- Restless Legs Syndrome is a painful condition which impairs the quality of life of the patient.
- Opioids and dopaminergic agents are the mainstays of treatment for this condition.
- Placebos show a positive response to a significant number of cases, as observed in a recent literature review.
Placebo response refers to a perceived or actual improvement in the subjective and objective symptoms of a disease or condition while taking an inert substance (dummy pill) as medication.
‘Placebo treatment for longer durations may affect outcome measures in patients with Restless Legs Syndrome (RLS).’
The researchers analyzed literature of trials by searching databases. Primary and secondary efficacy outcomes were defined and compared in the treatment and placebo groups. Primary outcomes included RLS severity and safety (adverse events) in the placebo group. Secondary outcomes included quality of life, quality of sleep, daytime sleepiness and PMLS (Periodic Leg Movements in Sleep).
Two researchers extracted the data from the databases and a third one was referred to remove bias and any differences. After screening trials for accuracy, bias and other criteria, a total of 85 studies were selected for analysis. These studies involved 5037 patients who received only placebo as treatment.
64 of the studies involved IRLS (International Restless Legs Scale) measurement, a scale which quantifies the severity of the condition. Out of these, 48 studies exhibited a clinically significant improvement in IRLS. The response was way beyond the threshold of clinical significance, according to the authors.
The following findings are worth mention:
- The majority of the studies demonstrated a positive effect of placebo on the primary efficacy outcome measure of RLS severity.
- Safety outcome was measured in terms of adverse effects which were observed in around 44% of the patients in the pooled placebo group.
- Secondary outcomes of quality of life and quality of sleep improved within the placebo group.
- Daytime sleepiness was found to be higher in the patients in placebo group.
- No placebo effect was observed in PMLS.
Another significant finding is that placebo effects were greater in studies that spanned over longer durations of time.
Uniqueness of RLS Makes It Prone to Placebo EffectRestless Legs Syndrome responds well to opioids, levodopa, and dopaminergic agents. This unique property makes it susceptible to placebo effect. Also, the placebo effect is mediated by dopamine and dopamine-like neurochemicals in the brain.
Placebo effect has been linked with anticipation of beneficial effects of being in a trial or treatment program. This is related to the production of endogenous opioids in the body and a research demonstrated that placebo-related pain relief is blocked by naloxone, an opioid inhibitor. This might be an important factor contributing to the significant placebo response seen in Restless Legs Syndrome trials.
Placebo response has also been observed in other disorders of the nervous system associated with RLS like depression and insomnia.
Trial Duration - A Predictor of Placebo EffectA salient finding of the study is that placebo effect is more pronounced in trials of longer duration.
Dr. Olga Klepitskya of the Department of Neurology at the University of Colorado opined, ''The major lesson to learn from this study is that RLS clinical trials should be longer to ascertain if the placebo response wears off with time."
According to Dr. Olga Klepitskya, the initial improvement in symptoms after starting treatment may be attributable to the placebo effect and worsening of symptoms after some time may be due to the waning off of the same and not due to progression of the disease as is thought.
The study and its findings may influence future trials and interventions in Restless Legs Syndrome.
"Indeed the placebo response exceeds the threshold for clinical significance, which is of enormous relevance to planning future trials", Dr. Maria Silva commented.
- Stephany Fulda and Thomas C.Wetter; Where Dopamine Meets Opioids: A Meta-Analysis of the Placebo Effect in Restless Legs Syndrome Treatment Studies; doi:10.1093/brain/awm244
- Systematic review and meta-analysis of randomized controlled trials to evaluate placebo response in Restless Legs Syndrome - (http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015027992)
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