Published: Feb 12, 2014 | Updated: Feb 13, 2014
By John Gever, Deputy Managing Editor, MedPage Today

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Patients with restless legs syndrome (RLS) treated with pregabalin (Lyrica) had as much symptom improvement as those receiving pramipexole (Mirapex) in a large year-long trial, with fewer showing “augmentation.”

Pregabalin was associated with significantly greater improvement relative to placebo during an initial 12-week placebo-controlled phase of the randomized trial and led to improvements similar to those assigned to the higher of two doses of pramipexole (0.25 or 0.5 mg/day), according to Richard Allen, PhD, of Johns Hopkins University, and colleagues.

Over the full 52-week study, during which the placebo-group was re-randomized to the three active drug treatments after 12 weeks, only 2.1% of those receiving pregabalin showed symptom worsening — termed augmentation in the RLS literature — compared with 7.7% of those taking high-dose pramipexole (P=0.001), the researchers reported in the Feb. 13 issue of the New England Journal of Medicine.

During the 12-week placebo-controlled phase, patients assigned to the 0.25-mg pramipexole dose had a symptom trajectory similar to those in the placebo group. The lower pramipexole dose was significantly less effective than the high dose or pregabalin during the second trial phase, but the augmentation rate of 5.3% did not differ significantly from that seen with pregabalin (P=0.08).

Allen and colleagues noted that RLS treatment has traditionally been founded on dopaminergic drugs such as pramipexole, “partly based on the assumption that RLS is due primarily to dopamine abnormalities.”

That pregabalin, an alpha-2-delta ligand with no known dopaminergic activity, was as effective as pramipexole in the trial casts strong doubt on that assumption, the researchers argued.

However, a sleep disorders specialist not involved in the trial told MedPage Today that it was unfortunate that the trial did not also test gabapentin, which is often prescribed off-label for RLS and is sold as a generic drug. (A branded formulation with the generic name gabapentin enacarbil and sold as Horizant is FDA-approved for RLS.)

“Both gabapentin and pregabalin share similar mechanisms of action,” explained Amy Guralnick, MD, of the University of Chicago. “Gabapentin is effective at controlling RLS symptoms and has a lower rate of augmentation than dopamine agonists. Comparing efficacy, adverse events, and augmentation rates in these two very closely related medications would seem logical.”

Noting that the study was funded by Pfizer, which sells pregabalin, Guralnick added, “Obviously, the fact that the study is funded by pregabalin’s manufacturer could have driven the head to head comparison of pregabalin with pramipexole and deliberately omitted comparison with gabapentin.”

Charles Bae, MD, of the Cleveland Clinic, who also was not involved with the study, toldMedPage Today that this is a valid criticism.

But, he said, large randomized trials usually require industry funding and this one is important in part because it clearly validates the role of nondopaminergic drugs for RLS — especially augmentation prevention — which had not previously been done for either drug.

Study Methods and Efficacy Results

The multicenter trial randomized 719 patients initially to placebo, 300 mg/day of pregabalin, or one of the two pramipexole doses for 12 weeks. The placebo group was then reassigned to the other three treatment arms, with all patients evaluated for a total of 52 weeks.

The primary outcome measures were scores on the International RLS Study Group (IRLS) system and the physician-rated Clinical Global Impression of Improvement (CGI-I). Other outcomes included measures of sleep quality, pain and discomfort, and quality of life. All of these secondary outcomes were evaluated with questionnaires; no actigraphy or polysomnography was used to measure sleep quality.

At baseline, IRLS scores averaged about 22 in all groups with standard deviations between 5 and 6.

All groups in the study showed improvements from baseline in each of these measures at the 12-week evaluation, including those assigned to placebo. Mean IRLS scores at that point ranged from 10.9 (SD 7.3) with pregabalin to 15.5 (SD 7.1) with placebo.

In those receiving pregabalin or the higher dose of pramipexole, the improvements were significantly greater than in the placebo group. This was the case for all measures with pregabalin, and for all measures with 0.5-mg pramipexole except for overall sleep quality and number of nighttime awakenings.

After the placebo group’s re-randomization, IRLS scores trended lower (indicating less symptom severity) with pregabalin versus high-dose pramipexole through the entire study period. According to prespecified criteria, Allen and colleagues indicated, pregabalin was superior to both doses of pramipexole in the reduction from baseline in IRLS scores over the full study interval.

CGI-I scores over the final half of the study showed that pregabalin and 0.5-mg pramipexole were virtually indistinguishable, with close to 90% of both groups showing improvement at the final evaluation.

Augmentation and Other Adverse Effects

However, the biggest difference between the two drugs was in augmentation. Allen toldMedPage Today that this feature of RLS is perhaps the most important clinical problem.

“RLS is a progressive disease,” he said, and it appears that, to a large extent, it is the result of treatment with dopaminergic agents.

When the analysis was restricted to the 521 patients who were on active drugs for the full 52 weeks (that is, excluding the initial placebo group), only 1.7% of those taking pregabalin showed symptom worsening, versus 6.6% of those assigned to low-dose pramipexole and 9% of those on high-dose pramipexole (P not reported).

Discontinuations because of adverse events were somewhat more common with pregabalin (28% of those taking the drug for all or part of the study), versus 22% of those who received high-dose pramipexole and 18% of those on low-dose pramipexole).

Dizziness, somnolence, constipation, and altered mental state (including suicidal ideation) appeared more frequent with pregabalin, while pramipexole was associated with higher rates of headache and nausea.

Serious adverse events of all kinds were evenly distributed among the active-drug arms, affecting from 5% to 7% of patients.

Limitations

Both Guralnick and the author of an editorial in NEJM accompanying the report, Sudhansu Chokroverty, MD, of the New Jersey Neuroscience Institute in Edison, N.J., indicated that the study would have been improved with objective measures of sleep quality.

As Guralnick told MedPage Today, “RLS is a clinical diagnosis, which does not need sleep study testing or other objective measures. It would have been supportive, however, if an objective measure of activity and/or sleep latency like actigraphy could have confirmed improvement, corroborating the subjective improvement in RLS symptoms.”

Chokroverty argued that, since some patients on pregabalin showed augmentation, the study did not prove that the phenomenon is purely the result of dopaminergic drug treatment.

“More head-to-head comparisons of treatments are needed, and future trials should include children and elderly patients, those with secondary RLS, and those with mild-to-moderate RLS,” he wrote.

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