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Peterson K, McDonagh M, Thakurta S, et al. Drug Class Review: Nonsteroidal Antiinflammatory Drugs (NSAIDs): Final Update 4 Report [Internet]. Portland (OR): Oregon Health & Science University; 2010 Nov.

Cover of Drug Class Review: Nonsteroidal Antiinflammatory Drugs (NSAIDs)

Drug Class Review: Nonsteroidal Antiinflammatory Drugs (NSAIDs): Final Update 4 Report [Internet].

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The main findings of this review are summarized in Table 6 below. Little evidence on the comparative effectiveness of NSAIDs was truly effectiveness or “real world” – while some trials evaluated longer-term (>6-12 months) and real life (symptoms, clinical ulcers, functional status, myocardial infarctions, pain relief) outcomes, none were conducted in primary care or office-based setting or used broad enrollment criteria.

Table 6. Strength of Evidence by Key Question.

Table 6

Strength of Evidence by Key Question.

For efficacy outcomes, there was high-strength evidence that there are no significant differences between oral NSAIDs. High-strength evidence indicated that 1.5% topical solution and oral diclofenac have similar effects on pain and physical function in a single treated knee. For comparisons among different topical diclofenac products, only low-strength, indirect evidence was available indicating that diclofenac 1.5% topical solution and 1.0% topical gel had similar significant improvements in pain, functional outcome measures, and response rate compared with vehicle with no direct comparisons of the products available.

With regard to gastrointestinal adverse events, there was high-strength evidence that celecoxib seemed to offer a short-term advantage over nonselective NSAIDs, but this has not been conclusively demonstrated in longer-term studies. Among partially selective NSAIDs, there was moderate-strength evidence of a significant reduction in short-term rates of gastrointestinal adverse events with nabumetone relative to nonselective NSAIDs, but long-term, moderate-strength evidence suggested no consistent advantage for meloxicam over nonselective NSAIDs. Among oral nonselective NSAIDs, there was high-strength evidence that all are associated with similar increases in short-term and long-term gastrointestinal risks.

Moderate-strength evidence indicated that there was no significant difference among different combinations of antiulcer medications plus an NSAID in reducing rates of ulcer. Only misoprostol had moderate-strength evidence that compared with taking an NSAID alone, older patients taking misoprostol with an NSAID had significantly lower risk of serious upper gastrointestinal clinical events, but with significant increases in nausea, diarrhea, and abdominal pain. While observational evidence in subgroups of higher-risk patients with recent ulcer bleeding indicated that taking celecoxib alone or taking a nonselective NSAID plus a proton pump inhibitor worked similarly well in preventing recurrent ulcer bleeding, subsequent moderate-strength evidence from a good-quality, long-term trial indicated that prevention of recurrent ulcer bleeding in similar patients was significantly improved with combination treatment with celecoxib plus esomeprazole compared with celecoxib alone.

High-strength evidence showed that diclofenac 1.5% solution resulted in similar improvements in efficacy, but with significantly improved gastrointestinal tolerability compared with oral NSAIDs. The topical solution resulted in a significant increased risk of dry skin at the application site but overall withdrawals due to adverse events were similar.

There was high-strength evidence from primarily short-term studies that there is no significant increase in risk of myocardial infarction or other cardiovascular or cerebrovascular events for celecoxib compared with nonselective NSAIDs. Meloxicam was the only partially selective NSAID with evidence on cardiovascular harms, with low-strength evidence indicating no significant increase in risk of myocardial infarction relative to nonuse after 2.4 years or relative to diclofenac over an unspecified duration. There was moderate-strength evidence that naproxen is risk-neutral with regard to myocardial infarction, whereas similar increases in myocardial infarction have been found for both high-dose ibuprofen and diclofenac.

Concerning differential effects in specific patient subgroups of interest, there was low-strength evidence that suggests there may be lower risks of serious gastrointestinal, cardiovascular, and renal adverse events in elderly patients with celecoxib compared with diclofenac or ibuprofen. In patients using low-dose aspirin concomitantly, celecoxib and nonselective NSAIDs, with or without a proton pump inhibitor, had no clear differential effects on endoscopic ulcer rates. Observational evidence from 2 studies of broadly defined populations did not suggest any significant interference of concomitant NSAID use on the cardioprotective effects of aspirin. However, limited evidence from 1 observational study suggested that ibuprofen may interfere with the cardioprotective effects of aspirin specifically in patients with pre-existing cardiovascular disease.

There were a number of important limitations for this review. Although we attempted to evaluate the overall trade-offs between topical diclofenac products and oral NSAIDs, the evidence was limited to 2 short-term trials that involved comparison of oral diclofenac to only the 1.5% solution of diclofenac, and we found no studies that directly compared different topical products. Additionally, evidence was lacking regarding the long-term risk of serious gastrointestinal and cardiovascular harms for the partially selective NSAIDs, nabumetone, and etodolac, as well for tenoxicam and tiaprofenic acid as compared with nonselective NSAIDs. Although we identified observational studies that evaluated the concomitant use of anticoagulants in patients taking NSAIDs, serious flaws in their design prevented us from reaching any reliable conclusions in this patient subgroup. Further, although many large observational studies were available for assessment of individual serious harms for celecoxib and nonselective oral NSAIDs, few simultaneously assessed the risks of serious cardiovascular and gastrointestinal harms in the same populations. Finally, insufficient evidence was available for evaluating the potential for disparate effects based on ethnicity/race, gender, or socioeconomic status. Our review was limited to studies published in the English language and to the scope outlined in the method section, such that studies applicable to other populations of patients were not reviewed here.

The majority of evidence and conclusions presented in this review are likely most applicable to highly selected patients with osteoarthritis and rheumatoid arthritis from primarily short-term trials conducted in ideal settings. The mean patient age in the trials generally ranged from 58 years to 61 years and women were more highly represented than men. Studies in adults with soft-tissue pain, back pain, and ankylosing spondylitis were fewer, had smaller sample sizes, and were generally shorter term in duration and their findings may not be applicable to populations seen in general clinical practice.

Copyright © 2010, Oregon Health & Science University.
Bookshelf ID: NBK53946


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