A stepwise approach for the management of primary erythromelalgia: A prospective single-arm study

Abstract

To the Editor: Primary erythromelalgia (PEM) is a rare and highly disabling genetic disease characterized by severe burning pain and erythema of the extremities. PEM is caused by gain-of-function mutations in SCN9A, leading to the overactivation of sodium channels Nav1.7.1Yang Y. Wang Y. Li S. et al.Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia.J Med Genet. 2004; 41: 171-174Crossref PubMed Scopus (584) Google Scholar,2Waxman S.G. Merkies I.S.J. Gerrits M.M. et al.Sodium channel genes in pain-related disorders: phenotype-genotype associations and recommendations for clinical use.Lancet Neurol. 2014; 13: 1152-1160Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar Its management remains challenging, with no consensus-based clinical guidelines. Sodium channel blockers such as mexiletine and carbamazepine have been used anecdotally to relieve pain in patients with PEM.3Tham S.W. Giles M. Current pain management strategies for patients with erythromelalgia: a critical review.J Pain Res. 2018; 11: 1689-1698Crossref PubMed Scopus (13) Google Scholar Rizatriptan is a 5-HT1B/1D receptor agonist that effectively controls acute migraine4Wellington K. Plosker G.L. Rizatriptan: an update of its use in the management of migraine.Drugs. 2002; 62: 1539-1574Crossref PubMed Scopus (34) Google Scholar and neuropathic pain.5Moore D. Chong M.S. Shetty A. Zakrzewska J.M. A systematic review of rescue analgesic strategies in acute exacerbations of primary trigeminal neuralgia.Br J Anaesth. 2019; 123: e385-e396Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar The rapid onset of action (within 30 minutes) of rizatriptan4Wellington K. Plosker G.L. Rizatriptan: an update of its use in the management of migraine.Drugs. 2002; 62: 1539-1574Crossref PubMed Scopus (34) Google Scholar might help alleviate acute pain attacks in patients with PEM; however, it has not been used previously in such cases. This prospective single-arm study investigated the efficacy and safety of a stepwise approach in treating PEM with these 3 drugs. Patients clinically diagnosed with PEM and molecularly confirmed by the presence of pathogenic mutations in SCN9A were recruited. PEM was managed using a stepwise approach that consisted of patient education and sequential addition of oral drugs as needed (Fig 1). The drugs included 2 controlling drugs mexiletine and carbamazepine that were taken daily to maintain symptomatic control and an alleviating drug rizatriptan that was taken only as needed, aiming to quickly alleviate acute pain attacks. Treatment response (pain and skin improvement) and adverse events were assessed by monthly follow-up for up to 24 months. The severity of pain was assessed using the numerical rating scale (NRS), ranging from 0 (no pain) to 10 (the worst pain possible). The detailed study design has been provided in Supplementary Methods (available via Mendeley at https://data.mendeley.com/datasets/56tp93t52r/1). The study enrolled 7 unrelated patients with PEM (4 females, 3 males), with an average age of 11.9 years (range, 7-22 years). The baseline NRS score, initial treatment plan, and treatment response are summarized in Table I. Six (85.7%) patients had complete pain improvement (Supplementary Table I, available via Mendeley at https://data.mendeley.com/datasets/56tp93t52r/1). The average final NRS score of all 7 patients was significantly lower than the baseline score (mean, 5.3 vs 0.8; P = .018), indicating the maintenance of favorable treatment response over the follow-up period. Complete skin improvement was achieved in 6 (85.7%) patients (Supplementary Fig 1, available via Mendeley at https://data.mendeley.com/datasets/56tp93t52r/1). The beneficial effect of this regimen was also reflected by improvement in sleep quality and spontaneous remission of comorbidities (hypertension and recurrent diarrhea). Notably, 3 patients returned to school after treatment (Supplementary Results, available via Mendeley at https://data.mendeley.com/datasets/56tp93t52r/1). Two patients reported temporary mild dizziness after taking carbamazepine. No cardiovascular or serious adverse events were observed.Table IClinical features, genotype, and treatment response of the 7 patientsPatientSexAge, yBody weight, kgSCN9AFamily historyOnset age, yPrior systemic treatmentsBaseline NRS scoreInitial treatment planTreatment responseAverage final NRS score∗Average final NRS score = the average NRS score in the last 12 months of follow-up for every patient. (range)Mexiletine, mg/dCarbamazepine, mg/dRizatriptan, mg each timePain improvementSkin improvement1F1442c.406A>GNone9Gabapentin, aspirin45002005 or 10CompleteComplete0.3 (0-1)2M825c.647T>CNone5Paracetamol, hydromorphone, prednisone, aspirin5400100NoneCompleteComplete1.8 (0-4)3F1241c.2543T>CNone3Gabapentin, amitriptyline, propranolol, vitamin B666002005CompleteComplete0 (0)4F832c.2572C>TNone4None5300None10CompleteComplete0.5 (0-2)5M729c.2572C>TNone6Phenytoin, aspirin, traditional Chinese medicine860040010MajorComplete2.8 (2-3)6M1248c.3923C>TYes7None4300200NoneCompleteMajor0 (0)7F2260c.3947T>CYes15Aspirin, codeine, gabapentin, lumbar sympathectomy (in 2014)540040010CompleteComplete0.1 (0-1)NRS, Numerical rating scale.∗ Average final NRS score = the average NRS score in the last 12 months of follow-up for every patient. Open table in a new tab NRS, Numerical rating scale. We propose a newly designed regimen incorporating patient education, treatment of underlying pathophysiology (mexiletine and carbamazepine), and symptomatic management of acute pain (rizatriptan). Despite some limitations, including a smaller sample size, uncertain safety profile, and relatively low NRS scores at baseline, this regimen might represent a reliable initial treatment plan for PEM, leading to significant long-term improvement with a favorable tolerability profile. It should be noted that the medications were used in a stepwise manner; this meant that not all 3 medications were required for each patient, and doses could be reduced or even discontinued after the pain reduced. Also, the regimen was trialed in a defined subset of patients with erythromelalgia (PEM with SCN9A mutations) and might not apply to all patients. None disclosed.