PRACTICE RECOMMENDATION
• In selecting an NSAID, assess a patient’s baseline cardiovascular (CV) and gastrointestinal (GI) risks and the potential for medication-related incremental CV and GI toxicity. C
• For patients with increased CV risk (taking aspirin for established CV risk) and low GI risk, the preferred agent is naproxen. Consider adding a proton pump inhibitor (PPI) or misoprostol, as dual therapy with aspirin and naproxen may warrant gastroprotection. A
• For patients with moderate GI risk and low CV risk, use a nonselective NSAID with a PPI or misoprostol; if GI risk is high, use a cyclooxygenase (COX)-2–selective NSAID and gastroprotection. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
Although clinicians have considerable experience in using analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) to relieve the pain of osteoarthritis (OA), emerging data have made the task of weighing benefits and risks of each agent more complex.1 In this article, we review the latest evidence for NSAIDs and provide a foundation on which you can make more informed decisions for controlling OA pain and—in conjunction with education, physical therapy, exercise, and cognitive and behavioral approaches2,3—improve patients’ daily function and quality of life.
Agents for OA pain relief: Benefits and trade-offs
Treatment options for OA pain are the analgesic acetaminophen and the NSAIDs, comprising both nonselective agents and the cyclooxygenase (COX)-2–selective inhibitors.
NSAIDs inhibit COX, a key enzyme in the biosynthesis of prostanoids, including the prostaglandins and leukotrienes, which are important mediators of pain. The COX-1 isoform is constantly expressed in tissue. It regulates protection of the gastric mucosa, platelet activation, and renal function. In contrast, COX-2 is induced primarily in response to inflammatory stimuli.
The nonselective NSAIDs inhibit both isoforms of COX. The anti-inflammatory and analgesic effects of the NSAIDs result primarily from COX-2 inhibition. Inhibition of COX-1 is largely responsible for the gastrointestinal (GI) ulceration and anti-platelet-promoted bleeding that can occur with these drugs.4
The COX-2–selective inhibitors were developed to spare the normal “housekeeping” functions of COX-1. This benefit, however, has been diminished by the adverse cardiovascular (CV) events occurring with selective inhibition of COX-2, owing to the expression of this isoform in vasculature and the kidneys.4 Increased risk of CV events may also occur with nonselective NSAIDs.
Acetaminophen’s mechanism of action is poorly understood. It is a weak inhibitor of COX-1 and COX-2, but it most likely acts centrally in the hypothalamus and spinal cord, rather than peripherally in joint cartilage where inflammation and damage occur.5
Revised treatment guidelines in brief
The American College of Rheumatology (ACR) and the Osteoarthritis Research Society International (OARSI) have published treatment recommendations for OA.1-3
The recent ACR publication noted that nonselective NSAIDs are more effective than acetaminophen for treating OA pain, but that the differences are small.1 Because of costs and the risk of adverse events associated with NSAID use, the ACR guidelines recommend that patients with mild to moderate OA pain receive a trial of acetaminophen initially; patients who do not respond could then receive NSAIDs. With moderate to severe OA pain, initial treatment with nonselective NSAIDs is appropriate.1,3
The OARSI guidelines2 state that “acetaminophen (up to 4 g/d) can be an effective initial oral analgesic for treatment of mild to moderate pain in patients with knee or hip OA.” The guidelines warn, however, that recent evidence has questioned both the efficacy and safety of long-term acetaminophen use in doses up to 4 g/d. The OARSI guidelines, like the ACR guidelines, recommend alternative pharmacotherapy when patients do not respond to acetaminophen for mild to moderate OA pain, or when OA pain is more severe. NSAIDs are most appropriately prescribed at the lowest effective dose for the shortest possible time.2
Accounting for risk factors. Current guidelines emphasize the importance of selecting treatments based on a patient’s CV and GI risk profiles. For patients with CV risk factors, use nonselective NSAIDs and COX-2–selective inhibitors with caution. For patients with increased GI risk, use either a COX-2–selective inhibitor or a nonselective NSAID with a proton pump inhibitor (PPI) or misoprostol.2
The evidence underlying guideline revisions
Selecting an agent that optimally balances efficacy and safety requires that we consider the complexities of 3 competing clinical concerns—relief of arthritis pain, CV toxicity, and GI toxicity.6 We review here the evidence supporting the revised recommendations.
Acetaminophen: A good option, but there are better ones
Acetaminophen relieves OA pain, but not as effectively as nonselective NSAIDs.1,3,7 A Cochrane meta-analysis showed that although acetaminophen was superior to placebo for reducing OA pain, it was less effective than either nonselective NSAIDs or COX-2–selective NSAIDs for reducing pain and improving functional status, especially in patients with moderate pain.7