Nasal Epinephrine Spray Appears Safe, Effective in CSU

A nasal-spray formulation of epinephrine may make it easier for patients with chronic spontaneous urticaria (CSU) to deal with acute flares or exacerbations.

A new study published in The Journal of Allergy and Clinical Immunology: In Practice found that patients who used an intranasal epinephrine spray known as ARS-2 to treat flares and exacerbations experienced improvement in both patient-reported and investigator-reported measures of symptom severity.¹

Epinephrine has long been used to treat acute urticaria, but its use has declined as oral and injectable forms of antihistamines have become available, the authors explained. Currently, treatment for CSU relies upon first-line use of second-generation H₁-antihistamines, followed by biologics such as omalizumab (Xolair; Genentech, Novartis) and dupilumab (Dupixent; Sanofi, Regeneron) if symptoms persist.² In some cases, cyclosporine is used as a third-line treatment, the authors noted. Glucocorticoids can be used to deal with long-term or frequent acute exacerbations, though the authors noted that these come with a significant risk of side effects.¹

ARS-2 was developed as a means to deliver epinephrine without the need for a needle. The new phase 2 study was designed to assess the nasal spray’s safety and efficacy among people experiencing CSU exacerbations. The investigators enrolled 21 patients who had either acute urticaria with known etiology or acute CSU exacerbations of unknown etiology at least twice per week while on a chronic daily antihistamine. Acute exacerbations were defined as cases in which the patient had pruritus and hive severity scores of 2 or above twice per day using the Urticarity Activity Score index. Patients taking beta blockers, those with prior nasal injuries, and those with abnormal cardiovascular examinations were excluded from participation. The participants were randomized to receive either ARS-2 at a dose of 1 mg or 2 mg or a placebo.

The investigators found that the therapy led to improved symptom control at both doses.

“Relative to placebo, both 1 mg and 2 mg doses of ARS-2 resulted in rapid decreases in both patient-reported itch and hive severity scores (P < 0.05),” the investigators wrote.

The higher dose led to faster results, with statistically significant changes in itch severity at 5 minutes and statistically significant improvements in hive severity at 15 minutes for the 2 mg cohort. The 1 mg cohort had statistically significant improvements in itch and hive scores at 15 and 30 minutes, respectively. These significant improvements lasted at least 2 hours, the investigators found.

Investigator-reported outcomes were likewise improved in patients receiving ARS-2, with lower extents of urticaria and erythema scores (P < 0.05). Investigators were more likely to consider patients to be “effectively treated,” and patients were more likely to report treatment satisfaction if they received ARS-2 compared to placebo, the authors said.

Adverse events were considered to be minor. Six patients reported adverse events following 1 mg doses of ARS-2, and 7 patients reported adverse events following a 2 mg dose. Adverse events reported by more than one patient were nasal discomfort and headache. No patients in the placebo group reported adverse events.

The authors cautioned that their study relied in part on subjective measures, and they noted that it was an open-label trial. They said larger, double-blind, and higher-powered studies should be carried out in order to confirm this report’s findings.

“Despite these limitations, the results indicate that ARS-2 may offer a safe, rapid, and effective treatment option for acute exacerbations of CSU, with fewer side effects than systemic corticosteroids,” the authors concluded.

References

1. Bernstein DI, Talreja N, Casale TB, et al. Efficacy of epinephrine nasal spray in the treatment of urticaria. J Allergy Clin Immunol Pract. Published online February 15, 2026. doi:10.1016/j.jaip.2026.02.010

2. Zuberbier T, Bernstein JA, Maurer M. Chronic spontaneous urticaria guidelines: What is new?. J Allergy Clin Immunol. 2022;150(6):1249-1255. doi:10.1016/j.jaci.2022.10.004