|Adverse effects of topical nonsteroidal antiinflammatory drugs in older adults with osteoarthritis: a systematic literature review
|Makris UE, Kohler MJ, Fraenkel L
The authors concluded that topical administration of non-steroidal anti-inflammatory drugs was safer than oral administration for osteoarthritis in older adults, but that many patients reported systemic adverse effects with topical agents. Reliance on a narrative synthesis, and some lack of reporting in the review process, means the reliability of these conclusions is unclear.
To systematically review literature on reported adverse effects associated with the use of topical non-steroidal anti-inflammatory drugs (NSAIDs) in older adults with osteoarthritis.
MEDLINE (from 1950 to November 2009), Scopus, EMBASE, Web of Science, and the Cochrane Library were searched for relevant studies published in English. Search terms were reported. Abstracts from dissertations and American College of Rheumatology meetings were also searched. Bibliographies of reviews and individuals studies were scanned for further studies.
Papers were excluded if they were obviously unrelated to topical non-steroidal anti-inflammatory drugs (NSAIDs) or osteoarthritis, or if the treatment groups were receiving both oral and topical NSAIDs, or if there was more than one indication for NSAIDs. In addition, articles were excluded if the mean participant age was under 60 years, if the study duration was under two weeks long, or if there was no mention of adverse events or an inability to assign the adverse events to the study participants with osteoarthritis.
In included studies, the mean age of participants ranged from 60 and 67 years; the proportion of females ranged from 52 to 91% (in randomised controlled trials - RCTs). The medication application site in most studies was the knee. NSAID treatments included diclofenac, eltenac, piroxicam, ibuprofen, ketoprofen, celecoxib, arnica gel, traxam gel, and methylsalicylate ointment. Modes of treatment included oral and topical (gels, solutions and ointments). The number of topical applications per day ranged from two to four (where reported). The use of placebo, drug vehicles and concomitant medication were reported in the papers. Study duration ranged from two to 12 weeks.
Outcome measures included the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) using either a Visual Analogue Scale (VAS) or Likert Scale; Lequesne index of severity (for knee) and algofunctional index; Hisskin's VAS and Goldberg knee score (where reported). Methods of reporting adverse events varied widely.
The number of reviewers who performed the study selection was not reported.
Assessment of study quality
The authors assessed RCT quality using the Jadad scale and criteria for randomisation, blinding and withdrawals/dropouts.
The number of reviewers who performed the quality assessment was not reported.
Two authors independently extracted data required for a narrative synthesis, including the range and percentage of adverse effects. Disagreements were resolved by consensus.
Methods of synthesis
A narrative synthesis was presented.
Results of the review
Nineteen studies were included in the review, including 16 RCTs, one case series and two case reports. Ten RCTs scored 5 out of 5 points on the Jadad scale; two RCTs scored 4, two scored 3, and two scored of 2.
Based on the RCTs only, the rates of topical adverse effects for topical applications of non-steroidal anti-inflammatory drugs (NSAIDs) ranged from 0.79 to 39.3% for dry skin, 1.4 to 21% for rash, 0 to 4.8% for dermatitis, 0 to 14% for paresthesia, 0 to 11% for pruritus, 0.3 to 1.4% for urticaria, and 0.6 to 5% for vesiculobullous rash. Within these trials, up to 21% of participants withdrew citing adverse effects from topical NSAIDs (and up to 25% due to adverse effects from oral NSAIDs). Systemic adverse effects following topical and oral administration of NSAIDs included gastrointestinal complaints and headache. Anaemia, liver function test and renal abnormalities and severe gastrointestinal adverse effects were reported following oral administration of NSAIDs.
Case series indicated the potential of warfarin anticoagulation following application of methylsalicylate ointment in five patients, with one case resulting in gastrointestinal bleeding.
Although topical non-steroidal anti-inflammatory drugs (NSAIDs) were safer than oral NSAIDs with fewer severe gastrointestinal events, a substantial proportion of older adults reported systemic adverse effects with topical agents. The withdrawal rate due to adverse events with topical agents was comparable to that of oral NSAIDs.
This review addressed a clear research question using broad but potentially reproducible study selection criteria. Multiple databases were searched, although only English language papers were considered for inclusion, which raised the risk of language bias. The inclusion of sources of unpublished studies meant that attempts were made to minimise publication bias. An appropriate checklist was used to assess the quality of RCTs. The risk of error and bias in the study selection process and quality assessment stages could not be ruled out, as these processes were poorly-reported.
Primary study characteristics were reported, which revealed substantial clinical heterogeneity between included studies. Given this heterogeneity, the use of a narrative synthesis seemed appropriate.
The validity of the authors' conclusion about the comparative safety of drug administration was limited by its reliance on this narrative synthesis of results. For this reason, and the absence of a fully-reported review process, the reliability of the authors' conclusions is unclear.
Implications of the review for practice and research
Practice: The authors did not state any implications for practice.
Research: The authors stated that observational studies of NSAIDs for osteoarthritis that include participants with various comorbidities are needed. Future studies should also consider the effect of the NSAID vehicle/carrier on application site and systemic adverse effects, and should also assess tolerability. Further research is needed to quantify the additional benefits of topical NSAIDs compared to other treatment modalities.
National Institute on Aging, USA, grant number T32 AG19134; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), USA, grant number K23 AR048826.
Makris UE, Kohler MJ, Fraenkel L. Adverse effects of topical nonsteroidal antiinflammatory drugs in older adults with osteoarthritis: a systematic literature review. Journal of Rheumatology 2010; 37(6): 1236-1243
Subject indexing assigned by NLM
Administration, Oral; Administration, Topical; Aged; Anti-Inflammatory Agents, Non-Steroidal /administration & dosage /adverse effects; Antirheumatic Agents /administration & dosage /adverse effects; Databases, Bibliographic; Female; Gastrointestinal Diseases /chemically induced; Health Status; Humans; Male; Middle Aged; Osteoarthritis /complications /drug therapy /physiopathology; Randomized Controlled Trials as Topic; Severity of Illness Index
Database entry date
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.