Acetaminophen at higher doses has been associated with GI toxicity.8 In a case-control study, acetaminophen at doses ≥2 g/d increased the risk of upper GI bleeding or perforation.9 A cohort study showed that doses of acetaminophen >3 g/d led to higher rates of upper GI events (GI hospitalization, ulcer, and dyspepsia) comparable to those seen with NSAIDs.10 It remains unclear if the acetaminophen in this trial caused GI adverse events among all patients due to the higher doses alone, or if the rates reflected increases in adverse events expected among high-risk GI patients or concomitant NSAID users.10 Furthermore, healthy adults who ingested 4 g acetaminophen each day for 2 weeks exhibited significant elevations of serum alanine aminotransferase levels, suggestive of liver injury.11
Caution is justified with prolonged use of acetaminophen at high doses, particularly in alcohol users. In cohort studies with women and men, acetaminophen has been associated with an increased risk of incident hypertension.12,13 In case-control studies, long-term use has also been dose-dependently associated with an increased risk of chronic renal failure.14,15
Nonselective NSAIDs: Keep GI risks in mind
All nonselective NSAIDs, when administered at equivalent therapeutic doses (same degree of COX inhibition), appear to have comparable efficacy in relieving OA pain. Analgesia is dose dependent, which enables patients to start therapy at lower over-the-counter (OTC) doses and escalate to higher prescription doses as needed.3 The OTC dose range of ibuprofen is 200 to 400 mg 3 times a day, to a maximum of 1200 mg/d;16 the maximum prescription dose is 3200 mg/d.17 Similarly, the maximum dose of OTC naproxen is 660 mg/d,18 although by prescription it can be given up to 1500 mg/d.19
NSAIDs confer a dose-related risk for GI adverse events, including ulcers and bleeding. Patients with a history of ulcers and those at advanced age are at greater risk;20 those with a history of an ulcer bleed are at the greatest risk for an adverse event. Also at increased risk are those taking high doses of an NSAID, multiple NSAIDs (eg, concomitant low-dose aspirin), or anticoagulant or antiplatelet agents.21
Recent data suggest that nonselective NSAIDs, with the exception of naproxen, may increase CV risk on a level seen with COX-2–selective inhibitors.22,23 In a meta-analysis of 91 randomized active-controlled trials, a comparison of COX-2–selective inhibitors and non-naproxen nonselective NSAIDs showed no significant difference in the risk of myocardial infarction (MI) (relative risk [RR]=1.20; 95% confidence interval [CI], 0.85–1.68); however, COX-2–selective inhibitors had an increased risk compared with naproxen (RR=2.04; 95% CI, 1.41–2.96).23 In another meta-analysis of 11 observational studies, naproxen reduced the risk of MI compared with COX-2–selective inhibitors and other nonselective NSAIDs (RR=0.86; 95% CI, 0.75–0.99).22 An increased risk of incident hypertension has been associated with frequent NSAID use in cohort studies in women and men.12,13
COX-2–selective NSAIDs: Good on gut, but increase MI risk
COX-2–selective NSAIDs lower the incidence of upper GI tract complications compared with nonselective agents, while maintaining comparable efficacy in pain relief, both when used alone (without concomitant aspirin therapy)20,24,25 and in combination with PPIs.26,27
But despite their GI safety profile, the COX-2–selective NSAIDs increased the risk of MI and ischemic cerebrovascular events in trials where they were being studied for arthritis pain and for GI polyp prevention.22,28,29 Among the proposed mechanisms for this effect is that selective COX-2 inhibition reduces the level of the antithrombotic prostanoid, prostacyclin, relative to the level of the prothrombotic prostanoid, thromboxane, thereby leading to a prothrombotic tendency.30
Rofecoxib and valdecoxib were withdrawn from the market in the United States by the manufacturers after the drugs were linked to serious CV adverse effects—and in the case of valdecoxib, to a serious skin reaction.30 Celecoxib remains commercially available in the United States.30 The CV risks associated with celecoxib are dose related, with once-daily dosing (400 mg/d) associated with a much lower risk than twice-daily dosing (200 or 400 mg twice a day).31 The recommended dose is 200 mg/d.32
The deleterious impact of combining low-dose aspirin with NSAIDs
Many patients who take NSAIDs also require aspirin for cardioprotection. Catella-Lawson and colleagues33 investigated the potential interactions between aspirin and several NSAIDs used in managing OA. They found that ibuprofen, when taken before aspirin, reduced aspirin’s inhibition of platelet aggregation, demonstrating potential impairment of aspirin’s cardioprotective effect.33 Subsequent observational studies have supported these in vitro findings.34