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16 Articles in Volume 19, Issue #2
Analgesics of the Future: Inside the Potential of Glial Cell Modulators
APPs as Leaders in Pain Management
Cases in Urine Drug Monitoring Interpretation: How to Stay in Control
Complex Chronic Pain Disorders
Efficacy of Chiropractic Care for Back Pain: A Clinical Summary
Hydrodissection for the Treatment of Abdominal Pain Caused by Post-Operative Adhesions
Letters: The Word "Catastrophizing;" AIPM Ceases Operations; Patient Questions
Management of Severe Radiculopathy in a Pregnant Patient
Managing Pain in Adults with Intellectual Disabilities
Pain in the Courtroom: An Excerpt
Q&A with Howard L. Fields: How Patients’ Expectations May Control Pain
Special Report: CGRP Monoclonal Antibodies for Chronic Migraine
The Management of Chronic Overlapping Pain Conditions
Vibration for Chronic Pain
What are the dangers of loperamide abuse?
When Patient Education Fails to Improve Outcomes: A Low Back Pain Case

Complex Chronic Pain Disorders

The pathophysiology of and approaches to 3 commonly seen pain conditions: CRPS, EDS, and SFN.
Pages 26-32
Page 3 of 4

Treatment for hEDS/JHS is similar, other than the important role of a geneticist in the diagnosis and management of hEDS.20 This approach may include genetic counseling and expert advice, such as cardiovascular and ophthalmologic monitoring, if classical EDS is suspected. Otherwise, the principles of treating EDS and JHS involve patient and family education, psychosocial therapy, joint function, skin and soft-tissue management, and chronic pain management (see Table VII). There are no studies, however, to determine optimal physical therapy, manual therapy, joint stabilization, or neuromuscular taping; avoidance of excessive stretching have been advocated. While medications play a role in pain management, there have been no systematic reviews on this approach; pharmacologic options are generally considered to be adjunct to non-pharmacologic multidisciplinary therapy.20

Peripheral nerve blocks or similar procedures have not been adequately studied but have been used in patients not responding to other chronic pain management. Dermatology referral may be recommended in selected patients and some experts have advocated using Vitamin C for its potential role in skin and joint healing.

Small Fiber Neuropathy

Diagnosis, Clinical Features

Small fiber neuropathy, or SFN, is a peripheral neuropathy affecting small, thinly myelinated or unmyelinated nerve fibers.21 The disorder has been associated with a variety of diseases, including diabetes mellitus, sarcoidosis, primary amyloidosis, and Sjogren’s syndrome.22 The most common symptoms may be divided into a pain or autonomic category (see Table VIII). A formal diagnosis may be considered in patients with distal extremity pain, numbness, and paresthesias with normal general neurologic examination and normal nerve conduction velocity studies.

Confirmatory diagnosis in most studies has been based on a skin biopsy, demonstrating reduced intraepidermal nerve fiber (IENF) density compared to normative data, using bright-field immunohistochemistry or immunofluorescence.23 This test is usually performed on the lateral distal leg and thigh. The sensitivity and specificity for SFN is 65% to 90%. Corneal confocal microscopy has demonstrated abnormal small fiber density in the sub-basal layer of the cornea, although this requires ophthalmologic expertise. Abnormal quantitative sensory testing (QST) for thermal pain, vibratory sensation, quantitative sweat testing, and autonomic testing such as heart rate variability have been advocated for confirming a SFN diagnosis in some studies. There is also evidence that medium or large nerve fibers may be affected in SFN based on plantar nerve conduction.24 However, electromyography and nerve conduction studies should be reserved for cases where there is a question of large fiber neuropathy causing symptoms, or in those with concurrent small and large fiber neuropathy.


The cause of SFN is unknown and no associated disease is present in 50% of cases. In a cohort of 921 patients with SFN, sodium channel gene mutations were found in 17%; immune disorders, most commonly sarcoidosis and Sjogren’s syndrome, in 13%; diabetes in 8%; and vitamin B12 deficiency in 5%.22

The mechanism of focal pain in SFN has been assumed to be related to peripheral nerve injury and damage. However, many patients with SFN also report chronic widespread pain. Interestingly, patients with fibromyalgia often report neuropathic symptoms and elevated neuropathic PainDETECT scores.25 A majority of fibromyalgia patients were found to have hyperexcitable C nociceptors, similar to those in SFN.26 Spontaneous pain hyperactivity was found in 31% of silent nociceptors in fibromyalgia, 34% in small fiber neuropathy, and 2.2% in controls.

In a group of fibromyalgia patients, 40% of skin biopsies were positive for SFN compared to 3% of controls.27 A systematic review of 222 fibromyalgia patients reported a 50% prevalence of SFN, confirmed by skin biopsy and/or corneal confocal microscopy.28 In patients with fibromyalgia, paresthesias and symptoms of dysautonomia may predict associated SFN.28 Compared to controls, fibromyalgia patients had reduced IENF density at both the thigh and calf.29 There was an inverse correlation between the calf IENF density and IL-2 levels, a marker of T-cell/macrophage activation. These investigators also reported a high prevalence of a mixed polyneuropathy, with evidence of SFN and electrodiagnostic changes suggestive of a chronic inflammatory demyelinating polyneuropathy.30

Another study found that 40% of fibromyalgia patients had reduced epidermal nerve fiber density (ENFD) including 28% in distal (calf) and 12% in the proximal (thigh) extremity.31 Sural and medial plantar nerve conduction abnormalities correlated with reduced IENF density. Obesity and metabolic syndrome were more common in the fibromyalgia subset with reduced IENF density. The finding of SFN in 40% to 50% of patients with fibromyalgia has fueled a reevaluation of the role of central versus peripheral pain in fibromyalgia and other poorly understood chronic pain conditions (see Table IX). Patients with SFN and chronic widespread pain/fibromyalgia both report allodynia and hyperalgesia, with neuropathic pain descriptors. However, in SFN this is usually confined to the distal extremities, whereas, in FM/CWP the pain is widespread. There is no neurophysiologic evidence of SFN in the neck, shoulders, chest wall, and buttocks, all painful locations in FM/CWP.

Autonomic nervous system dysfunction is prominent in SFN as well as in FM/CWP. Fibromyalgia or chronic widespread pain overlap with irritable bowel syndrome, chronic fatigue syndrome, and chronic pelvic/bladder pain syndromes. These conditions may also be associated with SFN. For example, 64% of patients with chronic pelvic pain had skin biopsy evidence for SFN.32 In those patients, 38% met criteria for fibromyalgia, 33% for irritable bowel syndrome, and 38% for migraine. Fibromyalgia, or chronic fatigue syndrome, are associated with chronic fatigue, mood disturbances, sleep disturbances, and chronic headaches in the vast majority of patients. These symptoms can be better explained by a central rather than peripheral nervous system unifying hypothesis. There are no neuroimaging studies of the central nervous system in SFN.

Last updated on: March 4, 2019
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