HONOLULU — Restless legs syndrome (RLS) affects as many as 10 percent of Americans, making it one of the most common of all neurological disorders. While the symptoms are only mildly bothersome to some people, others find sensations unpleasant and the urge to move can have a major impact on quality of life. Exactly how major was made clear in a study led by Richard P. Allen, PhD, Assistant Professor of Neurology at Johns Hopkins School of Medicine in Baltimore, MD. At the same time, dopamine agonists have emerged as a highly effective treatment for RLS, and a study led by Charles H. Adler, MD, PhD, indicated the potential of one such agent, ropinirole (Requip). Both studies were described at the AAN Annual Meeting here.
DECREASED QUALITY OF LIFE
Dr. Allen and colleagues at the JFK Medical Center and Robert Wood Johnson Medical School (both in New Jersey) surveyed 407 RLS patients using the Short Form-36 (SF-36), a widely used, patient-reported measure of health-related quality of life.
The 36 questions examine quality of life in eight domains, including physical, emotional, social, and mental health aspects. The patients, a typical cross-section of the RLS population, were 60 percent female with a mean age of 52 years. The duration of symptoms ranged from less than one year in 14 percent of patients to more than 10 years in 26 percent. One in six patients were being treated for depression or anxiety, but less than 1 percent were taking dopamine agonists for RLS symptoms.
Dr. Allen compared the SF-36 scores of RLS patients to published national averages for age- and sex-matched controls. In every domain but one, RLS patients rated their quality of life as significantly lower than the historical controls. Physical functioning, bodily pain, general health, and energy and vitality were all 15 to 20 percent lower in RLS patients, and social functioning and mental health were also lower, although not by as much. Only measures of “emotional role” were not significantly different for RLS patients and controls.
The RLS patients were then stratified by disease severity. For each domain, quality of life decreased as severity increased. While the physical functioning of mildly affected patients was equivalent to that of controls, the most severely affected patients had scores only half as good.
“The severely and moderately affected patients scored quite low on the SF-36,” said Dr. Allen, “and these are the patients we usually see in our clinic.” He noted that about one-third of RLS patients have severe symptoms.
COMPARABLE TO OTHER CHRONIC CONDITIONS
Finally, Dr. Allen compared the SF-36 scores of RLS patients to those with three other health conditions: hypertension, type-II diabetes, and acute myocardial infarction. In several domains, including physical functioning, social functioning, and general health, the scores for RLS patients were equivalent to those for the other three conditions.
Dr. Allen did not expect to see this great an impact of RLS on quality of life. “It's much more significant than I thought,” he said. “Perhaps I should have expected it, though, because patients indicate that this is very disturbing to their lives.”
Cynthia Comella, MD, agreed that RLS can affect quality of life in severely affected patients. “If patients have severe RLS, they can't ride in a plane, can't go to a movie at night, can't do many of the things we take for granted,” she said. “It makes sense that quality of life is reduced in this kind of chronic condition.” Dr. Comella is a movement disorder specialist at Rush-Presbyterian-St. Luke's Medical Center in Chicago, IL.
Mark W. Mahowald, MD, Director of the Minnesota Regional Sleep Disorders Center and Professor of Neurology at University of Minnesota Medical School in Minneapolis, noted that because the primary consequence of RLS is insomnia, the neurological etiology is often overlooked. “Traditionally, and regrettably, the complaint of insomnia is often discounted or ignored, and frequently misattributed to psychological or psychiatric causes,” he said. “The objective quality-of-life impairment found in Dr. Allen's study should be incentive enough to take the complaint of insomnia in general, and RLS in particular, most seriously.”
DOPAMINE AGONIST REDUCES SYMPTOMS
To test the efficacy of the dopamine agonist ropinirole for symptoms of RLS, Dr. Adler, Professor of Neurology and Chair of the Mayo Clinic Division of Movement Disorders in Scottsdale, AZ, conducted a double-blind, placebo-controlled crossover study. The study was funded by an unrestricted grant from the drug manufacturer, GlaxoSmithKline. At baseline, the mean score on the RLS rating scale was 25, out of a maximum possible of 40, which is in the middle of the severe range.
Dr. Adler explained that he has been interested in ropinirole for RLS because it has been Food and Drug Administration (FDA)-approved for Parkinson disease (PD), and PD medicines are effective for RLS. But, he noted, there are no data comparing dopamine agonists for RLS or PD.
[The FDA has not approved any drugs for RLS, but dopamine agonists, such as pergolide, pramipexole, and ropinirole have been found to be effective at low doses for RLS; however, the role of their long-term use is unknown. See the box, Pharmacologic Treatment for RLS, for the range of treatments used for RLS.]
Twenty-two patients met the entry criteria of having primary RLS and scoring at least 10 on the RLS rating scale, an indication of at least mild-to-moderate disease. [The scale goes from 0 to 40 based on 10 questions with answers ranging from 0 for “no symptoms” to 4 for “most severe” for each question. Thus, 0 is best, 40 is worst.]
Other RLS medications were stopped at least two weeks prior to study entry. Patients received either placebo or ropinirole for four weeks, followed by a one-week washout, and then crossover to the other treatment arm. Ropinirole was titrated up to a maximum of 3 milligrams twice daily during the study, taken in the late afternoon and at bedtime.
The mean score at the end of the placebo treatment was unchanged, but with ropinirole, the mean score fell to 13. “This was an excellent response,” said Dr. Adler. Three patients slightly worsened on ropinirole, but all others either remained the same or had a “marked improvement” in their scores, he said, and “eight of the 22 patients had complete resolution of their RLS symptoms during ropinirole treatment.”
Improvement was also seen on the secondary endpoint of global efficacy, as determined by the blinded investigators. When efficacy was rated from +3 to −3 versus baseline, ropinirole led to a 1.9 point improvement, while there was no benefit from placebo. Symptom frequency also declined significantly versus placebo. No significant difference between the two was seen on the Epworth sleepiness scale.
While no explicit quality-of-life measures were used in this study, the RLS rating scale does contain questions that relate to quality of life, Dr. Adler said, “and medications that improve the RLS rating scale score are likely to benefit quality of life for these patients.”
Adverse events were more common during ropinirole treatment, including the typical dopaminergic effects of dizziness and nausea. “These are the effects we could pretty much expect from other patients treated with this drug,” said Dr. Adler.
TREATMENT OF CHOICE
Commenting on Dr. Allen's study, Dr. Mahowald, whose center is participating in another GlaxoSmithKline-sponsored clinical trial of ropinirole in RLS, said: “The response to the new dopaminergic agonists is often stunning – even in cases previously incompletely responsive to carbidopa-levodopa in conjunction with benzodiazepines or opiates. Head-to-head studies of dopaminergic agonists currently available and those under development will be of great interest.”
Michael Thorpy, MD, who was not involved in the study, said in an e-mail that he also agreed with the study findings, and he noted that GlaxoSmithKline was applying for FDA approval for ropinirole for RLS.
“RLS has not been shown to be any better or worse with ropinirole than with other dopamine agonists,” said Dr. Thorpy, Director of the Sleep-Wake Disorders Center at the Montefiore Medical Center and Associate Professor of Neurology at Albert Einstein College of Medicine in the Bronx, NY. “But with ropinirole, we now have the most information about the use of dopamine agonists in RLS.”
“Pramipexole, another dopamine agonist, is effective, as is pergolide, but pergolide has more side effects, especially nausea,” he said, adding: “Pramipexole is effective but there is no evidence that it is more effective than ropinirole.”
Dr. Comella agreed that dopamine agonists have become an important treatment option for RLS. “In patients who have severe RLS, they have clearly become the treatment of choice,” she said, while recognizing there is not yet a lot of Class I evidence to support this. Unlike levodopa, she said, the dopamine agonists do not cause strong augmentation, or return of symptoms ever earlier in the day.
Dr. Adler noted that he is unaware of any evidence suggesting that one dopamine agonist is superior to another for this condition. “They all work,” he said. “Whether one works better than another, I can't conclude from this study. We'd need a head-to-head comparison to determine that.”
Article In Brief
- ✓ Two new studies on restless legs syndrome (RLS) offered perspective on its effect on patients and a possible treatment option. In one study, patients reported that RLS had a major effect on the quality of their life. Another small study found that ropinirole, a dopamine agonist, was more effective than placebo.