Daniel M. Keller, PhD

July 01, 2016

BERLIN — Placebos exert a strong effect in studies of interventions for restless legs syndrome (RLS), with longer studies showing a greater placebo effect on both efficacy outcomes and adverse events, a new systematic review and meta-analysis shows.

Researchers from the Institute of Molecular Medicine and the University of Lisbon, Portugal, led by Maria Silva, MD, searched medical literature databases as well as clinical trials registries in October 2015 to catalog all randomized, double-blind, placebo-controlled trials involving RLS.

They included in their analysis trials in which at least one of the outcomes of interest, as measured by a validated instrument, could be determined within the placebo group.

They presented their findings in a presentation here at the 20th International Congress of Parkinson's Disease and Movement Disorders.

Primary outcomes included efficacy, defined as within-group change from baseline of RLS severity or disability, and safety, defined as adverse events experienced within the placebo group.

Several secondary efficacy outcomes involved improvement ratings, quality of life, quality of sleep, periodic limb movements, and daytime somnolence. Secondary safety outcomes included study withdrawal for adverse events and the proportion of patients experiencing augmentation (worsening of RLS symptoms attributable to the therapeutic intervention).

Two reviewers independently extracted data from the record. Disagreements were solved by consensus or enlisting a third reviewer. After screening the published studies and deleting duplicates, ones with wrong study designs, those with wrong outcomes, and those meeting other criteria, 85 studies remained for analysis, which included 5037 patients receiving placebo.

Most of the studies showed a significantly positive effect of placebo on the severity of RLS symptoms. "Indeed, the placebo response exceeds the threshold for clinical significance, which is of enormous relevance to planning future trials," Dr Silva reported. That threshold is 5 to 6 points on the International Restless Legs Scale (IRLS).

Sixty-four of the studies (4111 patients) reported a validated RLS measurement, and of these, 48 showed a statistically significant effect of placebo on RLS severity. Sixty-two used the IRLS rating scale, on which the mean change from baseline was –6.6 points (95% confidence interval, –8.3 to –4.9).

Adverse effects in the placebo group ("nocebo" effects) occurred in 45.4% of patients. A clear correlation existed between the placebo and nocebo responses (r = 0.45; P < .001), both of which showed "substantial magnitudes" and "similar patterns of variation," the authors write.

Both the placebo and nocebo effects were greater in longer studies (12 weeks or longer vs less than 6 weeks), in parallel designed trials vs crossover ones, in idiopathic vs secondary RLS, with pharmacologic interventions, and in industry-sponsored trials.

Regarding secondary outcomes, quality of life and quality of sleep improved with placebo, but daytime somnolence was worse. The investigators reported that unlike for other outcomes, they did not see much change in periodic limb movements.

Olga Klepitskaya, MD, associate professor of neurology at the University of Colorado in Denver, who has a special interest in deep-brain stimulation to treat RLS, commented to Medscape Medical News that the presentation interests her because the placebo issue is one of the major criticisms in studies of RLS.

"The reason for that is RLS, being a dopa-mediated disorder, is really highly susceptible to placebo…The placebo effect in RLS and Parkinson's disease is one of the most significant out of all neurological disorders, in the range of neuropsychiatric disorders," she said.

She explained that the placebo effect is an anticipation effect, which is mediated through dopamine and dopamine-like neurochemicals in the brain. She cited randomized, blinded surgical intervention trials for Parkinson's disease that failed, probably in part because of placebo effect.

Dr Klepitskaya said a significant finding of the present study is that the placebo effect was apparent in many of the subgroup analyses. She noted that duration of treatment as a predictor of placebo effect has been found in other studies as well.

"The major lesson from this study is that RLS clinical trials should be longer" to see if the placebo may even wane over time, she suggested.

In practice, clinicians usually do not think about the placebo effect, but maybe they should. She said it is possible that temporary improvements after initiating therapy may be a result of it, and later disease worsening may be the result of the placebo effect wearing off and not necessarily disease progression.

There was no commercial funding for the study. Dr Silva and Dr Klepitskaya have disclosed no relevant financial relationships.

20th International Congress of Parkinson's Disease and Movement Disorders. Abstract 954. Presented June 21, 2016.

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