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

Neither Benadryl nor Atarax is Recommended for ESRD Pruritus

Both diphenhydramine (Benadryl) and hydroxyzine (Atarax) should be avoided for long-term treatment of uremic pruritus except in palliative care settings, as sedating antihistamines may predispose to dementia and have limited efficacy for this specific condition. 1, 2

Why Antihistamines Are Not Effective for Uremic Pruritus

• Antihistamines are now known to have little or no efficacy for uremic pruritus, despite being frequently prescribed 3
• Cetirizine has been specifically shown to be ineffective for uremic pruritus, even though it works for other pruritic conditions 1, 2
• The pathophysiology of uremic pruritus differs from histamine-mediated itch, involving neurophysiology similar to pain, systemic inflammation, and uremia-related metabolic abnormalities 3

Evidence Comparing Hydroxyzine to Better Alternatives

While one 2020 study showed that hydroxyzine 25 mg daily reduced pruritus severity comparably to gabapentin 100 mg daily in a crossover trial 4, this finding must be interpreted cautiously:

• The guideline evidence strongly recommends against long-term sedating antihistamines due to dementia risk 1, 2
• The study used very low doses and short duration (6 weeks), which doesn't reflect real-world chronic management 4
• Gabapentin remains the preferred first-line medication with stronger overall evidence 1

Recommended Treatment Algorithm for ESRD Pruritus

Step 1: Optimize Dialysis and Metabolic Parameters

• Ensure adequate dialysis with target Kt/V of approximately 1.6 1
• Normalize calcium-phosphate balance and control parathyroid hormone levels 1
• Correct anemia with erythropoietin if present 1
• Provide emollients for xerosis (dry skin) 1

Step 2: First-Line Pharmacologic Treatment

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

Step 3: Second-Line Options

• Topical capsaicin 0.025% cream applied four times daily—14 of 17 patients reported marked relief in trials 5, 1
• Broad-band UVB phototherapy is effective for many patients 1
• Non-sedating antihistamines like fexofenadine 180 mg may be tried, though evidence is limited 1

Step 4: Alternative Systemic Agents

• Sertraline 25-50 mg daily has shown efficacy in antihistamine-refractory cases 6, 7
• Ketotifen 1 mg daily may be as effective as gabapentin but has less supporting evidence 1

Critical Pitfalls to Avoid

• Do not use sedating antihistamines (diphenhydramine, hydroxyzine) for chronic management outside palliative care due to dementia risk 1, 2
• Do not rely on cetirizine—it is specifically ineffective for uremic pruritus 1, 2
• Do not skip optimization of dialysis parameters before adding medications 1
• Topical doxepin should be limited to 8 days maximum, 10% body surface area, and 12 g daily if used 1

Definitive Answer

If you must choose between Benadryl and Atarax for a patient not in palliative care, neither should be used. Instead, start with gabapentin 100-300 mg three times weekly after dialysis sessions, which has the strongest evidence for efficacy and safety in this population 1. The only scenario where hydroxyzine might be considered is in palliative care settings where dementia risk is less relevant than immediate symptom control 1, 2.