Drug treatment for myotonia

BACKGROUND: Abnormal delayed relaxation of skeletal muscles, known as myotonia, can cause disability in myotonic disorders. The main myotonic disorders are non-dystrophic myotonia and myotonic dystrophy. Non-dystrophic myotonia is a genetic muscle channelopathy predominantly causing myotonia. Myotonic dystrophic is a more systemic neuromuscular disorder causing myotonia as well as progressive myopathy and systemic manifestations, such as arrhythmias and cataracts. Myotonia manifests as stiffness, cramps, locking, pain, and fatigue, and can cause marked morbidity and disability. Sodium channel blockers, tricyclic antidepressive drugs, benzodiazepines, calcium antagonists, taurine, and prednisone may reduce myotonia. This is an update of a review first published in 2005 and updated in 2006. OBJECTIVES: To review evidence from randomised controlled trials (RCTs) on the efficacy and tolerability of drug treatment in people with clinical myotonia due to myotonic disorders. SEARCH METHODS: We searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and World Health Organization ICTRP on 29 March 2023. We handsearched the grey literature and contacted disease experts and antimyotonic drug manufacturers. SELECTION CRITERIA: We included RCTs involving participants with myotonia treated with any drug treatment versus no therapy, placebo, or any other active drug treatment. We included clinical trials where the reported primary outcome was a participant-reported measure of myotonia. We excluded non-RCTs and where myotonia may have been part of the condition (e.g. paramyotonia or Brody's disease). The primary myotonic conditions were myotonic dystrophy and non-dystrophic myotonia. Our primary outcome was participant-reported improvement in clinical myotonia. Our secondary outcomes were relaxation time, electromyographic relaxation time, adverse events, and quality of life. DATA COLLECTION AND ANALYSIS: Review authors independently extracted the data onto standardised extraction forms. Three review authors independently assessed risk of bias and we collected adverse events data from the included trials. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: This review includes 17 double-blind or single-blind RCTs involving a total of 392 participants, 219 with myotonic dystrophy type 1 and 173 with non-dystrophic myotonia. Seven RCTs were newly identified and included in this update. Four of these RCTs investigated the effect of mexiletine or lamotrigine versus placebo in people with non-dystrophic myotonia. The remaining RCTs explored mexiletine in myotonic dystrophy. Myotonic dystrophy Mexiletine No RCTs reported improvement in clinical myotonia according to validated scales. Mexiletine likely reduces hand grip relaxation time compared to placebo (mean difference (MD) 1.37 seconds better, 95% confidence interval (CI) 0.87 to 1.86; 2 RCTs, 56 participants; moderate-certainty evidence). Low-certainty evidence from four RCTs (91 participants) reported 55 adverse events with placebo and 84 adverse events with mexiletine. The most frequent adverse events with mexiletine were gastrointestinal symptoms, lethargy, and headache. There may be no difference in quality of life measures between mexiletine and placebo (36-item Short Form (SF-36) Physical Component Summary (PCS): MD -1.40, 95% CI -5.56 to 2.76; SF-36 Mental Component Summary (MCS): MD -1.10, 95% CI -6.17 to 3.97; 1 RCT, 38 participants; low-certainty evidence). Non-dystrophic myotonia Mexiletine Mexiletine likely reduces myotonia compared to placebo using the Interactive Voice Response Diary Stiffness score (across both treatment periods: MD -3.12, 95% CI -3.75 to -2.49; 2 cross-over RCTs, 89 participants; moderate-certainty evidence). There is likely no effect on relaxation times with no differences in eye closure or clinical hand grip between mexiletine and placebo (2 RCTs, 89 participants; moderate-certainty evidence). Mexiletine likely improves quantitative hand grip (MD -0.11, 95% CI -0.18 to -0.04; 2 RCTs, 89 participants; moderate-certainty evidence). Mexiletine likely improves electromyographic-based outcomes, including degree of needle electromyographic myotonia detected (MD -0.67, 95% CI -0.23 to -1.11; 2 RCTs, 89 participants; moderate-certainty evidence). Low-certainty evidence from four RCTs (136 participants) reported 29 adverse events with placebo and 94 adverse events with mexiletine. The most frequent adverse events were gastrointestinal symptoms, lethargy, and headache. There may be improvement in quality of life with mexiletine compared to placebo (SF-36 PCS: MD 6.45, 95% CI 4.32 to 8.58; SF-36 MCS: MD 6.78, 95% CI 1.89 to 11.67, entire treatment period; 2 cross-over RCTs, 89 participants; low-certainty evidence). Lamotrigine No RCTs reported improvement in clinical myotonia according to validated scales. There may be improvement in relaxation time with lamotrigine treatment (hand grip: MD 2.80 (log) seconds better, 95% CI 2.09 to 3.51; eyelid closure: MD 2.30 (log) seconds better, 95% CI 1.79 to 2.81; 1 RCT, 22 participants; low-certainty evidence). Moderate-certainty evidence from one RCT (26 participants) reported 23 adverse events with placebo and 44 adverse events with lamotrigine. The most common adverse events with lamotrigine were headache, fatigue, and rash. Quality of life is likely to improve with lamotrigine compared to placebo (SF-36: MD 5.00 points better, 95% CI 3.12 to 6.88 points better; 1 RCT, 22 participants; moderate-certainty evidence). Other medications Other medications, including phenytoin, imipramine, procainamide, clomipramine, nifedipine, tocainide, diazepam, quinine, diphenylhydantoin, and taurine, were either ineffective or had uncertain evidence with small numbers. Trials were small, with the participant numbers ranging from nine to 59, with high risk of bias. AUTHORS' CONCLUSIONS: More-recent trials are more robust, and well-conducted RCTs demonstrate moderate-certainty evidence for the efficacy of symptomatic treatments in non-dystrophic myotonias. Additionally, the data suggest that not all patients respond to therapy and research into aetiology and treatment options for non-responders is needed. Other agents that have not been tested in RCTs, such as acetazolamide, flecainide, ranolazine, and lacosamide, will need to be considered when planning future clinical trials. Moreover, the RCTs, in particular the small numbers of most trials, highlight the challenges in recruitment and design of robust trials in rare diseases, and research into trial design to improve recruitment in rare diseases will be important for future trials.