Lamotrigine useful alternative to Mexiletine for Non-dystrophic Myotonias: Lancet

Non-dystrophic myotonias are a group of rare genetic neuromuscular disorders stemming from ion channel dysfunction. They predominantly occur in the first two decades of life leading to lifelong morbidity. They affect skeletal muscle relaxation and typically affect the legs. There is no cure for this condition except for symptomatic management which includes usage of sodium channel blockers. Research done in the past has shown that Mexiletine which is a sodium channel blocker can be used symptomatically to improve the quality of life. Recent research has also shown the effectiveness of lamotrigine for the symptomatic management of myotonias. Hence, researchers conducted a head-to-head trial to compare mexiletine and lamotrigine and the non-inferiority of lamotrigine.

A randomized, double-blind, crossover, non-inferiority, phase 3 trial was carried out at the National Hospital for Neurology and Neurosurgery (London, UK) by including individuals aged ≥18 years who had genetically confirmed symptomatic non-dystrophic myotonia. The participants were randomly assigned (1:1), employing a block randomization 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.

Masking of the investigators and participants was done during 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. A mixed-effects model was used to assess the non-inferiority 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.

Findings:

• About 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).
• Among them, 53 participants contributed data to the primary analysis.
• Post-treatment with the drugs, the mean IVR stiffness score with mexiletine was 2·54 versus 2·77 with lamotrigine (mean mexiletine–lamotrigine difference −0·23).
• Indigestion–reflux was the most common adverse event reported (eight participants, 208 participant-days receiving mexiletine; seven participants, 130 participant-days receiving lamotrigine).
• No serious adverse events were reported.

Thus, the trial concluded that lamotrigine was as effective as mexiletine. Despite the lack of definitive evidence for non-inferiority both the medications displayed similar efficacy. This suggests that lamotrigine can be used as an alternative to mexiletine. This trial offers critical insights for clinicians to offer therapeutic options to patients based on patient's acceptance.

Further reading: Vivekanandam V, Skorupinska I, Jayaseelan DL, et al. Mexiletine versus lamotrigine in non-dystrophic myotonias: a randomised, double-blind, head-to-head, crossover, non-inferiority, phase 3 trial. Lancet Neurol. 2024;23(10):1004-1012. doi:10.1016/S1474-4422(24)00320-X