At least five studies have found significantly increased rates of small fiber neuropathy (SFN) in the skin of people with Fibromyalgia. SFN refers to the damage or destruction of the small unmyelinated sensory and/or autonomic nerve fibers. It’s believed that damage to these nerve fibers may cause symptoms such as tingling, burning sensations and pain.

bigstock-Woman-with-pain-inExactly how this happens isn’t clear, however, since the loss of these nerve fibers should result in the loss of sensation. One study which found that the remaining nerve fibers were in a hyperexcitable state could help explain how SFN could contribute to the pain found in FM.  That still doesn’t explain, though, why the remaining small nerve fibers are in a hyperexcitable state to begin with.

A German team that had found evidence of small fiber neuropathy in FM last year thought they had the answer. They hypothesized that increased levels of pro-inflammatory cytokines were sending those remaining nerves bananas and they had good reason to think so. An earlier study of theirs found increased cytokine expression in the skin of people with SFN (who didn’t have Fibromyalgia), and a study by another group found increased gene expression of cytokines and vastly increased expression of opioid receptors in the skin of people with Fibromyalgia.

All that was needed now was a validation study and researchers could start targeting pro-inflammatory cytokines. It wouldn’t explain why the SFN was present (although pro-inflammatory cytokines could play a role) –but it could help explain why it was causing symptoms in Fibromyalgia.

The Study

Skin cytokine expression in patients with fibromyalgia syndrome is not different from controls Nurcan Üçeyler1*, Susanne Kewenig1, Waldemar Kafke1, Sarah Kittel-Schneider2 and Claudia Sommer1. BMC Neurology 2014, 14:185. http://www.biomedcentral.com/1471-2377/14/185

Using very sensitive techniques they compared gene expression of pro and anti-inflammatory cytokines and opioid receptors in the skin of 25 people with FM, 10 people with major depression and 35 healthy controls.

In a surprise finding neither the gene expression of the cytokine or the opioid receptors were increased in the FM patients relative to the other groups.


Gene expression studies suggested that increased immune activation in the form of increased cytokines in the skin was not a factor

With that finding researchers are back to square one in their efforts to translate the nerve damage seen in some Fibromyalgia patients to the pain they’re experiencing. Other possibilities increased levels of immune factors called chemokines and problems with the ion channels in the remaining nerves.

The extent of small fiber neuropathy present was measured in the FM group, and as with the past studies, a subset of patients with SFN were found. The authors did not, however, state what percentage of FM patients had SFN. They did note, though, that cytokine gene expression of was not increased in this group.

Because chemokines essentially do the same thing as pro-inflammatory cytokines do – they provoke cells to respond – high levels of chemokines could play a role.

Ion Channelopathy A Possibility

Ion channel damage is another very real possibility. Ion channels play a key role in nerve signaling and ion channel alterations have been implicated in Fibromyalgia.  Dr. Martinez-Lavin’s 2012  study found that Mexican women with severe FM tended to have a particular SCN9A sodium channel gene variant and a recent review  fingered sodium channel problems in several types of painful SFN. Another recent review urgently urged more research into sodium channelopathies and peripheral neuropathy and asserted that research will reveal specific subsets of sodium channelopathy patients.


Sodium channel problems would also explain the increased pain in FM

Researchers have gone so far as to identify a specific ion channel (Na(v)1.7) in the dorsal root ganglia that is disturbed in several pain syndromes. Genetic mutations in this channel allow ion channels to become activated in response to weaker stimuli, or to remain open longer in response to stimulation. That, of course, is a recipe for “central sensitization”: a hyperactive-response to sensory stimuli.

Deeper Nerve Fiber Loss Found

“Small fiber neuropathies are often associated with myovascular denervation”. Dori et. al

Some people without SFN in the skin may have it in other regions

Some people without SFN in the skin may have it in other regions

Finally, another recent study found that in addition to small nerve fiber denervation many patients also have nerve fiber loss associated with the blood vessels. Intriguingly, some people without small nerve fiber loss in the skin , demonstrated nerve fiber loss in the myovascular region. These patients had more muscle discomfort and autonomic nervous system problems.

One of the researchers in the initial round of SFN FM studies suggested that the nerve loss   in  skin may extend into deeper  regions.   This study  did not involve FM patients but suggests it may indeed,  and that some FM patients without evidence of SFN in the skin could have it in other regions.

Researchers Jump on SFN Findings

While the results of this study – and it was a small one – were disappointing note how quickly researchers have jumped on the small nerve fiber findings in FM.  Not only have six studies over the course of a year or so been done, but researchers are already trying to understand how they are affecting FM patients with this problem.

Testing Lab Ramps Up SFN Testing Protocols


More validated skin testing sites are another indication this SFN field is expanding

One indication that SFN has been generating more interest is Therapath labs recent announcement that they’ve validated two more testing location on the body (between shoulder and elbow and above the wrist).  Prior to this only three spots on the body, all on the legs, met the requirements for testing because it was unclear what constituted an abnormal result.  That means more thorough testing for SFN is now available.

Expect to be hearing much more on the SFN problem in Fibromyalgia over the next year.

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