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Iron for the treatment of restless legs syndrome

Citation: Trotti LM, Becker LA. Iron for the treatment of restless legs syndrome. Cochrane Database of Systematic Reviews 2019, Issue 1. Art. No.: CD007834. DOI: 10.1002/14651858.CD007834.

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.

Selection criteria
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.

Data collection and analysis
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 I2 statistic. We used standard methodological procedures expected by Cochrane. We performed GRADE analysis using GRADEpro.

Main results 
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; I2= 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; I2 = 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; I2=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; I2= 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; I2 = 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; I2 = 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; I2 =45%, 6 studies, 298 participants). A single study reported that people treated with iron therapy experienced fewer adverse events than the active comparator pramipexole.

Authors’ conclusions 
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.


Die Ergebnisse der Studie zeigen, dass durch Eisensubstitution eine der Ursachen (zentraler Eisenmangel ) des RLS behandelt werden kann. Auch wenn weiter die Medikation mit Dopaminergen Substanzen die first line Therapie bleibt, so sollte jeder Eisenmangel (mit oder ohne Anämie) beim RLS substituiert werden. Laut Leitlinie wenn das Ferritin unter 50 μg pro L ist. 

Fazit Regen:

Wir werden Ferritin bei RLS-Patienten einmal messen und evtl. dann substituieren (12 Wochen) und nachbeobachten.
Frage: Haben Hämochromatosepatienten eventuell niedrigere RLS-Zahlen?