We must break through the iron gates to provide infusions for restless legs syndrome

By J. Andrew Berkowski, MD

Those afflicted by the often devastating sensorimotor sleep disorder of restless legs syndrome (RLS) continue to face obstacles in getting an otherwise obvious first-line treatment: intravenous (IV) iron infusion. Basic science and clinical research point most strongly to the role of deficiency and defective metabolism of iron in the central nervous system as the foundation of RLS pathophysiology. IV iron can often significantly impact this condition, even before medications are initiated. Removal of barriers to administration is particularly important since the former first-line treatment, dopamine agonist (DA) therapy, worsens RLS and leads to augmentation with long-term use in the vast majority of patients. Dopamine agonists are now recommended against for standard use in the 2025 AASM clinical practice guideline¹, and the recently published “Updated Algorithm for the Management of RLS” by the RLS Foundation² now places DAs very far down on the list of options with many warnings. In treatment-naïve individuals, though IV iron can be variably effective, a large percentage will experience enough improvement to their symptoms to avoid first-line gabapentinoid medications and second-line low-dose opioids, all of which come with a variety of potential risks and adverse effects.

Why is it so hard for someone with RLS to obtain an IV iron infusion? A variety of barriers exist, including a knowledge gap about the importance and implementation of iron in RLS, unfounded safety fears, insurance and logistical challenges, and overall unprofitability of iron infusion in the insurance-based healthcare system. Those who treat this condition need to be aware of the challenges facing patients and dedicate themselves to overcoming these obstacles.

Knowledge of iron levels and interpretation of results

The 2025 AASM guideline, also echoed by the RLS Foundation algorithm, contains a “good practice statement” that includes a recommendation that all patients with clinically significant RLS should have regular testing of fasting serum iron plus total iron binding capacity (TIBC) and ferritin. For someone with RLS, this should be as routine as the annual comprehensive metabolic panel performed by primary care physicians (PCPs). Patients with iron deficiency, those taking oral iron supplements, or those receiving IV iron should have levels drawn multiple times per year. This is not happening regularly, and many patients are struggling with symptoms while sitting on very low iron stores.

Even if the labs get done, the interpretation can be challenging on many levels. For serum iron deficiency, many lab “reference ranges,” based primarily on local population percentiles, can make very low iron levels seem “normal” such as a ferritin reference range of 5 ng/mL and transferrin saturation (TSAT) of 12% at the low end, when many hematology publications define serum iron deficiency as ferritin 3 has cast light on the extreme variability compared with a gold standard among different brands of ferritin assays, such that anything less than a very low ferritin could be falsely high by virtue of the assay brand itself.

Worse yet, even accurate blood testing does not reflect brain iron levels, which are central to RLS but cannot be measured practically at this time. With serum iron levels, unless very low, there is a lack of correlation with brain iron levels and even less correlation with predicted response to IV iron. The AASM guideline settled on a ferritin threshold of 100 ng/mL, which the research studies of IV iron used for study inclusion, but more recent research has shown no correlation between ferritin and response to IV iron, including in those with mid-normal ferritin levels⁴, so the RLS Foundation algorithm suggests anyone with ferritin

Safety concerns, many invalid

Unfamiliar clinicians often tell patients with RLS that IV iron is “dangerous” or “you will get iron overload.” The latter is not a concern because iron levels are always done prior to an infusion, and the goal is to have high normal or slightly high serum levels, which will not cause “overload.” The study of those with normal iron levels receiving iron infusions measured multiple safety domains with the infusions and confirmed their safety.

The risk of serious reactions based on clinical research amount to 5, making it more likely to have a serious health outcome in transit to the infusion center compared with the infusion itself. Mild infusion reactions or adverse effects can occur in roughly 5% of infusions, regardless of formulation, but are often transient and self-limited⁶. Many more adverse effects are due to inappropriate premedication used to prevent infusion reactions (e.g., diphenhydramine).

The latest erected barrier to IV iron, however, has been new basic science research furthering concerns that ferric carboxymaltose may not only cause hypophosphatemia but also significantly increase risk of bone fractures, likely with repeated infusions.⁷ This is the only form of IV iron to receive a STRONG recommendation in the AASM guideline behind the strength of four randomized, clinical trials showing efficacy in RLS. This has led the AASM RLS Task Force to consider amending the guideline to move ferric carboxymaltose to the CONDITIONAL recommended category like low molecular weight iron dextran and ferumoxytol, which have fewer long-term risks, but also fewer high-quality studies in RLS.

Insurance, unprofitability, and logistical obstacles

Third-party payers also lack awareness of the importance of evaluating and infusing iron. The Centers for Medicare and Medicaid Services (CMS) currently does not recognize the role of iron in RLS and may not even cover a simple blood test for iron with RLS as the diagnosis code.⁸ This can occur with private insurers as well. For IV iron, many restrict IV iron only to those with more profound iron deficiency, such as seen only in those with iron deficiency anemia.

Although one would think a treatment procedure would generate revenue for RLS in the fee-for-service healthcare system, IV iron is not a favored procedure via insurance and lacks the profit margins of newer biologics for infusion centers. Most independent national infusion centers will not do standalone IV iron unless piggybacking on another high-margin infusion at the same visit. Some centers offer only the two most costly products, ferric derisomaltose and ferric carboxymaltose, while an insurer may only reimburse for less expensive formulations like iron dextran and ferumoxytol, which the centers may not offer. Yet other times, the stars align for iron sucrose, which is the weaker, fast-release formulation that has not shown efficacy in adults with RLS and is not recommended in either guideline.

Future outlook

Nevertheless, the future can only be positive for IV iron. Publication of the AASM and RLS Foundation guidelines in the past two years could create a cascade of knowledge expansion and improved access to IV iron. These are now going to be the two most updated, referenced articles for education on RLS. With the demotion of DAs to sparing use only, clinicians may simply stumble upon IV iron as the reflexive DA-prescribing slowly extinguishes, and there is a search for other treatments. Third-party payers will have to start covering and reimbursing IV iron for this common condition due to these guidelines, as they represent the highest level of clinical evidence supporting coverage. This could lead to more availability, and eventually, more reimbursement, which may then expand access.

Though the field has a lot of uncertainty now regarding the management of RLS, IV infusions can eventually become one less thing to iron out.

Andy Berkowski, MD, is a sleep neurologist and founder of ReLACSHealth, a direct specialty care sleep clinic specializing in the management of RLS and complex sleep disorders. He volunteers on the Scientific and Medical Advisory Board of the RLS Foundation.

This article appeared in volume 11, issue 3 of Montage magazine.

References

1. Winkelman JW, Berkowski JA, DelRosso LM, et al. Treatment of restless legs syndrome and periodic limb movement disorders: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2025;21(1):137-152. https://doi.org/10.5664/jcsm.11390
2. Silber MH, Berkowski JA, Buechfuhrer MJ, et al; Scientific and Medical Advisory Board of the Restless Legs Syndrome Foundation. An Updated Algorithm for the Management of Restless Legs Syndrome. Mayo Clin Proc. 2026;S0025-6196(26)18546-2. https://doi.org/10.1016/j.mayocp.2026.05.010
3. Silber MH, Block DR, St Louis EK. Serum ferritin measurements differ according to the assay used: implications for iron therapy in restless legs syndrome. J Clin Sleep Med. 2025;21(1):65-67. https://doi.org/10.5664/jcsm.11332
4. Garcia-Malo C, Garcia-Borreguero D, Silber MH. Efficacy and safety of intravenous iron in patients with restless legs syndrome with normal serum ferritin levels: a stratified subanalysis. J Clin Sleep Med. 2025;21(12):2023-2029. https://doi.org/10.5664/jcsm.11846
5. Avni T, Bieber A, Grossman A, Green H, Leibovici L, Gafter-Gvili A. The safety of intravenous iron preparations: systematic review and meta-analysis. Mayo Clin Proc. 2015;90(1):12-23. https://doi.org/10.1016/j.mayocp.2014.10.007
6. Auerbach M, DeLoughery TG, Tirnauer JS. Iron Deficiency in Adults: A Review. JAMA. 2025;333(20):1813-1823. https://doi.org/10.1001/jama.2025.0452
7. Wagner SA, Panzer M, Pertler E, et al. Ferric Carboxymaltose Increases Fracture Risk in Patients and Reduces Bone Formation in Mice with Iron Deficiency Anemia. Blood. 2026;blood.2025031806. https://doi.org/10.1182/blood.2025031806
8. Centers for Medicare & Medicaid Services. National Coverage Analysis (NCA) Decision Memo for NCAID 178. https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=N&ncaid=178