Systematic evaluation of augmentation during treatment with ropinirole in restless legs syndrome (Willis-Ekbom Disease): Results from a prospective, multicenter study over 66 weeks
Sleep Research Institute, Madrid, Spain.Movement Disorders (Impact Factor: 5.68). 02/2012; 27(2):277-83. DOI: 10.1002/mds.24889
The purpose of this study was to evaluate the incidence of augmentation over 66 weeks of treatment with ropinirole in patients with primary restless legs syndrome (RLS). Augmentation is the main complication of long-term dopaminergic treatment of RLS. Despite widespread use of ropinirole in RLS, no studies have prospectively and systematically assessed the incidence of augmentation with its use. The study consisted of 26 weeks of double-blind flexible-dose treatment with ropinirole or placebo, followed by 40 weeks of open-label ropinirole treatment.. Patients had no previous history of augmentation. Potential cases of augmentation were identified with the Structured Interview for the Diagnosis of Augmentation and the Augmentation Severity Rating Scale and through reporting of adverse events. Cases were blindly evaluated by an expert panel using the NIH diagnostic criteria for augmentation. Four hundred and four patients participated in the double-blind study and 269 in the open-label phase, with a discontinuation rate of 42%. IRLS baseline scores improved at the end of the double-blind (DB) phase (mean ± SE) by -15.9 ± 0.76 for ropinirole, by -13.4 ± 0.77 for placebo (P < .05) and by -20.4 ± 0.55 during the open-label phase. The incidence rates of augmentation were 3.5% for ropinirole and <1% for placebo during the DB phase and 3% during the open-label phase. Clinically significant augmentation occurred in 3%, <1%, and 2%, respectively. Discontinuation of treatment occurred in 50% of all patients (7 of 14) with augmentation. The incidence of augmentation was 3.1% higher with ropinirole than with placebo. New patients with first episodes of augmentation continued to cumulate at a stable rate over the duration of this study.
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ABSTRACT: Safety and efficacy of non-ergot dopamine agonists for the treatment of idiopathic restless legs syndrome have been shown in short-term trials. We did a prospective open-label extension of a 6-week, double-blind randomised trial to assess the safety, tolerability, and efficacy of rotigotine transdermal patch for up to 5 years in patients with restless legs syndrome. Patients (aged 18-75 years) with moderate-to-severe idiopathic restless legs syndrome were treated with once-daily rotigotine transdermal patch in 33 centres in Austria, Germany, and Spain between July 31, 2003, and April 15, 2009. The dose was titrated in weekly increments (up to 4 weeks) from 0·5 mg/24 h to a maximum of 4 mg/24 h, and was followed by up to 5 years of maintenance at the optimum dose. Primary safety outcomes included occurrence of adverse events and dropouts. Efficacy assessments were secondary and included the International Restless Legs Syndrome study group severity rating scale (IRLS). Augmentation of symptoms was assessed by means of standard diagnostic criteria and was confirmed by an international expert panel. All patients who received at least one dose of study drug were included in assessments. This study is registered with ClinicalTrials.gov, number NCT00498186. 295 patients entered the open-label study, of whom 126 (43%) completed 5 years of follow-up. 169 (57%) patients discontinued treatment, 89 (30%) because of adverse events and 31 (11%) because of lack of efficacy. 70 patients (24%) discontinued during year 1 of maintenance. The most common adverse events were application site reactions, which occurred in 37% (106/290) of patients in year 1, 17% (38/220) of patients in year 2, 14% (27/191) of patients in year 3, and in less than 6% of patients during year 4 (8/159) and year 5 (8/147). 56 patients (19%) discontinued because of application site reactions. Mean rotigotine dose was 2·43 mg/24 h (SD 1·21) after initial titration and 3·09 mg/24 h (1·07) at the end of maintenance. Of 89 patients who discontinued because of adverse events, 28 (31%) were on 4 mg/24 h rotigotine. Mean IRLS score of patients entering the open-label study was 27·8 (SD 5·9) at baseline of the double-blind trial. In patients who completed the maintenance period, mean IRLS score was reduced from a baseline score of 27·7 (SD 6·0) by a mean of 18·7 points (SD 9·5) to a score of 9·0 (SD 9·2) at the end of maintenance. 39% (48/123) of patients who completed the trial were classified as symptom free according to the IRLS. Clinically significant augmentation was recorded in 39 patients (13%), of whom 15 (5%) were receiving a dose of rotigotine within the range approved by the European Medicines Agency (EMA; 1-3 mg/24 h) and 24 (8%) were receiving 4 mg/24 h rotigotine. Rotigotine transdermal patch is generally well tolerated after 1 year and provides sustained efficacy for patients with moderate-to-severe restless legs syndrome at a stable dose for up to 5 years. Thus, rotigotine transdermal patch is an appropriate long-term treatment option for moderate-to-severe restless legs syndrome, a disorder that often requires lifelong treatment. UCB BioSciences, on behalf of Schwarz Pharma, Ireland.
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ABSTRACT: Introduction: Restless legs syndrome (RLS) is a common neurological disorder that might impair nocturnal rest causing decreased alertness, depressed mood, reduced job performance, and poor quality of life. In patients affected by severe RLS, a pharmacological treatment is mandatory. Areas covered: The present review is based on a search using PubMed from 1994 to 2012. It is focused on the Absorption, Distribution, Metabolism, Elimination and Toxicology (ADMET) characteristics of the most used medications for RLS. In particular, the ADMET characteristics of dopaminergic agents, anticonvulsants able to improve neuropathic pain, and iron were discussed. Expert opinion: Clinical trials have showed that non-ergolic dopamine agonists are efficacious and safe for patients affected by moderate to severe idiopathic RLS. However, no head-to-head study has compared the long-term effects of the three dopamine agonists approved by the FDA for RLS (ropinirole, pramipexole, and rotigotine). Moreover, further studies should investigate the extended-release formulation of ropinirole and pramipexole in RLS patients affected by all day long distressing symptoms. A standardized treatment for symptomatic forms of RLS is lacking. Randomized, placebo-controlled trials should be performed at least in RLS patients with peripheral neuropathic and chronic kidney disease. Concerning RLS due to iron deficiency, a head-to-head study comparing efficacy, safety and compliance of oral iron versus intravenous one seems to be needed.
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