Acetaminophen messes with the immune and nervous systems to relieve pain and fever — here’s how.
(Image credit: Grace Cary via Getty Images)
Whether you’re contending with a headache, fever or sore throat, you might reach for an over-the-counter painkiller like acetaminophen to find relief. Also known as paracetamol and Tylenol, this drug is a medicine-cabinet staple — but have you ever wondered how it works?
If so, you’re in good company. Although Tylenol has been available over the counter for more than 60 years, scientists still aren’t completely sure how the drug controls pain. Nonetheless, they have found that it works by blocking a specific class of enzymes, called cyclooxygenase (COX) enzymes, in some fashion.
These COX enzymes normally spew signaling molecules called prostaglandins that worsen pain, fever and inflammation, such as that triggered by tissue damage or infection. So by blocking them, acetaminophen increases the body’s pain threshold and limits fever.
However, “most agree that paracetamol does not have any significant anti-inflammatory action,” Dr. Laurie Prescott, a clinical pharmacologist at the University of Edinburgh in the U.K., told Live Science in an email. This makes it less suitable than other painkillers, such as ibuprofen (Advil or Motrin), for treating inflammatory conditions, such as osteoarthritis.
Related: What happens in your body during a fever?
The reason acetaminophen doesn’t snuff out inflammation might be related to how it messes with COX enzymes. Instead of directly targeting the source of pain, it blocks pain signals from reaching the brain.
In pain-control centers of the brain and spinal cord — the central nervous system (CNS) — the drug lowers prostaglandin levels produced by COX enzymes to dampen the pain signal being sent to the brain from the affected site.
When mice and rats take acetaminophen, prostaglandin levels in the CNS drop; this led researchers to wonder if the drug directly inhibits COX enzymes. But lab-dish studies that probed acetaminophen’s interactions found that it only weakly inhibits the enzymes, suggesting additional factors drive down prostaglandin levels.
For example, acetaminophen might indirectly block COX activity by competing with the enzymes for hydroperoxides, molecules the enzymes need to make prostaglandins. Acetaminophen readily latches onto hydroperoxides and can sequester them away.
At sites of inflammation where hydroperoxides are plentiful, acetaminophen might be less able to deprive COX enzymes of the substances. But in the CNS, where hydroperoxides are scarce, COX enzymes might be more vulnerable to the drug. This hypothesis could explain why acetaminophen primarily works in CNS neurons; however, it has only been tested in test tubes, where the hydroperoxide concentrations used may not reflect those in the body.
There may be additional ways Tylenol blocks pain, besides its effects on COX enzymes. Inside the body, acetaminophen is broken down in the liver and brain to produce a second painkiller, called AM404. Researchers have suggested that AM404 might control pain by activating the endocannabinoid system — receptors and signaling molecules in the nervous system that regulate pain. Indeed, when researchers gave rats a drug that blocks the endocannabinoid system, they found that acetaminophen’s pain-relieving effects vanished.
As of now, though, these results haven’t been confirmed in humans, so acetaminophen’s workings remain somewhat mysterious.
Prescott discussed why acetaminophen research has lagged behind: “It is not at all difficult to study this drug, but there are other much more exciting things for investigators to study,” he said. Because acetaminophen is an old, familiar painkiller, scientists are less inclined to study its mechanism of action in lieu of investigating drugs whose safety and efficacy remain unclear, he explained.
Despite its mystery, we know the drug to be very safe when used properly — but consumers should be wary of taking too much, because it gets converted into a liver-damaging toxin at too-high doses, Prescott said.
This article is for informational purposes only and is not meant to offer medical advice.
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Kamal Nahas is a freelance contributor based in Oxford, U.K. His work has appeared in New Scientist, Science and The Scientist, among other outlets, and he mainly covers research on evolution, health and technology. He holds a PhD in pathology from the University of Cambridge and a master’s degree in immunology from the University of Oxford. He currently works as a microscopist at the Diamond Light Source, the U.K.’s synchrotron. When he’s not writing, you can find him hunting for fossils on the Jurassic Coast.
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