Mexiletine, an oral medicine to treat irregular heartbeats, is safe and effective for reducing muscle cramps in patients with amyotrophic lateral sclerosis (ALS), results from a Phase 4 clinical trial show.
To date, this is the only treatment shown to reduce both the number and intensity of cramps in patients with ALS, which is often a painful and debilitating symptom.
The findings were detailed in the report, “Mexiletine for Muscle Cramps in ALS: A Randomized Double-Blind Crossover Trial,” published in the journal Muscle & Nerve.
More than 90% of ALS patients have muscle cramps, but so far no medication has been shown to reduce this complication significantly. Reducing the pain caused by cramps could improve patients’ well-being.
Muscle cramps are sudden, painful, and involuntary contractions of a muscle, which are caused by nerve malfunction. Electrically, cramps consist of bursts of high-frequency impulses firing in the motor nerve cells — the cells diseased in ALS.
Motor neurons are the nerve cells that transmit messages from the brain and spinal cord to muscles.
In ALS, cramps are believed to result in an increase of persistent sodium currents in the sick lower motor nerve cells (that transmit signals from the spinal cord to the muscles).
There seems to be no agreement on how to treat cramps in ALS. The American Academy of Neurology (AAN) recently encouraged further studies of the treatment of muscle cramps and suggested lidocaine injections as a possible treatment, among others.
Mexiletine is a medication closely related to lidocaine that is taken as a pill (instead of being injected). It works by blocking the sodium signals thought to cause muscle cramps.
The safety profile of mexiletine is generally good, with the most frequent side effects being nausea or other abdominal symptoms. In patients with normal heart function, mexiletine should have a minimal effect on heart rhythm.
A prior Phase 2 clinical trial (NCT01849770) suggests that people may find significant relief from muscle cramp frequency and severity by taking 300 mg per day of mexiletine, over 12 weeks. A dose of 900 mg per day also was tested, but many patients dropped out due to side effects.
Led by Björn Oskarsson, MD, professor, and director of the ALS clinic at University of California Davis, a Phase 4 clinical trial (NCT01811355) was run to evaluate the safety and effectiveness of 150 mg capsules of mexiletine versus a placebo, given twice per day for two weeks.
After a one-week washout period, patients who received a placebo in the first half of the trial switched to mexiletine, and those who received mexiletine rolled over to the placebo. For the first three days, one 150 mg capsule was taken at bedtime and from day 4 to 14, two capsules were taken per day.
A total of 20 patients, enrolled at multiple sites in California, were assigned randomly to start either on mexiletine or placebo. Patients included could not have any contraindication to mexiletine, including heart or liver disease. All participants kept a journal recording the number and severity of the cramps they experienced each day.
Of the 20 patients completing the study, 18 had fewer muscle cramps while taking mexiletine, which was the primary efficacy outcome being measured. In 13 of these patients, this reduction in cramps was statistically significant, compared with placebo. Four patients became completely cramp-free while receiving mexiletine.
Conversely, two of the 20 patients experienced significant increases in muscle cramps while on mexiletine.
Despite high variation in treatment effect, the average reduction over the entire study period was 1.8 muscle cramps per day, which corresponded to a reduction from 5.3 with placebo to 3.5 with mexiletine.
No sex or age effects were observed, even though older patients had more cramps; per decade of age, patients had about 0.6 more cramps per day. Patients taking riluzole (brand names Rilutek and Tiglutik, also available as generics), had fewer cramps (less 0.19 cramps per day), but the effect of mexiletine was similar.
Patients also reported feeling less intense muscle cramps while on treatment with mexiletine, with an estimated reduction of 15 units in severity on a 100-unit scale.
As to safety, the heart rhythm of patients was monitored on electrocardiograms (EKG) three times during the study (at screening and at the end of each treatment period), but no abnormalities were noted on either mexiletine or placebo. Also, no clinically significant laboratory changes were observed, including toxic effects in the liver.
“Mexiletine is well-tolerated and effective medication for controlling the symptom of muscle cramps in ALS,” researchers wrote.
“Higher doses may provide additional benefit but more frequent adverse effects. Mexiletine is the only medication shown to reduce muscle cramp frequency and severity in ALS,” the team concluded.