The role of intravenous iron for the treatment of restless legs syndrome
Authors: Michael Auerbach
Journal: American Journal of Hematology (2014)

To the Editor: This is the 5th article in a series of short articles concerning iron deficiency and the role of intravenous (IV) iron. As the author of this series, for this article on the role of IV iron in restless legs syndrome (RLS), I will take a short license to describe our own experience. RLS, also known as Willis-Ekbom disease, is associated with largely nocturnal, rest-induced, distressing urges to move the legs 1. Insomnia, interference with partner comfort and cramps are common, resulting in decreased quality of life. Four years ago, two key opinion leaders in sleep medicine specializing in RLS, approached me with the query of infusing a total dose infusion of low molecular weight iron dextran in iron replete, but not overloaded, patients with RLS. Our observed initial clinical benefit was transformative, with an observed immediate clinical benefit of significant magnitude. It is, therefore, not surprising that the role of IV iron as primary therapy for RLS has become a major clinical research interest. Subsequently, in 2013 we began screening anemia referrals with, in addition to standard blood work, a 13-item sleep-vitality questionnaire and the 13-item Cambridge Hopkins RLS diagnostic questionnaire 2. These scales evaluate tiredness, weakness and energy levels. The remaining items evaluate aspects of sleep. Over a one year period, 343 new patients were screened with 252 meeting inclusion criteria. The results were enlightening, revealing a four to five fold increment, or 35% incidence of RLS in the iron deficient population. Treatment of RLS is suboptimal. Medications such as pregabalin and pramepexole are widely used but associated with significant fatigue. Subsequently, a far more felicitous and seamless, single infusion of IV iron may provide significant therapeutic advantage. This contention is supported by an observational study reporting that the significant majority of RLS sufferers have moderate to severe disease 3. RLS is associated with reduced brain iron making the total dose infusion of IV iron appealing. Oral iron, in addition to near ubiquitous dietary perturbation has limited benefit 4. In those with RLS without iron deficiency, iron absorption across the intestinal epithelium into the blood is limited. Two controlled studies using equivalent doses given in a total dose infusion (1,000 mg) but administered as multiple small boluses of iron sucrose revealed marginal and no benefit, respectively 5, 6. The role of total dose infusion is considered controversial. Published evidence reported extraordinary response rates but unacceptable toxicity. Ondo administered 1,000 mg of high molecular weight iron dextran, now no longer available, over 4–5 hr and observed a very high response rate. Unfortunately a 10% incidence of serious adverse events, blunted the enthusiasm for this therapy 7 High molecular weight iron dextran is known to be associated with a marked increase in observed serious adverse events, but now that it is removed from market, the relevancy is moot. In our series of 1,266 infusions of low molecular weight iron dextran in 888 patients, administered as 1,000 mg in 1 hr, no serious adverse events were observed 8. Of note, 162/888 patients were gravidas in the second or third trimester. Using the clinical paradigm of 1,000 mg of low molecular weight iron dextran in patients with iron deficiency and documented RLS, we observed a 50% complete remission, usually within the first 24–48 hr, with an additional 4% reporting marked improvement and another 16% significant improvement 2. This was supported by a Korean study reporting IV low molecular weight iron dextran resulted in a significant improvement of RLS symptoms in a majority of patients without any clinical significant adverse events 9. We are about to begin the first prospective, randomized, double-blind, placebo controlled study comparing oral iron to IV iron in RLS. If the results of this study corroborate previous observations, the infusion of large doses of IV iron in a single setting will offer a considerable improvement over other forms of therapy for RLS. This conclusion will be especially poignant with the approval of three new IV iron formulations which promise to offer complete replacement dosing in 15 min or less. Considering that iron deficiency anemia is estimated to occur in 5% of American adults and 20% of child-bearing aged women 10, in the United States alone there may be three million with iron deficiency and RLS, making iron deficiency anemia with RLS an overlooked public health issue which needs to be addressed. Michael Auerbach* Clinical Professor of Medicine, Georgetown University School of Medicine