NSAIDs

Core

Introduction

NSAIDs are taken by around 10% of the UK population in any given year and are amongst the most useful and the most dangerous drugs in routine prescribing. The pharmacology is conceptually simple; one enzyme target, one signalling pathway, but the consequences of inhibiting that pathway in different tissues explain both the benefits and the side effects.

The closely related drug paracetamol is included in this article because it is the standard non-opioid analgesic alternative, with a strikingly different side-effect profile. Opioid analgesia is covered in Opioids.

The Arachidonic Acid Pathway

Arachidonic acid is a polyunsaturated fatty acid stored in cell membrane phospholipids. When the cell is stimulated; by injury, inflammation, hypoxia, or hormonal triggers; phospholipase A₂ releases arachidonic acid into the cytoplasm, where it can take one of two routes:

• Cyclo-oxygenase (COX) pathway → prostanoids (prostaglandins, prostacyclin, thromboxane).
• Lipoxygenase pathway → leukotrienes.

The prostanoids and leukotrienes act locally as signalling molecules at G-protein coupled receptors. They are produced on demand and have a short half-life, allowing fine-grained control of inflammation, pain, fever, gastric protection, renal blood flow, and platelet aggregation.

Diagram: The arachidonic acid pathway and the points blocked by each drug class.

COX-1 and COX-2

There are two functional cyclo-oxygenase isoforms. Their distribution explains why NSAIDs cause the side-effect profile they do.

• COX-1: constitutively expressed in most tissues, including gastric mucosa (where it produces protective prostaglandins), kidneys (renal blood flow), and platelets (thromboxane A₂). Its products are mainly housekeeping.
• COX-2: mainly inducible, expressed at sites of inflammation. Constitutive expression is limited to the kidney, vascular endothelium and parts of the central nervous system.

Most of the analgesic and anti-inflammatory benefit of NSAIDs comes from COX-2 inhibition; most of the GI side effects come from COX-1 inhibition. This was the hypothesis that led to the development of selective COX-2 inhibitors in the late 1990s.

Mechanism of NSAID Action

All NSAIDs compete with arachidonic acid for the active site of cyclo-oxygenase, reducing the production of prostanoids. Most are reversible competitive inhibitors. Aspirin is the exception: it covalently acetylates a serine residue in the COX active site, irreversibly inactivating the enzyme.

The consequences depend on which prostanoids are reduced:

• Reduced PGE₂ and PGI₂ at sites of injury → less pain, less inflammation, less fever (when COX-2 in the hypothalamus is involved).
• Reduced thromboxane A₂ in platelets → reduced platelet aggregation. (See Antiplatelets, Anticoagulants and Thrombolysis.)
• Reduced protective prostaglandins in gastric mucosa → ulceration.
• Reduced renal prostaglandins → reduced GFR, salt and water retention.

The Four Actions of NSAIDs

A useful framework: NSAIDs share three core actions, plus an antiplatelet effect that is clinically meaningful only with aspirin.

• Analgesic: effective against musculoskeletal, dental and inflammatory pain. Less effective against visceral and neuropathic pain. Acts both peripherally (at the site of injury) and centrally (in the dorsal horn).
• Anti-inflammatory: reduces vasodilation and oedema, providing symptomatic relief in arthritis, soft-tissue injury and dysmenorrhoea.
• Antipyretic: reduces fever by blocking COX-2 in the hypothalamus, where pyrogenic cytokines normally trigger prostaglandin-mediated rise in temperature.
• Antiplatelet: aspirin alone has clinically useful, irreversible antiplatelet activity (covered in Antiplatelets, Anticoagulants and Thrombolysis). Other non-selective NSAIDs cause only a transient, reversible reduction in TXA₂ that is not used therapeutically. COX-2 selective inhibitors lack any antiplatelet effect.

The NSAID Drugs

Non-Selective NSAIDs

The drugs commonly prescribed in the UK:

• Ibuprofen: the over-the-counter standard. Lowest GI risk among non-selective NSAIDs at standard doses. Short half-life (~2 hours).
• Naproxen: a longer-acting agent (half-life ~14 hours). Considered the safest option for cardiovascular risk among non-selective NSAIDs and is often the BNF preferred choice when an NSAID is needed.
• Diclofenac: effective analgesic and anti-inflammatory but the cardiovascular risk profile is similar to that of selective COX-2 inhibitors. Now subject to MHRA cautions and contraindicated in established cardiovascular disease.
• Indomethacin: a powerful NSAID used in acute gout, ankylosing spondylitis, and traditionally to close patent ductus arteriosus in neonates.
• Mefenamic acid: used in dysmenorrhoea and menorrhagia.
• Ketorolac: potent injectable NSAID, sometimes used for renal colic and post-operative pain.

Selective COX-2 Inhibitors (Coxibs)

Celecoxib and etoricoxib are the COX-2 selective drugs available in the UK. Compared with non-selective NSAIDs they cause:

• Fewer GI side effects: less peptic ulceration and bleeding (the original rationale for the drug class).
• Similar renal side effects.
• Increased cardiovascular risk: selective inhibition of vascular COX-2 reduces prostacyclin (PGI₂, vasodilatory and antiplatelet) without affecting platelet TXA₂, tipping the balance toward thrombosis. Rofecoxib was withdrawn worldwide in 2004 because of excess MI events.

NICE restricts coxibs to patients with high GI risk and low cardiovascular risk who specifically need an NSAID, with co-prescribed PPI gastroprotection.

Aspirin

Aspirin deserves separate mention because it bridges the analgesic, anti-inflammatory and antiplatelet uses:

• At analgesic doses (300-900 mg) it is a non-selective NSAID with the typical action profile.
• At antiplatelet doses (75 mg daily) it predominantly inhibits platelet COX-1 with relatively spared endothelial COX-2, producing the cardiovascular benefit covered in Antiplatelets, Anticoagulants and Thrombolysis.
• At high doses aspirin metabolism becomes saturated and follows zero-order kinetics, the basis of salicylate overdose toxicity.
• Aspirin is contraindicated in children under 16: the UK BNF advises avoiding aspirin in any child under 16 unless specifically indicated (e.g. in Kawasaki disease or under specialist supervision), because of the risk of Reye's syndrome (acute encephalopathy and hepatic failure).

Adverse Effects

Gastrointestinal

By far the most important. The mechanism is reduced prostaglandin-mediated mucosal protection: less mucus and bicarbonate, increased acid secretion, reduced mucosal blood flow, increased mucosal hydrophobicity. NSAIDs increase the risk of peptic ulceration approximately fourfold and contribute to around 2,000 UK deaths a year from upper GI haemorrhage.

Risk factors:

• Older age (especially over 65).
• Prolonged use.
• Concurrent corticosteroids, anticoagulants, or another antiplatelet.
• Smoking, heavy alcohol.
• Past peptic ulcer disease.
• Helicobacter pylori infection.

For patients in whom an NSAID is unavoidable but GI risk is high, co-prescribed PPI is the standard mitigation, and a COX-2 selective drug may be preferred.

Renal

NSAIDs cause:

• Reversible reduction in GFR, particularly in patients dependent on prostaglandin-mediated afferent arteriolar dilation (CKD, heart failure, cirrhosis with ascites, hypovolaemia).
• Salt and water retention → worsening hypertension, oedema and heart failure.
• Hyperkalaemia: via reduced renin secretion.
• Acute interstitial nephritis: rare but well-described.
• Chronic high-dose use (especially historically with phenacetin): analgesic nephropathy.

The combination of NSAID + ACE inhibitor + diuretic in a hypovolaemic patient ("the triple whammy") is one of the most common preventable causes of AKI in UK practice.

Cardiovascular

All NSAIDs (with the partial exception of low-dose aspirin) increase the risk of MI, stroke, hypertension and heart failure to varying degrees. The risk is dose- and duration-dependent and highest with diclofenac and the coxibs. Naproxen appears to have the lowest cardiovascular risk among non-selective NSAIDs, which is one reason it is often the BNF preferred choice.

NSAIDs also reduce the antihypertensive effect of most blood-pressure-lowering drugs.

Asthma, Allergy and Other

• NSAID-exacerbated respiratory disease ("aspirin-sensitive asthma"): bronchospasm in around 10% of adult asthmatics, mediated by shunting of arachidonic acid down the leukotriene pathway when COX is blocked. Caution with all NSAIDs in this group.
• True hypersensitivity reactions: urticaria, angio-oedema, anaphylaxis. Cross-reactivity between NSAIDs is common.
• Pregnancy: per MHRA guidance, systemic NSAIDs are contraindicated from 28 weeks (third trimester), and should be avoided from 20 weeks unless clinically necessary, because of the risk of premature closure of the ductus arteriosus, oligohydramnios, and fetal renal impairment.
• Hepatotoxicity (rare).
• Headache and dizziness with indomethacin.

Drug Interactions

Most clinically important NSAID interactions involve other drugs that are highly protein bound or that depend on prostaglandin signalling:

• Anticoagulants and antiplatelets: additive bleeding risk.
• Corticosteroids: markedly increased GI bleeding.
• Sulphonylureas: potentiation, increasing risk of hypoglycaemia.
• Methotrexate: reduced renal clearance, accumulation, marrow suppression. Particular caution at high methotrexate doses.
• Lithium: reduced renal clearance, elevated lithium levels.
• Antihypertensives: reduced efficacy of ACE inhibitors, diuretics, beta-blockers.
• Aspirin: ibuprofen taken close to aspirin can compete for COX-1 binding and reduce the antiplatelet effect; the BNF advises spacing the doses.

Paracetamol

Mechanism

Paracetamol (acetaminophen) is an analgesic and antipyretic with negligible anti-inflammatory action. The mechanism is incompletely understood; the leading hypotheses are inhibition of a CNS-specific COX isoform (sometimes called COX-3) and modulation of endocannabinoid and serotonergic descending pain pathways.

What matters at pre-clinical level is the practical profile:

• Effective analgesic for mild-moderate pain and fever.
• No anti-inflammatory action at usual doses.
• No GI, renal or platelet effects at therapeutic doses: a major safety advantage over NSAIDs.
• Safe in pregnancy and breastfeeding (the analgesic of choice).
• Standard adult dose 1 g four times daily; reduce in patients under 50 kg or with significant hepatic risk factors.

Paracetamol Overdose

Paracetamol is the leading cause of acute liver failure in the UK. Around 10-15 g (20-30 standard tablets) can be fatal in an adult of average size; less in patients with depleted glutathione (chronic alcohol use, malnutrition, liver disease).

The toxicity stems from a minor metabolic by-product:

1. At therapeutic doses, paracetamol is conjugated with glucuronic acid and sulphate (Phase II) and excreted.
2. A small fraction is oxidised by CYP2E1 to NAPQI (N-acetyl-p-benzoquinone imine): a highly reactive intermediate.
3. NAPQI is normally inactivated by conjugation with hepatic glutathione.
4. In overdose, glutathione is depleted; NAPQI accumulates, oxidises critical thiol groups, and causes hepatocyte necrosis (centrilobular).

Clinical course of overdose:

• 0-24 hours: often asymptomatic, occasionally nausea, vomiting and abdominal discomfort.
• 24-48 hours: right upper quadrant pain, rising AST/ALT, prothrombin time (the most useful early indicator of severity).
• 3-4 days: peak hepatic damage; jaundice, coagulopathy, encephalopathy in severe cases.
• 4-14 days: recovery or progression to acute liver failure.

Antidote: N-acetylcysteine (NAC, Parvolex). NAC is a thiol donor that replenishes glutathione and detoxifies NAPQI. Most effective if started within 8 hours of ingestion, but is given even late if liver injury has developed. Treatment is guided by a 4-hour paracetamol level plotted on the treatment nomogram; current UK practice (since 2012) is to use a single treatment line at 100 mg/L at 4 hours.

Mnemonic for time course:

Paracetamol overdose: rule of 24s
Day 1 (0-24 h): asymptomatic / mild GI
Day 2 (24-48 h): rising LFTs, right upper quadrant pain
Days 3-4: peak hepatic damage
Beyond day 4: recovery or acute liver failure

Summary

• NSAIDs inhibit cyclo-oxygenase (COX-1 and COX-2), reducing prostanoid synthesis from arachidonic acid.
• The four actions of NSAIDs: analgesic, anti-inflammatory, antipyretic, antiplatelet.
• COX-1 is constitutive (gastric, renal, platelet); COX-2 is mainly inducible (inflammation). COX-2 selective drugs (celecoxib) reduce GI side effects but increase CV risk.
• Major NSAID side effects: GI ulceration and bleeding; reduced GFR; salt and water retention with worsening hypertension and heart failure; bronchospasm in aspirin-sensitive asthma.
• The triple whammy of NSAID + ACE inhibitor + diuretic in a dehydrated patient is a recurring cause of AKI.
• Aspirin is irreversible (acetylates COX-1); avoid in children under 16 (Reye's syndrome).
• Naproxen has the most favourable CV profile among non-selective NSAIDs.
• Paracetamol is not an NSAID. Effective analgesic and antipyretic; no anti-inflammatory action; safe in pregnancy. Overdose causes hepatic necrosis through accumulation of NAPQI; antidote is N-acetylcysteine.

Drug Summary Table

Reviewed by: Dr. Marcus Judge

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