Medline ® Abstracts for References 25,26

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.

QUESTIONS UNDER STUDY: To compare efficacy and safety of the dopamine agonist pramipexole (PPX) versus reference treatment with dual release levodopa/benserazide (L/B) in de novo patients with restless legs syndrome (RLS).

METHODS: A total of 39 men and women between 25 and 85 years old, fulfilling all clinical criteria for diagnosis of idiopathic RLS, previously untreated, participated. The study was performed as a randomised, double-blind, double-dummy crossover trial with two treatment periods of four weeks and took place in six Swiss certified sleep-centres. Interventions were PPX 0.25-0.75 mg and dual-release L/B 125-375 mg. The primary outcome measure was the frequency of periodic limb movements while in bed (PLM index, PLMI). Secondary endpoints included the changes in patient ratings on the International RLS Study Group Rating Scale (IRLS).

RESULTS: Both pramipexole and dual-release L/B were effective in reducing PLM and RLS symptoms. Mean PLMI reduction was -11.5 for PPX and -7.7 for L/B (baseline 21.1 and 21.5), and the mean IRLS score reduction was -7.2 and -4.0 (baseline 20.8 and 21.1). In patients with an IRLS score>20 (38%), a significantly (p = 0.047) higher PLMI reduction for PPX (-8.5), as compared to L/B (-4.3), was found. A higher incidence of "augmentations" and "involuntary movements" for L/B, and "nausea or vomiting" and "hypotension with dizziness" for PPX treatment were noted as adverse effects.

CONCLUSION: This study showed comparable effects of PPX versus dual-release L/B for short-term treatment of de novo patients with mild to moderate RLS.