Metronidazole in the treatment of rosacea: do formulation, dosing, and concentration matter?

Journal of Drugs in Dermatology, April, 2006 by Jane Yoo, David C. Reid, Alexa B. Kimball

Abstract

Background: Topical metronidazole is commonly used in the management of rosacea. No consensus on the optimal formulation, concentration, or dosing regimen exists.

Purpose: To assess the relative efficacy of metronidazole cream, gel, and lotion at concentrations of 0.75% and 1%, in dosing regimens of once and twice daily.

Methods: A meta-analysis of published metronidazole efficacy rates was performed.

Results: In non-weighted analysis, the mean efficacy was 28.2% (95% confidence interval [CI], 22.0%-34.4%) for the cream, 38.4% (95% CI, 18.4%-58.4%) for the gel, and 35% for the lotion. Confidence intervals for QD versus BID dosing and 0.75% versus 1% concentrations also overlapped. In weighted analysis, the mean reduction was 31.3% for the cream, 22.1% for the gel, and 35% for the lotion.

Conclusions: Metronidazole cream, gel, and lotion vehicles have similar efficacies. There were no substantial differences between concentrations of 0.75% and 1%, or between once daily and twice daily regimens.

Background

Rosacea is a common, chronic, inflammatory skin disorder that causes physical and psychological discomfort in middleaged and older adults. Clinically, rosacea is characterized by persistent and transient erythema, papules and pustules, and telangiectases primarily distributed over the central face. (1) In addition to cosmetic concerns, patients may complain of dry skin, facial edema, and facial pain/sensitivity.

Because rosacea is a chronic condition, with 70% of patients relapsing within 4 years, (2) treatment is directed at controlling acute eruptions and limiting outbreaks rather than curing disease. Mild rosacea is often controlled with topical agents, such as metronidazole, sodium sulfacetamide, and azelaic acid. Moderate to severe cases may necessitate systemic therapy with oral antibiotics, such as tetracyclines, macrolides, or metronidazole. (3) Laser and light therapies, though costly, may be useful in cases of serious erythema, flushing, and telangiectasia. (4)

Since its introduction in the late 1980s, topical metronidazole has been considered a mainstay of treatment, and it is recommended as maintenance therapy for various subtypes. (5) Its clinical efficacy is thought to result from both antioxidant and anti-inflammatory activities. (6) The FDA has approved multiple formulations and strengths, including a 0.75% cream, 0.75% aqueous gel, 1% gel, 0.75% lotion (Metrocream, Metrogel, and Metrolotion, Galderma Laboratories, Fort Worth, TX), and a 1% metronidazole cream (Noritate cream, Dermik Laboratories, Berwyn, PA). Though each formulation has been shown to have greater efficacy than vehicle alone, (7) no consensus exists on the optimal formulation, most effective strength, or most efficacious dosing regimen.

Purpose

The purpose of this study is to examine the comparative efficacy of topical metronidazole cream, gel, and lotion at concentrations from 0.75% to 1%, and at doses of once versus twice daily in a meta-analysis.

Methods

PubMed, the Cochrane Library, and phase III studies were examined for data sets reporting rosacea treatment with topical metronidazole. PubMed search terms consisted of "metronidazole" and "rosacea." The eligibility criteria for inclusion were: double-blind, randomized, placebo-controlled trial, treatment of rosacea with metronidazole cream, gel, or lotion, and clinical efficacy data for average percentage decrease in the presence of papules and pustules. We also included studies that reported on indicators such as erythema, telangiectasia, investigator-rated global improvement and adverse events. Trials that were controlled with other formulations or treatments (oral metronidazole, azelaic acid) but lacked a placebo group, or permitted application of other topical therapies (sunscreen) were excluded.

From 1976 to 2005, there were a total of 159 PubMed citations for metronidazole and rosacea. During that time, 23 randomized controlled clinical trials for metronidazole were cited. Of those, 7 met the inclusion criteria. One study (8) that included 4 treatment groups (metronidazole cream 1% QD, vehicle QD, metronidazole cream 1% BID, vehicle BID) was counted as 2 studies for the purpose of statistical analysis. Trials were referenced by the Cochrane Interventions for Rosacea (Review). In addition, phase III clinical trial data was gathered from the product insert of topical metronidazole formulations (0.75% cream, 0.75% lotion, 1% gel). These accounted for 3 more studies.

Efficacy was assessed by determining the average percentage decrease in papules/pustules from baseline in each of the clinical trials. Efficacies were compared across the studies, controlling for placebo effect. Vehicle effects and frequency of dosing were compared adjusting for the number of patients enrolled in each study.

Due to variation in scoring systems, direct measures of efficacy using erythema, telangiectasia, and investigator-rated global improvement could not be utilized for comparison. In addition, qualitative reporting on adverse events in some trials proved difficult for assessment.