The peripheral nervous system is a vast network of nerves carrying messages between the brain and spinal cord and every part of the body. Peripheral nerves are highly specialized and can cause a wide range of sensory, motor, and autonomic symptoms, making peripheral neuropathies hard to diagnose and hard to treat.1
There are more than 100 known types of peripheral neuropathy. Common acquired causes include diabetes, injury, autoimmune disease, and nutritional deficiency. However, peripheral neuropathies can also be inherited or caused by genetic mutations.1 Some genetic neuropathies cause pain due to hyperexcitability of pain-sensing nociceptors. Research into these conditions teaches us a lot about the pathophysiology of neurogenic pain.2
Sodium Channels and Painful Neuropathies
It has been known for a long time that voltage-gated sodium channels (VGSCs) control the flow of sodium ions that can trigger excitability of pain-sensing nociceptors in the peripheral nervous system. In humans, nine VGSCs have now been identified, and some have been linked to genes that alter their function.2,3
“We know that sodium channels play an important role in painful neuropathy. Genetic mutations that cause extreme pain have been linked to several disorders, and we may find that genetic polymorphisms play a role in more common peripheral neuropathies as well,” said Christina Ulane, MD, PhD, assistant professor of neurology at Columbia University Medical Center in New York City.
Gene mutations have now been linked to sodium channels Nav1.7, Nav1.8, and Nav1.9. Gain of function mutation in the gene SCN9A has been linked to Nav1.7 and a disorder called inherited erythromelalgia (IEM).2 IEM is also called “Man on Fire Syndrome,” because it causes excruciating burning pain in response to mild warmth.4
The gene SCN10A has been linked to Nav1.8 and small fiber neuropathy, a condition that causes severe pain attacks in the hands or feet..2. It may also cause autonomic pain symptoms such as palpitations, bowel problems, and abnormal sweating.2,5
Genetic mutations can also cause less excitability by reducing sodium flow through a VGSC. The gene SCN11A causes hyperpolarization of Nav1.9, which may cause loss of pain sensation.2 Nav1.9 has also been linked to mutation that causes painful neuropathy.3
Nav1.7 and Diabetes
A 2014 article published in the journal Trends in Molecular Medicine suggests that as we learn more about VGSCs and the genes that affect them, we could find that they play a much larger role in acquired peripheral neuropathy—and maybe even in some common diseases. The article notes that painful diabetic peripheral neuropathy (DPN) occurs in up to 25% of people with diabetes.
It has traditionally been believed that painful DPN is a direct result of hyperglycemia. Painful DPN may actually occur very early in diabetes and some people with long-standing diabetes never get DPN, the study authors noted. They proposed that painful DPN is not a complication of diabetes but rather the result of mutations at Nav1.7 that have been found in nerve cells and in pancreatic beta cells. Could these mutations increase both the risk for diabetes and painful DPN?6
“It may be that the diabetic pain we associated with metabolic changes may also be linked to genetic susceptibility. The pain medications we use for diabetic neuropathy now are mostly pregabalin (Lyrica, Pfizer) and duloxetine (Cymbalta, Lilly). Neither one is a sodium channel blocker, and they are only about 50% effective,” said Ulane.
Could Sodium Channels Offer Better Treatments for Neuropathic Pain?
“We already have sodium channel blockers, but they are not very effective and are limited by side effects. If we can find more targeted sodium channel blockers, we might be able to improve treatment of neuropathic pain,” Ulane said.
The problem with the sodium channel blockers now available is that they block all sodium channels. This includes VGSCs like Nav1.3 in the central nervous system and Nav1.5 in skeletal muscle. It also means these drugs can cause lots of unwanted adverse effects.7 For example, those associated with the sodium channel blocker lamotrigine include dizziness, joint pain, blurred vision, and uncontrollable shaking.8
This emphasizes the importance of the research on Nav1.7, Nav1.8, and most recently Nav1.9. These channels seem to be the ones that are specific to nerve pain. Pharmaceutical companies are actively working on drugs for Nav1.7 and Nav1.8 and will probably begin to include Nav1.9, now that it has also been linked to human pain. Finding drugs that selectively block just these channels could be the holy grail of neuropathic pain treatment.3,7
Chris Iliades, MD, is a full-time freelance writer based in Cape Cod, Massachusetts.
This article was medically reviewed by Pat F. Bass III, MD, MPH
- National Institute of Neurological Disorders and Stroke. Peripheral Neuropathy Fact Sheet.http://www.ninds.nih.gov/disorders/peripheralneuropathy/detail_peripheralneuropathy.htm. Updated September 26, 2014. Accessed October 28, 2014.
- Brouwer BA, Merkies ISJ, Gerrits MM, Waxman SG, Hoeijmakers JGJ, Faber CG. Painful neuropathies: the emerging role of sodium channelopathies. J Peripher Nerv Syst. 2014;19(2)53-65.
- Sutherland S. Third sodium channel implicated in painful small-fiber neuropathy. Pain Research Forum.http://www.painresearchforum.org/news/40751-third-sodium-channel-implicated-painful-small-fiber-neuropathy. Accessed October 28, 2014.
- Boyle AM. Sodium channels offer path to personalized pain management, U.S. Medicine Web site.http://www.usmedicine.com/agencies/department-of-veterans-affairs/sodium-channels-offer-path-to-personalized-pain-management/. Accessed October 28, 2014.
- Genetics Home Reference. Small Fiber Neuropathy. http://ghr.nlm.nih.gov/condition/small-fiber-neuropathy. Reviewed November 2012. Accessed October 28, 2014.
- Hoeijmakers JG, Faber CG, Merkies IS, Waxman SG. Channelopathies, painful neuropathy, and diabetes: which way does the causal arrow point? Trends Mol Med. 2014;20(10):544-550.
- Theile JW, Cummins TR. Recent developments regarding voltage-gated sodium blockers for the treatment of inherited and acquired neuropathic pain syndromes. Front Pharmacol. 2011;2:54.
- Lamotrigine. MedlinePlus Website.http://www.nlm.nih.gov/medlineplus/druginfo/meds/a695007.html. Accessed October 28, 2014.