Fibromyalgia is a condition characterized by chronic widespread musculoskeletal pain.

Fatigue, cognitive disturbances, insomnia, psychiatric, and multiple physical symptoms often accompany the disorder.

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Fibromyalgia has unclear etiology and uncertain pathophysiology [12].

There is no indication of tissue inflammation, despite symptoms of soft tissue pain (muscles, tendons, ligaments, fascia, nerves, fibrous tissues, fat, blood vessels, and synovial membranes).

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Fibromyalgia is a pain regulation disorder, as suggested by ongoing research, and often classifies as a form of central sensitization syndrome [3].

Central sensitization is considered the main mechanism involved in fibromyalgia and refers to an abnormally, increased response to stimulation – painful or not- through CNS signaling [4]

Today fibromyalgia is considered to be a neurosensory disorder where the individual is not able to process pain in the brain normally.

In fibromyalgia, patients often become hypersensitive to the perception of pain.

The constant hypervigilance of pain is also correlated with numerous psychological issues.



As with many chronic conditions, fibromyalgia is more common in women than men, and its prevalence is 2 to 3% in the USA and other countries.

It increases with age [56].

In most women between the ages of 20 to 55 years, the main cause of generalized, musculoskeletal pain is fibromyalgia.

Many studies have found that the prevalence of the disease in adolescents is similar to those in adults.

About 40% of the patients referred to a tertiary care pain clinic, meet the criteria for fibromyalgia [7].

The risk for fibromyalgia is higher if you have a pre-existing rheumatic or musculoskeletal disease, such as chronic joint pain.


The causes of fibromyalgia are unknown [89].

There is no evidence of any single underlying cause of this condition; instead, it is triggered or aggravated by multiple physical and/or emotional stressors, which include infections as well as emotional and physical trauma.

Fibromyalgia is considered a pain regulation disorder often classified under central sensitization [10].

Some research studies have shown a genetic predisposition for fibromyalgia, though there is no documentation of a definitive candidate gene [11].

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Pain and sensory processing alterations in the central nervous system (CNS) are present in fibromyalgia [12].

Fibromyalgia patients perceive noxious stimuli as being more painful compared to healthy controls [13].

Rapidly-repetitive brief noxious stimuli make fibromyalgia patients experience higher than normal increases in their perceived intensity of pain.

There appears to be a deficiency in the endogenous analgesic (pain-suppressing) systems in fibromyalgia patients.

Functional neuroimaging techniques, such as magnetic resonance imaging (MRI) and positron emission tomography (PET) have demonstrated differences in the activation of pain-sensitive areas of the brain in people with fibromyalgia.

In general, the main factors involved in fibromyalgia include dysfunction of the central and autonomic nervous systems, neurotransmitters, hormones, immune system, external stressors, and psychiatric aspects.

Central Nervous System (CNS)

Central sensitization is considered the main mechanism involved in fibromyalgia and refers to an abnormally, increased response to stimulation through CNS signaling [4].

Central sensitization occurs due to spontaneous nerve activity, enlarged receptive fields, and augmented stimulus responses transmitted by primary afferent nerves (nerves that carry signals from the periphery toward the central nervous system) [14]

An important phenomenon involved in fibromyalgia seems to be the “wind-up”, which refers to the increased excitability of spinal cord neurons; after a painful stimulus, subsequent stimuli of the same intensity are perceived as stronger [15].

This occurs normally in everyone [16], but it is excessive in fibromyalgic patients [17].

These phenomena are a manifestation of neuroplasticity and are mainly mediated by N-methyl-D-aspartate (NMDA) receptors located in the post-synaptic membrane in the dorsal horn of the spinal cord [18192021].

Another supposedly involved mechanism includes the well-known descending inhibitory pain pathways, which modulate spinal cord responses to painful stimuli.

They seem to be impaired in patients with fibromyalgia, helping to exacerbate the central sensitization [142223].

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Apart from augmented neuronal mechanisms, glial cell activation also seems to play an important role in the pathogenesis of fibromyalgia, because they help to modulate pain transmission in the spinal cord.

Glial cells are non-neuronal cells in the central and peripheral nervous system that do not produce electrical impulses, but maintain homeostasis, form myelin, and provide support and protection for neurons.

Glial cells, activated by various painful stimuli, release pro-inflammatory cytokines (i.e interleukins), nitric oxide, prostaglandins, and reactive oxygen species (ROS) that stimulate and prolong spinal cord hyperexcitability [242526].

In addition, various neurotransmitters seem to be involved in central sensitization.

Serotonin (5-HT) has a notable role in the modulation of pain [27], and several studies have been carried out looking for modified levels of this molecule in the serum and cerebrospinal fluid (CSF) of fibromyalgic patients.

Also, serotonin’s (5-HT’s) precursor tryptophan and its metabolites have been measured in the blood and cerebrospinal fluid (CSF), as well as in the urine with conflicting data.

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In some studies, serotonin (5-HT) was found at low levels, either in the serum [282930] or in the cerebrospinal fluid (CSF) [31], while other authors have not found statistical differences in serotonin (5-HT) levels between affected patients and controls, either in serum [28] or in the cerebrospinal fluid (CSF) [32].

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Serotonin is also involved in the regulation of mood and sleep [3334] and this could explain the association between fibromyalgia and sleep and mental disorders.

Other neurotransmitters, such as catecholamines, also play a role.

Data are suggesting the involvement of norepinephrine [32], dopamine [3536], substance P (whose levels are typically high in cases of fibromyalgia as its synthesis is inhibited by serotonin) [373839], endorphins, and met-enkephalins [4041].

These peptides of the human endogenous opioid system seem to be hyperactive, but somehow unable to modulate pain in these patients.

This could explain the reduced efficacy of use of exogenous opiates in this population [42].

Exogenous opiates are ineffective in fibromyalgia patients due to the occupancy of opioid receptors by endogenous opioids released in response to painful stimuli.

Harris et al. [40] tried to explain the apparently paradoxical hyperactivity of the endogenous opioid system in fibromyalgia patients.

He showed a significantly reduced overall μ opioid receptor binding potential in fibromyalgic patients.

Further functional neuroimaging studies also support the involvement of the brain in the pathogenesis of this condition.

In the first functional magnetic resonance imaging (fMRI) study of fibromyalgia [43] 16 patients and 16 controls underwent fMRI during painful stimulation.

First, the 2 groups were stimulated with the same pressure; then the stimulation intensity of controls was increased to deliver a subjective level of pain similar to that experienced by the fibromyalgia patients.

Neural activation patterns were similar only under the second condition of painful stimulation.

These findings support the hypothesis of a model of centrally augmented pain processing present in fibromyalgia.

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Cook et al. examined with functional magnetic resonance imaging (fMRI) the response of two groups of women (9 patients and 9 controls) to both painful and non-painful stimuli [44].

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In response to non-painful stimuli, patients showed significantly greater activity than controls in insular, prefrontal, supplemental motor, and anterior cingulate cortices.

In response to painful stimuli, the contralateral insular cortex was activated to a significantly greater extent in fibromyalgia patients than it was in controls.

Additional neuroimaging methods have been used to understand the central pathogenesis of fibromyalgia.

Voxel-based morphometry (VBM) uses magnetic resonance imaging (MRI) images to assess the volume of specific brain regions.

Various studies have shown a loss of grey matter (major component of the central nervous system) in fibromyalgic patients, involving the amygdala, the cingulate cortex, and the hippocampus [45464748].

The significance of this atrophy is not clear.

Diffusion tensor imaging (DTI) is based on the movement of water through brain tissue and provides information about the integrity of white matter (myelin-rich tissue through which messages pass between different areas of grey matter within the CNS).

Sundgren et al. showcased a reduced signal in the right thalamus in patients affected by fibromyalgia and the reduction was statistically greater in patients referring worse pain [49].

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The thalamus is a small structure within the brain, located just above the brain stem that connects the cerebral cortex with the midbrain through a dense network of nerves.

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Its main function includes the delivery of motor and sensory signals to the cerebral cortex (the outer layer of neural tissue of the cerebrum of the brain).

Magnetic resonance spectroscopy (MRS) evaluates the concentration of various molecules (e.g., glycine, glutamate, and aspartate) in relation to a standard molecule.

Fibromyalgic patients showed a different ratio of choline/creatine within the dorsolateral prefrontal cortex and a different ratio of glutamate/glutamine within the insula and the posterior gyrus [50, 51, 52].

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Autonomic Nervous System and Neuroendocrine Function

As fibromyalgia is classified as a stress-related disorder, it is easy to understand that the hypothalamic-pituitary-adrenal (HPA) axis is involved [53].

Different studies have shown elevated cortisol levels in patients, particularly in the evening, associated with a disrupted circadian rhythm [5455].

Additionally, patients with fibromyalgia showed high values of adrenocorticotropic hormone (ACTH) both in normal conditions [5657] and in response to stress—most likely as a consequence of a chronic hyposecretion of corticotropin-releasing hormone (CRH) [58].

These alterations are probably related to low levels of serotonin (5-HT) observed in cases of fibromyalgia, because serotoninergic neurons (neurons that produce serotonin in the brain) regulate the HPA axis function [59].

In fibromyalgia, growth hormone (GH) levels tend to be normal during the day and reduced during sleep.

The explanation for this is likely twofold.

First, growth hormone (GH) is mainly secreted during stage 4 of sleep and this phase is disrupted in patients affected by fibromyalgia.

Second, these patients have high levels of somatostatin, a GH inhibitor, induced by adrenocorticotropic hormone (ACTH), whose levels are high as previously mentioned [60].

Thyroid hormone levels are usually normal, even if the patients often show symptoms of hypothyroidism (fatigue, dry skin, cold sensitivity, weight gain, constipation, depression, etc.).

There is also some evidence suggesting an association of fibromyalgia with the abnormal secretion of thyrotropin-releasing hormone (TRH), as happens in thyroid hormone resistance [61].

Gonadotropin (FSH and LH) and gonadal steroid secretion are usually normal [626364], apparently without any correlation to the higher incidence of fibromyalgia in females.

Several studies, the most recent of which is based on methodologies, such as power spectrum analysis of heart rate variability [6566] and tilt table tests [81], seem to confirm that in fibromyalgia the sympathetic nervous system is persistently hyperactive, but paradoxically, hyporeactive to stress.

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This could explain some clinical symptoms, such as fatigue, morning stiffness, sleep disorders, anxiety, pseudo-Raynaud’s phenomenon, Sjogren syndrome-like symptoms, and bowel irritability [42].

High serum levels of neuropeptide Y (the most abundant peptide in the CNS), which is normally secreted along with norepinephrine, are also probably a sign of this dysautonomic state [67].

Sleep Problems

Patients with fibromyalgia often complain of sleep disorders [68] and these are probably involved in its pathogenesis [69].

As revealed by electroencephalographic examinations (EEG), the fourth phase of sleep (stage IV) is the most disturbed and a direct consequence should be a deficit of GH and insulin-like growth factor 1 (IGF-1) [7071].

Considering that these hormones are involved in muscle microtrauma repair, the healing of this tissue could be affected by sleep disturbances present in fibromyalgia [72].

Genetic Susceptibility

Genetic predisposition is likely to be an important factor as suggested by various familial studies [7374] and transmission is thought to be affected by multiple genes [75].

Among the various genes investigated, the most important are linked with neurotransmitters.

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The serotonin transporter gene is characterized by a single nucleotide polymorphism.

Particularly, the “S” (short) allele is more frequent in patients affected by fibromyalgia and by psychological distress [7677].

Other genes presumably involved are the catechol-O-methyltransferase gene [7879], the dopamine D4 receptor gene [80], and the HLA-region [81].

Immune Function

Fibromyalgia is common in patients suffering from autoimmune disease [828384].

Different studies in the scientific literature deal with autoantibodies in fibromyalgia [85868788] with equivocal results.

In particular, several authors have investigated the association between fibromyalgia and anti-polymer antibodies (APAs) [8990].

However, the results are controversial and APAs cannot be used as a marker for diagnosis [91].

Psychiatric Component

Psychiatric problems are major contributors to the development of fibromyalgia.

The prevalence of psychiatric conditions among patients suffering from fibromyalgia is higher than among subjects complaining of other rheumatic diseases [92].

The most common disorders associated are anxiety, somatization (manifestation of psychological distress in the form of physical symptoms), persistent depressive disorder (dysthymia), panic disorders, post-traumatic stress (PTSD), and overall depression [93, 94959697].

Depression is more commonly associated with fibromyalgia than with other musculoskeletal diseases [98] and the dysfunction of the serotonin (5-HT) system might play a role [99].

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Depression worsens the symptoms of fibromyalgia and vice versa, and anti-depressants represent a cornerstone of fibromyalgia therapy [100101102].

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Infections seem to be able to induce fibromyalgia, even if a direct causal relationship has not been established [103].

In particular, viruses such as HCV, HIV, Coxsackie B, and Parvovirus [104105106107] and bacteria like Borrelia [108109] are speculated to be involved.

An important role with regards to this association might be played by cytokines [110111112] and by glial cells, which, for example, express receptors for bacteria and viruses [113114].

Physical trauma [115], vaccinations [103], and chemical substances [116] are possible trigger factors.

Greenfield et al. [117] noticed that patients who reported having trauma, surgery, or a medical illness prior to the onset of fibromyalgia (reactive fibromyalgia), were more disabled than those with no precipitating event occurring before the onset of the disease (primary fibromyalgia), resulting in loss of employment in 70%, disability compensation in 34%, and reduced physical activity in 45%.  


Widespread musculoskeletal pain and fatigue are the main characteristics of fibromyalgia and are often accompanied by cognitive and psychiatric disorders [118].

Widespread Musculoskeletal Pain 

The primary complaint of a patient with fibromyalgia is widespread musculoskeletal pain, which is bilateral and involves both upper and lower parts of the body.

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The pain may be localized initially, commonly located in the neck and shoulders.

The predominant description of the pain is like muscle pain, but the patients may complain of joint pain as well [119].


The other chief symptom of fibromyalgia is fatigue [120].

Especially upon waking up from sleep, but also present in the mid-afternoon.

Minor physical activities may aggravate the pain and fatigue, though inactivity for prolonged periods also amplifies the symptoms.

There is joint and muscle stiffness when waking up in the morning.

Patients complain of light sleep with frequent awakenings during the early morning.

They feel groggy and unrefreshed in the morning, even if they complete 8 to 10 hours of sleep.

Cognitive Disturbances 

Often referred to as “fibro fog,”.

Essentially, patients have difficulty with attention and doing tasks that require rapid changes in thought.

Other Symptoms 

30 to 50 percent of patients have anxiety and/or depression at the time of diagnosis [121].

More than 50 percent of the patients experience headaches, which include migraines and tension-type headaches [122].

Patients often complain of paresthesias (tingling, burning, and numbness), in both arms and legs.

A detailed neurologic evaluation is typically unremarkable.

Concerning gastrointestinal syndromes, irritable bowel syndrome (IBS) is most commonly correlated with fibromyalgia.

Gastroesophageal reflux disease (GERD) also occurs more frequently in patients with fibromyalgia compared to the general population [123].

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Patients may as well complain of dry eyes, dyspnea (shortness of breath), dysphagia (swallowing difficulties), and heart palpitations.

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Fibromyalgia is known as a “diagnosis of exclusion”.

Often times, it is a write-off to patients that have some type of unclassified pain that can’t be pinpointed as having an exact cause.

No abnormalities are present in fibromyalgia during routine clinical laboratory testing or imaging.

However, research studies that include functional MRI (fMRI) and other specialized imaging techniques have revealed certain abnormalities in fibromyalgic patients compared to control subjects.

Generally, a patient fulfills the diagnostic criteria for fibromyalgia if the following three conditions are met:

1) Widespread pain index (WPI) is 7 and symptom severity (SS) scale score is 5, or the widespread pain index (WPI) equals 3 to 6 and the symptom severity (SS) scale score is 9.

2) Symptoms have been present at a similar level for at least 3 months.

3) The patient does not exhibit any other disorder that would otherwise explain the pain.

Widespread Pain Index (WPI)

It refers to the number of areas that cause pain to the patient (tender-points) for the last week prior to examination.

The score can be between 0 and 19.

These areas include: Shoulder girdle, left hip (buttock, trochanter), left jaw, left upper back shoulder girdle, right hip (buttock, trochanter), right jaw, right lower back upper arm, left upper leg, left chest neck upper arm, right upper leg, right abdomen lower arm, left lower leg, left lower arm, and right lower leg.

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Symptom Severity (SS) Scale Score

It refers to symptoms of fatigue, waking unrefreshed, and cognitive disturbances.

For each of the three symptoms above, the patient must indicate the severity level over the last week utilizing the following scale: 

A) 0- no problem 

B) 1- slight or mild problems, generally mild or intermittent 

C) 2- moderate, considerable problems, often present and/or at a moderate level 

D) 3- severe, pervasive, continuous, and life-disturbing problems

Concerning physical symptoms in general, it must be clear whether the patient has: 0 for no symptoms, 1 for a few symptoms, 2 for a moderate number of symptoms, 3 for many symptoms.

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The symptom severity (SS) scale score sums the severity of the 3 symptoms (fatigue, waking unrefreshed, cognitive disturbances), plus the severity of the general physical symptoms.

The final score can be between 0 and 12.

Treatment / Management

The therapeutic approach in fibromyalgia includes educating patients regarding the disease and treatment approaches, exercise regimen, and drug therapy for patients not responding to non-pharmacologic measures.

The goals of the treatment should focus on alleviating pain, increasing restorative sleep, and improving physical function through a reduction in associated symptoms [124].

The identification and treatment of all pain sources that may be present in addition to fibromyalgia, such as peripheral inflammatory or neuropathic pain generators (e.g., comorbid osteoarthritis or neuropathic pathologies) or visceral pain (e.g., comorbid irritable bowel syndrome) are fundamental to the proper clinical management of fibromyalgia [125].

Because pain, depression, and other symptoms of fibromyalgia are linked to inherited and environmental factors, a multifaceted, multi-disciplinary treatment approach is often required, including both non-pharmacological pain management strategies and medication [126].

Patient Education

It is important that patients with fibromyalgia understand their illness before the prescription of any drugs or medications [127128129].

The most important elements of patient education include:

1) Reassuring the patient that fibromyalgia is a real disease.

2) That stress and mood disturbances play a big role, and that patients with fibromyalgia should be encouraged to learn relaxation techniques, as well as become part of a formal stress reduction program.

About 30% of fibromyalgic patients have major depression at the time of diagnosis and the lifetime prevalence is 74%.

The lifetime prevalence of anxiety disorder is 60%.

These patients should be encouraged to get professional support.

3) Good sleep hygiene is an integral part of the management of fibromyalgia and recognizing and obtaining treatment of sleep disorders, which most likely contribute to symptoms of fibromyalgia, is equally important.


Cardiovascular fitness training is recommended in fibromyalgia as it helps with pain and improves mood and sleep [59130].

Recommended optimal cardiovascular fitness training constitutes a minimum of 30 minutes of aerobic exercise three times per week with the heart rate near the target range.

Low-intensity aerobic exercises, such as fast walking, biking, or swimming, appear to be the most helpful to people with fibromyalgia.

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For most patients, it is recommended to continue non-pharmacologic measures along with the use of certain medications.

Some patients, may, however, respond adequately to non-pharmacologic treatments alone.

The medications that have been well studied and proven to be consistently effective are specific anti-depressants and anti-convulsants.

The antidepressants include tricyclic medications, like amitriptyline and other selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (SNRIs), including duloxetine and milnacipran.

Cyclobenzaprine, a tricyclic medication, has also been found to be effective.

The beneficial anti-convulsants include gabapentin and pregabalin.

The three drugs for the treatment of fibromyalgia, approved by the US Food and Drug Administration (FDA) are pregabalin, duloxetine, and milnacipran.

Therapy most often starts with tricyclic anti-depressants.

An SNRI or one of the anti-convulsants is an option in patients with inadequate response or intolerance to tricyclic antidepressants.

However, in a patient with severe fatigue, depression, or severe sleep disturbances, an SNRI or an anti-convulsant is typically recommended.

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Treatment for Persistent Symptoms (Non-Responsive Fibromyalgia)

Despite the initial approach of non-pharmacologic measures and single pharmacologic agents at maximum tolerated dose, many patients continue to have symptoms.

For those patients, the current recommendations are the following:

In patients not responsive to a single medication (monotherapy), it is recommended to use a combination of drug therapy.

In addition, patients who face difficulties reaching a sufficient level of low-impact aerobic exercise should be encouraged to participate in a supervised physical exercise program.

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Referral to a physiatrist and/or a physical therapist would also be beneficial for these patients.

Water-based exercises, such as gentle swimming and yoga have also been found to be useful in a few studies.

Psychosocial interventions, such as cognitive-behavioral therapy (CBT) can be helpful in patients with inadequate response to initial treatments.

Specialty consultations with rheumatologists, physiatrists, and psychiatrists are advised in patients not responding adequately to initial therapies.

Treatment should be multi-faceted, multidisciplinary, and individualized with close attention to the patient’s symptoms [131].

There is limited data for the potential beneficial role of analgesics and anti-inflammatory drugs, as well as complementary and alternative therapies, like tai chi, yoga, and acupuncture.

Some studies have also shown benefits with neuromodulation techniques, such as transcranial stimulation, occipital and C2 nerve stimulation, and transcutaneous electrical nerve stimulation.


Fibromyalgia is a complex syndrome with vague and generalized symptoms that affect multiple organ systems, but mainly the musculoskeletal and nervous system.

For that reason, it is often difficult to diagnose, particularly for physicians who do not usually deal with this disease.

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Despite this, three main symptoms are referred to by almost every patient: chronic pain, fatigue, and sleep disturbances.

There is a substantial role of stress and mood disturbances in fibromyalgia, so patients should be encouraged to learn relaxation techniques, as well as participate in formal stress reduction programs.

Even though its pathogenesis is still not fully clear, modern functional neuroimaging techniques are giving us important data about the involvement of the central nervous system (CNS).

For successful treatment and management, a multidisciplinary approach is mandatory.

The physician should take into consideration both drugs (in particular anti-depressants and neuromodulating anti-epileptics / anti-convulsants) and non-pharmacological options, such as aerobic exercise, strength training, aquatic exercises, balneotherapy (immersion in mineral-rich water), cognitive-behavioral therapy (CBT), as well as emerging brain stimulation techniques, such as transcranial magnetic stimulation (TMS).

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About George Kelly

George Kelly M.Sc is a Sports Nutritionist, Functional Nutritional Therapy Practitioner (FNTP), and Metabolic Type expert. He is the CEO and lead author of Metabolic Body.




This content is for informational and educational purposes only. It is not intended to provide medical advice or to take the place of such advice or treatment from a personal physician. All readers/viewers of this content are advised to consult their doctors or qualified health professionals regarding specific health questions. Neither Metabolic Body nor the publisher of this content takes responsibility for possible health consequences of any person or persons reading or following the information in this educational content. All viewers of this content, especially those taking prescription or over-the-counter medications, should consult their physicians before beginning any nutrition, supplement or lifestyle program.