Effect of Topical Brimonidine on Alcohol-Induced Flushing in Asian Individuals

This randomized clinical trial determines whether brimonidine gel, 0.33%, decreases facial erythema in patients with alcohol flushing syndrome after consumption of alcohol.

Key Points

Question

Does brimonidine gel, 0.33%, decrease alcohol-induced facial erythema in patients with alcohol flushing syndrome?

Findings

In this randomized, placebo-controlled, double-blind split-face clinical trial of 20 individuals of East Asian descent, brimonidine gel was effective in reducing facial erythema in patients with alcohol flushing syndrome. Brimonidine decreased observed erythema by an average of 2.1 and 1.7 points as evaluated by the clinician and the patient, respectively, on an erythema grading scale of 0 to 4 points.

Meaning

This study demonstrates that brimonidine gel is effective in reducing the alcohol-induced facial erythema of alcohol flushing syndrome.

Abstract

Importance

Alcohol flushing syndrome (AFS, also known as Asian glow and Asian flush) affects 20% to 47% of East Asians and causes significant psychosocial distress. There are no approved treatments for this condition.

Objective

To determine whether brimonidine gel, 0.33%, decreases facial erythema in patients with AFS after consumption of alcohol.

Design, Setting, and Participants

In this randomized clinical trial, 20 healthy volunteers of East Asian descent with a self-reported history of AFS were recruited between April 2018 and March 2019.

Interventions

Participants were randomized to application of brimonidine gel to either the left or right half of their face. Placebo control was applied to the opposite side. After 30 minutes, participants ingested alcohol.

Main Outcomes and Measures

Outcomes were specified before data collection. The difference in erythema between the treated and placebo side of each participant’s face was measured 60 minutes after drug application (primary outcome) and at 90 and 120 minutes after drug application (secondary outcomes). Participants were asked to rate their likelihood of using the medication again and their likelihood of recommending the medication to a friend on a scale of 0 to 10.

Results

The mean (SD) age of the 20 individuals enrolled in the study was 30.5 (8.4) years, and there were 10 women (50%). There was a significant difference in erythema at 60 minutes after drug application as measured by the difference in Clinician Erythema Assessment score (2.1; 95% CI, 1.5-2.71; P < .001) and by the difference in Subject Self-Assessment score (1.7; 95% CI, 1.1- 2.3; P < .001). This effect persisted at 90 and 120 minutes. Individuals were likely to use the medication again (7.2; 95% CI, 6.0-8.3) and would also recommend it to a friend (7.6; 95% CI, 6.5-8.6).

Conclusions and Relevance

This study demonstrates that brimonidine gel is effective in reducing the facial erythema of AFS. Patients with psychosocial distress due to AFS may benefit from treatment with brimonidine.

Trial Registration

ClinicalTrials.gov identifier: NCT03497442

Introduction

Alcohol flushing syndrome (AFS, also known as Asian glow and Asian flush), is a genetic condition due to polymorphisms in alcohol dehydrogenase or aldehyde dehydrogenase, affecting 20% to 47% of individuals of East Asian descent. Alcohol flushing syndrome is characterized by severe flushing and burning sensation with minimal alcohol consumption.¹ This reaction can be aesthetically unattractive and socially limiting.

Many patients with AFS use oral antihistamines to reduce flushing. However, H₁ receptor antagonists can have sedating effects and may be dangerous in combination with alcohol, and H₂ receptor antagonists increase blood alcohol levels by slowing first pass metabolism.² Brimonidine is a selective α₂-adrenoceptor agonist that induces vasoconstriction.³ It is approved by the US Food and Drug Administration as a topical gel for rosacea but has not been evaluated for AFS. The objective of this pilot study was to determine whether topical brimonidine is effective in reducing the alcohol-induced flushing in individuals with AFS.

Methods

This was a prospective, randomized, double-blind, placebo-controlled clinical trial approved by the University of California, San Francisco institutional review board and executed in accordance with the Declaration of Helsinki.⁴ Consolidated Standards of Reporting Trials (CONSORT) reporting guideline were used. Healthy volunteers older than 21 years of East Asian descent with a self-reported history of AFS were recruited. Written informed consent was obtained. Individuals with rosacea were excluded. Full inclusion and exclusion criteria are provided in the trial protocol in Supplement 1. All study activities were performed during a single visit. Participants were randomized (1:1) to receive a thin layer of brimonidine gel, 0.33%, to either the left or right half of their face and a best-match available placebo (Neutrogena Hydro Boost Gel Cream) to the contralateral side.

At time 0, the participant and blinded investigator were asked to score each side of the participant’s face using the Subject Self-Assessment (SSA) grading scale and the Clinician Erythema Assessment (CEA) grading scale, respectively.^5,6 Brimonidine gel, 0.33%, was then applied to either the left or right half of each participants’ face, and placebo was applied to the contralateral side.

Thirty minutes after drug application, participants were asked to consume 80-proof vodka (44.36 mL for women and 88.72 mL for men). Clinician Erythema Assessment score, SSA score, standardized photographs, and blood alcohol concentration were recorded at 30-minute intervals. At 120 minutes, participants were assessed for blood alcohol concentration under the legal limit of 0.05 and ability to ambulate without assistance. All participants were offered a ride service home.

The primary end point was a 2-point reduction of CEA score at 60 minutes after application (30 minutes after alcohol). Secondary end points included reduction of CEA score at 90 and 120 minutes and reduction of SSA score at 60, 90, and 120 minutes. Exploratory patient-reported outcomes assessed at the end of the visit were patient likelihood of using the medication again and their likelihood of recommending the medication to a friend on a scale of 0 to 10.

Study data were collected and managed using REDCap version 8.10 (University of California, San Francisco). Statistical analysis was performed using R package version 3.5.3 (R Foundation for Statistical Computing). A 2-sided paired t test was used to detect differences between placebo and treatment at each point. A threshold of .05 was used for statistical significance. A Bonferroni correction was used to adjust for multiple hypothesis testing.

Results

Twenty participants enrolled in and completed the study (Figure 1). The mean (SD) age was 30.5 (8.4) years, and 10 women (50%) were included. Participants identified as Chinese (15 [75%]), Japanese (2 [10%]), Korean (1 [5%]), mixed Chinese-Japanese (1 [5%]), or mixed Chinese-Filipino (1 [5%]). There was a marked reduction in alcohol-induced erythema at 60 minutes after drug application, both as measured by the mean difference in CEA score (2.1; 95% CI, 1.5-2.7; P < .001) and in SSA score (1.7; 95% CI, 1.1-2.3; P < .001) (Figure 2). This difference persisted at 90 and 120 minutes (secondary end points).

Figure 1. Patient Flow Diagram.

Figure 2. Erythema Scores Plotted With Respect to Time After Drug Application.

Scores were assessed both by a blinded clinician (A) and by the blinded participant (B). Application of drug and placebo occurred immediately after the baseline evaluation (time 0). Ethanol was administered immediately after the 30-minute evaluation (time 30). Clinical photographs were taken at baseline (C, E) and 60 minutes after drinking alcohol (B, D). Both participants in these photographs had placebo applied to the right side of the face and brimonidine gel applied to the left side of the face. The periorbital area was not treated. NA indicates not applicable.

Peak blood alcohol concentration was observed 60 minutes after drug application (mean, 0.04%; max, 0.07%). Mean blood alcohol concentration at the end of each visit was 0.025%. One adverse reaction (vomiting) was observed at 120 minutes, which was attributed to alcohol consumption and not to the study drug. Participants reported that they would be likely to use the medication again (7.2; 95% CI, 6.0-8.3) and would recommend it to a friend (7.6; 95% CI, 6.5-8.6).

Discussion

Topical brimonidine gel, 0.33%, was effective in reducing alcohol-induced erythema in patients with AFS, as measured by the primary end point of 2-point reduction in CEA score at 60 minutes. The SSA score did not meet the 2-point reduction goal but demonstrated a statistically significant mean reduction at all points after alcohol consumption.

Off-label use of brimonidine for transient alcohol-induced flushing of AFS may reduce the significant psychosocial effect of this condition. The duration of response persisted to 120 minutes, similar to the time necessary to metabolize alcohol. Flushing due to alcohol consumption is typically planned and episodic, as opposed to the chronic nature of erythema in rosacea; therefore, the medication could be used on a pro re nata basis.

Ethical use of topical brimonidine should be considered in the context of the individual patient and should not be used to promote alcohol abuse. Like antihistamines, brimonidine may allow patients with AFS and mild phenotypes to engage in limited alcohol consumption in social settings. Patients with more severe AFS have systemic symptoms such as headache and nausea; these are not ameliorated by brimonidine. Clinicians should advise patients with AFS that heavy alcohol consumption increases their risk of esophageal squamous cell carcinoma.⁷ Clinicians should encourage moderation of alcohol consumption regardless of symptoms or treatment.

Limitations

Limitations of this study include the small sample size and lack of genetic confirmation of the AFS diagnosis. We were unable to obtain a vehicle control in this nonsponsored study and so relied on an over-the-counter emollient with a near-perfect color and texture match. It is possible that the emollient worsened redness and irritation on the control side, but this is unlikely. The findings may have been strengthened by an objective measure of colorimetry, but the subjective observer and patient assessments obtained here have direct clinical relevance.

Conclusions

This trial demonstrates that topical brimonidine is effective in decreasing erythema in Asian patients with AFS. Larger studies are warranted to further assess the long-term efficacy, potential for rebound erythema, and quality of life effect of topical vasoconstrictors in patients with AFS.

Supplement 1.

Trial protocol.

Supplement 2.

Data sharing statement.