As of 2022, the pathophysiology of fibromyalgia has not yet been elucidated and several theories have been suggested. Nervous system Pain processing abnormalities Chronic pain can be divided into three categories. Nociceptive pain is pain caused by inflammation or damage to tissues. Neuropathic pain is pain caused by nerve damage. Nociplastic pain (or central sensitization) is less understood and is the common explanation of the pain experienced in fibromyalgia. Because the three forms of pain can overlap, fibromyalgia patients may experience nociceptive (e.g., rheumatic illnesses) and neuropathic (e.g., small fiber neuropathy) pain, in addition to nociplastic pain. Nociplastic pain (central sensitization) Nociplastic pain is caused by an altered function of pain-related sensory pathways in the periphery and the central nervous system, resulting in hypersensitivity. Nociplastic pain is commonly referred to as "Nociplastic pain syndrome" because it is coupled with other symptoms. These include fatigue, sleep disturbance, cognitive disturbance, hypersensitivity to environmental stimuli, anxiety, and depression. Nociplastic pain is caused by either (1) increased processing of pain stimuli or (2) decreased suppression of pain stimuli at several levels in the nervous system, or both. Abnormalities in the ascending and descending pathways involved in processing pain have been observed in fibromyalgia. Fifty percent less stimulus is needed to evoke pain in those with fibromyalgia. A proposed mechanism for chronic pain is sensitization of secondary pain neurons mediated by increased release of proinflammatory cytokines and nitric oxide by glial cells. Neuropathic pain An alternative hypothesis to nociplastic pain views fibromyalgia as a stress-related dysautonomia with neuropathic pain features. This view highlights the role of autonomic and peripheral nociceptive nervous systems in the generation of widespread pain, fatigue, and insomnia. The description of small fiber neuropathy in a subgroup of fibromyalgia patients supports the disease neuropathic-autonomic underpinning. However, others claim that small fiber neuropathy occurs only in small group of fibromyalgia sufferers. Autonomic nervous system Autonomic nervous system abnormalities have been observed in fibromyalgia. These include decreased vasoconstriction response, increased drop in blood pressure, and worsening of symptoms in response to tilt table test. More specifically, some suggest that fibromyalgia is caused or maintained by a decreased vagal tone, which is indicated by low levels of heart rate variability, signaling a heightened sympathetic response. Accordingly, several studies show that clinical improvement is associated with an increase in heart rate variability. Some examples of interventions that increase the heart rate variability and vagal tone are meditation, yoga, mindfulness and exercise. Preliminary findings suggest that electrically stimulating the vagus nerve can potentially reduce fibromyalgia symptoms. Neurotransmitters Some neurochemical abnormalities that occur in fibromyalgia also regulate mood, sleep, and energy, thus explaining why mood, sleep, and fatigue problems are commonly co-morbid with fibromyalgia. Serotonin is the most widely studied neurotransmitter in fibromyalgia. It is hypothesized that an imbalance in the serotoninergic system may lead to the development of fibromyalgia. There is also some data that suggests altered dopaminergic and noradrenergic signaling in fibromyalgia. Supporting the monoamine related theories is the efficacy of monoaminergic antidepressants in fibromyalgia. Neuroimaging Neuroimaging studies have observed decreased levels of N-acetylaspartic acid (NAA) in the hippocampus of people with fibromyalgia, indicating decreased neuron functionality in this region. Altered connectivity and decreased grey matter of the default mode network, the insula, and executive attention network have been found in fibromyalgia. Increased levels of glutamate and glutamine have been observed in the amygdala, parts of the prefrontal cortex, the posterior cingulate cortex, and the insula, correlating with pain levels in FM. Decreased GABA has been observed in the anterior insular in fibromyalgia. However, neuroimaging studies, in particular neurochemical imaging studies, are limited by methodology and interpretation. Increased cerebral blood flow in response to pain was found in one fMRI study. Findings of decreased blood flow in the thalamus and other regions of the basal ganglia correlating with treatment have been relatively consistent over three studies. Decreased binding of μ-opioid receptor have been observed; however, it is unknown if this is a result of increased endogenous binding in response to pain, or down regulation. Neuroendocrine system Studies on the neuroendocrine system and HPA axis in fibromyalgia have been inconsistent. One study found fibromyalgia patients exhibited higher plasma cortisol, more extreme peaks and troughs, and higher rates of dexamethasone non-suppression. However, other studies have only found correlations between a higher cortisol awakening response and pain, and not any other abnormalities in cortisol. Increased baseline ACTH and increase in response to stress have been observed, hypothesized to be a result of decreased negative feedback. Sleep Disrupted sleep, insomnia, and poor-quality sleep occur frequently in fibromyalgia, and may contribute to pain by decreased release of IGF-1 and human growth hormone, leading to decreased tissue repair. Restorative sleep was correlated with improvement in pain-related symptoms. Immune system Inflammation has been suggested to have role in the pathogenesis of fibromyalgia. People with fibromyalgia tend to have higher levels of inflammatory cytokines IL-6, and IL-8. There are also increased levels of the pro-inflammatory cytokines IL-1 receptor antagonist. Increased levels of pro-inflammatory cytokines may increase sensitivity to pain, and contribute to mood problems. Anti-inflammatory interleukins such as IL-10 have also been associated with fibromyalgia. A repeated observation shows that autoimmunity triggers such as traumas and infections are among the most frequent events preceding the onset of fibromyalgia. Neurogenic inflammation has been proposed as a contributing factor to fibromyalgia. Digestive system Gut microbiome Some fibromyalgia patients frequently report worsening or remission of symptoms in response to certain foods, but there is no consistent data to back up these claims. There is a growing hypothesis that leakage from the gut microbiome into the body can impact nervous system processes. The leakage can be of complete bacteria, components of microorganisms, or microbe-associated compounds. A 2020 review indicated that high quality evidence is lacking, but gut bacteria may play a role in fibromyalgia. There is a bidirectional interplay between the gut and the nervous system. Therefore, the gut can effect the nervous system, but the nervous system can also effect the gut. Neurological effects mediated via the autonomic nervous system as well as the hypothalamic pituitary adrenal axis are directed to intestinal functional effector cells, which in turn are under the influence of the gut microbiota. Gut-brain axis The gut-brain axis, which connects the gut microbiome to the brain via the enteric nervous system, is another area of research. Fibromyalgia patients have less varied gut flora and altered serum metabolome levels of glutamate and serine, implying abnormalities in neurotransmitter metabolism. Microbiome variations in fibromyalgia have also been discovered in other research. However, it is still unclear if these changes have a direct role in the syndrome's pathophysiology or are only a predictor.
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