EVIDENCE-BASED ANSWER
Combining nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen for short courses provides more relief of pain in osteoarthritis with-out an increase in side effects (strength of recommendation [SOR]=B). Combining acetaminophen at 4 g/d with an NSAID can also decrease the daily dose of NSAID required for pain relief, thus reducing the potential risk from higher-dose NSAID therapy (SOR=B).
Over the long term, however, this combination may increase the risk of upper gastrointestinal (GI) bleeding more than that conferred by the NSAID alone (SOR=B). If combination therapy is necessary, limiting the dose of acetaminophen to 2 g/d minimizes gastrointestinal toxicity. Acetaminophen alone at the lowest dose to provide pain relief is the safest pharmacologic choice for patients with osteoarthritis.
Evidence summary
Clinical guidelines for osteoarthritis recommend acetaminophen as first-line therapy followed by an NSAID or cyclooxygenase-2 (COX-2) inhibitor, and many patients are treated with combination therapy.
Several small randomized controlled trials have compared the individual efficacy of NSAIDs and acetaminophen in osteoarthritis and have found that both provide more pain relief than placebo.1-3There is a trend toward improved pain relief with NSAIDs compared with acetaminophen in the initial treatment period; however, few long-term studies of efficacy have been reported. One randomized controlled trial comparing 750 mg/d naproxen (Aleve, Naprosyn) with 2600 mg/d acetaminophen for 2 years found similar pain relief for both medications and a dropout rate of 65% in both groups.2 Similar numbers of persons taking acetaminophen or naproxen dropped out because of adverse effects (20%) or lack of efficacy (19%), and no difference was seen in functional improvement between the 2 groups.
A 6-week randomized double-blind crossover trial of 227 patients comparing 75 mg diclofenac and 200 mg misoprostol (Arthrotec) with acetaminophen 4 g/d found the diclofenac-misoprostol combination provided more pain control than acetaminophen alone. Adverse events were slightly more common in the diclofenac group (54% vs 46%; P=.046).4
The COX-2 inhibitors rofecoxib (Vioxx) and celecoxib (Celebrex) have been shown to provide equal pain relief compared with naproxen for patients with osteoarthritis.5 One industry-sponsored randomized trial found rofecoxib superior to celecoxib, and both superior to acetaminophen in treatment of osteoarthritis pain.6 There was no difference in the incidence of side effects among the 3 medications. Thirty percent of patients taking 4 g/d acetaminophen discontinued the study because of lack of efficacy, compared with 20% of those taking either celecoxib or rofecoxib.6
Few studies have evaluated the safety or efficacy of the combination of NSAIDs and acetaminophen in osteoarthritis. One double-blind, double-dummy crossover trial of 18 patients with osteoarthritis of the hip compared naproxen at doses of 500 mg and 1000 mg, with and without 4 g/d of acetaminophen, and 1500 mg/d of naproxen alone over 5 one-week trial periods.7Adding acetaminophen improved patient-reported pain scores compared with naproxen alone. Higher doses of naproxen alone provided less pain relief than a lower dose of naproxen combined with acetaminophen. GI side effects increased with the increase in naproxen dose, but were unaffected by the addition of acetaminophen. Functional ability was not affected during this short study. A similar study by the same researchers of patients with rheumatoid arthritis found similar results.7