Elsevier

Sleep Medicine

Volume 10, Issue 9, October 2009, Pages 973-975
Sleep Medicine

Original Article
Efficacy of oral iron in patients with restless legs syndrome and a low-normal ferritin: A randomized, double-blind, placebo-controlled study

https://doi.org/10.1016/j.sleep.2008.11.003Get rights and content

Abstract

Background and Purpose

Restless Legs Syndrome (RLS) is a primary disorder of sensation that affects sleep and has been associated with iron deficiency. The purpose of this study was to determine if symptomatic RLS patients with low-normal serum ferritin levels benefit from oral iron replacement.

Patients and Methods

This was a randomized, placebo-controlled, double-blinded study. Eligible patients were randomized to oral iron therapy vs. appearance-matched placebo and followed over a 12 week period.

Results

Baseline International Restless Leg Scale (IRLS) scores for the treatment (24.8 ± 5.72) and placebo (23.0 ± 5.03) groups were similar. Baseline ferritin levels for the treatment (40.6 ± 15.3 ng/ml) and placebo (36.7 ± 20.8 ng/ml) groups were also similar. After 12 weeks, IRLS scores decreased more in the treatment arm (10.3 ± 7.40) than in the placebo arm (1.14 ± 5.64), (p = 0.01). Ferritin levels increased more in the treatment arm (25.1 ± 20.3 ng/ml) than in the placebo arm (7.5 ± 13.7 ng/ml), (p = 0.04). We observed a nonsignificant trend toward improved quality of life in the treated patients, (p = 0.07).

Conclusions

This is the first double-blinded, placebo-controlled study to demonstrate statistically significant improvement in RLS symptoms using oral iron therapy in patients with low-normal ferritin. The findings from this study suggest that additional larger randomized placebo-controlled trials of iron as treatment for patients with low-normal ferritin are warranted.

Introduction

Restless Legs Syndrome (RLS) is a primary disorder of sensation that can profoundly impact sleep [1]. RLS affects females twice as often as males and its incidence increases with age [2]. In 2005, a poll from the National Sleep Foundation showed that approximately 10% of the U.S. adult population reported RLS symptoms [2]. In addition, previous studies have reported prevalence as high as 24% in the primary care population [3]. Some of the earliest studies of the disease have shown that iron deficiency is present in 25% of RLS patients [4]. Furthermore, the prevalence of secondary RLS is increased in conditions associated with iron deficiency such as pregnancy and end-stage renal disease [5]. Dopaminergic agents have been shown in many studies to be effective in the initial treatment of RLS [5], [6], [7], leading to the view that decreased dopamine activity may play a role in the pathogenesis of RLS. The relationship between iron and RLS is not completely understood but may be related to the effect of iron on dopamine synthesis in the central nervous system [8]. Iron is involved in the rate limiting step required to convert tyrosine to levodopa, which is subsequently decarboxylated to form dopamine [9]. Therefore, low levels of iron may affect RLS by decreasing the activity of the dopamine system [10], [11].

Two previous studies used oral iron in the treatment of RLS. In the first, O’Keefe et al. performed an open label study with ferrous sulfate that showed greater RLS symptom improvement in patients with lower initial ferritin levels (less than 45 ng/ml) [12]. A subsequent double-blinded, placebo-controlled study by Davis et al. showed no statistically significant differences in RLS symptom improvement with ferrous sulfate treatment versus placebo. Patients in the treatment and placebo arms of this study had mean serum ferritin levels greater than 100 ng/ml [13]. Additionally, neither the O’Keefe nor Davis studies used a validated RLS symptom scale to measure outcomes.

To date, there has not been a placebo-controlled study of oral iron replacement in symptomatic RLS patients with low-normal serum ferritin levels (15–75 ng/ml) using a validated RLS symptom scale. The purpose of our study was to determine if symptomatic RLS patients with low-normal serum ferritin levels benefit from oral iron replacement.

Section snippets

Methods

We conducted an institutional review board approved, randomized, placebo-controlled, double-blinded study performed at Madigan Army Medical Center. Our center serves active duty personnel, military retirees, and their family members. Patients attending routine outpatient visits in the internal medicine, pulmonology, hematology/oncology, neurology, and family practice clinics were screened for RLS symptom severity using the International Restless Legs Scale (IRLS) survey. Patients gave written

Results

Three hundred seventy-three surveys were completed and reviewed. One hundred fifty-seven (42%) met essential diagnostic criteria for RLS. The mean IRLS scores in these patients were 20.2 ± 9.0. Of the 38 subjects who consented to participate in the study, 18 met inclusion criteria and were enrolled. Eleven patients were randomized to iron therapy and 7 to placebo (Fig. 1). All enrolled patients completed the 12 week study. Patient demographics and baseline characteristics are shown in Table 2.

Discussion

This is the first double-blinded, placebo-controlled study to demonstrate statistically significant improvement in RLS symptoms using oral iron therapy in patients with low-normal serum ferritin levels (15–75 ng/ml) with the use of a validated RLS symptom scale. This study was similar to the findings by O’Keefe et al. who showed reduced RLS symptoms following oral iron treatment in patients whose initial serum ferritin levels were less than 45 ng/ml [12]. A study by Sun et al. showed that

Acknowledgements

We thank David L. Greenberg, MD; Patricia Papadopoulos, MD; David Owshalimpur, MD; Collin Fischer, MD and Dustin Little, MD for their assistance and involvement with this study.

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