Sleep Medicine 10 (2009) 973–975

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Sleep Medicine

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Original Article

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

James Wang, Brian O’Reilly *, Ramesh Venkataraman, Vincent Mysliwiec, Angela MysliwiecDepartment of Medicine, Madigan Army Medical Center, 9040A Fitzsimmons Avenue, Tacoma, WA 98431-1100, United States

a r t i c l e i n f o a b s t r a c t

Article history:Received 24 September 2008Received in revised form 27 October 2008Accepted 2 November 2008Available online 18 February 2009

Keywords:Restless legs syndromeIron sulfateIron deficiencyInternational Restless Legs Scale (IRLS)Clinical trialFerritin

1389-9457/$ - see front matter Published by Elsevierdoi:10.1016/j.sleep.2008.11.003

* Corresponding author. Tel.: +1 253 968 0208; faxE-mail address: brian.oreilly@us.army.mil (B. O’Re

Background and Purpose: Restless Legs Syndrome (RLS) is a primary disorder of sensation that affects sleepand has been associated with iron deficiency. The purpose of this study was to determine if symptomaticRLS 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 patientswere 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 treatmentarm (10.3 ± 7.40) than in the placebo arm (1.14 ± 5.64), (p = 0.01). Ferritin levels increased more in thetreatment arm (25.1 ± 20.3 ng/ml) than in the placebo arm (7.5 ± 13.7 ng/ml), (p = 0.04). We observed anonsignificant 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 signifi-cant improvement in RLS symptoms using oral iron therapy in patients with low-normal ferritin. The find-ings from this study suggest that additional larger randomized placebo-controlled trials of iron astreatment for patients with low-normal ferritin are warranted.

Published by Elsevier B.V.

1. Introduction

Restless Legs Syndrome (RLS) is a primary disorder of sensationthat can profoundly impact sleep [1]. RLS affects females twice asoften as males and its incidence increases with age [2]. In 2005, apoll from the National Sleep Foundation showed that approxi-mately 10% of the U.S. adult population reported RLS symptoms[2]. In addition, previous studies have reported prevalence as highas 24% in the primary care population [3]. Some of the earlieststudies of the disease have shown that iron deficiency is presentin 25% of RLS patients [4]. Furthermore, the prevalence of second-ary RLS is increased in conditions associated with iron deficiencysuch as pregnancy and end-stage renal disease [5]. Dopaminergicagents have been shown in many studies to be effective in the ini-tial treatment of RLS [5–7], leading to the view that decreaseddopamine activity may play a role in the pathogenesis of RLS.The relationship between iron and RLS is not completely under-stood but may be related to the effect of iron on dopamine synthe-sis in the central nervous system [8]. Iron is involved in the ratelimiting step required to convert tyrosine to levodopa, which issubsequently decarboxylated to form dopamine [9]. Therefore,

B.V.

: +1 253 968 1168.illy).

low levels of iron may affect RLS by decreasing the activity of thedopamine system [10,11].

Two previous studies used oral iron in the treatment of RLS. Inthe first, O’Keefe et al. performed an open label study with ferroussulfate that showed greater RLS symptom improvement in patientswith lower initial ferritin levels (less than 45 ng/ml) [12]. A subse-quent double-blinded, placebo-controlled study by Davis et al.showed no statistically significant differences in RLS symptomimprovement with ferrous sulfate treatment versus placebo. Pa-tients in the treatment and placebo arms of this study had meanserum ferritin levels greater than 100 ng/ml [13]. Additionally, nei-ther the O’Keefe nor Davis studies used a validated RLS symptomscale to measure outcomes.

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

2. Methods

We conducted an institutional review board approved, random-ized, placebo-controlled, double-blinded study performed at Madi-gan Army Medical Center. Our center serves active duty personnel,

Table 1Four essential diagnostic criteria for RLS [14].

1 An urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs (sometimes the urge to move is present without theuncomfortable sensations and sometimes the arms or other body parts are involved in addition to the legs)

2 The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity such as lying or sitting3 The urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues4 The urge to move or unpleasant sensations are worse in the evening or night than during the day or only occur in the evening or night (when symptoms are very

severe, the worsening at night may not be noticeable but must have been previously present)

Patients contacted and consented for initial labs(N=38)

Completed 12 weeks placebo(N=7)

372 Surveys Screened

42% met diagnostic criteria for RLS

(N=157)

Randomized

(remainder met exclusion criteria)

(N=18)

373 Surveys Screened42% met diagnostic criteria for RLS

(N=157)

Patients Randomized(remainder met exclusion criteria)

(N=18)

Completed 12 weeks iron(N=11)

Fig. 1. Study design and randomization of patients to iron and placebo groups.

974 J. Wang et al. / Sleep Medicine 10 (2009) 973–975

military retirees, and their family members. Patients attendingroutine outpatient visits in the internal medicine, pulmonology,hematology/oncology, neurology, and family practice clinics werescreened for RLS symptom severity using the International RestlessLegs Scale (IRLS) survey. Patients gave written consent to be con-tacted if they met NIH diagnostic criteria for RLS (Table 1) [14],and received a score of P11 using the validated IRLS [15]. Thesepatients were further screened by measuring random levels ofhemoglobin, ferritin, iron, and iron saturation percentage. Onlythose patients with a measured ferritin level of 15–75 ng/ml wereincluded in the study. Patients were excluded from the study forpregnancy, hemochromatosis or other significant liver disease,end-stage renal disease, significant sleep disturbances for reasonsother than RLS (i.e., known obstructive sleep apnea, periodic limbmovements of sleep, etc.), iron saturation less than 15%, hemoglo-bin levels less than 11.1 g/dL for females and 14 g/dL for males,iron sulfate allergy, current or recent treatment with iron sulfateas defined by more than 325 mg each day for at least half of thedays in the past 2 months or any other potential medications fortreatment of RLS.

Table 2Patient demographics and baseline characteristics of patients in iron and placebogroups.

Iron group Placebo group p-Value*

Gender 5 male/6 female 2 male/5 female –Age (mean) 60 (range 36–82) 58 (range 33–72) –IRLS score (mean ± SD) 24.8 ± 5.72 23.0 ± 5.03 0.49Ferritin (mean ± SD) 40.6 ± 15.3 (ng/ml) 36.7 ± 20.8 (ng/ml) 0.68Hemoglobin (mean ± SD) 14.5 ± 1.30 (g/dL) 13.7 ± 1.50 (g/dL) 0.27Iron saturation (mean ± SD) 21.3 ± 5.53 (%) 16.9 ± 2.91 (%) 0.04

* Two-tailed p-value, 95% confidence interval.

2.1. Study design

Eligible patients were randomized to either oral iron therapy(ferrous sulfate 325 mg twice daily, placed in non-descriptive cap-sules) or an appearance-matched placebo (lactose). A clinicalinvestigative pharmacist, independent from the study, grouped pa-tients using a randomly generated sequenced number program.The clinical investigative pharmacist held the randomization codein a locked cabinet until the end of the study. All patients were alsoasked to take vitamin C 100 mg orally twice daily. Patients werefollowed at 6 and 12 weeks with a repeated IRLS survey, and hemo-globin and serum ferritin levels. At 12 weeks, patients were askedif their overall quality of life had improved, stayed the same, orworsened. Compliance was monitored at both 6 and 12 weeks witha medication diary and manual pill count.

The primary outcome measure was a reduction in IRLS scoresbetween baseline and 12 weeks. The secondary outcome measurewas a dichotomous variable (improved or stayed the same or wors-ened) in subjective reporting of overall quality of life at the end of12 weeks. A two-sample independent t-test, assuming unequalvariance, was used to compare baseline characteristics andchanges in IRLS scores. Fisher’s exact test was used to comparethe proportion of patients showing improvement in overall qualityof life.

3. Results

Three hundred seventy-three surveys were completed and re-viewed. One hundred fifty-seven (42%) met essential diagnosticcriteria for RLS. The mean IRLS scores in these patients were20.2 ± 9.0. Of the 38 subjects who consented to participate in thestudy, 18 met inclusion criteria and were enrolled. Eleven patientswere randomized to iron therapy and 7 to placebo (Fig. 1). All en-rolled patients completed the 12 week study. Patient demograph-ics and baseline characteristics are shown in Table 2. The meanbaseline IRLS scores for iron and placebo groups were 24.8 ± 5.72and 23.0 ± 5.03, respectively (p = 0.49). Mean decreases in IRLSscore after 12 weeks for iron and placebo groups were10.3 ± 7.40 and 1.14 ± 5.64, respectively (p = 0.01). The mean base-line serum ferritin levels for the iron group were 40.6 ± 15.3 ng/mland 36.7 ± 20.8 ng/ml for the placebo group (p = 0.68). The meanchange in serum ferritin after 12 weeks for the iron group was25.1 ± 20.3 ng/ml and 7.5 ± 13.7 ng/ml for the placebo group(p = 0.04). When comparing dichotomized variables at baselineand at week 12, a nonsignificant trend toward improved qualityof life was seen between iron and placebo groups (p = 0.07)(Table 3).

4. Discussion

This is the first double-blinded, placebo-controlled study todemonstrate statistically significant improvement in RLS symp-toms using oral iron therapy in patients with low-normal serumferritin levels (15–75 ng/ml) with the use of a validated RLS symp-tom scale. This study was similar to the findings by O’Keefe et al.who showed reduced RLS symptoms following oral iron treatment

Table 3Results values at baseline to 12 weeks for patients randomized to iron and placebogroups.

Iron group Placebo group p-Value*

IRLS baseline score(mean ± SD)

24.8 ± 5.72 23.0 ± 5.03 0.49

IRLS score change at 12 weeks(mean ± SD)

�10.3 ± 7.40 �1.14 ± 5.64 0.01

Ferritin baseline(mean ± SD)

40.6 ± 15.3(ng/ml)

36.7 ± 20.8(ng/ml)

0.68

Ferritin change at 12 weeks(mean ± SD)

+25.1 ± 20.3(ng/ml)

+7.5 ± 13.7(ng/ml)

0.04

Overall quality of lifea

Improved 7 1 0.07Stayed the same or

worsened4 6

a Dichotomous variable of improvement.* Two-tailed p-value, 95% confidence interval.

J. Wang et al. / Sleep Medicine 10 (2009) 973–975 975

in patients whose initial serum ferritin levels were less than 45 ng/ml [12]. A study by Sun et al. showed that patients with serum fer-ritin levels less than 50 ng/ml have more severe RLS symptoms anddecreased sleep efficiency than those with serum ferritin levelsabove 50 ng/ml [9]. Given these findings from previous studies, itis not surprising that the double-blinded, placebo-controlled studyby Davis et al. did not find a statistical improvement in the patientsreceiving oral iron therapy who had an average ferritin level ofgreater than 100 ng/ml.

Our study has several limitations. It is possible that patientscould detect a change in stool color and suspect they were receivingoral iron therapy; we feel this would not necessarily change theirperception of RLS symptoms. We did not assess for the presenceof concomitant sleep disorders; if present, these may have ad-versely affected the overall sleep quality of our patients. However,as the patients were randomly assigned to the treatment or placeboarm, there should have been no significant difference in the overallpercentage of affected individuals. We assessed quality of life basedon a limited question and not a validated questionnaire, which doeslimit its applicability. Our study was intended to be a 1:1 random-ization, with subjects randomly assigned by a predetermined meth-od by our clinical pharmacist. However, based on this method thetreatment and placebo arms were not equal in the final analysis.

In conclusion, we have shown that patients with low-normalferritin levels treated with oral iron sulfate have a significantimprovement in RLS symptoms. In addition, there is a nonsignifi-

cant trend in subjective improvement in quality of life in RLS pa-tients treated with oral iron therapy. These findings support datafrom prior studies suggesting that RLS patients should have ironreplaced until ferritin levels are at least greater than 50ng/ml.Additional larger randomized placebo-controlled trials of irontherapy for RLS patients with low-normal ferritin levels arewarranted.

Acknowledgements

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

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