Abstract: We included 35 placebo controlled and three active controlled RCTs (N = 7365). The mean reduction on the IRLS was −5.7 points lower in dopamine agonist treatment compared to placebo (95% confidence interval (CI) −6.7 to −4.7). Periodic limb movements in sleep per hour of sleep (PLMS-Index; PLMSI) were −22.4/h lower than in placebo (95% CI −27.8 to −16.9). Self rated quality of sleep and disease specific quality of life were improved by a standardised mean difference (SMD) of 0.40 (95% CI 0.33 to 0.47) and 0.34 (95% CI 0.23 to 0.44), respectively. Patients were more likely to drop out (odds ratio (OR) 1.82, 95% CI 1.35 to 2.45) and experienced more adverse events under dopamine agonist treatment than with placebo (OR 1.82, 95% CI 1.59 to 2.08). Visual inspection of forest plots showed the highest efficacy in three studies investigating cabergoline and pergolide (N = 3). Active controlled trials investigated effects of cabergoline, pergolide, and pramipexole in a number of outcomes. The IRLS score was lower with cabergoline and pramipexole compared to levodopa (MD −5.3, 95% CI −8.4 to −2.1). Only four studies investigated treatment efficacy up to seven months. The most severe side effect, augmentation, was not assessed reliably. The meta-analyses show the superiority of dopamine agonists over placebo in RCTs up to seven months. Cabergoline and pramipexole showed larger efficacy compared to levodopa in some but not all outcomes.

Plain-language summary: We could include 38 trials in the meta-analyses which investigated the efficacy and safety of dopamine agonist treatment compared to placebo or to other treatments for RLS. The studies were performed mostly in European and Northern American countries. Treatment durations varied from one week to seven months, but most treatments had durations of one to 12 weeks. Patients suffered from moderate to severe RLS and were treated with the dopamine agonists cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine, and sumanirole. Dopamine agonists lead to a larger improvement on the International RLS Severity Rating Scale (IRLS) compared to placebo. Clinicians rated RLS symptoms as more improved with dopamine agonists compared to placebo (CGI-I). Also periodic limb movements in sleep were significantly reduced by dopamine agonists compared to placebo. Sleep efficiency was also slightly improved. Patients rated their quality of sleep and quality of life as markedly improved. Patients were, however, more likely to discontinue dopamine agonist treatment and experienced more adverse events when treated with dopamine agonists compared to placebo. All dopamine agonists were superior to placebo except sumanirole. Indirect descriptive comparisons revealed the highest efficacy for the ergoline dopamine agonists cabergoline and pergolide, which has to be weighed against potentially serious side effects such as cardiac valve fibrosis. The non-ergoline dopamine agonists lisuride, pramipexole, rotigotine, and ropinirole showed adequate efficacy. Augmentation, a serious adverse event in dopaminergic treatment, has not been sufficiently assessed. Future studies need to investigate long-term efficacy of dopamine agonists against placebo or other active treatment and the frequency and the impact of augmentation on treatment outcome during dopaminergic treatment.