Elsevier

Sleep Medicine

Volume 9, Issue 8, December 2008, Pages 899-902
Sleep Medicine

Brief Communication
Clinical efficacy of ropinirole for restless legs syndrome is not affected by age at symptom onset

https://doi.org/10.1016/j.sleep.2007.08.017Get rights and content

Abstract

Objective

To determine whether clinical response to the dopamine agonist, ropinirole, in the treatment of primary restless legs syndrome (RLS), depends upon the age-at-onset of RLS symptoms.

Methods

Pooled data from four 12-week, randomized, double-blind, placebo-controlled studies of ropinirole in patients with moderate-to-severe primary RLS were analyzed post hoc. The relationship between age-at-onset and response to treatment, based on change from the baseline International Restless Legs Syndrome Study Group (IRLSSG) rating scale (the International Restless Legs Scale [IRLS]) total score and the proportion of responders (rated ‘much’/‘very much’ improved) on the Clinical Global Impression–Improvement (CGI-I) scale, was explored.

Results

The range of age-at-onset of RLS symptoms was 2–75 years. No relationship was observed between the age-at-onset of RLS symptoms and baseline IRLS total score (correlation r = −0.06), and between dose administered at Week 12 last observation carried forward (LOCF) and age-at-onset (r = −0.04). The age-at-onset by treatment interaction was non-significant (P = 0.952 for the IRLS and P = 0.716 for the CGI-I scale), indicating there was no significant relationship between age-at-onset and the magnitude of ropinirole treatment effect.

Conclusions

These data suggest that ropinirole provides effective relief of symptoms, regardless of age at RLS symptom onset.

Introduction

Restless legs syndrome (RLS) has been found to have two different phenotypes defined best by age-at-onset [1]. Early-onset RLS, defined as onset before the age of 45 years, has been shown to present with slowly progressing symptoms and high familiality, with an approximately 5-fold increase in risk of disease for first-degree relatives [1]. In contrast, late-onset RLS shows rapid symptom progression, little or no familial link, and appears to be influenced more by environmental than genetic factors [1].

Early-onset RLS shows clearer indications of iron deficiency in the brain, with cerebrospinal fluid (CSF) ferritin showing the most marked decrease for those with the earliest age-at-onset [2], [3]. Another study found that CSF levels of the iron-regulatory hormone, pro-hepcidin, were significantly lower in patients with early-onset RLS, but not in those with late-onset RLS, compared with controls [4]. These studies suggest an abnormality of iron regulation, leading to iron insufficiency in regions of the brain in patients with early-onset RLS, that has been confirmed in autopsy studies of early-onset RLS [5]. Patients with late-onset RLS may represent a more diverse pattern of abnormalities.

Given the differences in underlying pathology for early- versus late-onset RLS, an important question is whether or not these phenotypes also differ in treatment responses to dopamine agonists. If the treatment effects do not differ, then it could be argued that despite putative differences in etiology, RLS phenotypes share a common sensitivity to the status of the dopamine system, altering and presumably causing RLS symptoms. The analyses presented here aim to determine whether the clinical response to the dopamine agonist ropinirole – the first United States Food and Drug Administration-approved treatment for moderate-to-severe RLS – depends upon the age-at-onset of RLS symptoms.

Section snippets

Methods

Four 12-week, randomized, double-blind, placebo-controlled studies (RESET PLM, TREAT RLS 1, 2 and TREAT RLS US: protocols 101468/191, 190, 194 and 249) [6], [7], [8], [9] assessed the efficacy and safety of ropinirole in patients with primary RLS.

Patients had a baseline score of at least 15 points on the International Restless Legs Syndrome Study Group (IRLSSG) rating scale (the International Restless Legs Scale [IRLS]) [10]; and at least 15 nights of RLS symptoms during the previous month.

In

Results

Patient demographics (age, age-at-onset, sex and IRLS total score at baseline) within the pooled data set were similar for the ropinirole (n = 496) and placebo (n = 500) groups (Table 1). No relationship was observed between the age-at-onset of RLS symptoms and the baseline IRLS total score, correlation r = −0.06. Mean (standard deviation [SD]) IRLS total score was similar between the two subgroups: <35 years, 23.6 (5.4) points; ⩾35 years, 23.3 (5.7) points. In addition, there was no evidence that

Discussion

The exploration of pooled data from four 12-week pivotal efficacy studies illustrates that the clinical response to ropinirole was not related to the patient-recalled age-at-onset of RLS symptoms. Similarly, the dose of ropinirole after 12 weeks of treatment did not appear to be related to the age-at-onset.

In the literature, the critical onset age for defining RLS phenotypes varies across studies from 26–45 years, probably reflecting different methods for identifying patients and for

References (14)

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