Lamotrigine for Myotonia
October 1, 2017 3 minutes read
By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Rubin reports no financial relationships relevant to this field of study.
SYNOPSIS: In a randomized, double-blind, placebo-controlled treatment trial of patients with non-dystrophic myotonia, those treated with lamotrigine experienced significant improvement.
SOURCE: Andersen G, Hedermann G, Witting N, et al. The antimyotonic effect of lamotrigine in non-dystrophic myotonias: A double-blind randomized study. Brain 2017;140:2295-2305.
Myotonia causes troublesome and disabling symptoms in patients with the non-dystrophic myotonias: myotonia congenita and paramyotonia congenita. Several medications may be offered to treat the resultant muscle stiffness and pain, including carbamazepine, phenytoin, procainamide, propafenone, and flecainide, whereas quinine and procainamide are no longer recommended because of adverse effects on cardiac conduction. However, only mexiletine has been shown in double-blind, randomized clinical trials to be superior to placebo, to be well-tolerated, and without cardiac conduction or other serious side effects. However, it is expensive, not widely available because it is manufactured only in Mumbai, and patients often decline it because of common reactions including dizziness, tremor, insomnia, diarrhea, and headache. Lamotrigine, a sodium-channel blocker like mexiletine, may be an excellent alternative.
Between November 2013 and July 2015, the departments of Neurology, Neuromuscular Centers, of the Universities of Copenhagen and Aarhus, Denmark, conducted a Phase II, randomized, double-blind, placebo-controlled, crossover study in which patients received eight weeks of lamotrigine followed by a one-week washout period, and then eight weeks of placebo, or vice versa. Doses were escalated every other week, beginning at 25 mg, and increasing to 50 mg, 150 mg, and 300 mg. Primary and secondary outcome measures, performed at zero, six, and eight weeks, encompassed, respectively, the Myotonic Behavior Scale (MBS), and four functional timed tests assessing eye and hand closure relaxation times and leg myotonia using the Timed Up and Go (TUG) test and the 14 Step Stair Test (14SST). Statistical analysis included the Mann-Whitney and paired t-tests, the paired two-tailed t-test, or Wilcoxon signed rank test as appropriate, and the McNemar test, with a P value < 0.05 considered significant.
Among 26 patients (ages 19 to 74 years) enrolled, 22 completed the study and four dropped out because of illness. Lamotrigine-treated patients experienced a significant improvement in MBS, the primary outcome measure, as well as significant improvement in all four timed tests, the secondary outcome measures. Placebo had no effect on any of the outcome measures. Fifteen patients experienced side effects, most commonly headache, fatigue, muscle or joint pain, skin rash, sore throat, and nausea; two of the 15 patients were excluded from receiving further medication because of an allergic reaction in one patient and a bleeding bacterial ulcer in the other. Lamotrigine appears effective and safe, is widely available, and is less costly, and should be offered as first-line treatment for myotonia in non-dystrophic myotonia patients.
COMMENTARY
Approved in 1991 and a mainstay antiepileptic agent for focal and generalized tonic-clonic seizures ever since, lamotrigine also is beneficial in absence epilepsy and Lennox-Gastaut syndrome and is further licensed for the treatment of bipolar disorder. It may be given once or twice daily, has 95-100% absorption bioavailability with a half-life of 22 to 36 hours, and should be introduced slowly to reduce the risk of an allergic reaction. In addition to blocking the fast inactivation state of sodium channels, which may be its mechanism of action in myotonia, it also inhibits N-type and P-type high-voltage activated calcium currents, as well as enhancing potassium repolarizing currents. Centrally, it decreases the excitability of pyramidal neuron dendrites by acting directly on the hyperpolarization-activated calcium current. Insomnia is its one unusual, and often forgotten, adverse effect, not occurring with any other sodium channel blocker.
SYNOPSIS: In a randomized, double-blind, placebo-controlled treatment trial of patients with non-dystrophic myotonia, those treated with lamotrigine experienced significant improvement.
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