Recent findings may help explain some of the unexpected side effects of commonly used painkillers

Now, researchers at Yale have found a method that was previously unknown to science that some painkillers used to have an effect on the body. The discovery may help to understand why similar NSAIDs create a diversity of clinical outcomes, and it may also provide insight into how these medications may be used in the future. The study was published on May 23 in the journal Immunity.

It was believed up until recently that the anti-inflammatory effects of NSAIDs came about entirely as a result of the blockage of particular enzymes. However, this mechanism does not account for the vast majority of the clinical outcomes that are variable throughout the medication family.

Risk of heart disease reduced by NSAIDs:

For instance, certain nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of heart disease while others increase it, some NSAIDs have been related to a lower risk of colorectal cancer, and different nonsteroidal anti-inflammatory drugs (NSAIDs) can have a wide variety of effects on asthma.

In the treatment of pain and inflammation, nonsteroidal anti-inflammatory medications (NSAIDs) are frequently employed. NSAIDs include ibuprofen and aspirin. However, even at the same dosage, certain nonsteroidal anti-inflammatory drugs (NSAIDs) can have unexpected and unexplained effects on a variety of conditions, including cancer and heart disease.

Now, using cell cultures and mice, Yale researchers have uncovered a distinct mechanism by which a subset of NSAIDs reduce inflammation. And that mechanism may help explain some of these curious effects.

 

The research showed that only some NSAIDs, such as indomethacin, which is used to treat arthritis and gout, and ibuprofen, also activate a protein called nuclear factor erythroid 2-related factor 2, or NRF2, which, among other things, starts anti-inflammatory processes in the body.

“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.”

 

The research team can’t say for sure that NSAIDs’ unexpected effects are due to NRF2—that will require more research. “But I think these findings are suggestive of that,” Eisenstein said.

Looking into some of the drugs’ dermatological effects

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.

 

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 instance, 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.

 

The findings may also point to entirely new applications for NSAIDs, said Eisenstein.

 

NRF2 controls a large number of genes involved in a wide range of processes, including metabolism, immune response, and inflammation. And the protein has been implicated in aging, longevity, and cellular stress reduction.

Eisenstein says “that NRF2 does so much suggests that NSAIDs might have other effects, whether beneficial or adverse, that we haven’t yet looked for.”

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