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Non-dystrophic myotonias are skeletal muscle channelopathies caused by ion channel dysfunction. Symptom onset is frequently in the first decade of life, causing disability in a young cohort. Although there is no cure, symptomatic treatments exist. Previous trials provide evidence of the efficacy of mexiletine. More recently, lamotrigine has been shown to be effective. Both treatments have different profiles, including pharmacokinetics and adverse events. This trial aimed to investigate whether lamotrigine is non-inferior to mexiletine to directly inform clinical practice. We did a randomised, double-blind, crossover, non-inferiority, phase 3 trial at the National Hospital for Neurology and Neurosurgery (London, UK). Participants (aged ≥18 years) who had genetically confirmed symptomatic non-dystrophic myotonia were randomly assigned (1:1), by means of a block randomisation schedule created by a computer program, to receive either mexiletine for 8 weeks followed by lamotrigine for 8 weeks, or lamotrigine followed by mexiletine, with a 7-day washout period in between. Investigators and participants were masked to treatment allocation. The primary outcome measure was the mean interactive voice response (IVR) diary stiffness score (0–9 scale) over the participant's final 2 weeks of diary reporting in each treatment period. Non-inferiority was assessed using a mixed-effects model with a predefined margin of 0·5 and included all randomly assigned participants who contributed at least 7 days of IVR-diary data in either treatment period. The trial is registered at ClinicalTrials.gov, NCT05017155, and EudraCT, 2020-003375-17. Between Aug 1, 2021, and Dec 12, 2022, of 60 participants were screened (24 females and 36 males) and randomly assigned between Aug 1, 2021 and Dec 12, 2022, to either the mexiletine–lamotrigine sequence (n=30) or the lamotrigine–mexiletine sequence (n=30). 53 participants contributed data to the primary analysis. The mean IVR stiffness score after treatment with mexiletine was 2·54 (95% CI 1·98 to 3·10) versus 2·77 (2·21 to 3·32) with lamotrigine (mean mexiletine–lamotrigine difference −0·23 [95% CI −0·63 to 0·17]). The most common adverse event with both treatments was indigestion–reflux (eight participants, 208 participant-days receiving mexiletine; seven participants, 130 participant-days receiving lamotrigine). No serious adverse events were reported. We were unable to conclude that lamotrigine is non-inferior to mexiletine; however, improvements in all outcome measures from baseline were similar between lamotrigine and mexiletine. Lamotrigine is an important treatment consideration in non-dystrophic myotonias alongside mexiletine; we propose a treatment algorithm to guide clinical practice. Neuromuscular Study Group, Jon Moulton Charity Trust, UCLH BRC Fast Track Grant.

Measuring muscle velocity recovery cycles (MVRCs) is a method to obtain information on muscle cell excitability, independent of neuromuscular transmission. The goal was to validate MVRC as a pharmacodynamic (PD) biomarker for drugs targeting muscle excitability. As proof‐of‐concept, sensitivity of MVRC to detect effects of mexiletine, a voltage‐gated sodium channel (Nav) blocker, was assessed. In a randomized, double‐blind, two‐way crossover study, effects of a single pharmacologically active oral dose of 333 mg mexiletine was compared to placebo in 15 healthy male subjects. MVRC was performed predose, and 3‐ and 5‐h postdose using QTrac. Effects of mexiletine versus placebo were calculated using a mixed effects model with baseline as covariate. Mexiletine had significant effects on MVRC when compared to placebo. Early supernormality after five conditioning stimuli was decreased by mexiletine (estimated difference −2.78% [95% confidence interval: −4.16, −1.40]; p value = 0.0003). Moreover, mexiletine decreased the difference in late supernormality after five versus one conditioning stimuli (5XLSN; ED −1.46% [−2.26, −0.65]; p = 0.001). These results indicate that mexiletine decreases the percentage increase in velocity of the muscle fiber action potential after five conditioning stimuli, at long and short interstimulus intervals, which corresponds to a decrease in muscle membrane excitability. This is in line with the pharmacological activity of mexiletine, which leads to use‐dependent NaV1.4 blockade affecting muscle membrane potentials. This study shows that effects of mexiletine can be detected using MVRC in healthy subjects, thereby indicating that MVRC can be used as a tool to demonstrate PD effects of drugs targeting muscle excitability in early phase drug development.

Objective Patients with spinal and bulbar muscular atrophy (SBMA) often experience muscular weakness under cold exposure. Methods In our previously conducted observational study, we assessed nerve conduction and grip strength to examine the effect of cold exposure on motor function, based on which we conducted a randomized controlled trial to evaluate the efficacy and safety of mexiletine hydrochloride in SBMA (MEXPRESS). Results In the observational study, 51 consecutive patients with SBMA and 18 healthy controls (HCs) were enrolled. Of the patients with SBMA, 88.0% experienced cold paresis. Patients with SBMA exhibited greater prolongation of ulnar nerve distal latency under cold (SBMA, 5.6 ± 1.1 msec; HC, 4.3 ± 0.6 msec; p <0.001); the change in the distal latencies between room temperature and cold exposure conditions correlated with the change in grip power. In the MEXPRESS trial, 20 participants took mexiletine or lactose, three times a day for 4 weeks with a crossover design. There was no difference in distal latencies at room temperature and under cold exposure between mexiletine and placebo groups as the primary endpoint. However, tongue pressure and 10‐sec grip and release test under cold exposure were improved in the mexiletine group. There were no serious adverse events throughout the study period. Interpretation Cold paresis is common and associated with prolongation of distal latency in SBMA. The results of the phase II clinical trial revealed that mexiletine showed short‐term safety, but it did not restore cold exposure‐induced prolongation of distal latency.

Background 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. Methods/Design 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. Discussion 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. Trial registration ClinicalTrials.gov Identifier: NCT02045667

A 20-year-old woman was brought to the hospital in an ambulance after ingesting 18 g of caffeine and 3500 mg of mexiletine 80 min earlier. On arrival at the emergency department, her vital signs were as follows: blood pressure, 65/37 mmHg; heart rate, 140 beats/min; and Glasgow Coma Scale, E4V4M6. Laboratory analyses revealed hypokalemia and lactic acidosis. The patient was treated with mechanical ventilation after intratracheal intubation, intravenous noradrenaline infusion, gastric lavage, and activated charcoal administration. Shortly afterwards, she developed pulseless ventricular tachycardia, and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) was initiated. As the circulatory collapse continued, hemodialysis (HD) was performed with continuous intravenous infusion of noradrenaline. After the completion of HD, the noradrenaline dose was reduced. On hospital day 2, HD was performed on the second day of hospitalization. On hospital days 3 and 4, the patient was weaned off VA-ECMO and ventilator. The blood concentrations of caffeine and mexiletine at presentation were 387 μg/mL and 1.1 μg/mL respectively. During the first HD, blood concentrations of both drugs were markedly reduced. It has been reported that mexiletine may reduce the clearance of caffeine probably via inhibition of N-demethylation. In this case, the endogenous clearance of caffeine, calculated from blood concentrations, was considerably lower than estimated. If HD had not been performed, it may have taken longer to wean off the VA-ECMO because of reduced caffeine clearance in the presence of mexiletine. Notably, caffeine poisoning is more severe and prolonged when mexiletine is administered.

Despite impressive developments in the field of ventricular arrhythmias, there is still a relevant number of patients with ventricular arrhythmias who require antiarrhythmic drug therapy and may, e.g., in otherwise drug and/or ablation refractory situations, benefit from agents known for decades, such as mexiletine. Through its capability of blocking fast sodium channels in cardiomyocytes, it has played a minor to moderate antiarrhythmic role throughout the recent decades. Nevertheless, certain patients with structural heart disease suffering from drug-refractory, i.e., mainly amiodarone refractory ventricular arrhythmias, as well as those with selected forms of congenital long QT syndrome (LQTS) may nowadays still benefit from mexiletine. Here, we outline mexiletine’s cellular and clinical electrophysiological properties. In addition, the application of mexiletine may be accompanied by various potential side effects, e.g., nausea and tremor, and is limited by several drug-drug interactions. Thus, we shed light on the current therapeutic role of mexiletine for therapy of ventricular arrhythmias and discuss clinically relevant aspects of its indications based on current evidence.

Background and Objectives: Mexiletine is an oral sodium channel antagonist that has been reported to be effective in a variety of neuropathic pain syndromes. However, recent reports question the efficacy of oral mexiletine in neuropathic pain. The objectives of this study were to examine the effect of oral mexiletine on pain, neurosensation, allodynia, and quality of life. Methods: Twenty subjects suffering from neuropathic pain with prominent allodynia were enrolled in a randomized placebo-controlled crossover study. Patients were titrated to a maximum dose of 900 mg/d or dose-limiting side effects, whichever occurred first. At baseline and on days 0, 4, 7, and 10, the following tests were performed: (1) Quality of Life Questionnaires; (2) pain scores; (3) area of allodynia; (4) side effects; (5) neurosensory testing; and (6) peak and trough plasma mexiletine levels. Results: Peak plasma levels occurred on day 10 and were 0.54 μg/mL. There was no significant effect on any quality of life measurement. There was no significant effect on any neurosensory threshold or the area of allodynia. There was a significant effect of mexiletine on stroking-induced pain. There were no significant effects on any other pain score. Side effects were negligible. Conclusions: At doses of up to 900 mg/d, mexiletine has minimal effects on pain and allodynia of neuropathic pain. However, side effects may preclude higher doses. Reg Anesth Pain Med 2000;25:459-467.

Background The rare nature of dystrophic and non-dystrophic myotonia has limited the available evidence on the efficacy of mexiletine as a potential treatment. To address this gap, we conducted a systematic review and meta-analysis to evaluate the effectiveness and safety of mexiletine for both dystrophic and non-dystrophic myotonic patients. Methods The search was conducted on various electronic databases up to March 2023, for randomized clinical trials (RCTs) comparing mexiletine versus placebo in myotonic patients. A risk of bias assessment was carried out, and relevant data was extracted manually into an online sheet. RevMan software (version 5.4) was employed for analysis. Results A total of five studies, comprising 186 patients, were included in the meta-analysis. Our findings showed that mexiletine was significantly more effective than placebo in improving stiffness score (SMD =  − 1.19, 95% CI [− 1.53, − 0.85]), as well as in reducing hand grip myotonia (MD =  − 1.36 s, 95% CI [− 1.83, − 0.89]). Mexiletine also significantly improved SF-36 Physical and Mental Component Score in patients with non-dystrophic myotonia only. Regarding safety, mexiletine did not significantly alter ECG parameters but was associated with greater gastrointestinal symptoms (GIT) compared to placebo (RR 3.7, 95% CI [1.79, 7.64]). Other adverse events showed no significant differences. Conclusion The results support that mexiletine is effective and safe in myotonic patients; however, it is associated with a higher risk of GIT symptoms. Due to the scarcity of published RCTs and the prevalence of GIT symptoms, we recommend further well-designed RCTs testing various drug combinations to reduce GIT symptoms.

Background. Mexiletine, a class IB antiarrhythmic, is a structural analog of lidocaine. Our knowledge of mexiletine overdose is based on lidocaine overdose reports. Only a few cases of mexiletine overdose have been reported, including fatal overdoses. Mexiletine toxicity primarily affects the central nervous, cardiovascular, and gastrointestinal systems. Case. A 16-year-old female was brought to our hospital by ambulance after taking an unknown dose of mexiletine in a suicide attempt. Ventricular fibrillation developed while in the ambulance; cardiopulmonary resuscitation was started and spontaneous circulation returned within 1 min. The patient had been taking oral mexiletine for 1 month to treat primary erythromelalgia. Her vital signs were normal, but she was unconscious. Following gastric lavage she was transferred to the pediatric intensive care unit. Midazolam and levetiracetam were required due to uncontrolled seizures. During the first hour of hospitalization, severe dyskinesia characterized by abnormal involuntary large hyperkinetic movements in all 4 extremities was observed and successfully treated with 2 doses of intravenous biperiden. The patient was discharged on day 6 of hospitalization. Conclusions. Mexiletine overdose can be life-threatening. In addition to rapid and effective resuscitation, rapid identification and management of cardiovascular and central nervous system manifestations are key to preventing morbidity and mortality. The presented case had severe dyskinesia that was successfully treated with repeated doses of biperiden. Biperiden did not cause arrhythmia. Based on the presented case, we think biperiden should be considered for the treatment of movement disorders in cases of mexiletine overdose.

Background and Objectives: Mexiletine is a sodium channel blocker that has been used for the treatment of a variety of neuropathic pain syndromes. A recent double-blinded placebo-controlled study concluded that it was ineffective in the treatment of allodynia associated with neuropathic pain. However, this study failed to achieve adequate plasma levels of mexiletine. This was a study in healthy volunteers that sought to push the drug to dose-limiting side effects and then evaluate the effects on human experimental pain. Methods: Twelve healthy volunteers were studied using a randomized, double-blind, placebo-controlled crossover study. The subjects were titrated to a maximum dose of 1,350 mg/d or dose-limiting side effects, whichever occurred first. At baseline and day 10 and 17, neurosensory testing, train-of-three thermal pulses, and side-effect measurements were performed and on day 17, intradermal capsaicin was injected on the volar aspect of the forearm and the pain and secondary hyperalgesia to von Frey hair, stroking, and thermal stimuli were measured. Results: Peak plasma levels occurred on day 10 and were 0.36 ± 0.21 μg/mL. All subjects experienced dose-limiting side effects. The mean maximum tolerable daily dose achieved was 859 mg (range, 300 to 1,350 mg). The side effects reported by the subjects included nausea, lightheadedness, muscle twitching and weakness, blurred vision, headache, tremors, difficulty concentrating, dysphoria, sedation, pruritis, and rash. These side effects occurred at an average daily dose of 993 mg (range, 600 to 1,350 mg). Compared with placebo, mexiletine had no significant effects on any of the neurosensory thresholds and pain scores after intradermal capsaicin. There was a significant reduction in the area of secondary hyperalgesia to von Frey hair stimulation only. There was a significant correlation between plasma mexiletine level and flare response. Conclusions: Mexiletine has minimal effects on human experimental pain. It is severely limited by side effects and tolerable doses seem to be void of effects on normal neurosensation and facilitated pain induced by capsaicin and thermal heat pulses. Reg Anesth Pain Med 2000;25:468-474.