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Mexiletine for muscle cramps in amyotrophic lateral sclerosis: A randomized, double-blind crossover trial.

ABSTRACT: More than 90% of amyotrophic lateral sclerosis (ALS) patients have muscle cramps, but evidence-based treatments have not been available. A multicenter, double-blind, placebo-controlled crossover trial of mexiletine 150 mg twice daily was conducted in ALS patients requesting treatment of symptomatic muscle cramps. Muscle cramp frequency was reduced in 18 of 20 patients; 13 reductions were attributed to treatment (P < 0.05). The average reduction, based on t tests, was 1.8 cramps per day (a reduction from 5.3 with placebo to 3.5 with mexiletine). The estimated reduction of cramp severity was 15 units on a 100-unit scale (P = 0.01) from a baseline average of 46. No effect on fasciculations was noted. One patient discontinued the study because of dizziness, and another patient discontinued the study to start open-label mexiletine therapy. No serious adverse event occurred. Mexiletine is a well tolerated and effective medication for controlling the symptom of muscle cramps in ALS. Muscle Nerve, 2018.

SUBMITTER: Oskarsson B

PROVIDER: S-EPMC6126993 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Mexiletine for muscle cramps in amyotrophic lateral sclerosis: A randomized, double-blind crossover trial.

Oskarsson Björn B Moore Dan D Mozaffar Tahseen T Ravits John J Wiedau-Pazos Martina M Parziale Nicholas N Joyce Nanette C NC Mandeville Ross R Goyal Namita N Cudkowicz Merit E ME Weiss Michael M Miller Robert G RG McDonald Craig M CM

Muscle & nerve 20180306

<h4>Introduction</h4>More than 90% of amyotrophic lateral sclerosis (ALS) patients have muscle cramps, but evidence-based treatments have not been available.<h4>Methods</h4>A multicenter, double-blind, placebo-controlled crossover trial of mexiletine 150 mg twice daily was conducted in ALS patients requesting treatment of symptomatic muscle cramps.<h4>Results</h4>Muscle cramp frequency was reduced in 18 of 20 patients; 13 reductions were attributed to treatment (P < 0.05). The average reduction, ...[more]

PMID: 29510461

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Project description:Background and objectiveThe objective of this study was to evaluate the short-term physiologic effect and one-year functional effect of a 12-week inspiratory and expiratory respiratory strength training (RST) program in individuals with amyotrophic lateral sclerosis (ALS).MethodsA double-blinded, randomized, sham-controlled trial was conducted in 45 individuals with early-stage ALS. Participants were randomized into 12 weeks of active RST (30% load, n = 23) or sham RST (0% load, n = 22). An intent-to-treat analysis was conducted. Linear regression of pre-post change with group status and pretest scores as predictors was conducted. Primary outcomes included maximum expiratory and inspiratory pressure (MEP, MIP), and secondary outcomes were cough spirometry and forced vital capacity. Exploratory follow-up outcomes included one-year global and bulbar decline (ALS Functional Rating Scale-Revised [ALSFRS-R] total and bulbar subscale slope), oral intake status, and time to noninvasive ventilation (NIV).ResultsTheRST completion rate was 91% with no RST-related adverse events. A 12-week RST program led to increases in MEP (p = 0.004), but not MIP (p = 0.33). On average, MEP increased by 20.8 cm H2O after active RST (95% CI +7.6 to +33.9) and decreased by 1.0 cm H2O (95% CI -9.1 to +7.2) after sham RST. Mean MIP increased by 8.9 cm H2O (95% CI +1.5 to +16.3) and 4.8 cm H2O (95% CI -0.6 to +10.2) for the active and sham groups, respectively. Regarding secondary outcomes, RST led to significant increases in cough peak inspiratory flow (p = 0.02); however, it did not affect cough expiratory flow (p = 0.06) or FVC (p = 0.60). Regarding 12-month outcomes, a significant difference in the ALSFRS-R bulbar subscale slope was observed across treatment groups, with a more than two-fold faster rate of bulbar decline in the sham vs active RST groups observed (-0.29 vs -0.12 points/month, p = 0.02). Total ALSFRS-R slope, feeding status, and time to NIV did not differ across treatment groups (p > 0.05).DiscussionRST was well tolerated and led to improvements in some, but not all, short and long-term outcomes. RST represents a proactive rehabilitative intervention that could increase physiologic capacity of specific breathing and airway clearance functions during the early stages of ALS. Further work is needed to determine optimal training intensity, resistance load specifications, and potential long-term functional outcomes.Classification of evidenceThis study provides Class II evidence that a mild-intensity respiratory strength training program improves maximum expiratory pressure, but not maximum inspiratory pressure, in patients with early-stage ALS.

Project description:Introduction/aimsMuscle cramps are a common and often disabling symptom in amyotrophic lateral sclerosis (ALS), a devastating and incurable neurodegenerative disorder. To date, there are no medications specifically approved for the treatment of muscle cramps. Ameliorating muscle cramps in ALS may improve and sustain quality of life. A widely prescribed traditional Japanese (Kampo) medicine against muscle cramps, shakuyakukanzoto (TJ-68), has been studied in advanced liver disease, spinal stenosis, kidney failure, and diabetic neuropathy. The Japanese ALS Management Guideline mentions TJ-68 for difficult muscle cramps in ALS. Therefore, the rationale of our trial is to investigate the safety and effectiveness of TJ-68 in treating painful and disabling muscle cramps in people with ALS outside of Japan. Accordingly, we are conducting a randomized clinical trial to test the safety and efficacy of TJ-68 in participants with ALS reporting frequent muscle cramps using an innovative, personalized N-of-1 design. If successful, TJ-68 may be used for muscle cramps in a broader population of people with ALS.MethodsThis is a two-site, double-blind, randomized personalized N-of-1 early clinical trial with TJ-68. At least 22 participants with ALS and daily muscle cramps will receive drug or placebo for 2 weeks (one treatment period) followed by a 1-week washout in a four-period cross-over design. While the primary objective is to evaluate the safety of TJ-68, the study has 85% power to detect a one-point shift on the Visual Analog Scale for Muscle Cramps Affecting Overall Daily Activity of the Columbia Muscle Cramp Scale (MCS). Secondary outcomes include the full MCS score, a Cramp Diary, Clinical Global Impression of Changes, Goal Attainment Scale, quality of life scale and ALS functional rating scale-revised (ALSFRS-R).DiscussionThe study is underway. A personalized N-of-1 trial design is an efficient approach to testing medications that alleviate muscle cramps in rare disorders. If TJ-68 proves safe and efficacious then it may be used to treat cramps in ALS, and help to improve and sustain quality of life.Trial registrationThis clinical trial has been registered with ClinicalTrials.gov (NCT04998305), 8/9/2021.

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Mexiletine for muscle cramps in amyotrophic lateral sclerosis: A randomized, double-blind crossover trial.

Publications

Mexiletine for muscle cramps in amyotrophic lateral sclerosis: A randomized, double-blind crossover trial.

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