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

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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.

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Most cited references 38

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Random effects meta-analysis of event outcome in the framework of the generalized linear mixed model with applications in sparse data.

Theo Stijnen, Taye H. Hamza, Pinar Ozdemir (2010)

We consider random effects meta-analysis where the outcome variable is the occurrence of some event of interest. The data structures handled are where one has one or more groups in each study, and in each group either the number of subjects with and without the event, or the number of events and the total duration of follow-up is available. Traditionally, the meta-analysis follows the summary measures approach based on the estimates of the outcome measure(s) and the corresponding standard error(s). This approach assumes an approximate normal within-study likelihood and treats the standard errors as known. This approach has several potential disadvantages, such as not accounting for the standard errors being estimated, not accounting for correlation between the estimate and the standard error, the use of an (arbitrary) continuity correction in case of zero events, and the normal approximation being bad in studies with few events. We show that these problems can be overcome in most cases occurring in practice by replacing the approximate normal within-study likelihood by the appropriate exact likelihood. This leads to a generalized linear mixed model that can be fitted in standard statistical software. For instance, in the case of odds ratio meta-analysis, one can use the non-central hypergeometric distribution likelihood leading to mixed-effects conditional logistic regression. For incidence rate ratio meta-analysis, it leads to random effects logistic regression with an offset variable. We also present bivariate and multivariate extensions. We present a number of examples, especially with rare events, among which an example of network meta-analysis.

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An algorithm recommendation for the management of knee osteoarthritis in Europe and internationally: a report from a task force of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO).

Olivier Bruyère, Cyrus Cooper, Jean-Pierre Pelletier … (2014)

Existing practice guidelines for osteoarthritis (OA) analyze the evidence behind each proposed treatment but do not prioritize the interventions in a given sequence. The objective was to develop a treatment algorithm recommendation that is easier to interpret for the prescribing physician based on the available evidence and that is applicable in Europe and internationally. The knee was used as the model OA joint.

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Examination of overall treatment effect and the proportion attributable to contextual effect in osteoarthritis: meta-analysis of randomised controlled trials

Kun Zou, Jean Wong, Natasya Abdullah … (2016)

Objective To examine the overall treatment effect and the proportion attributable to contextual effect (PCE) in randomised controlled trials (RCTs) of diverse treatments for osteoarthritis (OA). Methods We searched Medline, Embase, Central, Science Citation Index, AMED and CINAHL through October 2014, supplemented with manual search of reference lists, published meta-analyses and systematic reviews. Included were RCTs in OA comparing placebo with representative complementary, pharmacological, non-pharmacological and surgical treatments. The primary outcome was pain. Secondary outcomes were function and stiffness. The effect size (ES) of overall treatment effect and the PCE were pooled using random-effects model. Subgroup analyses and meta-regression were conducted to examine determinants of the PCE. Results In total, 215 trials (41 392 participants) were included. The overall treatment effect for pain ranged from the smallest with lavage (ES=0.46, 95% CI 0.24 to 0.68) to the largest with topical non-steroidal anti-inflammatory drugs (ES=1.37, 95% CI 1.19 to 1.55). On average, 75% (PCE=0.75, 95% CI 0.72 to 0.79) of pain reduction was attributable to contextual effect. It varied by treatment from 47% (PCE=0.47, 95% CI 0.32 to 0.70) for intra-articular corticosteroid to 91% (PCE=0.91, 95% CI 0.60 to 1.37) for joint lavage. Similar results were observed for function and stiffness. Treatment delivered by needle/injection and other means than oral medication, longer duration of treatment, large sample size (≥100 per arm) and public funding source were associated with increased PCE for pain reduction. Conclusions The majority (75%) of the overall treatment effect in OA RCTs is attributable to contextual effects rather than the specific effect of treatments. Reporting overall treatment effect and PCE, in addition to traditional ES, permits a more balanced, clinically meaningful interpretation of RCT results. This would help dispel the frequent discordance between conclusions from RCT evidence and clinical experience—the ‘efficacy paradox’.

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Author and article information

Contributors

Germain Honvo:

ORCID: http://orcid.org/0000-0002-6992-6712

+32 4 366 20 88 , germain.honvo@uliege.be

Victoria Leclercq: victoria.leclercq@uliege.be

Anton Geerinck: anton.geerinck@uliege.be

Thierry Thomas: thierry.thomas@chu-st-etienne.fr

Nicola Veronese: ilmannato@gmail.com

Alexia Charles: alexia.charles@uliege.be

Véronique Rabenda: veronique.rabenda@uliege.be

Charlotte Beaudart: c.beaudart@uliege.be

Cyrus Cooper: cc@mrc.soton.ac.uk

Jean-Yves Reginster:

ORCID: http://orcid.org/0000-0001-6290-752X

jyreginster@uliege.be

Olivier Bruyère:

ORCID: http://orcid.org/0000-0003-4269-9393

olivier.bruyere@uliege.be

Journal

Journal ID (nlm-ta): Drugs Aging

Journal ID (iso-abbrev): Drugs Aging

Title: Drugs & Aging

Publisher: Springer International Publishing (Cham )

ISSN (Print): 1170-229X

ISSN (Electronic): 1179-1969

Publication date (Electronic): 9 May 2019

Publication date PMC-release: 9 May 2019

Publication date (Print): 2019

Volume: 36

Issue: Suppl 1

Pages: 45-64

Affiliations

[1 ]ISNI 0000 0001 0805 7253, GRID grid.4861.b, Department of Public Health, Epidemiology and Health Economics, , University of Liège, ; Liège, Belgium

[2 ]WHO Collaborating Centre for Public Heath Aspects of Musculoskeletal Health and Aging, Liège, Belgium

[3 ]ISNI 0000 0001 2150 7757, GRID grid.7849.2, Department of Rheumatology, Hôpital Nord, CHU de St-Etienne and INSERM 1059, , Université de Lyon, ; Saint-Étienne, France

[4 ]ISNI 0000 0001 1940 4177, GRID grid.5326.2, National Research Council, Neuroscience Institute, Aging Branch, ; Padua, Italy

[5 ]ISNI 0000 0004 1936 9297, GRID grid.5491.9, MRC Lifecourse Epidemiology Unit, Southampton General Hospital, , University of Southampton, ; Southampton, UK

[6 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Musculoskeletal Biomedical Research Unit, National Institute for Health Research (NIHR), , University of Oxford, ; Oxford, UK

[7 ]ISNI 0000 0004 1773 5396, GRID grid.56302.32, Chair for Biomarkers of Chronic Diseases, Biochemistry Department, College of Science, , King Saud University, ; Riyadh, Kingdom of Saudi Arabia

Author information

Germain Honvo http://orcid.org/0000-0002-6992-6712

Jean-Yves Reginster http://orcid.org/0000-0001-6290-752X

Olivier Bruyère http://orcid.org/0000-0003-4269-9393

Article

Publisher ID: 661

DOI: 10.1007/s40266-019-00661-0

PMC ID: 6509095

PubMed ID: 31073923

SO-VID: ba3a073d-90a3-4ef0-b8bb-30fb352fb078

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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

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Most cited references 38

Random effects meta-analysis of event outcome in the framework of the generalized linear mixed model with applications in sparse data.

An algorithm recommendation for the management of knee osteoarthritis in Europe and internationally: a report from a task force of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO).

Examination of overall treatment effect and the proportion attributable to contextual effect in osteoarthritis: meta-analysis of randomised controlled trials

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Cited by 28

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