Small Nerve Fibers and Fibromyalgia: Five Signposts to a New Paradigm


A discovery that patients with fibromyalgia showed signs of small fiber impairment not present in depressed patients or controls may point to the first objectively measurable alteration of the peripheral nervous system in this disorder.

Fibromyalgia syndrome (FMS) is clinically well-characterized as a chronic widespread pain condition with associated symptoms like sleep disturbance, depressiveness, or fatigue,9 as well as deep muscle pain that severely reduces quality of life.

We have investigated alterations of the peripheral nervous system in FMS, focusing on the so called “small fibers,” resulting in the first objectively measurable alteration of the peripheral nervous system in patients with FMS.

1.    The pathophysiology of pain in FMS is unknown. The experience of emotional, physical, and sexual abuse seems to play a role in the etiology.2 A genetic component is assumed, because familial aggregation has been observed, but no FMS-specific gene has been identified as yet. Nor is there evidence for a pathophysiological role of other factors including bacterial or viral infections, gonadal hormones, or structural muscle alterations.2.    Small fibers are abnormal in patients with FMS. Small fibers are small-caliber, thinly myelinated and unmyelinated nerve fibers whose peripheral terminals grow into the epidermis and conduct thermal and pain sensation. While routine nerve conduction studies of the large nerve fibers have not revealed consistent pathologic findings, the assessment of the so called “small fibers” have given first hints towards a possible impairment.1, 3-5 However, study results have been inconsistent.

In our study, we focused on function and morphology of these fibers in a group of 25 patients with FMS. Patients were recruited from all over Germany, and all underwent neurological examination by the same neurologist, who checked and confirmed the diagnosis of fibromyalgia syndrome according to the ACR 1990 criteria. We then compared their data with those from patients who have depression without pain (to control for the influence of depression, which is common in FMS)8 and from healthy controls.

We used quantitative sensory testing (QST) to assess thermal and mechanical sensation and pain thresholds from small nerve fibers, as well as pain-related evoked potentials to assess pain pathways and punch biopsies to analyze morphology of small nerve fibers. In all three tests, patients with FMS showed signs of small fiber impairment that were not apparent among either patients with depression or healthy controls.

The reason for small fiber impairment in FMS is unknown, and we do not yet have FMS-specific tools to diagnose or exclude FMS. However, these results have several important implications and challenge current paradigms about FMS.

3.    FMS is different from depression. Small fiber pathology was found only in patients with FMS and not in patients with depression. This underscores that FMS is not simply a variant of depression but is a distinct entity.

4.    FMS is a distinct syndrome involving neuropathic pain. A new discussion is needed on the question of whether FMS is a disease or not. Our findings also challenge the current concept of pain in FMS. Evidence for small fiber pathology means that FMS formally would fulfill the definition of neuropathic pain.75.    FMS is different from small fiber neuropathy. Small fiber neuropathy is a term reserved for a subgroup of peripheral neuropathies with a clinical presentation that is completely different from that in FMS. Patients with small fiber neuropathy experience superficial acral burning pain that is located mostly at the toes and feet. Pain spread over the entire body, as regularly reported by FMS patients, is not characteristic of small fiber neuropathy. Nor are comorbidities such as sleep disturbance or depressive symptoms observed in patients with small fiber neuropathy. This indicates that small fiber pathology in FMS and small fiber neuropathy are phenomena with different pathophysiological backgrounds.

FMS researchers now have a new trace to follow. Future studies can be expected to decipher the pathophysiological background of small fiber damage in FMS as a basis for the design of specific analgesic drugs.



1. Blumenstiel K, Gerhardt A, Rolke R et al.Quantitative sensory testing profiles in chronic back pain are distinct from those in fibromyalgia.Clin J Pain 2011;27:682-690.
2. Häuser W, Kosseva M, Üçeyler N et al.Emotional, physical, and sexual abuse in fibromyalgia syndrome: a systematic review with meta-analysis.Arthritis Care Res (Hoboken) 2011;63:808-820.
3. Hurtig IM, Raak RI, Kendall SA et al.Quantitative sensory testing in fibromyalgia patients and in healthy subjects: identification of subgroups.Clin J Pain 2001;17:316-322.
4. Klauenberg S, Maier C, Assion HJ et al. Depression and changed pain perception: hints for a central disinhibition mechanism. Pain 2008;140:332-343.
5. Pfau DB, Rolke R, Nickel R et al.Somatosensory profiles in subgroups of patients with myogenic temporomandibular disorders and Fibromyalgia Syndrome.Pain 2009;147:72-83.
6. Sommer C, Häuser W, Burgmer M et al.[Etiology and pathophysiology of fibromyalgia syndrome]. Schmerz 2012;26:259-267.
7. Treede RD, Jensen TS, Campbell JN et al.Neuropathic pain: redefinition and a grading system for clinical and research purposes.Neurology 2008;70:1630-1635.
8. Üçeyler N, Zeller D, Kahn AK et al.Small fibre pathology in patients with fibromyalgia syndrome.Brain 2013 doi:10.1093/brain/awt053
9. Wolfe F, Smythe HA, Yunus MB et al.The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee.Arthritis Rheum 1990;33:160-172. (Not available online.)

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