The current first line treatment for Non-Dystrophic Myotonia (NDM) - Mexiletine - is
ineffective in some patients, cannot be used in pregnancy, has side effects and is expensive
with limited access in the UK, prompting the clear need for an alternative. A recent open
label trial has demonstrated efficacy of Lamotrigine in treating NDMs, raising the
possibility of Lamotrigine superseding Mexiletine as the first line agent. As the nationally
commissioned highly specialised service for channelopathies, more patients are being seen
than in other centres, have a track record of trials in NDMs published in high impact factor
journals, and are best placed to conduct a trial of Mexiletine versus Lamotrigine.
Clinical morbidity: NDM impairs mobility, causes social embarrassment and impacts on quality
of life. NDMs are a group of rare genetic neuromuscular disorders caused by dysfunction of
ion channels that are critical for muscle membrane excitability. The hallmark of these
disorders is that symptoms occur in an episodic or paroxysmal fashion causing acute
disability. The NDMs include myotonia congenita (MC), sodium channel myotonia (SMC) and
paramyotonia congenita (PMC). They have a point prevalence in England of 1.12/100,000. MC is
due to mutations in the Chloride Channel gene (CLCN1), which codes for the muscle chloride
channel clc-1. SMC and PMC are caused by mutations in the Sodium Channel Gene (SCN4A), which
codes for the skeletal muscle voltage gated sodium channel Nav1.4. Both of these channels are
essential for regulating normal muscle membrane excitability, muscle contraction and
relaxation. NDMs are therefore unified by a common pathomechanism of altered muscle membrane
excitability. The membrane becomes hyper-excitable resulting in spontaneous depolarisation
and contraction after a motor nerve stimulus.
The primary clinical manifestation of NDM is myotonia - delayed relaxation of skeletal muscle
after contraction. Myotonia is experienced by patients as muscles "locking", "sticking" or
"cramping". Symptoms commonly affect the leg muscles and are precipitated by sudden or
initial movement leading to falls and injury. They are also exacerbated by prolonged sitting,
especially after preceding physical activity, and changes in environmental temperature. This
can be particularly problematic on public transport which may stop abruptly, causing falls or
inability to exit quickly enough, missing their destination. These difficulties can limit
independence, social activity, choice of employment and are often socially embarrassing. The
symptomatic relationship with activity often leads to sedentary behaviour which in turn is a
risk factor for additional co-morbidities e.g. heart disease or stroke. The condition is
frequently painful, with pain and impaired physical ability impacting significantly on
quality of life. Symptoms commonly worsen during pregnancy which can be compounded by the
need to discontinue current pharmacological therapies due to a lack of safety data during
pregnancy.
Limitations of current pharmacological therapies: There is currently no cure or
disease-modifying treatment for NDM. Sodium channel blockers are used for symptomatic relief.
Previously it was shown that Mexiletine is effective in reducing myotonia and improving
quality of life in an international randomised placebo controlled trial. Mexiletine has
become first line treatment for NDM but not all patients respond to mexiletine and a
significant proportion, up to a third develop side effects, the most common being
gastro-intestinal. Mexiletine has also been shown to be less beneficial for patients with MC
than those with Sodium Channel Myotonia (SCM) or PMC. Additionally, mexiletine cannot be
prescribed in pregnancy, when myotonia often worsens. Mexiletine is expensive and can only be
accessed by specialist centres. This can have practical difficulties and limit access to
treatment for some patients. There is a clear clinical need for an alternative therapeutic
option to Mexiletine for the treatment of NDM.
The study design has been chosen specifically to allow participants to be internal controls.
The degree of myotonia varies with changes in temperature and degree of activity. A highly
active participant cannot be directly compared to a sedentary participant, hence the use of
internal controls in an 'n of one' trial accounts for this variability.
The participants and investigators will be blinded with the use of over-encapsulated
mexiletine and lamotrigine dispensed via a predetermined randomisation scheduled. Blinding is
important to eliminate bias and in ensuring unbiased completion of subjective questionnaires.