Naproxen Versus Placebo as Adjunct Treatment of Cellulitis: A Randomized Controlled Trial (NVP)

Background and Importance: Cellulitis is a bacterial skin infection that is the 9th most common reason for an emergency department (ED) visit in Canada. This condition is treated with antibiotics; however, most people require rest and time off work due to the disabling symptoms of pain, redness and swelling. Cellulitis results in high healthcare costs and negatively impacts quality of life of affected persons. Although cellulitis is a bacterial infection, there is evidence that inflammation contributes to the symptoms of pain, redness and swelling. While antibiotics are the mainstay of treatment, adjunct non-steroidal anti-inflammatory drugs (NSAIDs) may control inflammation and speed time to recovery. The investigators conducted a meta-analysis which found that adjunct NSAIDs may improve early clinical response; however, these results must be interpreted with caution as the three available trials were small and underpowered. There is no consensus on whether NSAIDs are effective adjunct cellulitis treatments. A large, robust randomized controlled trial is required to evaluate the role of NSAIDs in treating cellulitis.

Goals/Research Aims: The investigators goal is to conduct a patient randomized controlled trial to determine whether naproxen (NSAID) improves outcomes among cellulitis patients receiving antibiotics.

Methods/Approaches/Expertise: Design: The investigators propose a double-blind randomized (1:1) trial of oral naproxen (500 mg twice daily) versus placebo as adjunct treatment to standard antibiotics for patients with cellulitis. Randomization will be stratified by site, age (<65 vs. ≥65 years), and infection location (lower limb vs. other). Setting: EDs of 3 large, tertiary care Canadian hospitals (Ottawa Hospital Civic and General campuses, Montfort Hospital). Subjects: Adults ≥18 years diagnosed with cellulitis and eligible for outpatient oral antibiotics. Interventions: a) Naproxen 500 mg orally twice daily for 7 days, b) placebo twice daily for 7 days. All participants will receive oral cephalexin antibiotic for 7 days. Both naproxen and placebo will be encased in identical capsules, prepared by an external pharmacy. Outcomes: In accordance with Food and Drug Administration recommendations, the primary outcome is early clinical response, defined as reduction of erythema ≥20% from baseline at 72 hours. Secondary outcomes include clinical cure, treatment failure, adverse events, intravenous antibiotic use, and unplanned hospitalization. Sample size: After accounting for 10% attrition, a total of 884 patients will be required to achieve 80% power to detect a 10% absolute increase in clinical response. Data Analysis: The primary analysis will be by intention to treat. The difference in the rate of early clinical response between the two treatment groups will be assessed using Poisson regression.

Expected Outcomes: The investigators have previously demonstrated feasibility by completing a double-blind pilot randomized trial involving ED adult patients with cellulitis comparing two doses of cephalexin antibiotic (N=69 patients enrolled over 6 months at two sites, demonstrating excellent recruitment and follow-up). If naproxen is found to be superior to placebo, this simple, low-cost intervention will speed time to recovery with less pain for patients, and may reduce treatment failure, intravenous antibiotic use, hospitalization, and time missed from work or school.