Erythromelalgia (EM) is a rare autosomal dominant neuropathy characterized by the combination of severe burning pain and erythematous warm extremities. Chronic pain control is most often unsuccessful and a completely effective therapy is yet to be identified. Recent studies have reported significant improvements in pain management using a combination of amitriptyline and ketamine in a topical formulation. We describe a 1-year follow-up pain control success case of a male patient with EM, proposed for topical use of a 2% Amitriptyline and 0.5% Ketamine gel.
La eritromelalgia (EM) es una rara neuropatía autosómica dominante caracterizada por la combinación de ardor intenso, extremidades eritematosas y cálidas. Con frecuencia el control del dolor crónico no tiene éxito, no habiéndose identificado aún una terapia efectiva. Los estudios recientes han identificado mejoras significativas en el manejo de dolor, utilizando una combinación de amitriptilina y ketamina en formulación tópica. Describimos un caso de respuesta positiva al dolor, con seguimiento de 1 año, de un paciente con EM usando un gel tópico de combinación de amitriptilina al 2% y ketamina al 0,5%.
Erythromelalgia (EM) is an unusual autosomal dominant debilitating neuropathy that was named according to its main symptoms (erythros-red, melos-limbs, algos-pain).1
Little is known about its global prevalence, but it is estimated to affect 0.36–1.1 per 100,000 population per year.1 EM can be classified as primary and secondary, based on the absence or presence of diseases or drugs that could be associated with the appearance or precipitation of symptoms, respectively.2 Although the aetiology and pathophysiology are not fully understood, genetic research has identified a link between cases of inherited EM and Nav1.7 sodium channel mutations encoded by the SCN9A gene.3 Nav1.7 subtypes are preferentially expressed in sensory and sympathetic ganglia neurons, and mutations lead to neuronal excitability, lowering the current threshold and increasing the frequency of firing in dorsal root ganglia.4,5
EM usually manifests as redness, severe burning pain, and warmth in the extremities, exacerbated by heat, ambulation, and physical exercise. Elevating and cooling the extremities can improve these symptoms. EM can occur at any age, although it is commonly diagnosed in the fifth and sixth decades of life.6 The absence of guidelines on pain management or therapies condemns patients to a life of severe pain, and physical, psychological and social disability.
According to early studies, treatment with different drug classes and combinations, including aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, anticonvulsants, antidepressants, corticosteroids, and topical lidocaine is ineffective.1,6,7 However, more recent studies8,9 have shown successful results in the management of EM pain with a combination of amitriptyline and ketamine in a topical formulation.
We describe the 1-year follow-up of a man with EM and previous uncontrolled pain who received topical 2% amitriptyline and 0.5% ketamine gel.
Case reportA 28-year-old Caucasian male was referred to our Chronic Pain Unit (CPU) by his internist for uncontrolled pain affecting his hands and feet associated with known EM.
During his first visit, in April 2018, he described burning pain with occasional episodes of electrical shocks and numbness, mainly located in the feet and occasionally in the hands.
The painful episodes had started in his feet 8 years earlier, spreading to his hands 5 years later. The episodes that affected his hands were self-limiting and slightly painful and associated with long periods of writing by hand. In his feet, painful episodes were increasingly frequent, especially during the summer months due to hot weather and humidity. They occurred during the day, and were precipitated by exercise, or simply by standing. He used to exercise regularly, but had to stop due to the increased frequency of the episodes, with pain starting after 5 min of standing during exercise. The pain was relieved by removing his shoes and socks, and submerging his feet in cold water. To relieve symptoms at night he slept with his feet uncovered. The treatments or drugs (paracetamol, NSAIDs and gabapentin) prescribed so far had relieved his pain by only 20%. His pathology interfered with his social life, his work, and also with his sleeping habits. The episodes of pain were becoming progressively worse, and were more frequent and difficult to manage.
In the short form Brief Pain Inventory (BPI), he scored 57 for walking ability, general activity and work (WAW), 55 for relationships with others, enjoyment of life and mood (REM), and 56% for pain interference in life activities at the time of the interview. The BPI correlated with significant pain severity and considerable impact on daily functioning. In the Hospital Anxiety and Depression Scale (HADS), he scored 7 for anxiety and 8 for depression (high depression score) and scored 5 on the Douleur Neuropathique 4 (DN4) scale, which demonstrated probable neuropathic pain.
He had no underlying morbidities, other than attention deficit/hyperactivity disorder, for which he had been taking daily bupropion 150 mg for the past 3 years. He had no family history of EM.
On his first visit he reported having taken gabapentin 200 mg 3 times daily for pain control, with unsatisfactory results. On physical examination, he presented hypoesthesia to touch and pinprick in both feet, with no other relevant findings.
Surprisingly, due to his high level of education (Masters in translation), the patient already had information about EM and provided us with a retrospective study from the Mayo Clinic,9 where response to a topical amitriptyline-ketamine compound had shown satisfactory results. He was eager to receive a similar topical treatment, and filled out an authorization form, which was submitted for approval by the clinical council and the pharmacy committee.
After this first visit, the patient was prescribed amitriptyline 10 mg daily, gabapentin 300 mg 3 times daily, and a 5% lidocaine patch (12 h on/12 h off) while waiting for authorization of the topical amitriptyline and ketamine gel.
After 1 month, the patient reported a scant 20%–30% improvement in pain control, so amitriptyline was increased to 20 mg daily.
In July 2018, he returned to the CPU for follow-up, describing worsening pain in the feet, particularly in high temperatures, with a mean pain score of 5. Permission to use the topical treatment was still under review, and when it was finally granted, the hospital pharmacy had difficulties in finding the right vehicle for the topical gel.
In February 2019, the patient was contacted to report pain management (slight reduction, with a mean pain score of 4): he had suspended amitriptyline due to lack of concentration at work.
Two months later, in April 2019, the patient was given a 100 mL gel of 2% methylcellulose, amitriptyline and 0.5% ketamine for topical use, applying 5 mL once a day in the morning on each foot. Over the next 2 weeks, the patient reported “very promising results”, with a 60% reduction in pain intensity, primarily burning pain.
In July 2019, he scored 6 on the Patient Global Impression of Change (PGIC) questionnaire—“Better and a definite improvement that has made a real and worthwhile difference”—and 33 for WAW, 28 for REM and 31% for pain interference in life activities.
When he returned to the CPU in September 2019 for follow-up, he reported a 70% reduction in pain intensity from the start of treatment, and a PGIC score of 7, describing less frequent (not daily, moderate to intense, and moderately warm temperatures or humidity) and less intense episodes (mean numerical pain score of 2) that did not interfere with activities of daily living (ADLs), and rated his subjective improvement in quality of life at 50% or more.
Application of the topical treatment produced no adverse effects. He also stopped all medication except for bupropion for his attention deficit/hyperactivity disorder.
The patient was told that he could increase the topical treatment to twice a day, which he considered not necessary as his pain was satisfactorily controlled and did not interfere with his ADLs.
We therefore decided to maintain the regimen of 5 mL of the topical amitriptyline-ketamine gel applied once daily, discontinue the other medication, and continue with follow-up.
DiscussionEM is a rare, debilitating, autosomal dominant neuropathy1 characterized by severe burning pain and hot, erythematous extremities. The pain can be excruciating, and is associated with exposure to heat induced by either exercise or high ambient temperature. Onset is often reported in the first decade of life.6
Mutations in sodium channels, such as SCN9A, can cause membrane hyperexcitability, and have been identified in the pathogenesis of hereditary EM. Despite major advances in our understanding of the pathophysiology of EM, the research findings have yet to be translated into clinical practice.
In the absence of position statements or established guidelines, this complicated pathology has so far been treated on the basis of trial and error. As a result, therapeutic outcomes have been poor, with a mixed response to medical treatment. No single agent has been shown to be completely effective, so most patients are given a combination of drugs.
In 2006, Sandroni and Davis8 reported the successful treatment of 4 out of 5 EM patients with a combination of topical amitriptyline and ketamine, and in 2011 a retrospective study in 36 patients with EM performed at the Mayo Clinic9 also reported a reduction in pain intensity with the topical application of amitriptyline plus ketamine. This topical formulation, therefore, has been put forward as an effective first-line treatment for EM.
The synergistic effect seems to be due to amitriptyline-mediated sodium channel blockade, which prevents nociceptor over-stimulation by blocking the action potential, combined with ketamine-mediated blockade of NMDA receptors located on the peripheral terminals of primary nociceptive afferents and modulation of AMPA and kainate receptors. It has also been speculated that these same biochemical effects could prevent vasodilation and thus reduce the redness and increased skin temperature characteristic of this disorder.8
Although a single case is insufficient to guarantee results, we also describe another case in which topical amitriptyline plus ketamine was successful in a patient with EM, thus supporting the use of this topical formulation in similar cases. The medication was well tolerated, and no adverse effects have been identified to date.
Pain questionnaires are essential tools to monitor the effect of pain therapy and measure patient satisfaction and return to ADLs.
Although we systematically use numerical scales to quantify pain and monitor therapeutic efficacy, pain should also be measured with respect to its interference in ADLs and the patient’s quality of life.
Aside from improving pain scores on a numerical scale, we believe the most important outcome of this therapy has been the patient’s return to his normal activities, to practising sport, and his tolerance of warm weather.
ConclusionEM is a rare, autosomal dominant neuropathy that is difficult to treat.
In our case, as in earlier studies, application of a topical gel containing 2% amitriptyline and 0.5% ketamine reduced the intensity of pain, improved the functional status and quality of life of a patient with EM compared to oral paracetamol, NSAIDs, gabapentin and amitriptyline The gel also allowed us to discontinue all other pain medication.
Should this formulation be considered for the treatment of EM? Randomized controlled trials are still needed to establish its efficacy and safety.
FundingThe authors have not received any specific grant from any financial institution in the public, commercial or non-profit sectors.
Conflict of interestsThe authors have no conflict of interest to declare.
Please cite this article as: Portugal F, Araújo A, Silva C, Campos M, Valentim A. Gel tópico de amitriptilina al 2% y ketamina al 0,5% para el tratamiento de la eritromelalgia: reporte de un caso con respuesta positiva al dolor. Rev Esp Anestesiol Reanim. 2021;68:293–296.
