Safety of Topical Non-steroidal Anti-Inflammatory Drugs in Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis

Abstract

Objective We aimed to assess the safety of topical non-steroidal anti-inflammatory drugs (NSAIDs) in the management of osteoarthritis (OA) in a systematic review and meta-analysis of randomized, placebo-controlled trials. Methods A comprehensive literature search was undertaken in the MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and Scopus electronic databases. Randomized, double-blind, placebo-controlled, parallel-group trials that assessed adverse events (AEs) with topical NSAIDs in patients with OA were eligible for inclusion. Authors and/or study sponsors were contacted to obtain the full report of AEs. The primary outcomes were overall severe and serious AEs, as well as the following MedDRA System Organ Class (SOC)-related AEs: gastrointestinal, vascular, cardiac, nervous system, skin and subcutaneous tissue, musculoskeletal and connective tissue. Results The search strategy identified 1209 records, from which 25 papers were included in the qualitative synthesis and 19 were included in the meta-analysis, after exclusions. Overall, more total AEs (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.04–1.29; I 2 = 0.0%) and more withdrawals due to AEs (OR 1.49, 95% CI 1.15–1.92; I 2 = 0.0%) were observed with topical NSAIDs compared with placebo. The same results were achieved with topical diclofenac, largely driven by an increase in skin and subcutaneous tissue disorders (OR 1.73, 95% CI 0.96–3.10), although the difference was not statistically significant compared with placebo. No significant difference in the odds for gastrointestinal disorders was observed between topical NSAIDs and placebo (OR 0.96, 95% CI 0.73–1.27). Conclusions Topical NSAIDs may be considered safe in the management of OA, especially with regard to low gastrointestinal toxicity. The use of topical NSAIDs in OA should be considered, taking into account their risk: benefit profile in comparison with other anti-OA treatments. Electronic supplementary material The online version of this article (10.1007/s40266-019-00661-0) contains supplementary material, which is available to authorized users.

Endorsement by Central European experts of the revised ESCEO algorithm for the management of knee osteoarthritis

“…Topical NSAIDs may be added to the treatment regimen in Step 1 therapy if the patient is still symptomatic, and may be used in preference to oral NSAIDs particularly in patients aged ≥ 75 years as they have similar efficacy to the oral medications in reducing pain (ES 0.44, 95% CI 0.27, 0.62) with a reduced risk of systemic AEs [4]. An increase in mild local skin reactions is observed with topical NSAIDs although this may be product-specific, and is notably higher with diclofenac [17]. Topical NSAIDs are recommended as add-on analgesia in Step 1 for patients who are still symptomatic, and prior to the use of oral NSAIDs [4].…”

Recommendations for the Reporting of Harms in Manuscripts on Clinical Trials Assessing Osteoarthritis Drugs: A Consensus Statement from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO)

“…Recently, the ESCEO commissioned several systematic reviews and meta-analyses of randomized, placebo-controlled trials to reassess the safety of various anti-OA medications, including topical nonsteroidal anti-inflammatory drugs (NSAIDs), symptomatic slow-acting drugs for OA (SYSADOAs) and intra-articular hyaluronic acid (IAHA) [30][31][32]. For this purpose, the MEDLINE, Cochrane Central Register of Controlled Trials, and Scopus databases were comprehensively searched.…”

“…The methodology and the outcomes of these systematic reviews have been extensively described in each manuscript. From the articles included in each systematic review, we collected information on how AE data were reported; details on how AE-related results were reported in each article retrieved from the systematic review processes can be found in the tables describing the characteristics of the included studies in each specific manuscript reporting the outcomes of these new meta-analyses (in this supplement) [30][31][32]. For the purpose of preparing the ESCEO recommendations for the reporting of harms in future manuscripts on trials on anti-OA medications, we summarized the ways in which harms-related data have been reported across the articles retrieved for these new ESCEO meta-analyses, and report here the common sub-standard harms reporting practices found in these prior manuscripts on RCTs on anti-OA drugs.…”

Topical Diclofenac, an Efficacious Treatment for Osteoarthritis: A Narrative Review

“…Adverse events associated with topical diclofenac are primarily local reactions at the application site (dry skin, redness/erythema, pruritus) with minimal systemic effects. A meta-analysis of topical NSAIDs found higher rates of overall adverse events (odds ratio [OR] 1.30; 95% CI 1.10-1.53) with topical diclofenac compared with placebo (N = 8 studies) in studies of knee or hand OA, driven predominantly by increased skin and subcutaneous tissue disorders (OR 1.73; 95% CI 0.96-3.10) [44]. However, there was no increase in gastrointestinal adverse events (OR 1.11; 95% CI 0.75-1.64) and no increase in severe events (OR 1.19; 95% CI 0.68-2.07) or serious events (OR 0.94; 95% CI 0.26-3.42) compared with placebo [44].…”

“…A meta-analysis of topical NSAIDs found higher rates of overall adverse events (odds ratio [OR] 1.30; 95% CI 1.10-1.53) with topical diclofenac compared with placebo (N = 8 studies) in studies of knee or hand OA, driven predominantly by increased skin and subcutaneous tissue disorders (OR 1.73; 95% CI 0.96-3.10) [44]. However, there was no increase in gastrointestinal adverse events (OR 1.11; 95% CI 0.75-1.64) and no increase in severe events (OR 1.19; 95% CI 0.68-2.07) or serious events (OR 0.94; 95% CI 0.26-3.42) compared with placebo [44]. Another meta-analysis reported no increase in systemic adverse events (RR 0.89; 95% CI 0.59-1.3) or gastrointestinal adverse events (RR 1.1; 95% CI 0.76-1.6) with topical diclofenac compared with carrier alone in knee and hand OA [30].…”