What is the initial treatment for a patient presenting with generalized hives, considering potential underlying causes and variable patient response?

Treatment of Generalized Hives

Second-generation non-sedating H1 antihistamines are the first-line treatment for generalized hives, with standard dosing that can be increased up to four times if symptoms are not adequately controlled. 1, 2

Initial Assessment: Rule Out Anaphylaxis First

Before treating isolated urticaria, you must distinguish it from anaphylaxis, which requires immediate epinephrine:

• Generalized hives ALONE (isolated urticaria) → treat with antihistamines 1
• Generalized hives PLUS respiratory symptoms (wheeze, stridor, dyspnea), hypotension, or GI symptoms → this is anaphylaxis → give epinephrine IM immediately 1

This distinction is critical because isolated allergen-associated urticaria responds to antihistamines, whereas anaphylaxis requires prompt epinephrine as first-line treatment. 1

First-Line Treatment: Non-Sedating Antihistamines

Offer the patient a choice of at least two different second-generation antihistamines because individual responses and tolerance vary significantly between patients. 1, 2

Recommended Options (once daily dosing):

• Cetirizine 10 mg - has the shortest time to maximum concentration, advantageous when rapid relief is needed 1, 2
• Fexofenadine 180 mg 2
• Desloratadine 5 mg 2
• Levocetirizine 5 mg 2
• Loratadine 10 mg 1

Dose Escalation Strategy:

If standard doses provide inadequate control after a reasonable trial (typically 1-2 weeks), increase the dose up to four times the standard dose before considering alternative therapies. 1, 2 This off-label practice is widely accepted when potential benefits outweigh risks. 1

Important Caveats:

• Avoid sedating first-generation antihistamines (diphenhydramine, hydroxyzine) as first-line therapy due to significant sedation and cognitive impairment without superior efficacy 2
• Cetirizine may cause sedation, especially at higher doses 1
• Adjust timing of medication so peak drug levels coincide with when urticaria is most problematic 1

Adjunctive Measures

Cooling antipruritic lotions (calamine or 1% menthol in aqueous cream) can provide symptomatic relief while antihistamines take effect. 1, 2

Identify and minimize aggravating factors:

• Overheating, stress, alcohol 2
• Avoid NSAIDs and aspirin in aspirin-sensitive patients 2
• Avoid codeine 2

Adding H2 Antihistamines

Consider adding an H2 antihistamine (ranitidine or cimetidine) to H1 antihistamines if response is inadequate, though evidence for additional benefit is limited. 1 This combination may be more helpful for accompanying dyspepsia than for urticaria itself if the H1 receptor is already saturated. 1

Renal and Hepatic Adjustments

In moderate renal impairment (creatinine clearance 10-20 mL/min):

• Avoid acrivastine 1
• Halve the dose of cetirizine, levocetirizine, and hydroxyzine 1

In severe renal impairment (creatinine clearance <10 mL/min):

• Avoid cetirizine and levocetirizine 1
• Use loratadine and desloratadine with caution 1

In hepatic impairment:

• Avoid mizolastine in significant hepatic impairment 1

When First-Line Treatment Fails

If high-dose antihistamines (up to 4x standard dose) fail after an adequate trial:

Second-line: Omalizumab (anti-IgE monoclonal antibody) 300 mg subcutaneously every 4 weeks, allowing up to 6 months for response. 2

Third-line: Cyclosporine with regular monitoring of blood pressure and renal function, effective in approximately 54-73% of patients, particularly those with autoimmune urticaria. 2, 3

Common Pitfalls to Avoid

• Do not use topical crotamiton cream or capsaicin - evidence does not support their use in urticaria 2
• Do not immediately pursue extensive investigations for acute urticaria, as a cause is unlikely to be found in most cases, but prognosis for recovery is excellent 1
• Do not add sedating antihistamines at night to non-sedating ones by day unless sleep is significantly disrupted - this likely provides little additional clinical benefit if H1 receptors are already saturated 1
• Do not confuse isolated urticaria with anaphylaxis - missing anaphylaxis can be fatal, while overtreating isolated urticaria with epinephrine is unnecessary 1