1. Pregabalin (Lyrica) provided significantly greater improvement in treatment outcomes in patients with restless legs syndrome (RLS) when compared to placebo.
2. Pregabalin was associated with lower rates of disease augmentation (iatrogenic worsening) as compared to pramipexole.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Restless legs syndrome (RLS), also known as Willis-Ekbom disease, has a prevalence of approximately 7% in North America and Europe according to epidemiologic studies. RLS can profoundly disturb sleep and quality of life in its more severe forms; however, due to a lack of understanding of its pathophysiology, development of a targeted and effective therapy remains elusive. The current first-line treatment is with dopamine agonists which has several drawbacks, including a phenomenon known as “augmentation” or iatrogenic worsening with prolonged treatment. There is also the possibility of more serious side effects such as psychosis and dyskinesia with dopaminergic therapies. The current study by Allen et al. reported that pregabalin, an α2δ ligand, was non-inferior to pramipexole, a dopamine agonist. Pregabalin was also shown to have a much lower rate of augmentation after one year of treatment compared to pramipexole. As a result, pregabalin may be an effective alternative for dopamine agonists in RLS patients when augmentation is a concern or if there is a contraindication for dopamine agonists. This study was an adequately powered, double-blind, placebo-controlled trial with over 700 patients.
The study was funded by Pfizer.
Relevant Reading: Restless legs syndrome
Study Author, Dr. Richard Allen, PhD, talks to 2 Minute Medicine: Associate Professor of Neurology, Johns Hopkins Bayview Medical Center
“This study supports a change in medical practice for treatment of RLS. It indicates there are alternatives to the currently commonly used pramipexole and ropinirole that are as effective and do not produce worsening of RLS with long-term treatment. Pregabalin unlike pramipexole affects a non-dopaminergic system and does not produce the RLS worsening.”
In-Depth [randomized, controlled, double-blind study]: This study compares the efficacy and safety of pregabalin to pramipexole and placebo in treating restless legs syndrome (RLS). Pramipexole is FDA-approved for treating RLS but may cause iatrogenic worsening of symptoms, known as augmentation. A total of 719 patients were randomized at approximately to receive one of the following daily regimens: 300 mg pregabalin, 0.25 mg pramipexole, 0.5 mg pramipexole, or placebo (for 12 weeks, followed by 40 weeks of a randomly assigned active treatment). Symptoms were evaluated using the International RLS (IRLS) Study Group Rating Scale (score 0 to 40, with higher score indicating worse symptoms) and the Clinical Global Impression of Improvement Scale (CGI-I).
Patients who received pregabalin had a significantly greater reduction (improvement) in the IRLS score compared to placebo at 12 weeks (mean change from baseline vs. placebo, -4.5; 95% CI, -5.9 to – 3.2). The pregabalin group also had a higher proportion of patients reporting very much or much improved symptoms on the CGI-I evaluation compared to placebo (71.4% vs. 46.8%, P<0.001). Among patients receiving 40 or 52 weeks of active treatment, augmentation occurred in 5 (2.1%) patients receiving pregabalin, as compared to 12 (5.3%) patients receiving 0.25 mg pramipexole (P=0.08) and 18 (7.7%) patients receiving 0.5 mg pramipexole (P=0.001).
The noninferiority assessment showed that pregabalin resulted in a greater reduction in the IRLS score at 12 and 52 weeks compared to both 0.25 mg pramipexole and 0.5 mg pramipexole (P<0.001 for all comparisons).
In safety analysis, the rate of discontinuation due to adverse events was higher in the pregabalin group (27.5%) compared to the pramipexole groups (18.5% for 0.25 mg and 23.9% for 0.5 mg). The most common adverse events were dizziness, somnolence, fatigue and headache.
By Xiaozhou Liu and Adrienne Cheung
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