What are the recommended medications and treatment options for a patient with restless legs syndrome (RLS)?

Restless Legs Syndrome Medications

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are the first-line pharmacological treatment for restless legs syndrome, with dopamine agonists like ropinirole now recommended against for standard use due to high risk of augmentation. 1

Initial Assessment and Iron Optimization

Before starting any medication, check serum iron studies in all patients with clinically significant RLS:

• Obtain morning fasting ferritin and transferrin saturation after avoiding iron supplements for at least 24 hours 1
• Supplement with iron if ferritin ≤75 ng/mL or transferrin saturation <20% (note this threshold differs from general population guidelines) 1
• IV ferric carboxymaltose (750-1000 mg in one or two infusions) is strongly recommended for rapid correction if oral iron is not tolerated or ineffective after 3 months 1
• Oral ferrous sulfate is conditionally recommended for appropriate iron parameters 1

Address exacerbating factors including alcohol, caffeine, antihistamines, serotonergic medications (SSRIs, SNRIs), antidopaminergic medications (antipsychotics), and untreated obstructive sleep apnea 1

First-Line Pharmacological Treatment

Alpha-2-delta ligands are strongly recommended with moderate certainty of evidence: 1

• Gabapentin: Start 300 mg at bedtime, titrate by 300 mg every 3-7 days to maintenance dose of 1800-2400 mg/day divided three times daily 1
• Gabapentin enacarbil: Allows once-daily dosing, strongly recommended 1
• Pregabalin: Allows twice-daily dosing with potentially superior bioavailability compared to regular gabapentin 1

These agents are preferred because they avoid augmentation—a paradoxical worsening of RLS symptoms characterized by earlier onset during the day, increased intensity, and spread to other body parts that occurs with long-term dopamine agonist use 1, 2

Medications to Avoid or Use with Extreme Caution

Dopamine agonists are now recommended against for standard use: 1, 2

• Pramipexole: Conditional recommendation against standard use (moderate certainty) 1
• Ropinirole: Conditional recommendation against standard use (moderate certainty) 1, 2, 3
• Rotigotine (transdermal): Conditional recommendation against standard use (low certainty) due to higher risk of dizziness, somnolence, and augmentation 1
• Levodopa: Conditional recommendation against standard use (very low certainty) 1
• Cabergoline: Strong recommendation against use (moderate certainty) 1

While ropinirole demonstrated efficacy in FDA trials with mean IRLS score improvements of 2.5-3.7 points over placebo at 12 weeks 3, the long-term risk of augmentation (occurring in 30-60% of patients on chronic dopamine agonist therapy) outweighs short-term benefits 1, 4, 5

Other medications specifically recommended against: 1

• Bupropion, carbamazepine, clonazepam, valproic acid, valerian

Second-Line and Refractory RLS Treatment

For patients who fail first-line therapy or have refractory RLS: 1

• Extended-release oxycodone and other low-dose opioids (methadone, buprenorphine) are conditionally recommended for moderate to severe refractory cases 1
• 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: Monitor for respiratory depression, especially in patients with untreated obstructive sleep apnea 1

Non-pharmacological option: 1

• Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty)

Alternative medication: 1

• Dipyridamole (conditional recommendation, low certainty)

Special Populations

End-stage renal disease patients: 1

• Gabapentin: Start 100 mg post-dialysis or at bedtime, maximum 200-300 mg daily (conditional recommendation, very low certainty)
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (conditional recommendation, moderate certainty)
• Vitamin C (conditional recommendation, low certainty)
• Avoid pregabalin due to 50-68% higher hazard for altered mental status and falls 1

Pediatric RLS: 1

• Oral ferrous sulfate if ferritin <50 ng/mL (conditional recommendation, very low certainty)

Pregnancy: 1

• Consider medication safety profiles carefully
• Iron supplementation particularly important given pregnancy-specific RLS prevalence

Managing Dopaminergic Augmentation

If a patient is already on a dopamine agonist and develops augmentation (earlier symptom onset, increased intensity, spread to upper extremities): 1, 2, 4, 5

• Do not increase the dopamine agonist dose—this worsens augmentation 1
• Add an alpha-2-delta ligand or opioid first before attempting to reduce the dopamine agonist 4
• Once adequate symptom control is achieved with the second agent, perform very slow down-titration of the dopamine agonist to avoid profound rebound RLS and insomnia 4
• Temporary strategies while transitioning: take doses earlier in the day or split into early evening and bedtime doses 1, 2

Critical Monitoring

• Reassess iron studies every 6-12 months even after symptom resolution, as brain iron deficiency may persist despite normal serum parameters 1
• Monitor for side effects of alpha-2-delta ligands including dizziness and somnolence (typically transient and mild) 1
• Evaluate for improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood) 1
• Screen for misuse potential with alpha-2-delta ligands, as there is increasing evidence these agents may be misused in certain populations 1