Hydroxyzine for Refractory Urticaria
Hydroxyzine is unlikely to work when other antihistamines have failed, and current guidelines recommend escalating to higher doses of second-generation antihistamines (up to 4-fold) or adding omalizumab rather than switching to hydroxyzine. 1
Why Hydroxyzine is Different from Benadryl and Claritin
Pharmacological Distinctions
Hydroxyzine differs from diphenhydramine (Benadryl) and loratadine (Claritin) primarily in its dual H1/H2 blocking properties and its sedative potency, but these differences do not translate to superior efficacy for urticaria control. 2
Hydroxyzine is a first-generation antihistamine like Benadryl, meaning both cross the blood-brain barrier and cause significant sedation, cognitive impairment, and anticholinergic effects (dry mouth, urinary retention, constipation). 3
Hydroxyzine has some H2-receptor blocking activity in addition to H1-blockade, which theoretically could provide additional benefit since human skin blood vessels possess both H1 and H2 receptors. 2
Claritin (loratadine) is a second-generation antihistamine that does not cross the blood-brain barrier at therapeutic doses, causing no sedation and no anticholinergic effects. 3
Critical Evidence Against This Approach
A head-to-head comparison showed no difference between loratadine 10mg and hydroxyzine 25mg for complete suppression of urticaria in short-term treatment (RR 1.00,95% CI 0.32 to 3.10). 4
Current urticaria guidelines explicitly recommend against using sedating first-generation antihistamines like hydroxyzine as first-line therapy because they cause significant sedation and cognitive impairment without superior efficacy compared to second-generation agents. 1, 3
Could Hydroxyzine Work When Others Have Not?
The Evidence Says No
The likelihood of hydroxyzine succeeding where Benadryl, Claritin, and steroids have failed is extremely low for the following reasons:
Hydroxyzine and Benadryl are both first-generation H1-antihistamines with similar mechanisms of action—if Benadryl failed, hydroxyzine is unlikely to succeed. 3
Approximately 40% of patients with chronic urticaria remain unresponsive to standard-dose antihistamines, and the recommended next step is dose escalation of second-generation antihistamines (up to 4-fold), not switching to a different first-generation agent. 5
When standard doses of second-generation antihistamines fail, updosing achieves response in 63.2% of patients, making this a more evidence-based approach than switching to hydroxyzine. 5
The H2-Receptor Theory
While hydroxyzine has some H2-blocking activity, a 1981 study showed that combined H1 (hydroxyzine) and H2 (cimetidine) therapy was more effective than H1 alone, but this does not support using hydroxyzine as monotherapy when other H1-antihistamines have failed. 2
If H2-blockade is desired, current guidelines recommend adding a dedicated H2-antihistamine (famotidine 20mg) to a second-generation H1-antihistamine rather than relying on hydroxyzine's weak H2 activity. 6
What Should Be Done Instead
Evidence-Based Algorithm for Refractory Urticaria
Step 1: Optimize Second-Generation Antihistamine Dosing
- Add or switch to a non-sedating second-generation antihistamine (loratadine 10mg, fexofenadine 180mg, or desloratadine 5mg) if not already tried. 1
- Escalate the dose up to 4-fold (e.g., loratadine up to 40mg daily) if standard dosing provides inadequate control after 2-4 weeks. 1, 4
Step 2: Add H2-Antihistamine
- Add famotidine 20mg daily for additional H2-receptor blockade, which may provide better urticaria control than H1-blockade alone. 6
Step 3: Consider Omalizumab
- For urticaria unresponsive to high-dose antihistamines, omalizumab 300mg subcutaneously every 4 weeks is the recommended next step, with up to 6 months allowed for response assessment. 1
Step 4: Rule Out Underlying Causes
- Ensure the patient is avoiding NSAIDs and aspirin, as these worsen urticaria through cyclooxygenase inhibition. 6
- Consider whether this could be antihistamine-induced urticaria, as rare cases of hypersensitivity to multiple antihistamines have been reported, including hydroxyzine. 7, 8
Critical Safety Concerns with Hydroxyzine
FDA Warnings
Hydroxyzine carries significant risks that must be considered:
QT prolongation and Torsade de Pointes have been reported, particularly in patients with pre-existing heart disease, electrolyte imbalances, or concomitant use of other QT-prolonging drugs. 9
Acute Generalized Exanthematous Pustulosis (AGEP) is a rare but serious skin reaction that can occur with hydroxyzine, characterized by fever and sterile pustules. 9
Sedation and CNS depression are potentiated when hydroxyzine is combined with other CNS depressants, requiring dose reduction of concomitant medications. 9
Elderly patients are at increased risk for confusion, over-sedation, falls, and fractures with hydroxyzine, and should start at low doses with close observation. 9
Cross-Reactivity Risk
If the patient's urticaria is actually antihistamine-induced hypersensitivity, hydroxyzine could worsen symptoms rather than improve them. 7, 8
- Cetirizine and hydroxyzine are piperazine derivatives with similar chemical structures, and cross-reactivity between them is well-documented. 7
- Patients who develop AGEP or hypersensitivity to hydroxyzine should avoid cetirizine and levocetirizine due to cross-sensitivity risk. 9
Common Pitfalls to Avoid
Do not assume that switching between first-generation antihistamines will provide benefit—if one fails, others in the same class are unlikely to succeed. 3
Do not use hydroxyzine as maintenance therapy for chronic urticaria—guidelines explicitly recommend against this approach. 1
Do not combine multiple first-generation antihistamines—this increases sedation and anticholinergic effects without improving efficacy. 6
Do not delay escalation to omalizumab in truly refractory cases—this is the evidence-based third-line therapy, not hydroxyzine. 1