New Research May Explain Unexpected Effects of Common Painkillers Including Ibuprofen and Aspirin

Non-steroidal anti-inflammatory medications (NSAIDs), such as ibuprofen and aspirin, are routinely used to relieve pain and inflammation. Different NSAIDs can have unexpected and unexplained impacts on numerous conditions, including heart disease and cancer, even at equal dosages.

A new Yale University-led study has discovered a previously unknown mechanism through which various NSAIDs influence the body. The discovery might explain why comparable NSAIDs create such a wide variety of clinical outcomes, and it could have implications for how the medications are used in the future.

NSAIDs' anti-inflammatory effects were previously assumed to be primarily due to the blockage of certain enzymes. This mechanism, however, does not explain for many clinical outcomes that differ among medication families. For example, some NSAIDs protect cardiac disease while others cause it; certain NSAIDs have been associated to a lower risk of colorectal cancer; and different NSAIDs can have a variety of asthmatic effects.

Yale researchers have discovered a different method through which a subset of NSAIDs decrease inflammation using cell cultures and animals. This process might explain some of the strange consequences.

Only some NSAIDs, such as indomethacin, which is used to treat arthritis and gout, and ibuprofen, were shown to activate a protein called nuclear factor erythroid 2-related factor 2, or NRF2, which, among its many functions, stimulates anti-inflammatory processes in the body, according to the study.

“It’s interesting and exciting that NSAIDs have a different mode of action than what was known previously,” said Anna Eisenstein, a Yale School of Medicine teacher and the study's primary author. “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 stated.

Eisenstein is currently investigating if NRF2 is involved in some of the medications dermatological effects, such as producing rashes, aggravating hives, and increasing allergies.

The researchers point out that this discovery has to be validated in people. However, if this is the case, the findings may have implications for how inflammation is managed and how NSAIDs are administered.

Several clinical trials, for example, are exploring whether NRF2-activating medications are useful in treating inflammatory disorders such as Alzheimer's disease, asthma, and different malignancies; this research might help determine the potential and limitations of those treatments. Furthermore, NSAIDs may be prescribed more successfully in the future, with NRF2-activating and non-NRF2-activating NSAIDs used to treat the disorders they're most likely to treat.

According to Eisenstein, the discoveries might lead to whole new uses for NSAIDs.

NRF2 is a transcription factor that regulates a vast number of genes involved in a variety of functions, including metabolism, immunological response, and inflammation. The protein has also been linked to cellular stress reduction, lifespan, and aging.

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