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?
Project description:To determine the safety and tolerability of mexiletine in a phase II double-blind randomized controlled trial of sporadic amyotrophic lateral sclerosis (SALS).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.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 = 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).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.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.
Project description:The objective of this study was to describe muscle cramps in an US sample of amyotrophic lateral sclerosis (ALS) patients. Utilizing an anonymous web based questionnaire we queried ALS patients regarding the severity, frequency, time-course, treatment of muscle cramps and their relationship to pain. The survey had 282 respondents with 92% reporting that they had cramps. For 20% of the sample, cramps were stated to be the presenting ALS symptom. Cramp severity was rated at a mean of 5.2/10 and the mean cramp frequency was 5.3 cramps per day. Cramp intensity and frequency did not correlate with duration or severity of ALS. Pain as measured with the Patient Reported Outcome Measurement Information System (PROMIS) pain scales was not statistically different from the US general population. Cramp severity and frequency significantly and positively correlated with the PROMIS pain scales. Patients with more severe cramps were more likely to use prescription medications for their cramps compared to patients with milder symptoms. Treatments directed at cramps were tried by 57%. In conclusion, cramps are a common symptom in ALS and it does not correlate with disease duration or severity. The severity of cramps is on average moderate and many patients try treatments.
Project description:This study aims to assess the frequency, location, severity, duration, and fluctuation over time of muscle cramps in Charcot-Marie-Tooth disease (CMT).Inherited Neuropathies Consortium Contact Registry participants recorded the occurrence and characteristics of muscle cramps using an 11-question survey administered 3 times over 8 weeks.A total of 110 adult patients with CMT completed the survey. Weekly cramp frequency was 9.3 (SD 12.3), and 23% had daily muscle cramps. Twenty-two percent reported a significant impact on quality of life. Over 8 weeks, the daily frequency and severity of muscle cramps did not change significantly.Patients with CMT have muscle cramps that vary little over an 8-week period, and they may interfere with quality of life. These data may be useful in the planning of clinical trials of agents to treat adults with CMT-associated muscle cramps.
Project description:BACKGROUND:Minimal treatment options exist for idiopathic muscle cramps. OBJECTIVE:We evaluated whether correction of vitamin D insufficiency relieved muscle cramps in postmenopausal women. METHODS:We conducted a post hoc analysis of a randomized, double-blind, placebo-controlled trial at a single academic medical center in the Midwest to evaluate the benefits of treating vitamin D insufficiency. Two hundred thirty postmenopausal women participated. Eligible women were ?75 years old, 5 years past menopause or oophorectomy, or ?60 years if they had previously undergone hysterectomy without oophorectomy. Women had vitamin D insufficiency at baseline (25-hydroxyvitamin D 14-27 ng/mL). We excluded subjects with a glomerular filtration rate <45 mL/minute. INTERVENTIONS FOR CLINICAL TRIALS:Participants completed food diaries, laboratory studies, and functional tests including the Timed Up and Go test, Physical Activity Scale for the Elderly, Health Assessment Questionnaire (a measure of disability), and pain scores. Subjects recorded muscle cramp frequency and severity using a standardized form at 6 visits over 1 year. RESULTS:During the trial, over half of participants (n=121, 53%) reported muscle cramps. Despite unequivocal vitamin D repletion, vitamin D had no effect on muscle cramps. Pain levels, disability, and dietary potassium predicted presence of cramps. Serum albumin and physical activity were inversely associated with, and disability was positively associated with, severity of muscle cramps. CONCLUSIONS:Further studies are needed to evaluate the link between pain, disability, dietary potassium intake, and muscle cramps.
Project description:Muscle cramping is a common symptom in amyotrophic lateral sclerosis (ALS) that lacks efficacious treatment. The natural history of this symptom is unknown, which hampers efforts to design optimal clinical trials.We surveyed early stage ALS patients about their experience with cramps each month by phone for up to 21 months.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).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.
Project description:Our objective was to explore if creatine kinase (CK) levels correlate with survival in amyotrophic lateral sclerosis (ALS), and whether a correlation is independent of other well-studied predictors such as location of onset, gender, age, fat free mass, spasticity, cramps, and fasciculations. We analyzed data from 80 ALS patients from a 48-week non-interventional longitudinal multicenter nutrition study with long term follow-up. The overall mean CK was 214 ± 191.8 U/l (range 22-1992 U/l). Forty-five percent of patients had at least one high CK value (> 200 U/l), and about half maintained a high CK value, but there was no trend over the study period. Male gender and extremity onset were significantly associated with high CK. In univariate analysis, age, bioelectric impedance spectroscopy (BIS) fat free mass, spasticity, and fasciculations were not associated with CK level. There was an association between CK and muscle cramps (p < 0.001). In survival analysis, low CK (? 200 U/l) was associated with a longer overall survival (p = 0.02), when adjusting for location of onset, age, race, gender, BIS fat free mass, and study site. In conclusion, CK may be a useful marker for ALS survival, which has implications for clinical care and the design of future clinical trials.
Project description:BACKGROUND: Skeletal muscle cramps affect over a third of the ambulatory elderly population. Quinine is the established treatment, but there are safety concerns, and evidence for efficacy is conflicting. A recent meta-analysis established a small advantage for quinine, but identified the need for additional studies. N-of-1 trials compare two treatments, in a randomised, double-blind, multiple crossover study on a patient-by-patient basis. They have been used to compare treatments in osteoarthritis and may be suitable for determining the individual efficacy of quinine. AIM: To establish efficacy and safety of quinine sulphate use for the treatment of leg-muscle cramp. DESIGN OF STUDY: Double-blind, randomised series of n-of-1 controlled trials of quinine versus placebo for muscle cramps. SETTING: New Zealand general practices. METHOD: The participants were 13 general practice patients (six males; seven females; median age = 75 years) already prescribed quinine. Following a 2-week washout, each patient received three 4-week treatment blocks of quinine sulphate and matched placebo capsules with an individual, randomised crossover design. The main outcome measures were: patient diaries of cramp occurrence, duration and severity; capsule counts; and blood quinine levels in the final treatment block. RESULTS: Ten patients completed the trial. Three patients were identified for whom quinine was clearly beneficial (P <0.05), six showed non-significant benefit and one showed no benefit. All patients elected to continue quinine post-study. CONCLUSION: Series of n -of-1 studies differentiated patients whom quinine had statistically significant effects; those with trend towards effectiveness; those for whom quinine was probably not effective. Ideally n-of-1 trial should be performed when a patient is commenced on quinine. More cycles in n-of-1 studies of quinine may address issues of statistical power.
Project description:Background: Amyotrophic lateral sclerosis (ALS) is a progressive fatal disease with a varying range of clinical characteristics. Objective: To describe the clinical characteristics in a large cohort of ALS participants enrolled in the National ALS Registry. Methods: Data from ALS participants who completed the Registry's online clinical survey module during 2010-2015 were analyzed to determine characteristics, such as site of onset, associated symptoms, time of symptom onset to diagnosis, time of diagnosis to hospice referral, and pharmacological and non-pharmacological interventions. Results: Of the 1758 participants who completed the survey, 60.9% were male, 62.1% were 50-69 years old, and 95.5% white. Approximately, 72.0% reported initial limb weakness onset of disease, followed by bulbar (22.1%), and trunk/global onset (6.1%). Other symptoms ever experienced included cramps (56.7%), fasciculations (56.3%), and dysarthria (33.0%). The median time between an increase of muscle cramps until an ALS diagnosis was 12 months; limb onset participants had cramps longer preceding diagnosis versus those with bulbar onset. The most frequent interventions used included riluzole (48.3% currently using), wheelchairs/scooters (32.8%), and noninvasive breathing equipment (30.0%). Participants with trunk/global onset were referred to hospice almost four times earlier than others. Conclusions: These data show how ALS clinical characteristics differ widely in a large cohort of participants preceding diagnosis and reflect variations in disease onset, progression, and prognosis. Better characterization of symptom onset may assist clinicians in diagnosing ALS sooner, which could lead to earlier therapeutic interventions.
Project description:Importance:In rare diseases it is difficult to achieve high-quality evidence of treatment efficacy because of small cohorts and clinical heterogeneity. With emerging treatments for rare diseases, innovative trial designs are needed. Objective:To investigate the effectiveness of mexiletine in nondystrophic myotonia using an aggregated N-of-1 trials design and compare results between this innovative design and a previously conducted RCT. Design, Setting, and Participants:A series of aggregated, double-blind, randomized, placebo-controlled N-of-1-trials, performed in a single academic referral center. Thirty Dutch adult patients with genetically confirmed nondystrophic myotonia (38 patients screened) were enrolled between February 2014 and June 2015. Follow-up was completed in September 2016. Interventions:Mexiletine (600 mg daily) vs placebo during multiple treatment periods of 4 weeks. Main Outcomes and Measures:Reduction in daily-reported muscle stiffness on a scale of 1 to 9, with higher scores indicating more impairment. A Bayesian hierarchical model aggregated individual N-of-1 trial data to determine the posterior probability of reaching a clinically meaningful effect of a greater than 0.75-point difference. Results:Among 30 enrolled patients (mean age, 43.4 [SD, 15.24] years; 22% men; 19 CLCN1 and 11 SCN4A genotype), 27 completed the study and 3 dropped out (1 because of a serious adverse event). In 24 of the 27 completers, a clinically meaningful treatment effect was found. In the Bayesian hierarchical model, mexiletine resulted in a 100% posterior probability of reaching a clinically meaningful reduction in self-reported muscle stiffness for the nondystrophic myotonia group overall and the CLCN1 genotype subgroup and 93% posterior probability for the SCN4A genotype subgroup. In the total nondystrophic myotonia group, the median muscle stiffness score was 6.08 (interquartile range, 4.71-6.80) at baseline and was 2.50 (95% credible interval [CrI], 1.77-3.24) during the mexiletine period and 5.56 (95% CrI, 4.73-6.39) during the placebo period; difference in symptom score reduction, 3.06 (95% CrI, 1.96-4.15; n?=?27) favoring mexiletine. The most common adverse event was gastrointestinal discomfort (21 mexiletine [70%], 1 placebo [3%]). One serious adverse event occurred (1 mexiletine [3%]; allergic skin reaction). Using frequentist reanalysis, mexiletine compared with placebo resulted in a mean reduction in daily-reported muscle stiffness of 3.12 (95% CI, 2.46-3.78), consistent with the previous RCT treatment effect of 2.69 (95% CI, 2.12-3.26). Conclusions and Relevance:In a series of N-of-1 trials of mexiletine vs placebo in patients with nondystrophic myotonia, there was a reduction in mean daily-reported muscle stiffness that was consistent with the treatment effect in a previous randomized clinical trial. These findings support the efficacy of mexiletine for treatment of nondystrophic myotonia as well as the feasibility of N-of-1 trials for assessing interventions in some chronic rare diseases. Trial Registration:ClinicalTrials.gov Identifier: NCT02045667.
Project description:To obtain evidence for the clinical and cost-effectiveness of treatments for patients with rare diseases is a challenge. Non-dystrophic myotonia (NDM) is a group of inherited, rare muscle diseases characterized by muscle stiffness. The reimbursement of mexiletine, the expert opinion drug for NDM, has been discontinued in some countries due to a lack of independent randomized controlled trials (RCTs). It remains unclear however, which concessions can be accepted towards the level 1 evidence needed for coverage decisions, in rare diseases. Considering the large number of rare diseases with a lack of treatment evidence, more experience with innovative trial designs is needed. Both NDM and mexiletine are well suited for an N-of-1 trial design. A Bayesian approach allows for the combination of N-of-1 trials, which enables the assessment of outcomes on the patient and group level simultaneously.We will combine 30 individual, double-blind, randomized, placebo-controlled N-of-1 trials of mexiletine (600 mg daily) vs. placebo in genetically confirmed NDM patients using hierarchical Bayesian modeling. Our results will be compared and combined with the main results of an international cross-over RCT (mexiletine vs. placebo in NDM) published in 2012 that will be used as an informative prior. Similar criteria of eligibility, treatment regimen, end-points and measurement instruments are employed as used in the international cross-over RCT.The treatment of patients with NDM with mexiletine offers a unique opportunity to compare outcomes and efficiency of novel N-of-1 trial-based designs and conventional approaches in producing evidence of clinical and cost-effectiveness of treatments for patients with rare diseases.ClinicalTrials.gov Identifier: NCT02045667.