Is there a role for montelukast (leukotriene receptor antagonist) in treating patients with chronic or acute urticaria, particularly those who have not responded to first-line treatments such as antihistamines?

Montelukast as Adjunctive Therapy in Urticaria

Montelukast should be considered as adjunctive therapy in patients with chronic urticaria who remain symptomatic despite standard or high-dose antihistamine treatment, particularly in those with aspirin-sensitive or autoimmune urticaria. 1, 2

Treatment Algorithm Position

The most recent international urticaria guidelines (2022) have streamlined management into a 3-step approach, and montelukast fits as an adjunctive option within this framework 3:

Step 1: Second-Generation Antihistamines

• Start with standard-dose non-sedating H1 antihistamines (cetirizine, loratadine, fexofenadine, desloratadine, or levocetirizine) 3
• If inadequate response after 2-4 weeks, increase up to 4 times the standard dose 3

Step 2: Add Omalizumab

• For patients failing high-dose antihistamines, omalizumab 300 mg every 4 weeks is the recommended second-line therapy 3
• Allow up to 6 months for response before considering alternatives 3

Step 3: Cyclosporine

• Reserved for patients not responding to high-dose omalizumab 3

Role of Montelukast as Add-On Therapy

Montelukast functions as adjunctive therapy rather than a replacement for antihistamines, and should be added to ongoing antihistamine treatment when control is inadequate. 1, 2, 4

Specific Indications for Montelukast

• Aspirin-sensitive urticaria: Montelukast is particularly recommended for patients with documented intolerance to aspirin or NSAIDs 1, 2
• Autoimmune urticaria: Patients with autoimmune-mediated disease may benefit from leukotriene receptor antagonist addition 1, 2
• Antihistamine-resistant cases: Can be tried before escalating to omalizumab in selected patients 1, 2, 4

Evidence for Efficacy

The evidence for montelukast shows mixed but promising results:

• In aspirin/food additive-sensitive patients: A double-blind, placebo-controlled trial demonstrated that montelukast 10 mg daily significantly increased symptom-free days and reduced interference with sleep compared to both cetirizine and placebo (P < 0.001) 5

• In general antihistamine-resistant urticaria: Response rates vary from 48% to 67% when added to combined H1/H2 antihistamine therapy 6, 7, 8

• In severe disease: A crossover study found that patients with the most severe urticaria (upper quartile symptom scores) showed significant benefit from montelukast addition, though the overall group did not 9

• Patient characteristics predicting response: Younger patients (mean age 33 years vs. 46 years) and those with shorter disease duration (16 months vs. 90 months) were more likely to respond to montelukast (P < 0.05 and P < 0.005, respectively) 8

Practical Implementation

Dosing

• Standard dose: Montelukast 10 mg once daily 9, 6, 7, 5, 8
• Continue existing antihistamine therapy at current doses 9, 6, 7, 8

Trial Duration

• Assess response after 1-4 weeks of treatment 7, 8
• If no benefit after 4 weeks, discontinue and consider alternative therapies 7, 8

Additional Adjunctive Options

Beyond montelukast, other adjunctive therapies to consider before advancing to omalizumab include:

• H2 antihistamines (ranitidine or famotidine) for resistant cases 1, 2, 4
• First-generation antihistamines (hydroxyzine or chlorpheniramine) at night for additional symptom control and sleep 1, 4

Important Caveats

Limitations of Evidence

• Most studies are small (n = 9-51 patients) and retrospective or open-label 9, 6, 7, 8
• The single high-quality RCT showing clear benefit was specifically in aspirin/food additive-sensitive patients 5
• No consistent clinical or laboratory markers predict response to montelukast 7

When NOT to Use Montelukast

• Do not delay omalizumab in patients with severe, refractory disease who clearly meet criteria for second-line therapy 3
• Do not use as monotherapy - always maintain antihistamine therapy 9, 6, 7, 8
• Avoid long-term corticosteroids while trialing montelukast; short courses (3-10 days) only for severe exacerbations 3, 1

Safety Considerations

• Montelukast has a favorable safety profile with low incidence of adverse events in urticaria trials 5
• Monitor for neuropsychiatric effects as per FDA warnings (though not specifically reported in urticaria studies) 5

Clinical Bottom Line

For patients with chronic urticaria inadequately controlled by high-dose antihistamines, add montelukast 10 mg daily as adjunctive therapy, particularly if aspirin-sensitive or autoimmune features are present, before escalating to omalizumab. 1, 2 Expect response within 1-4 weeks if the patient will benefit, with approximately 50% of antihistamine-resistant patients showing improvement 6, 7, 8. Younger patients with shorter disease duration are more likely to respond 8.