BACKGROUND: At the time of writing only dopamine agonists are licensed for the 
treatment of restless legs syndrome (RLS) in various countries, but randomized 
controlled trials (RCTs) have been performed with other treatments. We performed 
comprehensive meta-analyses and indirect comparisons of RCTs for all currently 
recommended treatments of RLS.
METHODS: We searched the Central, Medline, Embase, PsycINFO and CINAHL 
databases. Outcome measures were the international RLS study group severity 
scale (IRLS), clinical global impression-improvement, (CGI-I), periodic limb 
movement index (PLMI), and psychosocial parameters such as quality of life 
(QoL). We also conducted indirect comparisons by testing for heterogeneity 
between the substance groups.
RESULTS: Placebo (58 trials) and actively (4 trials) controlled RCTs with 
dopamine agonists (38 trials), levodopa (4 trials), anticonvulsants (13 trials), 
most of them with α₂δ ligands (11 trials), opioids (1 trial), and iron 
treatments (6 trials) were included (9596 patients). Although treatment effects 
showed large variations, changes in the IRLS in the substance groups were 
comparable (P = 0.78), with a mean reduction in the IRLS of -5.47 points for 
dopamine agonists, -5.12 points for anticonvulsants (α₂δ ligands and 
levetiracetam), and -4.59 points for iron treatments. The CGI-I indicated 
slightly different treatment effects between the substance groups, while PLMI 
changes during treatment differed (P = 0.002), showing a marked decrease with 
dopamine agonists (-22.50/h), levodopa (-26.01/h), and oxycodone (-34.46/h) 
compared with a slight decrease for anticonvulsants (α₂δ ligands and 
levetiracetam; -8.48/h) and iron treatments (-13.10/h). Quality of sleep and QoL 
improved moderately in most of the RCTs investigating these parameters 
(standardized mean difference, SMD) 0.40 and 0.33, respectively). In the few 
studies evaluating the change of depressive (n = 4) or anxiety symptoms (n = 3), 
these symptoms improved slightly (SMD -0.24, and -0.21). Adverse effects and 
dropouts were comparable in number across all substance groups. In 
meta-regressions, the treatment effect was predicted by the design of the trial 
(the more sites involved in a trial the lower the effect) and by the duration of 
action of a medication (the longer the duration of action, expressed as the 
half-life time of a substance, the greater the improvement), the latter 
indicating potential superiority of treatments with stable blood concentration.
CONCLUSION: This first meta-analysis of all RCTs for the pharmacological 
treatment of RLS provides evidence that, besides the well-defined efficacy of 
dopaminergic treatment, other treatments with different pharmacological 
principles show efficacy in small samples and may be well-tolerated alternatives 
for the treatment of RLS. In the group of anticonvulsants, only the trials 
performed with α₂δ ligands such as gabapentin, gabapentin enacarbil, and 
pregabalin showed good efficacy. This indicates a specific mechanism of action 
of these substances in RLS. The group of iron treatments consisted of a few 
trials with different compounds in oral and intravenous application form, 
respectively. For a more differentiated evaluation of the efficacy of iron 
treatments further studies are necessary. The large efficacy of one opioid RCT 
in RLS has to be confirmed in further studies.