Fast track — ArticlesEfficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial
Introduction
A recent genome-wide association study1 found a significant association of common genetic variants in three genomic regions with the risk for restless legs syndrome; one of these genomic regions was also found to be associated with periodic limb movements in patients with restless legs syndrome2 who have a substantially decreased quality of life compared with the general population.3, 4 These new findings suggest that restless legs syndrome might be regarded as a type of inborn error of the excitability of various structures, and accordingly needs to be treated as a general neurological disorder, rather than just a sleep disorder. Dopaminergic drugs but not hypnotics are currently the first-line treatment for this condition.5, 6
Previous treatment concepts have focused on the nocturnal aspects of restless legs syndrome, with single dopaminergic doses at bedtime to alleviate problems during the night. One possible treatment strategy, which also includes coverage of daytime symptoms, is via stable plasma concentrations of dopamimetics—ie, by administration of divided doses of an oral dopaminergic agent, or a transdermal patch with rotigotine, a non-ergot agonist of D3, D2, and D1 dopamine receptors. Rotigotine has already proven effective in the treatment of early and advanced Parkinson's disease7, 8 and has been approved for treatment of the signs and symptoms of early Parkinson's disease in the USA and for treatment of all stages of Parkinson's disease in Europe. A 1-week proof-of-concept trial9 and a 6-week dose-finding trial in patients with restless legs syndrome10 showed efficacy of the treatment and established the likely therapeutic window as rotigotine 1–3 mg every 24 h.10 Stable drug concentrations over 24 h might, in addition, be a favourable strategy to avoid augmentation, the main complication of long-term dopaminergic treatment.11, 12, 13 The primary objective of this trial was to investigate the efficacy of rotigotine in the treatment of idiopathic restless legs syndrome. We aimed to test whether transdermal administration of rotigotine for 24 h per day at the lowest levels of effctiveness can provide benefit to patients with restless legs syndrome during both day and night, and to investigate the safety of this transdermal system.
Section snippets
Patients
This double-blind, randomised, placebo-controlled, four-arm trial was done at 49 centres in eight European countries (Austria, Finland, Germany, Italy, Netherlands, Spain, Sweden, UK). Enrolment started in May, 2005; the trial was completed in August, 2006.
Patients aged 18–75 years with a diagnosis of idiopathic restless legs syndrome based on the four cardinal clinical features according to the International Restless Legs Syndrome Study Group (IRLSSG)14 who were either de-novo patients
Results
458 patients were randomly assigned to treatment (figure 2). The trial was completed by 313 (68%) patients; more patients in the placebo group than patients in each of the three rotigotine groups discontinued prematurely. In the rotigotine groups, withdrawal was highest in the 3 mg group. Lack of efficacy was the main reason for withdrawal in the placebo group, whereas adverse events were more frequent in the rotigotine groups (figure 2 and webtable 1). 447 (98%) patients were included in the
Discussion
The results of this 6-month trial indicate that transdermal delivery of low doses of rotigotine for 24 h per day are more effective than placebo in relieving the symptoms of restless legs syndrome in patients who are moderately to severely affected. This trial, together with a pilot study9 and dose-finding trial,10 suggest that, despite differences in treatment duration and other design features, there exists a clear therapeutic window in terms of dose of rotigotine to treat restless legs
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