Fibromyalgia

Etiology

Experts have not identified a single cause of fibromyalgia. Instead, experts believe that a combination of multiple physical and emotional stressors can trigger or worsen symptoms.[7][8] In patients with fibromyalgia, pain and sensory processing alterations occur in the CNS.[9] Some identified causes include infections such as Lyme disease and physical or emotional trauma. Fibromyalgia is considered a disorder of pain regulation and is classified as a condition of central sensitization.[10]

Patients with central sensitization experience hypersensitivity to pain due to amplified neural signaling in the CNS. They perceive noxious stimuli as painful at lower levels of physical stimulation compared to healthy controls.[11] Rapidly repetitive, short, noxious stimuli cause higher-than-normal increases in pain intensity, partly due to a deficiency in endogenous analgesic systems. This phenomenon is referred to as the temporal summation of pain.[10][12] Neuroimaging also reveals differences in activity within pain-sensitive brain areas.

Some studies suggest a genetic predisposition for fibromyalgia, although researchers have not identified a definitive candidate gene.[13] First-degree relatives of patients with fibromyalgia have a 13.6 times higher incidence of developing fibromyalgia.[14] Possible associated genes include COMT, the μ-opioid receptor, voltage-gated sodium and calcium channels, guanosine triphosphate cyclohydrolase I, and γ-aminobutyric acid (GABA)-ergic pathways.[13] A genome-wide study involving patients with chronic widespread pain has identified an association with the RNF123 locus and a possible association with the ATP2C1 locus, both of which are involved in calcium regulation.[15] 

Epidemiology

The prevalence of fibromyalgia in the United States and other countries is approximately 2% to 3%, with the incidence increasing with age.[1][16][17] The highest incidence occurs in females between the ages of 20 and 55 and is the leading cause of generalized musculoskeletal pain in women. In adults, females are twice as likely as males to be diagnosed with fibromyalgia. Among patients referred to tertiary care pain management clinics, over 40% meet the criteria for fibromyalgia.[18] The risk of developing fibromyalgia is higher in individuals with an existing rheumatic disease.

The prevalence of JPFS worldwide ranges from 1% to 6% in school-aged children and adolescents, and it accounts for 7% to 15% of all referrals to pediatric rheumatology clinics.[19][20] Nearly 84% of patients with JPFS are female, with a diagnostic age range of 9 to 20 and a mean age of 15.4.[21] Most patients with JPFS are non-Hispanic and White.[21] However, some experts question the validity of these statistics due to the underrecognition and undertreatment of pain in certain ethnic groups.

Pathophysiology

The subjective experience of pain involves processing and integrating nociceptive signals from the spinal cord to various brain "hubs," alongside input from somatic reflex pathways and areas associated with emotional, motivational, and cognitive dimensions of pain. The 2 primary regulators of stress response—the hypothalamic-pituitary-adrenocortical (HPA) axis and the sympathetic nervous system (SNS)—are also crucial. In patients with fibromyalgia, functional brain connectivity and neurochemical balances within the pain-processing system are altered.

Autonomic Nervous System Dysfunction

Many experts believe that dysfunction of the autonomic nervous system, characterized by reduced heart rate variability (HRV) and changes in skin conductance, combined with an overactive stress response and dysregulation of the HPA axis, contributes to the relationship between pain, sleep disturbances, and mood and cognitive symptoms. Several studies have shown reduced basal cortisol levels, decreased 24-hour urinary free cortisol excretion, and a blunted cortisol response to stimulation tests such as the corticotropin-releasing hormone test.[22][23] However, a recent meta-analysis suggests that although data indicate an association between fibromyalgia and HPA-axis dysfunction, the findings are partially contradictory and influenced by study designs, patient populations, and analytical methods. As a result, the evidence does not conclusively support abnormal HPA-axis function in individuals with fibromyalgia.[24] Physical signs of autonomic dysfunction include reduced HRV, indicating heightened sympathetic nervous system activity, as well as changes in skin conductance and sweating.

Central Nervous System Dysfunction

Changes in brain morphology and function: Magnetic resonance imaging (MRI) studies in patients with fibromyalgia have revealed several changes in brain morphology, including:

• Reduced total gray matter, which is the most pronounced in the anterior cingulate cortex and prefrontal cortex.
• Premature brain aging, which is indicated by a 3-fold increase in age-associated gray matter loss.
• Decreased cortical thickness, brain volume, and regional functional connectivity in the rostral anterior cingulate cortex.[25][26][27]

These changes tend to worsen with the duration of the disease.

Changes in neurotransmitters: In healthy individuals, the ventral tegmental area, which regulates sensory, affective, cognitive, and pain-modulatory processes, becomes activated during pain anticipation and stimulation, followed by deactivation when anticipating pain relief. However, a functional MRI (fMRI) study shows reduced activation in this area in patients with fibromyalgia, suggesting altered dopaminergic and GABAergic neurotransmission.[28] Elevated glutamate levels in the right posterior insular region are associated with a decreased pain threshold.[29] Additionally, transcranial magnetic stimulation of the motor cortex reveals deficits in intracortical GABAergic and glutamatergic modulation.[30][31] Additional studies show increased neuronal activity in pain-processing and pain-sensitive brain regions compared to healthy individuals.[32][33] The brain is made up of interconnected hubs, or highly connected regions, that integrate information from various parts of the brain and direct it to the appropriate areas. In patients with fibromyalgia, this hub structure is altered.[34]

Alterations in the topology of the insular hub are linked to pain intensity in fibromyalgia. Overall, the stability of neural hubs in patients differs from healthy controls, indicating reduced neural stability. In addition to deficits in GABAergic and glutamatergic modulation, patients with fibromyalgia also exhibit elevated levels of inositol in the right amygdala and right thalamus, corresponding to increased levels of pain, fatigue, and depression symptoms. 

Changes in resting-state functional connectivity: Patients with fibromyalgia demonstrate altered resting-state functional connectivity of the periaqueductal gray, leading to impaired descending pain inhibition.[35] Altered connectivity between the default mode network (DMN) and the insula, a key pain-processing region, is also evident. Additionally, researchers observe altered connectivity between DMN structures and the anterior midcingulate cortex, right parahippocampal gyrus, left superior parietal lobule, and left inferior temporal gyrus.

Notably, reduced functional connectivity between the DMN and the right parahippocampal gyrus is associated with a longer duration of symptoms. In contrast, enhanced connectivity between the anterior midcingulate and posterior cingulate cortices correlates with increased pain and depression scores. Additionally, imbalanced activity between the ventral and dorsal cervical spinal cord may indicate central sensitization, contributing to fatigue and other bodily symptoms associated with fibromyalgia.[36]

Sleep Abnormalities

Disordered sleep is a prominent component of fibromyalgia, and phasic α-sleep is the most characteristic. Some studies suggest that sleep disturbances may precede the onset of pain. A study in Norway found that nonrestorative sleep is the strongest predictor of widespread pain, and sleep disruption increases the risk of fibromyalgia.[37] Additionally, sleep disturbances significantly impact attention, cognition, and pain severity.[38]

Additional Changes

Small fiber neuropathy, typically presenting as hyperesthesia in a stocking distribution, is frequently observed in patients with fibromyalgia. Central sensitization may contribute to the development of small fiber neuropathy. Elevated glutamate levels in the insula can enhance pain behaviors and decrease the density of intraepidermal nerve fibers. Skin biopsies in patients with small fiber neuropathy show reduced intraepidermal nerve fiber density or altered electrochemical skin conductance.

History and Physical

The initial history and physical examination help clinicians differentiate fibromyalgia from other treatable causes of widespread musculoskeletal pain, fatigue, and sleep disturbances. Healthcare professionals can also identify common overlapping conditions that may mimic or exacerbate fibromyalgia symptoms.

Widespread Musculoskeletal Pain 

The hallmark feature of fibromyalgia is widespread musculoskeletal pain lasting at least 3 months. Patients typically describe the pain as aching, although it may also be dull, sharp, shooting, or burning. Common expressions include "I hurt all over" or "I feel like I always have the flu." Although the pain primarily affects the muscles, patients may also report joint pain and swelling, despite the absence of synovitis or structural changes on examination.[3][39][40] The pain may initially be localized, most commonly in the neck and shoulders. However, at least 6 soft tissue sites involving the upper and lower body are typically affected. As identified by the 1990 ACR classification criteria, common sites include the upper mid-trapezius, lateral epicondyle, second costochondral junction, and greater trochanter. Additional sites may include the head, lower back, buttocks, and abdomen. Patients often experience morning stiffness, and minimal activities exacerbate the pain. Conversely, prolonged inactivity also intensifies pain severity. Approximately 25% of patients with JPFS have joint hypermobility.[41]

Fatigue 

Debilitating fatigue, along with sleep disturbances, is a core feature of fibromyalgia.[42] As with the widespread pain, mild to moderate activity exacerbates fatigue, as does prolonged inactivity.[43] Patients with fibromyalgia often report light sleep, frequent early morning awakenings, difficulty falling back asleep, and not feeling well-rested in the morning.

Cognitive Disturbances 

Most patients with fibromyalgia experience cognitive disturbances, commonly reporting difficulty concentrating and performing tasks that require quick processing speed.[44]

Psychiatric Symptoms

Studies show that 30% to 50% of patients with fibromyalgia experience depression or anxiety.[45][46][47][48] In addition, bipolar disorder, posttraumatic stress disorder (PTSD), and personality traits such as catastrophizing and alexithymia are more prevalent in patients with fibromyalgia.[47] A recent systematic review also found that one-third of patients with fibromyalgia have a history of bipolar disorder, panic disorder, or PTSD.[47][49] 

Additional Symptoms  

In addition to the primary symptoms, patients with fibromyalgia often experience various somatic concerns. Tension, cluster, and migraine headaches are common, affecting nearly 50% of patients.[50] Paresthesias, particularly in both arms and legs, are frequently reported, despite a normal neurological examination. In some cases, skin biopsy reveals changes indicative of small fiber neuropathy. A significant symptom overlap also exists between juvenile-onset primary fibromyalgia syndrome, pediatric hypermobility syndromes, and systemic rheumatic diseases such as juvenile idiopathic arthritis.

Additional symptoms and disorders associated with fibromyalgia include:

• Irritable bowel syndrome (IBS)
• Gastroesophageal reflux disease (GERD)
• Dry eyes
• Dyspnea
• Dysphagia
• Palpitations
• Autonomic dysfunction, including Raynaud phenomenon, orthostatic hypotension, and altered HRV
• Hearing loss
• Dry eye syndrome
• Temporomandibular joint disorder
• Chest wall pain
• Pelvic pain
• Hyperesthesia in a stocking distribution
• Urinary urgency and frequency, consistent with painful bladder syndrome
• Hearing loss [51][52][53]

Evaluation

Clinicians should suspect fibromyalgia in patients presenting with widespread musculoskeletal pain, sleep disturbances, fatigue, cognitive impairment, psychiatric symptoms, and various somatic complaints.[54] Evaluation begins with a thorough patient history and physical examination. Clinicians should assess pain characteristics, sleep patterns, fatigue severity, psychiatric symptoms, and cognitive dysfunction. Additionally, they should screen for comorbid or alternative conditions, including inflammatory arthritis, osteoarthritis, thyroid disease, and localized pain syndromes. 

The physical examination should include a detailed joint and neurological assessment. Clinicians should palpate multiple soft tissue sites and joints, noting greater tenderness in the soft tissues and the absence of synovitis. Except for the Yunis and Masi criteria, current guidelines no longer recommend palpating specific soft tissue sites or documenting a specific number of tender points. Instead, diagnosis is based on widespread or multisite soft tissue tenderness in at least 4 of 5 regions. 

Laboratory or imaging tests cannot definitively diagnose fibromyalgia; testing is primarily used to rule out other conditions. In adults, evaluation typically includes a complete blood count and either C-reactive protein or erythrocyte sedimentation rate. For children and adolescents, a basic metabolic panel and thyroid stimulating hormone (TSH) are also recommended. Additional tests, such as 25-hydroxy vitamin D, vitamin B12, magnesium, iron studies, and creatine kinase levels, may be ordered based on clinical findings and symptoms. Unless clinical signs suggest an inflammatory rheumatic disease, tests such as rheumatoid factor and antinuclear antibody should be avoided. Given the impact of sleep disturbances on fibromyalgia symptoms, patients suspected of having obstructive sleep apnea or other primary sleep disorders should undergo a sleep study. Referral to a cardiology specialist may be necessary for tilt table testing to assess autonomic nervous system dysfunction in patients with tachycardia, orthostasis, and palpitations.

Classification and Diagnostic Criteria

Several diagnostic criteria exist for fibromyalgia. The initial diagnostic criteria, established in 1990, focused on a specific number of tender points. However, standardizing the examination proved difficult, leading to limited use among physicians. Additionally, the criteria failed to account for the somatic, psychiatric, and cognitive dysfunctions associated with fibromyalgia. As a result, the ACR updated the guidelines in 2010 to address these shortcomings. In 2016, the ACR modified the criteria to include a generalized pain criterion, requiring pain in 4 out of 5 regions to reduce misclassification of regional pain syndromes. Clinicians can use either the Yunis and Masi criteria or the ACR criteria to diagnose JPFS. Compared to the Yunis and Masi criteria as the gold standard, the ACR criteria demonstrate 88% to 89% sensitivity and specificity for diagnosing JPFS.[55]

Yunis and Masi criteria: Patients must meet all 4 major criteria and at least 3 of the 10 minor criteria.

Major criteria: The major criteria that must be met for a diagnosis of fibromyalgia are listed below.

• Generalized musculoskeletal aching at 3 or more sites for a minimum of 3 months
• No evidence of an underlying condition or cause
• Normal test results
• Presence of 5 tender and soft tissue points

Minor criteria: In addition to the major criteria, the minor criteria that may support a diagnosis of fibromyalgia are listed below.

• Chronic anxiety or tension
• Sleep disturbance
• Chronic headaches
• Fatigue
• Irritable bowel syndrome
• Subjective soft tissue swelling
• Numbness
• Pain modulation due to physical activity
• Pain modulation due to weather
• Pain modulation due to anxiety or stress

2010 American College of Rheumatology preliminary diagnostic criteria: Patients who meet the below-mentioned conditions fulfill the diagnostic criteria for fibromyalgia.

• A widespread pain index (WPI) score of 7 or more, a symptom severity (SS) score of 5 or more, or a WPI score of 3 to 6, and an SS score of 9 or more.
• Symptoms present at a similar level for a minimum of 3 months.
• No other condition accounts for the patient's pain.

The WPI measures the number of painful body parts from a list of 19, while the SS score estimates the severity of fatigue, cognitive dysfunction, and psychiatric and somatic symptoms. Please visit the American College of Rheumatology's website, "2010 Fibromyalgia Diagnostic Criteria," for a detailed copy of the ACR's diagnostic criteria, including the WPI and SS score index.

2016 American College of Rheumatology revised criteria: A patient fulfills the modified 2016 fibromyalgia criteria if they meet all the conditions mentioned below.

• WPI score of 7 or more with an SS score of 5 or more or a WPI score of 4 to 6 with an SS score of 9 or more.
• Generalized pain, which is defined as pain in at least 4 of 5 regions, excluding the jaw, chest, and abdomen.
• Symptoms should be present at a similar level for at least 3 months.

ACTTION-APS Pain Taxonomy criteria: The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), in collaboration with the US Food and Drug Administration (FDA) and the American Pain Society (APS), developed the ACTTION-APS Pain Taxonomy (AAPT) diagnostic system for chronic pain disorders, including fibromyalgia. In 2019, the working group proposed the below-mentioned core criteria for the AAPT diagnostic system.

• Multisite pain, which is defined as pain in 6 or more sites out of a total of 9 possible sites, including the head, left arm, right arm, chest, abdomen, upper back and spine, lower back and spine (including the buttocks), left leg, and right leg.
• Moderate-to-severe sleep problems or fatigue.
• The first 2 criteria must be present for a minimum of 3 months.[56]

According to the AAPT criteria, the presence of another pain disorder or related symptoms does not exclude the diagnosis of fibromyalgia. However, clinicians should conduct a thorough clinical assessment to evaluate for any condition that may fully explain the patient's symptoms or contribute to their severity.

Fibromyalgia is a clinical diagnosis. Healthcare professionals should remember that the criteria outlined above are intended to assist in diagnosis and should not replace clinical judgment. 

Treatment / Management

Effective treatment of fibromyalgia requires a balanced combination of pharmacological and nonpharmacological modalities. The primary focus of the treatment is symptom relief and equipping patients with strategies to manage daily life effectively. Key goals include:

• Reducing major symptoms such as chronic pain, fatigue, sleep disturbances, and mood disorders.
• Enhancing patient self-efficacy through education and nonpharmacological interventions.
• Personalizing treatment to address each patient’s unique symptom profile.
• Managing comorbid conditions that may influence symptoms or hinder treatment adherence.

Clinicians should tailor treatment regimens based on individual symptoms, comorbidities, and preferences while considering certain barriers to treatment, such as social determinants of health, medication costs, and prior treatment experiences or adverse effects from medications. 

Nonpharmacological Therapy

Nonpharmacological therapy for fibromyalgia focuses on patient education, cognitive behavioral therapy (CBT), and physical activity.

Patient education: Reassuring patients that fibromyalgia is a real condition and validating their symptoms are essential aspects of patient education. Clinicians should help patients understand their heightened pain sensitivity by explaining the difference between nociceptive pain, which is caused by tissue damage and inflammation, and centralized pain, which results from amplified signaling in the CNS. In addition, patients should understand that central and peripheral pain can intensify each other, meaning a knee injury may exacerbate fibromyalgia symptoms and vice versa. Clinicians should set realistic expectations for treatment outcomes to help mitigate frustration. Patients must recognize that while no cure exists, therapy can improve symptoms. However, some pain and fatigue may persist, and symptoms will likely fluctuate over time. 

Patients with comorbid conditions such as depression, anxiety, and sleep disorders should be encouraged to seek treatment, as these conditions can exacerbate one another. For example, disrupted sleep can increase pain, and pain can further disturb sleep. Clinicians should screen patients for sleep apnea and restless leg syndrome, referring those with suspected primary sleep disorders to sleep medicine. Emphasizing sleep hygiene is also a key component of patient education.

The following list outlines recommended sleep hygiene practices:

• Sleeping in a dark, quiet, and calm environment.
• Going to bed and getting up at the same time each day.
• Avoiding caffeine after lunch.
• Avoiding alcohol close to bedtime.
• Restricting the use of all electronic devices 30 to 60 minutes before bedtime.
• Avoiding strenuous exercise within 2 hours of bedtime.
• Avoiding nicotine.
• Avoiding eating a large meal before bedtime.

Physical activity: Exercise can help reduce pain, improve sleep, and alleviate fatigue in patients with fibromyalgia. Cardiovascular fitness training, resistance training, and movement therapies such as tai chi have shown significant benefits. Exercise routines should be individualized for each patient and include low-impact aerobic exercises such as brisk walking, biking, swimming, or water aerobics unless contraindicated or poorly tolerated by the patient.[56][57][58] The recommended level of cardiovascular fitness training is at least 30 minutes of aerobic exercise 3 times per week. However, patients who cannot meet this target should be encouraged to maintain an exercise routine at a level they can sustain. Patients should be informed that pain and fatigue may initially increase when starting an exercise program. Gradually increasing activity levels can help mitigate these effects.(A1)

Cognitive therapy: Cognitive therapy may involve CBT, mindfulness-based stress reduction, or meditation and relaxation techniques. CBT has been shown to reduce pain, sleep disturbances, and symptoms of depression and anxiety, especially when combined with patient education.[59][60][61] However, limited access and cost can be barriers to treatment. Online and telephone-based CBT programs can help improve accessibility for patients.  (A1)

Pharmacological Therapy

Pharmacological therapy should be considered for patients with moderate-to-severe symptoms or those with mild symptoms that do not respond to nonpharmacological interventions. Patients must understand that medications are moderately effective in approximately 50% of cases.[6] First-line treatments include tricyclic antidepressants (TCAs) such as amitriptyline, selective norepinephrine reuptake inhibitors (SNRIs) such as duloxetine and milnacipran, and α-2 ligands such as pregabalin and gabapentin.[62] Additionally, cyclobenzaprine, a tricyclic medication, has shown efficacy in managing fibromyalgia symptoms.

The choice of medication should be guided by associated symptoms and comorbidities. Patients with widespread diffuse pain without significant mood symptoms should begin with a TCA such as amitriptyline at a dosage beginning at 5 to 10 mg at bedtime. The dose should be taken 1 to 3 hours before sleep and increased by 5 mg every 2 weeks as needed. An effective dose typically ranges from 20 to 30 mg. Treatment should continue for 12 months, followed by a trial of weaning. Some patients may require ongoing therapy, while others may tolerate discontinuation. Cyclobenzaprine is a suitable alternative, starting at 5 mg before bedtime and gradually increasing to 10 to 20 mg as needed. 

SNRIs, such as duloxetine and milnacipran, are appropriate for patients with significant fatigue or depression associated with fibromyalgia. The initial dosing for these medications is mentioned below.

• Duloxetine: This drug is approved for use in adolescents aged 13 and older with fibromyalgia. Adult and adolescent dosing is 20 to 30 mg/d in the morning with food. The dose can be increased by 20 mg every few weeks, up to a maximum of 60 mg/d. The average daily dose based on clinical trials is 60 mg. Caregivers and patients should be aware that antidepressants may increase the risk of suicidal thoughts and behavior in pediatric and young adult patients. Immediate medical attention should be sought if this occurs.
• Milnacipran: This drug is initiated at 12.5 mg daily, and the dose is increased by 12.5 mg every few weeks until reaching a maximum of 50 to 100 mg, taken once or twice daily. Clinical trials indicate an average effective dose of 100 mg/d.

Patients with widespread pain and significant sleep disturbances should use pregabalin as a first-line option. Gabapentin is a suitable alternative when cost or availability limits pregabalin use. Adult dosing is as mentioned below.

• Pregabalin: The starting dosage of this drug is 25 to 50 mg at bedtime, titrated by 25 to 50 mg every 2 to 4 weeks. Dosing can be administered once in the evening or divided into 2 equal doses twice daily. Based on clinical trials, the typical recommended dosage is 300 to 450 mg/d, although some patients may respond to lower doses.
• Gabapentin: This drug should be initiated at a dose of 100 mg at bedtime, with gradual titration in 100 mg increments every few weeks. The recommended daily dosage ranges from 1200 to 2400 mg, divided into up to 3 doses per day.[63]
(A1)

Pregabalin and gabapentin are used off-label in children and adolescents and may be effective. However, further research is needed to establish specific recommendations regarding their safety and efficacy in juvenile patients with fibromyalgia.

Treatment for Persistent Symptoms

Clinicians should switch to a different medication class as a reasonable approach if the initial pharmacological agent does not provide adequate relief. Clinicians should gradually taper moderate-to-high doses of fibromyalgia medications to prevent withdrawal symptoms. If monotherapy with different agents remains ineffective, combination therapy using lower doses from different medication classes may be appropriate. The choice of combination therapy should consider cost, availability, and comorbid conditions. Common combinations include a low-dose SNRI in the morning with a low-dose TCA at bedtime or a low-dose SNRI in the morning with a low-dose α-2 ligand at bedtime.[62][64] (B3)

Alternative Therapeutic Considerations

• Selective serotonin reuptake inhibitors: Limited evidence reveals that the selective serotonin reuptake inhibitors fluoxetine, paroxetine, and fluvoxamine may be effective in treating fibromyalgia. These medications may be considered for patients who cannot tolerate or do not experience adequate relief from first-line therapies.
• Nonsteroidal anti-inflammatory drugs: Current evidence does not support the significant benefits of NSAIDs in managing fibromyalgia symptoms.
• Opioids: In general, clinicians should avoid prescribing opioids for fibromyalgia treatment. However, tramadol, a weak opioid, acts as a μ-receptor agonist and inhibits the reuptake of serotonin and norepinephrine. Studies suggest that tramadol can be effective in managing fibromyalgia, particularly in patients with refractory symptoms. 
• Low-dose naltrexone: Low-dose naltrexone, typically administered at 5 mg, is used for chronic pain management by upregulating endogenous opioid production.[65][66][67] 
• Nutrition: A specific dietary guideline for treating fibromyalgia has not been established. However, fibromyalgia symptoms are directly correlated with increasing BMI, and weight loss has been shown to improve pain and depression associated with the condition. Patients with obesity who lose 10% or more of their body weight tend to experience the most benefit. Plant-based diets and low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diets may also help improve symptoms, though further studies are needed to confirm these findings.[68][69]
• Acupuncture: Moderate evidence supports acupuncture as an effective treatment for fibromyalgia.[70]
• Neuromodulation: Peripheral nerve stimulation with a transcutaneous electrical nerve stimulation (TENS) unit, applied at high intensity over multiple sessions, has been shown to improve pain and fatigue in fibromyalgia patients.[71] Additionally, transcranial magnetic stimulation and transcranial direct current stimulation have been found to reduce pain perception and fatigue in those with fibromyalgia.[72][73]
• Trigger point injections: Small studies suggest that trigger point injections may offer some benefits in managing fibromyalgia symptoms.[74] 
• Massage therapy: Regular massage therapy has been shown to be beneficial in managing fibromyalgia symptoms.[75]
(A1)

Differential Diagnosis

Given the multiple nonspecific and overlapping symptoms, fibromyalgia may mimic other conditions. The differential diagnoses include:

• Polymyalgia rheumatica
• Spondyloarthritis
• Myositis
• Hypothyroidism
• Hyperparathyroidism
• Neuropathies
• Systemic lupus erythematosus
• Chronic fatigue syndrome
• Hepatitis
• Vitamin B12 deficiency
• Vitamin D deficiency
• Myofascial pain syndrome
• Hereditary myopathies
• Complex regional pain syndrome
• Dermatomyositis
• Juvenile idiopathic arthritis
• Chronic noninfectious osteomyelitis

Pertinent Studies and Ongoing Trials

HRV analysis may serve as a useful biomarker, and techniques such as HRV biofeedback hold potential as treatment modalities for improving HRV and managing symptoms.

Prognosis

Fibromyalgia significantly affects the quality of life in both juvenile and adult patients.[76] However, currently, the long-term effects of juvenile fibromyalgia into adulthood are not well understood. Studies suggest that most patients will continue to experience symptoms into early adulthood.[77][78] Similarly, the majority of adult patients with fibromyalgia experience chronic symptoms that can wax and wane, with varying severity from person to person. Notably, patients treated and followed at large tertiary care centers tend to have a worse prognosis compared to those treated at community primary care clinics.[79][80]

Depression, a history of abuse, catastrophizing, and multiple somatic concerns are the strongest predictors of poor outcomes. Additional factors, including female sex, low socioeconomic status, prolonged disease duration, untreated depression and anxiety, alcohol or drug dependence, high stress levels, and unemployment, further contribute to the disease burden. Patients with fibromyalgia report disability rates of 10% to 30% and face an increased risk of suicide.[81]

Complications

Fibromyalgia increases the risk of metabolic syndrome, largely due to reduced physical activity. Additionally, patients experience higher rates of disability and suicide compared to the general population. Recent research also suggests an elevated risk of mortality from accidents and infections.[82]