This article originally appeared on Time.com.
Ibuprofen, naproxen and celecoxib are among the most commonly used drugs in the U.S. They don’t require a prescription, and they’re a quick answer to all kinds of pain. But lately there’s been growing evidence that non-steroidal anti-inflammatory drugs (NSAIDs) may not be as benign as people think they are. (For more recent reporting on the potential side effects of NSAIDs, read this.)
In general, NSAIDs are considered safe when used as directed—which is to say occasionally, for spot relief of pain. More and more people, however, are relying on them for long term use, and at higher doses. Experts—and a growing body of science—say that’s where problems can start.
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In the latest study, published in the journal BMJ, researchers found that some risks can appear after even a few days of using NSAIDs. Compared with people who didn’t take the painkillers, those who did had a 20% to 50% greater chance of having a heart attack. The risk was higher for people who took 1,200 mg a day of ibuprofen—the equivalent of six standard tablets of Advil—and 750 mg a day for naproxen, the equivalent of roughly three and a half standard Aleves.
The researchers pooled data from several large studies on the drugs and their health effects. In all, more than 446,000 people who used the non-prescription painkillers were included. Among them, more than 61,000 had a heart attack. People who took NSAIDs for even a week had a significantly higher risk of having a heart attack; the highest risk occurred for those taking them for about a month. (After a month, the risk didn’t appear to increase further — the researchers think that’s because everyone who was vulnerable to the drugs’ effects on the heart would have experienced heart problems by then.)
The results confirm those from earlier studies that also found a heightened risk of heart problems in NSAID users, but the large number of people in this analysis—and the more detailed look at how long people were taking the drugs—makes the connection even stronger. The researchers also accounted for other possible factors that could connect NSAID users and heart problems, such as diabetes, high cholesterol levels and previous history of heart disease. Even after those adjustments, the linked remained significant.
The study also confirmed that newer NSAIDs like celecoxib, known as COX-2 inhibitors, which were originally thought to cause more heart problems than traditional NSAIDs, were not more risky when it comes to heart attacks.
As TIME reported previously, some studies found a 19% higher risk of having heart trouble among NSAID users compared to people who didn’t use the drugs. Other studies have found higher risk of hearing loss and miscarriage as well. Those led the Food and Drug Administration to add a warning on NSAID labels about the risks of taking the drugs, especially for long periods of time at high doses.