Introduction

Erythromelalgia (EM), a rare disorder in which an individual suffer with episodic burning pain associated with redness and heat. The feet and hands are most commonly affected.¹ The pain can worsen over time and compromise the patient's lifestyle, leading to severe disability.^{1, 2} 

Dermatologists are often the specialists these patients turn to for assistance. No guidelines exist for the treatment of this complex disorder. Management can be quite challenging and relies on lifestyle modifications and pharmacological treatment, including drugs approved for other conditions but prescribed off-label.³

Off-label and experimental treatments

The mainstay of therapy aims to avoid triggers, most often heat, exercise, and standing. Commonly used strategies include remaining in cool environments, reducing physical activity, elevating limbs, and avoiding excess clothing. In addition, some patients find relief with cool water immersion or portable fans.⁴

Regarding off-label use or other experimental treatments, there are topical and systemic uses. Topical medicines can all that is needed to manage this condition, so they are used as first-line treatment. Aspirin is the first-line systemic therapy for patients with erythromelalgia. Other systemic medications may then be considered.⁵

Topical medications 

Topical medications can be effective in suppressing pain or redness (or both) associated with EM and in reducing the need for systemic medications while causing fewer adverse effects as compared to systemic medications. 

A topical medication should be tried for at least 4 weeks to assess efficacy before the patient switches to another treatment. Several topical medications have been used to address the pain associated with EM.⁵ These include:

Lidocaine

A local anaesthetic that blocks sodium ion channels to reduce pain. It can be applied as a cream, ointment, or patch, with patches offering gradual delivery over 12–24 hours. Lidocaine 5% patches have shown benefit in many patients with erythromelalgia (EM), particularly on the feet.⁵

Amitriptyline in combination with Ketamine

First reported in 2006, topical amitriptyline-ketamine (eg, Lipoderm) applied up to 3 times daily has been effective for erythromelalgia (EM) pain. Amitriptyline blocks serotonin/norepinephrine reuptake and sodium channels, while ketamine antagonises NMDA receptors.⁵

Capsaicin

Evidence for erythromelalgia is limited: one case report showed benefit with capsaicin cream 0.025%, but surveys found little effect. Cream or lotion (0.025–0.075%) may be applied 3–4 times daily for 6 weeks, though initial stinging and burning are common. Topical capsaicin patches 0.025% and high-dose capsaicin patches (8%)(used for chronic pain), both off-label, may have potential, but data in EM are sparse.^5,6

Other potential topical treatments include over-the-counter diclofenac 1% gel and compounded gabapentin 6% ointment. Other topical medications that have only anecdotal evidence to support their use but may help reduce redness include: topical oxymetazoline 0.05% and brimonidine tartrate 0.33% applied daily. Both are approved for rosacea by the US Food and Drug Administration (FDA). Timolol maleate 0.5% is also included in this category. Patients should be advised about the risk of rebound erythema with continued use.⁵

Systemic therapy

If topical treatments alone are not helpful, systemic treatments can be considered. Some of the systemic therapies used include:

Aspirin

Aspirin, by inhibiting prostaglandin synthesis and platelet aggregation, is often considered first-line systemic therapy for erythromelalgia (EM) due to its safety, low cost, and accessibility. A daily dose of 325 mg for at least one month is recommended if no contraindications exist. In a case series of 57 patients, about half reported symptom relief, though other surveys show mixed results.⁷ For patients who have an aspirin allergy, other nonsteroidal anti-inflammatory drugs (NSAIDs) can be considered. 

Corticosteroids

Systemic corticosteroids may benefit some patients, particularly early in the disease course before irreversible sensitisation occurs. They appear most effective in cases with an acute onset, a clear trigger, or duration <1 year, likely by suppressing inflammatory neuropathy and stabilising membranes.⁵

Sodium channel blockers

Sodium channel blockers are a promising therapy for erythromelalgia (EM), particularly in primary, inherited cases and in SCN9a gene mutation. Lidocaine and mexiletine have been used clinically, with some patients experiencing pain relief. In 2004, we presented a case report of refractory EM of the ears in this journal.⁵ Since then, the patient has tried multiple therapeutic options without response. Mexiletine was given, resulting in a significant improvement in symptoms.⁶

Other pharmacological and supportive treatments 

• Antidepressants: Serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine, sertraline) show variable benefit, likely via effects on sympathetic fibres and vascular control⁵ 
• Anticonvulsants: Gabapentin and pregabalin may reduce neuropathic pain by binding voltage-gated calcium channels. Some patients report symptom improvement, though full remission is rare⁵
• Beta blockers and opioids: Beta blockers provide limited benefit, opioids may temporarily relieve pain, but are not recommended long-term⁵
• Multidisciplinary sare: Severe or refractory EM benefits from a team approach including dermatology, neurology, vascular medicine, pain specialists, and haematology for secondary EM. Central sensitisation and chronic pain management are often necessary⁵

New treatments

There is a study where a patient who has received a multimodal treatment with antihistaminic drugs, the quickest and most effective response he had was the use of hyper-dilute botulinum toxin to the full face. Hyper-dilute onabotulinum toxin A (BoNTA) is a novel and safe treatment for neuropathic pain and microvascular conditions such as erythromelalgia. This patient had rapid improvement in symptom severity and frequency in an otherwise refractory case of erythromelalgia.⁹

FAQs

What is erythromelalgia (EM)?

Erythromelalgia is a rare condition characterised by episodes of burning pain, redness, and warmth in the extremities, most often the feet and hands. Symptoms are typically triggered by heat, exercise, or stress.¹

What causes EM?

EM may be primary (often linked to genetic variants such as mutations in the SCN9A sodium channel gene) or secondary to conditions such as myeloproliferative disorders (e.g., essential thrombocythemia, polycythemia vera).²

What does “off-label treatment” mean?

It means prescribing currently available and marketed medications, but for an indication (eg, a disease or a symptom) that has never received approval from the drug regulatory body, such as the Food and Drug Administration (FDA) in the USA and the European Medicines Agency (EMA) in the European Union.¹⁰

Why are off-label treatments used for EM?

Because EM is rare and poorly understood, few treatments are formally approved. Many therapies, such as sodium channel blockers, corticosteroids, or antidepressant are prescribed off-label when standard options do not work.

How do doctors decide which off-label treatment to try?

Decisions are based on disease severity, triggers, underlying conditions, genetic factors, and the patient’s response to previous treatments.

How is EM diagnosed?

Diagnosis is clinical, based on symptoms and physical findings. Blood work, genetic testing, or evaluation for underlying conditions may be recommended to identify secondary causes.

Can EM be cured? 

There is no universal cure. Some patients achieve long-term relief through targeted treatments (such as aspirin in secondary EM), but others require ongoing management for chronic symptoms.

What lifestyle measures can help? 

Avoiding heat exposure, keeping affected areas cool, wearing breathable footwear, and pacing activities.

Is EM hereditary? 

Primary EM can be inherited, most often due to gain-of-function mutations in the SCN9A gene, though this accounts for only about 5% of cases.

Summary

Erythromelalgia is an uncommon, variable, but well-defined disorder. The distinction between primary and secondary erythromelalgia is important because secondary erythromelalgia may reflect otherwise treatable underlying disorders. 

Patients with this condition display a wide spectrum of clinical manifestations and severity. Chronic pain may lead to sleeping disorders, school difficulties, and poor participation in physical activity in children. Mutations in the SCN9A gene are not always detected.

The diagnosis and treatment of EM remain challenging. An appropriate and early diagnosis is crucial as it may provide psychological and emotional relief. 

To conclude, erythromelalgia management involves several medical fields, and the path from diagnosis to treatment, which involves all necessary specialists, may be frustrating for both patients and clinicians.