Introduction

Erythromelalgia is a rare syndrome that is classified as an orphan disease (a medical condition that affects only a small percentage of the population), making it difficult to diagnose and treat. The prevalence of erythromelalgia is approximately 0.36 to two people per 100,000 per year.¹ People with the condition experience episodes of sudden skin reddening, warmth, and a burning pain. These episodes are triggered by mild warming stimuli (changes in the internal or external environment that trigger a response within the body) such as exercise, exposure to warm temperatures, or even wearing warm clothes.² The episodes may last for minutes or hours and, between episodes, the skin may appear completely normal.³ Erythromelalgia is a condition that commonly affects the extremities, typically the lower limbs, and the pain can often be relieved by cooling the affected areas.⁴

Diagnosis of erythromelalgia

There are two types of erythromelalgia: primary and secondary. Primary erythromelalgia is an inherited disorder often caused by a mutation in the SCN9A gene, while secondary erythromelalgia is associated with other underlying medical conditions such as myeloproliferative disorders or autoimmune diseases.⁵

A comparison of the differences between primary and secondary erythromelalgia:⁶

The diagnosis of erythromelalgia is based on an individual's clinical history and physical examinations.¹ The characteristic symptoms of erythromelalgia include:

• Skin redness
• Skin warmth
• Burning pain

It is important to distinguish between the primary and secondary forms of erythromelalgia when making a diagnosis. In most cases, the diagnosis of primary erythromelalgia is made by looking for the presence of the characteristic symptoms and screening for mutations in the SCN9A gene. On the other hand, secondary erythromelalgia is diagnosed by ruling out different diseases associated with the condition.⁶

Pathophysiology of erythromelalgia

For an average person, exposure to warm temperatures or exercise results in the blood vessels within the extremities widening to help the body get rid of excess heat. This process is called vasodilation and it is important in maintaining the body's internal temperature. However, in the case of erythromelalgia, the vasodilation is excessive. As a result, the large increase in blood flow causes the affected areas to turn red and warm, as well as leading to the sensation of a burning pain.³

Neuropathic pain in erythromelalgia

The skin is a sensory organ that functions to detect various stimuli of varying intensity. This function of the skin is performed through a close interaction among its structures: epidermis, dermis, and a complex network of blood vessels innervated by sympathetic and sensory nerve endings.¹

The somatosensory system is a part of the nervous system consisting of a network of nerves in the brain and spinal cord that allows the perception of pain, pressure, and temperature stimuli.¹ In particular, the ability to feel pain is essential to survival as it informs the body of harmful stimuli and triggers a protective response.⁷ Neuropathic pain is a type of pain that is different from the pain caused by actual tissue injury such as a sprained ankle; instead, it is caused by dysfunction or damage in the nervous system.⁸

Sodium channels and their role in pain signalling

Nociceptors are sensory neurons that detect potentially harmful stimuli such as tissue injury or heat, and they send signals to the brain that are interpreted as pain. Some of these nociceptors are also involved in sending signals back to the site of injury. These signals promote the release of chemical messengers such as substance P and calcitonin gene-related peptide (CGRP), which cause blood vessels to widen and become more leaky, triggering the further release of histamine and other inflammatory mediators from immune cells.¹ This is part of the body's inflammatory response, which is why injured areas often become red, swollen, and painful.

Pain sensitivity depends on how easily neurons are able to send signals and this is controlled by ion channels in the neural membranes. There are many different types of ion channels that allow sodium, potassium, and calcium ions to move in and out of the neuron. Among these, the voltage-gated sodium channel known as Nav1.7 plays a key role in pain transmission by determining how excitable the pain-sensing neuron is. When these channels are open, they generate electrical impulses (action potentials) that the brain interprets as pain, and this triggers the release of inflammatory mediators to the injured area.¹

Sodium channel mutations in erythromelalgia

Primary erythromelalgia has been closely linked to a gain-of-function mutation in the SCN9A gene, which is a gene that provides instructions to produce a protein required for the formation of a functional voltage-gated sodium channel, Nav1.7. These sodium channels are primarily expressed in nociceptive sensory neurons of the dorsal root ganglia (DRG) and sympathetic ganglia, where they play an important role in pain signalling.⁹ The mutation in the SCN9A gene causes the sodium channel to open more easily and remain open for longer.⁵ As a result, the threshold for the activation and generation of electrical impulses is lowered, leading to abnormal firing of electrical impulses and the nociceptive neurons becoming hyperexcitable.¹⁰ These mechanisms underlie the intense burning pain in response to non-harmful stimuli experienced by people with primary erythromelalgia.⁵

However, although many people with primary erythromelalgia have mutations in the SCN9A gene, reports have found that some individuals do not have these mutations. This suggests that other genes may be involved in the development of primary erythromelalgia.⁵

Treatment options for erythromelalgia

Non-pharmacologic management

Lifestyle adjustments that may help individuals with erythromelalgia include:¹¹

• Avoiding triggers
• Heat: remain in cooler environments
• Exercise: reduce physical activity
• Clothing: avoid excess and tight clothing
• Food: avoid eating spicy food
• Alcohol: avoid drinking alcohol
• Cooling the affected area during episodes: be careful when using ice, as prolonged exposure to water and cold may lead to ulceration, infections, and maceration
• Elevating the affected area during episodes

Pharmacologic treatment

The current pharmacologic treatments available for erythromelalgia aim to manage the symptoms of the condition. As sodium channel dysfunction is a contributing factor that drives the burning pain in primary erythromelalgia, it makes sense that blocking these channels would reduce the pain experienced by individuals with the condition. One way the sodium channels can be targeted is with sodium channel blockers such as lidocaine and mexiletine. Lidocaine is a local anaesthetic that works by preventing the movement of sodium ions through the voltage-gated sodium channels, which helps stabilise the neuronal membranes and ultimately interrupts the pain sensation.⁵ However, studies have shown that some patients with primary erythromelalgia do not have the SCN9A mutation, and these patients may have a limited or no response to treatment with lidocaine.¹² This suggests that the burning pain in primary erythromelalgia is influenced by factors beyond sodium channel activity alone.⁵

Some other pharmacologic agents that have been explored in the treatment of both primary and secondary erythromelalgia include:¹¹

• Aspirin: shown to be effective for secondary erythromelalgia associated with polycythaemia or thrombocythaemia
• Prostaglandin analogues (misoprostol) and prostacyclin analogues (iloprost): reduced symptoms and sympathetic dysfunction
• Calcium channel blockers (amlodipine, nifedipine, and diltiazem): attenuated the vasoconstriction and reactive hyperaemia

No single pharmacologic treatment has demonstrated complete effectiveness in all patients, which has resulted in patients taking a combination of therapies in a trial-and-error approach. There is a need for more personalised treatment strategies for erythromelalgia due to the differences in treatment responses, resulting from differences in people's genetic profiles. By incorporating genetic testing into the diagnostic process, clinicians may be able to better predict which treatments will most likely lead to better outcomes. Unfortunately, the current genetic testing technologies are not perfect and they cannot always predict treatment response with complete certainty.⁵

Summary

Erythromelalgia is a rare condition that has a significant impact on the affected individual. The exact cause of erythromelalgia still remains uncertain. However, research has shown that the neuropathic pain in primary erythromelalgia may be driven by a mutation in the SCN9A gene, which causes dysfunction in the Nav1.7 sodium channel. Understanding how these sodium channels contribute to abnormal nerve signalling has helped to provide an explanation for why patients experience an intense burning pain in response to harmless triggers. Despite this, there is still difficulty in determining the most effective method to manage the condition due to the variability in disease presentation and response to treatments. The current treatment strategies that have been explored are focused on symptom management, including sodium channel blockers, aspirin, prostaglandin and prostacyclin analogues, and calcium channel blockers. However, there is a need for a more personalised approach to treatment due to the differences in treatment response resulting from differences in the genetic profiles of individuals with the condition. Future research on erythromelalgia should focus on better identifying the genetic variants to support the development of more effective, mutation-specific treatment.