A study from Yale University sheds light on several unknown effects of common painkillers like ibuprofen and aspirin on the human body. The study highlights that some NSAID (non-steroidal anti-inflammatory) painkillers activate a protein responsible for anti-inflammatory, anti-oxidative, and detoxification action in body cells.

When the cells or tissues in our body experience an imbalance between oxygen-containing molecules (called free radicals) and antioxidants, they are under oxidative stress. Prolonged oxidative stress can lead to cancer, diabetes, heart diseases, etc. If activated, a protein called NRF2 (nuclear factor erythroid 2-related factor 2) protects the body cells against the damage from oxidative stress and according to the researchers at Yale, some NSAIDs like ibuprofen can also activate NRF2. Explaining this further, Andrew Yang, assistant professor at Yale and one of the authors of the study told ZME Science:

“NRF2 is a transcription factor that orchestrates anti-oxidant and detoxification programs and can be activated in most cells of the body. We found that some NSAIDs engage this transcription, while others don’t. This suggests that some NSAIDs have “extra” actions other than inhibiting COX enzymes, for which they were designed.”

The apparently inexplicable behavior of NSAIDs

According to an estimate, about 30 million Americans take at least one NSAID on any given day. Another report from Harvard University suggests that these pain-relieving drugs are so popular that over 30 billion of them are sold annually. NSAIDs are a big deal, but surprisingly, we don’t understand them all that well.

There are numerous medicines that fall under the umbrella of NSAIDs and each of them acts in our body in its own way. For instance, NSAIDs like ibuprofen and aspirin can reduce the risk of a heart attack but at the same time, some studies indicate that these can increase the chances of cancer-related death and adversely affect the health of pregnant women.  

To get to the bottom of this, the researchers at Yale cultured mice cells and performed a pharmacological analysis of the effects. The analysis revealed a new method that the researchers believe could be useful in uncovering various roles of NSAIDs that are still unknown to us. For example, during their study, the researchers found that certain NSAIDs including common painkillers like ibuprofen and aspirin are involved in the activation of NRF2. These painkillers are commonly used to treat headaches, common cold, muscle pain, arthritis, etc, but this new find suggests their applications could extend well beyond that.

However, the new method is still needed to be tested on humans and for now, the researchers are not 100% sure that many unexplained effects of NSAIDs like ibuprofen and aspirin are caused due to NRF2 activation. According to lead author Anna Eisenstein, these initial findings are only “suggestive” and further research is required to study the interaction between NRF2 and NSAIDs in actual human organisms.

These could change the way painkillers are used

Since painkillers are used by so many people on a regular basis if the study is confirmed in humans, this could have large-scale implications. For example, can these findings affect the way NSAIDs are generally used by patients? When we asked the same question, researcher Andrew Yang replied,

“When If the studies are confirmed in humans, it could potentially affect prescription practices. For example, many NRF2 activating drugs are being developed for specific conditions, and one could imagine that these NRF2 activating NSAIDs could be considered in those diseases. On the flip side, we also demonstrated a cost to activating NRF2, and our studies might suggest that these NSAIDs might want to be avoided in diseases in which NRF2 activation leads to unintentional harm.” 

The researchers also highlight that the new method could reveal several advantages and limitations of NSAIDs in the treatment of inflammatory diseases like asthma, arthritis, cancer, and several other neurogenerative disorders. This would allow doctors to more selectively prescribe NSAIDs during treatment.  

The researchers are now looking forward to studying this effect in more realistic scenarios, which could shed light on how their findings could be useful in the case of modern diseases like allergies and autoimmune disorders. 

The study is published in the journal Immunity.