REVIEWS ­ ibromyalgia: an update on clinical F characteristics, aetiopathogenesis and treatment Piercarlo Sarzi-Puttini 1 ✉, Valeria Giorgi , Daniela Marotto 1 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 physiopathological factors), psychosocial 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. [email protected] 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 distinguishing 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 condition in the general population1,2; however, no consistently effective treatments are yet available owing to a lack of consensus regarding fibromyalgia diagnostic and classification criteria and, especially, regarding fibromyalgia aetiopathogenesis. Indeed, fibromyalgia 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 criteria developed over time. We also bring together various hypotheses of fibromyalgia aetiopathogenesis, keeping in mind the biopsychosocial model of medicine and the Nature Reviews | Rheumatology 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 nervous 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 inflammatory 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 depending on the diagnostic criteria used to define this condition. 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 Reviews 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. Paraesthesia A qualitative alteration of the sensitivity of the skin (which can be an abnormal sensation of pricking, tingling and numbness). Fibro-fog A symptom of fibromyalgia involving an inability to think clearly or difficulties in concentrating. Raynaud phenomenon A condition that causes decreased blood flow to the extremities (such as the fingers, toes, ears and nose) due to vasospasm; such spasms occur in response to cold, stress or emotional upset. 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 estimated by different studies for various countries1,5–16 are shown in Fig. 1. Fibromyalgia is the third most common musculoskeletal 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 inaccurate: discrepancies exist between administrative data (that is, rates reported by patients) and epidemiological data (that is, data based on a diagnosis made by the physician)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 double that of healthy individuals19, and total health-care costs are estimated to be three times higher for patients with fibromyalgia than for other individuals, as assessed by comparing costs among patients with those of a random population sample20. Indirect societal costs are also high, mainly because of lost working productivity21,22: one study showed that 24.3% of the patients involved in the study stopped working 5 years after fibromyalgia onset23. Clinical features and diagnosis The symptoms of fibromyalgia Fibromyalgia is a complex, chronic pain condition that primarily (but not only) involves the musculoskeletal system. Unlike other rheumatic diseases, fibromyalgia does not manifest by means of visible clinical signs: a physical examination only reveals greater sensitivity to pressure at some specific points (‘tender points’), although these regions tend to be more tender than other 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 fibromyalgia 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 tingling 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 activities, 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 fibromyalgia 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 frequent 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 (especially ‘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 diarrhoea 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 syndrome)44–46. Patients with fibromyalgia often report a feeling of instability or staggering as well, especially after standing upright for prolonged periods47. www.nature.com/nrrheum Reviews Canada 3.3% Denmark 0.7% France, Italy, Germany, Spain, Portugal 2.9–4.7% Japan 2.1% 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) 3.6 Turkey Turhanoglu et al. (2008)8 8.8 The 2010 ACR criteria 16 Japan Nakamura et al. (2014) 2.1 USA Vincent et al. (2013)12 6.4 Israel Ablin et al. (2012) LFESSQ-4: 2.6 LFESSQ-6: 2.0 France, Italy, Germany, Spain and Portugal Branco et al. (2009)5 LFESSQ-4: 4.7 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) 9.3 Lebanon Chaaya et al. (2011) 1 World Queiroz (2013)1 2.7 LFESSQ COPCORD and the 1990 ACR criteria 7 14 9 6 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 psychological suffering can accompany full-blown psychiatric disorders, which are frequent in patients with fibromyalgia 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 fibromyalgia 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 Nature Reviews | Rheumatology population51, which was confirmed by a subsequent systematic 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 diagnostic 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 Reviews various associated symptoms53, but the 1990 ACR classification 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 tender 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). Psychiatric symptoms • Anxiety • Depression • Post-traumatic stress disorder 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 useful 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. Cognitive dysfunctions • Concentration difficulties • Memory deficits Sleep disturbances • Insomnia • Frequent awakening • Non-restoring sleep Autonomic disturbances • Blurred vision, photophobia and xerophthalmia • Feeling of instability • Xerostomia • Variations in responses to cold at the extremities (including Raynaud phenomenon) • Orthostatic hypotension Pain • Generalized (head-to-toes) • Described in terms of neuropathic pain, 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 • Hypersensitivity to light, odours and sounds • Chemical sensitivity Stiffness • Morning stiffness not exceeding 60 min 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). www.nature.com/nrrheum Reviews Table 1 | the evolving classification and diagnostic criteria for fibromyalgia Criteria set measures of pain ACR 1990 classification criteria Widespread pain noted as pain in all four quadrants (both the left and right side of the body, above and below the waist); plus axial skeletal pain (pain in the cervical spine or anterior chest or thoracic spine or low back) Use of WPI: a 0–19 count of the body ACR 2010 regions reported as painful by the preliminary diagnostic criteria patient over the past weeka tender points Ref. Widespread pain and at least 11 tender points for at least 3 months 43 No Various symptoms included in an SSS, a score of the sum of severity of three symptoms (fatigue, waking unrefreshed, cognitive symptoms) plus somatic symptoms in general (on a 0–12 scale) WPI ≥7 and SSS ≥5; or WPI 3–6 and SSS ≥9 55 Various symptoms included 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 (on a 0–12 scale) WPI ≥7 and SSS ≥5; or WPI 3–6 and SSS ≥9 Various symptoms included 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 WPI ≥7 and SSS ≥5; or WPI 4–6 and SSS ≥9 Moderate to severe sleep problems or moderate to severe fatigue MSP ≥6 No 2016 revisions to the 2010/2011 ACR fibromyalgia diagnostic criteria No Use of WPI: a 0–19 count of the body regions reported as painful by the patient over the past weeka Use of MSP: a 0–9 count of the AAPT core diagnostic criteria number body sites reported as painful (the sites consisting of the head, right for fibromyalgia arm, left arm, chest, abdomen, upper back and spine, lower back and spine (including buttocks), left leg and right leg) Diagnosis or classification Yes (≥11 None included out of 18) ACR 2011 Use of WPI: a 0–19 count of the body modifications regions reported as painful by the of the ACR patient over the past weeka preliminary diagnostic criteria (designed for epidemiological and clinical studies, and not for clinical diagnosis)b Generalized pain defined as pain in at least 4 out of 5 regions (left upper region, right upper region, left 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 associated symptoms No Symptoms present at a similar level for at least 3 months The patient does not have a disorder that would otherwise explain the pain 54 Symptoms present at a similar level for at least 3 months The patient does not have a disorder that would otherwise sufficiently explain the painc The criteria also include a fibromyalgia severity score (the sum of WPI plus SSS), which is a quantitative measurement of fibromyalgia severity 56 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 40 Moderate to severe sleep problems or fatigue Symptoms have been present for at least 3 months 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 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 diagnosis, remains an elusive goal, mainly owing to the lack of Nature Reviews | Rheumatology established risk factors (see the section on hypothetical 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 Reviews 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 diagnosis 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. 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. 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 function 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 modifications 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 stimuli 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 neurobiological features that correlate with fibromyalgia nociplastic 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 anticipation) 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 cortex, 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 summation) 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 hypoactivity of the descending analgesic pathways during fibromyalgia, 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 stimulation 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 studies have identified notable familial clustering of fibromyalgia 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 initiate 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 rheumatic 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 www.nature.com/nrrheum Reviews Central nervous system • Activation of pain areas • Altered brain connectivity • ↓ Pain inhibitory signals and paradoxical stimulation • ↓ Noradrenaline, 5HT, dopamine and opioid receptors • ↑ Substance P and excitatory neurotransmitters (such as glutamate) • Low resilience • Maladaptive stress coping • Sleep alterations • Depression and anxiety • Autonomic alterations • Genetic factors Top down Bottom up Body periphery (sensory neurons, joints, viscera and immune cells) • Neuroinflammation • Small fibre neuropathy • Peripheral nociceptive stimuli or any chronic painful disease • Genetic factors Peripheral sensitization (↓ nociceptive threshold) Nociplastic alterations Pathogenic mechanisms Fig. 3 | hypothesized interplay between potential pathogenic mechanisms and nociplastic alterations in fibromyalgia. The aetiology of fibromyalgia and the underlying 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 lead to neuromorphological modifications (‘nociplastic pain’) and pain dysperception. This figure illustrates the potential interplay between various pathogenic mechanisms (shown in grey boxes) and major nociplastic alterations (shown in red boxes). These pathogenic mechanisms influence nociplastic alterations in a causal fashion, but the opposite is also thought to be true (for example, heightened pain perception negatively influences sleep). A reciprocal aetiopathogenic relationship might also occur between the central nervous system and the periphery of the body, which occurs in a both bottom-up and top-down fashion: the former is mainly inflammatory and algesic, whereas the latter is mainly psychological and cognitive-emotional. 5HT, 5-hydroxytryptamine. Dysaesthesia An unpleasant abnormal sensation (that can be spontaneous or evoked) that is usually associated with irritation or injury to a sensory nerve or nerve root. Small fibre neuropathy Damage to small myelinated (type Aδ) nerve fibres or unmyelinated C peripheral nerve fibres; these small somatic fibres have sensory functions including thermal perception and nociception. Dysautonomia An umbrella term used to describe several different medical conditions that cause a malfunction of the autonomic nervous system. Catastrophizing An exaggerated amplification of emotional aspects that leads individuals to consider pain terrible and intolerable. an association between fibromyalgia and traumas or abuse121–123. Patients with fibromyalgia might indeed have reduced levels of resilience and effective coping strategies30. This low resilience is strikingly reflected by the low heart rate variability (HRV) of these patients (HRV is a powerful indicator of sympathetic versus para­ sympathetic activation of the autonomic nervous sys­ tem in response to environmental demands)124–126. An interesting hypothesis is that the sympathetic autonomic nervous system is hyper-active but also hypo-reactive in fibromyalgia, blunting the response to stressors. Altered activation of the autonomic nervous system (dysautonomia) could be the cause of many fibromyalgia symptoms, such as balance disturbances and episodes of low blood pressure127. Low HRV is associated with neuromorphological alterations128 that are also present in patients with fibromyalgia, including the presence of low-density grey matter in the cingulate cortex128,129. In addition, a low level of resilience is associated with an increased probability of developing post-traumatic stress disorder, anxiety or mood disorders, which are very prevalent in the fibromyalgia population130. As the development of resilience-based strategies is an important factor in treating such disorders131,132, implementing resilience and coping strategies might be a promising means of treating fibromyalgia and chronic pain in general133. in the peripheral nervous system could also be involved. Researchers have attempted to explain fibromyalgia dysaesthesia in terms of small fibre dysfunction, and a number of studies have identified the presence of small fibre neuropathy (fibre loss and reduced axonal diameter) in patients with fibromyalgia114, although this finding might not be specific to fibromyalgia115. Moreover, an emerging hypothesis is that immune system activation is capable of modulating the excitability of nociceptive pathways116 as a result of what has been called neuro-inflammation. This hypothesis was first postulated on the basis of the detection of pro-inflammatory substances and organ-specific and non-specific autoantibodies in the serum of patients with fibromyalgia117,118. Some researchers have long argued that infections might trigger fibromyalgia, as fibromyalgia is more prevalent among individuals infected with hepatitis C virus, HIV or Borrelia burgdorferi, although the findings are not convincing119,120. Cognitive factors. Far from being a solely sensory experience, pain is a mental state that necessarily involves educational, social and cognitive factors, in line with the increasingly recognized biopsychosocial model of medicine134. Maladaptive coping styles when facing adverse situations (for example, a low level of selfefficacy, hypervigilance to pain stimuli, avoidance and catastrophizing ) can dysfunctionally modulate pain and affect the intensity of subjective pain and a patient’s general health, as well as increasing activation in painrelated areas of the brain135–139. This mechanism can be referred to as cognitive–emotional sensitization to pain. An additional complication is that patients with fibromyalgia more frequently have psychological alterations that might escalate to full-blown psychiatric disorders140. Depression is highly prevalent in patients with fibromyalgia, but is also a common denominator of other chronic painful conditions141. Determining whether these alterations come with the condition, precede the condition, or are secondary to the condition, can be difficult. The relationship between pain and depression seems to be bidirectional: chronic depression can induce central sensitization and thus lower the nociceptive threshold, and chronic pain can be associated with mood changes that can lead to a depressive state142. Moreover, among the different symptoms of depression (affective, cognitive and somatic symptoms), the somatic symptoms often overlap with the physical symptoms of many chronic dysfunctional pain syndromes (headache, low back pain and visceral pain)143. Central mechanisms Coping with stress. Many patients with fibromyalgia associate stressors with the onset and exacerbations of their condition33, and multiple studies have reported Sleep. The bilateral connection between fibromyalgia and psychological alterations might also be true for sleep alterations144. CWP disrupts sleep in a vicious circle that involves the autonomic nervous system145, but the quality Nature Reviews | Rheumatology Reviews of sleep is also causally related to pain severity146,147. A 1975 study was the first to show that people with fibrositis (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 improving 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 populationbased study in Norway suggest that poor sleep quality predisposes adolescents to mental illnesses150. 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 fibromyalgia is characterized by integrated and multidisciplinary interventions152. In this section, we describe the various interventions available for the management 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 strategy, 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 suggest starting pharmacological treatment straightaway, mainly because patients are usually diagnosed years after symptom onset153. Treatment Many factors contribute to the development of fibromyalgia in a unique manner61: genetic predisposition, personal experiences, emotional–cognitive factors, mind–body relationship 151 and a biopsychological Diagnosis of fibromyalgia Patient education CBT, hypnosis and/or relaxation techniques (according to the patient’s needs) Antidepressant (duloxetine or milnacipram) or anticonvulsant and analgesic (paracetamol) Physical activity, weight loss and a nutritional programme Lack of efficacy (patient reassessment) CBT, hypnosis and/or relaxation techniques (according to the patient’s needs) New modalities (such as hyperbaric oxygen therapy or neurostimulation) A different antidepressant or anticonvulsant and/or analgesic and/or muscle relaxant Physical activity, weight loss and a nutritional programme Any type of complementary intervention that is useful for the patient (such as acupuncture or TENS) Lack of efficacy (patient reassessment) CBT, hypnosis and/or relaxation techniques (according to the patient’s needs) Patient education Patient education and fitness Cannabinoids or weak opioids (tramadol) Psychotherapy Additional options Physical activity, weight loss and a nutritional programme Pharmacotherapy 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 nonpharmacological 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. www.nature.com/nrrheum Reviews 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 progressive 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 fibromyalgia, patients should be encouraged to learn good sleep hygiene and relaxation techniques, and take part in formal stress reduction programmes, including psychiatric consultations if necessary. Importantly, patients can be encouraged to continue non-pharmacological measures 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 fibromyalgia management stress the importance of first using non-pharmacological measures in fibromyalgia management, 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 modifications, 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 physical 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 regimens 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 effective in fibromyalgia, particularly antidepressants and anticonvulsants155, which increase the presence of pain-inhibitory neurotransmitters by facilitating descending pathways and decreasing dorsal horn sensitization, or decreasing systemic hyperexcitability155. Herein, we discuss commonly prescribed drugs for fibromyalgia that have the most consistent and Nature Reviews | Rheumatology 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 amitriptyline is quite effective at treating fibromyalgia, especially for reducing pain and fatigue165,166, although most of the studies reviewed were old and had methodological 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 depressive disorder. However, adverse effects can lead to dropouts, 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 extensively 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 fibromyalgia 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 generally avoided, not least because of their unfavourable risk-to-benefit profile183. The only opioid that has proved Reviews 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 Milnacipran SNRI Yes243 Yes246 Amitriptyline No Tricyclic antidepressant Anticonvulsants Pregabalin GABAergic drug Gabapentin GABAergic drug Muscle relaxants Cyclobenzaprine Serotoninergic muscle relaxant Tizanidine α2 receptor agonist Analgesic drugs Tramadol Paracetamol Yes247 No Sedation, dizziness, vertigo, asthenia, nausea and weight gain No Nausea, palpitations, headache, fatigue, xerostomia, constipation and serotonin syndromea Dizziness, asthenia, xerostomia, vomiting, constipation, liver test abnormalities, bradycardia, hypotension and blurred vision No Weak opioid and SNRI No Analgesic and antipyretic drug No Hypnotic drugs Zolpidem GABAergic and non-benzodiazepine hypnotic drug Antipsychotic drugs Quetiapine Atypical antipsychotic drug Cannabis or cannabinoids Nabilone Pure cannabinoid (tetrahydrocannabinol) Cannabis Phytopharmaceutical (different concentrations of tetrahydrocannabinol and cannabidiol) Nausea, palpitations, headache, fatigue, tachycardia, insomnia, xerostomia, constipation and serotonin syndromea(Refs244,245) Xerostomia, constipation, weight gain, urinary retention, sedation and serotonin syndromea Constipation, nausea, vomiting, dizziness, fatigue, headache, itching and xerostomia Nausea, vomit, constipation and liver disease No Dizziness, headache, somnolence, confusion, agitation, abdominal pain, constipation and xerostomia No Somnolence, headache, dizziness, extrapyramidal symptoms, weight gain, dyslipidaemia, hyperglycaemia, xerostomia, vomiting and nausea, and constipation No Drowsiness, dizziness, nausea, xerostomia, confusion, anxiety and tachycardia Drowsiness, dizziness, nausea, xerostomia, blurred vision, increased/decreased appetite, vertigo, tachycardia and hypotension No 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 tramadol, 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 studied 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, www.nature.com/nrrheum Reviews among which tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most relevant and most frequently 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 fibromyalgia. The proper use of pure cannabinoids, if any, is still to be defined. By contrast, cannabis has proved to be moderately 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 fibromyalgia 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 fibromyalgia. 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 inevitably prevented any specific recommendation concerning 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 anticonvulsant 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 systematic 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 coping strategies that can be used on a long-term basis, which is very useful in the case of a chronic condition. Nature Reviews | Rheumatology 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 ‘complementary’ or ‘alternative’ therapies. A 2014 meta-analysis suggested that the magnitude of the multidimensional effect of these approaches can exceed that of pharmacological treatments for fibromyalgia210. However, the benefit of these inventions is still an area of controversy, as the study designs are often weak and the quality of the evidence is usually low. Nevertheless, various non-pharmacological therapies are included in the EULAR recommendations for the management of fibromyalgia, and non-pharmacological treatments might at least be considered as adjunctive, if not the core, treatment for many patients4. Non-pharmacological or alternative 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 hydrotherapy. 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 particularly popular in many European countries. Hot thermal baths are thought to improve various fibromyalgia symptoms (for example, they have been shown to moderately decrease pain, improve the patients’ health-related quality 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 movement 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, depression, pain and the quality of life all improved, although the poor quality of the studies did not enable any definite 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. Reviews 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 difficulties. 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 catastrophizing or negative emotional component, as mindfulness 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 studies. 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 highlighted 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) recommended 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 different 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 evidence 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 fibromyalgia, 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 electrical 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 symptoms 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 condition 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 underlying pain perception and the body’s response to stressful 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 throughout the nociceptive system89, and are beginning to reveal the neurophysiological signature of fibromyalgia236. The finding of induced peripheral receptor sensitization 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 biopsychosocial model of medicine in relation to fibromyalgia and chronic pain conditions in general237. The multiple components of the pathogenesis and maintenance of the syndrome mean that multi-modal treatment is necessary, and non-pharmacological approaches can have a pivotal role4. Within this framework, the concept of an individually tailored treatment is preponderant in fibromyalgia. 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