What are the next management steps for a patient with restless‑leg syndrome who has failed rotigotine (Neupro) and ropinirole (resquit) therapy?

Management After Dopamine Agonist Failure in Restless Legs Syndrome

Switch immediately to an alpha-2-delta ligand (gabapentin, gabapentin enacarbil, or pregabalin) as these are now the strongly recommended first-line agents for RLS, and both rotigotine and ropinirole carry substantial augmentation risk that makes them inappropriate for standard use. 1

Why Your Current Medications Failed

Your patient has been on two dopamine agonists—rotigotine (Neupro) and ropinirole (Requip)—both of which the American Academy of Sleep Medicine now recommends against for standard use due to high augmentation risk. 1

• Augmentation is a paradoxical worsening of RLS that occurs in a substantial proportion of patients on dopamine agonists, characterized by:
  • Earlier onset of symptoms during the day (afternoon instead of evening) 1
  • Increased symptom intensity 1
  • Spread of symptoms to arms or trunk 1
• The 2025 AASM guidelines represent a major shift from older 2009 recommendations that favored dopamine agonists as first-line therapy. 2

Immediate Next Steps: Alpha-2-Delta Ligands

Start gabapentin, gabapentin enacarbil, or pregabalin—these are strongly recommended as first-line therapy with moderate certainty of evidence and carry NO augmentation risk. 1

Gabapentin Dosing

• Start 300 mg three times daily 1
• Increase by 300 mg/day every 3–7 days as tolerated 1
• Target maintenance dose: 1800–2400 mg/day divided three times daily 1
• Maximum studied dose: 3600 mg/day 1
• Common side effects: somnolence and dizziness (typically transient and mild) 1

Pregabalin Dosing (Alternative with Superior Convenience)

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

Gabapentin Enacarbil (Prodrug Alternative)

• Strongly recommended with moderate certainty of evidence 1
• Allows for more convenient dosing than regular gabapentin 1
• Cost consideration: Significantly more expensive than generic gabapentin or pregabalin, which are equally effective 1

Critical: Assess and Correct Iron Status FIRST

Before or concurrent with starting an alpha-2-delta ligand, check morning fasting serum ferritin and transferrin saturation after avoiding iron supplements for ≥24 hours. 1

Iron Supplementation Thresholds (Different from General Population)

• Supplement if ferritin ≤75 ng/mL OR transferrin saturation <20% 1
• These thresholds are higher than general population guidelines because brain iron deficiency plays a key role in RLS pathophysiology even when serum iron appears normal 1

Iron Supplementation Options

• Oral ferrous sulfate: Conditional recommendation with moderate certainty for appropriate iron parameters 1
• IV ferric carboxymaltose: Strong recommendation with moderate certainty for patients who don't respond to oral therapy or have severe symptoms—can be given as 750–1000 mg in one or two infusions 1
• Iron therapy can significantly improve RLS symptoms independent of other medications 1

If Alpha-2-Delta Ligands Fail: Second-Line Options

Extended-Release Opioids

• Extended-release oxycodone and other low-dose opioids are conditionally recommended for moderate to severe refractory RLS 1, 3
• Particularly effective for treating augmentation from dopamine agonists 1, 4
• Long-term studies show relatively low risks of abuse/overdose in appropriately screened patients, with only small dose increases over 2–10 years 1
• Critical safety consideration: Monitor for respiratory depression, especially if untreated sleep apnea is present 1

Other Alternatives

• Bilateral high-frequency peroneal nerve stimulation: Conditional recommendation with moderate certainty as a non-pharmacological option 1
• Dipyridamole: Conditional recommendation with low certainty of evidence 1

Critical Pitfalls to Avoid

• Do NOT increase dopamine agonist doses if symptoms worsen—this likely represents augmentation and will only make the problem worse 1, 5
• Do NOT restart another dopamine agonist (pramipexole, cabergoline)—the augmentation risk is a class effect 1
• Do NOT use clonazepam, carbamazepine, valproic acid, or cabergoline—these are specifically recommended against by the AASM 1
• Do NOT skip iron assessment—correcting iron deficiency can dramatically improve outcomes regardless of other therapy 1

Addressing Exacerbating Factors

While transitioning therapy, ensure the patient avoids: 1

• Alcohol and caffeine (especially in the evening)
• Antihistaminergic medications
• Serotonergic medications (SSRIs, SNRIs)
• Antidopaminergic medications (antipsychotics, metoclopramide)
• Untreated obstructive sleep apnea

Monitoring and Follow-Up

• Reassess iron studies every 6–12 months 1
• Monitor for side effects of alpha-2-delta ligands (dizziness, somnolence) 1
• Evaluate improvement in both nighttime RLS symptoms AND daytime functioning (alertness, concentration, mood) 1
• If symptoms persist despite adequate alpha-2-delta ligand dosing and iron correction, consider referral for opioid therapy or other advanced options 1, 3