Mexiletine Alleviates Key Source of Muscle Pain in ALS

Pain reduced. Mexiletine reduces the frequency and severity of cramps in people with ALS according to a new phase IV study.

This is part 3 of a 3-part series from the 69th Annual Meeting of the American Academy of Neurology in Boston. See also part 1 and part 2.

Mexiletine is safe, well-tolerated and reduces muscle cramps in people with ALS, a key source of pain, particularly early in the disease according to a phase IV randomized double-blind placebo-controlled study led by Bjorn Oskarsson. The 6-week study found that treatment with mexiletine 300 mg/day resulted in a 33% drop in muscle cramps in people with ALS compared to placebo. No serious side effects were reported.

“It is very exciting to have a drug that is proven to work against cramps,” said Oskarsson.

Bjorn Oskarsson presented the results on April 27 at the 69th Annual Meeting of the American Academy of Neurology in Boston, Massachusetts.

A pain reliever for ALS?

Muscle cramps affect more than 90% of people with ALS (Stephens et al., 2017; Chio et al., 2017). But there is no drug approved for the treatment of them.

Bjorn Oskarsson thought the FDA-approved heart medicine mexiletine may help reduce muscle cramps in people with ALS. The strategy aims to alleviate muscle cramps by reducing the overactivity of key sodium channels in motor neurons which is thought to be responsible for them (see Kanai et al., 2003). The approach is based on previous studies which found that the sodium channel blocker reduced muscle cramps in people with spinocerebellar ataxia type 3 (Kanai et al., 2003; Kuwabara et al., 2005).The strategy is an alternative to quinine, which is no longer recommended by the FDA for clinical use due to potentially fatal complications that can occur in the blood, kidney or heart.

Channel blocker. Mexiletine may reduce muscle cramps in ALS by blocking key overactive sodium channels in motor neurons. The approach aims to reduce the persistent sodium current which might underlie cramps in the disease. [Courtesy of Nature Publishing Group. Reproduced with Permission.]

The phase IV randomized placebo-controlled trial launched in 2013. People with ALS experiencing cramps were randomized to either mexiletine or placebo at 300 mg/day for two weeks, followed by a one-week washout period. Then, participants “crossed over” to the other treatment arm, taking either drug or placebo at 300 mg/day for a subsequent 2 weeks. The primary outcome measure was a reduction in self-reported cramp frequency. Reduction in severity of muscle cramps was a secondary outcome measure, recorded on a visual analog scale (VAS). A total of 23 people with ALS participated in the study.

The study found that the frequency of cramps in people with ALS dropped by 33%. Cramp severity was also reduced by 15% on the VAS scale. There was no difference in efficacy based on age, sex, or placebo/active treatment sequence. There was no effect on fasciculations. No serious side effects were reported.

The study according to Richard Bedlack of Duke University School of Medicine, convincingly demonstrated that mexiletine is safe, well tolerated and can reduce the frequency and severity of muscle cramps in people with ALS. “While I would like to see the results independently replicated, I will now begin offering this to people in my clinic,” said Bedlack.

The results come at the heels of a previous phase 2 study led by University of Washington’s Michael Weiss in Seattle which found that mexiletine at 300 mg/day reduced the frequency and intensity of muscle cramps by more than 30% (Weiss et al., 2016).

“Mexiletine seems to work well with few side effects,” said Weiss. “[It] is my now my first-line medication for muscle cramps in ALS. Some of my patients report reduction of cramp numbers from dozens a day to once or twice a week.”

But according to preclinical studies led by Universidad Andres Bello’s Brigitte van Zundert in Chile, in collaboration with University of Massachusetts Medical Center’s Robert Brown, mexiletine may do much for people with ALS than reduce muscle cramps. Mexiletine may help protect motor neurons against ALS by reducing hyperexcitability, a potential contributor to motor neuron toxicity in the disease (Fritz et al., 2013).

A phase 2 randomized placebo-controlled study of mexiletine is ongoing. Weiss is leading the study. 60 people with sporadic ALS are expected to participate.

Mexiletine is one of two FDA-approved medicines being evaluated as a potential treatment for ALS that aims to reduce motor neuron hyperexcitability. The other, retigabine, is also being investigated at the phase 2 stage (see March 2017 news).

In the meantime, mexiletine is being increasingly used as a treatment for muscle cramps. Mexiletine is one of two strategies being evaluated to reduce cramps in the disease (see May 2017 news).

Mexiletine is available as a generic. The FDA approved mexiletine as a treatment for cardiac arrhythmia in 1998. It carries a black-box warning against taking mexiletine within two years of experiencing a heart attack, Oskarsson said. “It is not clear that this has relevance to our patient population, but one should be aware of it.”

References

Stephens HE, Joyce NC, Oskarsson B. National Study of Muscle Cramps in ALS in the USA. Amyotroph Lateral Scler Frontotemporal Degener. 2017 Feb;18(1-2):32-36. [PubMed].

Kuwabara S1, Misawa S, Tamura N, Kanai K, Hiraga A, Ogawara K, Nakata M, Hattori T. The effects of mexiletine on excitability properties of human median motor axons. Clin Neurophysiol. 2005 Feb;116(2):284-9. [PubMed].

Kanai K, Kuwabara S, Arai K, Sung JY, Ogawara K, Hattori T. Muscle cramp in Machado-Joseph disease: altered motor axonal excitability properties and mexiletine treatment. Brain. 2003 Apr;126(Pt 4):965-73. [PubMed].

Fritz E, Izaurieta P, Weiss A, Mir FR, Rojas P, Gonzalez D, Rojas F, Brown RH Jr, Madrid R, van Zundert B. Mutant SOD1-expressing astrocytes release toxic factors that trigger motoneuron death by inducing hyperexcitability. J Neurophysiol. 2013 Jun;109(11):2803-14. [PubMed].

Weiss MD, Macklin EA, Simmons Z, Knox AS, Greenblatt DJ, Atassi N, Graves M, Parziale N, Salameh JS, Quinn C, Brown RH Jr, Distad JB, Trivedi J, Shefner JM, Barohn RJ, Pestronk A, Swenson A, Cudkowicz ME; Mexiletine ALS Study Group. A randomized trial of mexiletine in ALS: Safety and effects on muscle cramps and progression. Neurology. 2016 Apr 19;86(16):1474-81.  [PubMed].

Further Reading

Chiò A, Mora G, Lauria G. Pain in amyotrophic lateral sclerosis. Lancet Neurol. 2017 Feb;16(2):144-157. [PubMed].

cramps disease-als hyperexcitability mexiletine muscle pain topic-clinical topic-randd
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