In Adults with Restless Legs Syndrome, Pregabalin Has Greater Efficacy With Less Iatrogenic Worsening of Symptoms Than Higher Doses of Pramipexole

EBM Focus - Volume 9, Issue 9

Read the Complete EBM Focus and Earn CME.

Reference: N Engl J Med 2014 Feb 13;370(7):621 (level 2 [mid-level] evidence)

Dopamine agonists are currently the standard first-line treatment for patients with daily symptoms of restless legs syndrome (RLS). A Cochrane review has provided high-quality evidence that dopamine agonists reduce symptoms of RLS (Cochrane Database Syst Rev 2011 Mar 16;(3):CD006009), and the American Academy of Sleep Medicine guidelines currently recommend treatment of these patients with either pramipexole or ropinirole (Sleep 2012 Aug 1;35(8):1039 full-text). However, dopamine agonists may result in worsening of symptoms months after treatment, an effect referred to as augmentation. The anticonvulsant pregabalin is an alternative treatment that was previously found to be beneficial for RLS in a small randomized trial (Neurology 2010 Jun 8;74(23):1897). Now, a randomized trial compares pregabalin to placebo and to 2 separate doses of pramipexole in adults with RLS.

A total of 731 adults with moderate-to-severe RLS symptoms for ≥ 6 months were randomized to 1 of 4 oral treatments for 12 weeks: pregabalin 300 mg/day, pramipexole 0.25 mg/day, pramipexole 0.5 mg/day, or placebo. Patients initially randomized to placebo were re-randomized to active treatment with pregabalin, pramipexole 0.25 mg/day, or pramipexole 0.5 mg/day for an additional 40 weeks. RLS symptoms were assessed with the International RLS Study Group Rating Scale (range 0-40, with higher scores indicating greater symptom severity, and the minimal clinical important difference defined as 3 points). At baseline, all patients had an RLS symptom score ≥ 15 points (mean score 22.3 points). The 12-week change in RLS symptom score was a primary analysis, and included 696 patients (95% of those randomized) who received study treatment and had at least 1 post-baseline assessment.

The mean reduction from baseline in RLS symptom score at 12 weeks was 11.4 points with pregabalin (p < 0.001 vs. placebo), 7.8 points with pramipexole 0.25 mg/day (not significant vs. placebo), 10.1 points with pramipexole 0.5 mg/day (p < 0.001 vs. placebo), and 6.9 points with placebo. Pregabalin was associated with lower RLS symptom scores than pramipexole 0.25 or 0.5 mg/day at 52 weeks (p < 0.001 for each). The proportion of patients with a clinical global impression of “much improved” or “very much improved” symptoms at 12 weeks was 71.4% with pregabalin (p < 0.001 vs. placebo, NNT 4), 51.2% with pramipexole 0.25 mg/day (not significant vs. placebo), 62.7% with pramipexole 0.5 mg/day (p = 0.002 vs. placebo, NNT 7), and 46.8% with placebo. The augmentation rates at the end of trial were 2.1% with pregabalin (p < 0.001 vs. pramipexole 0.5 mg, NNT 18, and p = 0.08 vs. pramipexole 0.25 mg), 5.3% with pramipexole 0.25 mg, and 7.7% with pramipexole 0.5 mg.

Although dopamine agonists have demonstrated efficacy in reducing symptoms of restless legs syndrome, the augmentation of symptoms after treatment initiation is now recognized as an important limitation. A recent cohort study found that augmentation rates were consistent after the first year and persisted for up to 10 years, with only 58% of patients on pramipexole continuing with treatment after 5 years (Sleep Med 2011 May;12(5):440). This new randomized trial shows that pregabalin is at least as effective as pramipexole, with a significantly lower rate of augmentation. However, it is important to keep in mind that pregabalin has not been studied extensively in this patient population, and long-term safety and efficacy data are not yet available.

For more information see the Restless legs syndrome (RLS) topic in Dynamed.