22.5 — Painkillers

Paracetamol is on sale in every supermarket in the world, and it is the leading cause of acute liver failure in the UK and the US.

Not because it is a dangerous drug. Taken correctly it is one of the safest medicines that exists. Because the gap between the maximum safe dose and a harmful dose is narrower than almost anyone realises — around 4 grams a day is the limit, and serious liver damage can begin at doses not far above it.

This chapter is mostly about margins like that one.

Paracetamol

Known as acetaminophen in the US and Japan. Same molecule.

How it works is still not fully settled, which is remarkable for a drug in use since the 1950s. The best current understanding involves inhibition of prostaglandin production in the brain and spinal cord rather than in the tissues, plus effects on the body's own cannabinoid and serotonin pain systems.

Which explains its profile: it relieves pain and reduces fever, and it has essentially no anti-inflammatory effect in tissues — unlike the NSAIDs, whose action is peripheral.

Adult dose: 500 mg to 1 g, up to four times a day, with at least 4 hours between doses. Maximum 4 g in 24 hours.

And lower in specific situations: under 50 kg body weight, chronic malnutrition, regular alcohol use, or liver disease. Many guidelines use 3 g daily as the maximum in those groups.

Children are dosed by weight, never by age alone beyond the rough guides on the packet.

Why the overdose is so dangerous

And the mechanism is worth understanding, because it explains the treatment.

Most paracetamol is metabolised harmlessly. A small fraction is converted by liver enzymes into a toxic product called NAPQI.

Normally, glutathione — the liver's own detoxifying molecule — neutralises NAPQI immediately.

In overdose, glutathione runs out. The remaining NAPQI binds to liver cells and destroys them.

Which produces the most dangerous feature of paracetamol poisoning: for the first 24 hours, the person usually feels fine. Nausea at most.

Liver failure appears at 2 to 4 days, by which point treatment is far less effective and a transplant may be the only option.

So: someone who has taken an overdose and feels well is not reassuring. They are inside the silent window.

Treatment is acetylcysteine, which replenishes glutathione. It is close to completely effective if started within 8 hours, and progressively less effective after that — which is why paracetamol overdose is a go-to-hospital-now situation regardless of how the person feels (Chapter 23.6).

And the same logic covers staggered overdose — repeated doses slightly above the maximum over days, which is a common pattern in someone treating pain and is treated equally seriously.

The duplication trap

The commonest route to accidental overdose is taking two products that both contain paracetamol.

It is in a very large number of combination products: cold and flu remedies, "night-time" preparations, co-codamol and other combination painkillers, and many branded pain products.

Someone with flu taking a hot lemon drink, a cold and flu tablet and two paracetamol can exceed the daily maximum without taking anything they think of as an overdose.

Rule: read the ingredients of every product you take, and count total paracetamol from all sources.

NSAIDs

Ibuprofen, naproxen, diclofenac, aspirin, and the rest.

They block COX enzymes, which make prostaglandins — signalling molecules that sensitise nerve endings to pain, produce inflammation, and cause fever.

So NSAIDs relieve pain, reduce inflammation and lower temperature. And they are genuinely better than paracetamol for pain with an inflammatory component — injuries, joint pain, period pain, dental pain, gout.

But prostaglandins do other jobs, and blocking them everywhere is where the harm comes from.

Two COX enzymes:

COX-1 — present all the time, producing prostaglandins that protect the stomach lining, support kidney blood flow, and enable platelets to clump.

COX-2 — induced at sites of inflammation.

Which means the ideal drug would block COX-2 and leave COX-1 alone, and that is exactly what the coxibs were designed to do. They caused fewer ulcers — and it turned out they increased cardiovascular risk, because COX-2 also produces a prostaglandin that keeps blood vessels relaxed and platelets from aggregating. Rofecoxib was withdrawn. The lesson, which recurs throughout pharmacology, is that a pathway is rarely doing only the thing you noticed.

The four harms worth knowing

Stomach and gut. Ulcers and bleeding, because the protective prostaglandins are gone (Chapter 21.2). Risk rises with age, with higher doses, with longer use, with steroids, with anticoagulants and with previous ulcers. A proton pump inhibitor is added for people at risk.

And the ulcer can occur without warning pain, because the same drug is suppressing the pain signal.

Kidneys. Prostaglandins keep the small arteries feeding the kidney's filters open. Block them in someone dehydrated, elderly, or in heart failure and kidney function can fall sharply (Chapter 21.3).

The dangerous combination has a name in clinical practice — an NSAID plus an ACE inhibitor or ARB plus a diuretic — because together they remove three separate protections at once. It is a very common route into acute kidney injury.

Heart. All NSAIDs except low-dose aspirin carry some increase in cardiovascular risk with regular use. Naproxen appears among the lowest, diclofenac among the highest. It is modest for occasional use and real for long-term use.

Asthma. Around 10 percent of adults with asthma get bronchospasm from NSAIDs, sometimes severe. Anyone with asthma trying an NSAID for the first time should know this.

Also: raised blood pressure, fluid retention, and interference with some blood pressure drugs.

Ibuprofen: 200 to 400 mg up to three times daily over the counter; maximum 1200 mg daily without medical advice, and up to 2400 mg under supervision. Always with or after food.

Topical NSAIDs are underrated — gels for knee, hand and soft tissue pain deliver useful local relief with very little systemic absorption, which removes most of the risks above. For localised joint pain in an older person, this is frequently the right answer.

Aspirin

An NSAID with a distinct role, because it blocks COX-1 in platelets irreversibly.

Platelets have no nucleus, so they cannot make new enzyme (Chapter 7.1). One low dose of aspirin disables a platelet for its entire 7 to 10 day life.

Which is why 75 mg once daily is enough for an antiplatelet effect, and why the effect persists for days after stopping.

Used for secondary prevention — after a heart attack or stroke, where the benefit clearly outweighs the bleeding risk (Chapter 18.3).

And largely abandoned for primary prevention in healthy people, because trials found the bleeding risk cancels out the cardiovascular benefit in those without established disease.

Aspirin is not given to children under 16 because of Reye's syndrome — a rare but severe brain and liver injury — except in specific conditions such as Kawasaki disease under specialist care.

Opioids

Codeine, tramadol, morphine, oxycodone, fentanyl, buprenorphine, methadone.

They bind opioid receptors in the brain and spinal cord, the same receptors used by the body's own endorphins, reducing the transmission of pain signals and changing the emotional response to pain.

They are excellent for severe acute pain — after surgery, after major injury — and for cancer pain.

And they perform poorly for chronic non-cancer pain, which is the finding that reversed twenty years of practice. Long-term trials show modest pain benefit, no functional improvement, and substantial harm.

Side effects:

Constipation, which is universal and does not improve with time. Every person on regular opioids needs a laxative from day one, and this is one of the most consistently forgotten prescriptions in medicine.

Nausea and drowsiness, which usually settle over days.

Respiratory depression — the one that kills. Opioids suppress the brainstem's drive to breathe (Chapter 11.7). Risk rises with dose, with alcohol, with benzodiazepines, and in sleep apnoea.

Tolerance and dependence.

Opioid-induced hyperalgesia — long-term high-dose use can increase pain sensitivity, so more drug produces more pain. Counter-intuitive, real, and a reason for reduction rather than escalation.

Codeine is a prodrug that becomes morphine via CYP2D6 (Chapter 22.1). Which is why it does nothing for some people, too much for others, is not given to children after tonsil surgery, and is avoided in breastfeeding.

Tramadol also acts on serotonin and noradrenaline pathways, which brings a seizure risk and a serotonin syndrome risk when combined with antidepressants (Chapter 22.13).

And naloxone reverses opioid overdose within minutes, which every household with opioids in it should know about (Chapter 23.6).

The drugs for nerve pain

And they are here because ordinary painkillers do not work for it (Chapter 11.13).

Nerve pain — burning, shooting, electric, with numbness or tingling — comes from damaged nerves signalling incorrectly rather than from tissue damage. So there is no inflammation to block and no ordinary pain pathway to dampen.

Gabapentin and pregabalin — reducing abnormal nerve signalling. Titrated up slowly. Both cause drowsiness and dizziness, both need dose reduction in kidney disease, and both have recognised misuse potential, which was under-appreciated for years.

Amitriptyline — at low doses, far below antidepressant doses, working on descending pain-modulating pathways. Taken at night because it is sedating.

Duloxetine — with particularly good evidence in diabetic neuropathy.

Capsaicin cream and lidocaine patches for localised areas.

And realistic expectations again: a 30 to 50 percent reduction is a good result.

The other useful ones

Triptans for migraine (Chapter 20.1).

Muscle relaxants — modest evidence, sedating.

Steroids for pain from inflammation or from pressure on a nerve.

Local anaesthetics — blocking sodium channels so nerves cannot transmit at all (Chapter 11.1).

And non-drug approaches, which are not a consolation prize: exercise, heat and cold, physiotherapy, and psychological approaches for chronic pain, all of which have real evidence — particularly for pain that has lasted beyond healing time, where the nervous system rather than the tissue is the problem.

How to use painkillers well

Match the drug to the pain. Inflammatory pain responds to NSAIDs. Nerve pain responds to nerve pain drugs. Ordinary pain and fever respond to paracetamol. Using the wrong category is why people conclude nothing works.

Combining paracetamol and an NSAID works better than either alone, and they are safe together because the mechanisms are different.

Take regularly rather than waiting for pain to build, for pain that is constant. Getting on top of pain takes less drug than chasing it.

Use the lowest effective dose for the shortest time, particularly for NSAIDs.

Count your paracetamol from all sources.

Watch the days per month, because frequent painkiller use for headache causes medication overuse headache (Chapter 20.1).

And take NSAIDs with food, avoid them if you have kidney disease, heart failure or an ulcer history, and think twice if you are also on an ACE inhibitor and a diuretic.

What the next page fixes

Chapter 22.6 covers antibiotics — how they kill bacteria, why resistance is the problem it is, and why finishing the course turned out to be more complicated advice than anyone expected.