What is the recommended treatment for Restless Legs Syndrome (RLS) in a patient with Chronic Renal Insufficiency (CRI) and intolerance to gabapentin (Neurontin)?

Treatment Recommendation for RLS in CRI with Gabapentin Intolerance

For a patient with chronic renal insufficiency and RLS who cannot tolerate gabapentin, intravenous iron sucrose should be the next treatment if ferritin is <200 ng/mL and transferrin saturation is <20%, followed by vitamin C supplementation as adjunctive therapy. 1

Initial Assessment and Iron Status Evaluation

Before considering alternative pharmacological agents, iron status must be evaluated and optimized, as this represents the most evidence-based intervention in CKD patients with RLS:

• Check serum ferritin and transferrin saturation in the morning after avoiding iron supplements for at least 24 hours. 1, 2
• For patients with end-stage renal disease (ESRD) specifically, IV iron sucrose is recommended if ferritin <200 ng/mL and transferrin saturation <20%, with a conditional recommendation and moderate certainty of evidence. 1
• This threshold differs from the general RLS population (ferritin ≤75 ng/mL), reflecting the unique iron metabolism in CKD patients. 1, 2

First-Line Treatment Algorithm for CRI Patients

If Iron Deficient (Ferritin <200 ng/mL and Transferrin Saturation <20%):

• Administer IV iron sucrose as the primary intervention, with conditional recommendation and moderate certainty of evidence. 1
• Add vitamin C supplementation, which has a conditional recommendation with low certainty of evidence for ESRD patients with RLS. 1
• Regularly reassess iron status, as CKD patients may require ongoing monitoring and repeat supplementation. 1

If Iron Replete or After Iron Optimization:

Since gabapentin is not tolerated and represents the only alpha-2-delta ligand with evidence in CKD, the treatment pathway becomes more challenging:

• Pregabalin should be avoided in patients with end-stage renal disease due to increased hazard for altered mental status and falls (50-68% higher hazard), even at low doses. 2
• Dopaminergic agents (levodopa, pramipexole, ropinirole, rotigotine) are specifically recommended against as standard treatment due to high risk of augmentation, with conditional recommendation and low to moderate certainty of evidence. 1, 3

Alternative Treatment Options in Order of Preference

Non-Pharmacological Option:

• Bilateral high-frequency peroneal nerve stimulation is conditionally recommended with moderate certainty of evidence as a non-pharmacological alternative. 2

Pharmacological Options for Refractory Cases:

• Extended-release oxycodone and other low-dose opioids are conditionally recommended for moderate to severe refractory RLS, with moderate certainty of evidence. 2
• In CKD stage 4-5 (eGFR <30 mL/min), fentanyl and buprenorphine (transdermal or IV) are the safest opioid options as they do not accumulate toxic metabolites in renal failure. 2
• Avoid morphine, codeine, and tramadol in stage 4 CKD due to accumulation of toxic metabolites. 2
• Long-term studies show relatively low risks of abuse/overdose with methadone and buprenorphine in appropriately screened RLS patients, with only small dose increases over 2-10 years. 2

Critical Pitfalls to Avoid

• Do not use ropinirole or other dopamine agonists as standard treatment in CRI patients, despite older literature suggesting efficacy. 1, 3 The 2025 American Academy of Sleep Medicine guidelines represent a major shift from 2009 recommendations, now recommending against dopamine agonists due to augmentation risk. 3
• Do not attempt pregabalin as an alternative to gabapentin in dialysis patients, as the fall and altered mental status risk is unacceptably high. 2
• Do not overlook iron supplementation, even if the patient has "normal" ferritin by general population standards—CKD patients require higher thresholds (ferritin <200 ng/mL). 1
• Ensure any patient started on opioid therapy is screened for respiratory depression risk, particularly if untreated obstructive sleep apnea is present. 2

Medications to Eliminate That May Worsen RLS

• Review and discontinue or reduce antihistaminergic medications, serotonergic medications (SSRIs), antidopaminergic medications (antipsychotics), alcohol, and caffeine, particularly in the evening. 2

Monitoring and Follow-Up

• Reassess iron studies every 6-12 months in CKD patients with RLS. 1
• If dopaminergic agents are used despite recommendations against their standard use, watch closely for augmentation (earlier symptom onset, increased intensity, spread to upper extremities). 1
• Monitor for side effects of any pharmacological agent chosen, with particular attention to sedation, dizziness, and fall risk in the CKD population. 2