Can a patient with a history of Restless Legs Syndrome (RLS) who was previously treated with ropinirole (dopamine agonist) for 5 years, then experienced a 5-year remission without iron level testing or treatment, safely restart treatment with ropinirole or alternative medications if their RLS symptoms recur?

Can RLS Recur After Years of Remission and Is Restarting Ropinirole Appropriate?

Yes, RLS can absolutely recur after prolonged remission, but restarting ropinirole is NOT recommended based on current 2025 guidelines—you should instead check iron studies first and consider alpha-2-delta ligands (gabapentin, pregabalin) as first-line therapy. 1, 2

Understanding RLS Natural History and Recurrence

RLS is a chronic disorder with a variable course that can include spontaneous remissions lasting months to years, followed by symptom recurrence. 3 The scenario you describe—5 years of treatment, 5 years of remission, then recurrence—is entirely consistent with the natural history of this condition. 3

The critical error here is that no iron testing was ever performed, which represents a fundamental gap in proper RLS management. 1, 2

Mandatory First Step: Iron Studies

Before considering ANY medication restart, you must check morning fasting serum ferritin and transferrin saturation. 1, 2 This should be done:

• In the morning after avoiding iron-containing supplements for at least 24 hours 1
• Target thresholds for RLS are different from general population: ferritin ≤75 ng/mL or transferrin saturation <20% warrant supplementation 1, 2
• Brain iron deficiency plays a key role in RLS pathophysiology even when serum iron appears normal 1

If iron parameters are low:

• IV ferric carboxymaltose is strongly recommended (strong recommendation, moderate certainty) for rapid correction 1, 2
• Oral ferrous sulfate is an alternative but works more slowly (conditional recommendation, moderate certainty) 1, 2

Why NOT to Restart Ropinirole

The American Academy of Sleep Medicine now suggests AGAINST the standard use of ropinirole (conditional recommendation, moderate certainty of evidence) due to the high risk of augmentation. 3, 1, 4 This represents a major shift from older 2009 guidelines that recommended dopamine agonists as first-line therapy. 4

The Augmentation Problem

Augmentation is a paradoxical worsening of RLS symptoms that occurs with long-term dopaminergic therapy, characterized by: 4, 5

• Earlier onset of symptoms during the day
• Increased symptom intensity
• Spread of symptoms to other body parts (arms, trunk)
• Shorter duration of medication effect
• Need for progressively higher doses

All three FDA-approved dopamine agonists (ropinirole, pramipexole, rotigotine) carry this risk. 5 The fact that this patient previously took ropinirole for 5 years means they may be at even higher risk for augmentation if restarted. 4, 5

Current First-Line Treatment: Alpha-2-Delta Ligands

The American Academy of Sleep Medicine strongly recommends gabapentin, gabapentin enacarbil, or pregabalin as first-line therapy (strong recommendation, moderate certainty of evidence). 3, 1, 2

Specific Dosing Recommendations

Gabapentin: 1

• Start at 300 mg three times daily (900 mg/day total)
• Titrate by 300 mg/day every 3-7 days
• Target maintenance dose: 1800-2400 mg/day divided three times daily
• Avoid single nighttime dosing—it fails to address daytime symptoms 1

Pregabalin: 1, 2

• Allows twice-daily dosing with potentially superior bioavailability
• Strongly recommended as first-line therapy (strong recommendation, moderate certainty)

Advantages Over Dopaminergics

• Lower risk of augmentation 1, 6, 5
• Effective for both motor symptoms and sleep quality 6
• Better long-term safety profile 1, 5

Clinical Algorithm for This Patient

1. Check iron studies immediately (ferritin, transferrin saturation, morning fasting) 1, 2

2. If ferritin ≤75 ng/mL or transferrin saturation <20%:

   • Start IV ferric carboxymaltose (preferred) OR oral ferrous sulfate 1, 2
   • This alone may significantly improve symptoms 1

3. If pharmacological treatment is still needed:

   • Start gabapentin 300 mg three times daily OR pregabalin 1, 2
   • Titrate gabapentin by 300 mg/day every 3-7 days to 1800-2400 mg/day 1
   • Monitor for side effects (somnolence, dizziness—typically mild and transient) 1

4. Address exacerbating factors: 1

   • Eliminate/reduce alcohol, caffeine, nicotine (especially evening)
   • Review medications: avoid antihistamines, SSRIs, antipsychotics
   • Screen for untreated sleep apnea

5. Only consider dopamine agonists if:

   • Patient has failed alpha-2-delta ligands AND iron supplementation
   • Patient prioritizes short-term symptom relief over long-term safety
   • Use lowest effective dose with close monitoring for augmentation 3, 4

When Dopamine Agonists Might Be Considered (With Extreme Caution)

The FDA label notes that ropinirole may be used for moderate-to-severe primary RLS, but this must be weighed against current guideline recommendations. 7 If a dopamine agonist is absolutely necessary:

• Keep dosage as low as possible 4, 5
• Monitor closely for augmentation signs 4, 5
• Consider it only for short-term use 3, 1
• Patients should understand the risk of withdrawal symptoms if stopped 7

Critical Pitfalls to Avoid

• Do NOT restart ropinirole without first checking iron studies—you may be treating iron deficiency with a high-risk medication 1, 2
• Do NOT use single nighttime dosing of gabapentin—it provides inadequate 24-hour coverage 1
• Do NOT assume the previous 5-year remission means dopaminergics are safe—augmentation risk remains high 4, 5
• Do NOT ignore the 2025 guideline shift away from dopamine agonists—this represents significant new evidence 3, 1, 4

Special Monitoring Considerations

If symptoms recur despite treatment:

• Recheck iron studies every 6-12 months 1
• Assess for peripheral neuropathy (can mimic or coexist with RLS) 8
• Evaluate medication list for RLS-exacerbating drugs 1
• Consider referral to sleep specialist for refractory cases 1