Elsevier

Sleep Medicine

Volume 9, Issue 5, July 2008, Pages 572-574
Sleep Medicine

Brief Communication
Augmentation in restless legs syndrome is associated with low ferritin

https://doi.org/10.1016/j.sleep.2007.07.020Get rights and content

Abstract

Background and purpose: Augmentation is a major problem with dopaminergic therapy for restless legs syndrome (RLS), and predictors of augmentation have not yet been identified. We aimed to analyze the relationship between baseline ferritin level and occurrence of augmentation in a retrospective analysis of a prospective double-blind trial of cabergoline versus levodopa on augmentation in RLS.

Patients and methods: Patients who experienced augmentation were compared to patients who did not experience augmentation.

Results: Augmentation symptoms causing premature discontinuation from the study or which were tolerated (n = 36, ferritin: 85 + 59 ng/ml) were associated with lower levels of serum ferritin compared to patients without augmentation (n = 302, ferritin: 118 + 108 ng/ml, p = 0.0062).

Conclusions: Ferritin as a marker of iron storage may play an important role in the pathophysiology of RLS and may prove to be a biomarker for the development of augmentation under dopaminergic therapy.

Introduction

Augmentation is defined as a paradoxical worsening of restless legs syndrome (RLS) during long-term dopaminergic treatment, with involvement of other body parts and occurrence of symptoms earlier the day compared to the time when therapy started and an increase of the overall severity of symptoms [1], [2]. Augmentation has been reported to occur with different frequencies in patients treated with levodopa and dopamine agonists [3]. More severe RLS symptoms at baseline, higher levodopa dose, previous augmentation or familial forms of RLS have been discussed as possible risk factors for augmentation, but results are either contradictory or controlled data are lacking and augmentation seems to be closely linked to any dopaminergic therapy in RLS [4], [5], [6].

Based on the well-known links between low ferritin levels, presumed iron deficiency in RLS, and improvement of RLS by iron substitution [7], [8], we hypothesized that low ferritin levels might be a predictor for augmentation during treatment with dopaminergic drugs.

Section snippets

Methods

Data were re-analyzed from a randomized, double-blind, multi-center prospective controlled study which compared levodopa/benserazide (200–300 mg) and cabergoline (2–3 mg) with presumably different risks for augmentation during 30 weeks of treatment. Details of the study and efficacy results are described in a separate manuscript [9]. We report on the retrospective analysis of 338 evaluable patients with data on the relationship between baseline ferritin and augmentation.

Results

In total, 361 patients were treated in the prospective randomized trial, 183 patients in the l-DOPA group and 178 in the cabergoline group; 157 patients (83/74) dropped out prematurely for loss of efficacy (26/14) or other reasons (39/53 patients). Augmentation caused premature discontinuation from the trial in 25 of 361 patients, 18 of them in the levodopa group and 7 in the cabergoline group, and was tolerated in 11 additional patients (8/3). Fewer discontinuations due to augmentation

Discussion

Ferritin values at baseline were lower in patients who developed augmentation during treatment with either levodopa or cabergoline compared to those without augmentation. To participate in the trial, patients had to have at least “low normal” values of ferritin to exclude those with iron deficiency. Nonetheless, there were seven patients with very low ferritin values (<30 ng/ml) in this study; two of those dropped out prematurely due to augmentation (cabergoline group). It is, therefore, still

Acknowledgement

The treatment trial was sponsored by Pfizer Pharma Inc., Karlsruhe, Germany.

Cited by (105)

  • Special considerations for treatment of sleep-related movement disorders

    2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second Edition
View all citing articles on Scopus
View full text