Israeli study finds acetaminophen drug works by first blocking pain in nerves
In breakthrough, Hebrew University researchers say painkiller, in use since the 1950s, acts like a local anesthetic; research could lead to better pain management
Reporter at The Times of Israel
For decades, scientists believed that one of the world’s most common painkillers, acetaminophen — also known as paracetamol and sold under brand names including Tylenol and Panadol – relieved discomfort by working only in the brain and spinal cord.
However, Hebrew University scientists say that the painkiller prevents pain signals from reaching the brain by stopping them while they are still at nerve endings.
The study, led by Prof. Alexander Binshtok from the Hebrew University’s Faculty of Medicine and Center for Brain Sciences (ELSC) and Prof. Avi Priel from its School of Pharmacy, centers on a substance called AM404, which the body produces after taking acetaminophen.
The team found that AM404 works because it shuts off specific channels, called sodium channels, that help transmit pain signals. By blocking these channels, AM404 stops the pain message before it even starts.
“This is the first time we’ve shown that AM404 works directly on the nerves outside the brain,” Binshtok told The Times of Israel. “If we can find out the mechanism that can explain pain, then we can target it and treat it successfully.”
The study recently appeared in PNAS, a leading journal of the US National Academy of Sciences.
A go-to painkiller for 75 years
The generic acetaminophen is the basis of one of the most popular over-the-counter drugs for adults and children to help manage pain, including headaches, body pains, and fever.
Binshtok said that he and his wife have six daughters, and “we’ve used Tylenol all the time.”
“I’m a scientist, and I’m asking myself, so how does it work?” he mused. “It’s a very basic drug, so it shouldn’t be very complex, right?”
Joseph von Mering, a German physician, first used acetaminophen clinically in 1893. It began to be used as a commercial drug in the 1950s.
“It has been used for 75 years” without anyone understanding how it works, Binshtok said.
According to the National Health Services of the United Kingdom website, “it seems to work by blocking the chemical messengers in the brain that tell your body that you have pain.”
“The drug is successful, and we don’t understand its mechanism,” said Binshtok.
While Binshtok’s lab deals with pain physiology and pathophysiology, Priel’s lab focuses on the biophysics of brain-directed channels. Their work often focuses on peripheral neurons, the nerve cells located outside the central nervous system.
They examined on a molecular level what happens upon taking acetaminophen, when the body produces AM404.
“What really amazed us is that it works in a way that local anesthetics work,” he said. “It attacks or blocks sodium channels like local anesthetics.”
He explained that when “we go to the dentist, we are injected to not feel pain and the local anesthetics block all the pain, making everything numb.”
But AM404 acted like a “selective anesthesia,” a way to preferentially block the activity of peripheral pain neurons without affecting sensation.
“It is very exciting,” he said.
The scientists plan to continue their work to explore this mechanism to develop new selective therapies to deal with pain.
“We still need to work on the right concentration and deliver it, but theoretically, it was done,” he said. “To our big surprise, we saw that this changes our entire understanding of how acetaminophen fights pain. Actually, everything in the study was very surprising.”
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