Fibromyalgia

ABSTRACT

Fibromyalgia is a clinical entity characterized by the combination of chronic widespread pain and other non-pain symptoms, including fatigue, poor sleep, and cognitive disturbances, which can exhibit symptom variation not only between different patients, but also in the same patient during the course of the disease. These symptoms are relatively common and non-specific. They can be encountered in other disorders that may overlap with fibromyalgia, often without having clear boundaries, while their nature makes them difficult to be objectively defined and quantified. These issues have led to significant controversy over the definition and the diagnostic criteria of fibromyalgia. It has been suggested that the markers of physical and psychological distress have a continuous distribution in the general population with fibromyalgia patients being at the extreme end of this continuum. Genetic predisposition in combination with environmental factors, are responsible for each individual’s position in this this distribution. In recent years more knowledge has been obtained to better understand the environmental factors that seem to be important in triggering fibromyalgia. Most of them act as stressors superimposed onto a deranged stress-response system leading to dys-regulation of the nociceptive system and the appearance of clinical symptoms. The aim of the therapy is to relieve pain and motivate the patients to become more physically active using a multimodal individualized therapeutic strategy that includes education, exercise, cognitive-behavioral approaches and medications. The response to current therapeutic modalities varies significantly, with some patients responding adequately, while others do not seem to experience any long-term benefit. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Fibromyalgia is a clinical entity characterized by the combination of ill-defined symptoms including chronic widespread pain, with concomitant fatigue, sleeping disorders, and cognitive disturbances (1). The severity of these symptoms can vary significantly during the course of the disease. Fibromyalgia has been described as an arbitrarily created syndrome that lies at the extreme end of the spectrum of poly-symptomatic distress (2). The term poly-symptomatic was used to emphasize the variety of multiple different symptoms that can be found in fibromyalgia patients, while the distress can have a physical and/or a psychological component. This exact nature of fibromyalgia makes it difficult to be clearly defined, often overlapping with disorders that are characterized by similar symptoms. It is important to note that fibromyalgia is not an exclusion diagnosis as it can co-exist with other clinical conditions (3).

CLINICAL FEATURES

The main presenting complains of patients with fibromyalgia include chronic widespread pain (also called multisite pain), fatigue, and poor sleep. Usually the pain is initially localized, but eventually it involves many muscle groups. It is characterized as persistent with varying intensity, while it can often be described as a sensation of burning, gnawing soreness, stiffness, or aching. Excessive sensitivity to normally painful stimuli, such as pressure or heat (hyperalgesia) and painful sensation to normally non-painful stimuli, such as touch (allodynia) are significant features of fibromyalgia. Often patients complain of swollen joints and paresthesias without though the presence of any objective clinical findings during physical examination. Pain is often aggravated by cold and humid weather, poor sleep, physical and mental stress. Additionally the patients may have a variety of less well understood pain symptoms, including abdominal pain, chest wall pain, symptoms suggestive of irritable bowel syndrome, pelvic pain, and bladder symptoms of frequency and urgency suggestive of interstitial cystitis (4–9).

Fatigue is present in almost all patients with fibromyalgia, while many complain of non-refreshing sleep, frequent awakening during the night, and difficulty falling back to sleep. Sleep apnea and nocturnal myoclonus can also be present along with a sensation of light-headedness, dizziness, and faintness. In addition, cognitive difficulties such as short-term memory loss, groping for words and poor vocabulary, are common among patients with fibromyalgia. Mood disturbances, including depression, anxiety and heightened somatic concern, may often also occur. Headaches, either muscular or migraine type, are also commonly present (6,7). Other often co-existing conditions include multiple chemical sensitivity, “allergic” symptoms, ocular dryness, palpitations, dyspnea, vulvodynia, dysmenorrhea, premenstrual syndrome, sexual dysfunction, weight fluctuations, night sweats, dysphagia, restless leg syndrome, temporomandibular joint pain, chronic fatigue syndrome (systemic exertion intolerance disease), Raynaud`s phenomenon, autonomic dysfunction, and dysgeusia (6,8,9). These conditions cannot be used to support the diagnosis of fibromyalgia.

Approximately 40% of fibromyalgia patients have accompanying depression at the time of diagnosis, while 60% of patients have a lifetime history of depression. In addition, an anxiety disorder is present in 30% of the cases at the time of diagnosis while the lifetime prevalence of an anxiety disorder in fibromyalgia patients is approximately 60% (10–14). The levels of depression and anxiety in patients with fibromyalgia seem to be associated with the degree of cognitive impairment, as shown in a meta-analysis of 23 case-control studies (15). Based on the coexistence of depression and anxiety, fibromyalgia patients can be divided into 2 major groups. The first group comprises of patients without coexisting mood disorders, while the second of patients with concomitant depressive mood, often in combination with anxiety. According to the results of a study that intended to subgroup fibromyalgia patients based on: 1) mood status (evaluated by the Center for Epidemiologic Studies Depression Scale for depression and the State-Trait Personality Inventory for symptoms of trait-related anxiety), 2) cognition (by the catastrophizing and control of pain subscales of the Coping Strategies Questionnaire), and 3) hyperalgesia/tenderness (by dolorimetry and random pressure-pain applied at suprathreshold values), it was noted that fibromyalgia patients with depressive mood and anxiety are also ‘catastrophizing’. This term is used to indicate that such patients have a very negative, pessimistic view of what their pain is and what is causing, while they have no sense that they can control their pain. On the contrary fibromyalgia patients who are neither depressed nor anxious and therefore do not catastrophize, have a moderate sense that they can control their pain. These patients can be further divided into 2 subgroups based on the degree of hyperalgesia/tenderness, the first subgroup comprises of patients with high hyperalgesia/tenderness, while the second one of patients with moderate hyperalgesia/tenderness (11). In addition, it has been proposed that depressed fibromyalgia patients can also be divided into 2 subgroups, in the first one depression is a co-morbid condition, while in the second depression is the cause of fibromyalgia (16). All these fibromyalgia subgroups are illustrated in Figure 1.

Figure 1.

Subgroups of fibromyalgia patients.

In another study fibromyalgia patients were classified as dysfunctional, inter-personally distressed, or adaptive copers, based on their responses to the Multidimensional Pain Inventory. The dysfunctional patients experienced more pain behaviors and overt expressions of pain, distress, and suffering, such as slowed movement, bracing, limping, and grimacing compared to the inter-personally distressed or the adaptive copers (17).

It is of interest that up to 25% of patients correctly diagnosed with a systemic rheumatic disease (e.g. rheumatoid arthritis, systemic lupus erythematosus) will also fulfill the classification criteria for fibromyalgia (18). This is also the case for many patients who experience persistent various forms of pain (including widespread myalgias, arthralgias, and headache), fatigue, neurocognitive dysfunction, and sleep disturbances after an infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that caused a mild to moderate coronavirus disease 2019 (long COVID) (19,20). The most commonly encountered comorbid conditions in fibromyalgia patients are shown in Table 1.

Table 1.

The Most Commonly Encountered Co-Morbid Conditions in Fibromyalgia

ASSESSMENT

Fibromyalgia is a chronic illness, with a variety of symptoms that can change during the course of the disease and after treatment. Therefore, its core symptoms should be evaluated both in clinical practice and in treatment trials. A working group within OMERACT (Outcome Measures in Rheumatology) reached a consensus regarding the domains that need to be assessed in clinical trials for fibromyalgia, using Delphi exercises within patients and expert clinicians (21). The fibromyalgia core symptom domains include pain intensity, tenderness, fatigue, sleep disturbance, multidimensional function (including health related quality of life and physical function), patient global impression of change, cognitive dysfunction, and depression. However at the present time, there is no consensus on how to evaluate these domains, in order to quantify fibromyalgia disease activity state and/or response (22).

Pain intensity can be assessed using visual analog scales. It has been proposed to use the wording “please rate your pain by circling on the number that best describes your pain on average” and has anchors that vary from “no pain” to “pain as bad as you can imagine” (23).

Tenderness can be measured by evaluating the alteration of the severity of pain at the tender points, using visual or analog scales, but not by the change in their number. The change in the number of tender points is poorly correlated with improvement in fibromyalgia treatment trials. It has been noted that the tender points measure the combination of tenderness and distress an individual has, rendering them inadequate for the evaluation of tenderness per se (24).

Fatigue can be evaluated by the Fatigue Severity Scale (FSS), which measures the functional outcomes related to fatigue (25). It has been shown that FSS has the most robust psychometric properties of 19 reviewed fatigue measures, while it had the best ability to act as an outcome measure sensitive to change with treatment, in chronically ill patients (26). Other instruments that have been used to assess fatigue in fibromyalgia patients include the Multidimensional Fatigue Index and the Multidimensional Assessment of Fatigue.

Sleep disturbance in fibromyalgia patients has been evaluated by the Medical Outcome Studies (MOS) sleep scale, the Functional Outcomes of Sleep Questionnaire (FOSQ), and the Jenkins Sleep Scale (JSS). Of these instruments MOS sleep scale lacks validity to assess changes in sleep symptoms in fibromyalgia treatment trials, FOSQ has not been adequately validated in fibromyalgia patients, while JSS has been criticized for possible high-recall bias, since it requires the patients to rate the frequency of their symptoms over a period of a month (23).

Multidimensional function, including health related quality of life and physical function, can be evaluated using the fibromyalgia impact questionnaire (FIQ). This represents a useful tool in assessing functional abilities in daily life and measures patient status, progress and outcomes. FIQ is self-administered and is highly sensitive to changes during the course of the disease. However, its functional items are orientated toward high levels of disability, resulting in a possible floor effect, while its physical function items are addressed to women living in affluent countries, generating gender and ethnic bias. To address these issues the Revised Fibromyalgia Impact Questionnaire (FIQR) was developed, having modified physical function questions and including questions on memory, tenderness, balance and environmental sensitivity, while keeping questions that evaluate overall impact and symptoms (27). Other tools for assessing overall function and quality of life include the Health Assessment Questionnaire, the Symptom Interpretation Questionnaire, the Western Ontario and McMaster Universities Osteoarthritis Index, the Patient Global Impression of Change scale (PGIC), and psychometric scales (28).

Patient global impression of change can be evaluated by the Patient Global Impression of Change scale (PGIC), as recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) (29).

Cognitive dysfunction can be evaluated by the Multiple Ability Self-report Questionnaire (MASQ), which is a self-report questionnaire measuring language, visuoperception, verbal memory and attention (30). However self-assessment is poorly correlated with objective measures of cognitive function and has poor discriminating ability for patients with mild cognitive impairment (31).

Depression can be evaluated using the Hospital Anxiety and Depression Scale (HADS) depression subscale (HADS-D). The use of the original Beck Depression Inventory (BDI) as well as the current BDI-II, should be avoided, since they tend to overestimate the presence of major depressive disorder in fibromyalgia patients by evaluating a number of non-depressive symptoms, which are often encountered in fibromyalgia (23).

DIAGNOSIS

As already mentioned, fibromyalgia is characterized by symptoms that can vary in number and intensity not only between different patients, but also in the same patient during the course of the disease. These symptoms are also common in other disorders that can overlap with fibromyalgia, often without having clear boundaries. Additionally, the nature of the symptoms of fibromyalgia makes them difficult to be objectively defined and measured. All these issues have led to significant controversy over the definition and diagnosis of fibromyalgia. The clinical entity of fibromyalgia was first described in 1904, under the term “fibrositis”, after focusing on clinical evidence of muscle sensitivity (32). It was not until 1977 that specific criteria for the diagnosis of fibromyalgia were introduced (33). Since then a number of different criteria have been proposed, based on a combination of tender point examination and the presence of symptoms. In 1986 a committee of the American College of Rheumatology (ACR) started a multicenter study, trying to provide a definition of fibromyalgia and establish classification criteria (34). In 2013, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) public-private partnership with the US Food and Drug Administration (FDA) and American Pain Society (APS) initiated the ACTTION-APS Pain Taxonomy (AAPT) in an attempt to develop a diagnostic system that would be clinically useful and consistent across chronic pain disorders, including fibromyalgia (35).

In clinical practice either the 2016 revision of the 2010/2011 fibromyalgia diagnostic criteria or the AAPT criteria can be used to help physicians to diagnose fibromyalgia (36). However, these criteria should be viewed as an aid and not as a gold standard for diagnosing fibromyalgia in clinical practice. Good clinical judgment is necessary to interpret the findings of physical examination and to assess psychological factors and associated comorbidities so as to correctly identify the patients with fibromyalgia (37).

Relevant social, personal and family history can be helpful in establishing the diagnosis of fibromyalgia, since there is evidence that the symptoms of fibromyalgia can appear after a physical or emotional trauma, a medical illness, or a surgical operation, while a family history of fibromyalgia, makes the diagnosis of fibromyalgia more likely (38).

1990 ACR Classification Criteria

In 1990 the American College of Rheumatology (ACR) committee established criteria for the classification of fibromyalgia. According to these criteria fibromyalgia is defined as chronic widespread pain involving both sides of the body, above and below the waist, as well as the whole length of the spine, and excessive tenderness in the pressure of 11 of 18 specific muscle-tendon sites (9 pairs of tender points). The locations of the tender points are described in Figure 2 and Table 2. Pressure equivalent of 4 kg/cm is applied to these points using the pulp of the thumb or the first two or three fingers. This can be accurately measured with a dolorimeter or it can be estimated, since 4 kg/cm is the pressure needed to be applied so as to whiten the examiner’s fingernail bed. These criteria specifically state that fibromyalgia is not an exclusionary diagnosis (34).

Figure 2.

Fibromyalgia tender points.

Table 2.

Description of the Location of Fibromyalgia Tender Points

The tender points, which are examined in fibromyalgia, are not just areas that the patient feels pain. They are points that fibromyalgia patients are relatively more tender, compared to normal individuals, when pressure is applied on them. But fibromyalgia patients are more tender wherever you apply pressure, not only to some of these 18 specific tender points, including areas previously considered to be “control points” (39). There is evidence that these tender points are areas that everyone is generally more tender. In contrast, fibromyalgia patients are more tender not only to pressure but to other stimuli such as heat, cold and other sensory stimuli, most probably due to decreased pain threshold. The number of tender points an individual has is highly correlated with distress, as defined by the presence of anxiety, depression, sleep disturbance, fatigue and global severity. Tender points have been described as “a sedimentation rate of distress”. Consequently tender points measure the combination of tenderness and distress an individual has (24).

The use of the 1990 ACR classification criteria in clinical practice is surrounded by substantial controversy. Tender points were introduced as an objective physical finding. However, if the physician who performs the physical examination is not experienced enough, tender point counting is impossible to be performed accurately. Most of the physicians examining fibromyalgia patients did not know how to carry out the tender point examination. Consequently, tender point count was not routinely performed, and when performed it was performed inaccurately (40). Another shortcoming of the tender point counting is that it is not as objective as it was initially considered, since the physician can be biased by the patient’s interview that precedes the physical examination. These issues lead to a low inter-examiner reliability of the tender point count (41).

Other more sophisticated measures of assessing tenderness, such as applying stimuli randomly, when the individual cannot anticipate what the next stimulus is going to be, are equally abnormal in fibromyalgia patients, but do not correlate with distress (39). These methods require special training and are more time consuming than the trigger point count. Other alternative assessment methods include functional magnetic resonance imaging (fMRI) and nociceptive flexion reflex (NFR) testing, which documents abnormal pain processing in fibromyalgia. Functional MRI demonstrates similar brain activation in regions involved in pain processing in fibromyalgia patients and normal individuals. However fibromyalgia patients have increased pain sensitivity and brain activation during comparable stimulus (42). Nociceptive flexion reflexes are sensory-motor responses elicited by electrical noxious stimuli, which involve activation of spinal and supraspinal neuronal circuits, providing an objective and quantitative assessment of the function of the pain-control system. It has been demonstrated that the NFR threshold in patients with fibromyalgia is significantly decreased compared with that in controls (43). Of these methods fMRI is expensive and complex compared to NFR testing that appears to be more easily accessible and convenient, since standard electromyographic equipment can be used. This test also seems to eliminate subjective bias and dissimulation (44).

The 1990 ACR classification criteria, define fibromyalgia in terms of pain rather than its other features. However, patients with fibromyalgia apart from tenderness and pain, also have a number of other somatic symptoms. Although non-pain symptoms are important, there is no evidence to support the notion that they are more important than hyperalgesia and allodynia, which are key symptoms of fibromyalgia (44). Many clinicians with experience in fibromyalgia did not feel that the 1990 ACR classification criteria were sufficiently reliable for the diagnosis of fibromyalgia in clinical practice and were considering other aspects of the disease in an attempt to reach a more accurate diagnosis (38).

2010 ACR Preliminary Diagnostic Criteria

To address the aforementioned issues the ACR in 2010 proposed the preliminary diagnostic criteria for fibromyalgia (Table 3), that were not meant to replace the 1990 ACR classification criteria, but to represent an alternative simple and easy method of diagnosis in clinical practice (45). These diagnostic criteria do not require a tender point count. Instead, they rely only on symptoms for the diagnosis of fibromyalgia. They introduced the widespread pain index (WPI), which counts the areas that the patient feels pain during one week preceding the examination, and the symptom severity (SS) scale, which describes the severity of fatigue, unrefreshing sleep, cognitive problems, and a number of associated somatic fibromyalgia symptoms. These symptoms need to be assessed and rated by a physician, therefore the 2010 ACR preliminary diagnostic criteria are in-adequate for patient self-diagnosis.

Two more conditions need to be fulfilled so as to diagnose fibromyalgia. The symptoms need to be present at a similar level for at least 3 months while alternate disorders that would otherwise explain the pain need to be excluded (Table 3). The authors of the 2010 ACR preliminary diagnostic criteria have clarified that the latter condition does not mean that fibromyalgia is an exclusion diagnosis according to these criteria. The diagnosis of fibromyalgia should not be made only when there is not another disease that could explain the pain that would otherwise be attributed to fibromyalgia. It should be noted that rheumatic diseases usually do not cause pain that can be confused with fibromyalgia (3).

Table

Table 3. 2010 ACR Preliminary Diagnostic Criteria

There is evidence that there is good agreement between the 1990 ACR classification criteria and the 2010 ACR preliminary diagnostic criteria (46–53). However, these criteria are expected not to agree completely, as the former are focused on the presence of tender points while the latter on the presence of symptoms. The 1990 criteria can diagnose fibromyalgia in patients who do not have sufficiently high symptom score according to the 2010 criteria, while the 2010 criteria can diagnose fibromyalgia in patients who do not have sufficient tender points according to the 1990 criteria.

The introduction of the 2010 ACR preliminary diagnostic criteria was surrounded by controversy too. In particular, they have been criticized for being completely symptom focused, ill-defined, and lucking some mechanistic features of fibromyalgia, such as hyperalgesia, central sensitization and dysfunctional pain modulation (54). Additionally, these diagnostic criteria are based on the subjective assessment of the patient’s somatic symptoms by the physician, adding ambiguity and influencing repeatability among different physicians (55). A self-reported version of the 2010 ACR preliminary diagnostic criteria was developed in 2011, so as to be used in survey research, and not in clinical practice (56). These criteria are known as the modified 2010 ACR preliminary diagnostic criteria or the 2011 ACR survey criteria. They introduced the fibromyalgia severity (FS) score (originally called fibromyalgianess scale) which is the sum of the self-reported WPI and SS score. This score can be used as an approximate measure of the severity of fibromyalgia. The FS score has also been called polysymptomatic distress (PSD) scale. It has been proposed that the markers of physical and psychological distress have a continuous distribution in the general population with fibromyalgia patients being at the extreme end of this distribution (57). The PSD scale could be useful to define the position of each individual in this continuum, without having to differentiate between patients with fibromyalgia and those without, as this distinction can sometimes be unclear if not arbitrary (58).

2016 Revisions to the 2010/2011 Fibromyalgia Diagnostic Criteria

A limitation of the WPI is the fact that it counts the number of painful areas without considering their distribution in the body. Patients with regional pain disorders can fulfill the 2010 ACR preliminary diagnostic criteria since pain can be located in 3 or more areas in the same region (59). To overcome this issue the 2016 revision of the diagnostic criteria require the pain to be generalized (multisite pain). The areas WPI assesses are divided in 5 regions (Table 4) and the diagnosis of fibromyalgia requires the distribution of pain in 4 out of 5 regions (60). The jaw, the chest and the abdomen area are problematic when they are used to define a region. In this way they are excluded from the definition of generalized pain (61). Since pain needs to be located in at least 4 areas according to the 2016 revision, the previous criterion for diagnosis, WPI of 3-6 and SS scale score ≥9 was changed to WPI of 4-6 and SS scale score ≥9.

The 2010 and 2011 ACR preliminary diagnostic criteria are extremely similar. Their difference is that the 2010 criteria are physician-based and can be used in clinical practice for the diagnosis of fibromyalgia, while the 2011 criteria are self-reported and can be used only in survey research. According to the 2010 criteria the SS scale assesses a wide range of somatic symptoms, which makes them impractical for use in questionnaires. With the 2016 revision the assessment of somatic symptoms that is included in the SS scale is limited to headaches, pain and cramps in the lower abdomen and depression. In this way, there is no longer need for different criteria for clinical practice and for survey research. The same criteria can be used in both settings having 2 different methods of administration.

One prerequisite for diagnosis of fibromyalgia according to the 2010 ACR preliminary diagnostic criteria is the patient not to have a condition that would otherwise explain the pain. The authors of these criteria clarified that this does not mean that the diagnosis of fibromyalgia is an exclusion diagnosis. However, this phrasing was not considered clear enough and caused significant misunderstanding. In this way this criterion was removed in the 2016 revision. The diagnosis of fibromyalgia can be valid even if there is another condition that can cause the pain that is attributed to fibromyalgia. According to this definition fibromyalgia can coexist with other clinically significant conditions that can cause pain.

Table 4. 

2016 Revisions to the 2010/2011 Fibromyalgia Diagnostic Criteria

AAPT Diagnostic Criteria

In an attempt to improve the recognition of fibromyalgia in clinical practice, the AAPT fibromyalgia working group proposed new diagnostic criteria in 2018 (62). These criteria are similar to the ACR criteria as they require the pain to be generalized (multisite), require the presence of non-pain symptoms and require the symptoms to be present for at least 3 months (Table 5). These diagnostic criteria are more simple than the ACR criteria and they can be easily implemented in primary clinical practice, but some of their aspects have been criticized (63). According to the AAPT criteria the head, the abdomen and the chest are included in the areas that are assessed for the presence of generalized musculoskeletal pain. However, these regions are problematic since pain originating from the teeth, the heart and the bowel can be referred to these areas. Additionally, the AAPT criteria do not have the ability to quantify the severity of fibromyalgia as, apart from the generalized pain, they only assess the presence or absence of the 2 most common non-pain symptoms of fibromyalgia, abolishing all other somatic symptoms. Compared with the 2016 ACR diagnostic criteria, individuals with less symptom severity and fewer pain sites can be classified as fibromyalgia patients, when the AAPT diagnostic criteria are used (64).

Table 5.

AAPT Diagnostic Criteria

EPIDEMIOLOGY

The prevalence of fibromyalgia depends on the criteria used to define it. Most studies use either the 1990 ACR classification criteria or the modified 2010 ACR preliminary diagnostic criteria (2011 ACR survey criteria) and the prevalence varies between 2-4% (65). Using the 2016 ACR diagnostic criteria the prevalence of fibromyalgia in the general population is 3-4% while with the AAPT diagnostic criteria the prevalence of fibromyalgia is 73% higher, ranging from 5% to 7% (64). In the general population the prevalence increases with age from 2% at the age of 20 to 8% at age of 70. Fibromyalgia appears more often in relatives of patients suffering from fibromyalgia (66), whereas there is a significant difference on the women to men ratio depending on the criteria used to define fibromyalgia. When the 1990 ACR classification criteria are used the women to men ratio is 7:1 while when the 2011 ACR survey criteria are used, that do not use the tender point count, the ratio ranges from 4:1 to 1:1 (58,67–69). Using the 2016 ACR or the AAPT diagnostic criteria there is no statistically significant difference in the prevalence of fibromyalgia between women and men (64).

DIFFERENTIAL DIAGNOSIS

Several conditions can mimic or overlap with fibromyalgia. In order to reach a differential diagnosis, careful history taking should be followed by a thorough physical examination. Careful neurologic and musculoskeletal examination needs to be performed in all fibromyalgia patients in order to exclude the presence of such conditions. Mood and functional impairment should also be evaluated. This can be easily performed using simple self-administered questionnaires. Patients with obvious mood disturbances should have a formal evaluation by a mental health professional. Baseline blood tests should be limited to a complete blood count, erythrocyte sedimentation rate, a comprehensive metabolic panel, and thyroid function tests. These tests are usually normal in fibromyalgia patients. Consequently, the identification of abnormalities in any of these examinations might suggest that a different condition is present. Additional tests are not recommended for a diagnosis, unless they are clinically indicated. The disorders that can mimic and/or overlap with fibromyalgia and the characteristic clinical features which differentiate them from fibromyalgia are described in Table 6. The clinical features of fibromyalgia, chronic fatigue syndrome (systemic exertion intolerance disease), depression, migraine, and irritable bowel syndrome often overlap being so interchangeable that some authors consider that these conditions should be approached as a “spectrum” of associated disorders (10). They are also considered as part of the spectrum of post-traumatic stress disorder (70,71).

Table 1.

Disorders that can Mimic and/or Overlap with Fibromyalgia Along with Characteristic Clinical Features that Differentiate Them from Fibromyalgia

PATHOPHYSIOLOGICAL MECHANISMS

Pain sensitivity in the population occurs over a wide continuum, forming a classic bell-shaped curve, just like any other physiologic variable. Genetic predisposition in combination with environmental factors, determine the place that each individual takes in this continuum. People who are placed in the right end of this curve are very sensitive to pain and they can probably develop pain even without having any inflammation or damage in the peripheral tissues. This pain can be either regional or widespread (39).

In the past fibromyalgia was thought to be a primary muscle disease. However, controlled studies found no evidence of significant pathologic or biochemical muscle abnormalities that can be the cause of chronic widespread pain and tenderness. Most investigators believe that any muscle pathology is secondary to chronic pain and inactivity, rather than primary in nature (76–79). Current research suggests that altered central nervous system (CNS) physiology might underlie the symptoms of fibromyalgia. Abnormal central sensory processing of pain signals seems to play a significant role in the pathogenesis of fibromyalgia. This dysregulation of the nociceptive system can arise from a combination of interactions between neurotransmitters, cytokines, hormones, the autonomic nervous system, behavioral constructs, and external stressors.

Abnormalities in Sensory Processing

Fibromyalgia overlaps with several other similar syndromes including chronic fatigue syndrome (systemic exertion intolerance disease) and myophasial pain syndrome (Table 6). It has been proposed that these disorders should be considered as members of the central sensitivity syndromes (Table 7). These similar and overlapping syndromes are bound by the common mechanism of central sensitization that involves hyper-excitement of the second-order neurons, especially the wide-dynamic-range neurons (WDR) in the dorsal horns of the spinal cord, by various synaptic and neurotransmitter/neuromodulator activities (6). Central sensitization is clinically and physiologically characterized by hyperalgesia, allodynia, expansion of the receptive field (pain expanding beyond the area of the peripheral nerve supply, after the application of a nociceptive stimulus), prolonged electrophysiological discharge, and an after-stimulus unpleasant quality of the pain (e.g., burning, throbbing, tingling or numbness). Parallel to central sensitization, temporal summation takes place in the second-order neurons. It is characterized by a progressive increase in electrical discharges (and consequently increase in the perceived intensity of pain) in response to repetitive short noxious stimuli. Temporal summation involves the production of second pain, which is described as dull or burning, and leaves an after-stimulus unpleasant sensation (80).

Table 7.

Central Sensitivity Syndromes

N-methyl-D-aspartate (NMDA) receptors are mostly responsible for escalation of hyperexcitability of the second-order nociceptive neurons. The role of the major neurotransmitters of the nociceptive system that participate in signal conduction at the level of the spinal cord is briefly illustrated in Figure 3 (6).

Figure 3.

The role of the major neurotransmitters of the nociceptive system that participate in signal conduction at the level of the spinal cord. SP: Substance P, NGF: nerve growth factor, NMDA: N-methyl-D-aspartate, D: dopamine.

The second-order neurons have ascending projections to the thalamus, hypothalamus, the limbic system and the somatosensory cortex. These supraspinal structures are involved in the sensory, evaluative and affective dimensions of pain (e.g., unpleasantness, emotional reaction). Several descending pathways from the cortico-reticular system, locus ceruleus, hypothalamus, brain stem, and local spinal cord interneurons terminate to the dorsal horn cells. These pathways utilize neurotransmitters that include serotonin (5-HT), norepinephrine, γ-amino-butyric acid (GABA), enkephalins and adenosine (6). This descending system, once thought to be predominantly inhibitory, is now known to have a facilitatory potential (81). Evidence suggests that the 5-HT₃ receptor has a facilitatory function, while the 5H-T_1A receptor is inhibitory. The ascending and descending pathways should not be considered as dichotomous in function. They are interactive and their functions are bidirectional. Both pathways can either facilitate or inhibit pain, depending on the site of action and the neurotransmitters that are used (6).

The dysregulation of the nociceptive system, either at the level of the dorsal horns of the spinal cord, or at the level of the ascending and descending pathways, can lead to its hyper-excitability. In other words, it can lead to central sensitization. Several factors may amplify and sustain central sensitization through interactive and synergistic actions. These factors are summarized in Table 8 (80). Central sensitization can become self-sustained, even when the event that triggered it no longer exists, due to long-term CNS plasticity.

Table 8.

Factors that may Amplify and Sustain Central Sensitization

Neuroimaging studies provide moderate evidence for structural changes in the brain of patients with fibromyalgia. Gray matter volume appears to be reduced in areas related with pain processing, such as the cingulate, the insular, and the prefrontal cortices (82). Functional MRI studies reveal alterations in the functional connectivity of brain areas responsible for pain processing and provide support of functional dysregulation of the ascending and descending pain pathways in fibromyalgia patients (82–85). Additionally, alterations in neuronal activity between the ventral and the dorsal spinal cord have been demonstrated in fibromyalgia patients (86).

Although nearly all of the research on sensory processing in fibromyalgia has focused on the processing of pain, there are some data suggesting a more generalized disturbance in sensory processing. There is evidence that fibromyalgia patients have a hypersensitivity to unpleasant stimuli of other sensory systems. For example, many patients experience reduced tolerance to loud noises, bright lights, odors, drugs, and chemicals (87,88).

MANAGEMENT

The treatment of fibromyalgia is challenging because of our limited understanding of its pathogenesis and the poor response of patients to conventional pain treatments. The aim of the therapy is to relieve pain and increase function using a multimodal individualized therapeutic strategy which, in most cases, includes pharmacologic and non-pharmacologic interventions. Current clinical-based evidence supports the use of a multimodal program that includes education, exercise, cognitive-behavioral approaches and medications. The treatment should be individualized based on the symptoms, the comorbidities and the preferences of the patient, who should be encouraged to participate in the decision-making process of selecting the optimal therapies (144,145). Coexisting disorders are common in fibromyalgia patients. Their identification and effective treatment can have beneficial effects on fibromyalgia symptoms. It is also important to assure that adequate adherence to both pharmacological and non-pharmacological treatment is maintained, so as to achieve the optimal benefit from these treatments.

Pharmacologic Treatment

A wide range of drugs has been used in the treatment of fibromyalgia including antidepressants, sedatives, muscle relaxants and antiepileptic drugs. The choice of medication is influenced by patient preference; prominence of particular symptoms, including fatigue, insomnia, and depression; potential adverse effects; patient tolerance of individual medications; cost and regulatory limitations on prescription choice (163,164). Nonsteroidal anti-inflammatory drugs and opioids, although often prescribed for fibromyalgia, are not an effective form of treatment (39,165). However analgesics and anti-inflammatory medications can be useful in case of coexisting conditions that cause regional pain, like arthritis, which can aggravate or trigger the fibromyalgia symptoms. Regarding opioids, with the exception of tramadol, apart from not being effective for the treatment of fibromyalgia symptoms, their long-term use also curries a dose-dependent risk for serious adverse effects, including overdose, abuse, fractures, myocardial infarction and sexual dysfunction (166). Additionally opioids in fibromyalgia patients can reduce the effectiveness of psychological therapy (167), while their long-term use can cause sleep disturbances (168).

Patients should be informed that for most pharmacologic therapies several weeks may be needed until they experience a benefit. Initially a single drug should be administered. However, in the case of non-responsiveness combination therapy should be considered. Since therapeutic responses are rarely durable, physicians should not be surprised when the initial efficacy of a medication is abolished. Successful treatment of fibromyalgia may require regular reassessment and possible rotation or combination of medications (169). Adequate dose prescription and patient adherence are significant for the effectiveness and tolerability of pharmacologic treatment (170). The doses of the most commonly used medications with strong and moderate evidence of effectiveness are shown in Table 9.

ANTIDEPRESSANTS

Tricyclic Antidepressants (TCAs)

TCAs are often used as initial treatment for fibromyalgia. Their analgesic effect is independent of their antidepressant action and is thought to be mediated by inhibition of norepinephrine (rather than serotonin) reuptake at spinal dorsal horn synapses, with secondary activity at the sodium channels. The most widely studied drugs of this group are amitriptyline and cyclobenzaprine. They should be administered at lower doses than those required for the treatment of depression, a few hours before bedtime, and their dose should be escalated very slowly. A clinically important improvement is observed in 25-45% of patients treated with TCAs compared to 20% in those taking placebo (171–175). However their use is limited by the fact that they are ineffective or intolerable in 60-70% of patients (144), while their efficacy may decrease over time (171,176).

Amitriptyline is more efficient compared to the serotonin-norepinephrine reuptake inhibitors duloxetine and milnacipran in reducing pain, sleep disturbance, and fatigue, without differences in acceptability, as it was shown in a systematic review and meta-analysis (177). In a 2022 network meta-analysis comparing amitriptyline, duloxetine and pregabalin it was shown that treatment with amitriptyline 25 mg was superior to duloxetine and pregabalin for the reduction of pain intensity for at least 50% (178). The combination of 20 mg of fluoxetine in the morning with 25 mg of amitriptyline at bedtime has been shown to be more effective than either medication alone (179). Side effects of amitriptyline include dry mouth, constipation, fluid retention, weight gain, difficulty in concentrating and possibly cardiotoxicity.

Cyclobenzaprine has a similar tricyclic structure and presumed mode of action with amitriptyline in fibromyalgia, but is thought to have minimal antidepressant effect (163). A meta-analysis of five placebo-controlled trials has revealed improvement of the global functioning, with a similar effect size as this reported for amitriptyline. The group that received cyclobenzaprine had a significant decrease in pain for 4 weeks, compared to those treated with placebo, but the decrease in pain was not significantly different after 8 and 12 weeks. Sleep was improved at all time points in both cyclobenzaprine and placebo groups, while no effect was noted on fatigue (171–173). It has been demonstrated that the use of very low-dose cyclobenzaprine (1 to 4 mg at bedtime) can improve the symptoms of fibromyalgia, including pain, fatigue, and depression, compared to symptoms at baseline and to placebo. Significantly more patients who received the very low-dose of cyclobenzaprine experienced improved restorative sleep, based upon analysis of cyclic alternating pattern of sleep by electroencephalography. The increase in nights with improved sleep by this measure correlated with improvements in fatigue and depression (180).

Desipramine has fewer anticholinergic and sedative effects than other TCAs, which can make it a possible alternative, although its efficacy is not well studied in fibromyalgia.

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

SNRIs are similar to TCAs in their ability to inhibit the reuptake of both serotonin and norepinephrine, but they differ from TCAs in being devoid of significant activity at other receptor systems, resulting in diminished side effects and increased tolerance. Venlafaxine, duloxetine and milnacipran have been shown to be effective in diminishing fibromyalgia symptoms (147,181,182). These drugs can be used in fibromyalgia patients who do not respond to a trial of low-dose TCAs or who have intolerable side effects. They can also be administered as an alternative to amitriptyline for initial therapy especially for patients with significant fatigue or depression. Of these medications duloxetine and milnacipran are better studied and they are preferred to be administered to patients with fibromyalgia. There are more limited data regarding the efficacy of venlafaxine for fibromyalgia, while withdrawal symptoms if a dose is missed occur more often, because of the short half-life of this medication (183). A meta-analysis has shown that fibromyalgia patients treated with duloxetine at 60mg daily are more likely to have more than 50% reduction in pain, compared to patients taking placebo (184). However, duloxetine at 30mg daily does not significantly reduce pain (185). The efficacy of duloxetine can be maintained at 3 and 6 months of treatment (186). In a 2018 systematic review and meta-analysis it was shown that duloxetine and milnacipran were not superior to placebo in the frequency of pain relief of at least 50%, but there was a benefit in reducing the pain at least by 30% and in the patient's global impression to be much or very much improved. Additionally, there was not a significant difference in the reduction of fatigue, in the reduction of sleep problems, nor in the improvement of health-related quality of life (187). Another meta-analysis has shown that duloxetine, pregabalin and milnacipran were superior to placebo for pain relief, while duloxetine and pregabalin were superior to milnacipran. These drugs also differed in their effects on sleep disturbances, depression and fatigue (188). A fMRI study in fibromyalgia patients treated with milnacipran and placebo demonstrated that pain reduction with milnacipran treatment was associated with decreased functional connectivity between the insular cortex and the rostral part of the anterior cingulate cortex as well as the periaqueductal gray, while these changes were not demonstrated with the placebo (189). Regarding their side effects, headaches and nausea are more common with duloxetine and milnacipran treatment, while diarrhea is more common with duloxetine treatment. Other side effects related to SNRIs include dry mouth, constipation, somnolence, dizziness and insomnia (188).

Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors block the catabolism of serotonin, increasing its levels in the brain. It has been indicated that pirlindole and moclobemide have a significant beneficial effect on pain, without a significant effect on sleep nor fatigue. Their use for the treatment of fibromyalgia patients is limited (190).

ANTICONVULSANTS

Antiepileptic medications useful for the treatment of fibromyalgia patients include pregabalin and gabapentin. Both of these medications are structurally related to GABA and they bind with high affinity to the alpha2-delta subunit site of cellular voltage-dependent calcium channels. Although their exact mechanism of action is unknown their therapeutic effects can be mediated by blocking the release of various neurotransmitters. They can be used in cases where other medications initially administered to the fibromyalgia patients become intolerable or ineffective, or as the initial treatment for patients with significant sleep disturbance in addition to pain.

Pregabalin has been reported to be efficient against pain, sleep disturbances and fatigue in fibromyalgia. In a recent meta-analysis a reduction of at least 50% in pain intensity was found in 22-24% of patients taking pregabalin 300-600 mg per day, approximately 9% higher compared to the placebo group. A reduction in pain intensity of at least 30% was found in 39-43% of patients on pregabalin 300-600 mg per day, compared to 28% of patients taking placebo (191). In addition to pain, pregabalin at doses 300-600 mg per day can improve sleep and patient function, as it is demonstrated in a 2018 review of clinical trials, meta-analyses, combination studies and post-hoc analyses (192). The improvement in pain and sleep can be apparent as early as 1-2 days after the onset of treatment (193). In a 2022 network meta-analysis it was shown that treatment with pregabalin 450 mg per day was superior to duloxetine 30 mg for the reduction of pain intensity of at least 30% (178). A randomized placebo-controlled neuroimaging study demonstrated that the reduction in pain intensity from pregabalin was associated with a reduction in connectivity between the posterior insula and the default mode network (DMN) and that pregabalin but not placebo can reduce the response of the DMN to experimental pain (194). It is of interest that baseline patterns of brain connectivity have been used in a machine-learning model to successfully distinguish fibromyalgia patients who have a favourable response to pain intensity after the treatment with milnacipran from those who achieve a reduction of pain intensity after the treatment with pregabalin (195). Common side effects of pregabalin include somnolence, dizziness, weight gain and peripheral oedema. Discontinuation due to side effects is approximately 10% higher in patients treated with pregabalin compared to placebo, while discontinuation due to inefficiency of treatment is 6% lower (191). The intensity of adverse effects and the frequency of discontinuation of the treatment due to adverse effects is dose dependent. It is important for pregabalin to be titrated to the maximally tolerated therapeutic dose for each patient (192).

Gabapentin has been shown to be efficient in treating fibromyalgia associated pain, while it was well tolerated (196). Side effects include dizziness, sedation, lightheadedness, and weight gain. Its efficacy and tolerability is not well studied in fibromyalgia patients, however it can be considered as an acceptable alternative in case pregabalin cannot be administered due to its cost or due to regulatory limitations (197).

SEDATIVE HYPNOTIC AGENTS

Zopiclone and zolpidem have been used in fibromyalgia. It has been suggested that they can improve the sleep and perhaps fatigue, without any significant effects on pain (144).

Sodium oxibate, a precursor of GABA with powerful sedative properties has been shown to improve pain, fatigue and sleep architecture in fibromyalgia (198). However, in view of safety concerns the European Medicines Agency and the US Food and Drug Administration have not approved it for use in fibromyalgia patients.

TRAMADOL

Tramadol has multiple analgesic effects, since it inhibits norepinephrine and serotonin reuptake, and its major metabolite binds weakly to opioid μ receptors (144). The use of tramadol (with or without acetaminophen) is both effective and well tolerated for the management of pain in fibromyalgia (199,200). There are some concerns regarding the long-term potential of abuse of tramadol, although the risk is less than that of more potent narcotic analgesics that have also been used in fibromyalgia.

Table 2.

The Doses of the Most Commonly used Medications with Strong and Moderate Evidence of Effectiveness in Fibromyalgia

CONCLUSION

Fibromyalgia is a common disease that is often underdiagnosed. Genetic predisposition, in combination with exposure to external stressors may lead to dysregulation of the nociceptive system and to the appearance of clinical symptoms. Fibromyalgia patients do not form a homogenous group with some patients responding adequately to current therapeutic modalities, and some others not experiencing any long-term benefit. Patients treated by primary care physicians in the community have a much better prognosis, compared to patients treated in tertiary referral centers. Certain psychological factors, such as an increased sense of control over pain, a belief that one is not disabled, that pain is not a sign of damage, and behaviors like seeking help from others, decreased guarding during examination, exercising more and having pacing activities are associated with better prognosis. Conversely, catastrophizing is associated with increased awareness of pain and with worsening symptoms.

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