Restless legs syndrome (RLS) is a common neurologic disorder that is associated with
peripheral iron deficiency in a subgroup of patients. It is unclear whether iron therapy
is effective treatment for RLS. To evaluate the efficacy and safety of oral or parenteral
iron for the treatment of restless legs syndrome (RLS) when compared with placebo
or other therapies. We searched the Cochrane Central Register of Controlled Trials
(CENTRAL), MEDLINE, Embase, PsycNFO, and CINAHL for the time period January 1995 to
September 2017. We searched reference lists for additional published studies. We searched
Clinicaltrials.gov and other clinical trial registries (September 2017) for ongoing
or unpublished studies. Controlled trials comparing any formulation of iron with placebo,
other medications, or no treatment, in adults diagnosed with RLS according to expert
clinical interview or explicit diagnostic criteria. Two review authors independently
extracted data and assessed trial quality, with discussion to reach consensus in the
case of any disagreement. The primary outcome considered in this review was restlessness
or unpleasant sensations, as experienced subjectively by the patient. We combined
treatment/control differences in the outcomes across studies using random‐effects
meta‐analyses. We analysed continuous data using mean differences (MDs) where possible
and performed standardised mean difference (SMD) analyses when different measurements
were used across studies. We calculated risk ratios (RRs) for dichotomous data using
the Mantel‐Haenszel method and 95% confidence intervals (CIs). We analysed study heterogeneity
using the I 2 statistic. We used standard methodological procedures expected by Cochrane.
We performed GRADE analysis using GRADEpro. We identified and included 10 studies
(428 total participants, followed for 2‐16 weeks) in this review. Our primary outcome
was restlessness or uncomfortable leg sensations, which was quantified using the International
Restless Legs Scale (IRLS) (range, 0 to 40) in eight trials and a different RLS symptom
scale in a ninth trial. Nine studies compared iron to placebo and one study compared
iron to a dopamine agonist (pramipexole). The possibility for bias among the trials
was variable. Three studies had a single element with high risk of bias, which was
lack of blinding in two and incomplete outcome data in one. All studies had at least
one feature resulting in unclear risk of bias. Combining data from the seven trials
using the IRLS to compare iron and placebo, use of iron resulted in greater improvement
in IRLS scores (MD ‐3.78, 95% CI ‐6.25 to ‐1.31; I 2 = 66%, 7 studies, 345 participants)
measured 2 to 12 weeks after treatment. Including an eighth study, which measured
restlessness using a different scale, use of iron remained beneficial compared to
placebo (SMD ‐0.74, 95% CI ‐1.26 to ‐0.23; I 2 = 80%, 8 studies, 370 participants).
The GRADE assessment of certainty for this outcome was moderate. The single study
comparing iron to a dopamine agonist (pramipexole) found a similar reduction in RLS
severity in the two groups (MD ‐0.40, 95% CI ‐5.93 to 5.13, 30 participants). Assessment
of secondary outcomes was limited by small numbers of trials assessing each outcome.
Iron did not improve quality of life as a dichotomous measure (RR 2.01, 95% CI 0.54
to 7.45; I 2 =54%, 2 studies, 39 participants), but did improve quality of life measured
on continuous scales (SMD 0.51, 95% CI 0.15 to 0.87; I 2 = 0%, 3 studies, 128 participants),
compared to placebo. Subjective sleep quality was no different between iron and placebo
groups (SMD 0.19, 95% CI ‐0.18 to 0.56; I 2 = 9%, 3 studies, 128 participants), nor
was objective sleep quality, as measured by change in sleep efficiency in a single
study (‐35.5 +/‐ 92.0 versus ‐41.4 +/‐ 98.2, 18 participants). Periodic limb movements
of sleep were not significantly reduced with iron compared to placebo ( SMD ‐0.19,
95% CI ‐0.70 to 0.32; I 2 = 0%, 2 studies, 60 participants). Iron did not improve
sleepiness compared to placebo, as measured on the Epworth Sleepiness Scale (data
not provided, 1 study, 60 participants) but did improve the daytime tiredness item
of the RLS‐6 compared to placebo (least squares mean difference ‐1.5, 95% CI ‐2.5
to ‐0.6; 1 study, 110 participants). The GRADE rating for secondary outcomes ranged
from low to very low. Prespecified subgroup analyses showed more improvement with
iron in those trials studying participants on dialysis. The use of low serum ferritin
levels as an inclusion criteria and the use or oral versus intravenous iron did not
show significant subgroup differences. Iron did not result in significantly more adverse
events than placebo (RR 1.48, 95% CI 0.97 to 2.25; I 2 =45%, 6 studies, 298 participants).
A single study reported that people treated with iron therapy experienced fewer adverse
events than the active comparator pramipexole. Iron therapy probably improves restlessness
and RLS severity in comparison to placebo. Iron therapy may not increase the risk
of side effects in comparison to placebo. We are uncertain whether iron therapy improves
quality of life in comparison to placebo. Iron therapy may make little or no difference
to pramipexole in restlessness and RLS severity, as well as in the risk of adverse
events. The effect on secondary outcomes such as quality of life, daytime functioning,
and sleep quality, the optimal timing and formulation of administration, and patient
characteristics predicting response require additional study. Iron for the treatment
of restless legs syndrome Background Restless legs syndrome is a common medical condition
that causes uncomfortable urges to move the legs. These urges happen in the evening
and at night and can keep people from sleeping well. Low blood levels of iron are
often seen in people who have restless legs syndrome. Low blood iron levels may be
part of the cause of restless legs syndrome. Iron can be taken as a pill or given
as an injection into the bloodstream. We performed this review to see if iron treatment
reduces the symptoms of restless legs syndrome. Study characteristics We included
10 studies of iron. These 10 studies included 428 people with restless legs syndrome.
Not all participants had low blood levels of iron. All participants were adults. Most
of the studies used injections of iron, while three studies used iron in pill form.
Iron treatment was compared to a non‐active treatment (i.e. a placebo) in nine studies.
In one study, iron was compared to another restless legs syndrome treatment called
a dopamine agonist. The main measure of interest in our review was the severity of
restlessness. This was usually measured using a 10‐question survey regarding severity
and effects of urges to move the legs, called the International Restless Legs Syndrome
Severity Rating Scale (IRLS). This was measured 2‐4 weeks after injections of iron
and 12‐14 weeks after iron in pill form. Four trials were funded by the drug manufacturer.
Two trials were funded by the USA National Institutes of Health. Two trials were funded
by the workplaces of the study investigators. Two studies did not report who funded
the study. The four studies funded by drug manufacturers were the largest. The studies
funded by drug companies contributed over half of the total number of participants.
Key results and quality of evidence Overall, the studies showed that iron is better
than a placebo for reducing the severity of restless legs syndrome symptoms, although
the benefit was low to moderate. This is mostly based on studies using injections
of iron, rather than iron pills. Iron was helpful even if blood iron levels were normal
at the start of the study. The quality of the evidence was moderate, because not all
completed studies have been published, not all important outcomes have been measured,
and not enough people have been studied. Side effects were not more common with iron
than with placebo. Based on one study, side effects were less common with iron than
with another commonly used restless legs syndrome treatment, although the certainty
in this result is very low. More studies are needed to allow people with RLS and doctors
to make decisions about who should take iron for restless legs syndrome treatment,
using what type of iron, and for how long. The evidence is current to September 2017.