Elsevier

Sleep Medicine

Volume 13, Issue 10, December 2012, Pages 1280-1285
Sleep Medicine

Original Article
Long-term use of pramipexole in the management of restless legs syndrome

https://doi.org/10.1016/j.sleep.2012.08.004Get rights and content

Abstract

Objective

Few studies have examined the long-term use of dopamine agonists for restless legs syndrome (RLS). We report a cohort study of 50 patients initially prescribed pramipexole between 1998 and 2002. The objective was to determine duration of treatment, long-term efficacy, development of side effects and augmentation over an extended period.

Methods

We performed a long-term analysis on a previously reported group of patients initially followed for a mean of 27.2 months. Data were collected using retrospective chart reviews, written surveys and systematic telephone interviews.

Results

Pramipexole was used for a mean of 8 years (range 0.6–12 years). Nine (18%) discontinued pramipexole because of poor efficacy (four), impulse control disorders (ICD) (two), augmentation (one) and resolved symptoms (two). Pramipexole was reported completely effective in 40% (compared to 67% at the end of the initial study), partially effective in 58% and ineffective in 2%. The median daily dose increased from 0.38 mg after initial stabilization to 1.0 mg at the end of the study. As many as 74% of patients experienced side effects. A total of 56% reported daytime sleepiness including 10% reporting sleep attacks while driving and 10% developed ICDs. Augmentation developed in 42% of patients, after a mean of 16.5 months, and no later than 4.1 years after commencing treatment. A total of 28% needed additional non-dopaminergic medications.

Conclusion

The efficacy of pramipexole dropped with time, with increase in dose and addition of other agents, although the majority of patients remained on the drug. Problems included the development of augmentation within the first 4 years of therapy and side effects such as sleepiness increasing with time and the development of ICDs. The study highlights the need for further research into alternative non-dopaminergic treatments for RLS.

Introduction

Restless legs syndrome (RLS) (Willis–Ekbom disease) is characterized by an urge to move the legs, usually associated with uncomfortable sensations. RLS symptoms manifest during rest, are relieved with movement and are typically most severe in the evening or night [1], [2]. RLS is associated with insomnia in 50–85% of cases, affecting both sleep onset and sleep maintenance [3]. At least 80% of patients with RLS have periodic limb movements of sleep, which may lead to sleep disruption [4]. RLS is a common disorder affecting between 5% and 15% of the general population, and prevalence has been observed to rise with age [4], [5], [6], [7], [8], [9], [10]. The prevalence of symptomatic primary RLS in the United States and Europe is estimated to be 2.4–4.4%, and 1.5–2.7% experience symptoms at least twice a week, resulting in moderate to severe distress [5], [6], [7], [8], [9], [10], [11], [12]. Pharmacologic treatment options for RLS include dopamine agonists, opioids, benzodiazepines and anticonvulsants.

Dopamine agonists, including pramipexole, are the mainstay of treatment for daily RLS (defined as symptoms frequent and troublesome enough to require daily therapy) [13]. Multiple controlled studies have demonstrated their efficacy; however, long-term use in clinical practice is constrained by the development of side effects and augmentation in many patients [3]. Although the mechanism of dopamine agonists in treating RLS is uncertain, it likely involves stimulation of dopamine receptors in the striatum. Pramipexole, a non-ergot agonist, is primarily metabolized through the kidneys and has a half-life of 8–12 h [14].

We have previously reported a study of 60 RLS patients initiated on pramipexole and followed for a mean of 27 months [2]. We now report an extended study on a cohort of 50 of these patients followed for a mean of 8 years. The goals of our study were to determine over an extended period the duration of therapy in this patient cohort, dosing parameters, long-term efficacy, side-effect profile and development of augmentation.

Section snippets

Methods

Fifty of the original 60 adult patients were recruited from the previous study [2]. The other 10 patients had discontinued pramipexole within 4 months of initiation of therapy due to either side effects or lack of efficacy. Each patient was diagnosed with RLS in the Mayo Clinic Center for Sleep Medicine. Patients were initiated on pramipexole therapy between 1 January 1998, and 31 December 1999.

Our study used data obtained from a retrospective chart review (n = 50), a written survey (n = 22) (

Demographic information

Fifty patients were identified and studied. Forty-six patients (92%) resided in Minnesota, Iowa or Wisconsin. Thirty-one were females (62%); 19 were males (38%). The mean age at onset of RLS symptoms was 42 years. The mean age at time pramipexole therapy was initiated was 60 years. Co-existing medical, sleep and psychiatric conditions included peripheral neuropathy (two patients), parkinsonism (one patient), obstructive sleep apnea (eight patients), central sleep apnea (one patient) and

Discussion

The results of our study suggest that pramipexole decreases in efficacy over time, dose increases are required and patients frequently need adjunct therapies. Data previously gathered on this cohort over a mean follow-up time of 27 months demonstrated that pramipexole was completely effective in 67% of patients [2]. In our study, after a mean follow-up period of 8 years, pramipexole was found to be completely effective in only 40% of patients. Despite this decrease in efficacy, 82% of our

Conflict of interest

The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2012.08.004.

. ICMJE Form for Disclosure of Potential Conflicts of Interest form.

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