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Europace : European Pacing,... Nov 2022While mexiletine has been used for over 40 years for prevention of (recurrent) ventricular arrhythmias and for myotonia, patient access has recently been critically...
AIMS
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.
METHODS AND RESULTS
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).
CONCLUSIONS
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.
Topics: Humans; Infant, Newborn; Infant; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Mexiletine; Arrhythmias, Cardiac; Ventricular Fibrillation; Electrocardiography; Heart Ventricles
PubMed: 36036670
DOI: 10.1093/europace/euac087 -
Neurodegenerative Disease Management Dec 2020Mexiletine 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...
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. 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. 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%).
Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Female; Humans; Male; Mexiletine; Middle Aged; Muscle Cramp; Randomized Controlled Trials as Topic; Voltage-Gated Sodium Channel Blockers
PubMed: 32867586
DOI: 10.2217/nmt-2020-0026 -
Europace : European Pacing,... Oct 2022The 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...
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.
Topics: Adult; Amiodarone; Anti-Arrhythmia Agents; Catheter Ablation; Defibrillators, Implantable; Humans; Mexiletine; Prospective Studies; Retrospective Studies; Tachycardia, Ventricular; Treatment Outcome; Ventricular Fibrillation
PubMed: 35851797
DOI: 10.1093/europace/euac101 -
Neurological Sciences : Official... Feb 2024The 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,...
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.
PubMed: 38403671
DOI: 10.1007/s10072-024-07412-z -
Anesthesia and Analgesia Dec 2005We reviewed randomized controlled trials to determine the efficacy and safety of systemically administered local anesthetics compared with placebo or active drugs. Of 41... (Meta-Analysis)
Meta-Analysis Review
We reviewed randomized controlled trials to determine the efficacy and safety of systemically administered local anesthetics compared with placebo or active drugs. Of 41 retrieved studies, 27 trials of diverse quality were included in the systematic review. Ten lidocaine and nine mexiletine trials had data suitable for meta-analysis (n = 706 patients total). Lidocaine (most commonly 5 mg/kg IV over 30-60 min) and mexiletine (median dose, 600 mg daily) were superior to placebo (weighted mean difference on a 0-100 mm pain intensity visual analog scale = -10.60; 95% confidence interval: -14.52 to -6.68; P < 0.00001) and equal to morphine, gabapentin, amitriptyline, and amantadine (weighted mean difference = -0.60; 95% confidence interval: -6.96 to 5.75) for neuropathic pain. The therapeutic benefit was more consistent for peripheral pain (trauma, diabetes) and central pain. The most common adverse effects of lidocaine and mexiletine were drowsiness, fatigue, nausea, and dizziness. The adverse event rate for systemically administered local anesthetics was more than for placebo but equivalent to morphine, amitriptyline, or gabapentin (odds ratio: 1.23; 95% confidence interval: 0.22 to 6.90). Lidocaine and mexiletine produced no major adverse events in controlled clinical trials, were superior to placebo to relieve neuropathic pain, and were as effective as other analgesics used for this condition.
Topics: Anesthetics, Local; Humans; Lidocaine; Mexiletine; Pain; Peripheral Nervous System Diseases; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 16301253
DOI: 10.1213/01.ANE.0000186348.86792.38 -
Palliative Medicine Dec 2017Rectal tenesmus is a distressing symptom in patients with advanced cancer and challenging to treat. There is lack of consensus on the appropriate management of tenesmus... (Review)
Review
BACKGROUND
Rectal tenesmus is a distressing symptom in patients with advanced cancer and challenging to treat. There is lack of consensus on the appropriate management of tenesmus in this patient population.
AIM
To identify and examine the effectiveness of interventions to palliate rectal tenesmus caused by advanced cancer when surgery, radiotherapy or chemotherapy are no longer treatment options.
DESIGN
A systematic review of the literature following standard systematic review methodology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance.
DATA SOURCES
A comprehensive search of the electronic databases MEDLINE, EMBASE and the Cochrane Library was conducted from date of inception to April 2016. PubMed 'related articles' search, grey literature search and hand-searches of the bibliographies of relevant papers and textbooks were also performed. Non-cancer patients were excluded. Any studies involving surgery or radiotherapy to treat tenesmus were excluded. Studies involving interventions to treat pelvic pain syndromes without specific outcome measures on severity of tenesmus were excluded. The quality of the studies was assessed using a National Institute for Health and Clinical Excellence-recommended quality assessment tool.
RESULTS
From 861 studies, 9 met full criteria and were selected. All were case series investigating the use of pharmacological interventions (diltiazem, nifedipine, methadone, mexiletine hydrochloride, lidocaine and bupivacaine), anaesthetic interventions (lumbar sympathectomy, neurolytic superior hypogastric plexus block), and endoscopic laser interventions. The included studies showed substantial heterogeneity, and therefore, a meta-analysis was not feasible.
CONCLUSION
From this review, we identified a significant gap in research into the palliation of rectal tenesmus. A multimodal approach may be necessary due to the complexity of the pathophysiology of tenesmus. Future research should focus on randomised controlled trials of drug therapies whose potential effectiveness is suggested by case series.
Topics: Anesthesia; Anesthetics; Calcium Channel Blockers; Humans; Laser Therapy; Neoplasms; Palliative Care; Rectal Diseases
PubMed: 28590211
DOI: 10.1177/0269216317697897 -
Journal of Palliative Medicine Mar 2019Internationally, use of lidocaine infusions to treat cancer pain varies by center. Existing systematic reviews do not adequately inform use of lidocaine in cancer pain. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Internationally, use of lidocaine infusions to treat cancer pain varies by center. Existing systematic reviews do not adequately inform use of lidocaine in cancer pain.
OBJECTIVE
To assess the effects of systemic sodium channel blockers on cancer pain in adults, review the dose protocols for administration, and assess toxicity.
DESIGN
Databases CENTRAL, MEDLINE, Embase, LILACS, CareSearch, and OpenGrey were searched from inception to 2016. Conference abstracts and reference lists were handsearched, and the lead investigators of included trials and Australian manufacturers were contacted. Included studies were randomized controlled trials evaluating one or more of lidocaine via intravenous or subcutaneous route, or mexiletine, flecainide, or tocainide via oral route; delivered at a site distant to the pain locus. The methodological quality of studies was assessed using the "risk of bias" domain-based evaluation by Jadad. Protocol is available on PROSPERO:CRD42016047092.
RESULTS
One positive (n = 50) and three negative (n = 10 each) crossover trials evaluated lidocaine versus placebo, and one trial (n = 16) compared lidocaine with dexmedetomidine. Meta-analysis of pooled data in 60 patients demonstrated a significant benefit of lidocaine infusion of 4-5 mg/kg over 30-80 minutes compared with placebo for >50% reduction in cancer pain. Secondary outcomes did not show a significant difference.
DISCUSSION
Based on the current available evidence, lidocaine infusion could be considered in refractory cancer pain where agents with level 1 evidence are ineffective. Further research is necessary to understand the protocol and population in which lidocaine may improve cancer pain and capitalize on the promising opportunities identified.
Topics: Adult; Anesthetics, Local; Cancer Pain; Humans; Lidocaine; Sodium Channel Blockers
PubMed: 30614748
DOI: 10.1089/jpm.2018.0257 -
The Cochrane Database of Systematic... Oct 2005Lidocaine, mexiletine, tocainide, and flecainide are local anesthetics which give an analgesic effect when administered orally or parenterally. Early reports described... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Lidocaine, mexiletine, tocainide, and flecainide are local anesthetics which give an analgesic effect when administered orally or parenterally. Early reports described the use of intravenous lidocaine or procaine to relieve cancer and postoperative pain (Keats 1951; Gilbert 1951; De Clive-Lowe 1958; Bartlett 1961). Interest reappeared decades later when patient series and clinical trials reported that parenteral lidocaine and its oral analogs tocainide, mexiletine, and flecainide relieved neuropathic pain in some patients (Boas 1982; Lindblom 1984; Petersen 1986; Dunlop 1988; Bach 1990; Awerbuch 1990). With the recent publication of clinical trials with high quality standards, we have reviewed the use of systemic lidocaine and its oral analogs in neuropathic pain to update our knowledge, to measure their benefit and harm, and to better define their role in therapy.
OBJECTIVES
To evaluate pain relief and adverse effect rates between systemic local anesthetic-type drugs and other control interventions.
SEARCH STRATEGY
We searched MEDLINE (1966 through 15 May 2004), EMBASE (January 1980 to December 2002), Cancer Lit (through 15 December 2002), Cochrane Central Register of Controlled Trials (2nd Quarter, 2004), System for Information on Grey Literature in Europe (SIGLE), and LILACS, from January 1966 through March 2001. We also hand searched conference proceedings, textbooks, original articles and reviews.
SELECTION CRITERIA
We included trials with random allocation, that were double blinded, with a parallel or crossover design. The control intervention was a placebo or an analgesic drug for neuropathic pain from any cause.
DATA COLLECTION AND ANALYSIS
We collected efficacy and safety data from all published and unpublished trials. We calculated combined effect sizes using continuous and binary data for pain relief and adverse effects as primary and secondary outcome measurements, respectively.
MAIN RESULTS
Thirty-two controlled clinical trials met the selection criteria; two were duplicate articles. The treatment drugs were intravenous lidocaine (16 trials), mexiletine (12 trials), lidocaine plus mexiletine sequentially (one trial), and tocainide (one trial). Twenty-one trials were crossover studies, and nine were parallel. Lidocaine and mexiletine were superior to placebo [weighted mean difference (WMD) = -11; 95% CI: -15 to -7; P <0.00001], and limited data showed no difference in efficacy (WMD = -0.6; 95% CI: -7 to 6), or adverse effects versus carbamazepine, amantadine, gabapentin or morphine. In these trials, systemic local anesthetics were safe, with no deaths or life-threatening toxicities. Sensitivity analysis identified data distribution in three trials as a probable source of heterogeneity. There was no publication bias.
AUTHORS' CONCLUSIONS
Lidocaine and oral analogs were safe drugs in controlled clinical trials for neuropathic pain, were better than placebo, and were as effective as other analgesics. Future trials should enroll specific diseases and test novel lidocaine analogs with better toxicity profiles. More emphasis is necessary on outcomes measuring patient satisfaction to assess if statistically significant pain relief is clinically meaningful.
Topics: Administration, Oral; Anesthetics, Intravenous; Anesthetics, Local; Flecainide; Humans; Lidocaine; Mexiletine; Nervous System Diseases; Pain; Randomized Controlled Trials as Topic; Tocainide
PubMed: 16235318
DOI: 10.1002/14651858.CD003345.pub2 -
The Cochrane Database of Systematic... Aug 2015Coronary artery disease is a major public health problem affecting both developed and developing countries. Acute coronary syndromes include unstable angina and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Coronary artery disease is a major public health problem affecting both developed and developing countries. Acute coronary syndromes include unstable angina and myocardial infarction with or without ST-segment elevation (electrocardiogram sector is higher than baseline). Ventricular arrhythmia after myocardial infarction is associated with high risk of mortality. The evidence is out of date, and considerable uncertainty remains about the effects of prophylactic use of lidocaine on all-cause mortality, in particular, in patients with suspected myocardial infarction.
OBJECTIVES
To determine the clinical effectiveness and safety of prophylactic lidocaine in preventing death among people with myocardial infarction.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 3), MEDLINE Ovid (1946 to 13 April 2015), EMBASE (1947 to 13 April 2015) and Latin American Caribbean Health Sciences Literature (LILACS) (1986 to 13 April 2015). We also searched Web of Science (1970 to 13 April 2013) and handsearched the reference lists of included papers. We applied no language restriction in the search.
SELECTION CRITERIA
We included randomised controlled trials assessing the effects of prophylactic lidocaine for myocardial infarction. We considered all-cause mortality, cardiac mortality and overall survival at 30 days after myocardial infarction as primary outcomes.
DATA COLLECTION AND ANALYSIS
We performed study selection, risk of bias assessment and data extraction in duplicate. We estimated risk ratios (RRs) for dichotomous outcomes and measured statistical heterogeneity using I(2). We used a random-effects model and conducted trial sequential analysis.
MAIN RESULTS
We identified 37 randomised controlled trials involving 11,948 participants. These trials compared lidocaine versus placebo or no intervention, disopyramide, mexiletine, tocainide, propafenone, amiodarone, dimethylammonium chloride, aprindine and pirmenol. Overall, trials were underpowered and had high risk of bias. Ninety-seven per cent of trials (36/37) were conducted without an a priori sample size estimation. Ten trials were sponsored by the pharmaceutical industry. Trials were conducted in 17 countries, and intravenous intervention was the most frequent route of administration.In trials involving participants with proven or non-proven acute myocardial infarction, lidocaine versus placebo or no intervention showed no significant differences regarding all-cause mortality (213/5879 (3.62%) vs 199/5848 (3.40%); RR 1.02, 95% CI 0.82 to 1.27; participants = 11727; studies = 18; I(2) = 15%); low-quality evidence), cardiac mortality (69/4184 (1.65%) vs 62/4093 (1.51%); RR 1.03, 95% CI 0.70 to 1.50; participants = 8277; studies = 12; I(2) = 12%; low-quality evidence) and prophylaxis of ventricular fibrillation (76/5128 (1.48%) vs 103/4987 (2.01%); RR 0.78, 95% CI 0.55 to 1.12; participants = 10115; studies = 16; I(2) = 18%; low-quality evidence). In terms of sinus bradycardia, lidocaine effect is imprecise compared with effects of placebo or no intervention (55/1346 (4.08%) vs 49/1203 (4.07%); RR 1.09, 95% CI 0.66 to 1.80; participants = 2549; studies = 8; I(2) = 21%; very low-quality evidence). In trials involving only participants with proven acute myocardial infarction, lidocaine versus placebo or no intervention showed no significant differences in all-cause mortality (148/2747 (5.39%) vs 135/2506 (5.39%); RR 1.01, 95% CI 0.79 to 1.30; participants = 5253; studies = 16; I(2) = 9%; low-quality evidence). No significant differences were noted between lidocaine and any other antiarrhythmic drug in terms of all-cause mortality and ventricular fibrillation. Data on overall survival 30 days after myocardial infarction were not reported. Lidocaine compared with placebo or no intervention increased risk of asystole (35/3393 (1.03%) vs 14/3443 (0.41%); RR 2.32, 95% CI 1.26 to 4.26; participants = 6826; studies = 4; I(2) = 0%; very low-quality evidence) and dizziness/drowsiness (74/1259 (5.88%) vs 16/1274 (1.26%); RR 3.85, 95% CI 2.29 to 6.47; participants = 2533; studies = 6; I(2) = 0%; low-quality evidence). Overall, safety data were poorly reported and adverse events may have been underestimated. Trial sequential analyses suggest that additional trials may not be needed for reliable conclusions to be drawn regarding these outcomes.
AUTHORS' CONCLUSIONS
This Cochrane review found evidence of low quality to suggest that prophylactic lidocaine has very little or no effect on mortality or ventricular fibrillation in people with acute myocardial infarction. The safety profile is unclear. This conclusion is based on randomised controlled trials with high risk of bias. However (disregarding the risk of bias), trial sequential analysis suggests that additional trials may not be needed to disprove an intervention effect of 20% relative risk reduction. Smaller risk reductions might require additional higher trials.
Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Bradycardia; Humans; Lidocaine; Myocardial Infarction; Randomized Controlled Trials as Topic; Ventricular Fibrillation
PubMed: 26295202
DOI: 10.1002/14651858.CD008553.pub2 -
Journal of Neuromuscular Diseases 2021Skeletal muscle ion channelopathies include non-dystrophic myotonias (NDM), periodic paralyses (PP), congenital myasthenic syndrome, and recently identified congenital...
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.
Topics: Channelopathies; Humans; Hypokalemic Periodic Paralysis; Lamotrigine; Mexiletine; Muscle, Skeletal; Mutation; Myasthenic Syndromes, Congenital; Myotonic Disorders; Precision Medicine; Randomized Controlled Trials as Topic; Sodium Channel Blockers
PubMed: 33325393
DOI: 10.3233/JND-200582