A recent Yale-led study published in the journal Immunity has uncovered a previously unknown process by which commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) affect the body. These unexpected effects of common NSAIDs may explain why similar drugs produce a range of clinical outcomes and could inform patients and medical experts alike on how these drugs are used in the future.
To better understand these unexpected effects, let’s first take a look at what NSAIDs are, and how they can cause negative, unwanted effects on the body.
What Are NSAIDs?
NSAIDs, also known as nonsteroidal anti-inflammatory drugs, are the most commonly prescribed medication for treating chronic inflammatory conditions like arthritis. Most people are familiar with this type of medication and may know them better by their over-the-counter names such as ibuprofen or aspirin.
NSAIDs are more than just pain relievers. They can help reduce inflammation and lower fevers. In some cases, NSAIDs can also help prevent your blood from clotting, which can be beneficial in some cases, but not so much in others.
These risks are well-known in the medical field. For example, since some NSAIDs can help reduce clotting, especially aspirin, they may have a protective effect against heart disease. However, this reduced clotting effect may also cause you to bruise easily. NSAIDs can also cause nausea, upset stomach, or ulcers, and have also been linked to reduced kidney function.
It is for these reasons that studies such as this have linked NSAIDs to unexpected, oftentimes unwanted side effects.
What Unexpected Effects of Common NSAIDs Did the Study Find?
Until now, the anti-inflammatory effects of NSAIDs were thought to be due to the inhibition of certain enzymes. However, this mechanism does not account for the many clinical outcomes that can be observed across the family of drugs.
For example, some NSAIDs have been shown to decrease the risk of heart disease, while others have been found to cause it. Other NSAIDs have been linked to a lower risk of colorectal cancer, and others have had a wide range of effects on conditions like asthma.
Now, using cell cultures and mice, Yale researchers have uncovered a distinct mechanism by which a subset of NSAIDs reduce inflammation. It is this precise mechanism that they also believe may help explain some of the more curious side effects of common NSAIDs.
“It’s interesting and exciting that NSAIDs have a different mode of action than what was known previously,” said Anna Eisenstein, an instructor at the Yale School of Medicine and lead author of the study. “And because people use NSAIDs so frequently, it’s important we know what they’re doing in the body.”
Eisenstein and her colleagues found that only some NSAIDs—namely indomethacin which is primarily used to treat arthritis and gout, and ibuprofen— also activate a protein called nuclear factor erythroid 2 (NRF2). This protein, which, among many of its actions, triggers anti-inflammatory processes throughout the body.
The research team can’t say for sure that these unexpected effects of common NSAIDs are due to NRF2, and noted that theory will require more research. “But I think these findings are suggestive of that,” Eisenstein said.
Eisenstein is now looking into some of the drugs’ dermatological effects—causing rashes, exacerbating hives, and worsening allergies—and whether they are mediated by NRF2.
What Does This Mean for Future NSAID Use?
It’s important to note that this discovery still needs to be confirmed in humans, the researchers note. But if it is, the findings could have an impact on how inflammation is treated and how NSAIDs are used.
For example, several clinical trials are evaluating whether NRF2-activating drugs are effective in treating inflammatory diseases like Alzheimer’s disease, asthma, and various cancers; this research could inform the potential and limitations of those drugs.
Additionally, NSAIDs might be more effectively prescribed going forward, with NRF2-activating NSAIDs and non-NRF2-activating NSAIDs applied to the diseases they’re most likely to treat.
This study’s finding may also help point to an entirely new direction for NSAIDs, noted Eisenstein.
The researchers noted that NRF2 controls a large number of genes involved with a wide array of bodily processes. These include everything from metabolism to immune response, along with inflammation.
“NRF2 does so much suggests that NSAIDs might have other effects, whether beneficial or adverse, that we haven’t yet looked for,” said Eisenstein.
For now, should you have any questions about what NSAID you should be taking, it’s important to talk with your doctor before making any major changes to your medications. Studies such as these may provide preliminary information on the use of NSAIDs, but until they are confirmed it’s important to take them with a grain of salt. While other previous studies have pointed toward the potential negative effects of commonly used NSAIDs, for now, you should continue to follow your doctor’s recommendations.
Have You Heard of these Unexpected Effects of Common NSAIDs?
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I’ve been on NSAIDS since my 30s for osteoarthritis and am now 69. Recently had endoscopy and the found an ulcer which was treated. Now I feel like I’m at a crossroads trying to figure out what to do next as I’m thinking it’s time to get off them.
For too many years I was on 1500mg Naproxen and 4,000mg of Tylenol daily. Every single day without touching my pain. As not to Swiss cheese my liver, I was put on opioids. Problem solved. The NSAID side effects are countless and although we are all different, my asthma was far worse. Dunno- like everything, what is good for one, is horrible for another..
@eclecticzebra so frustrating isn’t it?
Another interesting point that I found happened to me – and has been demonstrated in medical literature – is the time effect of NSAIDs. Over time we build up resistance to a mechanism of action, so sometimes you just have to change medications after a while.
Well, that explains a lot. :(