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

Treatment of Restless Legs Syndrome

The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacological therapy for RLS, with dopamine agonists now recommended against for standard use due to high risk of augmentation. 1, 2

Initial Assessment and Iron Correction

Before initiating any pharmacological treatment, check morning fasting serum ferritin and transferrin saturation after avoiding iron supplements for at least 24 hours. 1, 2

Iron supplementation is indicated if ferritin ≤75 ng/mL or transferrin saturation <20%—note this threshold is higher than general population guidelines because brain iron deficiency plays a key pathophysiologic role in RLS even when serum iron appears normal. 1, 2

• IV ferric carboxymaltose is strongly recommended for rapid correction in patients meeting these iron parameters (strong recommendation, moderate certainty). 1, 2
• Oral ferrous sulfate is conditionally recommended as an alternative but works more slowly (conditional recommendation, moderate certainty). 1, 2
• Continue iron supplementation indefinitely with ongoing monitoring every 6-12 months, as RLS symptoms may recur if iron stores decline below therapeutic thresholds. 1

Address Exacerbating Factors

Eliminate or reduce alcohol, caffeine, and nicotine, particularly in the evening hours when RLS symptoms are most pronounced. 1, 2

Discontinue medications that worsen RLS, including:

• Antihistaminergic medications 1
• Serotonergic medications (SSRIs, tricyclic antidepressants) 1
• Antidopaminergic medications (antipsychotics like lurasidone) 1
• Screen for and treat untreated obstructive sleep apnea 1

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

Gabapentin (strong recommendation, moderate certainty):

• Start at 300 mg three times daily (900 mg/day total). 1
• Titrate by 300 mg/day every 3-7 days until reaching maintenance dose of 1800-2400 mg/day divided three times daily. 1
• Avoid single nighttime dosing—this fails to address daytime RLS symptoms and provides suboptimal 24-hour coverage. 1
• Common side effects include somnolence and dizziness, which are typically transient and mild. 1

Pregabalin (strong recommendation, moderate certainty):

• Allows twice-daily dosing with potentially superior bioavailability compared to gabapentin. 1, 2

Gabapentin enacarbil (strong recommendation, moderate certainty):

• A prodrug of gabapentin with improved pharmacokinetics. 1

The key advantage of alpha-2-delta ligands over dopamine agonists is that they avoid the augmentation phenomenon—a paradoxical worsening of symptoms with earlier onset, increased intensity, and anatomic spread to arms or other body regions. 1, 3

Medications to Avoid or Use with Extreme Caution

Strongly recommended AGAINST:

• Cabergoline (strong recommendation, moderate certainty) 1, 2

Conditionally recommended AGAINST for standard use:

• Pramipexole (conditional recommendation, moderate certainty) due to high augmentation risk 1, 3
• Ropinirole (conditional recommendation, moderate certainty) due to high augmentation risk 1
• Transdermal rotigotine (conditional recommendation, low certainty) due to augmentation risk and higher rates of dizziness/somnolence that increase fall risk 1
• Levodopa (conditional recommendation, very low certainty) due to very high augmentation risk 1, 2
• Clonazepam (conditional recommendation, very low certainty)—insufficient evidence of efficacy, only improves subjective sleep quality without reducing objective periodic limb movement index 1
• Bupropion, carbamazepine, valproic acid, valerian (conditional recommendations, varying certainty) 1, 2

Second-Line Options for Refractory Cases

Extended-release oxycodone and other low-dose opioids (conditional recommendation, moderate certainty):

• Particularly effective for refractory RLS or when treating augmentation during transition off dopamine agonists. 4, 1, 2
• Evidence from long-term studies (2-10 years) shows relatively low risks of abuse and overdose in appropriately screened patients, with only small dose increases over time. 4
• Methadone and buprenorphine are commonly used and have lower risk profiles compared to other opioids, as they are also used for long-term maintenance therapy in opioid use disorder. 4
• Critical caution: Risk of central sleep apnea and respiratory depression increases with higher morphine equivalent dosing (except buprenorphine, which has reduced respiratory depression risk). 4
• This risk is compounded by concurrent use of other CNS depressants including sedative hypnotics, muscle relaxants, and alpha-2-delta ligands. 4
• Screen for untreated obstructive sleep apnea before initiating opioids. 1

Other second-line options:

• Dipyridamole (conditional recommendation, low certainty) 1, 2
• Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty)—a wearable device placed below the knees providing noninvasive nonpharmacological treatment. 4, 1, 2

Managing Augmentation from Dopamine Agonists

If a patient is already on a dopamine agonist and develops augmentation (earlier symptom onset during the day, increased intensity, spread to arms):

1. Add an alpha-2-delta ligand or low-dose opioid first—do not immediately reduce the dopamine agonist, as this causes profound rebound RLS and insomnia. 5
2. Once adequate symptom relief is achieved with the second agent, initiate very slow down-titration of the dopamine agonist. 5
3. Opioids are particularly effective for relieving worsening symptoms when decreasing or eliminating dopamine agonists. 1

Special Populations

End-stage renal disease (ESRD):

• Gabapentin (conditional recommendation, very low certainty): 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% (conditional recommendation, moderate certainty). 1, 2
• Vitamin C (conditional recommendation, low certainty). 1, 2
• Critical warning: Gabapentinoids are associated with 50-68% higher hazard for altered mental status and falls in dialysis patients, even at low doses. 1

Pediatric RLS:

• Oral ferrous sulfate if ferritin <50 ng/mL (conditional recommendation, very low certainty). 1, 2
• Monitor for constipation as a common side effect. 4, 1

Pregnancy:

• Iron supplementation is particularly important given pregnancy-specific RLS prevalence, with safety profile favoring oral formulations throughout gestation. 1

Critical Pitfalls to Avoid

• Never use dopamine agonists as first-line therapy—the 2025 American Academy of Sleep Medicine guidelines represent a paradigm shift away from dopaminergic agents due to augmentation risk. 1, 2, 3
• Never use single nighttime dosing of gabapentin—divide doses throughout the day for adequate 24-hour symptom control. 1
• Never abruptly discontinue dopamine agonists if augmentation develops—add alternative therapy first, then taper very slowly. 5
• Never assume "normal" ferritin is adequate—use the RLS-specific threshold of ≤75 ng/mL, not general population guidelines. 1, 2
• Never prescribe opioids without screening for untreated sleep apnea and assessing concurrent CNS depressant use. 4, 1
• Never use magnesium as monotherapy for clinically significant RLS without first addressing iron status and considering guideline-recommended treatments. 1