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Abstract & Commentary
Source: Trenkwalder C, et
al. Ropinirole in the treatment of restless legs syndrome: Results from the
TREAT RLS 1 study, a 12-week, randomized, placebo controlled study in 10 European
countries. J Neurol Neurosurg Psychiatry. 2004;
Men and women with restless legs syndrome (RLS), aged 18-79 years, were included in this randomized, 12-week, double-blind, placebo-controlled study conducted at 43 centers in 10 European countries, designed to assess the efficacy of ropinirole, a dopamine agonist, in the treatment of RLS. Diagnosis was made using International RLS Study Group (IRLSSG) diagnostic criteria, and an IRLSSG score of 15 or more was needed for inclusion. Exclusionary criteria included other movement or sleep disorders: renal failure, iron deficiency anemia, pregnancy, alcoholism, drug abuse, or dopamine agonist intolerance. Ropinirole was begun at 0.25 mg/d with upward titration over 7 weeks to a maximum of 4.0 mg/d, after which it was held constant until week 12. Mean change in IRLSSG score at 12 weeks was the primary end point. Secondary end point measures included general improvement assessment using the clinical global impression-global improvement (CGI-I) scale, improvement in quality of sleep, work and other activities, and quality of life, work productivity, and activity impairment questionnaires. Analyses of covariance, logistic regression, and Cox’s regression model provided statistical analysis.
Among 284 patients, 146 treated with ropinirole and 138 with placebo, 112 (76.7%) and 109 (79%), respectively, completed the study. Ropinirole significantly improved IRLSSG score at 12 weeks compared to placebo, with benefit evident even at week 1. Secondary end points also were significantly improved by ropinirole, including the CGI-I scale, sleep adequacy and quantity, reduction of daytime somnolence and sleep disturbance, and quality-of-life questionnaire. Nausea and headache were the most frequent side effects, but only 6 patients withdrew due to nausea, and no serious adverse event (urinary tract infection, fever, syncope, abdominal pain) was attributed to active medication. Ropinirole is a safe and effective alternative for treatment of RLS.
Mandatory diagnostic criteria for RLS include (1) a subjective urge to move the legs, which (2) worsens with rest and inactivity, as well as (3) at night, and (4) improves with movement. Given the nocturnal worsening, circadian rhythms have been touted as possibly modulating RLS. To test this hypothesis, 7 RLS patients and 7 healthy age- and sex-matched controls were monitored over a continuous 28-hour period while assessing circadian variations in leg discomfort, periodic leg movements, core body temperature, and salivary melatonin.1 None had medical conditions associated with RLS such as renal failure or anemia or other neurological or psychiatric illness, and none had traveled across the international dateline in the preceding 6 months. Surprisingly, both groups (more so the RLS group) demonstrated a significant circadian variation in leg discomfort and periodic leg movements that correlated with core body temperature and salivary melatonin. However, only changes in melatonin secretion preceded motor and sensory symptoms in RLS patients, with a 2-hour lag time until symptoms were at their worst. These findings clearly demonstrate a circadian rhythm in RLS and implicate melatonin in the nocturnal worsening, possibly by inhibiting central dopamine secretion. — Michael Rubin, MD, Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus and Assistant Editor of Neurology Alert.
1. Michaud M, et al. Ann Neurol. 2004;55:372-380.