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