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

Publication ,  Journal Article
Statland, JM; Bundy, BN; Wang, Y; Rayan, DR; Trivedi, JR; Sansone, VA; Salajegheh, MK; Venance, SL; Ciafaloni, E; Matthews, E; Meola, G ...
Published in: JAMA
October 3, 2012

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.

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Published In

JAMA

DOI

EISSN

1538-3598

Publication Date

October 3, 2012

Volume

308

Issue

13

Start / End Page

1357 / 1365

Location

United States

Related Subject Headings

  • Young Adult
  • Sodium Channels
  • Severity of Illness Index
  • Quality of Life
  • Pain
  • Myotonia
  • Muscle, Skeletal
  • Middle Aged
  • Mexiletine
  • Male
 

Citation

APA
Chicago
ICMJE
MLA
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Statland, J. M., Bundy, B. N., Wang, Y., Rayan, D. R., Trivedi, J. R., Sansone, V. A., … Consortium for Clinical Investigation of Neurologic Channelopathies, . (2012). Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial. JAMA, 308(13), 1357–1365. https://doi.org/10.1001/jama.2012.12607
Statland, Jeffrey M., Brian N. Bundy, Yunxia Wang, Dipa Raja Rayan, Jaya R. Trivedi, Valeria A. Sansone, Mohammad K. Salajegheh, et al. “Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial.JAMA 308, no. 13 (October 3, 2012): 1357–65. https://doi.org/10.1001/jama.2012.12607.
Statland JM, Bundy BN, Wang Y, Rayan DR, Trivedi JR, Sansone VA, et al. Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial. JAMA. 2012 Oct 3;308(13):1357–65.
Statland, Jeffrey M., et al. “Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial.JAMA, vol. 308, no. 13, Oct. 2012, pp. 1357–65. Pubmed, doi:10.1001/jama.2012.12607.
Statland JM, Bundy BN, Wang Y, Rayan DR, Trivedi JR, Sansone VA, Salajegheh MK, Venance SL, Ciafaloni E, Matthews E, Meola G, Herbelin L, Griggs RC, Barohn RJ, Hanna MG, Consortium for Clinical Investigation of Neurologic Channelopathies. Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial. JAMA. 2012 Oct 3;308(13):1357–1365.
Journal cover image

Published In

JAMA

DOI

EISSN

1538-3598

Publication Date

October 3, 2012

Volume

308

Issue

13

Start / End Page

1357 / 1365

Location

United States

Related Subject Headings

  • Young Adult
  • Sodium Channels
  • Severity of Illness Index
  • Quality of Life
  • Pain
  • Myotonia
  • Muscle, Skeletal
  • Middle Aged
  • Mexiletine
  • Male