The US Food and Drug Administration (FDA) states that “healthcare professionals should be aware of an interaction between low-dose aspirin (81 mg/d) and ibuprofen, which might render aspirin less effective when used for its antiplatelet cardioprotective effect.” To minimize the interaction, the FDA recommends taking ibuprofen 8 hours before or 30 minutes after the ingestion of immediate-release (not enteric-coated) aspirin.35 It is not clear if this strategy can circumvent the interaction. For those who depend on aspirin’s lifesaving antiplatelet activity, it would seem more prudent to avoid medications known to interact with it.
This interaction, thought to be due to the competitive binding of ibuprofen and aspirin to the COX-1 molecule, has not been clinically demonstrated with other NSAIDs, such as diclofenac33 and naproxen, or with acetaminophen.36,37
A small, open-label, crossover study in healthy volunteers showed that both low-dose aspirin and naproxen (500 mg, twice daily) produced persistent and nearly complete suppression of platelet thromboxane production when naproxen was given 2 hours before aspirin or 2 hours after aspirin, suggesting no interference with aspirin’s effect.
An additional analysis in the same study examined thromboxane production in ex vivo platelets and showed that naproxen, like aspirin, inhibited thromboxane production in a concentration-dependent fashion, but reversibly, whereas aspirin’s effect was irreversible.38 Lower, nonprescription doses of naproxen 220 mg 2 and 3 times a day resulted in antiplatelet effects similar to the 550 mg twice-daily prescription dose used in a study of healthy volunteers whose blood was tested for inhibition of serum thromboxane as a measure of platelet COX-1 activity and inhibition of platelet aggregation.39
The propensity of aspirin cotherapy to increase the risk of NSAID-related GI adverse events is an underappreciated concern. A recent review of low-dose aspirin use emphasizes that concomitant NSAID use exacerbates GI bleeding, and low-dose aspirin may significantly offset the reduced GI toxicity of COX-2–selective NSAIDs.40
New recommendations in detail
In choosing an NSAID for a patient with OA, consider the patient’s baseline health risks, the potential for incremental medication-related GI and CV risks, and known hyper-sensitivity reactions or drug intolerance.41 The following recommendations also take into account the impact of aspirin cotherapy.
The presence of GI risk may necessitate using a PPI or misoprostol with the selected NSAID. Both PPIs and misoprostol decrease the rate of gastroduodenal ulceration in NSAID users. Additionally, misoprostol reduces ulcer complications, and PPIs reduce recurrent ulcer bleeding.42-44 One drawback with misoprostol is that it is not well tolerated. Thus PPIs, given their once-daily administration and superiority to histamine-2 (H2) blockers, are the preferred gastroprotective agent.42 The TABLE summarizes the following recommendations.7,41
Patients with no CV risk (not receiving aspirin) and little or no GI risk. Any non-selective NSAID would be reasonable initial therapy for patients with uncomplicated, mild to moderate OA pain.7,41,45 Acetaminophen at doses of up to 4 g/d is an acceptable alternative, but does not relieve pain as effectively as a nonselective NSAID.1,3,8 The risk of GI adverse events is very low with short-term use of OTC NSAID doses.46
Patients with no CV risk (not receiving aspirin) but moderate to high GI risk. For patients with moderate GI risk (eg, age ≥70 years, receiving concomitant corticosteroids or anticoagulants), a COX-2–selective NSAID or any nonselective NSAID with a gastroprotective agent (PPI) is appropriate. If all else is equal in your clinical assessment, cost favors low OTC dosing with nonselective NSAIDs over more costly COX-2–selective agents.7,41,45,47 However, for patients with very high GI risk (eg, prior complicated upper GI event or multiple GI risk factors), choose a COX-2–selective NSAID in combination with a PPI for gastroprotection.7,41,45
Patients with no GI risk and increased CV risk (receiving aspirin). For patients who have an increased CV risk (10-year risk ≥10% according to the Framingham equation for primary prevention; or a history of ischemic heart disease, or cerebrovascular or peripheral vascular disease [secondary prevention]), avoid NSAIDs, with the exception of naproxen.7,45 Large meta-analyses have shown that naproxen is associated with a lower risk of adverse CV events compared with other nonselective NSAIDs and COX-2–selective agents.22,23 Concomitant treatment with a PPI may be appropriate for patients taking naproxen and aspirin, because the risk of gastric ulcers may be increased with cotherapy.7,41,45