Mexiletine is Effective in Reducing Myotonia in Myotonic Dystrophy Type 1

July 1, 2010


Eric Logigian, MD, and Richard T. Moxley, III, MD, from the University of Rochester School of Medicine and Dentistry, discuss their paper "Mexiletine is an effective antimyotonia treatment in myotonic dystrophy type 1" that was recently published in Neurology (2010;74:1441-1448). They spoke with José Merino, MD, Science Editor of Among patients with myotonic muscular dystrophy (MD1), how debilitating are the myotonias? 

Logigian and Moxley: Admittedly, most patients with DM1 are bothered more by the consequences of muscle weakness than by those of delayed muscle relaxation or myotonia. However, in our experience, there are a significant number of DM1 patients who do have functionally debilitating myotonia manifested by muscle stiffness and inability to relax activated muscles for whom treatment with mexiletine is a therapeutic consideration. What is the cause of the myotonia in these patients? 

Logigian and Moxley: Recent investigations have shown that toxic, triplet repeat-containing RNA produced from the DM gene accumulates in the myonucleus, resulting in abnormal splicing of the C1C-1 chloride channel pre-mRNA. This leads to a loss of hyper-polarizing chloride channel conductance in muscle fiber membranes and the development of spontaneous repetitive muscle fiber discharges (e.g., electrical myotonia), and slowed muscle relaxation. What is the best way to elicit myotonia in the clinic?

Logigian and Moxley: Observing the speed with which patients can open their closed fist or their closed eyes is one way. Another is to observe the delay in muscle relaxation after reflex activation of thenar, finger, or wrist extensor muscles evoked by direct percussion of these muscles with a reflex hammer. Whether activated voluntarily or reflexively, myotonic muscles are slow to relax and become "hung up."  In addition, DM1 patients exhibit a "warm up" phenomenon in which muscle relaxation improves with serially repeated muscle contractions.  How have clinical trials evaluated myotonia? 

Logigian and Moxley: As we mentioned in our paper, ergonomic techniques using force transducers, similar to the method we have reported, have been used to measure myotonia in patients with myotonic dystrophy for many years. Other methods have utilized timed measurements of eye and hand opening, stair climbing, and surface EMG-recorded myotonic afterdischarges.

The method of measuring grip myotonia employed in our report has previously been shown by our group to have good test-retest reproducibility, and to yield grip relaxation times that increase and grip peak forces that decrease as CTG repeat lengths increase. Please summarize the methodology of your study.

Logigian and Moxley: The right arm was used for measuring grip relaxation times (RTs) after a maximal voluntary isometric contraction. The hand grip force recordings were analyzed off line utilizing an automated computer program that first determined peak force (PF) in kg units and then placed cursors on the declining, relaxation phase of the force recording at various levels of PF: 90%, 50%, and 5%. The RTs we reported were the times required for decline in hand grip force from 90% to 5%, 90% to 10%, and 50% to 5% of PF. Your study was a crossover trial. Why is this the best way to answer your question? 

Logigian and Moxley: The advantage of a crossover design in a rare disease like DM1 is that it maximizes the power of a placebo-controlled trial when the number of patients in the trial is relatively small. For example, in the first treatment trial of mexiletine at 150 mg p.o. t.i.d. versus placebo in 18 patients, a standard, non-crossover trial would compare nine randomized placebo patients with nine randomized mexiletine patients. The crossover design allowed us to double the number to 18 in both the placebo and mexiletine groups. What was the main outcome measure in your study? 

Logigian and Moxley: The primary outcome measure was time for isometric grip force to relax from 90 percent to 5 percent of peak force after a 3-second maximum grip contraction. Secondary outcome variables included other average RTs (90%–10% of PF, 50%–5% of PF) and average PF. EKG outcomes, including PR interval, QRS interval, and QTc interval, were of interest from the perspective of safety. You wanted to "detect a treatment effect of at least 0.66 SD units."  What does this change in mean relaxation time mean clinically? 

Logigian and Moxley: Detection of a treatment effect of 0.66 SD units was purely a statistical "target" that we employed to power the study. It is a legitimate question to ask whether such a treatment effect is clinically meaningful. We cannot answer that question currently, but hope to do so in a second study of mexiletine and DM1 patients utilizing a DM1 specific quality of life instrument. You found a statistically significant reduction in grip relaxation time. Was this difference clinically significant? 

Logigian and Moxley: Grip relaxation time declined by about 50 percent in both mexiletine treatment groups. The study did not include a functional outcome measure to determine if this dramatic reduction in grip relaxation time was clinically significant. We believe strongly that this difference is clinically significant, but we will require a second follow-up study to prove it unequivocally. What were the major adverse effects of mexiletine and how can these be managed? 

Logigian and Moxley: In our two small studies including a total of 30 DM1 patients, there were no major adverse effects, and only one patient discontinued the medicine due to an adverse event (e.g, diarrhea). Minor side effects were observed in both the placebo and the mexiletine groups. Mild gastrointestinal distress (e.g., heartburn, nausea, vomiting, diarrhea, abdominal pain) and lightheadedness seemed to be the most common adverse side effects in the mexiletine versus the placebo group. We believe that these side effects can be managed by keeping the mexiletine dose on the low side, and by encouraging patients to take the medicine with food. Do other sodium channelopathies benefit from treatment with type Ib antiarrhytmic agents? 

Logigian and Moxley: Yes, mexiletine is effective in several skeletal muscle sodium channelopathies associated with myotonia such as potassium aggravated myotonia and paramyotonia congenita. Are other type Ib antiarrhytmic agents useful in MD1 patients? 

Logigian and Moxley: Yes, several small studies have provided evidence that tocainide, another type Ib antiarrhythmic agent, improved myotonic symptoms in patients with various types of myotonic myopathy. However, bone marrow suppression and pulmonary fibrosis can occur with this medication, and therefore it is no longer available in the United States. In your opinion, is there enough evidence to recommend the routine use of mexiletine for myotonia in patients with MD1?  Or should clinical trials that evaluate long-term functional effects be completed before the treatment is recommended? 

Logigian and Moxley: Currently, we do not recommend routine use of mexiletine in patients with DM1. We reserve the drug for those who have functionally disabling symptomatic myotonia. If patients do not have clear-cut functional improvement in muscle specific activities of daily living on mexiletine, we do not continue therapy. How do you identify patients who are likely to benefit from this treatment? 

Logigian and Moxley: We consider mexiletine treatment in DM1 patients who have clinical evidence of disabling myotonia. Such patients typically have symptoms of "stiffness," or myalgia, and signs of delayed hand grip relaxation or prominent percussion myotonia. By contrast, DM1 patients with prominent muscle weakness and minimal myotonia are not likely to benefit from mexiletine. What are the contraindications to mexiletine? 

Logigian and Moxley: Other than drug allergy, we are most concerned about the pro-arrhythmic potential of mexiletine. In a DM1 patient with disabling myotonia and with no cardiac history, no cardiac risk factors, and a normal EKG, it could be argued that mexiletine could be prescribed without cardiology input. It is our practice to obtain cardiac consultation on all patients prior to starting the medication. How do you start patients on the medication?

Logigian and Moxley: After reviewing the risks and benefits of the medication, obtaining a baseline EKG and cardiac consultation, we begin treatment with mexiletine. In our study, improvement in hand grip relaxation time was similar for the two dose regimens tested. Therefore, we would recommend beginning treatment with the lower mexiletine dose, using a dose escalation protocol as follows: 150 mg p.o. q.a.m. for three days, then 150 mg p.o. b.i.d. for three days, then 150 mg p.o. t.i.d. To minimize associated nausea or GI side effects, we suggest that the patient take the medicine with meals. We also encourage patients to keep track of certain target symptoms for which mexiletine was prescribed (e.g., buttoning, zipping, handwriting, ease of  walking, myalgia, etc.) in order to determine if the medication is providing benefit in muscle specific activities of daily living. How often should clinicians monitor response to treatment?

Logigian and Moxley: We would expect improvement in targeted myotonic symptoms to begin within a week of initiating treatment. Typically patients can be seen back in the office within a few weeks of starting the medication, but we encourage patients to call us immediately for any potential adverse side effects. Are there risks to the use of the drug for more than seven weeks? 

Logigian and Moxley: We are not aware of long-term risks. Although we believe that a seven-week trial should uncover significant adverse events, a very low frequency adverse event might only become obvious with longer term therapy in a larger group of patients. Longer term studies are required to answer this question.

Clearly, a longer term clinical trial is required to prove that mexiletine enhances quality of life, that its beneficial effect is durable over the long term, and that significant adverse events do not occur or occur rarely. However, for a DM1 patient who is functionally impaired from his or her myotonia, and who has no significant cardiac risk factors, our study suggests to us that the risks and benefits of treatment with mexiletine could be presented to the patient as a therapeutic option, at least for short-term trial of the medication to see if it provides clinical benefit in muscle specific activities of daily living. However, we believe that treatment with mexiletine should not be used for nonfunctionally disabling symptoms of myotonia.

Author Disclosure

Dr. Logigian serves on the editorial board of Muscle and Nerve.

Within the past five years, Dr. Moxley has served as principal investigator for research projects funded by the Centers for Disease Control, Food and Drug Administration, Insmed Inc., Muscular Dystrophy Association, and National Institutes of Health.

Dr. Merino performed a one-time consultation with staff from Bell, Falla and Associates.