The Science Behind Painkillers: How Paracetamol Actually Works

Paracetamol (also known as acetaminophen) is one of the most widely used painkillers in the world. It is taken for headaches, fever, muscle pain, post-surgical discomfort, and is often the first medication recommended for mild to moderate pain. Despite its ubiquity, paracetamol remained something of a scientific mystery for decades. Unlike aspirin or ibuprofen, its mechanism of action is subtle, complex, and still not completely resolved.

This makes paracetamol an unusually interesting drug: simple in appearance, yet sophisticated in how it interacts with the body.

Pain and Prostaglandins

To understand how paracetamol works, it is first necessary to understand how pain is generated. When tissue is damaged or inflamed, the body produces chemical messengers called prostaglandins. These molecules sensitise nerve endings, making them more responsive to pain signals. They also act on the hypothalamus in the brain to raise body temperature, causing fever.

Most painkillers work by interfering with prostaglandin production. Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and aspirin, block an enzyme called cyclooxygenase (COX). This reduces inflammation, pain, and fever, but also explains why NSAIDs can irritate the stomach and increase bleeding risk: prostaglandins also protect the stomach lining and regulate blood clotting.

Paracetamol behaves differently.

Why Paracetamol Is Not an Anti-Inflammatory

Paracetamol reduces pain and fever effectively, but it has very weak anti-inflammatory effects. This is because it does not significantly block COX enzymes in inflamed tissues. Instead, its action is largely central, meaning it works mainly in the brain and spinal cord rather than at the site of injury.

This distinction is crucial. It explains why paracetamol is gentler on the stomach than NSAIDs, why it does not reduce swelling effectively, and why it is often recommended for children, elderly patients, and those with gastrointestinal conditions.

Action in the Brain

In the central nervous system, paracetamol inhibits a variant of the COX enzyme involved in producing prostaglandins that amplify pain signals. By reducing prostaglandin synthesis in the brain, paracetamol raises the pain threshold, meaning painful stimuli feel less intense.

Paracetamol also acts on the hypothalamus, the region of the brain responsible for regulating body temperature. By lowering prostaglandin levels there, it helps reset the body’s “thermostat,” reducing fever.

This central mechanism explains why paracetamol is effective even when inflammation is minimal, such as in tension headaches or post-operative pain.

The Role of Serotonin

Research suggests that paracetamol also interacts with the serotonin system, a neurotransmitter pathway involved in mood, pain modulation, and sleep. Paracetamol appears to enhance descending inhibitory pain pathways in the spinal cord, which suppress incoming pain signals before they reach the brain.

In simple terms, paracetamol not only reduces the generation of pain signals but also strengthens the brain’s ability to dampen them.

A Drug With Limits

Although paracetamol is considered safe at recommended doses, it has a narrow safety margin. The liver metabolises paracetamol into several by-products, one of which is toxic. Under normal circumstances, this toxic compound is rapidly neutralised. However, in overdose, or in people with existing liver disease, the detoxification system can be overwhelmed, leading to severe liver damage.

This is why paracetamol overdose is a major cause of acute liver failure worldwide, despite the drug’s everyday reputation as “mild.”

Why Paracetamol Still Matters

Paracetamol’s importance lies not in its power, but in its precision. It provides pain relief without many of the risks associated with stronger analgesics or NSAIDs. Its central action makes it particularly useful when inflammation is not the primary cause of pain, and its relative safety makes it suitable for widespread use when taken correctly.

What makes paracetamol especially fascinating is that a drug used daily by millions still challenges scientists to fully explain its effects. It is a reminder that even the most familiar medicines can have complex and elegant biology beneath the surface.