What is the recommended pharmacologic treatment and dosing for an adult with typical restless‑leg syndrome, including first‑line dopamine agonists, second‑line options, iron supplementation, and adjunct therapies?

Pharmacologic Treatment of Restless Legs Syndrome

First-Line Therapy: Alpha-2-Delta Ligands

The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacologic treatment for restless legs syndrome, NOT dopamine agonists. 1, 2

Specific Dosing Regimens

Gabapentin:

• Start 300 mg three times daily (900 mg/day total) 1
• Increase by 300 mg/day every 3–7 days based on symptom response 1
• Target maintenance dose: 1800–2400 mg/day divided three times daily 1
• Maximum studied dose: 3600 mg/day 1
• Critical pitfall: Avoid single nighttime dosing—this fails to address daytime symptoms and provides suboptimal 24-hour coverage 1

Pregabalin:

• Allows twice-daily dosing with potentially superior bioavailability compared to regular gabapentin 1, 2
• Strongly recommended as first-line therapy with moderate certainty of evidence 1, 2

Gabapentin enacarbil:

• Prodrug of gabapentin with improved pharmacokinetics 1
• Strongly recommended with moderate certainty of evidence 1

Rationale for Alpha-2-Delta Ligands Over Dopamine Agonists

The shift away from dopamine agonists as first-line therapy is driven by the high risk of augmentation—a paradoxical worsening of RLS symptoms characterized by: 1, 2, 3

• Earlier onset of symptoms during the day 1
• Increased symptom intensity 1
• Spread to upper extremities or trunk 1
• Annual augmentation incidence of 7–10% with dopaminergic therapy 1

Iron Supplementation: Essential First Step

Before initiating any medication, check morning fasting serum ferritin and transferrin saturation after avoiding iron supplements for ≥24 hours. 1, 2

Iron Supplementation Thresholds (Different from General Population)

Adults: Supplement if ferritin ≤75 ng/mL OR transferrin saturation <20% 1, 2

Children: Supplement if ferritin <50 ng/mL 1, 2

Iron Formulations

IV ferric carboxymaltose:

• Strongly recommended for rapid correction in patients meeting iron parameters 1, 2
• Dose: 750–1000 mg in one or two infusions 1
• Preferred when oral iron is not tolerated or ineffective after 3 months 1

Oral ferrous sulfate:

• Conditionally recommended alternative 1, 2
• Works more slowly than IV formulations 2

Medications to AVOID or Use with Extreme Caution

Strongly Recommended AGAINST

Dopamine agonists (pramipexole, ropinirole, rotigotine):

• The American Academy of Sleep Medicine suggests AGAINST standard use due to high augmentation risk 1, 2, 4
• May be considered only for short-term use in patients who prioritize immediate relief over long-term safety 1
• If augmentation develops, do NOT increase the dose—this worsens the problem 1

Other medications strongly recommended against: 1, 2

• Cabergoline (strong recommendation, moderate certainty)
• Bupropion (conditional recommendation, moderate certainty)
• Carbamazepine (conditional recommendation, low certainty)
• Clonazepam (conditional recommendation, very low certainty)
• Valproic acid (conditional recommendation, low certainty)
• Valerian (conditional recommendation, very low certainty)

Levodopa:

• Suggested against for standard use (conditional recommendation, very low certainty) 1
• High risk of augmentation 1

Second-Line Options for Refractory Cases

Extended-release oxycodone and other low-dose opioids:

• Conditionally recommended for moderate to severe refractory RLS 1, 2, 3, 5
• 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 1
• Evidence shows only small dose increases over 2–10 years 1
• Caution: Assess for respiratory depression risk, especially in patients with untreated obstructive sleep apnea 1

Other second-line options:

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

Special Population: End-Stage Renal Disease

Gabapentin dosing in ESRD:

• Start 100 mg post-dialysis or at bedtime 1, 2
• Maximum 200–300 mg daily 1, 2
• Conditional recommendation with very low certainty of evidence 1

IV iron sucrose:

• Indicated when ferritin <200 ng/mL AND transferrin saturation <20% 1, 2
• Conditional recommendation with moderate certainty 1

Vitamin C supplementation:

• Conditionally recommended to enhance iron utilization 1, 2

Avoid pregabalin in ESRD:

• Associated with 50–68% higher hazard for altered mental status and falls in dialysis patients 1

Addressing Exacerbating Factors

Eliminate or reduce: 1, 2

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

Screen for and treat:

• Untreated obstructive sleep apnea 1
• Iron deficiency (as above) 1, 2

Treatment Algorithm Summary

1. Check iron studies (morning fasting ferritin and transferrin saturation) 1, 2
2. Supplement iron if ferritin ≤75 ng/mL or transferrin saturation <20% 1, 2
3. Eliminate exacerbating factors (medications, substances, sleep apnea) 1, 2
4. Initiate alpha-2-delta ligand (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacologic therapy 1, 2
5. Reserve opioids for refractory cases or augmentation management 1, 2
6. Avoid dopamine agonists as first-line therapy due to augmentation risk 1, 2, 4

Critical Pitfalls to Avoid

• Do NOT use dopamine agonists as first-line therapy—the evidence now clearly favors alpha-2-delta ligands 1, 2
• Do NOT use single nighttime dosing of gabapentin—divide doses throughout the day for optimal 24-hour coverage 1
• Do NOT increase dopamine agonist doses if augmentation is suspected—this paradoxically worsens symptoms 1
• Do NOT skip iron assessment—brain iron deficiency plays a key role in RLS pathophysiology even when serum iron appears normal 1
• Do NOT assume "normal" ferritin levels are adequate—RLS requires higher thresholds (≤75 ng/mL) than general population guidelines 1, 2