Chest Pain Medication May Help Ease Muscle Cramps in ALS

Vanda Pinto, PhD avatar

by Vanda Pinto, PhD |

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An approved medication for heart-related chest pain reduced the frequency and severity of muscle cramps in people with amyotrophic lateral sclerosis (ALS) in a small pilot study.

Called ranolazine, the medication was found to be safe and generally well-tolerated — the clinical trial’s key endpoints, or goals. Gastrointestinal problems were the most frequent side effect, impacting 40% of patients, but ranolazine was linked to fewer adverse events than other similar medications being investigated as potential new treatments for ALS.

Larger, placebo-controlled trials are needed to confirm these findings, the researchers said. But they concluded that “growing evidence” shows that this type of medication “offers an exciting novel therapeutic target for treatment of ALS” for muscle cramps. 

Titled “Open-label Pilot Study of Ranolazine for Cramps in Amyotrophic Lateral Sclerosis,” the study was published in the journal Muscle & Nerve.

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About 90% of patients experience muscle cramps as a main symptom of ALS, and many identify them as their sole source of pain. However, no medication is yet approved in the U.S. to treat muscle cramps in people with the neurological disorder.

In ALS, muscle cramps are thought to be associated with the overactivation of motor neurons. These nerve cells, which transmit messages from the brain and spinal cord to muscles, progressively die in ALS patients. As these cells malfunction and die, they may send strong electrical signals to muscles, which can cause painful muscle cramps.

This overactivation mainly results from the dysfunction of channel proteins at the surface of motor neurons that control the flow of ions, such as sodium. These ions help the transmission of signals along nerve fibers.

Findings from previous clinical trials showed that mexiletine — an orally available sodium channel blocker that is approved for treating an irregular heartbeat — decreases the transmission of electrical signals from nerve cells to muscles, lessening the frequency and intensity of muscle cramps in people with ALS.

However, the therapy “was not tolerated at higher doses due to gastrointestinal (GI) toxicity,” the researchers wrote. Gastrointestinal problems already are common in many ALS patients.

Now, a team of researchers at the University of Kansas Medical Center, in the U.S., hypothesized that ranolazine, a different type of oral sodium channel blocker, would be better tolerated than mexiletine. Sold under the brand name Ranexa, by Gilead Sciences, ranolazine also is available in generic forms.

In collaboration with Gilead, the researchers conducted a Phase 2 clinical trial (NCT03472950) to evaluate the safety and effectiveness of ranolazine in up to 20 adults with ALS who experienced four or more cramps per week.

Due to the COVID-19 pandemic, recruitment at the study’s single site in Kansas City ended prematurely, and 14 patients — 11 men and three women — ultimately entered the study.

Their median age was 54, and they had been living with the disease for a mean of 39 months, or a little over three years. Most (78.6%) were receiving riluzole — sold as Rilutek and other brand names — while three were on Radicava (edaravone).

Following a two-week run-in period to assess cramp frequency, eligible participants received either 500 mg (six patients) or 1,000 mg (eight patients) of the therapy, twice daily for up to four weeks. While the groups showed similar features before the start of ranolazine treatment, the lower dose group had less frequent muscle cramps.

After completing the four-week treatment period, participants were followed for six weeks.

The trial’s main goal was to investigate the frequency and type of adverse events experienced by participants throughout the study. A questionnaire assessing cramp frequency, severity, and nighttime awakenings due to muscle cramping was completed by patients as part of the trial’s secondary goals.

Other secondary goals included changes in forced vital capacity, a measure of lung function, and ALS Functional Rating Scale-Revised, an assessment of functional disability.

Results showed that both doses were generally safe and well-tolerated, with no reports of serious adverse events. While most participants (85%) experienced one or more adverse events during the study’s course, only half reported such side effects while on treatment — and most were mild in severity.

Nearly one-third of all adverse events (31%) were suspected to be related to the therapy, with gastrointestinal problems as the most frequent treatment-related adverse event, occurring in 40% of participants. Two patients (25%) in the higher dose group discontinued the therapy due to constipation.

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Researchers noted that in a previous trial, 32% of patients treated with high doses of mexiletine discontinued treatment, and there was one serious adverse event that required hospitalization for loss of balance.

These findings suggest that “ranolazine is better tolerated; however, owing to differing [group] sizes, dosing regimens and definitions for tolerability in the two studies, direct comparisons cannot be made,” the researchers wrote.

Regarding efficacy, four weeks of ranolazine treatment resulted in a 54.8% drop in the frequency of muscle cramps and a 46.3% reduction in cramp severity as compared with values reported in the two-week run-in period. These benefits appeared to be dose-dependent, the team noted.

Patients also woke up less frequently due to painful muscle cramping while sleeping while on ranolazine. However, there were no changes in lung function or functional disability. The experimental therapy also had no effect on the frequency of muscle twitches, called fasciculations, as assessed through ultrasound imaging.

“This study has provided preliminary evidence for peripheral drug-target engagement, evidenced by apparent dose-dependent reductions in cramp frequency, severity, and nocturnal awakening due to cramps,” the researchers wrote.

These results support the investigation of ranolazine for the treatment of ALS-related muscle cramps “in a future placebo-controlled trial,” they concluded.