How Painkillers Work

Headaches, sprained ankles, toothache, sore throats: pain is one of the most common reasons people reach for medicine. The painkillers in a typical bathroom cabinet work in completely different ways. Some stop the body making molecules that amplify pain; some mimic the body’s own pain-control chemicals; some simply stop nerves from firing. Understanding their chemistry explains why they’re used for different kinds of pain and why each has its own risks.

How pain starts

When tissue is damaged or inflamed, specialised nerve endings called nociceptors detect harmful heat, pressure or chemicals. Damaged cells release substances that trigger or sensitise these nerves, including:

• prostaglandins, lipid messengers made from a fatty acid called arachidonic acid, which make nerve endings more sensitive and cause inflammation, swelling and fever;
• bradykinin, histamine and hydrogen ions (acidity).

The nerve signals travel to the spinal cord and then to the brain, where they’re perceived as pain. The body also has its own pain-control system, using endorphins to dampen signals (see endorphins).

Painkillers (analgesics) interrupt this chain at different points.

NSAIDs: aspirin and ibuprofen

Non-steroidal anti-inflammatory drugs (NSAIDs) include aspirin, ibuprofen and naproxen. They relieve pain, reduce fever and reduce inflammation.

How they work: blocking COX

Prostaglandins are made from arachidonic acid by enzymes called cyclooxygenases (COX). There are two main forms:

• COX-1: always active in many tissues, producing prostaglandins that protect the stomach lining and help platelets clot blood.
• COX-2: switched on mainly at sites of inflammation, producing prostaglandins that cause pain and swelling.

NSAIDs inhibit COX enzymes, so fewer prostaglandins are made (see competitive vs non-competitive inhibition). The result is less pain, less swelling and a lower fever.

Aspirin: an irreversible inhibitor

Aspirin is acetylsalicylic acid, C₉H₈O₄. It’s unusual: it transfers its acetyl group onto a serine amino acid in the active site of COX, permanently blocking it. It’s an irreversible inhibitor.

That has a special consequence for platelets, which have no nucleus and can’t make new COX. A single dose of aspirin blocks their clotting ability for the rest of their lifespan, about a week to ten days. That’s why low-dose aspirin is used to reduce the risk of heart attacks and strokes in some people, and why it increases bleeding risk.

Aspirin has a long history. Willow bark was used against fever and pain for thousands of years; its active compound, salicin, is converted in the body to salicylic acid. Salicylic acid itself works but irritates the stomach badly. In 1897, the chemist Felix Hoffmann at the German company Bayer made a purer, more stable form of acetylsalicylic acid by reacting salicylic acid with ethanoic anhydride, and it was sold as Aspirin from 1899.

Ibuprofen: reversible and chiral

Ibuprofen is a reversible, competitive inhibitor of COX. It’s a chiral molecule, and only the (S)-enantiomer is active against COX. It’s usually sold as a racemic mixture (both forms), but the body converts much of the inactive (R)-form into the active (S)-form.

Side effects

Because they also block COX-1, NSAIDs can reduce the stomach’s protective prostaglandins, causing stomach irritation, ulcers and bleeding, especially with long-term or high-dose use. They can also affect the kidneys. COX-2-selective inhibitors (such as celecoxib) were designed to avoid stomach problems by blocking mainly the inflammatory COX-2, but some were later linked to increased risk of heart problems.

Paracetamol (acetaminophen): the puzzle

Paracetamol, known as acetaminophen in the US, is one of the most widely used medicines in the world. It relieves pain and reduces fever, but has little anti-inflammatory effect and is gentler on the stomach than NSAIDs.

Surprisingly, exactly how it works is still not fully understood, more than a century after it was first made. Current evidence suggests it acts mainly in the brain and spinal cord, possibly by inhibiting COX enzymes there (where conditions allow it to work, unlike in inflamed tissue), and through a metabolite that acts on the endocannabinoid and serotonin systems.

Overdose chemistry

Paracetamol is safe at recommended doses (for adults, typically no more than 4 g a day), but an overdose can cause severe liver damage:

1. Most paracetamol is made harmless in the liver by attaching it to other molecules and excreting it.
2. A small fraction is converted by liver enzymes into a highly reactive molecule, NAPQI.
3. Normally, NAPQI is immediately neutralised by glutathione, a small sulfur-containing peptide that acts as an antioxidant.
4. In an overdose, glutathione is used up, and NAPQI attacks liver proteins, killing liver cells.

The antidote, acetylcysteine, works by helping the liver replenish glutathione. It’s most effective when given early, which is why suspected overdoses need urgent treatment even if the person feels well at first.

Opioids: using the body’s own system

Opioids include morphine, codeine, oxycodone and fentanyl. They’re the most powerful painkillers, used for severe pain after surgery or injury and in cancer care.

They work by binding to opioid receptors, the same receptors the body’s endorphins act on. This:

• reduces the release of pain-signalling neurotransmitters in the spinal cord;
• changes how pain is perceived in the brain.

Chemically, morphine is an alkaloid extracted from the opium poppy. Codeine is morphine with one –OH group converted into an –OCH₃ (methyl ether) group; it’s weaker and is partly converted to morphine in the body. Chemists have made many synthetic opioids, some, like fentanyl, far more potent than morphine.

Risks: opioids cause drowsiness, constipation and, crucially, suppression of breathing, which is the cause of death in overdose. Repeated use leads to tolerance and dependence. Naloxone reverses overdoses by displacing opioids from their receptors.

Local anaesthetics: stopping the signal

Local anaesthetics such as lidocaine (used by dentists) and benzocaine (in throat sprays) don’t affect pain chemistry at all. They block the sodium ion channels in nerve cell membranes. Without sodium ions flowing in, a nerve can’t generate electrical signals, so no pain message leaves the area.

The first local anaesthetic was cocaine, used in eye surgery from 1884. Chemists later developed safer, non-addictive molecules with similar channel-blocking properties. Local anaesthetics are weak bases: they cross the nerve membrane in their neutral form, then become protonated inside the cell to block the channel. They work less well in inflamed, acidic tissue, where more of the drug is already protonated outside the nerve (see pH and pKa).

Comparing common painkillers

Painkiller	Main mechanism	Anti-inflammatory?	Main risks
Aspirin	Irreversible COX inhibition	Yes	Stomach bleeding; not for children (risk of Reye’s syndrome)
Ibuprofen	Reversible COX inhibition	Yes	Stomach irritation; kidney effects
Paracetamol	Mainly central effects (not fully understood)	Little	Liver damage in overdose
Codeine, morphine	Opioid receptor activation	No	Breathing suppression, dependence
Lidocaine	Blocks nerve sodium channels	No	Toxic if too much enters the blood

Key takeaways

• NSAIDs (aspirin, ibuprofen) block COX enzymes, reducing prostaglandins that cause pain, fever and inflammation; aspirin does so irreversibly by acetylating the enzyme.
• Paracetamol acts mainly in the central nervous system; its toxic metabolite NAPQI is neutralised by glutathione, and acetylcysteine treats overdose.
• Opioids activate the same receptors as the body’s endorphins; they’re powerful but carry risks of dependence and breathing suppression.
• Local anaesthetics block sodium channels, stopping nerve signals.
• For the body’s own pain chemistry, see endorphins and neurotransmitters.