How to Calm Rosacea-Related Facial Erythema, Flushing

LAS VEGAS — When patients with rosacea consult Julie C. Harper, MD, about persistent facial erythema, she often recommends brimonidine 0.33% gel or oxymetazoline 1% cream.

These agents “work fast” and “improve redness quickly,” Harper, a dermatologist who practices in Birmingham, Alabama, said at the Society of Dermatology Physician Associates (SDPA) 22nd Annual Fall Dermatology Conference. In addition, she said, “You’re going to know within 30 minutes or an hour whether it’s going to work or not.”

Brimonidine 0.33% gel, an alpha-2 adrenergic receptor agonist, was approved by the US Food and Drug Administration (FDA) in 2014 for persistent facial erythema of rosacea. It does not treat telangiectasia and is not approved for flushing (transient erythema). Patients are advised to apply the gel daily in the morning. In phase 3 pivotal trials of patients with moderate to severe erythema of rosacea, which excluded individuals with more than two papules, a composite (investigator- and patient-reported) 2-grade improvement was seen as early as 30 minutes after application on day 1, and erythema was reduced for 9-12 hours.

Oxymetazoline 1% cream, an alpha-1a adrenergic receptor agonist, was approved by the FDA in 2017 for persistent facial erythema of rosacea. It neither treats telangiectasia nor is approved for flushing. Phase 3 trials of patients with moderate to severe persistent erythema of rosacea excluded individuals with more than three inflammatory papules or pustules. A composite (investigator- and subject-reported) 2-grade improvement was seen as early as 1 hour after application on day 1, and erythema was reduced for 9-12 hours.

Receptor Selectivity Differences

According to Harper, there are more reports of worsening erythema with brimonidine 0.33% gel than with oxymetazoline 1% cream, perhaps because of the different receptor selectivity between the two products. She explained that alpha-1 receptors are located only postsynaptically in vascular smooth muscle, while alpha-2 receptors are located presynaptically, which can inhibit norepinephrine and lead to vasodilation. Alpha-2 receptors are also located postsynaptically in vascular smooth muscle and in the endothelial wall, which can mediate nitric oxide release and cause vasodilation.

No head-to-head studies exist that compare brimonidine 0.33% gel with oxymetazoline 1% cream. But in a 52-week study of oxymetazoline 1% cream for persistent facial erythema associated with rosacea published in 2018, at week 52, 36.7% and 43.4% of patients achieved a 2-grade or greater composite improvement from baseline in both Clinician Erythema Assessment and Subject Self-Assessment 3 and 6 hours after a dose, respectively. Also, fewer than 1% of patients experienced a rebound effect following treatment cessation.

“What we learned from this study is that maybe patients do better if they use oxymetazoline 1% cream consistently,” Harper said. “Does that mean that everybody I give this to uses it daily? Probably not, but I think we can change the vascular tone by using it consistently every day.”

Oral Beta-Blockers Another Option

Alpha agonists can also help quell flushing associated with rosacea, Harper continued, but oral beta-blockers may be the better choice. In a 2020 review that drew from nine studies, researchers evaluated the use of carvedilol, propranolol, nadolol, and beta-blockers in general for rosacea-associated facial erythema and flushing. Articles studying carvedilol and propranolol showed a large reduction of erythema and flushing during treatment with a rapid onset of symptom control, while bradycardia and hypotension were the most commonly reported adverse events. “All of these agents are studied in rosacea, but none of them are FDA-approved for rosacea,” Harper noted.

In a separate study, five patients with rosacea who had either severe frequent flushing episodes or persistent erythema and burning sensations were treated with carvedilol, a nonselective beta-blocker. Prior treatments included cetirizine and doxycycline, or isotretinoin combined with topical application of metronidazole gel or ivermectin without sufficient improvement in erythema. Carvedilol was added to the above treatments and titrated up to 12.5 mg twice a day and continued for at least 6 months.

The Clinician Erythema Assessment 5-point scale before therapy was 3.4 and dropped to 0.4 during therapy, while the patient self-assessment before therapy was 3.8 and dropped to 0.8 during therapy.

Another study evaluated the use of propranolol and/or doxycycline in 78 patients with rosacea. The propranolol and combination treatment groups showed more rapid improvement at weeks 4 and 8, but there was no statistically significant difference between them by week 12. Rosacea clinical scores also decreased in all groups, but there were no significant differences between them. Reduction of Assessment of Rosacea Clinical Score was 51%, 52.2%, and 57.3% in the propranolol, doxycycline, and combination groups, respectively.

Harper disclosed ties with Almirall, Cutera, Galderma, Journey, Ortho Dermatologics, and Sun Pharmaceutical Industries.