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-Borreguerro, 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 here 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.
In addition, he noted, augmentation symptoms can spread and become less focal, moving from the bottom to the top of the legs and ultimately to the arms. Further, he noted that 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 in RLS, as well as the rate of augmentation with pregabalin in comparison with pramipexole, the researchers conducted a 52-week multicenter study in Europe and the United States that included 719 RLS patients.
Patient demographics and clinical characteristics were similar. 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.
The first 12 weeks of the trial included 4 arms — placebo, pramipexole 0.25 mg/day, pramipexole 0.5 mg/day, and pregabalin 300 mg/day. After 12 weeks, the participants in the placebo group were randomly assigned to 1 of the 3 remaining study arms.
The study´s coprimary endpoints included the following:
Change in baseline symptom severity, as assessed by International RLS Study Group Rating Scale (IRLS), for pregabalin vs placebo over 12 weeks The proportion of patients responding to treatment with pregabalin compared with placebo over 12 weeks, as measured by the Clinical Global Impression–Improvement (CGI-I) scale Rate of augmentation during 40 or 52 weeks of treatment with pregabalin vs pramipexole In the 12-week phase of the study, the investigators found that the efficacy of pregabalin 300 mg/day was superior to placebo and to pramipexole at both doses.
“RLS treatment outcomes were significantly improved with pregabalin compared with placebo, as measured by IRLS total score (P < 0.0001) and proportion of CGI-I responders — those reporting symptoms of ´very much improved´ or ´much improved´ — (P < 0.0001),” the investigators report.
Role as First-Line Therapy?
At 40/52 weeks, augmentation in the pregabalin group was 2.1%. This compared with 5.3% and 7.1% in the pramipexole 0.25 mg/day (P = .083) and 0.5 mg/day (P = .0012) groups, respectively.
Although current guidelines recommend dopamine agonists as first-line therapy for clinically relevant RLS, Dr. Garcia-Borreguero said that on the basis of these results, it may be worthwhile to consider alpha-2-delta ligands as another potential first choice.
“Right now, dopamine agonists are the treatment of choice. Period. But in light of evidence from studies like this one, this is being reviewed. 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,” said Dr. Garcia-Borreguero.
He added that anecdotal evidence suggests there is a role for combination therapy.
“We normally start with dopamine agonists, but whenever we reach a point where efficacy is not sufficient, we use an alpha-2-delta ligand. The problem is that we don´t have any data for combination therapy at the moment, and these types of studies are strongly needed,” said Dr. Garcia-Borreguero.
“But the important finding from this study is that if you can sufficiently reduce symptoms with an alpha-2-delta ligand, I would probably start treatment with that,” he said.
American Academy of Neurology (AAN) 64th Annual Meeting. Emerging Science Abstract 001. Presented April 26, 2012.