A meta-analysis of 36 clinical trials evaluating treatments for patients with restless legs syndrome (RLS) demonstrated a pooled placebo response rate of 40%. Furthermore, placebo response rates seemed to increase with longer duration of treatment, reported Stephany Fulda, MSc, and Thomas C. Wetter, MD, of the Max Planck Institute of Psychiatry in Munich, in the April Brain.
The researchers analyzed all randomized, double-blind, placebo-controlled studies of drug treatments for RLS to determine the magnitude of the placebo response in patients with this condition. They identified 60 studies, of which 36 were eligible for the meta-analysis.
Twenty-four studies reported response rates during placebo treatment. Response was defined as much or very much improved. The pooled response rate was 40.09% (range, 0% to 60%) in patients taking placebo, compared with 68.32% in the treatment groups. The placebo effect was greatest for the International Restless Legs Severity Scale, which was the primary outcome measure in most studies. The authors predicted, based on the data, that for an estimated placebo response rate of 22.26% at the end of the first week of treatment, the response rate would increase by almost 3% per week with continued treatment.
Placebo effects were moderate for quality-of-life measures and smaller for daytime sleepiness, sleep quality, and total sleep time. There was no placebo effect for sleep efficiency. Periodic leg movement during sleep was more placebo-resistant than other outcome measures, but its usefulness as an outcome measure is limited by the fact that only about 80% of RLS patients have this symptom.
“Although in our meta-analysis the placebo (and treatment) effect for sleep measures was considerably smaller than the effect for RLS severity, the association with sleep and mood disturbances may predispose subjects with RLS to the occurrence of a placebo response,” the authors stated.
Because RLS treatment studies are likely to be affected by a substantial placebo effect that increases with study duration, the researchers advocated for long-term trials that include large numbers of subjects. In addition, because patients with RLS respond to both dopaminergic and opioid agents, imaging studies of these two systems in subjects with a placebo response might be beneficial, according to the researchers. They suggested the inclusion of a no-treatment control group in a future trial. “Without such data, there is no way to differentiate between the natural course of the disease as opposed to the placebo effect,” the authors concluded.
—Janis Kelly