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

ABSTRACT: INTRODUCTION:More than 90% of amyotrophic lateral sclerosis (ALS) patients have muscle cramps, but evidence-based treatments have not been available. METHODS: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. RESULTS:Muscle cramp frequency was reduced in 18 of 20 patients; 13 reductions were attributed to treatment (P?

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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Natural history of muscle cramps in amyotrophic lateral sclerosis.

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Open-label pilot study of ranolazine for cramps in amyotrophic lateral sclerosis.

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Ropinirole hydrochloride identified by iPSC drug discovery for amyotrophic lateral sclerosis: a single-centered, randomized, double-blind, placebo-controlled phase 1/2a trial

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Bromocriptine Mesylate Attenuates Amyotrophic Lateral Sclerosis: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Research in Japanese Patients.

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Granulocyte colony-stimulating factor for amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled study of Iranian patients.

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A randomized trial of mexiletine in ALS: Safety and effects on muscle cramps and progression.

Project description:ObjectiveTo determine the safety and tolerability of mexiletine in a phase II double-blind randomized controlled trial of sporadic amyotrophic lateral sclerosis (SALS).MethodsSixty participants with SALS from 10 centers were randomized 1:1:1 to placebo, mexiletine 300 mg/d, or mexiletine 900 mg/d and followed for 12 weeks. The primary endpoints were safety and tolerability. Secondary endpoints were pharmacokinetic study from plasma and CSF, ALS Functional Rating Scale-Revised (ALSFRS-R) score, slow vital capacity (SVC), and muscle cramp frequency and severity.ResultsThe only serious adverse event among active arm participants was one episode of imbalance. Thirty-two percent of participants receiving 900 mg of mexiletine discontinued study drug vs 5% on placebo (p = 0.026). Pharmacokinetic study demonstrated a peak plasma concentration 2 hours postdose and strong correlation between plasma and CSF (p < 0.001). Rates of decline of ALSFRS-R and SVC did not differ from placebo. Analysis of all randomized patients demonstrated significant reductions of muscle cramp frequency (300 mg: rate = 31% of placebo, p = 0.047; 900 mg: 16% of placebo, p = 0.002) and cramp intensity (300 mg: mean = 45% of placebo, p = 0.08; 900 mg: 25% of placebo, p = 0.005).ConclusionsMexiletine was safe at both doses and well-tolerated at 300 mg/d but adverse effects at 900 mg/d led to a high rate of discontinuation. Mexiletine treatment resulted in large dose-dependent reductions in muscle cramp frequency and severity. No effect on rate of progression was detected, but clinically important differences could not be excluded in this small and short-duration study.Classification of evidenceThis study provides Class I evidence that mexiletine is safe when given daily to patients with amyotrophic lateral sclerosis at 300 and 900 mg and well-tolerated at the lower dose.

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Correction: Bromocriptine Mesylate Attenuates Amyotrophic Lateral Sclerosis: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Research in Japanese Patients.

Project description: Not available

| S-EPMC4809614 | biostudies-literature

Effects of Mexiletine and Lacosamide on Nerve Excitability in Healthy Subjects: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study.

Project description:Selective voltage-gated sodium channel blockers are of growing interest as treatment for pain. For drug development of such compounds, it would be critical to have a biomarker that can be used for proof-of-mechanism. We aimed to evaluate whether drug-induced changes in sodium conductance can be detected in the peripheral nerve excitability profile in 18 healthy subjects. In a randomized, double-blind, 3-way crossover study, effects of single oral doses of 333 mg mexiletine and 300 mg lacosamide were compared with placebo. On each study visit, motor and sensory nerve excitability measurements of the median nerve were performed (predose; and 3 and 6 hours postdose) using Qtrac. Treatment effects were calculated using an analysis of covariance (ANCOVA) with baseline as covariate. Mexiletine and lacosamide had significant effects on multiple motor and sensory nerve excitability variables. Depolarizing threshold electrotonus (TEd40 (40-60 ms)) decreased by mexiletine (estimated difference (ED) -1.37% (95% confidence interval (CI): -2.20, -0.547; P = 0.002) and lacosamide (ED -1.27%, 95% CI: -2.10, -0.443; P = 0.004) in motor nerves. Moreover, mexiletine and lacosamide decreased superexcitability (less negative) in motor nerves (ED 1.74%, 95% CI: 0.615, 2.87; P = 0.004, and ED 1.47%, 95% CI: 0.341, 2.60; P = 0.013, respectively). Strength-duration time constant decreased after lacosamide in motor- (ED -0.0342 ms, 95% CI: -0.0571, -0.0112; P = 0.005) and sensory nerves (ED -0.0778 ms, 95% CI: -0.116, -0.0399; P < 0.001). Mexiletine and lacosamide significantly decrease excitability of motor and sensory nerves, in line with their suggested mechanism of action. Results of this study indicate that nerve excitability threshold tracking can be an effective pharmacodynamic biomarker. The method could be a valuable tool in clinical drug development.

| S-EPMC9795956 | biostudies-literature

Erythropoietin in amyotrophic lateral sclerosis: a multicentre, randomised, double blind, placebo controlled, phase III study.

Project description:ObjectiveTo assess the efficacy of recombinant human erythropoietin (rhEPO) in amyotrophic lateral sclerosis (ALS).MethodsPatients with probable laboratory-supported, probable or definite ALS were enrolled by 25 Italian centres and randomly assigned (1:1) to receive intravenous rhEPO 40,000 IU or placebo fortnightly as add-on treatment to riluzole 100 mg daily for 12 months. The primary composite outcome was survival, tracheotomy or >23 h non-invasive ventilation (NIV). Secondary outcomes were ALSFRS-R, slow vital capacity (sVC) and quality of life (ALSAQ-40) decline. Tolerability was evaluated analysing adverse events (AEs) causing withdrawal. The randomisation sequence was computer-generated by blocks, stratified by centre, disease severity (ALSFRS-R cut-off score of 33) and onset (spinal or bulbar). The main outcome analysis was performed in all randomised patients and by intention-to-treat for the entire population and patients stratified by severity and onset. The study is registered, EudraCT 2009-016066-91.ResultsWe randomly assigned 208 patients, of whom 5 (1 rhEPO and 4 placebo) withdrew consent and 3 (placebo) became ineligible (retinal thrombosis, respiratory insufficiency, SOD1 mutation) before receiving treatment; 103 receiving rhEPO and 97 placebo were eligible for analysis. At 12 months, the annualised rate of death (rhEPO 0.11, 95% CI 0.06 to 0.20; placebo: 0.08, CI 0.04 to 0.17), tracheotomy or >23 h NIV (rhEPO 0.16, CI 0.10 to 0.27; placebo 0.18, CI 0.11 to 0.30) did not differ between groups, also after stratification by onset and ALSFRS-R at baseline. Withdrawal due to AE was 16.5% in rhEPO and 8.3% in placebo. No differences were found for secondary outcomes.ConclusionsRhEPO 40,000 IU fortnightly did not change the course of ALS.

| S-EPMC4515982 | biostudies-literature

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