Fibromyalgia syndrome is a common chronic pain disorder affecting 3% to 8% of the general population. The syndrome also occurs in 20% to 40% of patients with osteoarthritis, rheumatoid arthritis, and systemic immune disorders, such as systemic lupus erythematosus and Sjogren’s syndrome. Diagnosis is typically made based on the symptom of chronic widespread pain and associated symptoms, particularly fatigue and sleep disturbances. The widespread pain must be present for at least 3 months and cannot be attributed to any other condition.
Fibromyalgia (FM) is widely considered to be the prototypic, centralized pain disorder, which I have addressed in previous publications. Centralized pain, also referred to as central pain, central sensitization, or, recently, nociplastic pain, includes any chronic pain disorder with no identifiable mechanism of action outside the central nervous system (CNS). The International Association for the Study of Pain (IASP) has defined nociplastic pain as “pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain.”
In the past, peripherally derived painwas classified as either nociceptive or neuropathic. In 2019, the IASP defined nociceptive pain as “pain that arises from actual or threatened damage to non-neural tissue and is due to activation of nociceptors” and neuropathic pain as “pain caused by a lesion or dysfunction of the nervous system.”
Classification of chronic pain has traditionally distinguished centralized pain from nociceptive pain, as in rheumatoid arthritis, and from neuropathic pain, as in diabetic neuropathy (see Figure 1). Chronic neuropathic pain has been sub
divided into peripheral neuropathic pain, such as a peripheral neuropathy, and central pain, as in post-stroke pain and multiple sclerosis. These classification systems are too restrictive and fail to take into consideration the overlap of these mechanistic pain divisions. This has promoted the term “mixed pain,” which does not exist in IASP taxonomy. For example, many patients with chronic low back pain have nociceptive, neuropathic, and nociplastic components.
There is substantial evidence that FM is related to aberrant pain processing. Multiple neuroimaging techniques have demonstrated CNS structural, functional, and chemical differences in FM patients compared to controls. Such changes correlate with pain severity and can be partially reversed with treatment.
For example, various therapies, including medications, cognitive behavioral therapy, acupuncture, exercise, and transcranial electrical stimulation, can cause treatment-related changes in brain functional connectivity, which correlate with clinical improvement in FM symptoms.
Despite the widely accepted notion that FM is a centralized pain condition, some investigators have questioned whether neuropathic pain is involved in the syndrome. Numbness and/or tingling are present in a majority of patients with fibromyalgia and sensory changes, including to light touch, temperature, and vibration, are common. Traditionally, the term neuropathic pain has been reserved for disorders with demonstrable pathology in the peripheral nervous system. Until recently, such pathologic changes had not been reported in patients with the syndrome.
In the past few years, however, a number of investigators have reported that FM may be linked to a small fiber neuropathy (SFN). SFN is defined as a structural abnormality of small nerve fibers with degeneration of the distal nerve terminal. Currently, there are no consensus diagnostic criteria for SFN. The diagnosis is considered in patients with pain, numbness, and paresthesias in the legs and an abnormal neurophysiologic test suggestive of SFN.
Traditional tests for a peripheral neuropathy, such as an electromyogram (EMG) or sural nerve biopsy, tend to provide normal results in those with SFN. The diagnostic test now most often utilized is a skin biopsy demonstrating a reduction in intraepidermal nerve fiber (IENF) density. Other tests used to confirm the clinical suspicion of SFN include abnormal quantitative sensory testing (QST), heart rate variability, or corneal confocal microscopy. SFN has been associated with diabetes, sodium channel gene mutations, certain drugs, and immune/infiltrative systemic diseases, including amyloidosis, sarcoidosis, and Sjogren’s syndrome.
SFN, diagnosed by a reduction in IENF density, has been found in 20% to 60% of FM subjects. The prevalence of an abnormal skin biopsy in patients with FM has varied with the prevalence and severity of neuropathic symptoms, patient age, and the presence of any abnormal immune test results. In the largest series, 155 FM patients with neuropathic symptoms underwent skin biopsies and nerve conduction velocity studies. Sixty percent had negative skin biopsies, 28% had distal extremity reduced IENF density, and 12% had proximal extremity reduced IENF density. Sural and medial plantar nerve conduction slowing correlated with reduced IENF density as did tests for diabetes/metabolic syndrome.
On clinicians’ minds are the questions: Does the finding of reduced IENF density in FM patients mean that many patients with FM are suffering from peripheral, rather than central, pain? Should these patients be treated differently, with therapies that target neuropathic pain?
According to the literature, a reduction in IENF density is not specific to any disease; it has been found in a number of neurologic and systemic conditions. These include multiple sclerosis, Parkinson’s disease, amyotrophic lateral sclerosis, post-Lyme disease syndrome, Sjogren’s syndrome, chronic regional pain syndrome (CRPS), as well as in fibromyalgia.
Distal extremity burning pain, numbness, and paresthesias – the clinical characteristics of neuropathic pain – are not prominent in these disorders. Seventy percent of patients with ALS, a condition not typically associated with pain, had evidence of IENF loss. Sixty percent of patients with chronic pelvic pain had positive skin biopsies for SFN. The other tests often used to confirm the diagnosis of SFN, including an abnormal QST, heart rate variability, or corneal confocal microscopy, also tend to be abnormal in patients with FM and related conditions, such as irritable bowel and chronic fatigue syndrome (see Table I).
The symptoms of FM and overlapping chronic pain disorders include chronic pelvic, bowel, and bladder pain, exhaustion, sleep disturbances, mood disturbances, and chronic headaches. These are not symptoms usually attributable to a peripheral neuropathy but rather to centralized pain.
No skin biopsies of body parts (eg, neck, shoulders, chest wall, and lower back) – often painful in patients with fibromyalgia – have been done to determine the presence of SFN. The finding of reduced IENF density in these overlapping chronic pain disorders is much more likely to be an epiphenomenon rather than the mechanism driving the pain.
It is possible that a causal link of reduced IENF density with FM could be established if treatment directed at the small fiber neuropathy improved disease symptoms. In uncontrolled studies, selected FM patients with evidence of SFN have had therapeutic improvement with intravenous immunoglobulin (IVIg). In one small series of seven patients with FM and SFN, IVIg treatment resulted in symptom improvement as well improvement in the skin biopsy findings.
Rather than debating whether fibromyalgia is primarily a central or neuropathic pain disorder, clinicians may benefit more from understanding that these pain categories intersect and overlap (see Figure 1). There are countless examples where peripheral pain, such as related to knee or hip osteoarthritis, gradually morphs into a generalized or centralized pain. Removing the peripheral source of pain, such as a joint replacement in osteoarthritis, might reverse the symptoms of centralized pain, especially if such intervention is done early. In patients with rheumatoid arthritis and comorbid FM, the peripheral joint inflammation causes pro-nociceptive patterns of brain connectivity. Reducing that joint inflammation may improve symptoms of central sensitization.
So too, SFN cannot be considered to be a pure disorder of the peripheral nervous system. Reduced functional connectivity in pain-related brain networks is present in patients with this disorder.16 This finding, a hallmark of central sensitization, correlates with the degree of skin nerve degeneration present in patients with SFN. Another study found that the changes noted in the small nerves of patients with FM undergoing skin biopsy were different from those in patients diagnosed with SFN.
During the past half-century, neurologists have generally played little role in the research and management of fibromyalgia and related centralized pain conditions, with rheumatologists often taking the lead in this area. The finding of SFN in a subset of FM patients may change that in the future. In fact, some neurologists have concluded that all patients with FM should be screened for SFN and, if SFN is identified on skin biopsy, then treatment for neuropathic pain should be warranted.
When neuropathic pain is caused by direct nerve injury, identifying and removing the physical cause of that injury
may cure the condition. With diabetic neuropathy, getting blood sugar under optimal control can improve the outcome. In zoster neuropathy, antiviral therapy might lessen its severity. With trigeminal neuropathy, removing the anatomic compression of the fifth cranial nerve can cure the condition. If large RCTs demonstrate that patients with fibromyalgia meeting criteria for SFN improve clinically and pathologically with treatments such as IVIg, then I propose that the pain research and management communities rethink the notion that FM is primarily a centralized pain disorder. •