Mexiletine May Lessen Motor Neuron ‘Excitability’ to Ease Cramps, Small Trial Suggests

Joana Carvalho, PhD avatar

by Joana Carvalho, PhD |

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Mexiletine trial report

Mexiletine, a heart medication used off-label to treat muscle cramps due to amyotrophic lateral sclerosis (ALS), was found to be well-tolerated and to stabilize the “hyperexcitability” of motor neurons in a small group of ALS patients in a pilot Phase 2 trial.

Data from the study (NCT02781454) also showed that the medication, given over the course of four weeks, lessened the intensity of muscle cramps, but not their frequency. Its small size and limited treatment time, however, mean its findings are preliminary.

Their study, “Effects of mexiletine on hyperexcitability in sporadic amyotrophic lateral sclerosis: Preliminary findings from a small phase II randomized controlled trial,” published in the journal Muscle & Nerve.

Originally developed to treat disorders that cause the heart to beat irregularly (cardiac arrhythmias), mexiletine can be used off-label to treat muscle cramps in ALS patients. It works by blocking the activity of sodium channels in nerve cells, slowing the transmission of the electrical impulses these cells use to communicate with each other, and with muscle fibers.

Muscle cramps in ALS patients are thought to be caused by the over-activation of diseased motor neurons — the nerve cells that communicate with muscle fibers and are responsible for controlling voluntary movements.

By blocking sodium channels, mexiletine is expected to lower the excessive transmission of electrical signals sent to muscle fibers, a phenomenon known as motor neuron hyperexcitability, easing muscle cramps.

Scientists in the U.S. and Australia reported the findings from a research institute-sponsored Phase 2 trial that aimed to assess mexiletine’s safety and efficacy in lowering motor neuron hyperexcitability and treating muscle cramps in ALS patients.

The researchers call their findings preliminary, rather than conclusive, partly because they were only able to recruit 20 patients rather than the 60 planned.

These 20 adults with sporadic ALS were enrolled at 10 clinical sites, all belonging to the Northeast ALS Consortium (NEALS), from February 2017 to September 2018.

Patients were randomly assigned to one of two daily doses of oral mexiletine (300 or 600 mg), or to a placebo, for four weeks.

The study’s main goal was changes in the resting motor threshold (RMT), a measure of motor neuron excitability, from the beginning until the end of the four-week treatment period.

Investigators also analyzed changes in other measures of neuronal excitability, such as the motor evoked potential (MEP) amplitude.

All measures were taken while patients underwent transcranial magnetic stimulation (TMS), a noninvasive form of brain stimulation that uses a magnetic field to create an electrical current that stimulates a specific region of the brain.

Additional study goals included safety, as well as the therapy’s effects on the intensity and frequency of muscle cramps and muscle twitching.

Data showed that RMT remained stable over the four weeks of treatment in patients on either mexiletine dose, with results from each group pooled in this analysis. In patients given with the placebo, RMT increased over this period.

These findings were not “expected given the known inhibitory effects of the study medication on neuronal sodium channels,” the investigators wrote. Previous studies had also reported that treatment with sodium channel blockers increased RMT, which is thought to indicate lower neuron excitability.

They suggest that “the stabilization of RMT with treatment may be attributed to chance, unforeseen technical considerations, or unknown medications influencing TMS,” or even be caused by a neuromodulating effect. Larger and longer studies are needed to clarify these findings, they noted.

However, a dose-dependent reduction in MEP amplitude, a measure of cortical motor neuron excitability, was found after four weeks in patients treated with mexiletine.

Study data also showed that mexiletine did lower the intensity of muscle cramps after four weeks of treatment, compared with placebo. Cramps were not fewer in number among mexiletine-treated patients, but those on the highest dose experienced 56% fewer cramps after the four-week period. This result, however, did not reach statistical significance.

Treatment effects on muscle twitching episodes were not assessed, due to the lack of variability among enrolled patients.

Both doses of mexiletine were found to be safe and well-tolerated, with no significant differences reported among the three groups regarding side effects. One patient failed to complete the study’s final week, due to difficulty swallowing a capsule.

“While the effect seen on RMT … was the opposite of expected … other neurophysiological parameters do provide evidence supporting a reduction of excitability by mexiletine of cortical motor neurons,” the investigators concluded.

“Given these findings demonstrating target engagement, a longer and larger study using mexiletine may be warranted to determine more definitively its effects on disease progression,” they added.