Elsevier

Sleep Medicine

Volume 9, Issue 8, December 2008, Pages 874-881
Sleep Medicine

Original Article
Effect of pramipexole on RLS symptoms and sleep: A randomized, double-blind, placebo-controlled trial

https://doi.org/10.1016/j.sleep.2008.09.001Get rights and content

Abstract

Background

Patients with Restless Legs Syndrome (RLS) often seek treatment because of sleep problems related to nocturnal symptoms. Our goal was to test the ability of pramipexole to improve sleep in RLS patients and to reconfirm its efficacy for primary RLS symptoms.

Methods

Adults with moderate or severe RLS were randomized to receive placebo or pramipexole (flexibly titrated from 0.25 to 0.75 mg), 2–3 h before bedtime for 12 weeks. The co-primary outcome measures were change in Medical Outcomes Study (MOS) sleep disturbance score and International RLS Study Group Rating Scale (IRLS) score at 12 weeks.

Results

The intent-to-treat population included 357 patients: 178 received pramipexole and 179 received placebo. At 12 weeks, the adjusted mean change from baseline was greater for pramipexole (vs. placebo) for IRLS score (−13.4 ± 0.7 vs. −9.6 ± 0.7) and MOS sleep disturbance score (−25.3 ± 1.5 vs. −16.8 ± 1.5) (p  0.0001; ANCOVA). Responder rates (clinical and patient global impression and IRLS) were also significantly higher in the pramipexole group. RLS-QOL score was improved over placebo at Week 12 (p < 0.01) as were MOS sleep adequacy (p = 0.0008) and quantity (p = 0.08) scores. Nine percent of patients in each group withdrew because of adverse events.

Conclusions

Pramipexole is effective and well-tolerated for RLS and related sleep disturbance.

Introduction

Restless Legs Syndrome (RLS) is a common sensorimotor disorder whose predominant symptom is an urgent need to move the legs that is usually accompanied by uncomfortable leg sensations [1]. By definition, the symptoms of RLS are at their worst in the evening and night and during periods of inactivity. Sleep-related problems were reported by nearly 90% of sufferers in a primary care study, with 43% reporting a sleep-related symptom as most troublesome [2]. RLS patients typically report difficulties falling asleep or staying asleep, disturbed sleep, or excessive daytime sleepiness [2], [3], [4]. The severity of sleep disturbance correlates with the severity of RLS symptoms [5] and patients with severe RLS may sleep only 3–5 h per night [6].

Chronic sleep deprivation can negatively affect daytime functioning; up to 85% of RLS patients report impairments during the day [4]. Lack of energy, exhaustion, sleepiness, poor concentration, and mood disturbance are common daytime complaints in RLS [2], [4]. Productivity is affected and 13% of patients report missing work because of RLS-related tiredness [4]. Based on Short Form 36 Health Survey data, quality of life (QOL) is significantly reduced in RLS as compared with age- and sex-adjusted US population norms and is similar to that reported by patients with clinical depression or type 2 diabetes [4]. Because of the substantial physical and psychological burden associated with RLS, prompt diagnosis and appropriate treatment is critical in patients with moderate or severe disease.

Pramipexole is a nonergoline D2/D3 dopamine agonist with proven efficacy for the treatment of RLS. Results from several double-blind, placebo-controlled studies demonstrated the superiority of pramipexole for the broad range of RLS symptoms as measured by the International RLS Study Group Rating Scale (IRLS), global improvement scales (Patient Global Impression [PGI] and Clinical Global Impressions – Global Improvement [CGI-I]), QOL scales, and other assessments [7], [8], [9], [10]. An objective improvement in sleep latency was noted in a polysomnography study [8] and subjective sleep improvements were documented using a visual analog scale that evaluated satisfaction with sleep [7], [9], [10]. A detailed assessment of subjective sleep improvements was not performed in these studies, however.

Because sleep disruption is a frequent and troubling consequence of RLS, the primary objective of this study was to more fully describe the effects of pramipexole on sleep-related outcomes, while also confirming its efficacy for RLS. Sleep is a multi-dimensional construct requiring a multi-dimensional tool for thorough assessment. To assess sleep in our study, we used a self-rated scale developed for the Medical Outcomes Study (MOS) that measured several important sleep-related dimensions including sleep disturbance, sleep adequacy, daytime somnolence, respiratory problems, and sleep quantity [11]. The MOS sleep scale is a reliable, validated instrument that has been used in studies of various chronic conditions including neuropathic pain [11], congestive heart failure [12], and clinical depression [12], in addition to RLS [13].

Section snippets

Patients

From August 2006 until May 2007, men and women (18–80 years old) with RLS diagnosed according to International RLS Study Group criteria [1] were enrolled at 49 outpatient centers in Europe. Patients were required to have RLS symptoms at least 2–3 times per week in the 3 months before study entry and a score >15 on the International RLS Study Group Rating Scale (IRLS) at baseline. Patients were excluded for medical disorders that might compromise the evaluation of study results or increase a

Patients and treatment

The safety population comprised 369 patients, 182 in the pramipexole and 187 in the placebo group. Twelve patients had no post-treatment efficacy data, thus the ITT population contained 357 patients, 178 in the pramipexole and 179 in the placebo group. Fig. 1 depicts patient disposition. Seventy-nine (21.4%) patients discontinued the study drug prematurely. The most common reason for study discontinuation was lack of efficacy (33 [17.6%] in the placebo group vs. 5 [2.7%] in the pramipexole

Discussion

Sleep disturbance is a common and disabling RLS-related symptom and is often the presenting complaint when a patient with undiagnosed RLS seeks treatment [17]. Poor sleep may impair next-day function, contributing to fatigue, depressed mood, impaired concentration, and reduced QOL [2], [4]. Specific examination of RLS patients using the Fatigue Severity Scale also shows high fatigue scores in many RLS patients [18]. Three large double-blind trials have previously documented subjective

Disclosures

Luigi Ferini-Strambi received personal compensation for serving on a scientific advisory board for Boehringer Ingelheim, UCB, GSK, Sanofi-Aventis, and Schwarz Pharma. Markku Partinen has received speaker honoraria and consulting compensation from GSK, Boehringer Ingelheim, Orion, Sanofi-Aventis, and UCB. K. Ray Chaudhuri has received honoraria for lectures in sponsored symposiums by Boehringer Ingelheim, Schwarz, Orion, Novartis, GSK, and Britannia Pharmaceuticals. Mandy Sohr, Daniela Verri,

Acknowledgements

This study was supported by Boehringer Ingelheim GmbH.

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