What are the treatment guidelines for restless legs syndrome in patients with End-Stage Renal Disease (ESRD)?

Treatment Guidelines for Restless Legs Syndrome in ESRD Patients

For patients with end-stage renal disease and RLS, gabapentin is the recommended first-line pharmacological treatment, with IV iron sucrose as an adjunct if ferritin <200 ng/mL and transferrin saturation <20%. 1, 2

Initial Assessment and Iron Management

Before initiating any pharmacological therapy, check morning fasting iron studies including serum ferritin and transferrin saturation. 1, 2

Iron supplementation thresholds differ in ESRD patients compared to the general RLS population:

• In ESRD patients with RLS: Administer IV iron sucrose if ferritin <200 ng/mL AND transferrin saturation <20% (conditional recommendation, moderate certainty). 1, 2
• In general RLS population: Supplement if ferritin ≤75 ng/mL OR transferrin saturation <20%. 1, 2

The higher ferritin threshold in ESRD reflects the altered iron metabolism and inflammatory state in dialysis patients. 1

First-Line Pharmacological Treatment

Gabapentin is conditionally recommended for ESRD patients with RLS, though the certainty of evidence is very low. 1, 2

Gabapentin Dosing in ESRD:

• Start with 100 mg post-dialysis or 100 mg at bedtime. 1
• Maximum dose: 200-300 mg daily. 1
• Critical safety warning: Gabapentinoids carry a 31-41% higher hazard for altered mental status and falls in hemodialysis patients, even at low doses. 1

This represents a major departure from the general RLS population where gabapentin is dosed at 1800-2400 mg/day divided three times daily. 1 The dramatic dose reduction in ESRD is necessary due to renal elimination and accumulation risk.

Alternative and Adjunctive Therapies

Vitamin C is conditionally recommended for ESRD patients with RLS (low certainty of evidence). 1, 2 One study showed vitamins C and E helped RLS symptoms with minimal side effects (nausea and dyspepsia), though more evidence is needed. 3

Aerobic resistance exercise during dialysis sessions showed significant reduction in RLS severity compared to no exercise (MD -7.56,95% CI -14.20 to -0.93), though evidence quality is limited. 3

Medications to Avoid in ESRD

Dopamine agonists (pramipexole, ropinirole, rotigotine) are NOT recommended as standard treatment due to high augmentation risk, even though older literature suggested their use in ESRD. 1, 2, 4, 5 The 2026 American Academy of Sleep Medicine guidelines represent a paradigm shift away from these agents. 4

Pregabalin carries an even higher risk than gabapentin in dialysis patients: 50-68% higher hazard for altered mental status and falls, making it unsuitable for ESRD despite being first-line in general RLS. 1

Opioids require extreme caution in ESRD. If needed for refractory cases:

• Fentanyl and buprenorphine (transdermal or IV) are safest as they don't accumulate toxic metabolites. 1
• Avoid morphine, codeine, and tramadol due to accumulation of toxic metabolites in renal failure. 1

Critical Pitfalls to Avoid

• Do not use standard gabapentin dosing from general RLS guidelines (1800-2400 mg/day) in ESRD patients—this will cause severe toxicity. 1
• Do not assume ferritin ≤75 ng/mL is the threshold for iron supplementation in ESRD—use <200 ng/mL instead. 1, 2
• Monitor closely for falls and altered mental status when initiating gabapentin, even at low doses. 1
• Recognize that evidence quality is very low for all interventions in ESRD-associated RLS, with most studies having small sample sizes and short follow-up (2-6 months). 5, 3

Treatment Algorithm for ESRD-Associated RLS

1. Check iron studies (ferritin and transferrin saturation). 1, 2
2. If ferritin <200 ng/mL AND transferrin saturation <20%: Give IV iron sucrose. 1, 2
3. Initiate gabapentin 100 mg post-dialysis or at bedtime, titrate cautiously to maximum 200-300 mg/day. 1
4. Consider vitamin C supplementation as adjunctive therapy. 1, 2
5. Encourage intra-dialytic aerobic resistance exercise if feasible. 3
6. For refractory cases only: Consider fentanyl or buprenorphine with appropriate monitoring, avoiding other opioids. 1

The limited evidence base and altered pharmacokinetics in ESRD make treatment challenging, requiring lower doses, careful monitoring, and realistic expectations about symptom control. 5, 3