What is the preferred treatment between Benadryl (diphenhydramine) and Atarax (hydroxyzine) for itching in patients with End-Stage Renal Disease (ESRD)?

Antihistamine Selection for ESRD-Associated Pruritus

Neither Benadryl (diphenhydramine) nor Atarax (hydroxyzine) should be used for itching in ESRD patients—both first-generation antihistamines should be avoided due to increased sedation, fall risk, and potential long-term dementia risk, with gabapentin being the preferred first-line pharmacologic treatment. 1, 2

Why Avoid Both Diphenhydramine and Hydroxyzine

Safety Concerns with First-Generation Antihistamines

• Long-term use of sedating antihistamines like diphenhydramine and hydroxyzine predisposes patients to dementia and should be avoided except in palliative care settings. 1, 2, 3
• First-generation antihistamines carry increased risk of sedation and falls in ESRD patients. 1
• Diphenhydramine is highly protein-bound, limiting dialysis clearance and predisposing to side effects and toxicity in ESRD patients. 4
• Safety profile and appropriate dosing information for diphenhydramine in ESRD populations is lacking, warranting caution. 4

Limited Efficacy for Uremic Pruritus

• Antihistamines generally have limited efficacy specifically for uremic pruritus, despite effectiveness in other pruritic conditions. 1, 3
• Cetirizine has been specifically shown to be ineffective for uremic pruritus in hemodialysis patients. 1, 3

Contradictory Evidence

While one 2020 crossover trial found both hydroxyzine 25 mg/day and gabapentin 100 mg/day significantly reduced pruritus with no significant difference between them 5, this conflicts with current guideline recommendations that prioritize gabapentin and advise against sedating antihistamines due to safety concerns. 1, 2, 3 The guideline recommendations should take precedence given the broader safety considerations beyond efficacy alone.

Recommended Treatment Algorithm for ESRD Pruritus

Step 1: Optimize Non-Pharmacologic Management First

• Ensure adequate dialysis with target Kt/V around 1.6. 1, 3
• Normalize calcium-phosphate balance and control parathyroid hormone levels. 1, 3
• Correct anemia with erythropoietin if present. 2, 3
• Apply emollients liberally for xerosis (dry skin), which is the most common cutaneous sign in dialysis patients. 3

Step 2: First-Line Pharmacologic Treatment

• Gabapentin 100-300 mg after each dialysis session (three times weekly) is the most effective medication for uremic pruritus. 1, 2, 3
• These doses are significantly lower than non-ESRD populations due to reduced renal clearance. 3
• Common side effect is mild drowsiness. 3

Step 3: Alternative/Adjunctive Treatments

• Topical capsaicin 0.025% cream applied four times daily can provide marked relief. 2, 3
• Broad-band UVB phototherapy is effective for many patients. 2, 3
• Ketotifen 1 mg daily may be considered as an alternative antihistamine with some evidence, though less supporting data than gabapentin. 1, 3

Step 4: If Antihistamine Absolutely Required

If an antihistamine must be used (e.g., for true urticaria rather than uremic pruritus):

• Fexofenadine 180 mg daily is the preferred second-generation antihistamine requiring no dose adjustment in renal impairment. 2
• Avoid cetirizine and levocetirizine in severe renal impairment (CrCl <10 mL/min). 1, 2
• Use loratadine with extreme caution in severe renal impairment. 1, 2

Critical Pitfalls to Avoid

• Do not use antihistamines as first-line treatment for uremic pruritus—they have limited efficacy for this specific condition. 1, 3
• Do not prescribe first-generation sedating antihistamines (diphenhydramine, hydroxyzine) except in palliative care. 1, 2, 3
• Do not overlook non-pharmacologic interventions—optimizing dialysis adequacy is essential. 1, 3
• Preserve peripheral veins in stage III-V CKD patients for future hemodialysis access. 6