Hyperexcitable C nociceptors in fibromyalgia.

This paper provides electrophysiological evidence of small-fiber neuropathy that complements and enriches the pathological evidence of small-fiber polyneuropathy (SFPN) from three independent laboratories. [Editors’ note: See PRF related news story.] The changes in brain functioning revealed by prior functional imaging studies of fibromyalgia patients may be secondary to primary peripheral nervous system abnormalities, at least in the roughly half of fibromyalgia patients with PNS abnormalities.

So the overlap between SFPN and fibromyalgia is now firmly established and needs to be translated to clinical practice. The reason that fibromyalgia patients might want to consider being evaluated for SFPN is that potentially treatable causes are identifiable in some cases of SFPN, whereas there have been no definitive treatment options for fibromyalgia. Given the prevalence of fibromyalgia, this poses considerable logistic challenges for both rheumatologists and neurologists.

For many years, there has been widespread acceptance of the idea that symptomology of fibromyalgia represented sensitization of the pain sensory system; however, there was little to indicate whether the primary pathophysiology was in the periphery or central nervous system. Interestingly, many of the medications that showed efficacy for neuropathic pain were also at least somewhat effective in fibromyalgia. Over the past few years, anatomical evidence has emerged documenting that some fibromyalgia patients have a pathological process affecting their peripheral nervous system. This paper extends our understanding by presenting physiological evidence that the unmyelinated primary afferent nociceptors of fibromyalgia patients are sensitized. The challenge ahead will be to determine whether the sensitization represents pathology in the primary afferent nociceptor or is an inflammatory process secondarily affecting the primary afferent. Once the offending tissue is identified, the inquiry into the actual pathological process can begin.

Reflecting upon the comments of Howard Fields and others makes me wonder whether we might be looking at a situation where both the central and peripheral nervous systems have become sensitized in the course of undamped activation of stress response systems.

The findings reported in the peripheral nervous system may at least explain dermagraphia, which can be an association of chronic widespread pain (aka Fibromyalgia Syndrome). 

The idea that there always has to be a "driver" has overlooked the possibility that in some patients once they have been activated by a stressor or stressors, these systems may no longer be unable to switch themselves off. Epigenetic changes that have occurred involving stress response genes could be the key.

Our group has recently published an hypothesis in support of these possibilities: 

Lyon P, Cohen ML, Quintner JL. An evolutionary stress-response hypothesis for chronic widespread pain (Fibromyalgia Syndrome). Pain Medicine 2011; 12: 1167-1178.

This paper is a start to bridging the gap between the anatomical findings in the peripheral nervous system by my laboratory and by others and the symptoms that patients with fibromyalgia suffer from. It may give an answer to the often posed question of why a reduced density of nociceptors is associated with pain: They are not merely reduced in number, but also the remaining fibers are ill with pathological function or are sensitized by some not yet determined mediator. We may even speculate that the pathological function precedes the reduction of innervation density, but this would be a question to ask in longitudinal studies. There is a lot to find out, still. We would like to know if and how these findings in the peripheral nervous system relate to the central nervous system symptoms that patients suffer from, like the depression and the fatigue. Of course we would like to know what underlies the malfunction at the molecular level, so that people can start developing drugs that address this very special mechanism. 

Claudia, have you considered "cytokine-induced autotoxicity" as a possible mechanism to explain the observed anatomical changes in the peripheral nervous system? As you correctly say, "there is still a lot to find out".