Israel Ablin et al. (2012)14
LFESSQ-4: 2.6
LFESSQ-6: 2.0
France, Italy, Germany, Branco et al. (2009)5 LFESSQ-4: 4.7
Spain and Portugal LFESSQ-6: 2.9
COPCORD Brazil Rodrigues Senna et al. (2004)10 2.5

LFESSQ and the 1990 ACR criteria Canada White et al. (1999)11 3.3
Tunisia* Guermazi et al. (2008) 9
9.3
COPCORD and the 1990 ACR criteria Lebanon Chaaya et al. (2011) 6
1
World Queiroz (2013)1 2.7

Fig. 1 | estimated prevalence of fibromyalgia in different regions using different diagnostic criteria or questionnaires.
The prevalence of fibromyalgia has been estimated in different regions worldwide using various diagnostic criteria and
questionnaires, such as the London Fibromyalgia Epidemiology Study Screening Questionnaire (LFESSQ; shown in light
green), the Community Oriented Program for the Control of Rheumatic Diseases (COPCORD; shown in dark green), the
ACR 1990 classification criteria (shown in blue) and the ACR 2010 diagnosis criteria (shown in red). It should be noted
that direct comparisons of the prevalence in different regions cannot be made owing to the use of different assessment
methodologies. *Individuals with a positive screening test were invited for examination to confirm or exclude the presence
of fibromyalgia by applying the 1999 ACR criteria.

Psychologically, patients with fibromyalgia are
characterized by a preponderant negative affect, that
is, the presence of negative emotions associated with
a generalized distress state48. This state of psycholog-
ical suffering can accompany full-blown psychiatric
disorders, which are frequent in patients with fibro-
myalgia and can notably affect the lives of the patients
and even the severity of the syndrome49. The lifetime
prevalence of anxiety disorders in patients with fibro-
myalgia is 60%, and depression is observed in 14–36%
of patients compared with 6.6% of healthy individuals50.
In a Danish population of patients with fibromyalgia, the
risk of suicide was ten times higher than in the general
population51, which was confirmed by a subsequent sys-
tematic review52. However, depressive symptoms are not
reported more frequently for patients with fibromyalgia
than for patients with other painful conditions such as
rheumatoid arthritis or cancer, and might be related to
maladaptive coping with psychological distress30.
Diagnostic criteria
Ongoing research has so far led to the publication of
at least five different sets of classification and diagnos-
tic criteria for fibromyalgia over the past 30 years or so
(a summary is shown in Table 1). The earliest criteria
sets described fibromyalgia as a CWP disorder with

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various associated symptoms53, but the 1990 ACR clas-
sification criteria43 only considered CWP (defined as
pain on the left and right sides of the body, above and
below the waist, and axial skeletal (cervical or thoracic
spine, anterior chest or low back) pain), and tenderness
(defined as pain upon the palpation of ≥11 out of 18 ten-
der point sites), and did not include other symptoms or
exclusion criteria. However, the requirement of a tender
point examination (which is examiner dependent and
intrinsically intra-individually and inter-individually
variable) made the 1990 ACR criteria impractical for
use in a clinical setting. The subsequent 2010 and 2011
ACR criteria54,55 changed the definition of fibromyalgia
to that of a multi-symptom disorder and removed the
tender point examination as a diagnostic requirement;
however, although the criteria returned to considering
the associated symptoms as important, there was perhaps
too little emphasis on the core symptom of chronic pain.
The 2016 revisions to the 2010/2011 ACR diagnostic
criteria56 highlighted the concept of ‘generalized pain’,
which also lies at the heart of the ACTTION-APS Pain
Taxonomy diagnostic criteria published in 2018 (ref.40).
In developing these criteria, the Fibromyalgia Working
Group concentrated on generalized pain (defined as
multi-site pain), sleeping problems and fatigue, but
also considered other supportive diagnostic features
such as cognitive disturbances, tenderness to the touch,
musculoskeletal stiffness and environmental sensitivity
(for example, sensitivity to cold, light or noise) with the
aim of providing more practical criteria.
The central problem and barrier to fibromyalgia
diagnosis is a lack of biomarkers. Researchers over the
past 5 years have investigated new molecules that might
help diagnosis and monitoring (including microRNA,
and proteome and metabolome analysis), but, although
the results have been promising, this area of research is
still in its infancy57.
In brief, the diagnosis of fibromyalgia is exquisitely
clinical. A physical examination is not diagnostically use-
ful because of its poor validity and poor reproducibility18,
but is essential for excluding other diseases that might
explain the presence of pain and fatigue. Fibromyalgia has
no pathognomonic feature, and so diagnostic clues have
to be collected by means of thorough history taking18.

Psychiatric symptoms Cognitive dysfunctions Sleep disturbances

• Anxiety • Concentration • Insomnia
• Depression difficulties • Frequent awakening
• Post-traumatic stress • Memory deficits • Non-restoring sleep
disorder

Autonomic disturbances
• Blurred vision, photophobia
and xerophthalmia
• Feeling of instability
Pain • Xerostomia
• Variations in responses
• Generalized to cold at the extremities
(head-to-toes) (including Raynaud
• Described in terms phenomenon)
of neuropathic pain, • Orthostatic hypotension
paraesthesias
Fatigue
• Physical
• Mental Regional pain syndromes
• Migraine or headache
• Stomach ache or dyspepsia
• Abdominal pain or
irritable bowel syndrome
• Dysmenorrhoea
• Vulvodynia
• Dysuria

Hypersensitivity to external
stimuli
Stiffness • Hypersensitivity to light,
• Morning stiffness not odours and sounds
exceeding 60 min • Chemical sensitivity

Cardinal features Other common features

Fig. 2 | Principal fibromyalgia symptoms. Fibromyalgia has a complex symptomatology. Symptoms can be are divided in
two groups: cardinal features (shown in pink), which include the most characteristic fibromyalgia symptoms that are
pivotal for a diagnosis according to the latest criteria, and other common features (shown in in grey).

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Table 1 | the evolving classification and diagnostic criteria for fibromyalgia

Criteria set measures of pain tender associated symptoms Diagnosis or classification Ref.
points
ACR 1990 Widespread pain noted as pain in all Yes (≥11 None included Widespread pain and at least 11 43

classification four quadrants (both the left and right out of tender points for at least 3 months
criteria side of the body, above and below the 18)
waist); plus axial skeletal pain (pain in
the cervical spine or anterior chest or
thoracic spine or low back)
ACR 2010 Use of WPI: a 0–19 count of the body No Various symptoms included WPI ≥7 and SSS ≥5; or WPI 3–6 55

preliminary regions reported as painful by the in an SSS, a score of the sum
diagnostic criteria patient over the past weeka of severity of three symptoms
(fatigue, waking unrefreshed,
cognitive symptoms) plus
somatic symptoms in general (on
a 0–12 scale)
ACR 2011 Use of WPI: a 0–19 count of the body No Various symptoms included
and SSS ≥9
Symptoms present at a similar
level for at least 3 months
The patient does not have a
disorder that would otherwise
explain the pain
WPI ≥7 and SSS ≥5; or WPI 3–6 54

modifications regions reported as painful by the in an SSS, a score of the sum and SSS ≥9
of the ACR patient over the past weeka of severity of three symptoms
Symptoms present at a similar
preliminary (fatigue, waking unrefreshed,
level for at least 3 months
diagnostic criteria cognitive symptoms) plus
(designed for the sum of the number of the The patient does not have a
epidemiological following symptoms occurring disorder that would otherwise
and clinical during the previous 6 months: sufficiently explain the painc
studies, and not headaches, pain or cramps in the The criteria also include a
for clinical lower abdomen and depression fibromyalgia severity score (the
diagnosis)b (on a 0–12 scale) sum of WPI plus SSS), which is
a quantitative measurement of
fibromyalgia severity
2016 revisions to Generalized pain defined as pain in No Various symptoms included WPI ≥7 and SSS ≥5; or WPI 4–6 56

the 2010/2011 at least 4 out of 5 regions (left upper
ACR fibromyalgia region, right upper region, left
diagnostic criteria lower region, right lower region and
axial region). Pain in the jaw, chest
and abdomen are not evaluated as
part of the generalized pain definition
Use of WPI: a 0–19 count of the body
regions reported as painful by the
patient over the past weeka
AAPT core Use of MSP: a 0–9 count of the
in an SSS, a score of the sum
of severity of three symptoms
(fatigue, waking unrefreshed,
cognitive symptoms) plus
the sum of the number of the
following symptoms occurring
during the previous 6 months:
headaches, pain or cramps in the
lower abdomen and depression
No Moderate to severe sleep
and SSS ≥9
The presence of generalized pain
Symptoms have been present at a
similar level for at least 3 months
A diagnosis of fibromyalgia is valid
irrespective of other diagnoses
and does not exclude the
presence of other illnesses
MSP ≥6 40

diagnostic criteria number body sites reported as painful problems or moderate to severe
Moderate to severe sleep
for fibromyalgia (the sites consisting of the head, right fatigue
problems or fatigue
arm, left arm, chest, abdomen, upper
back and spine, lower back and spine Symptoms have been present for
(including buttocks), left leg and at least 3 months
right leg)
AAPT, ACTTION-American Pain Society Pain Taxonomy; MSP, multisite pain; SSS, Symptom Severity Score; WPI, Widespread Pain Index. aRegions assessed by the
WPI: left shoulder girdle, right shoulder girdle, left hip (buttock or trochanter), right hip (buttock or trochanter), left jaw, right jaw, upper back, lower back, left
upper arm, right upper arm, left upper leg, right upper leg, chest, neck, abdomen, left lower arm, right lower arm, left lower leg and right lower leg. bThis
modification enabled the use of these criteria in epidemiological and clinical studies without the requirement for an examiner (but should not be used for
self-diagnosis). cNote that the 2011 criteria are based on the possibility of self-administration of the questionnaires.

Screening tools established risk factors (see the section on hypothetical

Some routine screening tools have been developed to
help general practitioners to identify those patients who
are most at risk of developing fibromyalgia. These tools
include the Fibromyalgia Rapid Screening Tool, which
consists of six general questions58, and the FibroDetect
test59, which covers pain and all fibromyalgia-influenced
domains, as well as the patient’s attitude and history.
The Simple Fibromyalgia Screening Questionnaire was
also validated as a useful screening tool in 2019 (ref.60).
General practitioners could take advantage of these tools
to detect patients with or even at risk of fibromyalgia, so
that they can refer the patient to a specialist.
Prevention, as well as very early fibromyalgia diagno-
sis, remains an elusive goal, mainly owing to the lack of
pathogenic mechanisms). In addition, insufficient data
are available on the effect of early diagnosis on clinical
progression; nonetheless, early recognition could enable
the commencement of non-pharmacological approaches,
such as psychotherapy or physical reconditioning, at an
early stage and prevent the need for pharmacological
treatments, therefore limiting adverse effects.
Patient assessment
The assessment of fibromyalgia should be holistic and
not only consider all of the symptoms experienced by
patients but also alleviating or aggravating factors and
the effect of fibromyalgia on everyday life, functional
status and working ability. This approach is crucial for

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Nociplastic pain
A clinical definition of
pain arising from altered
nociception, despite no
evidence of tissue damage
causing the activation of
nociceptors or evidence
of disease or lesions of the
somatosensory system causing
the pain.
Central sensitization
A neurophysiological process
of pain amplification in the
central nervous system; this
process occurs physiologically
after injuries to elicit a
protective behaviour and
maximize the healing process.
Hyperalgesia
A condition in which a painful
stimulus is perceived as being
even more painful.
Allodynia
A condition in which a normal
stimulus is perceived as being
painful.
Temporal summation
The perception of repetitive
noxious stimulation as being
increasingly painful.
establishing treatment goals that are shared by patients
and their physicians.
The presence and severity of fibromyalgia symptoms
(such as sleep disturbances, fatigue, cognitive and somatic
symptoms) in the general population usually follow a
bell-shaped curve61. This variation means that the diag-
nosis of the syndrome is completely arbitrary and involves
the dichotomization of a continuum often referred to
as ‘fibromyalgianess’62, a scale that can essentially be
interpreted as the likelihood of having fibromyalgia63,64.
Using various scales to assess fibromyalgia in individual
patients is important not only to discover the degree of
‘fibromyalgianess’ or severity of the condition but also
to establish a baseline against which improvement can be
assessed during follow-up. These assessments need to
be reliable, easy to use, and validated in clinical practice,
but, most importantly, they should take into account the
multidimensional nature of chronic pain65.
Fibromyalgia and CWP can be assessed using vali­
dated single and composite tests66. The most widely
used tests include the Fibromyalgia Impact Question­
naire (FIQ)67 and its revised version (FIQR)68,69, the
Fibromyalgia Assessment Status (FAS)70,71, the Fibro­
myalgia Survey Criteria (FSC)72 and the Patient Health
Questionnaire 15 (PHQ15)73. Various studies have
hypothesized the level of fibromyalgia activity that can
be considered remission for each questionnaire (<39 for
the FIQ, <12 for the FSC and <5 for the PHQ15)67,70,73,
but the target of clinical improvement should be an
improvement in function from the patient’s point of view.
Hypothetical pathogenic mechanisms
Pain
An important symptom of fibromyalgia is chronic
widespread musculoskeletal pain. Generally speaking,
pain can be divided into three categories: nociceptive,
neuropathic and nociplastic pain74. Physiologically, pain
functions as an alarm system that warns the body of the
presence of a potentially harmful situation, known as
‘nociceptive pain’. In some situations, pain loses its func-
tion as an alarm signal, such as when pain persists after
the end of the original stimulus or when pain is started by
a stimulus that is completely innocuous. Such pain can
be caused by real damage to the nervous system, known
as ‘neuropathic pain’, or by mostly reversible modifica-
tions to the nervous system, known as ‘nociplastic pain’.
In the latter case, the changes increase the sensitivity
of the control system that usually decides which stim-
uli should be interpreted as painful and which should
not. This type of pain is in line with the description of
fibromyalgia as part of the nosological group of central
sensitivity syndromes75. Clinically, fibromyalgia has
many of the features of central sensitization (also known
as central hyperactivation)76,77: hyperalgesia, allodynia78,
temporal summation79,80 and hypersensitivity to various
external stimuli such as sounds or lights81–83.
Nociplastic pain in fibromyalgia
Over the past 20 years, researchers have identified neuro-
biological features that correlate with fibromyalgia noci-
plastic pain84. Emerging evidence suggest that diffuse
pain processing in the brain is altered in fibromyalgia,
as indicated by increased activation in areas of the brain
dedicated to pain (that is, patients with fibromyalgia
require less pressure than healthy individuals to show the
same level of brain activity)85–89, altered connectivity90 and
a reduction in brain activity associated with visual cues
that signal an imminent painful stimulus (pain antici-
pation) or its imminent end (anticipatory analgesia)91.
Various studies have shown that the functional activation
and connectivity of endogenous pain inhibitory signals
are altered in patients with fibromyalgia (meaning that
there is an imbalance between the various nociceptive
and anti-nociceptive systems)92–95. Furthermore, patients
with fibromyalgia have less grey matter in the cortical
and subcortical areas involved in processing nociceptive
stimuli, particularly at the level of the cingulate cor-
tex, frontal orbit and insula96, than healthy individuals,
although whether these alterations causally precede the
experience of CWP and hypersensitivity is unclear.
This imbalance between the nociceptive and
anti-nociceptive systems also subsists at a microscopic
level. Increased levels of substance P (a neurotransmitter
that mediates pain facilitation, especially temporal sum-
mation) have been detected in the cerebrospinal fluid of
patients with fibromyalgia compared with that in healthy
individuals97. Patients with fibromyalgia also have a
lower μ-opioid receptor availability in regions of the
brain involved in pain modulation (including the nucleus
accumbens, the amygdala and the dorsal cingulate) and
higher levels of opioids in the cerebrospinal fluid than
healthy individuals98,99. In keeping with the hypoactiv-
ity of the descending analgesic pathways during fibro-
myalgia, the levels of noradrenergic and serotoninergic
neurotransmitters in the biological fluid of patients with
fibromyalgia are lower than in healthy individuals100,101,
and brain dopaminergic activity during painful stimula-
tion is attenuated102,103. Finally, hypersensitivity might be
mirrored by an excess of excitatory neurotransmitters in
brain areas important for pain modulation104,105.
Identifying the cause of these nociplastic alterations is
difficult, but what is clear is that fibromyalgia is unlikely
to have a single aetiology. Genetic background seems to
have a fundamental role, as patients with fibromyalgia
often report a family history of chronic pain and stud-
ies have identified notable familial clustering of fibro-
myalgia or muscle tenderness106–108, as well as various
polymorphisms in genes of the nociceptive pathway
that are associated with fibromyalgia109,110. In addition
to this genetic substrate, a variety of other peripheral
and central mechanisms also have a role. The relative
contribution and relationship among these pathogenic
mechanisms is represented in Fig. 3.
Peripheral mechanisms
Painful stimuli coming from the periphery might ini-
tiate or reinforce the nociplastic process, and the fact
that some of these peripheral sources of pain could
originate from the joints might explain both the higher
prevalence of fibromyalgia among patients with rheu-
matic diseases111,112 and the beneficial effects of extensive
treatment of rheumatic conditions such as osteoarthritis
on fibromyalgia symptoms113. In addition to peripheral
sources of pain (such as joint inflammation), alterations
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Central nervous system an association between fibromyalgia and traumas or

abuse121–123. Patients with fibromyalgia might indeed
• Activation of pain areas have reduced levels of resilience and effective coping
• Altered brain connectivity • Low resilience
• ↓ Pain inhibitory signals and strategies30. This low resilience is strikingly reflected by
• Maladaptive stress coping
paradoxical stimulation • Sleep alterations the low heart rate variability (HRV) of these patients
• ↓ Noradrenaline, 5HT, • Depression and anxiety (HRV is a powerful indicator of sympathetic versus para­
dopamine and opioid • Autonomic alterations
receptors • Genetic factors
sympathetic activation of the autonomic nervous sys­
• ↑ Substance P and excitatory tem in response to environmental demands)124–126. An
neurotransmitters (such as interesting hypothesis is that the sympathetic autonomic
glutamate)
nervous system is hyper-active but also hypo-reactive
in fibromyalgia, blunting the response to stressors.
Top Bottom Altered activation of the autonomic nervous system
down up (dysautonomia) could be the cause of many fibromyalgia
symptoms, such as balance disturbances and episodes
Body periphery (sensory neurons, joints, viscera and immune cells) of low blood pressure127. Low HRV is associated with
neuromorphological alterations128 that are also present
• Neuroinflammation in patients with fibromyalgia, including the presence of
Peripheral sensitization • Small fibre neuropathy low-density grey matter in the cingulate cortex128,129. In
(↓ nociceptive threshold) • Peripheral nociceptive stimuli
or any chronic painful disease addition, a low level of resilience is associated with an
• Genetic factors increased probability of developing post-traumatic stress
disorder, anxiety or mood disorders, which are very prev-
alent in the fibromyalgia population130. As the develop-
Nociplastic alterations Pathogenic mechanisms ment of resilience-based strategies is an important factor
in treating such disorders131,132, implementing resilience
Fig. 3 | hypothesized interplay between potential pathogenic mechanisms and and coping strategies might be a promising means of
nociplastic alterations in fibromyalgia. The aetiology of fibromyalgia and the underlying
treating fibromyalgia and chronic pain in general133.
cause of fibromyalgia-related nociplastic alterations are not fully understood. Interplay
between various mechanisms, including genetic predisposition, stressful life events and
peripheral (inflammatory) and central (cognitive–emotional) mechanisms, are thought to Cognitive factors. Far from being a solely sensory expe-
lead to neuromorphological modifications (‘nociplastic pain’) and pain dysperception. This rience, pain is a mental state that necessarily involves
figure illustrates the potential interplay between various pathogenic mechanisms (shown educational, social and cognitive factors, in line with
in grey boxes) and major nociplastic alterations (shown in red boxes). These pathogenic the increasingly recognized biopsychosocial model of
mechanisms influence nociplastic alterations in a causal fashion, but the opposite is also medicine134. Maladaptive coping styles when facing
thought to be true (for example, heightened pain perception negatively influences sleep). adverse situations (for example, a low level of self-
A reciprocal aetiopathogenic relationship might also occur between the central nervous efficacy, hypervigilance to pain stimuli, avoidance and
system and the periphery of the body, which occurs in a both bottom-up and top-down catastrophizing ) can dysfunctionally modulate pain
fashion: the former is mainly inflammatory and algesic, whereas the latter is mainly
and affect the intensity of subjective pain and a patient’s
psychological and cognitive-emotional. 5HT, 5-hydroxytryptamine.
general health, as well as increasing activation in pain-
related areas of the brain135–139. This mechanism can be
Dysaesthesia in the peripheral nervous system could also be involved. referred to as cognitive–emotional sensitization to pain.
An unpleasant abnormal Researchers have attempted to explain fibromyalgia An additional complication is that patients with
sensation (that can be dysaesthesia in terms of small fibre dysfunction, and fibromyalgia more frequently have psychological alter-
spontaneous or evoked)
that is usually associated with
a number of studies have identified the presence of ations that might escalate to full-blown psychiatric
irritation or injury to a sensory small fibre neuropathy (fibre loss and reduced axonal disorders140. Depression is highly prevalent in patients
nerve or nerve root. diameter) in patients with fibromyalgia114, although with fibromyalgia, but is also a common denominator
this finding might not be specific to fibromyalgia115. of other chronic painful conditions141. Determining
Small fibre neuropathy
Moreover, an emerging hypothesis is that immune sys- whether these alterations come with the condition,
Damage to small myelinated
(type Aδ) nerve fibres or tem activation is capable of modulating the excitability of precede the condition, or are secondary to the condi-
unmyelinated C peripheral nociceptive pathways116 as a result of what has been called tion, can be difficult. The relationship between pain and
nerve fibres; these small neuro-inflammation. This hypothesis was first postu- depression seems to be bidirectional: chronic depression
somatic fibres have sensory lated on the basis of the detection of pro-inflammatory can induce central sensitization and thus lower the noci-
functions including thermal
perception and nociception.
substances and organ-specific and non-specific autoan- ceptive threshold, and chronic pain can be associated
tibodies in the serum of patients with fibromyalgia117,118. with mood changes that can lead to a depressive state142.
Dysautonomia Some researchers have long argued that infections might Moreover, among the different symptoms of depression
An umbrella term used to trigger fibromyalgia, as fibromyalgia is more prevalent (affective, cognitive and somatic symptoms), the somatic
describe several different
among individuals infected with hepatitis C virus, HIV symptoms often overlap with the physical symptoms of
medical conditions that cause
a malfunction of the autonomic or Borrelia burgdorferi, although the findings are not many chronic dysfunctional pain syndromes (headache,
nervous system. convincing119,120. low back pain and visceral pain)143.

Catastrophizing Central mechanisms Sleep. The bilateral connection between fibromyalgia

An exaggerated amplification
of emotional aspects that leads
individuals to consider pain
terrible and intolerable.
Coping with stress. Many patients with fibromyalgia and psychological alterations might also be true for sleep
associate stressors with the onset and exacerbations of alterations144. CWP disrupts sleep in a vicious circle that
their condition33, and multiple studies have reported involves the autonomic nervous system145, but the quality

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of sleep is also causally related to pain severity146,147.
A 1975 study was the first to show that people with fibro-
sitis (an old term for fibromyalgia) experience objective
sleep disturbances and that the same symptoms can be
induced in sleep-deprived healthy individuals148. Since
this initial study, clinical trials have shown that improv-
ing the quality of sleep by means of pharmacological or
non-pharmacological treatment can reduce pain and
fatigue in patients with fibromyalgia144. Furthermore,
some evidence suggests the existence of a bidirectional
relationship between sleep disturbances and anxiety
or depression149, and data from a large population-
based study in Norway suggest that poor sleep quality
predisposes adolescents to mental illnesses150.
Treatment
Many factors contribute to the development of fibro-
myalgia in a unique manner61: genetic predisposition,
personal experiences, emotional–cognitive factors,
mind–body relationship 151 and a biopsychological
ability to cope with stress. In this sense, fibromyalgia
can be seen as a condition that represents a mind–
body hyper-connection, rather than a mind–body
disconnection3. Consequently, fibromyalgia treatment
needs to be holistic and comprehensive. Indeed, the
therapeutic approach to managing patients with fibro-
myalgia is characterized by integrated and multidis-
ciplinary interventions152. In this section, we describe
the various interventions available for the manage-
ment of fibromyalgia. We propose that the treatment
of fibromyalgia can be divided into four pillars: patient
education, fitness, pharmacological treatment and
psychotherapy (Fig. 4). Our suggested treatment strat-
egy, shown in Fig. 4, takes into account not only the
latest EULAR recommendations for fibromyalgia
management4 but also real-life clinical experience and
realistic patient expectations and goals. Indeed, we sug-
gest starting pharmacological treatment straightaway,
mainly because patients are usually diagnosed years
after symptom onset153.

Diagnosis of fibromyalgia

Patient CBT, hypnosis Antidepressant Physical activity,

education and/or relaxation (duloxetine or weight loss and
techniques milnacipram) or a nutritional
(according to anticonvulsant programme
the patient’s needs) and
analgesic
(paracetamol)

Lack of efficacy (patient reassessment)

CBT, hypnosis A different Physical activity, Any type of

and/or relaxation antidepressant or weight loss and complementary
techniques anticonvulsant a nutritional intervention that
(according to and/or programme is useful for the
the patient’s needs) analgesic and/or patient (such as
muscle relaxant acupuncture
New modalities or TENS)
(such as
hyperbaric
oxygen therapy or Lack of efficacy (patient reassessment)
neurostimulation)

CBT, hypnosis Cannabinoids Physical activity,

and/or relaxation or weak opioids weight loss and
techniques (tramadol) a nutritional
(according to programme
the patient’s needs)

Patient education Psychotherapy Pharmacotherapy

Patient education and fitness Additional options

Fig. 4 | Proposed treatment strategy for fibromyalgia. Our proposed therapeutic flowchart for managing patients
with fibromyalgia is shown, which was built on the basis of scientific literature (discussed in the main text), the latest
EULAR recommendations4 and real-life clinical experience. The main difference between this flowchart and the EULAR
recommendations is that herein we start with both pharmacological and non-pharmacological treatments simultaneously
(the EULAR recommendations has a sequential workflow, rather than a parallel workflow, that begins with non-
pharmacological treatment) and follow the ‘four pillar concept’ described in the text (patient education (grey),
psychotherapy (dark green), pharmacotherapy (light green) and fitness (blue)). The main idea is that all treatment pillars
should be applied from the beginning of fibromyalgia management, and that if there is a lack of efficacy of one approach
(mainly the pharmacological therapy), the treatment approach should be modified according to the patient’s needs.
This scheme should not be rigidly applied in clinical practice, but rather should always be individualized according to
patients’ needs and preferences. CBT, cognitive-behavioural therapy; TENS, transcutaneous electric nervous stimulation.

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Patient education
An important step in managing patients with fibromyalgia
is ensuring that the patients understand their illness before
they are prescribed any medications154–157. It is crucial to
reassure patients that fibromyalgia is a real pathological
condition and to legitimize their suffering, making it clear
that, although disabling, the condition is not progres-
sive and is not due to peripheral tissue damage. Patients
should also be told that they will have a predominant role
in fibromyalgia management, and should develop their
own particular techniques and approaches to maximize
their quality of life. This approach is paradigmatic of
the ‘self-management’ approach that should be used in the
case of any chronic condition. Moreover, as stress, mood
and sleep disturbances have an important role in fibro-
myalgia, patients should be encouraged to learn good
sleep hygiene and relaxation techniques, and take part in
formal stress reduction programmes, including psychi-
atric consultations if necessary. Importantly, patients can
be encouraged to continue non-pharmacological meas-
ures on the basis of their individual needs as long as the
interventions do not cause any harm. Pharmacological
treatment might be helpful in relieving some symptoms,
but patients rarely improve substantially without adopting
these core self-management strategies154,158.
Fitness
The latest EULAR recommendations on fibromyal-
gia management stress the importance of first using
non-pharmacological measures in fibromyalgia manage-
ment, but the only ‘strong’ recommendation is in favour
of exercise4. As in the case of other chronic conditions,
fitness is pivotal and should involve weight loss, aerobic
and strengthening exercises as well as dietary modifi-
cations, all of which are important disease-modifying
factors4. Weight loss improves posture and well-being,
and decreases both obesity-induced inflammation and
peripheral nociceptive inputs159. Aerobic exercise is
strongly recommended as it can improve pain and phys-
ical function in patients with fibromyalgia160, although
the commencement of training can be difficult for some
patients because of deconditioning and psychological
factors161. The recommended optimal cardiovascular
fitness training consists of a minimum of 20 min of aero­
bic exercise three times a week4. Regarding nutrition,
although patients with fibromyalgia might have a higher
rate of nutritional deficiencies or incorrect dietary reg-
imens than the general population162, no precise diet or
vitamin integration is recommended, as no clear data are
available on the correct nutritional protocol163.
Pharmacological treatment
Pharmacotherapy should be aimed at analgesia in
a mechanism-oriented fashion164. In line with this
approach, centrally acting medications can be effec-
tive in fibromyalgia, particularly antidepressants
and anticonvulsants155, which increase the presence
of pain-inhibitory neurotransmitters by facilitating
descending pathways and decreasing dorsal horn sen-
sitization, or decreasing systemic hyperexcitability155.
Herein, we discuss commonly prescribed drugs
for fibromyalgia that have the most consistent and
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largest amount of evidence. These drugs, along with
their associated adverse effects, are listed in Table 2.
Antidepressants. Systematic literature reviews and
meta-analyses suggest that the antidepressant amitrip-
tyline is quite effective at treating fibromyalgia, espe-
cially for reducing pain and fatigue165,166, although most
of the studies reviewed were old and had methodologi-
cal limitations167. The mean number of patients needed
to treat to achieve a 30% pain reduction was four4,165.
Interestingly, amitriptyline was found to also have a
moderate effect on sleep and a slight effect on fatigue165.
Both duloxetine and milnacipran have proved to be
more effective than placebo in treating fibromyalgia
pain and are FDA-approved for fibromyalgia, although
the incremental benefit is small and these drugs do not
have any effect on other fibromyalgia symptoms168. Data
from one systematic review169 indicate that, in the case
of duloxetine, the number needed to treat is eight169
and, importantly, that this drug improves pain severity
regardless of the presence of a comorbid major depres-
sive disorder. However, adverse effects can lead to drop-
outs, which have ranged from 9% to 23% in short-term
studies, and from 11.4% to 27.2% in long-term studies167,
but these adverse effects can be limited by using a slow
dose-titration approach. It should also be noted that the
results of a randomized controlled trial of milnacipran170
were unfavourable in terms of pain modulation, global
pain, mechanical and thermal thresholds, allodynia,
cognition and tolerance.
Anticonvulsants. Anticonvulsants have been exten-
sively investigated for fibromyalgia treatment171. Among
the gabapentinoids, the benefits of gabapentin are
uncertain172, whereas the results of various meta-analyses
suggest that pregabalin is effective and safe for some
patients with fibromyalgia173–175. Pregabalin is currently
the only anticonvulsant that has been approved by the
FDA for fibromyalgia, although adverse effects are
frequent, particularly dizziness171.
Muscle relaxants. Cyclobenzaprine is structurally related
to tricyclic antidepressants but is approved as a muscle
relaxant; this drug improves pain and the quality of life
(especially sleep) of patients with fibromyalgia, but not
fatigue176. Tizanidine is an α2 receptor agonist that has
anxiolytic, analgesic and sedative properties177, has been
used for the treatment of myofascial pain disorders178
and can be of help in fibromyalgia179.
Analgesic drugs. The role of opioids in the treatment
of fibromyalgia is limited180. Patients with fibromyal-
gia have altered endogenous opioid activity, with little
opioid receptor availability but high concentrations
of opioid peptides in biological fluids98,99, which might
explain why opioids are generally not very effective and
naltrexone (an opioid receptor antagonist that also has
antagonist effects on non-opioid receptors and can have
neuroprotective and analgesic effects) was hypothesized
to be of some benefit181,182. Therefore, opioids are gen-
erally avoided, not least because of their unfavourable
risk-to-benefit profile183. The only opioid that has proved
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Table 2 | Commonly prescribed drugs for fibromyalgia treatment and their adverse effects
Drug Class of drug FDa-approved adverse effects169,174,184,187,203,239–242
drugs for
fibromyalgia
Antidepressants
Duloxetine SNRI Yes243 Nausea, palpitations, headache, fatigue,
Milnacipran SNRI Yes246 tachycardia, insomnia, xerostomia, constipation
and serotonin syndromea(Refs244,245)
Amitriptyline Tricyclic antidepressant No Xerostomia, constipation, weight gain, urinary
retention, sedation and serotonin syndromea
Anticonvulsants
Pregabalin GABAergic drug Yes247 Sedation, dizziness, vertigo, asthenia, nausea and
Gabapentin GABAergic drug No weight gain
Muscle relaxants
Cyclobenzaprine Serotoninergic muscle No Nausea, palpitations, headache, fatigue,
relaxant xerostomia, constipation and serotonin syndromea
Tizanidine α2 receptor agonist No Dizziness, asthenia, xerostomia, vomiting,
constipation, liver test abnormalities, bradycardia,
hypotension and blurred vision
Analgesic drugs
Tramadol Weak opioid and SNRI No Constipation, nausea, vomiting, dizziness, fatigue,
headache, itching and xerostomia
Paracetamol Analgesic and antipyretic No Nausea, vomit, constipation and liver disease
drug
Hypnotic drugs
Zolpidem GABAergic and No Dizziness, headache, somnolence, confusion,
non-benzodiazepine agitation, abdominal pain, constipation and
hypnotic drug xerostomia
Antipsychotic drugs
Quetiapine Atypical antipsychotic drug No Somnolence, headache, dizziness, extrapyramidal
symptoms, weight gain, dyslipidaemia,
hyperglycaemia, xerostomia, vomiting and nausea,
and constipation
Cannabis or cannabinoids
Nabilone Pure cannabinoid No Drowsiness, dizziness, nausea, xerostomia,
(tetrahydrocannabinol) confusion, anxiety and tachycardia
Cannabis Phytopharmaceutical No Drowsiness, dizziness, nausea, xerostomia, blurred
(different concentrations of vision, increased/decreased appetite, vertigo,
tetrahydrocannabinol and tachycardia and hypotension
cannabidiol)
All these drugs target neurotransmitters, and their classification is based on the disease for which they were initially approved (for
example, antidepressants for depression). The adverse effects of anticonvulsants are dose dependent, whereas the adverse effects
of antidepressants depend on the metabolism of the individual. Treatment with a combination of antidepressants should be
avoided owing to the risk of serotonin syndrome. SNRI, serotonin–norepinephrine reuptake inhibitor. aA potentially
life-threatening syndrome characterized by the combination of mental status alteration (such as agitation, anxiety, disorientation
and excitement), neuromuscular hyperactivity (such as tremors, hyperreflexia, muscle rigidity and clonus) and autonomic
hyperactivity (such as vomiting, diarrhoea, hypertension and tachycardia, and mydriasis).

to be effective in patients with fibromyalgia is trama-
dol, alone or combined with paracetamol4. Tramadol
functions as a weak agonist of µ-opioid receptors and
as a serotonin–norepinephrine reuptake inhibitor
(SNRI). Substantial evidence suggests that traditional
analgesic drugs such as paracetamol and non-steroidal
anti-inflammatory drugs are not effective in treating
fibromyalgia184, but these drugs are fundamental for
treating concomitant peripheral forms of pain such as
osteoarthritic pain because peripheral nociceptive inputs
can promote central sensitization185.
Hypnotic and antipsychotic drugs. Benzodiazepines and
other hypnotic drugs, such as zolpidem, can be used
in the short term to improve sleep, but tend not to be
efficacious for fibromyalgia pain4,186.
Quetiapine has been so far the most frequently stud-
ied antipsychotic drug for fibromyalgia. A Cochrane
review187 suggested that this drug shows some benefit
in treating fibromyalgia-related pain, sleep problems,
depression and anxiety, but, owing to the low quality of
evidence of the trials, this drug should only be taken
for a short period of time for fibromyalgia treatment.
Interestingly, one trial comparing amitriptyline with
quetiapine showed no difference between the two drugs
in terms of their ability to reduce various symptoms in
patients with fibromyalgia, including pain, fatigue, sleep
problems, anxiety and depression188.
Cannabis and cannabinoids. The cannabis plant is very
different from pure, synthetic cannabinoids, insofar
as it contains about 100 different active cannabinoids,

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among which tetrahydrocannabinol (THC) and can-
nabidiol (CBD) are the most relevant and most fre-
quently studied. Most trials have investigated nabilone,
a semi-synthetic THC analogue that is ten times more
potent than THC itself189. One Cochrane review190 does
not recommend the use of nabilone to treat fibromyal-
gia. The proper use of pure cannabinoids, if any, is still to
be defined. By contrast, cannabis has proved to be mod-
erately effective in the treatment of a number of chronic
non-cancer pain conditions191–193, and for this reason it
was hypothesized that it could be beneficial for fibro-
myalgia as well194–196. The effectiveness of preparations
with different THC to cannabidiol ratios is still under
investigation197–199, and well-conducted randomized
clinical trials are still needed; however, a US National
Pain Report survey of the efficacy of three drugs duly
approved for fibromyalgia in comparison with that of
cannabis had 1,300 respondents and proved favourable
towards cannabis200.
Drug combinations and sequences. In brief, there is no
gold standard pharmacological treatment for fibromy-
algia. Maximum doses of a single drug are rarely used
because of safety concerns201. Moreover, single drugs
tend to have a clinically relevant effect in fewer than
half of the treated patients202. Therefore, a combination
of drugs is usually preferred using a patient-centred,
symptom-based stepwise approach202 that has inev-
itably prevented any specific recommendation con-
cerning which type of combined treatment should be
used203. However, empirical evidence, and our own
experience, suggest that treatment should be started
with an SNRI antidepressant, followed by one of the
anticonvulsants for patients who respond inadequately
or cannot tolerate antidepressants. An SNRI or an anti-
convulsant could be beneficial for patients with severe
fatigue, depression, or a severe sleep disturbance. The
efficacy and safety of combinations of anticonvulsants
and antidepressants have been investigated in various
studies204–206.
Psychotherapy
Cognitive-behavioural therapy is the most widely
studied and practised psychotherapy for fibromyalgia.
This approach is aimed at helping patients to identify
condition-related maladaptive thoughts to develop
effective coping strategies and behaviour. Developing
effective coping strategies is particularly important in
a condition such as fibromyalgia because dysfunctional
pain modulation is a fundamental factor in exacerbating
and protracting pain (as discussed earlier). In a system-
atic review207, the investigators concluded that patients
who received cognitive-behavioural therapy (including
acceptance-based cognitive-behavioural therapy) might
have shown greater improvements in pain, physical
functioning and mood than patients receiving usual care,
on the waiting list, or being treated with other active,
non-pharmacological methods. Cognitive-behavioural
therapy might be particularly useful in patients with
fibromyalgia as this intervention teaches effective cop-
ing strategies that can be used on a long-term basis,
which is very useful in the case of a chronic condition.
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Investigations along these lines have begun in the past
year, and one non-controlled study found promising
results 1 year after the start of treatment208. Ensuring
greater access to treatment (perhaps by means of the
Internet) will probably be the next step209.
Other non-pharmacological treatments
Non-pharmacological treatments include a wide range
of interventions that are usually referred to as ‘comple-
mentary’ or ‘alternative’ therapies. A 2014 meta-analysis
suggested that the magnitude of the multidimensional
effect of these approaches can exceed that of pharma-
cological treatments for fibromyalgia210. However, the
benefit of these inventions is still an area of contro-
versy, as the study designs are often weak and the qual-
ity of the evidence is usually low. Nevertheless, various
non-pharmacological therapies are included in the
EULAR recommendations for the management of fibro-
myalgia, and non-pharmacological treatments might at
least be considered as adjunctive, if not the core, treat-
ment for many patients4. Non-pharmacological or alter-
native measures can be introduced depending on the
limitations of cost, availability and patient preference.
Some of the most frequently used non-pharmacological
treatments are briefly described below.
Spa therapy. Spa therapy consists of multiple methods
that are based on the curative effects of thermal water
and include balneotherapy, mud packs and hydrother-
apy. These approaches have been used empirically since
ancient times to treat a wide range of conditions211.
If available and affordable to the patient, hot thermal
baths are an option for some patients and are particu-
larly popular in many European countries. Hot thermal
baths are thought to improve various fibromyalgia symp-
toms (for example, they have been shown to moderately
decrease pain, improve the patients’ health-related qual-
ity of life212–214 and also have a small effect on mood)212.
Balneotherapy might even be considered as a first-line
treatment together with patient education and aerobic
exercise215: the mechanism of action of this approach
is still a matter of discussion but probably involves
an interplay of many hormonal, inflammatory and
cognitive-emotional factors216.
Tai chi, qigong and yoga. Tai chi, qigong and yoga are
forms of alternative exercises or ‘meditative move-
ment therapies’ that have been increasingly adopted by
patients with fibromyalgia. These exercises are based on
physical movement integrated with mental relaxation
and breathing techniques, and two meta-analyses217,218
have indicated that these approaches can be efficacious
and safe in treating fibromyalgia. The results suggested
that the fibromyalgia symptoms of sleep, fatigue, depres-
sion, pain and the quality of life all improved, although
the poor quality of the studies did not enable any defi-
nite conclusions to be drawn. The effect of tai chi has
also been investigated in another meta-analysis219, which
found that this approach had a notable positive effect on
many aspects of the patients’ lives, and that tai chi could
become a promising alternative to conventional exercise
by possibly attracting less compliant patients220.
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Mindfulness. Mindfulness is based on the principle of
the non-judgemental acceptance of one’s condition,
thoughts and suffering. This approach is different from
cognitive-behavioural therapy insofar as it does not
address any particular maladaptive behaviour or thought,
but rather endorses a general view of coping with dif-
ficulties. The difference between these two techniques
was investigated in a randomized controlled trial, the
results of which suggested that mindfulness techniques
were more effective than cognitive-behavioural therapy
in improving various symptoms of fibromyalgia221.
Recognizing that nothing is intrinsically positive or
negative might be particularly helpful for patients with
fibromyalgia whose condition has a preponderant cata-
strophizing or negative emotional component, as mind-
fulness and acceptance-based interventions seem to have a
small to moderate effect on many aspects of the syndrome,
including pain, depression, anxiety, sleep and the quality
of life222,223. However, although the results achieved so far
are promising, the effects are still uncertain because of the
poor quality of evidence provided by the individual stud-
ies. An interesting new approach called acceptance and
commitment therapy can be seen as an intermediate form
between cognitive-behavioural therapy and mindfulness.
Two studies224,225 found that acceptance and commitment
therapy can lead to a greater improvement in functional
status in patients with fibromyalgia compared with usual
care and pharmacological treatment, thus confirming the
importance of the mind–body connection.
Hypnosis. In the past 3 years, hypnosis has captured the
interest of the scientific community as an increasing
number of studies have shown its efficacy in targeting
chronic pain226. One systematic review from 2017 high-
lighted the potential of hypnosis as a possible treatment
for patients with fibromyalgia as this approach not only
improved pain and sleeping problems at the end of the
sessions (across a study duration ranging between 8, 12,
14 and 26 weeks), but also after 3 months of follow-up227.
However, more methodologically valid studies are
needed, as the quality of evidence is still poor.
Acupuncture. Acupuncture is frequently sought by
patients with fibromyalgia and is (albeit weakly) recom-
mended by EULAR because of the moderate quality of the
evidence in the literature4. Two meta-analyses228,229 have
underlined its efficacy in improving stiffness and pain,
although whether and how acupuncture differs in terms
of efficacy from sham (random) acupuncture is unclear.
Other modalities. Physical-agent modalities use differ-
ent forms of energy such as thermal energy (for example
thermotherapy and cryotherapy) and electric energy (for
example electrotherapy) that are passively administered
to patients. In 2018, a meta-analysis214 provided evi-
dence that transcutaneous electrical nerve stimulation,
electromagnetic therapy and, most importantly, thermal
therapy have positive effects on pain and the quality of
life (as measured using the FIQ) of patients with fibro-
myalgia, although the overall quality of the evidence
was poor. Researchers have speculated that these effects
are caused by changes in local inflammatory reactions,
pain thresholds and perceptions214. Various studies
have also investigated hyperbaric oxygen therapy230,231
and neurostimulation232. Hyperbaric oxygen therapy
facilitates oxygen delivery to the peripheral tissues by
increasing the partial pressure of oxygen in the arterial
system, decreasing the expression of pro-inflammatory
mediators233. Neurostimulation, operated by means of
electrical or magnetic currents (transcranial electri-
cal stimulation and transcranial magnetic stimulation,
respectively) at the level of the primary motor cortex,
seems to be a promising treatment232. A 2019 structured
review234 suggested that direct current stimulation is
effective in modulating fibromyalgia pain, although the
data suggested that it has less effect on cognitive and
affective symptoms, and the length of time that the
effects lasted was unclear. Notably though, one study
suggested that the reduction in pain and other symp-
toms of fibromyalgia (fatigue and quality of life-related
aspects) induced by monthly transcranial magnetic
stimulation could be maintained for at least 6 months235.
Conclusions
The exponential number of clinical and other research
studies on fibromyalgia in the rheumatic field and other
biomedical fields reflects the interest recently aroused by
fibromyalgia, even though the real nature of this condi-
tion has not yet been completely clarified. After a century
of unsuccessful research aimed at identifying alterations
in the structures in which pain is perceived (the skin,
muscles and tendons), the most interesting findings
from the past 2–3 years concern the mechanisms under-
lying pain perception and the body’s response to stress-
ful situations. Techniques such as functional MRI of the
brain have shown that chronic pain is related to changes
in the sensitivity to and processing of stimuli through-
out the nociceptive system89, and are beginning to reveal
the neurophysiological signature of fibromyalgia236.
The finding of induced peripheral receptor sensitiza-
tion in situations of psychological stress supports the
hypothesis that chronic pain is a result of interactions
between neurophysiological factors (neuroplasticity)
and socio-environmental stressors, and reflects the
increasingly recognized importance of the biopsycho-
social model of medicine in relation to fibromyalgia and
chronic pain conditions in general237. The multiple com-
ponents of the pathogenesis and maintenance of the syn-
drome mean that multi-modal treatment is necessary,
and non-pharmacological approaches can have a pivotal
role4. Within this framework, the concept of an individ-
ually tailored treatment is preponderant in fibromyalgia.
Therefore, it is difficult to interpret the results of ran-
domized controlled trials that enrol a random sample
of the fibromyalgia population and measure average
treatment effectiveness, and such results might actually
be misleading given the potential existence of various
subgroups of patients with fibromyalgia with different
clinical characteristics. Being patient-centred, the thera-
peutic approach will inevitably be empirical238, although
evidence-based, and should adopt therapeutic goals that
are shared between the patient and the physician.
Published online xx xx xxxx
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Author contributions
P.S.-P., V.G. and D.M. wrote the article. P.S.-P. and F.A. sub-
stantially contributed to discussion of content. P.S.-P., V.G.,
D.M. and F.A. researched data for the article and reviewed
and edited the manuscript before submission.
Competing interests
The authors declare no competing interests.
Peer review information
Nature Reviews Rheumatology thanks M.-A. Fitzcharles,
G. Littlejohn and the other, anonymous, reviewer(s) for their
contribution to the peer review of this work.
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