Where dopamine meets opioids: a meta-analysis of the placebo effect in restless legs syndrome treatment studies

The restless legs syndrome (RLS) is a common sensory-motor disorder of sleep/wake motor regulation with prevalence rates between 3% and 10%. In its more severe forms, RLS is a burdening disorder with disturbed sleep and significantly impaired quality of life. Restless legs symptoms are dramatically relieved with levodopa and dopamine agonists, which are first-line treatment for this disorder. In addition, opioids have been shown to provide a marked symptomatic relief. This unique responsiveness of RLS to both dopaminergic agents and opioids places it at the crossroad of the two systems implicated in the placebo response. Indeed, in recent large-scale studies a substantial placebo response was observed. We performed a meta-analysis to provide an evidence-based estimate of the magnitude of the placebo response in RLS. Search strategies included the electronic databases PubMed and the Cochrane Clinical Trials Registry (from 1966 to March 2007), the reference lists of retrieved articles, hand-searching abstract books of sleep, neurology and movement disorder congresses and visiting clinical trial register web sites. All randomized, double-blind, placebo-controlled studies exploring a pharmacological treatment in subjects with RLS were considered. Outcome measures from five domains were extracted: RLS severity, subjective sleep parameters, sleep parameters derived from nocturnal polysomnography, periodic leg movements during sleep (PLMS) and daytime functioning. We identified 60 clinical trials and 36 of them were eligible for the meta-analysis. In 24 trials, the pooled placebo response rate was 40.09% (95% CI: 31.99-48.19). The placebo effect was large for the primary outcome measure in most studies, which is the International Restless Legs Severity Scale (-1.48, CI: -1.81 to -1.14), notably smaller for other RLS severity scales, moderate for daytime functioning, small to moderate for subjective and objective sleep parameters, very small for PLMS and absent for sleep efficiency. This meta-analysis yields several implications for the planning of both clinical RLS treatment studies and basic research programs.