Secondary erythromelalgia can result from small fiber peripheral neuropathy of any cause, polycythemia vera, essential thrombocythemia,[1] hypercholesterolemia, mushroom or mercury poisoning, and some autoimmune disorders.

In 2004 erythromelalgia became the first human disorder in which it has been possible to associate an ion channel mutation with chronic neuropathic pain,[2] when its link to the SCN9A gene was initially published in the Journal of Medical Genetics.

[3] Later that year, in an article in The Journal of Neuroscience, Cummins et al., demonstrated, using voltage clamp recordings, that these mutations enhanced the function of NaV1.7 sodium channels, which are preferentially expressed within peripheral neurons.

[4] One year later, in an article in Brain, Dib-Hajj et al., demonstrated that NaV1.7 mutants channels, from families with inherited erythromelalgia (IEM), make dorsal root ganglion (DRG, peripheral and sensory), neurons hyper excitable, thereby demonstrating the mechanistic link between these mutations and pain, thereby firmly establishing NaV1.7 gain-of-function mutations as the molecular basis for IEM.

[5] Conversely, in December 2006 a University of Cambridge team reported an SCN9A mutation that resulted in a complete lack of pain sensation in a Pakistani street performer and some of his family members.

[9] In rural areas of southern China, outbreaks of erythromelalgia have occurred during winter and spring at 3-5 year intervals among secondary school students.

Common triggers for daytime episodes are exertion, heating of the affected extremities, and alcohol or caffeine consumption, and any pressure applied to the limbs.

[9] The coexistence of erythromelalgia and Raynaud's phenomenon is rare, but case studies of patients with both diagnoses have been reported in medical journals.

[17] Symptoms may present gradually and incrementally, sometimes taking years to become intense enough for patients to seek medical care.

[18][19][20] Several medications, including verapamil and nifedipine, as well as ergot derivatives such as bromocriptine and pergolide, have been associated with medication-induced erythromelalgia.

[13] Subsequently, a virus - erythromelalgia-related poxvirus (ERPV) - was repeatedly isolated from throat swabs of six separate patients from two different counties and Wuhan city in Hubei province.

This results in channels that are open for a longer of period of time, producing larger and more prolonged changes in membrane potential.

[citation needed] Some of these mutant channels have been expressed in dorsal root ganglion (DRG) or sympathetic neurons.

Here, there is also a notable change in resting membrane potential, being depolarized by 4-7 mV versus wild-type channel expressing cells.

Fast inactivation is affected in a similar manner in both wild-type and L858F mutant channel and is, thus, unlikely to contribute to symptom resolution due to cooling.

Mechanical cooling of the limbs by elevating them can help or managing the ambient environment frequently is often necessary constantly as flares occur due to sympathetic autonomic dysfunction of the capillaries.

Patients are strongly advised not to place the affected limbs in cold water to relieve symptoms when flaring occurs.

A possible reduction in skin damage may be accomplished by enclosing the flaring limb in a commonly available, thin, heat transparent, water impermeable, plastic food storage bag.

Specific management tactics include avoidance of attack triggers such as: heat, change in temperature, exercise or over exertion, alcohol and spicy foods.

Whilst a cool environment is helpful in keeping the symptoms in control, the use of cold water baths is strongly discouraged.

[citation needed] Strong anecdotal evidence from EM patients shows that a combination of drugs such as duloxetine and pregabalin is an effective way of reducing the stabbing pains and burning sensation symptoms of erythromelalgia in conjunction with the appropriate analgesia.

[citation needed] Some suffering with EM are prescribed ketamine topical creams as a way of managing pain on a long-term basis.

[42] Feedback from some EM patients has led to reduction in usage as they believe it is only effective for short periods.Living with erythromelalgia can result in a deterioration in quality of life resulting in the inability to function in a work place, lack of mobility, depression, and is socially alienating; much greater education of medical practitioners is needed.

As with many rare diseases, many people with EM end up taking years to get a diagnosis and to receive appropriate treatment.Research into the genetic mutations continues but there is a paucity of clinical studies focusing on living with erythromelalgia.

(This delay in appropriate pain management can be a result of insurer-mandated or legally-required step therapy, or merely overly-cautious prescribing on the part of sufferers' doctors.

[44] The first reported case was in 1878 by Silas Weir Mitchell who suggested the term erythromelalgia to describe a syndrome of red congestion and burning pain in the hands and feet.

[51] Some confusion was introduced when Smith and Allen suggested changing the name to erythermalgia in order to emphasise the symptoms of painful inflammation and warmth.

[55] In their paper they described secondary erythromelalgia as being associated with another disease, often related to a myeloproliferative disorder and has also seen cases of: hypertension, diabetes mellitus, rheumatoid arthritis, gout, systemic lupus erythematosus, multiple sclerosis, astrocytoma of the brain, vasculitis, and pernicious anemia.

In 1903 H. Batty Shaw reported that in three cases the pain was so severe, and that the affected extremities so useless, that amputation was performed.

[59] Back in 1899 Thomas Barlow had already summarized with great detail the contrast between erythromelalgia and Raynaud's disease as following: Dependence produces considerable increase of the dusky red or violaceous tint of the extremity affected; the arteries in this position of the limb may pulsate forcibly; pain is common, sometimes constant, and more especially when the limb is dependent or parts pressed upon; in wintry weather, or on the application of cold, the conditions are relieved; on the other hand, warmth and summer weather increases pain; there is no loss of sensation, but there may be increased sensitiveness; the local temperature of the affected parts may be raised or lowered; gangrene does not occur; the affection is asymmetrical; there is a certain amount of swelling, sometimes allowing pitting on pressure, sometimes not; incisions over such swelling, even down to the bone, have proved useless; excessive pain on pressure upon the nerves supplying the parts affected is not found; muscular wasting is found, but explainable by the disuse of the limb, and is not at all as severe as in cases of disease of the peripheral nerves; a reaction of degeneration in the nerves of the affected parts has not been found; the deep reflexes, with few exceptions, are not reduced.