What are the treatment options for restless leg syndrome during bedtime?

Treatment for Restless Leg Syndrome During Bedtime

The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacological therapy for RLS at bedtime, with all three agents receiving strong recommendations based on moderate certainty of evidence. 1

Initial Assessment and Iron Status

Before initiating any pharmacological treatment, you must address iron deficiency, which is a critical and often overlooked component of RLS management:

• Check serum ferritin and transferrin saturation in all patients with clinically significant RLS, ideally in the morning after avoiding iron-containing supplements for at least 24 hours. 1

• Institute iron supplementation if serum ferritin ≤75 ng/mL or transferrin saturation <20% using oral or IV formulations; if ferritin is between 75-100 ng/mL, use only IV iron. 1 These thresholds are higher than for the general population because brain iron deficiency plays a key role in RLS pathophysiology. 2

• IV ferric carboxymaltose receives a strong recommendation (moderate certainty of evidence) for patients meeting these iron parameters. 1, 2

Address Exacerbating Factors

Before prescribing medications, eliminate factors that worsen RLS:

• Discontinue or substitute medications that exacerbate RLS: antihistamines, serotonergic antidepressants (SSRIs), antidopaminergic agents (antipsychotics like lurasidone), and tricyclic antidepressants. 1, 2

• Reduce or eliminate alcohol, caffeine, and nicotine, as these substances can worsen symptoms. 1

• Treat untreated obstructive sleep apnea, which commonly coexists with and exacerbates RLS. 1

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

The 2025 AASM guidelines represent a significant shift away from dopamine agonists due to augmentation risk:

Gabapentin Enacarbil

• Strong recommendation, moderate certainty of evidence 1
• Prodrug of gabapentin with superior bioavailability allowing for more convenient dosing 2

Gabapentin

• Strong recommendation, moderate certainty of evidence 1
• 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 2
• If symptoms persist after 3-7 days, increase by 300 mg/day every few days 2
• Common side effects include somnolence and dizziness, which are typically transient and mild 2

Pregabalin

• Strong recommendation, moderate certainty of evidence 1
• Allows twice-daily dosing with potentially superior bioavailability compared to gabapentin 2

These agents are now preferred over dopamine agonists because they avoid the augmentation phenomenon—a paradoxical worsening of RLS symptoms with long-term dopaminergic treatment. 2

Second-Line and Alternative Treatments

Oral Iron Supplementation

• Conditional recommendation, moderate certainty of evidence for oral ferrous sulfate in patients with ferritin ≤75 ng/mL or transferrin saturation <20% 2

Opioids for Refractory Cases

• Extended-release oxycodone and other low-dose opioids receive conditional recommendations for moderate to severe refractory cases or when treating augmentation from dopaminergic agents. 2
• Long-term studies show relatively low risks of abuse and only small dose increases over 2-10 years in appropriately screened patients. 2
• Critical caveat: Use extreme caution in patients with untreated obstructive sleep apnea or chronic obstructive pulmonary disease due to risk of respiratory depression. 2

Non-Pharmacological Options

• Bilateral high-frequency peroneal nerve stimulation receives a conditional recommendation based on moderate certainty of evidence as a newer noninvasive option. 2, 3

Medications to Avoid or Use with Extreme Caution

The 2025 guidelines represent a major departure from previous recommendations regarding dopamine agonists:

Strongly Recommended Against

• Cabergoline: Strong recommendation against use (moderate certainty of evidence) 2

Conditional Recommendations Against Standard Use

• Pramipexole: Conditional recommendation against (moderate certainty of evidence) due to significant augmentation risk with long-term use 1, 4
• Ropinirole: Conditional recommendation against (moderate certainty of evidence) 2, 5
• Transdermal rotigotine: Conditional recommendation against (low certainty of evidence) 2
• Levodopa: Conditional recommendation against (very low certainty of evidence) 2

The augmentation phenomenon is characterized by: earlier onset of symptoms during the day, increased symptom intensity, spread of symptoms to other body parts, and shorter duration of medication effect. 2, 4

Other Medications Not Recommended

• Bupropion, carbamazepine, clonazepam, valproic acid, and valerian all receive conditional recommendations against use. 2

Special Populations

Pregnancy

• Consider pregnancy-specific safety profiles for each treatment being considered, as RLS is common in pregnancy. 1

End-Stage Renal Disease

• Gabapentin receives a conditional recommendation (very low certainty of evidence) 2
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (conditional recommendation, moderate certainty of evidence) 2
• Vitamin C receives a conditional recommendation (low certainty of evidence) 2, 3

Pediatric Patients

• Oral ferrous sulfate for serum ferritin <50 ng/mL (conditional recommendation, very low certainty of evidence) 2
• Monitor for constipation with iron supplementation 2

Critical Pitfalls to Avoid

• Do not start dopamine agonists as first-line therapy despite their historical use and FDA approval; the 2025 AASM guidelines clearly prioritize alpha-2-delta ligands due to lower augmentation risk. 1, 2

• Do not ignore iron status—this is a modifiable factor that can significantly improve outcomes and potentially prevent the need for higher medication doses. 1, 2

• Do not use single nighttime dosing of gabapentin—this fails to address daytime RLS symptoms and provides suboptimal coverage; use divided dosing throughout the day. 2

• Monitor for augmentation if dopamine agonists were previously prescribed, and have a plan to transition to alpha-2-delta ligands or opioids if augmentation develops. 2, 4

• Evaluate for and treat obstructive sleep apnea before attributing all symptoms to RLS alone, as OSA commonly coexists and exacerbates RLS symptoms. 1