Management of restless legs syndrome when gabapentinoids fail: intravenous iron and opioids

This review addresses the management of restless legs syndrome (RLS) when first-line gabapentinoid therapy fails or is not tolerated. We provide an update on treatment options in the context of the 2025 American Academy of Sleep Medicine (AASM) guideline, which substantially reorganized the treatment hierarchy for RLS.

The 2025 AASM guideline elevated all gabapentinoids and intravenous ferric carboxymaltose to strong first-line recommendations while repositioning dopamine agonists away from routine long-term use because of augmentation and impulse control disorder risk. Emerging data suggest the ferritin and transferrin saturation thresholds guiding iron repletion may be more permissive than previously appreciated, extending benefit to a broader range of patients. Long-term registry data now extending to 5 years show that low-dose opioids remain effective and largely stable over time in RLS, a pattern distinct from the dose escalation seen in chronic pain, and a mechanistic rodent model has identified a dopaminergic pathway distinct from nociceptive pain pathways that may underlie this difference. Device-based tonic motor activation has emerged as a well tolerated, conditionally recommended nonpharmacologic option, including as an adjunct that may enable opioid dose reduction.

The management of gabapentinoid-refractory RLS is no longer a single default step toward dopamine agonist therapy. Clinicians now have a broader set of well supported options, including expanded intravenous iron candidacy, low-dose opioids, and device-based therapy, that should be selected through a shared decision-making process weighing the durability and risks specific to each patient.