We May Finally Understand How This Painkiller That Nearly Everyone Has Taken Actually Works

Almost everybody has reached for paracetamol at one time or another. Otherwise known as acetaminophen, and often just by brand names like Tylenol® or Panadol®, the drug is a staple of household medicine cabinets, used for everything from headaches to fevers to period pain. It’s so common, in fact, that it will probably surprise you to learn that we don’t fully understand how it actually works, but a new study is changing all that. 

It’s certainly not impossible for drugs to be approved for use without a complete understanding of their mechanism of action. Clinical trials test whether the drug is safe, whether it causes serious side effects, and whether it works more effectively than other treatments that may be out there, but even all the years of research that go into a drug’s development may not be enough to fully get to grips with how its effects are achieved.

Paracetamol has been around for well over 100 years – it was first synthesized in 1878, but its potential took decades to be fully realized. Nowadays, it can be purchased widely as both a standalone drug and as an ingredient in other formulas, like cold and flu medicines. It’s affordable, costing literally pennies to buy over-the-counter in some places, and may be suitable for people who are unable to take other pain relievers like aspirin.

For years, scientists believed that paracetamol only worked by acting directly on the brain and spinal cord, but now a study led by researchers at the Hebrew University of Jerusalem has found that it also works outside the brain – specifically, on the peripheral nerves that first detect pain. 

Recent research has shown that a major factor in paracetamol’s painkilling abilities is the metabolite N-arachidonoylphenolamine (AM404). 

When the drug enters the body, it is first metabolized in the liver to produce 4-aminophenol. This travels via the bloodstream to other organs in the body, including the brain, where it is then converted to AM404 with the help of the enzyme fatty-acid amide hydrolase (FAAH).

What was not fully understood before was exactly how the AM404 that is produced in this process helps to relieve pain. 

Well, it turns out that AM404 is also produced directly in nerve endings. The researchers behind the new study showed how it then shuts off the sodium channels that are needed to transmit pain signals back to the central nervous system, effectively cutting off pain at the source. 

“This is the first time we've shown that AM404 works directly on the nerves outside the brain. It changes our entire understanding of how paracetamol fights pain,” said author Professor Alexander Binshtok in a statement.

As well as helping solve the longstanding puzzle of one of our most commonly used drugs, the findings could help inspire a new generation of medicines. By leveraging AM404’s ability to specifically target pain neurons, it could be possible to develop local anesthetics that avoid common side effects like muscle weakness. 

“If we can develop new drugs based on AM404, we might finally have pain treatments that are highly effective but also safer and more precise,” said co-author Professor Avi Priel.

So next time you reach for that unassuming bottle of pills in your cupboard, remember that it’s taken us nearly 150 years to figure out exactly what it does, and the mystery is not quite solved yet. 

The study is published in PNAS.