Treatment of Restless Legs Syndrome
Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are the first-line pharmacological treatment for RLS, but only after checking and correcting iron deficiency. 1
Initial Assessment and Iron Management
Before starting any medication, you must address iron status in every patient with clinically significant RLS:
- Check serum ferritin and transferrin saturation in the morning after avoiding iron supplements for at least 24 hours 1, 2
- Supplement with iron if ferritin ≤75 ng/mL or transferrin saturation <20%—this threshold is much higher than general population cutoffs because brain iron deficiency is central to RLS pathophysiology 1, 2
- For oral supplementation, use ferrous sulfate 65 mg elemental iron daily (conditional recommendation, moderate certainty) 1, 3
- For ferritin 75-100 ng/mL or failed oral therapy, use IV ferric carboxymaltose 1000 mg (strong recommendation, moderate certainty) 1, 3
Critical pitfall: Do not use general population ferritin cutoffs (<15-30 ng/mL) for RLS—you will miss the majority of patients who would benefit from iron therapy. 2
Identify and Eliminate Exacerbating Factors
Before escalating treatment, systematically address:
- Alcohol and caffeine intake 1
- Antihistaminergic medications (including over-the-counter sleep aids) 1
- Serotonergic medications (SSRIs, SNRIs) 1
- Antidopaminergic medications (antipsychotics like lurasidone, metoclopramide, prochlorperazine) 1
- Untreated obstructive sleep apnea 1
First-Line Pharmacological Treatment
After addressing iron status and exacerbating factors, start an alpha-2-delta ligand:
- Gabapentin enacarbil (strong recommendation, moderate certainty) 1, 3
- Gabapentin (strong recommendation, moderate certainty) 1, 3
- Pregabalin (strong recommendation, moderate certainty) 1, 3
These agents are preferred over dopamine agonists because they avoid augmentation—a paradoxical worsening of symptoms with earlier onset, increased intensity, and anatomic spread that occurs with long-term dopaminergic use. 1, 4
Dosing guidance for gabapentin: Start at 300 mg three times daily (900 mg/day total) and titrate up to 1800-2400 mg/day divided three times daily based on response, with doses up to 3600 mg/day well-tolerated. 1 Single nighttime dosing is inadequate for 24-hour symptom control. 1
Common side effects: Somnolence and dizziness are typically transient and mild. 1 Monitor for misuse potential in at-risk populations. 1
What NOT to Use: Dopamine Agonists
The American Academy of Sleep Medicine now recommends AGAINST standard use of dopamine agonists due to augmentation risk:
- Pramipexole (conditional recommendation against, moderate certainty) 1, 3
- Ropinirole (conditional recommendation against, moderate certainty) 1
- Rotigotine transdermal (conditional recommendation against, low certainty) 1
- Levodopa (conditional recommendation against, very low certainty) 1, 3
- Cabergoline (strong recommendation against, moderate certainty) 1, 3
Despite FDA approval of ropinirole for RLS 5, current guidelines prioritize long-term outcomes over short-term efficacy. While ropinirole showed statistically significant improvements in 12-week trials 5, the high risk of augmentation with chronic use outweighs these benefits. 1, 4
These agents may only be considered for short-term use in patients who prioritize immediate symptom relief over long-term adverse effects. 1, 3
Second-Line and Refractory Treatment Options
If alpha-2-delta ligands fail or are not tolerated:
- Extended-release oxycodone and other low-dose opioids (methadone, buprenorphine) are conditionally recommended for moderate to severe or refractory cases (conditional recommendation) 1, 4
- Opioids show relatively low risks of abuse and overdose in appropriately screened patients, with only small dose increases over 2-10 years 1
- Caution: Monitor for respiratory depression and central sleep apnea, especially in patients with untreated OSA or COPD 1
Non-pharmacological option:
- Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty) 1, 3
Managing Dopaminergic Augmentation
If a patient is already on a dopamine agonist and develops augmentation (earlier symptom onset, increased intensity, spread to arms or daytime):
- Do NOT abruptly stop the dopamine agonist—this causes profound rebound RLS and insomnia 4
- Add an alpha-2-delta ligand or opioid first 4
- Once adequate symptom control is achieved with the second agent, perform very slow down-titration and discontinuation of the dopamine agonist 4
- This approach can lead to dramatic long-term relief 4
Special Populations
End-stage renal disease:
- Gabapentin (conditional recommendation, very low certainty) starting at 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, 3
- Warning: Gabapentinoids carry 31-68% higher hazard for altered mental status and falls in dialysis patients 1
Pregnancy:
- Consider medication safety profiles carefully 1, 3
- Non-pharmacologic approaches may be preferred 3
- Iron supplementation is particularly important given pregnancy-specific RLS prevalence 1
Pediatric RLS:
- Oral iron supplementation if ferritin <50 ng/mL (conditional recommendation, very low certainty) 1, 2
- Monitor for constipation 1
Medications to Explicitly Avoid
The American Academy of Sleep Medicine recommends against:
- Bupropion (conditional recommendation, moderate certainty) 1
- Carbamazepine (conditional recommendation, low certainty) 1
- Clonazepam (conditional recommendation, very low certainty)—only improves subjective sleep quality without reducing objective disease markers, with risks of sedation, hepatotoxicity, and teratogenicity 1
- Valproic acid (conditional recommendation, low certainty) 1
- Valerian (conditional recommendation, very low certainty) 1