What medications, other than Requip (ropinirole), can be prescribed for restless legs syndrome?

Medications for Restless Legs Syndrome Beyond Ropinirole (Requip)

The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands—specifically gabapentin, gabapentin enacarbil, or pregabalin—as first-line therapy for restless legs syndrome, replacing dopamine agonists like ropinirole due to the high risk of augmentation (paradoxical worsening of symptoms). 1, 2

First-Line Pharmacological Options

Alpha-2-Delta Ligands (Preferred First-Line)

• Gabapentin is strongly recommended with moderate certainty of evidence 1, 2

  • Start 300 mg three times daily
  • Titrate by 300 mg/day every 3–7 days
  • Target maintenance dose: 1800–2400 mg/day divided three times daily
  • Maximum studied dose: 3600 mg/day 1

• Gabapentin enacarbil (prodrug of gabapentin) is strongly recommended with moderate certainty of evidence 1, 2

  • Offers more consistent absorption than regular gabapentin
  • Allows for simplified dosing 1

• Pregabalin is strongly recommended with moderate certainty of evidence 1, 2

  • Start 50 mg three times daily or 75 mg twice daily
  • After 3–7 days, increase to 300 mg/day
  • Titrate by 150 mg every 3–7 days as tolerated
  • Maximum dose: 600 mg/day
  • Advantage: twice-daily dosing with potentially superior bioavailability compared to gabapentin 1

These alpha-2-delta ligands represent a major guideline shift from 2009 recommendations that listed dopamine agonists as first-line agents. The change reflects accumulating evidence of a 7–10% annual augmentation risk with dopamine agonists. 1

Iron Supplementation (Essential First Step)

Before starting any medication, check morning fasting serum ferritin and transferrin saturation after withholding iron supplements for ≥24 hours 1, 2:

• Oral ferrous sulfate (325 mg daily or every other day) is conditionally recommended if ferritin ≤75 ng/mL or transferrin saturation <20% 1, 2

• IV ferric carboxymaltose (750–1000 mg in one or two infusions) is strongly recommended with moderate certainty for patients who cannot tolerate oral iron, fail oral therapy, or have ferritin 75–100 ng/mL despite oral treatment 1, 2

Note: RLS-specific iron thresholds differ from general population guidelines—the cutoff is ≤75 ng/mL for adults, not the typical 30 ng/mL. 1

Second-Line Options for Refractory Cases

Opioids (For Moderate to Severe Refractory RLS)

• Extended-release oxycodone (5–10 mg at bedtime) is conditionally recommended with moderate certainty of evidence 1, 3

  • Long-term studies show only modest dose escalation over 2–10 years
  • Relatively low risk of abuse when patients are appropriately screened 1

• Methadone (5–10 mg daily) provides 24-hour symptom coverage with stable dosing 1

• Buprenorphine (transdermal or sublingual) has a similar safety profile 1

Critical safety considerations before opioid initiation:

• Screen for opioid-use-disorder risk using validated tools
• Evaluate for untreated obstructive sleep apnea (opioids increase respiratory depression risk)
• Monitor respiratory status closely during the first weeks
• Prescribe prophylactic stool softeners for constipation 1

Non-Pharmacological Option

• Bilateral high-frequency peroneal nerve stimulation is conditionally recommended with moderate certainty as a non-invasive alternative for patients who refuse or cannot tolerate opioids 1, 2

Medications to AVOID

The American Academy of Sleep Medicine explicitly recommends against the following agents:

• Dopamine agonists (pramipexole, ropinirole, rotigotine): Conditional recommendation against standard use due to 7–10% annual augmentation risk 1, 2

  • May be considered only for short-term use in patients prioritizing immediate relief over long-term safety 1

• Cabergoline: Strong recommendation against use (moderate certainty) due to cardiac valvular fibrosis risk 1, 2

• Clonazepam: Conditional recommendation against use (very low certainty)—provides only sedation without reducing periodic limb movements 1

• Bupropion, carbamazepine, valproic acid, valerian: Conditional recommendations against use due to limited efficacy and/or safety concerns 1, 2

Special Populations

End-Stage Renal Disease (ESRD)

• Gabapentin: 100 mg post-dialysis or at bedtime (max 200–300 mg daily) 1, 2
• IV iron sucrose: If ferritin <200 ng/mL and transferrin saturation <20% 1, 2
• Vitamin C supplementation: May improve iron utilization 1
• Avoid pregabalin in ESRD—markedly increases hazard of altered mental status and falls 1

Pediatric RLS

• Ferrous sulfate: Conditionally recommended if ferritin <50 ng/mL 1, 2

Critical Pitfalls to Avoid

• Do not use dopamine agonists as first-line therapy given current evidence favoring alpha-2-delta ligands 1
• Do not label RLS as refractory without first optimizing iron status (ferritin target >75 ng/mL) 1
• Do not use single nighttime dosing of gabapentin—this fails to address daytime symptoms and provides suboptimal coverage 1
• Do not combine multiple sedating agents (opioids + alpha-2-delta ligands + benzodiazepines) without first treating obstructive sleep apnea 1
• Do not assume "normal" ferritin (e.g., 50 ng/mL) is adequate for RLS—the disease-specific threshold is ≤75 ng/mL 1

Non-Pharmacological Interventions (Concurrent with Medication)

• Eliminate or reduce alcohol, caffeine, and nicotine, especially in the evening 1, 2
• Discontinue antihistaminergic and serotonergic medications that exacerbate RLS 1, 2
• Screen for and treat untreated obstructive sleep apnea 1, 2
• Implement moderate exercise (morning/afternoon, not close to bedtime) 1