Restless Legs Syndrome Calmed by Dopamine Agonists

Caroline Cassels

September 19, 2006

September 19, 2006 — Two studies of 2 dopamine agonists — pramipexole and cabergoline, which are traditionally used to treat Parkinson's disease — have shown that they significantly improve symptoms of restless legs syndrome (RLS), including sleep satisfaction and patients' quality of life.

Both studies are published online August 23 in Neurology.

In the first study, researchers found that, compared with placebo, pramipexole produced an early response and significantly improved baseline RLS measures at every studied dose.

"Even after 1 week, pramipexole was superior to placebo — even at the lowest dose of 0.25 mg/day — in relieving core symptoms of RLS," the study's first author, John W. Winkelman, MD, PhD, from Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, told Medscape.

In the second trial, the Cabergoline in the Treatment of Patients with Idiopathic Restless Legs Syndrome (CATOR) study, researchers at Philipps-University in Marburg, Germany used polysomnography (PSG) to compare the safety and efficacy of cabergoline vs placebo in the treatment of severely affected patients with idiopathic restless legs syndrome.

They found cabergoline was superior to placebo and normalized the periodic leg movements during sleep arousal index (PLMS-AI) in 75% of patients. This compared with improvement in only 1 patient in the placebo group.

The authors note, "PLMS-AI is regarded as one of the most relevant PSG variables because it directly indicates how severely sleep is fragmented by PLMS. Accordingly, the PLMS-AI is both an indicator for the assessment of sleep disturbances at baseline and the efficacy measure most relevant to RLS trials."

Furthermore, there were similar clinically relevant improvements in patients' daytime leg-movement symptoms compared with placebo.

"This study provides evidence that cabergoline considerably improves objective PSG parameters and subjective sensorimotor symptoms and enhances the quality of sleep and quality of life in RLS patients," the authors write.


First-Line Therapy

According to Dr. Winkelman, dopamine agonists are now considered first-line therapy for RLS. Although there are several of these agents available, currently the only FDA-approved treatment for RLS is the dopamine agonist ropinirole.

Traditional RLS therapy includes benzodiazepines and levodopa, which for various reasons are less than ideal.

Benzodiazepines carry a risk for tolerance and daytime side effects, and levodopa can cause RLS symptoms to worsen over time in up to 50% of patients. As a result, he said, levodopa is generally reserved for patients with intermittent RLS.

Therefore, he said, it is important for the medical community to seek out new and better treatment options for RLS, which can have a major impact on patients' quality of life, largely due to its disruptive effect on sleep.

"Population-based studies show that RLS in patients who are affected at least twice a week has as great an impact on quality of life as many major medical illnesses, including hypertension, osteoarthritis, insulin-dependent diabetes, and major depression," he said.

Pramipexole Study

This 12-week, double-blind, placebo-controlled trial included 339 RLS patients who were randomly assigned to receive placebo or pramipexole of 0.25, 0.50, or 0.75 mg/day.

To date, most studies of pramipexole in RLS have been small and uncontrolled.

Patients were recruited for the study between April and October 2004 at 43 centers in the United States. Study subjects were men and women aged 18 to 80 years who met diagnostic criteria for primary moderate to severe RLS. All had symptoms 2 to 3 days per week for a minimum of 3 months and baseline scores of greater than 15 on the International RLS Study Group Rating Scale (IRLS).

Individual visual analog scales (VAS) were used to assess RLS severity while getting to sleep, at night, and during the day and to determine satisfaction with sleep.

The pramipexole study's 2 primary end points were a reduction in symptom severity rated by patients using the IRLS and by clinicians using the Clinical Global Impressions-Improvement (CGI-I) scale. Secondary end points included response rate, ratings of daytime somnolence, quality of life, and drug safety.

Scores on the IRLS were rated from baseline to the end of week 12. The CGI-I primary end point was the responder rate based on ratings at week 12 or, for patients who withdrew early from the trial, as last observation carried forward (LOCF).

A responder was defined as a patient with a CGI-I score of "very much improved" or "much improved" at the end of the trial. To ensure independence of the primary end points, physicians who performed the CGI-I assessment were unaware of the patient's IRLS self-ratings and of reported adverse events.

Of the 339 patients included in the full analysis, 281 (82.9%) completed the trial. LOCF was used for 48 pramipexole recipients (18.9% of 254) and 10 placebo recipients (11.8% of 85).

The authors report there were no differences in demographic or baseline characteristics between patients on the study drug vs those on placebo.

Pramipexole Results

At the end of the 12-week study, the mean IRLS change from baseline to the end of treatment was greater in patients receiving each pramipexole dose than in those receiving placebo, with a mean treatment difference of –4.3 on IRLS. Interestingly, there was no significant difference among the 3 pramipexole dosages. In fact, adjusted treatment effects "exhibited substantial overlap" in 95% confidence intervals.

A total of 72.0% of subjects on pramipexole were considered CGI-I responders vs 51.2% of those on placebo.

Secondary end points including sleep complaints were significantly improved with pramipexole. In particular, subjects on pramipexole reported reduced symptom severity while getting to sleep, during the course of the night, and through the day.

This improved effect on sleep may also explain the study subjects' improved quality of life, which was significantly enhanced by pramipexole.

Because of side effects when dopamine agonists are used to treat Parkinson's disease, which include daytime sleepiness, their use to date for the treatment of RLS has been limited. However, Dr. Winkelman said, doses used to treat RLS are one fifth to one tenth of those used in Parkinson's disease, and as a result, side effects are usually mild and transient.

CATOR Results

The 5-week CATOR study included a total of 83 patients, both male and female, between the ages of 18 and 75 years with moderate to severe RLS from 7 centers across Germany. Subjects were randomly assigned to receive a single evening dose of 2 mg of cabergoline (43) or placebo (40). Primary outcomes included improvement in the PLMS-AI and sleep efficiency.

The investigators found cabergoline reduced the PLMS-AI from more than 20 per hour at baseline to a normal level of 2 or less per hour of total sleep time in 75% of all patients vs only a single patient in the placebo group. As a result of improvement in the PLMS-AI, patients taking cabergoline experienced larger improvements in sleep efficiency and sleep quality compared with those on placebo.

Furthermore, the authors report the drug had a similar positive impact on day and nighttime RLS symptoms and a greater effect than placebo on patients' quality of life.

Of the 43 subjects receiving cabergoline, 3 dropped out of the study due to intolerable adverse events that included gastrointestinal symptoms, dizziness, and fatigue. However, the authors note, the drug was generally well tolerated.

"Overall, the study strongly confirms that single-evening cabergoline is highly efficacious in the short-term therapy of idiopathic RLS and generally well tolerated by the patients," the authors write.


Neurology . Published online August 23, 2006.

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