Yes, you can safely take Benadryl (diphenhydramine) at night and Zyrtec (cetirizine) in the morning for hives.
This combination is explicitly supported by clinical guidelines and represents an established treatment strategy for urticaria, though the added benefit may be limited if the H1 receptor is already saturated by the daytime antihistamine 1.
How This Combination Works
The British Journal of Dermatology guidelines specifically state that "addition of a sedating antihistamine at night (e.g. chlorphenamine 4–12 mg, hydroxyzine 10–50 mg) to a non-sedating antihistamine by day may help patients sleep better" 1. While diphenhydramine (Benadryl) is not specifically mentioned in this list, it functions identically as a first-generation sedating antihistamine.
Key points about this regimen:
Cetirizine (Zyrtec) in the morning provides 24-hour coverage with minimal sedation and has the shortest time to maximum concentration among non-sedating antihistamines, which may be advantageous 1
Diphenhydramine (Benadryl) at night can help with sleep disruption from itching, though it likely provides little additional clinical effect on the hives themselves if the H1 receptor is already blocked by cetirizine 1
Important Caveats
Limited Additional Benefit for Urticaria Control
Recent research challenges the widespread belief that adding nighttime sedating antihistamines improves urticaria control. A 2014 randomized controlled trial found that adding hydroxyzine 50 mg at night to levocetirizine did not improve urticaria symptoms compared to higher-dose levocetirizine alone, and actually increased daytime somnolence 2. This suggests the primary benefit is sleep improvement, not better hives control.
Sedation and Safety Concerns
The FDA label for Benadryl warns about marked drowsiness, and cautions against:
- Driving or operating machinery
- Combining with alcohol, sedatives, or tranquilizers
- Use in patients with glaucoma, breathing problems, or prostate enlargement 3
Diphenhydramine carries risks of adverse effects including sedation, anticholinergic effects, and potential toxicity, especially with rapid IV administration or excessive doses 4.
Alternative Approach
If cetirizine alone is insufficient, guidelines recommend increasing the dose of the non-sedating antihistamine (up to 4 times the standard dose) before adding a sedating antihistamine 1. This means you could try cetirizine 20-40 mg daily before adding nighttime Benadryl.
Practical Algorithm
- Start with cetirizine 10 mg once daily in the morning
- If inadequate control after 2-7 days, increase cetirizine to 20 mg daily (double dose)
- If still inadequate, consider cetirizine 20 mg daily PLUS diphenhydramine 25-50 mg at bedtime if sleep is disrupted
- If this fails, increase to cetirizine 30-40 mg daily before considering other therapies
The combination you're asking about is safe and guideline-supported, but understand that the nighttime Benadryl primarily helps with sleep rather than providing substantial additional urticaria control 1, 2.