What medications are recommended for a patient with restless leg syndrome?

Medications for Restless Leg Syndrome

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

Initial Assessment Before Medication

Before starting any medication, you must address two critical factors:

• Check iron status with morning fasting serum ferritin and transferrin saturation (avoid iron supplements for 24 hours before testing) 1
• Supplement with iron if ferritin ≤75 ng/mL or transferrin saturation <20% (higher threshold than general population) 1
• Identify and eliminate exacerbating factors including alcohol, caffeine, antihistamines, antidepressants (SSRIs, tricyclics), antipsychotics, and untreated 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 to 1800-2400 mg/day divided into multiple doses (typically three times daily) 1
• Gabapentin enacarbil: Allows once or twice-daily dosing with superior bioavailability 1
• Pregabalin: Twice-daily dosing option 1

These medications are preferred because they avoid augmentation (paradoxical worsening of symptoms seen with dopamine agonists) and effectively treat both RLS symptoms and comorbid conditions like chronic pain, anxiety, and insomnia 1, 2

Iron Supplementation Options

For patients with appropriate iron parameters (ferritin ≤75 ng/mL or transferrin saturation <20%): 1

• Oral ferrous sulfate: Conditional recommendation with moderate certainty 1
• IV ferric carboxymaltose: Strong recommendation with moderate certainty for rapid correction, especially if oral iron fails after 3 months 1
• IV low molecular weight iron dextran or ferumoxytol: Conditional recommendations 1

Medications to AVOID or Use with Extreme Caution

Dopamine agonists are now recommended AGAINST for standard use: 1

• Pramipexole, ropinirole, rotigotine: Conditional recommendation against due to high risk of augmentation 1, 3, 4
• Levodopa: Suggested against with very low certainty of evidence 1
• Cabergoline: Strong recommendation AGAINST with moderate certainty 1

Other medications to avoid: 1

• Bupropion, carbamazepine, clonazepam, valproic acid, valerian 1

Understanding Augmentation

Augmentation is a treatment-related worsening characterized by: 1, 5, 6

• Earlier onset of symptoms during the day
• Increased symptom intensity
• Spread to other body parts (arms, trunk)
• Paradoxical worsening despite dose increases

This occurs commonly with all dopamine agonists and is the primary reason they are no longer first-line therapy 1, 6

Second-Line and Refractory RLS Treatment

For patients who fail first-line therapy: 1

• Extended-release oxycodone and other opioids (methadone, buprenorphine): Conditional recommendation for moderate to severe refractory cases 1, 5, 7

  • Long-term studies show relatively low abuse risk in appropriately screened patients with only small dose increases over 2-10 years 1
  • Particularly effective for treating augmentation when transitioning off dopamine agonists 1, 7
  • Critical caution: Monitor for respiratory depression, especially in patients with untreated sleep apnea 1

• Bilateral high-frequency peroneal nerve stimulation: Conditional recommendation as non-pharmacological option 1

• Dipyridamole: Conditional recommendation with low certainty 1

Special Populations

End-stage renal disease (ESRD): 1

• Gabapentin: Conditional recommendation, start 100 mg post-dialysis or at bedtime, maximum 200-300 mg daily 1
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% 1
• Vitamin C: Conditional recommendation 1
• Avoid pregabalin due to increased risk of altered mental status and falls 1

Pediatric RLS: 1

• Oral ferrous sulfate if ferritin <50 ng/mL (different threshold than adults) 1
• Monitor for constipation 1

Pregnancy: 1

• Consider medication safety profiles carefully
• Iron supplementation particularly important given pregnancy-specific RLS prevalence 1

Treatment Algorithm Summary

1. Assess and correct iron deficiency (ferritin ≤75 ng/mL or transferrin saturation <20%) 1
2. Eliminate exacerbating medications and substances (antidepressants, antihistamines, alcohol, caffeine) 1
3. Start alpha-2-delta ligand (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacological treatment 1
4. If refractory, consider opioids (extended-release oxycodone, methadone, buprenorphine) 1, 7
5. Monitor regularly for side effects (dizziness, somnolence with gabapentinoids) and reassess iron studies every 6-12 months 1

Critical Pitfalls to Avoid

• Do not start with dopamine agonists despite their FDA approval—augmentation risk outweighs benefits for long-term use 1, 6
• Do not ignore iron status—correcting iron deficiency can significantly improve symptoms independent of other treatments 1
• Do not use clonazepam as monotherapy—insufficient evidence of efficacy and does not reduce objective disease markers 1
• Do not abruptly discontinue dopamine agonists if patient is already taking them—severe rebound RLS and withdrawal symptoms can occur; taper very slowly while adding alternative agent first 1, 5
• Monitor for misuse potential with alpha-2-delta ligands, as there is increasing evidence of misuse in certain populations 1