Old Heart Drug Works in Nondystrophic Myotonias

Megan Brooks

October 03, 2012

October 3, 2012 — The antiarrhythmic drug mexiletine led to significant improvement in muscle stiffness in patients with nondystrophic myotonias (NDMs), results of a randomized trial show.

The NDMs are rare disorders caused by mutations in skeletal muscle chloride and sodium channels that lead to functionally limiting stiffness, pain, fatigue, and weakness.

"Stiffness is the big symptom and we thought it would make sense to test the effects of this old cardiac drug mexiletine that works on the sodium channel in muscle," Richard J. Barohn, MD, from the Neurology Department at University of Kansas Medical Center in Kansas City and member of the Consortium for Clinical Investigation of Neurologic Channelopathies (CCINC), told Medscape Medical News.

"We showed that this generic drug, which has been around for a long time, worked dramatically," Dr. Barohn said.

Dr. Richard J. Barohn

The trial, led by the CCINC, is published in the October 3 issue of the Journal of the American Medical Association.

Moderate to Large Effect Sizes

In vitro and animal models have suggested that mexiletine reduces muscle fiber excitability caused by common NDM mutations; case reports suggest the drug can help reduce myotonia, and it's been used off-label to treat myotonia for some time.

To test it in a controlled study, the researchers enrolled 59 patients with NDMs, with random allocation to oral 200-mg mexiletine or placebo capsules 3 times daily for 4 weeks, followed by the opposite treatment for 4 weeks, separated by a 1-week washout period.

"The real challenge wasn't in designing the trial, it was in finding the patients," Dr. Barohn said. Collaborating with 7 neuromuscular referral centers — 4 in the United States, 1 each in the United Kingdom, Canada, and Italy — the researchers were finally able to enroll 59 patients in their study.

Mexiletine significantly improved patient-reported severity score of stiffness recorded on an interactive voice response (IVR) diary, and this result was supported by broad improvement in clinical, quantitative, and electrophysiologic measures of myotonia, they say.

Overall, most effect sizes for outcome measures were greater than 0.5, and some were greater than 0.8, indicating a moderate to large response to treatment, the investigators point out.

Mexiletine was well tolerated, with gastrointestinal discomfort the most common adverse event and no serious study-related adverse events.

The authors of a linked editorial say this trial "demonstrates the ability of robust clinical research consortia to conduct well-controlled clinical trials of rare disorders."

"Another triumph of this study was its rapid completion," write Eric P. Hoffman, PhD, from Children's National Medical Center, Washington, DC, and Henry J. Kaminski, MD, from George Washington University, also in Washington, DC. "Fifty-nine patients were randomized and the study was completed in 28 months; this is noteworthy for a group of diseases with a worldwide prevalence of 1 per 100 000," they note.

An "innovative" feature of this study is the use of the patient-centered IVR system, they say.

"The system eliminated the need for cumbersome paper diaries, which are burdensome for most participants and research coordinators. The IVR system also provided a clear time stamp for documentation, and it may have improved adherence due to reminder calls. Patient participation with calls to the IVR at the primary end point time of 3 to 4 weeks was excellent and pill counts also indicated greater than 90% adherence," Drs. Hoffman and Kaminski note.

Access Iffy

"The problem," Dr. Barohn told Medscape Medical News, "is that this generic drug can be hard to come by both in the US and Europe. We've had periods over the last 10 years where a doctor tries to order mexiletine and can't get it; it's just not a top priority for the companies that make it. We are hoping that showing that this drug really works well in this rare disease population will somehow encourage the generic manufacturers to keep it available."

He said this study may have started a "mini epidemic" of researchers interested in mexiletine. There are now 2 trials that are getting underway to look at mexiletine for muscle cramps in patients with amyotrophic lateral sclerosis, he explained. Another trial in progress is assessing this drug for myotonic dystrophy.

The study was supported by the Food and Drug Administration Orphan Products Division, the National Center for Research Resources, and the National Institutes of Health (NIH). Dr. Barohn reported receiving support from the Grifols and Genzyme speakers bureaus and being a consultant for Pfizer, MedImmune, Novartis, and NuFactor. A complete list of author disclosures is provided with the original paper. Dr. Hoffman reported serving as board member, holding founder shares in, and owning stock in ReveraGen Biopharma. Dr. Kaminski reported receiving fees from legal firms for expert testimony and receiving grants from the NIH and MG Foundation of America.

JAMA. 2012;308:1357-1365, 1377-1378. Abstract Editorial