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

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.

• Authors: Jeffrey M Statland, Brian N Bundy, Yunxia Wang, Dipa Raja Rayan, Jaya R Trivedi, Valeria A Sansone, Mohammad K Salajegheh, Shannon L Venance, Emma Ciafaloni, Emma Matthews, Giovanni Meola, Laura Herbelin, Robert C Griggs, Richard J Barohn, Michael G Hanna, Consortium for Clinical Investigation of Neurologic Channelopathies
• Journal: JAMA (JAMA) Vol. 308 Issue 13 Pg. 1357-65 (Oct 03 2012) ISSN: 1538-3598 [Electronic] United States
• PMID: 23032552 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Arrhythmia Agents
• Sodium Channels
• Mexiletine

Topics

• Administration, Oral
• Adolescent
• Adult
• Aged
• Anti-Arrhythmia Agents (adverse effects, therapeutic use)
• Cross-Over Studies
• Double-Blind Method
• Female
• Humans
• Male
• Mexiletine (adverse effects, therapeutic use)
• Middle Aged
• Muscle, Skeletal (physiopathology)
• Myotonia (drug therapy)
• Pain (drug therapy, etiology)
• Quality of Life
• Severity of Illness Index
• Sodium Channels (drug effects)
• Young Adult