Commonly used drug could transform treatment of rare muscle disorder

The study, published in Lancet Neurology, detailed the “head-to-head” trial implemented by the researchers to test two drugs, mexiletine and lamotrigine, on people with the condition.

The trial, which was conducted at the UCL Queen Square Multidisciplinary Centre for Neuromuscular Diseases and the National Hospital for Neurology and Neurosurgery, UCLH, involved 60 adults with confirmed non-dystrophic myotonia.

Patients were randomly assigned to receive either mexiletine for eight weeks followed by lamotrigine for eight weeks, or the reverse order, with a seven-day break in between treatments. Neither the participants nor the researchers knew which treatment was being given at any time.

At the end of the trial, lamotrigine was found to reduce stiffness – the main symptom of non-dystrophic myotonia – by around the same amount as mexiletine.

Chief investigator, Dr Vino Vivekanandam (UCL Queen Square Institute of Neurology and consultant neurologist), said: “Approximately one in 17 people in the UK have a rare disease and the majority have no treatment. Many are neurological diseases and rarity makes clinical trials to develop treatments very difficult. Head-to-head trials comparing drugs are important in order to allow us to identify which treatments are ideal.

“The trial results are very exciting and important for patients with this muscle channelopathy.”

Non-dystrophic myotonias are life-changing muscle disorders caused by problems with ion channels in the muscles. Symptoms (such as muscle stiffness, pain, weakness, and fatigue) usually start in childhood and can cause significant disability – reducing quality of life and employability. There is currently no cure.

In 2012, the same UCL team led a multi-centred international trial that repurposed mexiletine – a sodium channel blocker – and showed it was effective in treating non-dystrophic myotonia and improving quality of life.

As a result, mexiletine became the first-line treatment for non-dystrophic myotonias world-wide.

However, not all patients respond to the treatment and one third developed significant side-effects, the most common being reflux or gastrointestinal side effects. Additionally, mexiletine can’t be prescribed during pregnancy, when myotonia often worsens.

Lamotrigine provides an alternative solution, as the trial showed that the drug was well tolerated by patients, and has additional advantages as it can be used in pregnancy and is cheaper. No serious side effects were reported.

Senior author Professor Michael Hanna (UCL Queen Square Institute of Neurology Director and consultant neurologist) said: “Drug repurposing is an important strategy in developing treatments for rare diseases. This is the first head-to-head trial in this rare muscle disease and the results will directly inform patient care and provide more ‘real-world’ options for patients.”

This research will impact clinical practice globally as mexiletine is often not accessible in developing countries or is expensive in developed countries. The results demonstrate that lamotrigine is a comparable treatment and therefore provides an excellent treatment option for affected patients.

Dr Vivekanandam said: “Based on this trial data, we have already developed a personalised treatment algorithm for clinical practice which is already in use in our clinical service, which takes into consideration several aspects of the trial and the mechanism of actions of lamotrigine and mexiletine as well as local economic considerations.”

The research was funded by the Neuromuscular Study Group, Jon Moulton Charity Trust, and a fast track grant from the National Institute for Health and Care Research biomedical research centre at UCLH. The team are grateful to the patients involved and their families for their support throughout the trial.