The major finding in these randomized, double-blind, placebo-controlled trials of mexiletine in DM1 is that dosages of 150 and 200 mg TID for 7 weeks significantly improve myotonia, as measured by hand grip relaxation time, but do not cause significant adverse events or produce EKG conduction abnormalities in the short term.
These trials have several advantages over previous myotonia treatment trials in patients with DM1. 1) These studies are the largest we are aware of in that 20 genetically defined DM1 patients participated in each of the 2 trials. Previous trials have included relatively small numbers of DM1 patients, have often included participants with different forms of myotonic myopathy, and none have provided genetic confirmation. 2) These trials were double-blind; previous trials of mexiletine or tocainide for myotonia in DM1 have been single blind7
3) The improvement in myotonia noted in our first trial was corroborated by the second. 4) Plasma concentrations of mexiletine were measured, a requirement for the tocainide study,8
but not in the previous mexiletine study.7
5) These trials employed a carefully tested method of measuring grip myotonia28,29
that has good test-retest reproducibility, and yields grip relaxation times that increase and grip peak forces that decrease as CTG repeat lengths increase. Ergonomic techniques have been used to measure myotonia in patients with myotonic dystrophy for some time,9,30
but they have not been as carefully tested. The previous study of mexiletine7
utilized timed measurements of eye and hand opening, stair climbing, and the opponens pollicis, surface EMG-recorded myotonic afterdischarge that have merit as outcome measures, but again, have not been as carefully validated as our method.
Mexiletine is a lidocaine analog.31
Both drugs are type Ib anti-arrhythmics and produce state-dependent block of inactivated and to a lesser extent open (but not resting) sodium channels in cardiac and skeletal muscle; therefore, the channel block produced by these medications is mainly action potential-dependent. The 2 drugs differ in that sodium channel block induced by mexiletine is slightly slower to recover than that from lidocaine. In addition, hepatic metabolism is greatly reduced for mexiletine, which makes it suitable as an oral medication. Mexiletine is effective in cardiac patients with ventricular arrhythmias31
and long QT syndrome32
and in neuromuscular patients with myotonic disorders such as potassium aggravated myotonia or paramyotonia congenita.33,34
These myotonic disorders are skeletal muscle sodium channelopathies which typically manifest a slowed rate of fast sodium channel inactivation. This results in abnormally persistent sodium currents leading to repetitive firing of muscle fibers and delayed muscle relaxation (myotonia).33–35
Mexiletine ameliorates myotonia in sodium channelopathies by enhancing fast-inactivation of the sodium channels, resulting in use-dependent sodium channel block.33,34,36,37
In addition, mexiletine may also produce open channel block of late-opening channels38
at lower serum concentrations than those required to block channels that are closed and inactivated. By contrast, mexiletine is not known to affect skeletal muscle chloride channels, and its beneficial effects in patients with chloride channel myotonic disorders, such as DM1 or myotonia congenita, probably result from block of normal sodium channels which thereby decrease repetitive motor unit discharges.33,34
Our data show that even moderate oral dosages of 150 mg TID with drug levels in the low to mid-therapeutic range (by cardiac standards) reduce handgrip myotonia in DM1. Importantly, although mexiletine produces use-dependent sodium channel blockade and could result in loss of muscle strength, there was no decline in grip peak force on mexiletine at either dosage. On the contrary, peak force significantly improved on mexiletine 150 mg TID, but this was not confirmed by the 200 mg TID trial. In any case, the preservation of grip force on mexiletine is consistent with the absence of significant cardiac hemodynamic compromise in patients on mexiletine for ventricular arrhythmia.31
Given that patients with DM1 may have abnormalities of cardiac conduction,39
a major aim of these trials was to establish that mexiletine did not affect cardiac conduction in patients with DM1 with no baseline cardiac risk factors except first-degree AV block. It is recognized that lidocaine or mexiletine can potentially increase QRS duration particularly at higher heart rates, may shorten the QT interval, may compromise hemodynamic function in patients with heart failure,31
and can increase pacing threshold and the energy required for defibrillation.31
Still, treatment with these drugs in cardiac patients typically has little effect on PR, QRS, and QT duration, or on hemodynamic function.31
Similarly, previous studies of mexiletine and tocainide7,8
in patients with myotonic myopathy of various types have also shown no significant changes in EKG measurements. Our study supports the view that mexiletine at dosages of 150 to 200 mg TID has no significant effect on cardiac conduction over a 7-week treatment period in patients with DM1 who have no significant cardiac risk factors except for first-degree AV Block. However, we recognize that our conclusions about the cardiac safety of mexiletine in DM1 are somewhat tentative given that 1) mexiletine is rarely associated with a pro-arrhythmic response that can aggravate underlying ventricular arrhythmias,40
and 2) our studies involved a total of only 30 patients with DM1 followed for 7 weeks on mexiletine and excluded patients with significant heart disease. As a result, our practice is to obtain cardiac consultation before beginning mexiletine therapy for symptomatic myotonia in patients with DM1 who have current or remote cardiac symptoms or an abnormal baseline EKG.
In our trials, adverse events were observed in participants on placebo and on both dosages of mexiletine (); none were considered serious, and only 1 participant discontinued the drug due to an adverse event. For those completing the trial, the occurrence of upper gastrointestinal distress and lightheadedness appeared to be more common with mexiletine than with placebo. Tremor occurred in only 1 participant taking mexiletine 200 mg TID. These results are similar to those observed previously.7
Overall, our data suggest that mexiletine at oral dosages of 150–200 mg TID may be considered as an effective, symptomatic treatment in patients with DM1 with functionally significant myotonia, and appears to be safe in the short term. Moreover, because the study required the presence of clinical myotonia, but did not specifically require moderate or severe myotonia as in 2 prior trials,7,8
we believe that our data are generalizable to typical patients with DM1 with clinically evident myotonia. The percentage improvement in grip RT was not significantly greater in the 200 mg TID trial than in the 150 mg TID trial. We do not know why our study did not demonstrate a clear dose response effect of mexiletine on grip RT. This may be due to the different baseline characteristics of the 2 groups (e.g., the grip RTs were longer in the 200 mg TID than the 150 mg TID trial) or possibly that the effect of mexiletine on RT plateaus over the 150–200 mg TID dosage range.
One limitation of our trials is that they show relatively short-term benefits of mexiletine on handgrip relaxation. We do not know if this effect is durable over months to years, or if it is associated with improvement in quality of life. Our findings warrant long-term clinical trials with mexiletine in order to determine whether 1) its minimal risk and significant benefit in relieving myotonia are maintained over time, 2) it results in functional improvement in muscle-related activities of daily living, 3) it has a beneficial effect in maintaining muscle strength and mass, 4) it has a beneficial role in reducing or preventing musculoskeletal pain, and 5) it improves quality of life.