Stem cell-derived sensory neurons modelling inherited erythromelalgia: normalization of excitability.

Effective treatment of pain remains an unmet healthcare need that requires new and effective therapeutic approaches. NaV1.7 has been genetically and functionally validated as a mediator of pain. Preclinical studies of NaV1.7-selective blockers have shown limited success and translation to clinical studies has been limited. The degree of NaV1.7 channel blockade necessary to attenuate neuronal excitability and ameliorate pain is an unanswered question important for drug discovery. Here, we utilize dynamic clamp electrophysiology and induced pluripotent stem cell-derived sensory neurons (iPSC-SNs) to answer this question for inherited erythromelalgia, a pain disorder caused by gain-of-function mutations in Nav1.7. We show that dynamic clamp can produce hyperexcitability in iPSC-SNs associated with two different inherited erythromelalgia mutations, NaV1.7-S241T and NaV1.7-I848T. We further show that blockade of approximately 50% of NaV1.7 currents can reverse neuronal hyperexcitability to baseline levels.

Topical treatments for erythromelalgia.

Erythromelalgia is a rare neurovascular disease that causes episodes of pain, redness, and warmth in the extremities, and can be debilitating. Currently, there is no universally effective treatment for erythromelalgia. As the precise etiology of erythromelalgia remains obscure, presently available treatments are aimed at alleviating erythromelalgia's wide-ranging symptoms. In general, topical therapies for erythromelalgia are preferred for their more limited side effects and for those with contraindications to systemic therapies. This review will summarize the current topical therapies available to treat erythromelalgia and discuss emerging therapies based on our growing understanding of erythromelalgia pathophysiology.

Hormone replacement therapy-induced pain and redness of the feet.

We report the first case, to our knowledge, of a patient who developed erythromelalgia after receiving oestrogen-progestin replacement therapy (Femoston). The patient had complete remission after taking glycyrrhizin and pregabalin for 3 months. This case expands the spectrum of erythromelalgia and provides a therapeutic option.

Intravenous Ketamine Infusion as an Adjunctive Pain Treatment for Erythromelalgia: A Pediatric Case Report.

Erythromelalgia is a rare neurovascular pain condition characterized by erythematous, warm, and painful extremities. Symptoms are exacerbated by heat and relieved by cooling. Treatment is challenging and focuses on symptom control with various medications and therapies targeted toward eliminating destructive cooling behaviors. This pediatric case was notable because the patient's pain dramatically improved after a short-term, low-dose ketamine infusion, allowing her to finally wean off detrimental cooling practices of her extremities. Intravenous ketamine has rarely been described as an adjunctive analgesic strategy for erythromelalgia.

Successful treatment of knee erythromelalgia with topical oxymetazoline.

Erythromelalgia is an infrequent syndrome with a profound impact on quality of life. Its management is usually challenging and multiple treatments have been reported with variable response rates. To the best of our knowledge, we present the first case of erythromelalgia successfully treated with topical oxymetazoline.

Combination gel of 2% amitriptyline and 0.5% ketamine to treat refractory erythromelalgia pain - a case report of pain control success.

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.

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 / Combination gel of 2% amitriptyline and 0.5% ketamine to treat refractory erythromelalgia pain-a case report of pain control success

La eritromelalgia (EM) es una neuropatía inusual 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 un año de un paciente con EM usando un gel tópico de combinación de amitriptilina al 2% y ketamina al 0,5%.(AU)

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.(AU)

Population Pharmacokinetics of Vixotrigine in Healthy Volunteers and Subjects with Trigeminal Neuralgia, Painful Lumbosacral Radiculopathy and Erythromelalgia.

BACKGROUND: Vixotrigine is a voltage and use dependent sodium channel blocker currently under development for treatment of various neuropathic pain indications. OBJECTIVE: The objective of this work was to develop a population pharmacokinetic model and assess effects of various covariates on pharmacokinetic parameters of vixotrigine. METHOD: Plasma concentration-time data from 12 Phase 1 or 2 studies were included in the analyses. The data were obtained following administration of single or multiple doses of vixotrigine in healthy volunteers and patients. One- and two-compartment pharmacokinetic models were evaluated as base structural pharmacokinetic models. The inclusion of selected covariates was assessed using a stepwise backward elimination approach (α = 0.001) once the base/full model was developed. The predictive ability of the model was evaluated using a visual predictive check (VPC). The final model was used to evaluate effect of covariates on exposure of vixotrigine. RESULTS: A total of 10,263 pharmacokinetic samples collected from 465 subjects were included in the analyses. The pharmacokinetics of vixotrigine was adequately described by a two-compartment model with two transit absorption compartments and first-order elimination. Predictability of the model was also established by VPC. The final model included covariates of age, weight and carbamazepine co-administration on clearance, weight on central volume of distribution, food on absorption rate constant and formulation and Japanese race on bioavailability. None of the covariates identified had a clinically relevant effect, as impact on area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) was within ± 25%. CONCLUSION: The model characterizes the pharmacokinetics of vixotrigine well, and the exposure of vixotrigine was comparable between healthy subjects and patients. None of the covariates evaluated have a clinically relevant impact on the pharmacokinetics of vixotrigine.

Eritromelalgia secundaria: informe de caso / Secondary Erythromelalgia - Case Report

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Eritromelalgia. Informe de un caso / Erythromelalgia. Case Report

Resumen La eritromelalgia es una enfermedad rara, crónica, poco conocida, de difícil diagnóstico y tratamiento. Caracterizada por enrojecimiento, calor, dolor intenso y ardor en la parte distal de las extremidades. Afecta fundamentalmente manos, pies, nariz y orejas. El rubor, el dolor y el calor de las extremidades aumentan al exponerse a altas temperaturas, así como después de realizar ejercicio. Los síntomas suelen aliviarse mediante la inmersión de la extremidad afectada en agua fría. Se presenta un caso de una mujer de 33 años de edad, blanca, con afectación predominantemente en las manos. A través del interrogatorio minucioso y la realización de los exámenes complementarios realizados se concluyó que la variante etiológica que presentó la paciente era una eritromelalgia primaria o idiopática. Se impuso tratamiento con aspirina y nifedipino. La evolución clínica de la paciente fue favorable (AU).

ASBTRACT Erythromelalgia is a rare, chronic, little known disease, of difficult diagnosis and treatment. It is characterized by redness, heat, and intense pain and burning in the distal part of the extremities. It mainly affects hands, feet, nose and ears. The flushing, pain and warmth of the extremities increase when exposed to high temperatures as well as after exercise. The symptoms are usually relieved by immersing the affected limb in cold water. The authors present the case of a white, 33-years-old woman, with predominantly involved hand. Through a detailed interview and complementary tests they concluded that the etiological variant presented by the patient was a primary or idiopathic erythromelalgia. Treatment with aspirin and nifedipine was prescribed; the clinical progress of the patient was successful (AU).

Extensive Lumbar Sympathetic Ganglion Block Combined With Epidural Block for Primary Erythromelalgia: A Case Report.

A 19-year-old-woman experienced severe burning pain in the lower extremities with erythema and swelling. She was diagnosed with primary erythromelalgia (PE). The pain was unresponsive to medications but relieved by immersing her feet in cold water. We performed a multilevel lumbar sympathetic ganglion block (LSGB) with 5% phenol at second lumbar vertebra (L2) and third lumbar vertebra (L3), and additional fourth lumbar vertebra (L4) levels. An epidural block was intermittently combined. The pain and skin lesions dramatically improved after the procedures, and she no longer needed medications or to soak her feet in cold water. This case demonstrated that extensive LSGB may be a therapeutic option for intractable PE.

Acute monophasic erythromelalgia pain in five children diagnosed as small-fiber neuropathy.

The small-fiber polyneuropathies (SFN) are a class of diseases in which the small thin myelinated (Aδ) and/or unmyelinated (C) fibers within peripheral nerves malfunction and can degenerate. SFN usually begins in the farthest, most-vulnerable axons, so distal neuropathic pain and symptoms from microvascular dysregulation are common. It is well known in adults, e.g. from diabetes, human immunodeficiency virus, or neurotoxins, but considered extremely rare in children, linked mostly with pathogenic genetic variants in voltage-gated sodium channels. However, increasing evidence suggests that pediatric SFN is not rare, and that dysimmunity is the most common cause. Because most pediatric neurologists are unfamiliar with SFN, we report the diagnosis and management of 5 Swiss children, aged 6-11y, who presented with severe paroxysmal burning pain in the hands and feet temporarily relieved by cooling-the erythromelalgia presentation. Medical evaluations revealed autoimmune diseases in 3 families and 3/5 had preceding or concomitant infections. The standard diagnostic test (PGP9.5-immunolabeled lower-leg skin biopsy) confirmed SFN diagnoses in 3/4, and autonomic function testing (AFT) was abnormal in 2/3. Blood testing for etiology was unrevealing, including genetic testing in 3. Paracetamol and ibuprofen were ineffective. Two children responded to gabapentin plus mexiletine, one to carbamazepine, two to mexiletine plus immunotherapy (methylprednisolone/IVIg). All recovered within 6 months, remaining well for years. These monophasic tempos and therapeutic responses are most consistent with acute post-infectious immune-mediated causality akin to Guillain-Barré large-fiber polyneuropathy. Skin biopsy and AFT for SFN, neuropathic-pain medications and immunotherapy should be considered for acute sporadic pediatric erythromelalgia.

Pain management in children with erythromelalgia: case report / Tratamento da dor em criança com eritromelalgia: relato de caso

Abstract Erythromelalgia is a neuropathic pain syndrome due to an autosomal dominant gene, characterized by erythema, increased skin temperature and burning pain in hands and feet, whose treatment is often unsatisfactory. In this paper, we report a case of a 9 years old female patient whose first episode of burning pain, erythema and edema of the hands, without triggering factors, had instant relief after immersion in cold water. She presented with systemic arterial hypertension and had seizures. The patient was treated with gabapentin (150 mg.8 h−1) and amitriptyline (12.5 mg) orally, intravenous lidocaine infusion (120 mg), without relieving pain complaints. Due to the lack of response to the proposed treatment, it was decided to gradually reduce these medications and to introduce carbamazepine (200 mg) orally and, after 4 days of treatment, there was complete relief of the manifestations.

Resumo Eritromelalgia é uma síndrome dolorosa neuropática decorrente de gene autossômico dominante, caracterizada por eritema, aumento da temperatura da pele e dor em queimação, em mãos e pés, e o tratamento é muitas vezes insatisfatório. Neste caso, está o relato de uma paciente do sexo feminino, com nove anos e primeiro episódio de dor em queimação, eritema e edema em mãos, sem fatores desencadeantes, com alívio instantâneo após imersão em água fria. Apresentava hipertensão arterial sistêmica e teve crises convulsivas. Foi tratada com gabapentina (150 mg.8 h-1) e amitriptilina (12,5 mg) via oral, lidocaína (120 mg) venosa em infusão, sem alívio das queixas álgicas. Devido à ausência de resposta ao tratamento proposto, decidiu-se redução gradativa dessas medicações e introdução de carbamazepina (200 mg) via oral e após quatro dias de tratamento houve alívio completo das manifestações.