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FIBROMYALGIA (FM) PATHOPHYSIOLOGY - Study of the disturbance of normal functions Pathophysiology

The prevailing model for the development of Fibromyalgia (FM) involves:

  1. Certain vulnerability elements (female sex, genes, abuse or other adverse experiences during childhood when the brain is still developing)

  2. Persistent stress or distress. Psychologic variables (eg, distress, mood and anxiety disorders, personality traits and disorders, catastrophizing, coping, self-efficacy for pain control) play a central role in the pain experience, overall morbidity, and prognosis in patients with FM.

Choose from the links below to learn more:

Anxiety - Stress - Trauma

High levels of anxiety and distress, less certainty of pain resolution, and a history of trauma are predictors of whether the acute pain will progress to chronic pain. Consistent with the relationship between pain and distress is the improvement in measures of self-efficacy, coping, depression, pain, health status, and disease activity that accompany the application of stress-management programs.

The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" (Merskey, 1986). Implicit here is the threat associated with pain, which can be trivial or profound. Neurophysiologically, the pain experience derives from a complex sensation-perception interaction involving the simultaneous parallel processing of nociceptive input from the spinal cord to multiple regions of the brain.

In addition to strictly sensory-discriminative elements of pain receptors and afferent input from somatic reflexes, major contributions from pathways and regions of the brain that are associated with emotional, motivational, and cognitive aspects of pain are evident and help determine the subjective intensity of pain. The two principal effectors of the stress response, the hypothalamic-pituitary-adrenocortical (HPA) axis and the sympathetic nervous system (SNS), are also activated.

Although normally adaptive, the stress response may become maladaptive in patients with chronic pain and fatigue syndromes, such as FM. Negative emotions (eg, depression and anxiety) and other negative psychologic factors (eg, loss of control, unpredictability in one's environment) and certain cognitive aspects (eg, negative beliefs and attributions, catastrophizing) can all function as stressors with actions in these systems.

In some patients with FM, such negative emotional, motivational, and cognitive stressors may dominate the clinical picture, potentially leading to a self-sustaining neuroendocrine cascade that contributes to flu-like symptoms, depressed mood, fatigue, myalgias, cognitive difficulties, and poor sleep. The important biologic elements here include proinflammatory cytokines, the HPA axis, other neuroendocrine axes, and the autonomic nervous system. Growth-hormone abnormalities are also thought to contribute to symptomatology in FM.

Pain in patients with FM derives partly from a generalized decrease in the pain perception threshold, reflecting discrimination of a nociceptive quality from a nonnociceptive quality (eg, touch, warmth, cold), and in the threshold for pain tolerance, reflecting an unwillingness to receive more-intense stimulation. These phenomena can be demonstrated clinically by pressure algometry (dolorimetry) or in research settings with quantitative sensory testing (QST) using pressure, heat, cold, or electricity as stimuli. Underlying these changes in thresholds is altered processing of nociceptive stimuli in the CNS (central sensitization).

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Abnormalities in Pain Processing in FM Include:

  1. Excess excitatory (pronociceptive) neurotransmitters (eg, substance P, glutamate levels in the insula)

  2. Low levels of inhibitory neurotransmitters (eg, serotonin and norepinephrine) in descending antinociceptive pathways in the spinal cord

  3. Maintained enhancement of temporal summation of second pain.

  4. Altered endogenous opioid analgesic activity in several brain regions known to play a role in pain modulation, and (5) dopamine dysregulation, among others.

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Single Nucleotide Polymorphism (SNP)

High throughput genotyping is rapidly identifying a series of single nucleotide polymorphism (SNP) haplotypes that influence neurotransmitter levels and receptor levels in the brain that contribute to the various abnormalities in pain processing. Such SNP haplotypes constitute vulnerability elements in the development of FM and other central sensitivity syndromes. Pharmacologic agents known to be effective in reducing pain in FM function in this regard by either increasing levels of inhibitory neurotransmitters (eg, duloxetine) or decreasing levels of excitatory neurotransmitters, in turn increasing levels of substance P (eg, gabapentin or pregabalin). Because FM is a polygenic syndrome with multiple different underlying genetic polymorphisms, genetic testing to tailor therapy and to predict response to therapy will soon become available.

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The HPA Axis and Fibromyalgia

Fibromyalgia (FM) can be broken down into five causal subtypes. All five subtypes have one important thing in common; they all result in Hypothalamus Pituitary Adrenal Axis (HPA Axis) dysfunction. The HPA Axis controls most hormone levels in our bodies. The result of HPA Axis dysfunction is hormone level irregularities. Because most of the hormones in our bodies are very finely regulated, the end result is a system in chaos.

The diagram to the right represents how the HPA axis works: The central nervous system sends signals via the spinal cord and brain to the hypothalamus. These signals tell the hypothalamus important messages about the body, such as the need for more blood circulation, sexual stimulation, amount of light outside, and many more. The hypothalamus then responds to these messages by stimulating the body to perform necessary functions, such as speed up the heart to circulate more blood when exercising.

The hypothalamus also releases a hormone (corticotropin releasing hormone, or CRH) that stimulates the pituitary gland to go to work. The pituitary gland, located just above the roof of the mouth and behind the nose, controls the release of a number of hormones. A few important ones include:

  • Human Growth Hormone (HGH) - important for muscle recovery and immune function
  • Thyroid‐stimulating hormone (TSH) - "turns on" thyroid gland
  • Adrenocorticotropic hormone (ACTH) - stimulates adrenal glands to release cortisol

ACTH from the pituitary gland stimulates the adrenal glands to release cortisol. Cortisol plays an important role in the symptoms of most FM and CFS/ME sufferers.

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The Vicious Cycle of Fibromyalgia

In FM sufferers, the HPA Axis is disrupted. This results in system‐wide hormone irregularities. The following diagram breaks down the pattern of disruption:

The above cascade of events is unofficially referred to as the vicious cycle of fibromyalgia. The causal event results in decreased signals to the hypothalamus. When this occurs, the entire HPA axis operates at a lower level. The result is many of the symptom of FM. Once this vicious cycle begins, it loops back and continues to make matters worse. This is part of the reason why FM sufferers continue to degrade.

The vicious cycle of fibromyalgia has many negative consequences. The following are some of the deleterious effects of each stage of the cycle:

  • Central sensitization occurs when sensory organs of the body become oversensitive, causing an increased response to painful stimuli. Hormone imbalances can initiate sympathetic nervous system abnormalities, which result in central sensitization.

  • Decreased hypothalamus function results in a wide array of symptoms. Common symptoms include sleep disturbances, decreased libido, sensitivity to cold temperatures, change in appetite, poor digestion, balance and coordination problems, blood pressure abnormalities, and heart rate abnormalities.

  • Decreased pituitary function leads to decreased thyroid function. This can cause hypothyroid symptoms, such as fatigue and weight gain. Human growth hormone (HGH) is decreased as well. HGH is released while you sleep, and is responsible for helping your muscles recover from the damage done during the day. It also is important in immune function.

  • Decreased adrenal function results in decreased cortisol. Cortisol imbalance is associated with fatigue, depression, weight gain, and immune dysfunction. Since cortisol also suppresses inflammation and cellular immune activation, reduced cortisol tends to aggravate inflammatory responses.

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Cellular Effects of Fibromyalgia

Fibromyalgia has known negative effects on a cellular level. Most often, these negative effects are the result of HPA Axis dysfunction.

Mitochondria Dysfunction

Studies show that there is mitochondrial dysfunction in most FM and CFS/ME sufferers. Mitochondria are the energy factories for the cells, where sugar is burned and energy is produced in the form of ATP (adenosine Triphosphate). Mitochondria can be poisoned by numerous substances, including environmental toxins, pesticides, chronic bacterial, viral and fungal infections, neurotoxins, and nutritional and hormone deficiencies.

When the mitochondria are not working properly the cells and tissues of the body are starved for energy. This abnormality may be the common endpoint for all the dysfunctions present in FM and CFS/ME. No sugar is burned resulting in weight gain, and no energy is produced, resulting in fatigue, muscle pain, poor concentration, gastrointestinal dysfunction, headaches, etc.


Cytokines are small secreted proteins which mediate and regulate immunity, inflammation, and hematopoiesis (the development of blood cells). Abnormal cytokine levels are found in many fibromyalgia sufferers. Research suggests this is secondary to the effects of fibromyalgia. Factors that could contribute to cytokine abnormalities are other immune problems, abnormal hormone activity, or sleep disturbances.

Natural Killer Cells

There is an increased risk of cancer in patients with widespread muscle pain. This is likely due to these individuals having low natural killer cell function and/or numbers. Over half of FM and CFS/ME sufferers have low natural killer cell numbers or activity.

The function of the natural killer cells (NKC) is to kill viruses and intracellular bacteria. They roam throughout the body in search of infected cells to destroy. If the natural killer cells are low in number (NKC number) or poorly functioning (NKC activity), there is a diminished ability to fight infection, resulting in the inability to eradicate chronic infections. NKCs also kill cancer cells in the body. Therefore low NKC numbers cause increased risk for all types of cancer. Every FM and CFS/ME sufferer should know both their NKC number and activity.

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