Comparative efficacy and safety of antihistamines, increased antihistamine dosing, and antihistamine adjuncts for chronic urticaria: a systematic review, dose-response, and network meta-analysis of randomized trials.

Abstract

Chronic urticaria is a common immune-mediated condition characterized by wheals (itch and hives), angioedema, or both, lasting for greater than six weeks. It is managed with H1 antihistamines as the first-line therapy. Fundamental unresolved questions remain regarding the comparative benefits and harms of antihistamines and their adjuncts, and of H1 antihistamine dose-escalation. To analyze the comparative benefits and harms of antihistamines and their adjuncts (H2 blockers or montelukast), and of H1 antihistamine dose-escalation. As part of updating the American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters Chronic Urticaria guidelines, we searched MEDLINE, EMBASE, CENTRAL, and regulatory databases from inception to March 17, 2025, for randomized trials addressing antihistamines or their adjuncts for chronic urticaria. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random effects network and dose-response meta-analyses addressed urticaria activity (composed of itch and wheal scores), angioedema activity, urticaria-related quality of life, and harms including sedation. The GRADE approach informed certainty of evidence ratings. CRD42022367280. 211 trials (22,187 participants) evaluated 55 unique treatments. Bilastine, desloratadine, fexofenadine, and levocetirizine are among the most effective in improving overall urticaria activity, urticaria-related quality of life, and sleep disturbance. Cetirizine and loratadine are among the most effective in reducing overall urticaria activity and its subcomponents, with cetirizine also among the most effective in improving urticaria-related quality of life. Escalating from a single to quadruple daily dose may yield diminishing additional benefit. Second-generation agents as a class may be more effective than first-generation agents in improving urticaria activity and sleep disturbance. Sedation risk likely increases with higher doses, with first-generation agents (e.g., diphenhydramine, hydroxyzine) and doxepin among the most sedating; cetirizine, ketotifen, levocetirizine, and rupatadine among the intermediate sedating; and bepotastine, bilastine, desloratadine, ebastine, fexofenadine, and loratadine among the least sedating. Adding montelukast (moderate certainty) or an H2 blocker (very low certainty) to a second-generation agent may further reduce urticaria activity. For chronic urticaria, second-generation agents differ in their efficacy and safety. First-generation agents are less beneficial and more harmful. Escalating to higher daily doses may provide additional benefits but likely increases sedation.