What are the treatment options for a patient with Restless Legs Syndrome (RLS) and stage 4 Chronic Kidney Disease (CKD)?

Treatment of RLS in Stage 4 CKD

For patients with RLS and stage 4 chronic kidney disease, start with alpha-2-delta ligands (gabapentin or pregabalin) as first-line pharmacological therapy after optimizing iron status, while avoiding dopamine agonists due to augmentation risk. 1

Initial Assessment and Iron Optimization

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

Iron supplementation is critical if ferritin ≤75 ng/mL or transferrin saturation <20%, as correcting iron deficiency can significantly improve RLS symptoms independent of other treatments. 1

• Oral ferrous sulfate is the first-line iron supplementation option for stage 4 CKD patients with appropriate iron parameters. 1
• IV iron formulations (ferric carboxymaltose, iron dextran) should be reserved for patients who fail oral therapy or have severe symptoms requiring rapid correction. 1, 2

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

Gabapentin is strongly recommended as first-line therapy with moderate certainty of evidence, starting at 300 mg at bedtime and titrating to 1800-2400 mg/day divided into multiple doses. 1

• In stage 4 CKD (eGFR 15-29 mL/min), dose adjustment is necessary but gabapentin remains effective and safe. 1
• Common side effects include somnolence and dizziness, which are typically transient and mild. 1
• Gabapentin can be removed by hemodialysis if toxicity occurs, providing a safety margin. 3

Pregabalin is an equally effective alternative with twice-daily dosing and potentially superior bioavailability compared to regular gabapentin. 1

• Pregabalin requires dose adjustment in stage 4 CKD but remains a viable first-line option. 1
• The twice-daily dosing may improve adherence compared to gabapentin's three-times-daily regimen. 1

Medications to Avoid

Dopamine agonists (pramipexole, ropinirole, rotigotine) are NOT recommended as standard treatment due to high risk of augmentation—a paradoxical worsening of symptoms with earlier onset, increased intensity, and anatomic spread to arms or trunk. 1, 4, 5

• The American Academy of Sleep Medicine suggests against standard use of these agents with conditional to strong recommendations. 1, 4, 5
• Levodopa is also not recommended due to very low certainty of evidence and high augmentation risk. 1

Second-Line and Refractory Treatment Options

For patients who fail first-line therapy with alpha-2-delta ligands and optimized iron status:

Extended-release oxycodone and other low-dose opioids are conditionally recommended for moderate to severe refractory cases. 1

• Opioids are particularly useful when treating augmentation from prior dopamine agonist use. 1
• Monitor for respiratory depression, especially in patients with untreated sleep apnea. 1
• Long-term studies show only small dose increases over 2-10 years with relatively low abuse risk in appropriately screened patients. 1

Bilateral high-frequency peroneal nerve stimulation is a non-pharmacological option with conditional recommendation for patients who prefer to avoid or cannot tolerate medications. 1

Special Considerations for Stage 4 CKD

Address potential exacerbating factors that are particularly relevant in CKD patients:

• Avoid antihistaminergic medications, serotonergic medications, and antidopaminergic medications that can worsen RLS. 1
• Screen for and treat obstructive sleep apnea, which is highly prevalent in CKD patients. 1
• Counsel patients to avoid alcohol and caffeine, especially in the evening hours when RLS symptoms are most pronounced. 1

Critical Pitfalls to Avoid

Do not start dopamine agonists as first-line therapy despite their historical use—the 2025 American Academy of Sleep Medicine guidelines represent a paradigm shift away from these agents due to long-term harms outweighing short-term benefits. 1, 5

Do not neglect iron status assessment—even patients with "normal" serum iron may have brain iron deficiency contributing to RLS, and the threshold for supplementation (ferritin ≤75 ng/mL) is higher than general population guidelines. 1

Do not assume single nighttime dosing of gabapentin is adequate—effective RLS control typically requires divided doses throughout the day to address both daytime and nighttime symptoms. 1

Monitoring and Follow-Up

Reassess iron studies every 6-12 months, as RLS symptoms may recur if iron stores decline below therapeutic thresholds. 1

Monitor for side effects of alpha-2-delta ligands, particularly dizziness and somnolence, which may increase fall risk in CKD patients. 1

Evaluate improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood) to assess treatment efficacy. 1