Ibuprofen and the NSAIDs

TL;DR. NSAIDs block the enzyme that makes prostaglandins. Prostaglandins cause pain, inflammation, and fever, which is why blocking them works. They also protect your stomach lining, maintain kidney blood flow, and regulate platelets, which is why blocking them causes ulcers, kidney injury, and bleeding. Every risk and every benefit of this drug class comes from that same single action. Ibuprofen at over-the-counter doses for a few days is low risk for most people; the danger is in long-term use, in older people, in dehydration, and in combination with other drugs.

1. What they are

Non-steroidal anti-inflammatory drugs: a large family with the same mechanism and different profiles.

2. How they work

Arachidonic acid, released from cell membranes when tissue is damaged, is converted by cyclooxygenase (COX) into prostaglandins, prostacyclin, and thromboxane. These are local signalling molecules with a wide range of jobs.

NSAIDs inhibit COX. That single action explains everything.

There are two main COX enzymes, and the distinction is the key to the whole class:

So the ideal drug would block COX-2 and leave COX-1 alone. That was the logic behind the coxibs (rofecoxib, celecoxib), and it worked for the stomach: COX-2-selective drugs cause substantially fewer ulcers.

The problem it created is the reason rofecoxib was withdrawn in 2004. Platelet thromboxane (pro-clotting) comes from COX-1; vascular prostacyclin (anti-clotting) comes substantially from COX-2. Blocking COX-2 selectively removes the brake and leaves the accelerator, tilting the balance toward clotting. Rofecoxib increased heart attacks and strokes, and it had been taken by tens of millions of people.

The subsequent understanding is that all NSAIDs except low-dose aspirin carry some cardiovascular risk, with diclofenac and high-dose ibuprofen at the higher end and naproxen at the lower end.

Where each effect comes from:

3. How they are made

Ibuprofen was discovered in the 1960s by Stewart Adams and John Nicholson at Boots in Nottingham, searching for a better anti-inflammatory for rheumatoid arthritis than aspirin. Adams reportedly tested an early dose on his own hangover before giving a speech. It was launched on prescription in 1969 and became available over the counter in 1983.

The original synthesis was six steps; the BHC (Boots-Hoechst-Celanese) green chemistry route developed in the 1990s reduced it to three catalytic steps with roughly 80 percent atom economy and recoverable catalysts. It won a Presidential Green Chemistry Challenge Award and is a textbook case of industrial process improvement.

Formulations: standard tablets (200 and 400 mg OTC, 600 and 800 mg prescription), liquid capsules (faster onset, absorbed in around 20 minutes rather than 45), modified release, oral suspension for children, effervescent (fast but high sodium), topical gels, and intravenous.

Topical NSAIDs deserve their own note, because they are under-used. For localised musculoskeletal pain (knee osteoarthritis, sprains, tendinopathy), topical diclofenac or ibuprofen gel produces meaningful pain relief with systemic absorption of only around 5 to 10 percent of the oral dose. Cochrane reviews support them. For older people and anyone with GI, renal, or cardiovascular risk, a topical NSAID is often the right answer where an oral one is not.

4. Dose, timing, and how to take it

Illustrative adult doses from standard over-the-counter labelling. Follow your product and your clinician.

Ibuprofen (adult, OTC):

• 200 to 400 mg every 4 to 6 hours
• Maximum 1,200 mg in 24 hours over the counter (up to 2,400 mg under medical supervision)
• Take with or after food
• Use the lowest effective dose for the shortest time. This is not boilerplate; the risks are dose- and duration-dependent

Naproxen: 250 to 500 mg twice daily; longer half-life means fewer doses.

Children: ibuprofen 5 to 10 mg/kg per dose, up to 3 to 4 doses in 24 hours, from 3 months of age and over 5 kg. Not for children with dehydration, chickenpox, or significant vomiting or diarrhoea, because of kidney risk and, for chickenpox, a possible association with severe skin infection.

"Take with food" is partly a misconception worth correcting. Food does reduce direct topical irritation, and most NSAID ulcers are caused by the systemic prostaglandin effect, not by the tablet touching the stomach. Food therefore helps somewhat and does not remove the risk. Taking ibuprofen with food is sensible; believing it makes you safe is not.

Onset: 20 to 45 minutes depending on formulation. Half-life about 2 hours, which is why it is dosed frequently.

5. What they do well

Established and genuinely superior to paracetamol for:

• Inflammatory pain: sprains, strains, tendinitis, gout, rheumatoid arthritis, dental pain.
• Period pain (dysmenorrhoea), where the pain is directly prostaglandin-mediated and NSAIDs are the clear first-line treatment. Starting them a day before the period begins works better than waiting.
• Osteoarthritis, where they outperform paracetamol in head-to-head evidence.
• Migraine, where high-dose ibuprofen or aspirin has good evidence.
• Fever, comparably to paracetamol and with slightly longer duration.

Combination with paracetamol works better than either alone for moderate acute pain, because the mechanisms differ. In dental pain, ibuprofen 400 mg plus paracetamol 1,000 mg outperforms most opioid combinations, which is a genuinely useful and under-known fact.

6. Side effects

Common (1 in 100 to 1 in 10): indigestion, nausea, abdominal pain, heartburn, diarrhoea, headache, dizziness.

The four serious ones, all mechanistic:

1. Gastrointestinal. Ulceration, bleeding, and perforation. Risk is dose- and duration-dependent and can occur without warning symptoms: a substantial proportion of NSAID ulcer bleeds present as the first sign. Estimated at roughly 1 to 2 percent per year of regular use, much higher in older people. NSAID-related GI bleeding causes thousands of deaths annually in the UK and US.

Risk factors that stack: age over 65, previous ulcer, H. pylori infection, concurrent steroids, anticoagulants, SSRIs, aspirin, high dose, and long duration. People with several of these who need an NSAID are usually co-prescribed a proton pump inhibitor, which substantially reduces the risk (Chapter 71).

2. Kidney. In a well-hydrated healthy person, prostaglandins are not essential for renal blood flow. When blood flow is already compromised (dehydration, heart failure, cirrhosis, pre-existing kidney disease, older age), prostaglandin-mediated dilation of the afferent arteriole becomes essential, and removing it can precipitate acute kidney injury.

The "triple whammy" is worth knowing by name: an ACE inhibitor or ARB, plus a diuretic, plus an NSAID. Each affects renal perfusion differently, and together they substantially raise the risk of acute kidney injury, particularly during an intercurrent illness with vomiting or diarrhoea. This combination is a recognised cause of avoidable hospital admissions. If you take a blood pressure medicine and a water tablet, do not add ibuprofen without asking.

3. Cardiovascular. Increased risk of heart attack, stroke, and heart failure, roughly 20 to 50 percent relative increase with regular use, higher with diclofenac and high-dose ibuprofen, lower with naproxen. Risk appears within weeks of starting. In absolute terms it is small for a healthy person taking ibuprofen for a few days and meaningful for someone with existing cardiovascular disease taking it long term.

4. Respiratory. Aspirin-exacerbated respiratory disease (AERD) affects around 7 to 10 percent of adults with asthma, more in those with nasal polyps. Blocking COX shunts arachidonic acid into the leukotriene pathway, causing bronchospasm within minutes to hours. It is a pharmacological reaction, not an allergy, and it cross-reacts across all NSAIDs.

Others: fluid retention and raised blood pressure (which is why NSAIDs undermine antihypertensives), rare severe skin reactions, and rare aseptic meningitis.

7. Who should be careful, and who should avoid

Avoid or use only under medical advice if you:

• Have an active or previous peptic ulcer or GI bleed
• Have significant kidney disease
• Have heart failure, or established cardiovascular disease
• Have severe liver disease
• Have aspirin/NSAID-sensitive asthma
• Are pregnant, particularly after 20 weeks and absolutely from 30 weeks (see below)
• Are taking anticoagulants (warfarin, DOACs) or antiplatelets
• Are dehydrated or acutely unwell with vomiting or diarrhoea

Pregnancy. NSAIDs are avoided throughout where possible and contraindicated from around 20 weeks: the FDA warned in 2020 about oligohydramnios (reduced amniotic fluid) from fetal kidney effects after 20 weeks, and from 30 weeks they can cause premature closure of the ductus arteriosus, a fetal blood vessel that must stay open until birth. Paracetamol is the analgesic of choice in pregnancy.

Breastfeeding: ibuprofen is considered compatible; very little enters milk.

Older adults: this is the group where NSAIDs cause the most harm. Reduced kidney function, higher GI risk, more comorbidity, and more concurrent medication. Topical NSAIDs and paracetamol are usually preferred.

8. Interactions

9. Overdose

Less dramatic than paracetamol. Moderate overdose causes nausea, vomiting, abdominal pain, drowsiness, and tinnitus. Large overdoses can cause seizures, metabolic acidosis, kidney failure, and coma. There is no specific antidote; treatment is supportive. It is still a medical emergency and should be treated as one.

10. Brand names and formulations

Ibuprofen: Nurofen, Advil, Motrin, Brufen, Calprofen (children's), plus every supermarket own brand. Nurofen Plus and similar contain codeine as well. Nurofen Express and liquid capsules are the same drug in a faster-absorbed form at a higher price.

Naproxen: Naprosyn, Aleve, Feminax Ultra.

Diclofenac: Voltarol (oral and topical). Oral diclofenac was moved to prescription-only in the UK in 2015 because of its cardiovascular profile; the topical gel remains available.

Topical: Voltarol gel, Ibuleve, Traxam.

11. Myths and confusions

Don't be confused: taking an NSAID with food does not protect you from ulcers. It reduces direct irritation and heartburn. Most NSAID ulcers come from the systemic loss of protective prostaglandins, which happens whatever is in your stomach. The genuine protection, for people at risk, is a proton pump inhibitor.

• "Ibuprofen is stronger than paracetamol." They do different things. Ibuprofen is better for inflammation; paracetamol is safer for many people.
• "You can't take ibuprofen and paracetamol together." You can, and the combination is more effective than either alone.
• "Ibuprofen makes COVID worse." A claim from March 2020 based on a hypothesis, not evidence. Investigated by the EMA, WHO, and MHRA, and not supported.
• "NSAIDs are safe because they are sold in supermarkets." They cause thousands of deaths a year from GI bleeding.
• "If I have no stomach pain, my stomach is fine." A large share of NSAID ulcers bleed without prior symptoms.
• "Topical NSAIDs don't really work." They do, for localised musculoskeletal pain, with a fraction of the systemic exposure.

12. The bottom line

• Every effect of an NSAID, good and bad, comes from blocking cyclooxygenase. The therapeutic effect and the ulcers, kidney injury, and bleeding are the same action in different tissues.
• Short courses at OTC doses are low risk for most healthy adults. The harm concentrates in long-term use, in older people, and in combination with other drugs.
• The triple whammy (ACE inhibitor or ARB + diuretic + NSAID) causes acute kidney injury and is a common avoidable hospital admission.
• Naproxen has the lowest cardiovascular risk and higher GI risk; diclofenac has the highest cardiovascular risk. Ibuprofen at low OTC doses is a reasonable default.
• Combine with paracetamol rather than escalating; the combination beats most opioid alternatives for acute pain.
• Use topical NSAIDs for localised pain, especially if you are older or have any GI, kidney, or heart risk.
• Avoid in pregnancy, and absolutely from 30 weeks.

Sources and notes

Doses, cautions, and interactions follow the British National Formulary and the electronic Medicines Compendium; US figures follow FDA labelling. COX-1 and COX-2 physiology follows Vane's Nobel-winning work and FitzGerald's subsequent prostacyclin-thromboxane balance model, which explains the coxib cardiovascular signal. The rofecoxib withdrawal follows Bresalier et al., NEJM, 2005 (APPROVe), and the FDA record. Comparative cardiovascular risk across NSAIDs follows the Coxib and traditional NSAID Trialists' Collaboration, The Lancet, 2013, and PRECISION (Nissen et al., NEJM, 2016). GI bleeding risk and PPI co-prescription follow NICE guidance and Lanas' epidemiology. NSAID nephrotoxicity and the "triple whammy" with ACE inhibitors or ARBs plus diuretics follows Lapi et al., BMJ, 2013, and NHS patient safety alerts. Aspirin-exacerbated respiratory disease prevalence follows Rajan et al.'s meta-analysis. NSAIDs in pregnancy follow the FDA's 2020 oligohydramnios warning and standard ductus arteriosus guidance. Topical NSAID efficacy follows the Cochrane reviews by Derry et al. The ibuprofen-aspirin antiplatelet interaction follows Catella-Lawson et al., NEJM, 2001, and the FDA advisory. The ibuprofen synthesis and the BHC green chemistry route follow the Presidential Green Chemistry Challenge award documentation. Ibuprofen and COVID-19 was investigated and dismissed by the EMA, WHO, and MHRA in 2020.

Open questions. Whether taking an NSAID with food meaningfully reduces ulcer risk, as opposed to dyspepsia, has not been well tested. Individual variation in cardiovascular susceptibility to NSAIDs is not predictable in practice.

👉 Next: aspirin, which is an NSAID and behaves like nothing else in the class.