What is the best treatment for a patient with typical restless legs syndrome, considering non-pharmacological and pharmacological interventions, including dopamine agonists such as pramipexole and ropinirole, and potential underlying medical conditions like impaired renal function?

Best Treatment for Restless Legs Syndrome

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are the first-line pharmacological treatment for restless legs syndrome, but iron supplementation must be addressed first if ferritin ≤75 ng/mL or transferrin saturation <20%. 1, 2

Initial Assessment: Check Iron Status First

Before starting any medication, obtain morning fasting iron studies including serum ferritin and transferrin saturation (avoid iron supplements for 24 hours prior). 1, 2

Iron supplementation is critical if:

• Ferritin ≤75 ng/mL, OR 1, 2
• Transferrin saturation <20% 1, 2

Note 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 replacement options:

• IV ferric carboxymaltose (strong recommendation, moderate certainty): Preferred for rapid correction, especially if oral therapy fails 1, 2
• Oral ferrous sulfate (conditional recommendation, moderate certainty): Alternative but works more slowly 1, 2

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

The American Academy of Sleep Medicine strongly recommends these agents over dopamine agonists due to superior long-term safety and lack of augmentation risk. 1, 2

Gabapentin dosing:

• Start 300 mg three times daily (not single nighttime dosing) 1
• Titrate by 300 mg/day every 3-7 days 1
• Target maintenance dose: 1800-2400 mg/day divided three times daily 1
• Single nighttime dosing fails to address daytime symptoms and provides suboptimal coverage 1

Pregabalin alternative:

• Allows twice-daily dosing with potentially superior bioavailability 1, 2
• Strong recommendation, moderate certainty of evidence 1, 2

Gabapentin enacarbil:

• Prodrug of gabapentin with strong recommendation 1
• Significantly more expensive than regular gabapentin with equivalent efficacy 1

Critical: Avoid Dopamine Agonists as Standard Treatment

The American Academy of Sleep Medicine suggests AGAINST standard use of:

• Pramipexole (conditional recommendation, moderate certainty) 1, 3
• Ropinirole (conditional recommendation, moderate certainty) 1, 3, 4
• Transdermal rotigotine (conditional recommendation, low certainty) 1
• Levodopa (conditional recommendation, very low certainty) 1

Why avoid these agents? Augmentation—a paradoxical worsening of symptoms with earlier onset, increased intensity, and spread to arms/trunk—occurs in a substantial proportion of patients on dopamine agonists. 1, 3, 5 The 2026 guidelines represent a paradigm shift away from these medications because long-term harms outweigh short-term benefits. 3

Address Exacerbating Factors

Eliminate or reduce:

• Alcohol, caffeine, and nicotine (especially within 3 hours of bedtime) 1, 6
• Antihistaminergic medications 1
• Serotonergic medications (SSRIs, SNRIs) 1
• Antidopaminergic medications (antipsychotics) 1

Screen for and treat:

• Untreated obstructive sleep apnea 1

Lifestyle modifications:

• Regular moderate exercise (morning/afternoon, not close to bedtime) 1, 7
• Good sleep hygiene (dark, quiet, comfortable temperature) 1
• Avoid heavy meals within 3 hours of bedtime 1

Second-Line Options for Refractory Cases

If alpha-2-delta ligands and iron optimization fail:

Extended-release oxycodone or other low-dose opioids:

• Conditional recommendation, moderate certainty 1, 2
• Particularly effective for treating augmentation when transitioning off dopamine agonists 1, 2
• Long-term studies show relatively low risks of abuse/overdose in appropriately screened patients with only small dose increases over 2-10 years 1
• Caution: Risk of respiratory depression, especially with untreated sleep apnea 1

Other options:

• Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty) 1, 2
• Dipyridamole (conditional recommendation, low certainty) 1

Medications Strongly Recommended AGAINST

• Cabergoline (strong recommendation against, moderate certainty) 1
• Clonazepam (conditional recommendation against, very low certainty): Does not reduce periodic limb movement index, only improves subjective sleep quality 1
• Bupropion, carbamazepine, valproic acid, valerian (all conditional recommendations against) 1, 2

Special Populations

End-stage renal disease:

• Gabapentin (conditional, very low certainty): Start 100 mg post-dialysis or at bedtime, max 200-300 mg daily 1
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (conditional, moderate certainty) 1, 2
• Warning: Gabapentinoids carry 31-68% higher hazard for altered mental status and falls in dialysis patients 1

Pediatric RLS:

• Ferrous sulfate if ferritin <50 ng/mL (conditional, very low certainty) 1, 2

Pregnancy:

• Iron supplementation particularly important given pregnancy-specific RLS prevalence 1
• Oral formulations favored throughout gestation 1

Monitoring and Follow-Up

• Reassess iron studies every 6-12 months even with symptom resolution 1
• Monitor for side effects of alpha-2-delta ligands (dizziness, somnolence—typically transient and mild) 1
• Evaluate improvement in both nighttime RLS symptoms and daytime functioning 1
• If using dopamine agonists despite recommendations, monitor closely for augmentation signs 1, 3

Common Pitfalls to Avoid

• Do not use single nighttime gabapentin dosing—it fails to provide 24-hour coverage 1
• Do not increase dopamine agonist doses if augmentation is suspected—this worsens the problem 1
• Do not assume "normal" ferritin levels are adequate—RLS requires ferritin >75 ng/mL 1, 2
• Do not use magnesium or clonazepam as monotherapy without first addressing iron status and trying alpha-2-delta ligands 1
• Do not prescribe dopamine agonists as first-line therapy—the evidence now clearly favors alpha-2-delta ligands 1, 2, 3