Elsevier

Sleep Medicine

Volume 11, Issue 6, June 2010, Pages 512-519
Sleep Medicine

Original Article
A randomized, double-blind, 6-week, dose-ranging study of pregabalin in patients with restless legs syndrome

https://doi.org/10.1016/j.sleep.2010.03.003Get rights and content

Abstract

Objective

This study evaluated the dose-related efficacy and safety of pregabalin in patients with idiopathic restless legs syndrome (RLS).

Methods

This six-arm, double-blind, placebo-controlled, dose–response study randomized patients (N = 137) with moderate-to-severe idiopathic RLS in an equal ratio to placebo or pregabalin 50, 100, 150, 300, or 450 mg/day. The dose–response was characterized using an exponential decay model, which estimates the maximal effect (Emax) for the primary endpoint, the change in the International Restless Legs Study Group Rating Scale (IRLS) total score from baseline to week 6 of treatment. Secondary outcomes included Clinical Global Impressions-Improvement Scale (CGI-I) responders, sleep assessments, and safety.

Results

The separation of treatment effect between placebo and pregabalin began to emerge starting at week 1 which continued and increased through week 6 for all dose groups. The IRLS total score for pregabalin was dose dependent and well characterized for change from baseline at week 6. The model estimated 50% (ED50) and 90% (ED90) of the maximal effect in reducing RLS symptoms that occurred at pregabalin doses of 37.3 and 123.9 mg/day, respectively. A higher proportion of CGI-I responders was observed at the two highest doses of pregabalin (300 and 450 mg/day) versus placebo. Dizziness and somnolence were the most common adverse events and appeared to be dose-related.

Conclusions

In this 6-week phase 2b study, pregabalin reduced RLS symptoms in patients with moderate-to-severe idiopathic RLS. The symptom reduction at week 6 was dose-dependent with 123.9 mg/day providing 90% efficacy. Pregabalin was safe and well tolerated across the entire dosing range.

Introduction

Restless legs syndrome (RLS) is a commonly occurring sensorimotor disorder characterized by the urge to move the legs and usually accompanied by uncomfortable or unpleasant sensations engendered by rest, relieved by movement, and occurring mostly in the evening and the first part of the night [1]. Moderate-to-severe RLS severely disrupts sleep and impairs health-related quality of life (QoL) [2], [3]. Despite gains in understanding the neuropathology of the disorder, current treatment options are mostly limited to long-term, possibly life-long symptomatic therapies.

The range of therapies with government regulatory approval for the treatment of RLS is limited to only levodopa and dopamine receptor agonists (e.g., ropinirole and pramipexole). These have been shown in large, well controlled studies to provide effective and safe treatment for RLS, significantly reducing all of the primary symptoms [4]. Polysomnogram studies, however, indicate that they generally fail to fully correct the sleep disturbance of RLS. In particular, they do not consistently provide significant improvement in total sleep time [5], [6], [7] and, conversely, consistently reduce amounts of slow-wave sleep [5], [7], [8]. Moreover, experience with long-term use of dopaminergic agents in managing RLS has revealed significant problems with early morning rebound of symptoms, augmentation, and the development of compulsive/impulsive behaviors [9], [10], [11], [12], [13], [14]. Augmentation is a complication of dopamine agonist therapy in which RLS symptoms become more severe, occur earlier in the day, or spread to previously unaffected body areas [15], [16], [17]. Thus, there is a need for developing alternative therapies that address some of the limitations of current dopaminergic treatments. Recent studies have suggested that pregabalin (binding to calcium-channel α2δ subunit [18]) may be effective for treatment of RLS [19], [20]. Results from a double-blind, cross-over study showed that gabapentin, another compound of the same class (α2δ ligand), improved sensory and motor symptoms in RLS as well as sleep architecture and periodic leg movements during sleep [21].These agents offer the possibility of developing an approved nondopaminergic treatment that might address some of these limitations. Therefore, this phase 2b study was undertaken to evaluate the efficacy, safety, and the dose response for pregabalin treatment in RLS.

Section snippets

Study population

Male and female patients aged 18–65 years were eligible for this study if they had been diagnosed with idiopathic RLS based on the International Restless Legs Scale Study Group criteria [22]. The diagnosis of RLS must have been confirmed by an RLS Diagnostic Confirmation Panel Member using the structured, validated John Hopkins telephone diagnostic interview [23]. Patients were included if for the last 6 months their RLS symptoms occurred for ⩾15 nights predominantly between 5:00 pm and 7:00 am and

Patient characteristics

Baseline demographic and clinical characteristics for the 137 patients randomized to pregabalin or placebo treatment are provided in Table 1. Most patients were white (95.7%, 95.5%, 91.3%, 95.3%, 83.3%, and 91.3% for placebo, 50-, 100-, 150-, 300-, and 450-mg/day pregabalin groups, respectively) and slightly more were female (Table 1). At baseline, most patients had CGI-S ratings of moderately, markedly, or severely ill with no patients rated as normal, not at all ill, or borderline ill.

Discussion

In the current study, dose-dependent reductions in RLS symptoms were observed in patients with moderate-to-severe RLS who received pregabalin for 6 weeks. The pharmacodynamic profile for the dose–response relationship at week 6 for IRLS total score was well described using a non-linear three-parameter exponential decay model, which estimates the Emax. The study results indicated that doses of ⩾150 mg/day would provide the greatest response to drug. Further support for the week 6 results comes

Acknowledgements

This study was funded by Pfizer Inc. The authors gratefully acknowledge the assistance of Alison Gagnon of UBC Scientific Solutions in editing the manuscript and working closely with the first author to incorporate many edits introduced during the writing process by the authors in this multi-author process. Her professional medical writing support was funded by Pfizer Inc. Richard Allen has research grants funded by the National Institutes of Health (USA) and GlaxoSmithKline and in the last 12 

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