Mexiletine Associated With Better Reduction in Muscle Stiffness Than Placebo in Nondystrophic Myotonia

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Findings support the efficacy of mexiletine and the potential value of N-of-1 trials for assessing interventions in some chronic rare diseases.

Mexiletine conferred a greater reduction in mean daily muscle stiffness compared with placebo in patients with nondystrophic myotonia, according to a study published in JAMA.

Researchers from a single academic referral center performed a series of aggregated, double-blind, placebo-controlled N-of-1-trials. A total of 30 patients (mean age, 43.4 [SD, 15.24] years; 22% men) with confirmed nondystrophic myotonia were enrolled. The researchers compared outcomes of 600 mg/day mexiletine vs placebo during several 4-week treatment periods. Participants were assessed in regard to reductions in daily reported muscle stiffness according to a 1-to-9 scale (higher scores = greater impairment).

A total of 27 patients completed the study, of whom 19 had a mutation in the skeletal muscle chloride channel gene CLCN1 and 11 had a mutation in the skeletal muscle sodium channel gene SCN4A. In the overall cohort, the median muscle stiffness score was 6.08 (interquartile range, 4.71-6.80) at baseline, and there was a greater reduction from baseline in the median muscle stiffness score during the mexiletine period vs the placebo period of 2.50 (95% credible interval [CrI], 1.77-3.24) vs 5.56 (95% CrI, 4.73-6.39), respectively. The difference in symptom score reduction was 3.06 (95% CrI, 1.96-4.15), favoring mexiletine.

Gastrointestinal discomfort was the most frequently reported adverse event in the mexiletine vs placebo group (70% vs 3%, respectively). Mexiletine vs placebo was associated with a mean reduction in daily reported muscle stiffness of 3.12 (95% CI, 2.46-3.78).

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Limitations of the study include its small sample size and nonrandomized design, and the determination of minimal clinically important difference by only expert opinion.

Findings from this study indicate that “the efficacy of mexiletine for treatment of nondystrophic myotonia as well as the feasibility of N-of-1 trials for assessing interventions in some chronic rare diseases.”


Stunnenberg BC, Raaphorst J, Groenewoud HM, et al. Effect of mexiletine on muscle stiffness in patients with nondystrophic myotonia evaluated using aggregated N-of-1 trials. JAMA. 2018;320(22):2344-2353.