Mexiletine Banishes Muscle Cramps in Phase 2 Trial of ALS

Mexiletine, a drug already on the market, may assuage the frequent, painful muscle cramps that vex people with amyotrophic lateral sclerosis, according to a study in the February 24 Neurology online. People in a Phase 2 trial who took the sodium channel blocker reported fewer and milder cramps than those on placebo, discovered researchers led by Michael Weiss of the University of Washington in Seattle. Scientists suspect the medication, thought to dial down excitability of both peripheral and central nerves, might also slow ALS progression, but the 60-person study could neither confirm nor refute this hypothesis.

Mexiletine

The majority of people with ALS have muscle cramps, which scientists believe are due to excessive activation of the peripheral nerves that stimulate contractions. “It is the same thing as a Charley horse, a transient painful muscle contraction,” said Weiss. Cramps affect 92 percent of people with ALS, according to a survey that Björn Oskarsson of the University of California, Davis, conducted among nearly 300 National ALS Registry members. Oskarsson was not involved in the trial, but reported at the International Symposium on ALS/MND in Orlando in 2015 that ALS patients can have up to 75 cramps per day. They are often the only source of pain for people with ALS, he found. This jibes with a recently published paper reporting cramping in 95 percent of people with ALS (Caress et al., 2015). 

“For most people cramps are a nuisance,” Oskarsson told Alzforum. “But for a minority, it is a really big deal.” Some people with ALS avoid movements that they know trigger cramps, he said, restricting their mobility even more than the partial paralysis already caused by the disease. Plus, Oskarsson pointed out, a paralyzed person cannot stretch to relieve the cramp, and hence needs someone else to stretch their muscles for them. Oskarsson found that about 20 percent of people with ALS were so bothered by cramping that they would take medication for it, if available. Some take quinine for relief, but the FDA does not recommend this because the drug can be toxic, Weiss said.

Mexiletine is a sodium channel blocker, originally approved to treat cardiac arrhythmia. In 2003, researchers reported it alleviated cramping in Machado-Joseph disease, a form of spinocerebellar ataxia (Kanai et al., 2003). That inspired Oskarsson to prescribe it off-label for ALS; Weiss and some other physicians do the same. Ten people in Oskarsson’s survey were already taking it. “It works like a charm,” Oskarsson said. However, no randomized controlled trials support the practice. Weiss’ study, as well as Oskarsson’s 30-person Phase 4 trial underway in people with severe cramps, attempt to fill that gap.

Weiss and an array of collaborators, including senior author Merit Cudkowicz of Massachusetts General Hospital in Boston, recruited 60 volunteers with ALS to 10 different study sites in the Northeast ALS Consortium (NEALS, see Oct 2011 news series). People were eligible for the study regardless of how many cramps they had had before. The authors randomized volunteers into three groups for the oral medication: one-third received placebo, one-third took 300 milligrams of mexiletine per day, and one-third 900 milligrams daily. The main goal for the 12-week Phase 2 trial was to determine if the medication was safe and tolerable. It appeared safe, but the high dose proved intolerable. More than a quarter of people taking 900 milligrams complained of known side effects including nausea, tremors, and dizziness. Nearly one-third of people on the high dose stopped taking the study medication.

During the trial, clinicians sent participants home with a diary to record how often they had cramps and how intense they were on a scale of zero to 10.  When the authors averaged results from everyone in the study—whether they had originally complained of cramps or not—the drug more than halved both the number of cramps per week and their intensity. When the researchers limited their analysis to people who reported 10 or more cramps per month at baseline, they saw even more impressive results. People on placebo reported an average of nine cramps per week; those on low-dose mexiletine averaged two, and those on the high dose had fewer than one.

“This is a well-designed study that attacks a novel ALS mechanism, hyperexcitability,” commented Richard Bedlack of Duke University in Durham, North Carolina, who did not participate in the work. “It shows that mexiletine is safe at these doses and that it appears very effective against cramps” (see full comment below).

The authors assume that mexiletine works by obstructing sodium channels and diminishing peripheral nerve excitability; however, the study did not confirm this, pointed out Jonathan Glass of the Emory University School of Medicine in a Neurology editorial. Glass mentioned a method to measure this excitability called threshold tracking; scientists in Japan used threshold tracking in a six-month, Phase 2 mexiletine trial and observed no effect of the drug (Shibuya et al., 2015). That could be because the authors only tested one nerve in the wrist, while neuromuscular symptoms of ALS can crop up anywhere in the body, noted study author Satoshi Kuwabara of Chiba University. Kuwabara and colleagues did not assess cramping in their subjects, though they did find that the treatment reduced fasciculations—muscle twitches that are also caused by hyperexcitable nerves. “A direct relationship among mexiletine, sodium conductance, and cramping remains to be determined,” Glass wrote.

Weiss plans to include threshold tracking in an upcoming mexiletine trial. It will again enroll 60 people, at nine different centers, in placebo, 300 milligram, or 600 milligram groups. The main goal of this eight-week study, Weiss said, will be to study the pharmacodynamics of the drug and effects on both peripheral and cortical nerve hyperexcitability. It will use transcranial magnetic stimulation to assess excitability in the brain, which is known to be amped-up in people with ALS (see Sep 2015 news). The new study will also include a quality-of-life questionnaire, Weiss said, to determine how stopping cramps affects participants overall.

The new study is not powered to test if the drug affects survival of people with ALS, and mexiletine did not affect metrics for ALS progression, such as the ALS Functional Rating Scale, in either the U.S. or Japanese studies. “This might be due to the small sample size and short duration of the studies,” wrote Kuwabara and colleague Kazumoto Shibuya in an email to Alzforum. “To detect the neuroprotective effects of mexiletine, we have to try a large dose for a longer intervention period.”

Scientists have reason to suspect that mexiletine might slow the progression of the disease in addition to relieving an unpleasant symptom. For one, Weiss and colleagues found it in cerebrospinal fluid they collected from study participants, indicating it gets into the central nervous system where it could theoretically help degenerating motor neurons. In addition, people with ALS whose peripheral nerves are hyperexcitable, as measured by threshold tracking, tend to die sooner than other patients (Kanai et al., 2012). Hyperexcitability leads to release of excess glutamate, a known problem in the disease. In fact, the only drug known to slow down ALS a bit, riluzole, hinders glutamate release. Riluzole may prevent hyperexcitability, too, though it does not affect cramps (Fritz et al., 2013). Oskarsson said the rationale for mexiletine as a potential ALS-slowing drug makes sense, though based on his own clinical experience with the drug he doubts its effect on disease progression, if any, will be large.

Separately, scientists are also testing the potassium channel opener retigabine in a Phase 2 trial with nearly 200 subjects in hopes of reducing excitotoxicity and ALS progression.—Amber Dance

 

Comments

  1. Fasciculations and muscle cramp arise from motor neuronal/axonal hyperexcitability, and previous studies have indicated increased excitability in peripheral motor axons, as well as motor cortex, of amyotrophic lateral sclerosis (ALS) patients (Menon et al., 2015; Nihei et al., 1993; Kanai et al., 2003). In particular, threshold tracking studies indicate that persistent nodal sodium currents are higher in ALS patients than in normal controls (Kanai et al., 2006), and that the greater sodium currents are associated with shorter survival in ALS (Kanai et al., 2012). These findings suggest that axonal hyperexcitability not only causes fasciculations and muscle cramp, but also could contribute to motor neuronal death in ALS.

    Mexiletine is a cardiac antiarrhythmic agent and a sodium channel blocker. Weiss and colleagues have performed a randomized trial of mexiletine in ALS and nicely revealed the agent significantly reduced the frequency and severity of muscle cramps. Sixty patients were randomized to placebo, mexiletine 300mg/day, or 900mg/day and were followed up for 12 weeks. The results are reasonable because mexiletine suppresses excessive axonal sodium currents, and thereby muscle cramp. However they found no effects on disease progression as assessed by functional and vital capacity testing. We also have just published results of a randomized clinical trial with mexiletine for ALS, using 300mg/day (n=30) or placebo (n=30). We monitored axonal sodium currents by excitability testing (strength-duration time constant measurements) for six months (Shibuya et al., 2015). While no effects of mexiletine on sodium currents or clinical progression were apparent, fasciculations decreased in the mexiletine group. In this regard, the two clinical trials showed similar results. In both trials, decline of clinical scores was similar in the mexiletine and placebo groups, but this might be due to the small sample size and short duration of the studies.

    To detect the neuroprotective effects of mexiletine, we have to try larger doses for longer intervention periods. Furthermore, we may need to select an appropriate patient population with apparently increased axonal persistent sodium currents measured by strength-duration time constant. We are now planning such clinical trials with mexiletine or other sodium channel blockers.

    References:

    Menon P, Geevasinga N, Yiannikas C, Howells J, Kiernan MC, Vucic S. Sensitivity and specificity of threshold tracking transcranial magnetic stimulation for diagnosis of amyotrophic lateral sclerosis: a prospective study. Lancet Neurol. 2015 May;14(5):478-84. Epub 2015 Apr 3 PubMed.

    Nihei K, McKee AC, Kowall NW. Patterns of neuronal degeneration in the motor cortex of amyotrophic lateral sclerosis patients. Acta Neuropathol. 1993;86(1):55-64. 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.

    Kanai K, Kuwabara S, Misawa S, Tamura N, Ogawara K, Nakata M, Sawai S, Hattori T, Bostock H. Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage. Brain. 2006 Apr;129(Pt 4):953-62. Epub 2006 Feb 8 PubMed.

    Kanai K, Shibuya K, Sato Y, Misawa S, Nasu S, Sekiguchi Y, Mitsuma S, Isose S, Fujimaki Y, Ohmori S, Koga S, Kuwabara S. Motor axonal excitability properties are strong predictors for survival in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2012 Jul;83(7):734-8. Epub 2012 May 7 PubMed.

    Shibuya K, Misawa S, Kimura H, Noto Y, Sato Y, Sekiguchi Y, Iwai Y, Mitsuma S, Beppu M, Watanabe K, Fujimaki Y, Tsuji Y, Shimizu T, Mizuno T, Nakagawa M, Sawaguchi K, Hanaoka H, Kuwabara S. A single blind randomized controlled clinical trial of mexiletine in amyotrophic lateral sclerosis: Efficacy and safety of sodium channel blocker phase II trial. Amyotroph Lateral Scler Frontotemporal Degener. 2015;16(5-6):353-8. Epub 2015 May 11 PubMed.

    View all comments by Kazumoto Shibuya View all comments by Satoshi Kuwabara

  2. This is a well-designed study that attacks a novel ALS mechanism, hyperexcitability. It shows that mexiletine is safe at these doses and that it appears very effective against cramps (a common symptom in patients with ALS, and one for which we have no other evidence-based treatment). I look forward to seeing a larger study that is powered to look for slowing of ALS progression.

    View all comments by Richard Bedlack

  3. I appreciate the comments from Drs. Bedlack and Kuwabara. I concur with Dr. Bedlack that only a bigger study with sufficient power will be able to determine if mexiletine can slow progression in addition to its effects on muscle cramps. Dr. Kuwabara may prove to be correct that future studies of mexiletine or other medications that block sodium channels are more likely to be successful by including only subjects with evidence for increased persistent sodium current and peripheral nerve hyperexcitability reflected by the strength-duration time constant. One question also is how well muscle cramp severity and frequency correlate with this measure. The new mexiletine study will hopefully answer this question.

    View all comments by Michael Weiss

  4. Muscle cramps are a challenging problem in patients with ALS, and many of the currently available options for treatment are not effective or have unwanted side effects. There have been few randomized, placebo-controlled trials focused on ameliorating this symptom. This study was originally conceived not as a symptomatic treatment, but as a way to decrease hyperexcitability. Abnormal neuronal excitability has become increasingly recognized in multiple neurodegenerative syndromes, including ALS. Mexiletine may be a well-tolerated (at the lower dose tested) symptomatic therapeutic for cramps in ALS. A larger trial will be needed to confirm this finding.

    In summary, mexiletine was overall safe in ALS patients, paving the way for a larger trial to test whether modulating hyperexcitability may be beneficial in ALS. The current trial was not powered to show a benefit on ALS disease progression. A major challenge for this and other excitability targeted therapeutics in ALS will be defining clinical read outs for the effect of the drug on modulating excitability.

    View all comments by Timothy Miller

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References

Conference Coverage Series Citations

  1. Northeast ALS Consortium 2011

News Citations

  1. Magnet Test Finds Cortex Overexcitable in All ALS

Therapeutics Citations

  1. Riluzole

Paper Citations

  1. Caress JB, Ciarlone SL, Sullivan EA, Griffin LP, Cartwright MS. Natural history of muscle cramps in amyotrophic lateral sclerosis. Muscle Nerve. 2015 Sep 2; PubMed.
  2. 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.
  3. Shibuya K, Misawa S, Kimura H, Noto Y, Sato Y, Sekiguchi Y, Iwai Y, Mitsuma S, Beppu M, Watanabe K, Fujimaki Y, Tsuji Y, Shimizu T, Mizuno T, Nakagawa M, Sawaguchi K, Hanaoka H, Kuwabara S. A single blind randomized controlled clinical trial of mexiletine in amyotrophic lateral sclerosis: Efficacy and safety of sodium channel blocker phase II trial. Amyotroph Lateral Scler Frontotemporal Degener. 2015;16(5-6):353-8. Epub 2015 May 11 PubMed.
  4. Kanai K, Shibuya K, Sato Y, Misawa S, Nasu S, Sekiguchi Y, Mitsuma S, Isose S, Fujimaki Y, Ohmori S, Koga S, Kuwabara S. Motor axonal excitability properties are strong predictors for survival in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2012 Jul;83(7):734-8. Epub 2012 May 7 PubMed.
  5. 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. Epub 2013 Mar 13 PubMed.

External Citations

  1. Phase 2 trial
  2. National ALS Registry
  3. Phase 4 trial
  4. Phase 2 trial 

Further Reading

Papers

  1. Bostock H, Cikurel K, Burke D. Threshold tracking techniques in the study of human peripheral nerve. Muscle Nerve. 1998 Feb;21(2):137-58. PubMed.
  2. Rojas F, Cortes N, Abarzua S, Dyrda A, van Zundert B. Astrocytes expressing mutant SOD1 and TDP43 trigger motoneuron death that is mediated via sodium channels and nitroxidative stress. Front Cell Neurosci. 2014;8:24. Epub 2014 Feb 7 PubMed.
  3. Schanz O, Bageac D, Braun L, Traynor BJ, Lehky TJ, Floeter MK. Cortical hyperexcitability in patients with C9ORF72 mutations: Relationship to phenotype. Muscle Nerve. 2016 Aug;54(2):264-9. Epub 2016 May 25 PubMed.
  4. Geevasinga N, Menon P, Sue CM, Kumar KR, Ng K, Yiannikas C, Kiernan MC, Vucic S. Cortical excitability changes distinguish the motor neuron disease phenotypes from hereditary spastic paraplegia. Eur J Neurol. 2015 May;22(5):826-31, e57-8. Epub 2015 Feb 12 PubMed.
  5. Menon P, Kiernan MC, Vucic S. Cortical hyperexcitability precedes lower motor neuron dysfunction in ALS. Clin Neurophysiol. 2014 Aug 28; PubMed.

Primary Papers

  1. 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. Epub 2016 Feb 24 PubMed.
  2. Glass JD. Calming the excitement in ALS. Neurology. 2016 Apr 19;86(16):1468-9. Epub 2016 Feb 24 PubMed.

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