LONG-TERM EFFICACY OF PREGABALIN TRUMPS E FOR RLS

The alpha-2-delta ligand pregabalin is more effective and has less augmentation than the dopamine agonist pramipexole for the long-term treatment of restless legs syndrome (RLS), new research shows.

«Over the long-term, we found pregabalin produces more efficacy and less augmentation than pramipexole, but I believe this is a drug class effect and not a peculiarity of this particular drug, such that all alpha-2-delta ligands would offer more efficacy and less augmentation over the long term than dopamine agonists,» principal investigator Diego Garcia-Borreguero, MD, PhD, director of the Sleep Research Institute, Madrid, Spain, told Medscape Medical News.

The study, which is the first long-term active comparator efficacy and augmentation trial in RLS, was presented at the American Academy of Neurology (AAN) 64th Annual Meeting. A chronic neurological disorder, clinically significant RLS affects approximately 2% to 4% of the population, and in the majority of cases long-term treatment is necessary. All of the currently approved treatments are dopamine agonists, which have been primarily tested in short-term studies.

Although efficacious, said Dr. Garcia-Borreguero, a major drawback of these drugs is «augmentation,» in which symptom severity increases over time as a result of treatment. He noted that these symptoms can be severe and can cause significant distress, pain, and loss of sleep. Augmentation symptoms can also spread and become less focal, moving from the bottom to the top of the legs and ultimately to the arms; and as time goes on, moving the limbs offers less and less relief. Pregabalin, he said, has shown promise in RLS, and the researchers hypothesized that its nondopaminergic mechanism of action might induce less augmentation.

To assess the efficacy of pregabalin in comparison with placebo and pramipexole, as well as the rate of augmentation, the researchers conducted a 52-week multicenter study in Europe and the United States that included 719 RLS patients. The mean age of the study population was 54.8 years; 61% were women, and the mean number of years since onset of RLS was 5.0.

Significant Improvement. The first 12 weeks included four arms — placebo, pramipexole 0.25 mg/day, pramipexole 0.5 mg/day, and pregabalin 300 mg/day. After 12 weeks, the placebo group was randomly assigned to one of the three remaining arms. In the 12-week phase, the efficacy of pregabalin 300 mg/day was superior to placebo and to pramipexole at both doses, as measured by the International RLS Study Group Rating Scale (IRLS) and the proportion of Clinical Global Impression–Improvement (CGI-I) responders.

Role as First-Line Therapy? At 40/52 weeks, augmentation in the pregabalin group was 2.1%, compared with 5.3% and 7.1% in the pramipexole 0.25 mg/day and 0.5 mg/day groups, respectively. Although current guidelines recommend dopamine agonists as first-line therapy, Dr. Garcia-Borreguero said that, in light of these results, it may be worthwhile to consider alpha-2-delta ligands as another potential first choice: «We know from retrospective studies that augmentation rates grow year by year, so the effect is cumulative. So if dopamine agonists are used, I think they should be used at the lowest possible level.» He added that anecdotal evidence suggests a role for combination therapy, although data are still lacking.