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 “These results reinforce the proposal of fibromyalgia as a neuropathic pain syndrome. Our results also show that fibromyalgia patients have multiple autonomic dysfunction symptoms.” Authors

The destruction of small nerve fibers in the skin of fibromyalgia patients (small fiber neuropathy – SFN) is one the most intriguing developments to show up in fibromyalgia in years. Not only does it indicate in striking fashion that fibromyalgia is a real, physical disease but it provides opportunities to rethink it and thus possibly open up new options for treatment.  Studies suggest that 40-50% of fibromyalgia patients have SFN.

Small fiber neuropathy in women with fibromyalgia: an in vivo assessment using corneal
confocal bio-microscopy. Manuel Ramírez MD, Laura-Aline Martínez-Martínez, Everardo Hernández-Quintela MD, Jorge Velazco-Casapía MD, Angélica Vargas MD, Manuel Martínez-Lavín MD. Seminars in Arthritis and Rheumatism, http://dx.doi.org/10.1016/j. semarthrit.2015.03.003

Cornea-diagramNow FM researcher and physician Dr. Martinez-Lavin takes the exploration of the SFN to a  new realm – the cornea of the eye. Why the cornea? It turns out that the cornea – that liquid, transparent film covering the front part of the eye –  is one of the most sensitive tissues of the body. Innervated with sensory nerve fibers running from the trigeminal nerve, the cornea is loaded with pain receptors: the slightest touch or disturbance is immediately felt. In fact, the cornea has 300-600 times more  pain receptors  than the skin and 20-40 more pain receptors than the oh so sensitive dental pulp.  It has the densest array of small nerve fibers in the entire body.

Given that, Dr. Martinez-Lavin figured, that if SFN was going to show up anywhere it was going to show up there.  The added bonus was that new microscopic techniques allowed him to assess small fiber density quickly and non-invasively – no skin biopsy required.

In an email exchange he stated:

“The cornea is the place to go when studying small nerve fibers. Corneal confocal microscopy is a rapidly evolving technique. Normative values for corneal nerve fibers distribution are being developed. So, it is likely that with corneal confocal microscopy we will soon have a non invasive objective technique to confirm  fibromyalgia diagnosis.”

The Study

In this small study (17 FM patients and 17 healthy controls), an expert in corneal pathology  performed blinded (to diagnostic category) analyses of nerve density in two places in the cornea: the stromal nerves and the sub-basal plexus nerves. The study participants also assessed their level of neuropathic pain and autonomic nervous system symptoms  using questionnaires.

Results

The questionnaires indicated almost every FM patient experienced high levels of neuropathic pain and autonomic nervous system dysfunction (sympathetic nervous system activation). (Neuropathic pain is often described as  burning, stabbing, tingling, numb, hot, cold or itching pain, that (unfortunately) often worsens at night. Allodynia (sensitivity to touch) and altered perceptions of heat and cold can be present as well.)

The FM patients displayed about a 15% reduction of corneal  stroma nerve fiber density (p<.01) and a 20% reduction in nerve fiber density in the sub-basal plexus area (p<.o2) relative to the controls. The reductions were not associated with disease duration or symptom severity. When the healthy controls and FM patients were lumped together, however, patients with more slender corneal nerves were found to have increased levels of neuropathic pain. The “ceiling effect”; i.e. too many FM patients clustered at the top of the neuropathic pain scale may have prevented the researchers from finding an association there.

Wrong Channel

Voltage-gated sodium (Na+) channels….have a critical role in the development and maintenance of several pain syndromes, including inflammatory pain, neuropathic pain, and central pain associated with spinal cord injury. The increasing understanding of the molecular organization, function, and regulation of voltage-gated Na+ channels, their plasticity of expression following injury…provide insight into the important role of these channels in the pathophysiology of pain and rationale for development of channel subtype-specific drug therapy. Sodium Channels and Pain – Bennaroch

The authors proposed that sodium channel problems in the dorsal root ganglia may be behind the  declining numbers of small nerve fiber problems in FM patients and the pain they experience.  Voltage-gated sodium channels are the venues through which the electrical impulses that run along the nerves are transmitted. The more active those sodium channels are – the more active the nerves are.

Nav1.7 sodium channels

Damaged sodium channels in the nerves transmitting pain and autonomic nervous system signals could contribute to the pain in fibromyalgia.

Sodium channel problems or channelopathies are a relatively  new and exciting finding in chronic pain research. Dr. Sommer  recently called the findings on the voltage-gated sodium and other ion channels   “eye-openers” that could explain much about pain sensitization. Of the nine sodium channels found, four are known to play important roles in the production of pain.

The dorsal root ganglia (DRG) are cell bodies located just outside of the spinal cord  that provide a relay station and filter for the sensory stimuli  coming from the body.  The axons or “limbs” of the DRG neurons extend into the tissues of the body.  Sensory information from the body travels along nerve axons to the DRG and ultimately the brain. Herpesviruses are known to take up residence in these critical relayers of both pain and autonomic nervous system stimuli.

Turning the sensory and pain transmission lines to the brain on full blast may be all that’s needed to trip the brain into producing its own hyperexcitable, sensitized state.

Waxman proposed that sodium channel problems  in these nerves  are responsible for many cases of peripheral neuropathy and autonomic dysfunction. Studies indicate that genetic variants of one type of sodium channel  (Nav1.7)  found on the dorsal root ganglia (DRG), trigeminal ganglia and sympathetic ganglion neurons are able to throw the DRG into a hyperexcitable state.  Martinez-Lavin’s study indicating severely ill fibromyalgia have these genetic variants, suggests this sodium channel could play a hefty role in FM.

Dr. Martinez-Lavin believes abnormal sodium-calcium exchange caused by issues in the DRG may be causing the small fiber degeneration in the skin and corneas of FM patients. When I asked him about the possibility that other areas in the body may be affected he suggested that the skin and the eyes are the most likely candidates,  but that the mucous membranes (mouth (burning mouth syndrome), vaginal areas (vulvodynia), (gut?)) could be affected as well. It would be difficult to study SFN in those areas, however.

SFN Causing Autonomic Nervous System Dysfunction But Not Pain?

People with fibromyalgia often experience symptoms associated with both nerve (tingling, pain, numbness) and autonomic nervous system (gut, heart and standing issues) dysfunction. Many people with ME/CFS who don’t experience significant pain, however, do experience ANS symptoms (problems standing, gut issues, heat/cold intolerance). Could sodium channel problems affect only the autonomic nervous system nerves in some people? Dr.  Martinez-Lavin thought that was possible.

Eye Damage?

cornea fibromyalgia

Sight is not affected by the nerve loss found but eye pain might be a possibility

Because the nerves involved are pain sensing nerves and do not affect sight the reductions in nerve density found will not affect eyesight. One wonders, though, if the nerve issues Dr. Martinez-Lavin found could play a role in some cases of  eye-pain that are not connected with dryness or other factors.

Exercise

Since exercise enhances SNS activity I asked him if exercise induced SNS activity  might be causing the symptom flares seen in ME/CFS and FM?   Martinez-Lavin noted that in FM at least, gradually increased exercise may actually enhance parasympathetic nervous function and restore ANS homeostasis. Acute exercise on the other hand is pretty much guaranteed to throw the ANS out of balance – once again favoring the SNS – and increasing the symptoms associated with SFN such as burning pain, tingling, etc.

Treatment

With regards treatment Dr. Martinez-Lavin reported that the  structure of the sodium channel he believes is producing the pain in FM (Nav1.7) is known, and that “specific blockers can be developed as potent and refined analgesics for small fiber neuropathy and for fibromyalgia.”

The growing incidence of diabetes and the painful peripheral neuropathies often accompanying it are surely driving much research. Similar reductions in corneal nerve density have been found in diabetes.

Pain researchers are paying increasing interest to the Nav1.7 and other ion channels and treatment options are being explored. This is a growth field.

neuropathic pain drugs

Some ion channel drugs are being tested or used in neuropathic pain but better drugs are probably in the future.

Some studies suggest that drugs may need to target specific genetic mutations on these ion channels. That said, phenytoin (anti-epileptic drug), lamotrigine (anti-convulsant/anti-epileptic), ranolazine (angina) and lacosamide (anticonvulsant) target forms of the Nav1.7 channel,  that are implicated in neuropathic pain.  A  blood-depressing substance from sea anenomes (BDS-I) may be able to help tone down hyperexcitable sodium channels. An antiarrythmic, mexiletine, is able to normalize sodium channel activity in sodium channels with a specific mutation. Xenon402, a novel Nav1.7 blocker, is being tested.

Medical marijuana can be helpful in reducing neuropathic pain and something called ajulemic acid, a synthetic cannabanoid, may help explain why. It inhibited the activity of all sodium channels associated with pain in a recent study.

Lamotrigine is a good example of incredibly varied uses modern day drugs can achieve. Lamotrigine is used to treat epilepsy, bi-polar disorder, several types of seizures on label. Off-label it’s used in peripheral neuropathy, trigeminal neuralgia, cluster headaches, migraines, depersonalization disorder, schizoaffective disorder, borderline personality disorder, and post-traumatic stress disorder.

Our data indicate that spider venoms are a rich natural source of  Nav1.7 inhibitors that might be useful leads for the development of novel analgesics. Klint et. al. 2015

Perhaps the most interesting substances, though, may come from studies of spider venom. Forty percent of 205 spider venoms were found to have at least one Nav1.7 inhibiting substance. Seven novel Nav1.7 modulators were found during sequencing of spider venom.

Some of the drugs listed have issues that may preclude their use, and it’s not clear that any breakthroughs have been found yet. Interest in understanding the roles sodium channels play in producing pain, however, is high. With new techniques allowing researchers to be able to better understand the structure of these minute ion channels, the better drugs are clearly in the future.

Wrapup

The results of this small study using a new technique need to be validated, but they fit with prior findings in FM. The small nerve pathology found is probably restricted to the skin and eyes and perhaps the mucous membranes as well.  The association of reduced nerve width with neuropathic pain suggested that the SFN found is contributing to the pain in FM patients.

sodium channel

Voltage-gated sodium channels relay electrical signals: too much current equals too much nerve activity – and increased pain.

These findings offer a possible explanation for one of the most puzzling aspects of FM and the other so-called “functional disorders”: the inability to detect trauma or inflammation at the site of the pain.  They suggest the trauma is there in the form of damage to very small, unmyelinated nerves and, digging deeper, in the ion channels found in those nerves.

It’s not clear if the sodium channel blockers available now would be effective in FM or not. Given the recent advances in understanding sodium ion channel structure, however, Dr. Martinez-Lavin expects the the development of effective drugs to occur.

Inquiry of the Day

How effectively is your neuropathic pain being treated? Let us know in the Neuropathic Pain Treatment Poll on the Health Rising Forums.

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