What medications are used to treat Restless Legs Syndrome (RLS)?

Medications for Restless Legs Syndrome (RLS)

Alpha-2-delta ligands like gabapentin should be considered as first-line pharmacological treatment for Restless Legs Syndrome, rather than dopaminergic agents which carry a significant risk of augmentation with long-term use. 1

First-Line Treatment Options

Alpha-2-Delta Ligands

• Gabapentin - Strongly recommended as first-line therapy, particularly for patients with chronic kidney disease (CKD) or end-stage renal disease (ESRD) 1
• Benefits include comparable efficacy to dopaminergics with significantly lower risk of augmentation 2

Iron Supplementation

• Recommended for patients with ferritin ≤75 ng/mL or transferrin saturation <20% 1
• Options include:
  • Oral iron supplementation for most patients
  • IV ferric carboxymaltose strongly recommended for iron deficiency
  • IV iron sucrose specifically recommended for ESRD patients with ferritin <200 ng/mL and transferrin saturation <20% 1

Second-Line Treatment Options

Dopaminergic Agents

• While historically considered first-line, now recommended only for short-term use due to augmentation risk 1
• FDA-approved options include:
  • Ropinirole - Demonstrated efficacy in multiple clinical trials for moderate-to-severe RLS 3
  • Pramipexole
  • Rotigotine (transdermal)
• Caution: Augmentation is a major limitation of dopaminergic therapy, characterized by earlier symptom onset, increased severity, and spread to other body parts 4, 5

Opioids

• Extended-release oxycodone may be considered for severe to very severe RLS as a second-line treatment 1
• Oxycodone-naloxone has shown efficacy in treatment-resistant RLS 2

Alternative Pharmacological Options

• Other medications that may be considered include:
  • Pregabalin (a gabapentinoid with evidence of efficacy) 2
  • Bupropion
  • Carbamazepine (though not currently recommended) 6
  • Clonazepam and other benzodiazepines (primarily for sleep quality improvement rather than direct RLS symptom relief) 6

Non-Pharmacological Approaches

• Should be implemented concurrently with medication:
  • Regular exercise tailored to patient capabilities
  • Good sleep hygiene practices (consistent sleep-wake schedule, limiting stimulants)
  • Bilateral high-frequency peroneal nerve stimulation
  • Cool dialysate for patients on hemodialysis 1

Important Clinical Considerations

Medication Selection Algorithm

1. Check iron status first - Measure serum ferritin and transferrin saturation
2. If iron deficient - Start iron supplementation (oral or IV based on severity)
3. For initial pharmacological treatment - Start with gabapentin or another alpha-2-delta ligand
4. For inadequate response - Consider short-term dopaminergic agent or opioid for severe cases
5. For patients with comorbid depression - Consider antidepressants that don't worsen RLS (bupropion, agomelatine) 5

Monitoring and Management of Augmentation

• Watch for earlier symptom onset, increased severity, and spread to other body parts
• If augmentation occurs with dopaminergic agents:
  • Gradually taper the dopaminergic medication
  • Switch to an alpha-2-delta ligand
  • Consider temporary use of a benzodiazepine during transition 5

Common Pitfalls

• Failure to check iron status - Iron deficiency is a common and treatable cause of RLS
• Overreliance on dopaminergic agents - Despite their immediate efficacy, long-term use often leads to augmentation
• Overlooking comorbidities - Peripheral neuropathy may reduce response to dopaminergic medications 5
• Prescribing contraindicated medications - Many antidepressants (mirtazapine, mianserin, tricyclics) can worsen RLS symptoms 5

By following this evidence-based approach to RLS treatment, clinicians can effectively manage symptoms while minimizing the risk of treatment complications, particularly augmentation with dopaminergic agents.