Treatment of idiopathic restless legs syndrome (RLS) with slow-release valproic acid compared with slow-release levodopa/benserazid. L-DOPA/carbidopa for nocturnal movement disorders in uremia. Pergolide: treatment of choice in restless legs syndrome (RLS) and nocturnal myoclonus syndrome (NMS). A double-blind randomized crossover trial of pergolide versus L-Dopa. Rapid onset of action of levodopa in restless legs syndrome: a double-blind, randomized, multicenter, crossover trial. L-dopa therapy of uremic and idiopathic restless legs syndrome: a double-blind, crossover trial. Treatment of restless legs syndrome and periodic movements during sleep with L-dopa: a double-blind, controlled study. Restless legs syndrome treatment with dopaminergic drugs. Cabergoline compared to levodopa in the treatment of patients with severe restless legs syndrome: results from a multi-center, randomized, active controlled trial.
We aimed to compare the efficacy of valproic acid (VPA) on paresthesias and sleep in RLS to that of levodopa (LD). Twenty patients with idiopathic restless legs syndrome (RLS) were treated with 600 mg slow-release VPA and 200 mg slow-release LD+50mg benserazid in a randomized, placebo-controlled, cross-over, double-blind setting with polysomography (PSG) at the end of each 3-week treatment periods. There was no major difference between the efficacy of valproic acid or LD. Periodic leg movements in sleep (PLMS) and PLM arousal index (PLMAI) significantly decreased with LD (p < or= 0.005). However, LD, but not VPA, significantly increased arousals not associated with PLMS (p = 0.002). Decrease of intensity and duration of RLS symptoms were more pronounced with VPA (p < or= 0.022) than with LD (NS). We conclude that slow-release VPA provides a treatment alternative for RLS. Restless legs syndrome (RLS) and periodic limb movements during sleep (PLMS) are sleep disorders that are common and distressing to uremic patients. There are few data regarding effective treatment in this population. Five chronic hemodialysis patients completed a double-blind, placebo-controlled, crossover study using a single bedtime dose of controlled release L-DOPA/carbidopa (100/25 mg) for treatment of RLS and sleep disruption. Leg movements per hour of sleep and percentage of sleep time accompanied by leg movements were decreased with treatment (101.0 +/- 29.1 events/hour on placebo vs. 61.0 +/- 28.3 events per hour on drug, p = 0.006; and 15.1 +/- 4.9% of sleep time with leg movements on placebo vs. 8.6 +/- 4.0% on drug, p = 0.014). In addition, arousals associated with leg movements (mean 209 +/- 49 events on placebo, mean 108 +/- 46 events on drug) and the leg movement arousal index (mean 59 +/- 23 events/hour on placebo, mean 23 +/- 9 events/hour on drug) were decreased by active medication (p = 0.03 and 0.04, respectively). Patients, however, continued to have very disrupted sleep and we could not document consistent subjective or objective improvement in overall sleep except for an increase in slow-wave sleep (SWS) from 9.0% to 22.8% (p = 0.01). The patterns of movements during sleep were not uniform in different patients, and the movements, although often periodic, were much longer than defined for PLMS. Because of this, finding suitable objective parameters to analyze was problematic. Measuring the percentage of sleep time during which there were leg movements was probably the most efficient and reproducible means of quantitating this disorder. Thus, although controlled-release L-DOPA/carbidopa at a dose of 100/25 mg given once nightly reduced leg movements and increased SWS, sleep continued to be disrupted. Whether higher doses or more frequent dosing is effective requires further investigation. A double-blind randomized crossover study of 0.125 mg Pergolide (Lilly) at bedtime versus 250mg L-Dopa + Carbidopa (Roche) was conducted in 16-day phases in 11 patients with idiopathic restless legs syndrome. Two patients reported a partial and 9 patients a complete relieve of motor restlessness while receiving Pergolide. Only 1 patient experienced an improvement of restlessness after L-Dopa. The patients showed polysomnographically a mean decrease in NMS cluster disturbed time by 45% from control on L-Dopa (p < 0.025) and by 79% from control on Pergolide (p < 0.001). In addition, Pergolide increased the total sleep time compared to L-Dopa (p < 0.05). In conclusion, the dopamine agonist Pergolide is superior to L-Dopa in the treatment of RLS and NMS. To investigate the efficacy and safety of levodopa plus benserazide in the treatment of restless legs syndrome (RLS), in terms of the frequency of periodic limb movements (PLMs), objective and subjective criteria of sleep, onset of action, and withdrawal effects.
                A randomized, double-blind, placebo-controlled, multicenter, crossover trial, with two 4-week treatment periods.
                Outpatient units of three specialist centers in Germany.
                Eligible patients had to fulfill the diagnostic criteria of the International RLS Study Group and have sleep disturbances and PLMs during sleep shown on polysomnography at screening. Thirty-five patients were recruited, of whom 32 (13 men, 19 women) completed the study.
                Patients received a single dose of standard-release levodopa/benserazide 100/25 mg or placebo at bedtime each night for 4 weeks, before crossing over to receive the alternative treatment for a further 4 weeks; the dose could be doubled if required. The average dosages were 159 +/- 31 mg of levodopa and 1.56 +/- 0.29 capsules of placebo.
                Levodopa/benserazide significantly reduced the number of PLMs per hour (p<0.0001), increased the time in bed without limb movements (p<0.0001), and improved subjective quality of sleep (p=0.0004). The onset of action was rapid after the first dose, and full efficacy was achieved within the first few days of therapy; these improvements disappeared immediately when treatment was discontinued. Levodopa/benserazide treatment was well tolerated and safe.
                Levodopa/benserazide is effective and safe in the treatment of RLS. Objective and subjective measures of sleep improved rapidly after the first dose. RLS symptoms recurred immediately after treatment was discontinued. We report the effects of a single bedtime dose of L-dopa 100-200 mg on sleep quality, frequency of periodic leg movements (PLM) and daily living in patients with idiopathic and uremic restless legs syndrome (RLS). Seventeen patients with idiopathic and 11 with uremic (on continuous hemodialysis) RLS were evaluated comparatively by polysomnography, actigraphy and subjective ratings in a randomized, controlled and double-blind crossover trial with L-dopa and placebo for 4 weeks each. Neurophysiologic assessments showed significant reduction of the number of periodic leg movements (p = 0.003) and the PLM-index (p = 0.005) most pronounced during the first 4 hours of bedtime after L-dopa (p = 0.001). Subjective evaluation confirmed improvement of sleep quality (p = 0.002) and showed significantly higher quality of life during daytime (p = 0.030) while the patients received L-dopa therapy. We conclude that L-dopa 100-200 mg proved to be effective in idiopathic RLS and for the first time under controlled conditions in uremic RLS without any severe side effects. Six patients with restless legs syndrome (RLS) and periodic movements during sleep (PMS) received placebo or L-dopa in a double-blind study. We recorded patients for 36 consecutive hours in the sleep laboratory during a baseline investigation and at the end of each treatment period. Daily evening questionnaires and a suggested immobilization test (SIT) performed at bedtime on each recording night documented the effect of L-dopa in RLS. A nocturnal EMG recording of the anterior tibialis muscles revealed the effect of L-dopa on PMS. L-Dopa proved effective in treating both RLS and PMS. Although not present in every patient, leg movements recorded during the SIT exhibited a clear periodicity. These observations support the hypothesis that RLS and PMS are two manifestations of the same central sensorimotor disorder. Sixteen patients with symptoms of restless legs syndrome and resulting insomnia are included in this study. They were nine women and seven men with a mean age of 50.8 years and with a mean duration of symptoms of 6.3 years. The purpose of the study is to determine the drugs that are useful for the treatment of restless legs syndrome. In 13 patients L-Dopa plus benserazide, in two patients bromocriptine, and in the remaining one patient piribedil were used orally at night approximately 1 h before bedtime. Compared with placebo these dopaminergic drugs decreased the times of waking up and staying awake periods at a statistically significant level (p changed between 0.025 and 0.01, t test). In this susceptibility of CNS there is dysfunction of the dopamine system triggered by sleep, and resting and dopaminergic potentiation by drugs affect the symptoms. We report the first large-scale double-blind, randomly assigned study to compare two active dopaminergic therapies for Restless Legs Syndrome (RLS), the dopamine agonist cabergoline (CAB) and levodopa/benserazide (levodopa). Patients with idiopathic RLS were treated with fixed daily doses of 2 or 3 mg CAB or 200 or 300 mg levodopa for 30 weeks. Efficacy was assessed by changes in the IRLS (International RLS Severity Scale) and by time to discontinuation of treatment due to loss of efficacy or augmentation. 361 of 418 screened patients (age 58 +/- 12 years, 71% females) were randomly assigned and treated (CAB: n = 178; levodopa: n = 183) in 51 centers of four European countries. Baseline IRLS total score was 25.7 +/- 6.8. The baseline-adjusted mean change from baseline to week 6 in IRLS sum score was d = -16.1 in the CAB group and d = -9.5 in the levodopa group (d = -6.6, P < 0.0001). More patients in the levodopa group (24.0%) than in the CAB group (11.9%, P = 0.0029, log-rank test) discontinued because of loss of efficacy (14.2% vs. 7.9%, P = 0.0290) or augmentation (9.8% vs. 4.0%, P = 0.0412). Adverse events (AEs) occurred in 83.1% of the CAB group and in 77.6% of the levodopa group. In both groups, most frequent AEs were gastrointestinal symptoms (CAB: 55.6%, levodopa: 30.6%, P < 0.0001). This first large-scale active controlled study in RLS showed superior efficacy of cabergoline versus levodopa after a 30-week long-term therapy. Tolerability was found more favorable with levodopa than with cabergoline.
Levodopa is efficacious for the short-term treatment of RLS. Augmentation, the clinically most relevant adverse event, was not investigated sufficiently.