Gain-of-function mutations in SCN9A, which encodes the Nav1.7 voltage-gated sodium channel, are known to cause primary erythromelalgia (PEM). This condition is characterized by recurrent episodes of erythema, burning pain, and warmth in the extremities. These genetic insights have spurred the development of Nav1.7 blockers as a promising therapeutic strategy for PEM. However, translating these findings into effective clinical treatments has remained challenging. In this study, we demonstrate that mepyramine, a compound previously shown to alleviate pain in animal models, effectively targets hNav1.7 channels carrying PEM-associated gain-of-function mutations, providing substantial pain relief in PEM patients. Using voltage-clamp recordings in human embryonic kidney (HEK) 293 cells, we demonstrated that mepyramine inhibits hNav1.7 channels carrying three distinct PEM mutations, I848T, L858F, and L1267V, which differentially affect the gating properties of hNav1.7. Importantly, mepyramine's efficacy was consistent regardless of how these mutations altered channel activation or inactivation properties. To evaluate its clinical potential, we administered a high-dose topical formulation of mepyramine to a group of PEM patients suffering from severe pain that was unresponsive to conventional analgesics, including cases with identified SCN9A mutations. This treatment rapidly and durably reduced burning pain and erythema, providing meaningful relief for patients who had not responded to, or could not tolerate, previous therapies. These results suggest that mepyramine can inhibit PEM-associated Nav1.7 channel mutants and may offer a new therapeutic approach for PEM patients.

Primary erythromelalgia (PEM) is a rare neuropathic pain disorder characterized by debilitating burning pain of the extremities relieved by cold exposure. We report a pediatric patient who developed severe, full-thickness lower extremity ulcerations infected with Alternaria alternata and complicated by osteomyelitis following consistent direct skin cooling with window air conditioning. This case demonstrates serious infectious complications that can arise from cooling measures commonly employed for PEM symptom relief.

Erythromelalgia is a rare neurovascular syndrome characterized by intense, episodic burning pain that primarily affects the feet and hands and, occasionally, the face. Symptoms are often triggered by heat and exercise, with relief typically achieved through cooling methods. However, improper use of these techniques can lead to serious complications, such as trench foot and cellulitis. The condition can also have significant psychological effects, contributing to anxiety and depression. An 18-year-old Lebanese woman with primary erythromelalgia and a family history of the condition presented with worsening bilateral pain and erythema in her lower extremities. Her pain was poorly controlled, prompting her to engage in prolonged ice-water immersion, which resulted in skin abrasions, necrotic ulcers, and cellulitis. On admission, she exhibited bilateral lower extremity erythema, edema, tenderness, and macerated skin with necrotic ulcers on her left foot. Her nails showed white discoloration and onycholysis. Laboratory tests were normal, and Doppler ultrasound revealed increased blood flow, supporting the diagnosis of erythromelalgia. A multidisciplinary team managed her care, addressing infection, pain, and anxiety. She received antibiotics, wound care, and antifungal therapy for onychomycosis. Pain management included aspirin, pregabalin, topical lidocaine, acetaminophen, nefopam, and opiates; however, due to persistent pain, her regimen was adjusted to incorporate morphine and additional agents. Duloxetine was also introduced to address both anxiety and pain. After two days on the revised treatment plan, her pain improved significantly, allowing for discharge. Follow-up visits confirmed skin healing, and Doppler ultrasound again demonstrated increased blood flow. This case highlights the complexity of managing severe erythromelalgia, underscoring the importance of appropriate pain management, patient education, and multidisciplinary care. It represents the first reported case of erythromelalgia requiring hospitalization in Lebanon and illustrates the potential complications of inadequate management and inappropriate use of cooling techniques.

Erythromelalgia is a condition characterized by intense burning pain, redness, and heat in the extremities that has garnered increasing attention in recent years. This literature review provides a comprehensive historical perspective and current update on primary erythromelalgia or PEM, categorizing and tracing the clinical knowledge of the condition and identifying key milestones of historical research. In a sequential fashion, the review explores the evolution of understanding of PEM, starting from its initial descriptions in the medical literature to the present day. Early case reports and pivotal studies that contributed to recognizing and characterizing the disorder are examined. Important discoveries, diagnostic criteria, and therapeutic approaches that have shaped the management of erythromelalgia over time are highlighted. Additionally, the impact of genetic studies and molecular investigations on current understanding of PEM is discussed. Identifying mutations in the SCN9A gene is emphasized as a significant breakthrough, shedding light on the role of sodium channels in the disorder's pathogenesis. Overall, this review consolidates the wealth of clinical knowledge and research milestones related to PEM. Integrating historical research milestones offers a comprehensive overview of the condition, from early descriptions to the current state of knowledge. This knowledge serves as a foundation for further research and can assist in improving diagnosis and management strategies for individuals with PEM.

Gain-of-function variants in the voltage-gated sodium channel Nav1.7, encoded by the SCN9A gene, have previously been identified in patients with erythromelalgia, a clinical diagnosis defined by intermittent attacks of painful, hot, swollen, and red skin, predominantly involving the hands and feet. Symptoms are induced or aggravated by warming and relieved by cooling. In primary erythromelalgia there is no known underlying disease. This study investigated the frequency of SCN9A variants in a cohort of primary erythromelalgia patients collected at a single centre, and examined the clinical signs and symptoms associated with identified variants. One hundred patients with possible erythromelalgia were collected prospectively and evaluated by clinical examination. Thirty-five patients fulfilling the clinical criteria of primary erythromelalgia were screened for variants in SCN9A. Five were found to carry likely causal variants, including a variant found in 2 related individuals and a variant not previously described in patients with erythromelalgia. The clinical findings differed significantly between the patients. Overall, in this cohort only 4/34 (11.7%) of unrelated patients had erythromelalgia likely caused by gain-of-function variants in SCN9A. Variants in SCN9A are therefore likely to cause or contribute to primary erythromelalgia in only a small proportion of patients.