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JAMA. 2012 Oct 3;308(13):1357-65. doi: 10.1001/jama.2012.12607.

Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial.

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  • 1Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA.

Abstract

CONTEXT:

Nondystrophic myotonias (NDMs) 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 small studies; however, 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 patients with NDMs.

DESIGN, SETTING, AND PARTICIPANTS:

A randomized, double-blind, placebo-controlled 2-period crossover study at 7 neuromuscular referral centers in 4 countries of 59 patients with NDMs conducted between December 23, 2008, and March 30, 2011, as part of the National Institutes of Health-funded Rare Disease Clinical Research Network.

INTERVENTION:

Oral 200-mg mexiletine or placebo capsules 3 times daily for 4 weeks, followed by the opposite intervention for 4 weeks, with 1-week washout in between.

MAIN OUTCOME MEASURES:

Patient-reported severity score of stiffness recorded on an interactive voice response (IVR) diary (scale of 1 = minimal to 9 = worst ever experienced). Secondary end points included IVR-reported changes in pain, weakness, and tiredness; clinical myotonia assessment; quantitative measure of handgrip myotonia; and Individualized Neuromuscular Quality of Life summary quality of life score (INQOL-QOL, percentage of maximal detrimental impact).

RESULTS:

Mexiletine significantly improved patient-reported severity score stiffness on the IVR diary. Because of a statistically significant interaction between treatment and period for this outcome, primary end point is presented by period (period 1 means were 2.53 for mexiletine and 4.21 for placebo; difference, -1.68; 95% CI, -2.66 to -0.706; P < .001; period 2 means were 1.60 for mexiletine and 5.27 for placebo; difference, -3.68; 95% CI, -3.85 to -0.139; P = .04). Mexiletine improved the INQOL-QOL score (mexiletine, 14.0 vs placebo, 16.7; difference, -2.69; 95% CI, -4.07 to -1.30; P < .001) and decreased handgrip myotonia on clinical examination (mexiletine, 0.164 seconds vs placebo, 0.494 seconds; difference, -0.330; 95% CI, -0.633 to -0.142; P < .001). The most common adverse effect was gastrointestinal (9 mexiletine and 1 placebo). Two participants experienced transient cardiac effects that did not require stopping the study (1 in each group). One serious adverse event was determined to be not study related.

CONCLUSION:

In this preliminary study of patients with NDMs, 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: NCT00832000.

Comment in

PMID:
23032552
[PubMed - indexed for MEDLINE]
PMCID:
PMC3564227
Free PMC Article

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