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Pregabalin Reported to Improve Restless Legs Symptoms and Sleep

SEATTLE, WA—Pregabalin (Lyrica) may be a new therapeutic option for patients with restless legs syndrome (RLS), according to a double-blind, placebo-controlled study reported here at a late-breaking session at the AAN annual meeting by Diego Garcia-Borreguero, MD, director of the Sleep Research Institute in Madrid, Spain. The study was supported by a grant from Pfizer, Ltd.


DR. MICHAEL SILBER said the study was promising, in view of its positive results on RLS symptoms, and the level of evidence provided by a double-blind, randomized study.

“RLS symptoms worsen at night, and patients often do not get adequate sleep. Pregabalin is a promising alternative to other drugs used to treat RLS, especially because of its superior effects on sleep quality,” Dr. Garcia-Borreguero said.

Pregabalin, an alpha-2 delta receptor modulator, is approved for epilepsy, neuropathic pain, generalized anxiety, and fibromyalgia. Drugs approved for RLS include pramipexole (Mirapex) and ropinerole (Requip), both dopamine agonists. “Dopamine agonists, although highly effective, are not universally effective. They are well tolerated in the short- and long-term, but they don't improve sleep. Further, some patents develop augmentation of RLS, that is, worsening of symptoms from before starting treatment,” Dr. Garcia-Borreguero said.


In the 12-week treatment study 30 patients diagnosed with idiopathic RLS were randomized to pregabalin and 28 to placebo. After a placebo run-in phase for two weeks, there was a 12-week treatment period. “We had a placebo run-in phase to minimize the number of placebo responders,” he explained.

Pregabalin was titrated up to 300 mg/day orally, with a weekly flexible adjustment to a maximum of 600 mg/day. Doses under 450 mg/day were taken at 9 PM. Doses over 450 mg/day were given twice a day at 2 PM and 9 PM. Mean dose at week 12 was 337.5 mg/day of pregabalin; mean dose of placebo 400 mg/day.

The main endpoints were changes in several sleep and restless leg scales. At baseline, both treatment groups were assessed to have severe RLS, based on scores on the International Restless Legs Syndrome Study Group Rating Scale (IRLS).

The group taking pregabalin experienced significantly greater improvements in symptoms compared to those on placebo based on IRLS scores (p=.02). There were similar improvements on other measures, including RLS symptom remission (defined as final IRLS score <7), which was reached by 63.3 percent of the pregabalin-treated group and 28.6 percent for placebo.

“The placebo response was sizable, which may have resulted from the flexible dose design, which pushes up the final effective dose,” he said.

Dr. Garcia-Borreguero noted that the improvements in IRLS scores were similar to those for pramipexole, reported in 2008 in Sleep Medicine.

In other areas, the number of periodic leg movements per hour, as measured by the periodic leg movement index (PLMI), was significantly improved in 66 percent who took pregabalin compared with those on placebo, whose PLMs worsened by 29 percent (p > .001).

Those taking pregabalin also were able to have near normal restoration of sleep, with an increase of about 30 minutes of slow wave restorative sleep, Dr. Garcia-Borreguero said, and the treatment was well tolerated. The most common treatment-related effect was unsteadiness, reported in 33.3 percent of pregabalin-treated patients versus 16.7 percent of placebo patients. Both groups had similar bouts of daytime sleepiness at about 10.1 percent for pregabalin versus 11.1 percent for placebo, and headaches were more common in the placebo group at 22 percent versus none for the experimental group.


“This is exciting news for our patients. Pregabalin is a different class of medication and represents another option for our patients,” said David Charles, MD, vice-chair of neurology and director of the Movement Disorders Clinic at Vanderbilt University in Nashville, TN. Dr. Charles, who was not involved in the study, said he eagerly awaits the publication of the full manuscript in a peer-reviewed journal.

Michael Silber, MD, professor of neurology and co-director of the Center for Sleep Medicine at Mayo College of Medicine in Rochester, MN, said that the study of pregabalin was promising, in view of its positive results on RLS symptoms, and the level of evidence provided by a double-blind, randomized study. He applauded the use of sleep endpoints in a study of RLS, calling the benefits of pregabalin on sleep architecture “intriguing.”

“I always prefer to see a double-blind study,” Dr. Silber said. “Ideally, we would have head-to-head randomized, double-blind comparisons of drugs available to treat RLS, but this is unlikely to happen.”

At present, Dr. Silber would initiate treatment of RLS with either pramipexole or ropinerole, because these drugs have the most supportive evidence and the longest experience. Gabapentin or pregabalin would be reasonable off-label alternatives if the dopamine agonists did not provide optimal relief or side effects developed, he said.


• Ferini-Strambi L, Aarskog D, Albrecht S, et al. Effect of pramipexole on RLS symptoms and sleep: A randomized, double-blind, placebo-controlled trial. Sleep Med 2008;9:874–881.