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For RLS, New Clues on Why Symptoms Worsen Over Time

Talan, Jamie

doi: 10.1097/01.NT.0000445556.89092.99
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Investigators reported that pregabalin provided significantly improved treatment outcomes as compared with placebo for restless legs syndrome, and augmentation rates were significantly lower with pregabalin than with 0.5 mg of pramipexole.

In recent years, experts on restless legs syndrome (RLS), also called Willis-Ekbom disease, have worried that many patients prescribed intermediate to short-acting dopamine agonists were getting worse over the course of treatment.

“It's been an uphill battle to get clinicians to understand that this is a real problem,” said Richard P. Allen, PhD, an associate professor of neurology at Johns Hopkins University, who has been treating and researching the condition for years. “We were openly worried that clinicians kept prescribing these medications. If patients got worse, the tendency was to up the dose, which made things even worse,” he said.

Dr. Allen and colleagues wanted to determine whether this iatrogenic worsening (augmentation) was due to the dopamine agonist or a natural progression of the disease itself.

In a multicenter randomized trial, they compared treatment results over the course of a year with pregabalin (Lyrica), a non-dopamine drug that works on alpha-2-delta receptors; pramipexole (Mirapex), a commonly used dopamine agonist for RLS; and a placebo for the first 12 weeks followed by 40 weeks of active treatment. They reported in the Feb. 13 edition of the New England Journal of Medicine that pregabalin offered significantly improved treatment outcomes compared with placebo, and augmentation rates were significantly lower with pregabalin than with lower-dose pramipexole.



The results suggest that the augmentation is in response to the medication pramipexole, and not the disease, Dr. Allen said. “We have been talking about this for years but now we finally have the proof that intermediate-acting dopamine agonists cause augmentation.”

He and colleagues concluded that pregabalin is an effective alternative to the short-acting dopamine agonists to avoid potential augmentation, which can be painful and severe.

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The trial included 719 RLS study participants at 102 centers in the US and Europe: 182 received 300 mg per day of pregabalin; 185 took 0.25 mg of pramipexole; 180 took 0.5 mg of pramipexole; and 179 took placebo. Pregabalin was previously shown effective for RLS at 300 mg a day in a 2010 study in the journal Sleep Medicine, and the pramipexole dosing was based on the highest and lowest doses approved for treatment for RLS.

To assess efficacy, the investigators used the International RLS (IRLS) Group Rating Scale — a scale of 0 to 40, with a higher score indicating more severe symptoms — and the Clinical Global Impression of Improvement scale, which determined the proportion of patients with symptoms that were “very much improved” or “much improved.” Over a period of 12 weeks, the improvement (reduction) in mean scores on the IRLS scale was greater, by 4.5 points, among participants receiving pregabalin than among those receiving placebo (p<0.001), and the proportion of patients with symptoms that were very much improved or much improved was also greater with pregabalin than with placebo (71.4 percent vs. 46.8 percent, p<0.001). The rate of augmentation over a period of 40 or 52 weeks was significantly lower with pregabalin than with pramipexole at a dose of 0.5 mg (2.1 percent vs. 7.7 percent, respectively, p=0.001) but not at a dose of 0.25 mg (2.1 percent vs. 5.3 percent, respectively, p=0.08).



The rate of study discontinuation due to adverse events, however, was lower in the groups receiving pramipexole — 18.5 percent for those receiving 0.25 mg and 23.9 percent for those receiving 0.5 mg — than for the group receiving pregabalin (27.5 percent). The most common adverse events prompting discontinuation in the pregabalin group were somnolence and dizziness; while nausea and headache were the main reasons people dropped out in the group taking pramipexole. Most adverse events were mild to moderate in severity, the study authors reported.

Dr. Allen believes it is the repeated off- and on-stimulation of dopamine that leads to the worsening of symptoms in RLS. The longer-acting dopamine agonists, such as rotigotine delivered through a patch, do not seem to cause significant augmentation, he said. “But we need more experience with this class of drugs,” he said.

“The preference for dopaminergic treatment of RLS has been partly based on the assumption that RLS is due primarily to dopamine abnormalities. Our findings that pregabalin, which has no direct effect on dopaminergic systems, is effective in the treatment of RLS casts doubt on this basic rationale,” the scientists concluded.

Pfizer, which manufactures pregabalin, sponsored the study, though the investigators who were the authors on this report supported the design of the study, analyzed the clinical data, and drafted the published report. “Pfizer is not going after an indication for restless leg syndrome for the drug possibly because of the limited patent life on the drug,” Dr. Allen said, adding generic versions will follow.

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Philip Becker, MD, clinical professor in the department of psychiatry at the University of Texas Southwestern Medical Center in Dallas, said that the latest treatment guidelines from the International Restless Leg Study Group suggests a combination of low-dose medicines for moderate to severe RLS.

He is not surprised by the latest study findings. “I changed my prescribing habits a while back,” he said. “I continue to use first-line dopamine agents, but in lower doses. The use of combined therapies makes the most sense. A little bit of a lot of different things is better than a lot of one thing.”

What he found most interesting is that the findings suggest that “our supposition that dopamine is central to restless leg has to be rethought. The interaction with other neurotransmitter systems must be considered.”

Mark J. Buchfuhrer, MD, consulting assistant professor at Stanford University and head of the RLS Clinic, said that this is one of the first head-to-head comparisons of an alpha-2-delta drug and a dopamine agonist.

He said that this is a wake-up call to doctors who prescribe these medicines to their patients with restless legs syndrome. “Most physicians who treat restless leg syndrome give more and more medicine, and they are ultimately adding fuel to the fire,” he said. “These patients end up being referred to RLS specialists like us. We are seeing a lot of patients with very serious symptoms. It took several years to discover that it is a bigger problem than we ever realized.”

“I don't like to start short-acting dopamine agonists in new patients,” said Dr. Buchfuhrer. “But often that is what insurance companies will pay for.”

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•. Allen RP, Chen C, Garcia-Borreguero D, et al. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med 2014; 370:621–631.
    •. Allen R, Chen C, Soaita A, et al. A randomized, double-blind, 6-week, dose ranging study of pregabalin in patients with restless legs syndrome. Sleep Med 2010;11:512–519.
      © 2014 American Academy of Neurology