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Over 100 years after it was first discovered, we are now learning what the mechanism of action is that makes paracetamol such an effective and useful medicine. It now appears paracetamol has a highly targeted action in the brain, blocking an enzyme involved in the transmission of pain.

As with many medicines, the effectiveness of paracetamol was discovered without knowing how it works. Its mode of action was known to be different to other pain relievers, but although it produces pain relief throughout the body the exact mechanism was not clear.

The production of prostaglandins is part of the body's inflammatory response to injury, and inhibition of prostaglandin production around the body by blocking the cyclooxygenase enzymes known as COX-1 and COX-2 has long been known to be the mechanism of action of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen. However, their action in blocking COX-1 is known to be responsible for also causing the unwanted gastrointestinal side effects associated with these drugs.

Paracetamol has no significant action on COX-1 and COX-2, which left its mode of action a mystery but did explain its lack of anti-inflammatory action and also, more importantly, its freedom from gastrointestinal side effects typical of NSAIDs.

Early work (1) had suggested that the fever reducing action of paracetamol was due to activity in the brain while its lack of any clinically useful anti-inflammatory action was consistent with a lack of prostaglandin inhibition peripherally in the body.

Now, recent research (2) has shown the presence of a new, previously unknown cyclooxygenase enzyme COX-3, found in the brain and spinal cord, which is selectively inhibited by paracetamol, and is distinct from the two already known cyclooxygenase enzymes COX-1 and COX-2. It is now believed that this selective inhibition of the enzyme COX-3 in the brain and spinal cord explains the effectiveness of paracetamol in relieving pain and reducing fever without having unwanted gastrointestinal side effects.


1. Flower RJ and Vane JR, 1972, Inhibition of prostaglandin synthetase in brain explains the anti-pyretic activity of paracetamol (4-acetamidophenol), Nature. 240, 410-411.

2. Chandrasekharan NV et. al., 2002, COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression, Proc. Natl. Acad. Sci. USA, 99, 13926-13931.