Restless Legs Syndrome: Contemporary Diagnosis and Treatment

Neurotherapeutics. 2021 Jan;18(1):140-155. doi: 10.1007/s13311-021-01019-4. Epub 2021 Apr 20.


Restless legs syndrome (RLS) is characterized by an uncomfortable urge to move the legs while at rest, relief upon movement or getting up to walk, and worsened symptom severity at night. RLS may be primary (idiopathic) or secondary to pregnancy or a variety of systemic disorders, especially iron deficiency, and chronic renal insufficiency. Genetic predisposition with a family history is common. The pathogenesis of RLS remains unclear but is likely to involve central nervous system dopaminergic dysfunction, as well as other, undefined contributing mechanisms. Evaluation begins with a thorough history and examination, and iron measures, including ferritin and transferrin saturation, should be checked at presentation and with worsened symptoms, especially when augmentation develops. Augmentation is characterized by more intense symptom severity, earlier symptom occurrence, and often, symptom spread from the legs to the arms or other body regions. Some people with RLS have adequate symptom control with non-pharmacological measures such as massage or temperate baths. First-line management options include iron-replacement therapy in those with evidence for reduced body-iron stores or, alternatively, with prescribed gabapentin or pregabalin, and dopamine agonists such as pramipexole, ropinirole, and rotigotine. Second-line therapies include intravenous iron infusion in those who are intolerant of oral iron and/or those having augmentation with intense, severe RLS symptoms, and opioids including tramadol, oxycodone, and methadone. RLS significantly impacts patients' quality of life and remains a therapeutic area sorely in need of innovation and a further pipeline of new, biologically informed therapies.

Keywords: Alpha-2-delta ligand; Cardiovascular risk; Dopamine agonist; Iron deficiency.; Opiate; Periodic leg movements; Periodic limb movement disorder; Restless legs syndrome; Treatment.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Dopamine Agonists / therapeutic use*
  • Humans
  • Quality of Life*
  • Restless Legs Syndrome / diagnosis*
  • Restless Legs Syndrome / therapy


  • Dopamine Agonists