Treating Severe Refractory and Augmented Restless Legs Syndrome

Chest. 2022 Sep;162(3):693-700. doi: 10.1016/j.chest.2022.05.014. Epub 2022 May 21.


Restless legs syndrome (RLS) is a sensory-motor neurologic disorder present to a clinically significant degree in 2% to 3% of the adult population, more commonly with advancing age and in women, that dramatically affects sleep and quality of life. Addressing factors that worsen RLS (eg, iron deficiency, antidepressant or antihistamine administration, OSA) is an important first step in treatment. RLS can generally be well treated with medications such as the alpha2-delta calcium channel ligands (A2Ds) gabapentin, pregabalin, and gabapentin enacarbil or, if these are poorly tolerated or lack efficacy, the dopamine agonists (DAs) pramipexole, ropinirole, or rotigotine. Oral or IV iron supplementation is often efficacious as initial treatment in patients with low normal serum indexes. However, at least one-third of patients do not achieve acceptable symptom relief from initial treatments. Furthermore, DAs, the most commonly used medications for RLS, commonly produce augmentation, a progressive, long-term, iatrogenic worsening of RLS symptoms characterized by increasing severity as well as temporal and anatomic extension of symptoms. If dopaminergic augmentation of RLS is present, substitution of an A2D or opioid for the DA is the primary goal. However, given the profound rebound RLS and insomnia that occurs with even small dose reductions of DAs, the initial change should be the addition of one of these alternate treatments. Once adequate doses, or symptom relief, are achieved with the second agent, subsequent very slow down-titration and discontinuation of the DA is often possible and can lead to dramatic long-term relief of RLS symptoms and improvement in sleep.

Keywords: augmentation; dopamine agonists; gabapentin; guideline; iron; opioid; pregabalin; restless legs syndrome.

Publication types

  • Review

MeSH terms

  • Adult
  • Analgesics, Opioid / therapeutic use
  • Dopamine Agonists / therapeutic use
  • Female
  • Gabapentin / therapeutic use
  • Humans
  • Quality of Life
  • Restless Legs Syndrome* / diagnosis
  • Restless Legs Syndrome* / drug therapy


  • Analgesics, Opioid
  • Dopamine Agonists
  • Gabapentin