It tested the approach of offering patients with broken bones and sprains over-the-counter pills first.
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And it found that ordinary over-the-counter pain relievers such as Tylenol and Motrin worked as well as opioids at reducing severe pain.
The results challenge common ER practice for treating short-term, severe pain and could prompt changes that would help prevent new patients from becoming addicted.
The study only looked at short-term pain relief in the emergency room and didn't evaluate how patients managed their pain after leaving the hospital.
But given the scope of the U.S. opioid epidemic - more than 2 million Americans are addicted to opioid painkillers or heroin - and that many addictions begin with prescription opioids, experts say any dent in the problem could be meaningful.
Results were published Tuesday in the Journal of the American Medical Association.
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Past studies have shown opioids were prescribed in nearly one-third of ER visits and about 1 out of 5 ER patients are sent home with opioid prescriptions.
The study involved 411 adults treated in two emergency rooms at Montefiore Medical Center in New York City.
Their injuries included leg and arm fractures or sprains. All were given acetaminophen, the main ingredient in Tylenol, plus either ibuprofen, the main ingredient in Motrin, or one of three opioids: oxycodone, hydrocodone or codeine.
They were given standard doses and were not told which drug combo they received.
Patients rated their pain levels before taking the medicine and two hours later.
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On average, pain scores dropped from almost 9 on a 10-point scale to about 5, with negligible differences between the groups.
Ibuprofen and acetaminophen affect different pain receptors in the body so using the two drugs together may be especially potent, said Dr. Andrew Chang, an emergency medicine professor at Albany Medical College in upstate New York, who led the study.
He noted that a pill combining ibuprofen and acetaminophen is available in other countries; his findings echo research from Canada and Australia testing that pill against opioids for pain relief.
"Preventing new patients from becoming addicted to opioids may have a greater effect on the opioid epidemic than providing sustained treatment to patients already addicted," wrote Dr. Demetrios Kyriacou, an emergency medicine specialist at Northwestern University, in an accompanying editorial.