Restless Legs Syndrome (RLS)
- Restless Legs Syndrome is a painful
condition which impairs the quality of life of the
- 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.
is a bothersome neurological disorder in which the patient feels an irresistible urge to move the legs. Around 80% of these patients demonstrate Periodic Leg Movement during Sleep (PLMS)
. The condition is associated with disturbance of sleep and excessive daytime tiredness.
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).’
Placebo effect on the outcome measures in
Restless Leg Syndrome (RLS) was studied by a team of researchers from the
Institute of Molecular Medicine and the University of Lisbon, Portugal. The
findings were presented by the lead author Maria Silva, MD at the 20th
International Congress of Parkinson's Disease and Movement Disorders recently.
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:
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
- No placebo effect was observed in PMLS.
This was not given much weight as PMLS is observed
in only 80% of the patients to some degree. The fact that it is not a symptom
that occurs during the waking hours of the patient may be the reason why it is
not influenced by cognition which plays a role in the placebo effect.
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 Effect
Restless 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
- A Predictor
of Placebo Effect
A 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
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)