Treatment for cramps in amyotrophic lateral sclerosis/motor neuron disease

Baldinger, Reto; Katzberg, Hans D.; Weber, Markus

doi:10.1002/14651858.cd004157.pub2

Cited by 47 publications

(36 citation statements)

References 169 publications

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“…For symptoms that have spread to the abdomen, calcium channel blockers (i.e., amlodipine) and antimotility (e.g., loperamide), antimuscarinic (e.g., trimebutine), or anticholinergic agents (e.g., scopolamine) may be useful. Although a number of agents, including vitamin E, baclofen, riluzole, l -threonine, xaliproden, indinavir, memantine, carbamazepine, and oxcarbazepine, have been investigated in patients with amyotrophic lateral sclerosis/motor neuron disease, none has shown any significant benefit in reducing cramping [46]. The FDA has advised against the use of quinine for cramps because of potentially dangerous and life-threatening side effects (QT prolongation, thrombocytopenia, and hypersensitivity reactions) [47], although, in non-U.S. countries, cautious use for severe cramps is permitted.…”

Section: Introductionmentioning

confidence: 99%

Characterization and Management of Hedgehog Pathway Inhibitor-Related Adverse Events in Patients With Advanced Basal Cell Carcinoma

Dréno²,

et al. 2016

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Vismodegib and sonidegib are Hedgehog pathway inhibitors (HPIs) approved for treatment of patients with advanced basal cell carcinoma. The adverse events (AEs) associated with these therapies can impact clinical outcomes as a result of decreased quality of life and treatment discontinuation. The incidence, clinical presentation, putative mechanisms, and management strategies for AEs related to administration of HPIs are described in this article.

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Section: Introductionmentioning

confidence: 99%

Characterization and Management of Hedgehog Pathway Inhibitor-Related Adverse Events in Patients With Advanced Basal Cell Carcinoma

Dréno²,

et al. 2016

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“…There have been a number of randomized treatment trials addressing this often disabling symptom but none has been successful to date. 21 These have included the use of gabapentin, 22 vitamin E, 23 L-threonine, 24 memantine, 25 xaliproden, 26 indinavir, 27 and baclofen. 28 Though riluzole, like mexiletine, is a use-dependent sodium channel blocker, it has not been shown to have any significant effects on muscle cramps.…”

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confidence: 99%

A randomized trial of mexiletine in ALS

et al. 2016

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Objective: To determine the safety and tolerability of mexiletine in a phase II double-blind randomized controlled trial of sporadic amyotrophic lateral sclerosis (SALS).Methods: Sixty 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.Results: The 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 5 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 5 31% of placebo, p 5 0.047; 900 mg: 16% of placebo, p 5 0.002) and cramp intensity (300 mg: mean 5 45% of placebo, p 5 0.08; 900 mg: 25% of placebo, p 5 0.005). Conclusions:Mexiletine 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 evidence:This 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. Neurology ® 2016;86:1474-1481 GLOSSARY AE 5 adverse event; ALS 5 amyotrophic lateral sclerosis; ALSFRS-R 5 revised ALS Functional Rating Scale; AUC 5 area under the concentration curve; DSMB 5 data safety monitoring board; SAE 5 serious adverse event; SALS 5 sporadic amyotrophic lateral sclerosis; SF-36 5 Short Form-36 Health Survey; SVC 5 slow vital capacity.Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by death of cortical, brainstem, and spinal motor neurons. Riluzole, the sole Food and Drug Administration-approved therapy for ALS, has only a limited effect on slowing progression. 1 Recent in vivo 2-5 and in vitro 6-12 studies support a role for hyperexcitability of both peripheral motor nerve axons and cortical motor neurons as a possible pathogenic mechanism of ALS. Additionally, cortical motor neuronal hyperexcitability has been demonstrated in patients with

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“…There are many inherent difficulties in studying cramps, because they are variable, subjective, and self‐reported. There have been no formal natural history studies of muscle cramps in ALS assessing features such as their prevalence, duration, or intensity . The lack of natural history data makes it difficult to plan outcome measures and sampling intervals for clinical trials .…”

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confidence: 99%

Natural history of muscle cramps in amyotrophic lateral sclerosis

et al. 2015

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Introduction Muscle cramping is a common symptom in amyotrophic lateral sclerosis (ALS) without efficacious treatment. The natural history of this symptom is unknown, which hampers efforts to design optimal clinical trials. Methods We surveyed early stage ALS patients about their experience with cramps each month by phone for up to 21 months. Results Cramps developed in 95% of patients over the course of their disease. The number of cramps experienced by an individual varied widely from month-to-month and trended lower after the first year of illness (P = 0.26). Those with limb-onset and age >60 years had more cramps than bulbar-onset (P<0.0001) and younger patients (P<0.0001). Discussion The high variability of the number of cramps experienced suggests that clinical trials will need to use crossover designs or large numbers of participants, even when the treatment effect is substantial.

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Treatment for cramps in amyotrophic lateral sclerosis/motor neuron disease

Cited by 47 publications

References 169 publications

Characterization and Management of Hedgehog Pathway Inhibitor-Related Adverse Events in Patients With Advanced Basal Cell Carcinoma

Characterization and Management of Hedgehog Pathway Inhibitor-Related Adverse Events in Patients With Advanced Basal Cell Carcinoma

A randomized trial of mexiletine in ALS

Natural history of muscle cramps in amyotrophic lateral sclerosis

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