Research Timeline

Supporting medical research leading to a cure for EM is a core mission of TEA. Since its founding in 1999, TEA has raised money for its Research Fund, which is restricted to use for research.


Following a decade of laboratory research at Yale and other universities showing that sodium channel Nav 1.7 is linked to the transmission of pain, more than three biotechnology companies are moving ahead with development of drugs that aim to block the channel. One of these companies is Chromocell Corporation, which in 2016 began Phase 1 of the multi-phase process of testing its drug for U.S. Federal Drug Administration approval. Similar to Pfizer’s discontinued drug, it is anticipated to block the flow of sodium ions into nerve cells, resulting in a reduction in the transmission of pain signals to the brain. Read more about this study in FootSteps, Winter 2017.


EM studies were underway at Norway’s Oslo University Hospital, undertaken by Mari Skylstad Kvernebo, M.D. Her mentors from the University of Oslo and the Norwegian University of Science and Technology in Trondheim previously contributed much to the understanding of blood flow abnormalities in EM.

Mark Davis, M.D. and colleagues found that topically applied midodrine may be a viable treatment for the pain of EM. In a two-year study, 12 EM patients at the Mayo Clinic in Rochester, MN, U.S., applied a midodrine hydrochloride 0.2 % cream three times a day. All but one patient reported improvement from the topical midodrine. Four of these claimed “substantial” improvement and 7 “some” improvement.

Davis MD, Morr CS, Warndahl RA, Sandroni P. Topically applied midodrine, 0.2%, an α1-agonist, for the treatment of erythromelalgia. JAMA Dermatology. 2015 Sep;151(9):1025-6.


Researchers in Dunedin, New Zealand found that the incidence of EM may be as high as 15 per 100,000 people. A previous study by the Mayo Clinic in Olmstead County, MN, U.S., reported a much lower 1.3 per 100,000. (The Mayo study included people diagnosed with EM during a 30-year period, and the study statistically adjusted findings with the U.S. 2000 Census.) The Otago Medical School, University of Otago, Dunedin study recruited participants with the classic symptoms of EM—red, hot, painful feet that are made worse by heat and improved by cooling. While 42 percent of participants showed strong evidence of EM, only 16 percent had received a diagnosis of EM. These findings suggest that the incidence of EM may be much greater than expected and that the majority of cases go unrecognized. Researchers conclude that EM needs to be better understood and awareness of the syndrome needs to be raised. Read more about this study in FootSteps, June 2014.

Friberg D, Chen T, Tarr G, van Rij A. 2013. Erythromelalgia? A clinical study of people who experience red, hot, painful feet in the community. International Journal of Vascular Surgery. 2013:864961.


During 2013, the experimental EM drug discovered by Canadian biopharmaceutical company Xenon made progress. The global Teva Pharmaceuticals announced a license agreement with Xenon to develop the drug and handle regulatory and marketing efforts for the drug, now TV-45070. The U.S. Food and Drug Administration granted orphan drug status for TV-45070, a designation encouraging development of drugs to treat rare disorders and granting special incentives to developers. Read more in FootSteps, December 2013.

Researchers from Pfizer Neusentis, a UK-based research unit of the global pharmaceutical company reported finding that people with inherited erythromelalgia vary considerably in the frequency and severity of pain attacks. Their 2013 study followed the natural history of pain in 13 patients with inherited EM during a three-month period, which represents one of the most detailed investigations in EM patients and their symptoms over time. See more in FootSteps, December 2013.

Pfizer Neusentis also conducted a clinical trial of a new compound to relieve the pain of inherited EM. This clinical trial was preceded by an enabler study done in collaboration with Stephen Waxman M.D., PhD., and his group at Yale. The clinical trial involved five people with inherited erythromelalgia, most of whom experienced less heat-induced pain on days when they received the experimental substance compared to when they received a placebo. But, this drug was in a very early stage of development and Pfizer later suspended its trials when it dissolved Pfizer Neurentis. See FootSteps, December 2013 and FootSteps, Winter 2015.

Cao L, McDonnell A, Nitzsche A, Alexandrou A, Saintot PP, Loucif AJ, Brown AR, Young G, Mis M, Randall A, Waxman SG, Stanley P, Kirby S, Tarabar S, Gutteridge A, Butt R, McKernan RM, Whiting P, Ali Z, Bilsland J, Stevens EB. Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia. Science Translational Medicine. 2016 Apr 20;8(335):335ra56.


Findings of a study done at the Mayo Clinic supported the conclusion that neuropathy underlies the EM diagnosis. A review of the medical records of 41 patients diagnosed with EM between 1994 and 2008 at the Rochester, MN, U.S., facility examined the results of computer-assisted sensory tests used to determine the EM diagnosis. Some 82  percent of the 41 patients had abnormal results confirming that the sensory status of most patients with EM is abnormal. The most common finding was a hypersensitivity to heat. This quantifiable sensory abnormality corresponds closely with the clinical finding of warmth, swelling and discomfort in the limbs. Read more about this in FootSteps, Fall 2012, a Special Research Edition.

Genebriera J, Michaels JD, Sandroni P, Davis MD. Results of computer-assisted sensory evaluation in 41 patients with erythromelalgia. Clinical and Experimental Dermatology. 2012 Jun;37(4):350-4.

Another laboratory study at Yale, reported in 2012, showed that sodium channel Nav 1.7, even with no genetic mutations, is responsible for the burning-type pain after burn injuries. This study adds to mounting evidence that Nav 1.7 is a key player in pain sensation in everybody, including people with non-inherited erythromelalgia.

Shields SD, Cheng X, Uçeyler N, Sommer C, Dib-Hajj SD, Waxman SG. Sodium channel Na(v)1.7 is essential for lowering heat pain threshold after burn injury. The Journal of Neuroscience. 2012 Aug 8;32(32):10819-32.

Summarizing his team’s progress, Joost P.H. Drenth, M.D., PhD., reported that they have discovered that genetic variants (mutations) within the EM gene can cause a spectrum of diseases, including one that causes patients to feel no pain at all. Using the same advanced molecular techniques they used to discover the EM gene, his team screened more than 450 patients who have symptoms reminiscent of EM. (The EM gene encodes a sodium channel that is located on nerve endings. In inherited EM there are variants within this gene that cause the disease.) Of the 450 people screened, just 18 percent have gene variants causing EM. He concluded that there may be more genes with variants causing painful feet and hands. His team is continuing the search for new variants in the already identified EM gene and for genes not yet identified. See FootSteps, Fall 2012.


In January 2011, Stephen Waxman, M.D., PhD., director of the EM research group at Yale, summarized their recent discoveries made in understanding of the EM gene: Their study of how genes affect a person’s response to drugs for EM pain is paving the way for personalized medicine. They have found that individual differences in the EM gene, while not causing the disease, can affect a person’s susceptibility to pain. They are continuing to investigate why people with inherited EM develop its symptoms when they do, leading to a better understanding of what keeps people from developing EM until a certain age. Finally, they are committed to shortening the distance between discovery research and delivery of treatments to EM patients and are working across international and institutional boundaries in a multinational battle against EM. (Outside the U.S., the two largest centers for EM research are in China and Europe.)

In May 2011, Yale announced it was collaborating with international drugs giant Pfizer Inc. and a small biopharmaceutical company on developing a new compound that may be useful in treating pain in people with inherited EM. The Waxman team had previously shown that mutations of Nav 1.7 sodium channels occur in patients suffering from inherited EM. These genetic mutations increase activity in these neurons leading to the pain associated with inherited EM. The collaboration between Yale and the drug companies may lead to future clinical studies of this new substance in treating inherited EM and other pain disorders.

In a Phase 2 clinical trial, an ointment form of XEN402—the experimental drug trialed in people with inherited EM–was shown to provide significant pain relief in people with shingles (post herpetic neuralgia.) Xenon Pharmaceuticals, Inc. is developing XEN402 as a topical treatment for a variety of painful disorders including EM. Like EM, shingles causes neuropathic pain. And like EM there are few if any effective treatments. See FootSteps, Fall 2011 for more.


Based on laboratory research breakthroughs into inherited EM made during the first 10 years of the 21st Century, clinical research (research in humans) began in 2010. A clinical trial with four human subjects with inherited EM was performed by Xenon Pharmaceuticals Inc., Vancouver, BC, Canada. The experimental substance to relieve the pain of EM showed some positive results, but severe side effects led the company to halt the trial. Read more about this in FootSteps, June 2010 and FootSteps, November 2010.

Also in 2010, TEA donated $15,000 each to the research programs at Yale and Radboud University in The Netherlands. In 2010, Joost PH Drenth, M.D., PhD., and colleagues in Holland found mutations to SCN9A—the same gene linked to IEM—cause unexplained small fiber neuropathy. This establishes inherited SFN as another one of the group of pain syndromes, including IEM, caused by mutations in SCN9A. Yale researchers are following up on discoveries that move toward helping those with non-inherited EM.

Faber CG, Hoeijmakers JG, Ahn HS, Cheng X, Han C, Choi JS, Estacion M, Lauria G, Vanhoutte EK, Gerrits MM, Dib-Hajj S, Drenth JP, Waxman SG, Merkies IS. Gain of function Naν1.7 mutations in idiopathic small fiber neuropathy. Annals of Neurology. 2012 Jan;71(1):26-39.


A Mayo Medical School/Mayo Clinic study reported the incidence of EM was 1.3 per 100,000 people per year during a 30-year period in Olmstead County, MN, U.S., a rural county that includes the city of Rochester where the Mayo Clinic is located. Incidence rates among patients in the study were statistically sex- and age-adjusted to the structure of the U.S. white population in 2000, taken from U.S. Census data. By doing this adjustment, researchers can make meaningful comparisons between two very different groups like the population of Olmsted County and the population of the U.S. The findings have a 95 percent confidence level. The rates reported in this study were five times higher than those estimated by a 1998 Norwegian study, which is the only other known research describing EM incidence. Read more about this in FootSteps, Winter 2009.

Reed KB, Davis MD. Incidence of erythromelalgia: a population-based study in Olmsted County, Minnesota. Journal of the European Academy of Dermatology and Venereology. 2009 Jan;23(1):13-5.

Also in 2009, researchers at Yale analyzed mutations to the EM gene in people who reacted differently to certain drugs like lidocaine. The findings of these studies point the way toward personalized, genetically based treatments. Another study showed mutations that relate to severity of the disorder act differently in a teenager than in those who first develop symptoms of inherited EM under the age of ten. Other studies found a common genetic variation in Nav 1.7 that may increase susceptibility to pain. Read more about these findings in FootSteps, June 2010.

Han C, Dib-Hajj SD, Lin Z, Li Y, Eastman EM, Tyrrell L, Cao X, Yang Y, Waxman SG. Early- and late-onset inherited erythromelalgia: genotype-phenotype correlation. Brain: A Journal of Neurology. 2009 Jul;132(Pt 7):1711-22.
Sheets PL, Jackson JO 2nd, Waxman SG, Dib-Hajj SD, Cummins TR. A Nav1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity. The Journal of Physiology. 2007 Jun 15;581(Pt 3):1019-31.
Fischer TZ, Gilmore ES, Estacion M, Eastman E, Taylor S, Melanson M, Dib-Hajj SD, Waxman SG. A novel Nav1.7 mutation producing carbamazepine-responsive erythromelalgia. Annals of Neurology. 2009 Jun;65(6):733-41.
Choi JS, Zhang L, Dib-Hajj SD, Han C, Tyrrell L, Lin Z, Wang X, Yang Y, Waxman SG. Mexiletine-responsive erythromelalgia due to a new Na(v)1.7 mutation showing use-dependent current fall-off. Experimental Neurology. 2009 Apr;216(2):383-9.
Estacion M, Harty TP, Choi JS, Tyrrell L, Dib-Hajj SD, Waxman SG. A sodium channel gene SCN9A polymorphism that increases nociceptor excitability. Annals of Neurology. 2009 Dec;66(6):862-6.


In 2008, TEA donated $45,000 to Yale, restricting use of the donation to support collaborative efforts with scientists from China and The Netherlands. For two years, Yale hosted Dr. Yang as a visiting scientist working directly with Yale EM researchers. These collaborations pursued new avenues in EM research, including study of factors that increase or decrease an individual’s susceptibility to chronic pain. Read about TEA’s donation and “What TEA’s Gift Will Do,” in FootSteps, Spring 2008.


In FootSteps, June 2007, Joost PH Drenth, M.D., PhD., summarized the value of TEA’s donations to research: “The fruits of the research funded by TEA are multifold. Funding research has not only resulted in better understanding of the causes of EM, but has also shifted the disease into the spotlight and put EM on the agenda of many laboratories. Testament to this are the recent discoveries of two other disorders caused by Nav1.7. One painful disorder (paroxysmal extreme pain disorder) enhances Nav1.7 function, while the second is characterized by the complete absence of pain sensation. Had the researchers who discovered these facts not known about EM and Nav1.7, it would have taken them many years to solve their puzzles. Lastly, big pharmaceutical companies have now begun a search for a drug that specifically blocks Nav1.7 and alleviates the pain. And this is what we really want.”

Drs. Drenth and Waxman co-authored an article summarizing major advances in EM research that was published in December 2007. Read more about this in FootSteps, Winter 2008.

Drenth JP, Waxman SG. Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders. The Journal of Clinical Investigation. 2007 Dec;117(12):3603-9.

Also in 2007, Dr. Waxman’s group at Yale began an active collaboration with Yong Yang, M.D., PhD., who directs another group of EM researchers in Beijing. Among other accomplishments, Yale’s published work had already sparked much interest within the pharmaceutical industry toward the search for drugs that target mutant Nav1.7 in EM. Read the research review in FootSteps, Winter 2008.

Han C, Lampert A, Rush AM, Dib-Hajj SD, Wang X, Yang Y, Waxman SG. Temperature dependence of erythromelalgia mutation L858F in sodium channel Nav1.7. Molecular Pain. 2007 Jan 19;3:3.
Sheets PL, Jackson JO 2nd, Waxman SG, Dib-Hajj SD, Cummins TR. A Nav1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity. The Journal of Physiology. 2007 Jun 15;581(Pt 3):1019-31.
Novella SP, Hisama FM, Dib-Hajj SD, Waxman SG. A case of inherited erythromelalgia. Nature Clinical Practice. Neurology. 2007 Apr;3(4):229-34.


In 2006, Mayo Clinic doctors reported that sweat testing revealed an absence of sweating and decreased small nerve fiber density in people with EM. In another paper, Mayo doctors reported that skin biopsies of EM patients show decreased nerve density.

Davis MD, Genebriera J, Sandroni P, Fealey RD. Thermoregulatory sweat testing in patients with erythromelalgia. Archives of Dermatology. 2006 Dec;142(12):1583-8.
Davis MD, Weenig RH, Genebriera J, Wendelschafer-Crabb G, Kennedy WR, Sandroni P. Histopathologic findings in primary erythromelalgia are nonspecific: special studies show a decrease in small nerve fiber density. Journal of the American Academy of Dermatology. 2006 Sep;55(3):519-22.

Researchers at Yale reported another significant discovery in 2006—they demonstrated how a single genetic mutation causes not only the pain of inherited EM but also the redness. They showed that a single mutation can produce opposing effects depending on the nerve cells in which it operates, and thus can produce multiple symptoms.  Researchers showed the EM genetic mutation (that results in a defect in the sodium channel Nav 1.7) causes over-excitability in one type of neuron (nerve cell) and under-excitability in another type of neuron. Read more about this in FootSteps, June 2006.

Rush AM, Dib-Hajj SD, Liu S, Cummins TR, Black JA, Waxman SG. A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proceedings of the National Academy of Sciences of the United States of America. 2006 May 23;103(21):8245-50.

Also in 2006, TEA announced that the research groups at Yale and in The Netherlands were collaborating on new studies. These two research programs, along with the program directed by Yong Yang, M.D., PhD., in Beijing, China, are the world leaders in research into inherited EM. Helped by TEA’s donations to Yale and the program in Holland, these highly specialized molecular biological laboratories made enormous strides. Read more in FootSteps, December 2006.


TEA funded a $30,000, one-year grant in 2005 for a study by Joost PH Drenth, M.D., Ph.D., Radboud University, Nijmegen, The Netherlands. Awarded through the National Organization for Rare Disorders, the grant was administered and monitored by NORD. You can read more about this in FootSteps, December 2005. Two research papers published by Dr. Drenth and colleagues in 2005 about five families with inherited EM are summarized by TEA member and scientist Jean Jeffery in FootSteps, Fall 2007.

Drenth JP, te Morsche RH, Guillet G, Taieb A, Kirby RL, Jansen JB. SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels. The Journal of Investigative Dermatology. 2005 Jun;124(6):1333-8.
Michiels JJ, te Morsche RH, Jansen JB, Drenth JP. Autosomal dominant erythermalgia associated with a novel mutation in the voltage-gated sodium channel alpha subunit Nav1.7. Archives of Neurology. 2005 Oct;62(10):1587-90.

Also in 2005, Mark Davis, M.D., and Paul Sandroni, M.D., of the Mayo Clinic, Rochester, MN, U.S., published their findings that the EM pain of 18 out 34 patients improved with the use of lidocaine patches. (Mayo doctors track their findings as clinical research—often reviews of treatments of their patients.) Read more about this in FootSteps, June 2007.

Davis MD, Sandroni P. Lidocaine patch for pain of erythromelalgia: follow-up of 34 patients. Archives of Dermatology. 2005 Oct;141(10):1320-1.


The year 2004 was significant for TEA—the year when the dream of actually funding research into EM became reality. TEA donated $60,000 to help fund research into inherited EM at Yale University’s Center for Neuroscience and Regeneration Research under the direction of Stephen G. Waxman, M.D., Ph.D., Professor, Department of Neurology at Yale’s School of Medicine. TEA had first helped these neuroscientists by asking members with inherited EM to send samples of their blood to the Yale laboratories. Using state-of-the-art molecular biological technology to analyze DNA from the blood, the researchers found a mutation in the gene (SCN9A) that had been linked to EM in earlier studies. The mutation the neuroscientists identified is in a sodium channel (Nav1.7) found along the length of nerve fibers. It acts as a molecular battery generating and transmitting nerve signals. The researchers demonstrated that the genetic mutation causes the pain of inherited EM by causing pain-signaling nerve cells to be over-excitable, firing when they should not and causing pain. You can read more about this in FootSteps, December 2004.

Waxman SG, Dib-Hajj SD. Erythromelalgia: a hereditary pain syndrome enters the molecular era. Annals of Neurology. 2005 Jun;57(6):785-8.


Joost PH Drenth, M.D., Ph.D., and colleagues at Radboud University, Nijmegen Medical Center in Nijmegen, The Netherlands in 2001 identified the gene linked to erythromelalgia—SCN9A—on chromosome 2. They later confirmed its role in EM by finding mutations to the gene in six families with inherited EM. In 2006, Dr. Drenth would go on to look into why variations in one gene explain inherited EM in some people, but other families with EM don’t carry the same genetic mutation. An explanation written by Dr. Drenth appears in FootSteps, June 2007.

Drenth JP, te Morsche RH, Guillet G, Taieb A, Kirby RL, Jansen JB. SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels. The Journal of Investigative Dermatology. 2005 Jun;124(6):1333-8.