Fibromyalgia Pathophysiology and Treatment Implications

Studies have looked for alterations in hormones or immune factors that might account for inappropriate pain signaling.

Fibromyalgia is a condition characterized by widespread pain, abnormal pain processing, sleep disturbance, fatigue, and psychological distress. There appears to be heterogeneity among fibromyalgia patients, but the pathophysiology of the disease is not completely understood, making it a difficult condition to treat. 

“It is a very heterogeneous condition, more like a syndrome. The range of pain varies a lot from intermittent to continuous. So does the severity,” said Christopher Coe, PhD, professor in the department of psychology at the University of Wisconsin, Madison.

Neurobiological Mechanisms Underlying Fibromyalgia

Many researchers have attempted to explain fibromyalgia as alterations in the periphery, at the level of sensory nerves, which may send errant signals about pain. 

“Peripheral sensory neuron changes, we believe, may occur with fibromyalgia based on some of our recent preclinical studies,” said Michael Jankowski, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio. “The neurobiological mechanisms involved in fibromyalgia pain and symptoms may be likely due to the chemically sensitive muscle sensory neurons that are separate functionally, under normal conditions, but now have overlapping function in certain disease states or after injuries in the muscle. That is to say, the ‘fatigue-sensing neurons’ may respond to painful metabolites and/or the ‘pain-producing muscle sensory neurons’ become sensitive to metabolites that are not normally painful in fibromyalgia.”

Another unique feature of these muscle sensory neurons in particular is that they not only transmit sensations of fatigue and pain, but they also are involved in mediating other functions. 

According to Jankowski, this includes enhanced cardiovascular responses to exercise such as increased blood pressure and heart rate. 

“Due to this involvement, an interesting possibility in the context of fibromyalgia is that a vicious cycle may occur in which improper feedback throughout the system leads to fibromyalgia pain from an altered cardiovascular response to muscle contractions via the muscle sensory neurons. This idea is supported by the fact that we not only see pain in these patients but also some cardiovascular symptoms as well,” said Jankowski.

In addition, others have noted that alterations in brain neurocircuitry, and even non-neuronal cells (such as microglial cells), may contribute to the long-term, widespread pain fibromyalgia patients experience. In a recent study published in Brain, Loggia and colleagues found the first human evidence of glial activation in the brains of chronic pain patients, which may lead to clinical benefits for fibromyalgia patients as well.1 

“In fibromyalgia, we find that regions of the brain that are known to be important for the detection of pain, seem to be more connected with other brain networks that are typically not involved in pain processing. The degree of this connectivity is highly correlated with subjective clinical pain report, again suggesting that this outcome may be related to pain in this condition,” said Richard Harris, PhD, assistant professor of anesthesiology at the University of Michigan Health System in Ann Arbor.

Alterations in the Brain’s Functional Connectivity

Magnetic resonance imaging (MRI) studies have also demonstrated specific areas of the brain associated with pain, and these areas have increased activation in patients with fibromyalgia. 

Specifically, functional MRI studies have shown that fibromyalgia patients show enhanced activation (compared to controls) in pain-processing brain regions when stimulation is applied.

In a 2014 study published in Arthritis & Rheumatology, Robert Edwards, PhD, associate professor of anesthesiology at Harvard Medical School and staff psychologist at the Pain Management Center at Brigham and Women’s Hospital in Boston, Massachusetts, and colleagues evaluated whether there were differences in anticipatory brain changes when patients were expecting a pain stimulus to begin or end.2

The investigators found that fibromyalgia patients showed disrupted brain responses to reward and punishment. “More specifically, fibromyalgia patients showed greatly reduced brain responses to anticipatory cues, suggesting potential disruptions in the neurocircuitry underlying pain-related reward and punishment, and raising the possibility that these low levels of anticipatory activation might partly explain why patients with fibromyalgia are so pain-sensitive in laboratory studies,” Edwards said.

In addition, Mira Meeus, PhD, associate professor of rehabilitation sciences and physiotherapy at Antwerp & Ghent University in Belgium, and colleagues analyzed the literature to identify structural and functional changes in the brain of fibromyalgia related to pain using specific brain-imaging techniques.3 

“Based on this literature study, we can say that there is evidence [of] structural changes – decreased gray matter volume – in specific brain regions, while the global gray matter volume remains unchanged,” Meeus said. “Gray matter is the cortex of the brain, which contains the nerve cell bodies, serving to process information in the brain. So the loss of important cell bodies is mainly present in brain regions that are related to pain processing (affective components of pain) and stress.”

Immune Alterations in Fibromyalgia Patients

Other studies have looked for alterations in hormones or immune factors that might account for inappropriate pain signaling. 

According to Coe, these results remain equivocal. 

Sometimes these factors are found in one patient but not another. A number of researchers have reported that fibromyalgia involves an exaggerated pro-inflammatory state. However, Coe and colleagues found that the immune responses of women with fibromyalgia tended to be somewhat suppressed. 

Other researchers speculate that fibromyalgia may be an autoimmune disorder because some fibromyalgia patients have autoimmunity, and fibromyalgia is common in some autoimmune diseases. However, fibromyalgia does not have an inflammatory mechanism, like other autoimmune disorders, though some patients with fibromyalgia do have autoantibody in their blood.4 

“It could mean that this subset of women will go on to develop a real autoimmune disease later in life, although the prognostic value of knowing about autoantibody is not great. However, what we did find was that women with fibromyalgia who were seropositive for autoantibody tended to have more severe pain. So it may be helpful information in that regard,” said Coe. 

Implications for Understanding and Treating Patient Subgroups

According to Edwards, if central and peripheral mechanisms contribute to fibromyalgia symptoms, then eventually it will be possible to subgroup, or subtype, patients to tailor the optimal treatments to the most relevant mechanisms in each individual. Some of these efforts are starting to happen in various neuropathic pain conditions, but implementation into the clinical practice is not yet on the horizon.

Medically reviewed by Pat F. Bass III, MD, MS, MPH      


1.     Loggia ML et al. Brain. 2015; 1-12.

2.     Loggia ML et al Arthritis Rheum. 2014; 66 (1): 203-212.

3.     Cagnie B et al. Seminars in Arthritis and Rheumatism. 2014; 44 (1): 68-75.

4.     Buskila D and Sarzi-Puttini P. Israel Medical Association Journal. 2008; 10: 77-78.