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Non-steroidal Anti-inflammatory Drugs for Pain: A Review of Safety

Last updated: August 20, 2013
Project Number: RC0471-000
Product Line: Rapid Response
Research Type: Drug
Report Type: Summary with Critical Appraisal
Result type: Report

Report in Brief

Non-steroidal anti-inflammatory drugs (NSAIDs) play an important role in pain management for clinical conditions such as headaches, menstrual disorders, post-operative pain, spinal and soft tissue pain, rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.

NSAIDs reduce pain by blocking cyclooxygenase (COX) enzymes needed to produce prostaglandin. There are two forms of the enzyme: COX-1 and COX-2. Traditional NSAIDs, called “non-selective NSAIDs,” block both forms. NSAIDs that target only the COX-2 form are called “COX-2 selective NSAIDs” or “COX-2 inhibitors.”

Celecoxib (Celebrex) is the only COX-2 inhibitor currently available at in Canada.

Based on their mechanism of action, COX-2 inhibitors are thought to be safer than non-selective NSAIDs in terms of gastrointestinal (GI) bleeding. However, COX-2 inhibitors are associated with an increased risk of major cardiovascular events such as heart attacks and strokes. The COX-2 inhibitor rofecoxib (Vioxx) was removed from the Canadian market in 2004 for this reason. Generic versions of celecoxib will soon be available in Canada.

A review of the comparative safety of NSAIDs will help inform decisions on their use for the management of pain.

A limited literature search was conducted of key resources, and titles and abstracts of the retrieved publications were reviewed. Full-text publications were evaluated for final article selection according to predetermined selection criteria (population, intervention, comparator, outcomes, and study designs).

The literature search identified 275 citations, with an additional 8 articles identified from other sources. Of these, 13 were deemed potentially relevant and 6 met the criteria for inclusion in this review — 5 systematic reviews and 1 health technology assessment.

Key Messages

  • The COX-2 inhibitor, celecoxib, appears to be associated with:
    • a cardiovascular risk similar to diclofenac and ibuprofen, and a higher risk than naproxen
    • a GI bleeding risk similar to diclofenac, and a lower risk than ibuprofen and naproxen.
  • Among non-selective NSAIDs:
    • diclofenac may be associated with a higher cardiovascular risk than ibuprofen or naproxen
    • naproxen may be associated with a lower cardiovascular risk than diclofenac, ibuprofen, or indomethacin.
  • Interpret these results with caution as:
    • study durations were short (generally less than three months)
    • studies used different NSAID doses.


  1. What is the comparative safety of non-steroidal anti-inflammatory drugs when used for the management of pain?

Key Message

In pain management, celecoxib and non-selective NSAIDs seem to have a similar overall risk of major cardiovascular adverse events even though cardiovascular risk was reportedly statistically significantly higher in celecoxib compared with naproxen. Statistically significantly fewer gastrointestinal adverse events were reported with the use of celecoxib compared with non-selective NSAIDs in the short term. Different non-selective NSAIDs appear to be associated with similar risks of serious gastrointestinal events. All non-selective NSAIDs except for naproxen were associated with similar risks of serious cardiovascular events.