Mexiletine for Symptoms and Signs of Myotonia in Nondystrophic Myotonia

Abstract

Context Non-dystrophic myotonias (NDM) are rare diseases caused by mutations in skeletal muscle ion channels. Patients experience delayed muscle relaxation causing functionally-limiting stiffness and pain. Mexiletine-induced sodium channel blockade reduced myotonia in case studies and one single blind trial. As is common in rare diseases, larger studies of safety and efficacy have not previously been considered feasible. Objective To determine the effects of mexiletine for symptoms and signs of myotonia in NDM. Design, Setting, and Participation Fifty-nine patients with NDM participated in a randomized, double-blind, placebo-controlled two-period crossover study conducted between December 23, 2008 and March 30, 2011 at 7 neuromuscular referral centers in 4 countries, as part of the NIH-funded Rare Disease Clinical Research Network. Intervention Oral 200 mg mexiletine or placebo capsules three times daily for 4 weeks, followed by the opposite intervention for 4 weeks, with 1 week wash-out between periods. Main Outcome Measures Patient-reported stiffness recorded on an interactive voice response diary (IVR) was the primary endpoint (1 ‘minimal’ to 9 ‘worst ever experienced’). Secondary endpoints included IVR-reported changes in pain, weakness, and tiredness, clinical myotonia assessment, quantitative grip myotonia, Individualized Neuromuscular Quality of Life (INQoL, percent of maximal detrimental impact), SF-36, electrophysiological exercise testing, and needle EMG. Results Mexiletine significantly improved patient-reported stiffness on the IVR. Because of a statistically significant interaction between treatment and period for this outcome, primary endpoint is presented by period (period 1 means were mexiletine 2.53 versus placebo 4.21, difference −1.68, 95% Confidence Interval [CI] −2.66, −0.706, P<0.001; period 2 means were mexiletine 1.60 versus placebo 5.27, difference −3.68, 95% CI −3.85, −0.139, P=0.04). Mexiletine improved the INQoL QOL score (mexiletine 14.0, placebo 16.7, difference −2.69, 95% CI −4.07, −1.30, P<0.001) and decreased handgrip myotonia on clinical exam (seconds: mexiletine 0.164, placebo 0.494, difference −0.330, 95% CI −0.633, −0.142, P<0.001). The most common adverse effect was gastrointestinal (9 mexiletine, 1 placebo). Two participants experienced transient cardiac effects that did not require stopping the study (1 placebo, 1 mexiletine). One serious adverse event was determined to be not study-related. Conclusion In this preliminary study of patients with NDM, the use of mexiletine compared with placebo resulted in improved patient-reported stiffness over 4 weeks of treatment, despite some concern about the maintenance of blinding. Trial Registration Clinicaltrials.gov identifier: NCT 00832000

Influences of Pregnancy on Different Genetic Subtypes of Non-Dystrophic Myotonia and Periodic Paralysis

“…In order to balance risks and benefits of mexiletine intake, the dosage had been reduced to 200 mg daily for safety reasons in both pregnancies of case 2. In severe disease courses, mexiletine has been shown to be effective [9] and teratogenic risks can be regarded to be small at the normally prescribed daily dosage of 200-300 mg. Nonetheless, experiences with mexiletine or other antiarrhythmic agents in pregnancy and lactation are very limited and caution is warranted.…”

SCN4A variants and Brugada syndrome: phenotypic and genotypic overlap between cardiac and skeletal muscle sodium channelopathies

“…42,43 Caution during a challenge test is therefore required. In contrast, Mexiletine, a class Ib antiarrhythmic, is considered to be safe in reducing myotonia 44 and is known to restore trafficking defects in BS. 45,46 More intriguing is the presence of a rare pathology such as Thomsen disease (o1/100 000) in one BS family (J).…”

Lamotrigin reduziert die Symptome bei nicht dystrophen Myotonieerkrankungen

“…Nur für Mexiletin ist eine Wirksamkeit auf die Myotoniesymptomatik belegt [1], es steht in Deutschland jedoch nicht zur Verfügung. Kürzlich wurde für Ranolazin, einem weiteren Natriumkanalblocker, eine Verbesserung der Myotonie beobachtet, dies allerdings nur auf der Basis einer o enen, nicht placebokontrollierten Pilotstudie [2].…”