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.
CONCLUSIONS: 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: To evaluate the clinical outcomes of oral mexiletine (oMXT) to treat ventricular tachyarrhythmias (VTAs) in the era of implantable cardioverter-defibrillator (ICD) technology.
METHODS: A systematic search was conducted using PubMed, Embase and Cochrane databases following the PRISMA guidelines to collect literature data reporting oMXT efficacy and safety outcomes in treating VTAs in ICD recipients.
RESULTS: Final analysis included four studies accounting for a total of 91 patients with recurrent VTAs treated with oMXT. Amiodarone therapy was initially attempted in most patients (91.2%), while catheter ablation was performed in one-third of patients. VTA recurrences were observed in 55/91 patients (60.4%) during oMXT treatment compared to 91/91 (100%) before treatment (P<0.001). Appropriate therapies occurred in 55/88 ICD patients (62.5%) during oMXT treatment compared to 80/88 (90.9%) before treatment (P<0.001). After oMXT introduction, there was a significant reduction of the individual burden of VTA episodes and appropriate ICD therapies per patient, showing Hedges\'g values of -1.103 (P=0.002) and -1.474 (P=0.008), respectively. Safety analysis showed a sample-weighted overall side-effect rate of 30%, while 21% of patients required drug reduction or discontinuation. Aggregated meta-regression analysis of the included studies and remote literature revealed a linear correlation between oMXT dosage and the overall side effects rate (r2 = 0.48; P=0.014).
CONCLUSIONS: Oral mexiletine provides an adjunctive treatment to manage VTAs and reduces appropriate therapies in ICD patients with moderate efficacy and acceptable safety profiles. These observations await confirmation through randomised clinical trials.

While mexiletine has been used for over 40 years for prevention of (recurrent) ventricular arrhythmias and for myotonia, patient access has recently been critically endangered. Here we aim to demonstrate the effectiveness and safety of mexiletine in the treatment of patients with (recurrent) ventricular arrhythmias, emphasizing the absolute necessity of its accessibility.
Studies were included in this systematic review (PROSPERO, CRD42020213434) if the efficacy or safety of mexiletine in any dose was evaluated in patients at risk for (recurrent) ventricular arrhythmias with or without comparison with alternative treatments (e.g. placebo). A systematic search was performed in Ovid MEDLINE, Embase, and in the clinical trial registry databases ClinicalTrials.gov and ICTRP. Risk of bias were assessed and tailored to the different study designs. Large heterogeneity in study designs and outcome measures prompted a narrative synthesis approach. In total, 221 studies were included reporting on 8970 patients treated with mexiletine. Age ranged from 0 to 88 years. A decrease in ventricular arrhythmias of >50% was observed in 72% of the studies for pre-mature ventricular complexes, 64% for ventricular tachycardia, and 33% for ventricular fibrillation. Electrocardiographic effects of mexiletine were small; only in a subset of patients with primary arrhythmia syndromes, a relative (desired) QTc decrease was reproducibly observed. As for adverse events, gastrointestinal complaints were most frequently observed (33% of the patients).
In this systematic review, we present all the currently available knowledge of mexiletine in patients at risk for (recurrent) ventricular arrhythmias and show that mexiletine is both effective and safe.

The aim of the study was to systematically review evidence on the effectiveness and safety of oral mexiletine administered in monotherapy or in combination with other antiarrhythmic drugs for recurrent ventricular arrhythmia (ventricular tachycardia/ventricular fibrillation, VT/VF) in adult patients with structural heart disease (SHD) and implantable cardioverter defibrillators (ICDs). We systematically searched MEDLINE, Embase, and CENTRAL databases from inception to 27 August 2021 for prospective and retrospective studies investigating mexiletine in the target population. The main outcome was the reduction of ICD therapy. The main safety outcome was the presence of any serious adverse events (SAEs) leading to mexiletine discontinuation. Study quality was assessed using the Cochrane risk of bias tool or the Newcastle-Ottawa scale. Four studies comprising 86 mexiletine recipients were included in the review. We also obtained individual data of 50 patients from two studies. Ischaemic cardiomyopathy (ICM) was present in 86% of patients. The quality of included studies was moderate/low. A narrative review was undertaken as studies varied widely in terms of study population and treatment. Across studies, mexiletine treatment (with or without amiodarone) seemed to consistently reduce the number of ICD therapies especially in a population where catheter ablation (CA) was unsuccessful or contraindicated. In ICM patients deemed eligible for CA, mexiletine seemed to be inferior to CA. Mexiletine was discontinued in 14% of cases, mainly for gastrointestinal or neurological SAE. Mexiletine seems to be an option for the long-term treatment of recurrent VT/VF in adult patients with SHD, especially ICM, and ICD in whom CA was unsuccessful or not suitable.

Background: Early diagnosis of long QT type 3 (LQT3) syndrome during the neonatal period is of paramount clinical importance. LQT3 syndrome results in increased mortality and a mutation-specific response to treatment compared to other more common types of LQT syndrome. Mexiletine, a sodium channel blocker, demonstrates a mutation-specific QTc shortening effect in LQT3 syndrome patients. Case Presentation: A neonate manifested marked QTc prolongation after birth. An electrocardiogram (ECG) recording was performed due to positive family history of genetically confirmed LQT3 syndrome (SCN5A gene missense mutation Tyr1795Cys), and an association with sudden cardiac death was found in family members. The mexiletine QTc normalizing effect (QTc shortening from 537 to 443 ms), practical issues related to oral mexiletine treatment of our young patient, along with a literature review regarding identification and mexiletine treatment in infants with LQT3 syndrome are presented. Conclusions: Mexiletine could be considered in the treatment of high-risk LQT3 patients already in the neonatal period in addition to b-blocker therapy. Availability of standardized commercial mexiletine pediatric formulas, serum mexiletine level analyses, and future prospective studies are needed to evaluate the potential beneficial effect of early mexiletine treatment on the incidence of future acute cardiac events in these high-risk LQT syndrome patients.

β-Blockers are first-line therapy in patients with long QT syndrome (LQTS). However, β-blockers had genotype dependent efficacy (LQT1>LQT2>LQT3). Sodium channel blockers have been recommended as add-on therapy for LQT3 patients. However, the pooled effect of sodium channel blockers in all LQTS patients remains unknown.
We conducted a systematic electronic search of PubMed, Embase, and the Cochrane Library. Fixed effects model was used to assess the effect of sodium channel blockers on QTc, cardiac events (CEs), and the proportion of QTc ≥ 500 ms and QTc ≤ 460 ms in LQTS patients.
Pooled analysis of 14 studies with 213 LQTS (9 LQT1 + 63 LQT2 + 135 LQT3 + 6 others) patients showed that sodium channel blockers significantly shortened QTc by nearly 50 ms (mean difference [MD], -49.43; 95% confidence interval [CI], -57.80 to -41.05, p < .001), reduced the incidence of CEs (risk ratio [RR], 0.23; 95% CI, 0.11-0.47; p < .001) and the proportion of QTc ≥ 500 ms (RR, 0.33; 95% CI, 0.24-0.47; p < .001), and increased the proportion of QTc ≤ 460 ms (RR, 10.33; 95% CI, 4.62-23.09; p < .001). Sodium channel blockers significantly shortened QTc both in LQT3 and LQT2 patients, while the QTc shortening effect in LQT3 was superior to that in LQT2 (57.39 vs. 36.61 ms). Mexiletine, flecainide, and ranolazine all significantly shortened QTc, and the QTc shortening effect by mexiletine was the best (60.70 vs. 49.08 vs. 50.10 ms).
Sodium channel blockers can be useful both in LQT3 and LQT2 patients. Mexiletine, flecainide and ranolazine significantly shortened QTc in LQTS patients, and the QTc shortening effect by mexiletine was the best.

BACKGROUND: Skeletal muscle ion channelopathies include non-dystrophic myotonias (NDM), periodic paralyses (PP), congenital myasthenic syndrome, and recently identified congenital myopathies. The treatment of these diseases is mainly symptomatic, aimed at reducing muscle excitability in NDM or modifying triggers of attacks in PP.
OBJECTIVE: This systematic review collected the evidences regarding effects of pharmacological treatment on muscle ion channelopathies, focusing on the possible link between treatments and genetic background.
METHODS: We searched databases for randomized clinical trials (RCT) and other human studies reporting pharmacological treatments. Preclinical studies were considered to gain further information regarding mutation-dependent drug effects. All steps were performed by two independent investigators, while two others critically reviewed the entire process.
RESULTS: For NMD, RCT showed therapeutic benefits of mexiletine and lamotrigine, while other human studies suggest some efficacy of various sodium channel blockers and of the carbonic anhydrase inhibitor (CAI) acetazolamide. Preclinical studies suggest that mutations may alter sensitivity of the channel to sodium channel blockers in vitro, which has been translated to humans in some cases. For hyperkalemic and hypokalemic PP, RCT showed efficacy of the CAI dichlorphenamide in preventing paralysis. However, hypokalemic PP patients carrying sodium channel mutations may have fewer benefits from CAI compared to those carrying calcium channel mutations. Few data are available for treatment of congenital myopathies.
CONCLUSIONS: These studies provided limited information about the response to treatments of individual mutations or groups of mutations. A major effort is needed to perform human studies for designing a mutation-driven precision medicine in muscle ion channelopathies.

Background: Mexiletine is a potential drug in amyotrophic lateral sclerosis (ALS) that has been tested in clinical trials. The objective of this study was to determine the efficacy and safety of mexiletine in ALS via systematic review of existing evidences. Materials & methods: Relevant records were searched using major healthcare electronic databases. Data on functional disability, impairment, survival, muscle cramp frequency and severity, and adverse events were obtained. Results & conclusion: Three relevant randomized controlled trials with 141 patients were included in this review. Mexiletine has no effect on the functional disability, impairment and survival in ALS. However, significant improvement in reducing muscle cramp severity and frequency was shown. The most common adverse effect associated with mexiletine intake among ALS patients are nausea (n = 11, 7.8%) and tremors (n = 5, 3.6%).

BACKGROUND: The role of systemic use of local anesthetics in the treatment of neuropathic pain (NP) is still unclear.
OBJECTIVE: To assess the efficacy and safety of systemic local anesthetics for NP.
METHODS: To summarize and to discuss the rehabilitation perspective on the published Cochrane Systematic Review \"Systemic administration of local anesthetic agents to relieve neuropathic pain\" by Challapalli V et al.RESULTS:The review included 30 RCTs including patients with NP treated with iv lidocaine, oral mexiletine, lidocaine and mexiletine, or oral tocainide. Low-to-moderate quality of the evidence suggest that intravenous lidocaine or oral mexiletine may slightly reduce NP vs placebo, but the efficacy of these drugs is comparable to anticonvulsants or morphine.
CONCLUSIONS: Systemic administration of local anesthetics is not supported by scientific evidence for pain relief as well as for functional improvement.

UNASSIGNED: Myotonia is found in a number of muscle diseases, including myotonic dystrophy and non-dystrophic myotonia. The resulting symptoms of myotonia can interfere with daily activities such as walking or climbing the stairs. Due to the rarity of both these conditions, pharmacological treatment of myotonia is largely anecdotal and is led by specialist clinicians who tend to favour the use of mexiletine, a class 1b antiarrhythmic sodium antagonist.
UNASSIGNED: To identify and review randomised controlled trials in order to assess the efficacy and safety of use of mexiletine in myotonic dystrophy and non-dystrophic myotonia for two different patient cases.
UNASSIGNED: The literature search was conducted using MEDLINE, EMBASE and The Cochrane Library (from January 1990 to December 2014). Specialist neurology centres were also contacted.
UNASSIGNED: All randomised controlled trials between January 1990 and December 2014 which compared the use of mexiletine for the treatment of myotonia in patients who suffer from myotonic dystrophy and non-dystrophic were included in this review. Primary outcome: reduction of clinical myotonia.
UNASSIGNED: Two randomised controlled trials were included for review. Both studies are underpowered; however, there is evidence to support the use of mexiletine for the improvement of clinical myotonia.
UNASSIGNED: Larger randomised controlled trials are required, which look at the functional effect of myotonia as a primary outcome (ie, stair test) and the long-term use of mexiletine. This is needed to establish the ongoing efficacy and safety of the long-term use of mexiletine in the management of myotonia.