Do acetaminophen and an NSAID combined relieve osteoarthritis pain better than either alone?

One randomized, double-blind, crossover trial compared single doses of tolmetin (Tolectin, 100, 150, 200 mg) and acetaminophen (400 mg) alone and in combination with placebo in the control of experimentally induced pain (thermal and electrical stimulation). Acetaminophen alone did not differ from placebo in pain control; however, the combinations of acetaminophen with tolmetin provided similar pain relief to higher doses of tolmetin alone.⁸ No studies have evaluated the efficacy or safety of acetaminophen combined with rofecoxib or celecoxib.

Regarding the risks of combining acetaminophen with NSAIDs, 1 nested case-control study based on the entire enrollment panel of the British National Health Service characterized the risk of upper GI side effects among persons taking NSAIDs or acetaminophen alone or in combination. The study evaluated medications in use at the time of an upper GI bleed, controlling for age, sex, and concomitant medications (corticosteroids, H₂ receptor antagonists, omeprazole, anticoagulants, and others) and excluding patients with varices, alcohol-related disorders, liver disease, and cancer; no attempt was made to control other comorbidities. The relative risk of upper GI perforation or bleeding for patients taking 2g/d acetaminophen or high-dose NSAIDs was 2.4 (95% confidence interval [CI], 1.7–3.5) and 3.6 (95% CI, 2.9–4.3), respectively. Concomitant use of an NSAID with 2 g/d of acetaminophen showed a relative risk of upper GI perforation or bleed of 16.6 (95% CI, 11.0–24.9). Acetaminophen doses <2 g/d conferred no additional risk for serious upper GI side effects.⁹

A systematic review of selective COX-2 inhibitors vs naproxen found fewer endoscopically detected ulcers in patients taking celecoxib but no difference in serious gastrointestinal bleeds.⁵ A meta-analysis of randomized controlled trials found a higher incidence of serious thrombotic cardiovascular events among patients taking COX-2 inhibitors compared with naprosyn.¹⁰ The safety profile of rofecoxib and celecoxib in the long-term treatment of pain is not fully understood at this time.

Recommendations from others

The American College of Rheumatology (ACR) recommends acetaminophen up to 4 g/d as a first-line pharmacologic treatment for osteoarthritis of the hip and knee, and advises NSAIDs be used at the lowest effective dose if they are necessary for pain control.¹¹ The ACR does not specifically comment on combining NSAID and acetaminophen use. The American Academy of Orthopaedic Surgeons recommends initial use of an NSAID or acetaminophen, but does not comment on the combination of NSAIDs and acetaminophen.¹²