NSAIDs

Indications

NSAIDs are widely used in the treatment of pain, pyrexia and inflammation. In single doses, paracetamol produces a similar analgesic effect to NSAIDs and is often preferred for the treatment of simple pain due to a better safety profile. For pain relief related to inflammation (e.g. musculoskeletal pain, dysmenorrhoea, and arthritis), NSAIDs are often preferred at therapeutic doses to paracetamol, due to their prolonged analgesic and anti-inflammatory effects. The full analgesic effect is predicted to be reached within 1 week, however anti-inflammatory effect may not be reached for up to 3 weeks. 

Mechanism of Action

NSAIDs inhibit the cyclooxygenase (COX) enzymes, COX-1 and COX-2, which are responsible for the synthesis of prostaglandins via oxidation of arachidonic acid.

Prostaglandin G2 and H2 are initially produced, and then transformed into a range of other prostanoids (prostaglandins and thromboxanes). 

The actions of some of the prostanoids inhibited by NSAIDs are summarised below:

Prostacyclin (inhibited via COX-2 inhibition)

• Vasodilation
• Inhibition of platelet aggregation 

Thromboxane (inhibited via COX-1 inhibition) 

• Platelet aggregation 
• Vascoconstriction 

Prostaglandin E2

• Fever and pain
• Contraction and relaxation of bronchial and gastrointestinal smooth muscle
• Inhibition of gastric acid secretion
• Increases gastric mucus secretion 

COX selectivity

NSAIDs have differing selectivity for COX-1 and COX-2 enzymes, leading to differing effectiveness and safety profiles. NSAIDs that are selective for COX-2 are often referred to as “coxibs”, which often have fewer gastrointestinal side effects.

Created in BioRender. Boucher, M. (2026) https://BioRender.com/oe7e650

Fig 1: Mechanism of action of NSAIDs

Pharmacokinetics

Although NSAIDs share a similar mechanism of action, they differ in their pharmacokinetic properties, which can influence dosing frequency, onset of action, and clinical use. Ibuprofen has a short half-life and typically requires multiple daily doses, whereas naproxen and etoricoxib have longer half-lives, allowing less frequent dosing. 

Diclofenac accumulates in synovial fluid, which may contribute to its effectiveness in inflammatory joint conditions, while celecoxib is primarily metabolised by CYP2C9 and may accumulate in poor metabolisers. Understanding these pharmacokinetic differences can help guide NSAID selection in clinical practice.

Contraindications

Heart failure

NSAIDs can increase blood pressure and salt and water retention, therefore may worsen heart failure. 

• Avoid all NSAIDs in severe heart failure where possible
• Avoid coxibs, diclofenac and high-dose ibuprofen in any degree of heart failure
• In mild – moderate heart failure, ibuprofen up to 1.2g daily or naproxen up to 1g daily are often first line options when an NSAID is indicated.    

Severe renal impairment

• Ideally avoid, but if used then monitoring of renal function is recommended 

Uncontrolled hypertension

• Avoid etoricoxib and high-dose ibuprofen 

Other

• Severe hepatic impairment 
• Active peptic ulcer disease or GI bleeding, history of GI bleeding/perforation related to NSAIDs or if two or more distinct episodes non-related to NSAID use. 
• History of allergy to NSAID 
• Inflammatory bowel disease (IBD) (mefenamic acid and piroxicam) – increase risk of developing or exacerbating IBD
• NSAIDs in the third trimester of pregnancy due to risk of premature closure of the ductus arteriosus, fetal renal dysfunction, prolongation of maternal bleeding time, and inhibition of uterine contractions during labour. This advice does not apply to aspirin which is commonly prescribed in pregnancy to reduce the risk of pre-eclampsia

Cautions

The following cautions should be noted for NSAID use:

• History of peptic ulceration or in those at high risk 
• Asthma/COPD
• Heart failure 
• Coagulation disorders 
• Hypertension 
• Hepatic impairment 
• Elderly
• Caution in pregnancy: prolonged use of NSAIDs between 20-28 weeks gestation (MHRA alert June 2023).
  • Increased risk of fetal growth restriction and cardiac dysfunction 
  • Contraindicated after 28 weeks and see note about aspirin (see contraindication section)

Adverse Effects

Due to the risk of adverse effects, NSAIDs should be used at the lowest dose for the shortest duration possible. 

Gastrointestinal toxicity

NSAIDs increase the risk of gastrointestinal bleeding and toxicity. This is mediated by COX-1 inhibition, therefore is less likely with selective COX-2 inhibitors and low dose ibuprofen. Patients should be advised to take NSAIDs with or after food to reduce dyspeptic symptoms; however, this does not completely prevent gastrointestinal ulceration or bleeding. 

High risk patients for GI toxicity should be considered for gastroprotection, often with a proton pump inhibitor and use of a COX-2 selective NSAID is preferred due to the reduced risk of gastrointestinal toxicity. 

Renal Impairment

Renal impairment can be caused by all NSAIDs, due to vasoconstriction of the afferent arteriole, which supplies blood to the glomerulus. This effect is mediated via NSAID inhibition of the prostaglandins PGE2 and PGI2. 

Created in BioRender. Boucher, M. (2026) https://BioRender.com/jczica4

Fig 2: The effect of NSAIDs on the kidneys: constriction of the afferent arteriole reduces renal blood flow and cause cause acute kidney injury

Cardiovascular Risk

There is a slightly increased risk of cardiovascular adverse events such as stroke and heart attack with selective COX-2 inhibitors due to suppression of prostacyclin, increasing thrombosis risk. This effect has also been observed with high dose ibuprofen and diclofenac which are non-selective NSAIDs. 

Other Adverse Effects

• Bronchospasm can occur with NSAID use via the inhibition of prostaglandins which cause pulmonary vasodilation, therefore NSAIDs may exacerbate or precipitate asthma. 
• Severe skin reactions and angioedema 
• Severe hepatic reactions 
• Eosinophilic pneumonia 
• Fluid retention and oedema 
• Headache, dizziness and gastrointestinal disturbances with indometacin 
• Diarrhoea and haemolytic anaemia with mefenamic acid 

Interactions

Increased risk of gastrointestinal (GI) adverse events with the following:

• Corticosteroids which also inhibit the induction of COX
• SSRIs (GI bleeding)
• Anticoagulants (GI bleeding)
• Antiplatelets (GI bleeding)
• Alendronate 
• Nicorandil (Ulceration)

Increased risk of renal impairment with the following 

• ACE inhibitors and ARBs
• Diuretics 

In addition to this, there is an increased risk of elevated ciclosporin, methotrexate and lithium levels when co-administered with NSAIDs due to risk of renal impairment with NSAID therapy.  Furthermore there is an increased risk of cisplatin-induced nephrotoxicity when cisplatin is used alongside NSAIDs.

Moreover, when given alongside antihypertensives, NSAIDs may reduce the antihypertensive effect. 

Probenecid reduces the excretion of NSAIDs due to competitive inhibition of renal tubular secretion. 

References

1. Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan DJ. Rang & Dale’s Pharmacology. 9th ed. London: Elsevier; 2019.
2. Hitchings BSc, M., Lonsdale, D., Burrage, D., Baker, E. (2022). The Top 100 Drugs – E-Book. Netherlands: El
3. Cox-2 selective inhibitors and Non-steroidal anti-inflammatory drugs (NSAIDs): Cardiovascular safety – GOV.UK  Published Jan 2015. Accessed 1/6/26
4. Non-steroidal anti-inflammatory drugs | Treatment summaries | BNF | NICE  Accessed 1/6/26
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6. Celebrex 100mg capsule – Summary of Product Characteristics (SmPC) – (emc) | 5533 Accessed 1/6/26
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