AAN 2009: Pregabalin Shows Promise in Restless Legs Syndrome

Pauline Anderson

April 29, 2009

April 29, 2009 (Seattle, Washington) — Pregabalin (Lyrica, Pfizer), a drug already used to treat seizures, neuropathic pain, and generalized anxiety, may be an effective treatment for the estimated 1 in 10 people who have restless legs syndrome (RLS).

A 12-week double-blind trial showed that almost two-thirds of patients with RLS who took pregabalin experienced symptom remission and improved sleep quality.

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"There was a quasi-complete normalization of sleep," Diego Garcia-Borreguero, MD, director of the Sleep Research Institute in Madrid, Spain, told a press conference here. Disrupted sleep is a main complaint of patients with RLS, he said. The drug improved motor as well as sensory symptoms, he added.

The results were presented here at the American Academy of Neurology (AAN) 61st Annual Meeting.

Problems With Current RLS Agents

Dr. Diego Garcia-Borreguero

Currently, RLS is typically treated with 1 of 2 agents that target dopaminergic activity, pramipexole (Mirapex, Boehringer Ingelheim) and ropinirole (Requip, GlaxoSmithKline). These agents have 3 main problems, said Dr. Garcia-Borreguero. One is that although they can be highly effective, not all patients respond to them. Another drawback is that while these drugs treat restless leg symptoms, they do not significantly improve sleep symptoms. In addition, these drugs are effective only over the short term; a significant percentage of patients taking them over a longer period experience a worsening of symptoms called RLS augmentation.

"So taken together, there’s a need for research into new drugs with a different mechanism of action that might not have these kinds of problems," he said.

Pregabalin, a modulator of the alpha-2 delta receptor, has been approved for epilepsy, neuropathic pain, generalized anxiety, and fibromyalgia. This is the first controlled trial of this agent in the treatment of RLS, he noted.

Drug is "Unselective"

Calling the drug "unselective," Dr, Garcia-Borreguero said pregabalin could have effects on several neurotransmitters, including dopamine, norepinephrine, glutamate, and serotonin. He added that the drug works in a similar way to gabapentin (Neurontin, Pfizer), another agent being investigated in RLS.

For this study, researchers randomized 58 patients with RLS to receive treatment with either pregabalin (28 patients) or placebo (30 patients) for 12 weeks. They used flexible dosing: doses that started at 150 mg per day could be decreased or increased every 2 weeks to a maximum of 600 mg/day. The medication was administered once a day at 9 PM, but doses over 450 mg a day were administered twice daily, at 2 PM and 9 PM.

Researchers assessed RLS symptoms using the International RLS (IRLS) scale and sleep architecture using polysomnography at the beginning and end of the trial.

The change in IRLS score was significantly more pronounced with the active drug. Of the patients taking pregabalin, 63.3% achieved symptom remission, defined as a final IRLS score of less than 7, compared with 28.6% of patients taking placebo.

"Virtually all symptoms disappeared in 63% of patients," said Dr. Garcia-Borreguero.

The active treatment also resulted in an improvement of 66% in the Periodic Leg Movement Index, while placebo was associated with worsening on this index by 29% (P < .001).

The approximately 30 to 35 movements per hour were reduced to about 10, which is within the normal range, said Dr. Garcia-Borreguero.

Sleep Quality Improved

As for sleep quality, the study found that those taking the active treatment spent more time in stages 3 and 4 (deep or slow-wave sleep) and less time in lighter sleep stages than those taking placebo. "They had a mean of 30 more minutes of slow-wave sleep," said Dr. Garcia-Borreguero.

The mean effective dose of pregabalin to achieve these benefits was about 337.5 mg per day.

RLS, which has a strong genetic component, affects an estimated 10% of the population. As many as one-third of these require treatment, said Dr. Garcia-Borreguero.

The study was supported by Pfizer but run independently by Dr. Garcia-Borreguero's group.

Asked for his comment by Medscape Neurology & Neurosurgery, David Charles, MD, vice chair of neurology and director of the Movement Disorders Clinic at Vanderbilt University, in Nashville, Tennessee, said: "It's exciting news that this medication may prove useful in the treatment of RLS, a very troubling condition for many of our patients. The authors are to be commended for conducting this study, and I look forward to seeing the final publication." 

Another double-blind randomized study of pregabalin released at the AAN meeting found that this drug is also effective in the treatment of posttraumatic peripheral neuropathic pain. In this study, 252 patients with a pain score of 4 or more (0 – 10 scale) received either placebo or pregabalin (150 – 600 mg). As well as reducing pain, the drug also significantly improved sleep interference, the researchers, with first author Robert van Seventer MD, from Amphia Ziekenhuis, in Breda, the Netherlands, report.

Pregabalin is not currently approved for RLS in the United States or Europe, and Dr. Garcia-Borreguero said he does not recommend any off-label use of this drug.

The study was supported by Pfizer. Dr. Garcia-Borreguero reports he has served as a consultant and speaker for Pfizer, GlaxoSmithKline, Boehringer-Ingelheim, UCB, Jazz Pharma, Sanofi-Aventis, Lundbeck, and OrionPharma.

American Academy of Neurology 61st Annual Meeting: Abstracts LB1.002, P05.056. Presented April 29, 2009. Abstract

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