The widely used painkiller acetaminophen has little effect on osteoarthritic pain even at high doses, according to results from a new meta-analysis, while several other agents, including diclofenac, improve pain more robustly.

The study, published online March 17 in The Lancet ( doi: 10.1016/S0140-6736(16)30002-2 ), reviewed results from 74 randomized trials enrolling nearly 60,000 patients with knee or hip osteoarthritis.

Patients were assigned different single-agent treatment regimens, comprising various dosages of seven nonsteroidal anti-inflammatory drugs (rofecoxib, lumiracoxib, etoricoxib, diclofenac, celecoxib, naproxen, and ibuprofen) or acetaminophen; in the included trials some treatments were compared head to head, and others to placebo.

First author Bruno R. da Costa, Ph.D., of the University of Bern (Switzerland) and his colleagues found to their surprise that acetaminophen had a nearly null effect on pain symptoms at doses ranging from under 2,000 mg a day to as much as 4,000 mg.

The study’s preestablished cutoff for clinically important pain reduction was an effect size of –0.37. While the most effective regimens in the study had effect sizes approaching –0.6, compared with placebo, acetaminophen’s effect size was only –0.17 across the doses studied.

Acetaminophen “is clinically ineffective and should not be recommended for the symptomatic treatment of osteoarthritis, irrespective of the dose,” the researchers concluded.

Diclofenac, meanwhile, had one of the greatest effect sizes at the maximum dose of 150 mg per day (–0.57), and etoricoxib 60 mg and rofecoxib 25 mg were comparably effective. All three agents at these maximum daily doses had 100% probability to reach the minimum clinically important difference established in the study when used to reduce osteoarthritic pain.

By comparison, maximum daily doses of ibuprofen (2,400 mg) and naproxen (1,000 mg) had 83% and 78% probability, respectively, of achieving clinically important reductions. Treatment effects increased with dosage, but reached statistical significance only for celecoxib, diclofenac, and naproxen.

“Although our findings suggest that some NSAIDs have a clinically relevant treatment effect on osteoarthritis pain,” the investigators wrote, their benefit has to be weighed against their potential harmful effects, which include cardiovascular risk associated with diclofenac and gastrointestinal complications linked to naproxen.

“Appropriate drug selection is a major challenge in patients with osteoarthritis, who are often elderly with polypharmacy. Our study will help to put the available safety data into perspective,” they wrote.

The agents were used short-term, reflecting real-life practice, with average follow-up in the study less than 3 months. However, trials with longer-term follow-up may be needed to compare effectiveness of regimens “on a continuous fixed-dose versus NSAIDs on an as-needed basis,” the researchers acknowledged.

The Swiss National Science Foundation and the Arco Foundation of Switzerland sponsored the study. One investigator disclosed institutional research support from AstraZeneca, Biotronik, Biosensors International, Eli Lilly, and the Medicines Company, while another is currently employed by Novartis and holds shares in Cogitars.


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