Less is more: pathophysiology of dopaminergic-therapy-related augmentation in restless legs syndrome

Lancet Neurol. 2006 Oct;5(10):878-86. doi: 10.1016/S1474-4422(06)70576-2.


Therapy-related augmentation of the symptoms of restless legs syndrome (RLS) is an important clinical problem reported in up to 60% of patients treated with levodopa and, to a lesser extent, with dopamine agonists. The efficacy of low-dose dopaminergic drugs for RLS has been established, but the mode of action is unknown. Here, we review the existing data and conclude that augmentation is a syndrome characterised by a severely increased dopamine concentration in the CNS; overstimulation of the dopamine D1 receptors compared with D2 receptors in the spinal cord may lead to D1-related pain and generate periodic limb movements; iron deficiency may be a main predisposing factor of augmentation, probably caused by a reduced function of the dopamine transporter; therapy with levodopa or dopamine agonists should remain at low doses and; iron supplementation and opiates are the therapy of choice to counter augmentation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Circadian Rhythm / physiology
  • Dopamine / deficiency
  • Dopamine Agents / therapeutic use*
  • Dopamine Agonists / therapeutic use
  • Humans
  • Iron / physiology
  • Levodopa / therapeutic use
  • Receptors, Dopamine D2 / drug effects
  • Restless Legs Syndrome / drug therapy*
  • Restless Legs Syndrome / physiopathology*


  • Dopamine Agents
  • Dopamine Agonists
  • Receptors, Dopamine D2
  • Levodopa
  • Iron
  • Dopamine