NSAIDs: relieve inflammatory pain, but prescription safety is part of the treatment
Non-steroidal anti-inflammatory drugs (NSAIDs) are chemically diverse medicines that reduce pain, fever and inflammation mainly by reducing prostaglandin synthesis through cyclo-oxygenase (COX) inhibition. They are particularly useful for inflammatory nociceptive pain, but they can cause peptic ulcer/bleeding, acute kidney injury, fluid retention, hypertension, heart failure decompensation and cardiovascular events. Choosing an NSAID therefore means choosing the least-risk option for this patient, at the lowest effective dose for the shortest necessary duration.
Do not prescribe before this safety screen
Ask about ulcer or GI bleed, kidney disease/eGFR, dehydration, heart failure/ischaemic heart disease/stroke, hypertension, asthma triggered by aspirin/NSAIDs, pregnancy, anticoagulants/antiplatelets, corticosteroids, SSRIs/SNRIs, diuretics and ACE inhibitors/ARBs. Do not combine two systemic NSAIDs. A “painkiller” bought over the counter may already contain one.
Lesson map
Arachidonic acid, COX-1/COX-2 and prostanoids.
Traditional, preferential and selective COX-2 drugs.
Aspirin, ibuprofen, naproxen, diclofenac, indomethacin, ketorolac, mefenamic acid, piroxicam and coxibs.
Pain, fever, rheumatic disease, dysmenorrhoea, gout and PDA.
GI, renal, CV, pregnancy, interactions and monitoring.
1. What makes an NSAID different from an opioid or paracetamol?
- NSAIDs: analgesic, antipyretic and (at adequate doses) anti-inflammatory; no opioid receptor action, no euphoria, no physical dependence. Best for inflammatory/nociceptive pain.
- Opioids: act mainly in CNS at opioid receptors; can treat severe pain but have sedation, respiratory depression, tolerance and dependence risks.
- Paracetamol (acetaminophen): analgesic-antipyretic with negligible peripheral anti-inflammatory effect. It is not a classic NSAID and does not substitute for an anti-inflammatory drug in active inflammatory arthritis.
- Neuropathic pain: burning/electric/shooting pain from nerve lesion often responds poorly to NSAIDs; identify the mechanism rather than escalating an NSAID.
NSAIDs reduce prostaglandin-mediated peripheral nociceptor sensitisation. They are therefore more effective for toothache, dysmenorrhoea, sprain, inflammatory arthritis, gout and postoperative inflammatory pain than for pure visceral colic, ischaemic pain or neuropathic pain.
2. Arachidonic-acid pathway and COX isoenzymes
| Pathway component | Normal/clinical role | What inhibition explains |
|---|---|---|
| Phospholipase A2 | Releases arachidonic acid from membrane phospholipid. | Glucocorticoids act upstream here; NSAIDs do not block all inflammatory mediators. |
| COX-1 | Constitutive “housekeeping” prostanoids in gastric mucosa, platelets and kidney. | Loss of mucus/bicarbonate and mucosal blood flow → ulcer/bleeding; loss of TXA2 → platelet effects; reduced renal perfusion reserve. |
| COX-2 | Induced at inflammation; also constitutive in kidney, brain, vascular/endothelial and reproductive sites. | Analgesia, antipyresis and anti-inflammatory effect; COX-2 selectivity does not eliminate renal/CV risk. |
| PGE2/PGI2 | Vasodilation, pain sensitisation, fever set-point, gastric/renal protection; PGI2 opposes platelet aggregation. | Less pain/fever/swelling but GI injury, reduced renal blood flow, salt-water retention and possible CV risk. |
| TXA2 | Platelet aggregation and vasoconstriction. | Aspirin’s irreversible platelet COX-1 inhibition produces sustained antiplatelet effect. |
Mechanism summary: most NSAIDs reversibly inhibit COX-1 and COX-2. Aspirin irreversibly acetylates both, so the antiplatelet effect outlasts the drug concentration because platelets cannot synthesize new COX. Selective COX-2 drugs spare platelet COX-1 but reduce endothelial PGI2, which helps explain their prothrombotic concern.
3. Pharmacological actions
| Action | Mechanism | Clinical consequence |
|---|---|---|
| Analgesic | Less PGE2/PGI2 sensitisation of nociceptors; some central spinal effect. | Relieves inflammatory mild-moderate pain; ceiling effect occurs. |
| Antipyretic | Less hypothalamic PGE2 resets a raised fever set-point. | Lowers fever, not normal temperature; does not treat heat stroke—use cooling/supportive care. |
| Anti-inflammatory | Less prostaglandin-mediated vasodilation, oedema and inflammatory-cell effects. | Reduces pain, tenderness, swelling and stiffness but does not cure RA or prevent structural disease progression. |
| Antiplatelet | Reduced TXA2; sustained only with aspirin. | Low-dose aspirin has a distinct cardiovascular indication; other NSAIDs are not substitutes. |
| Ductus closure | Reduced PGE2/PGI2 maintains less ductal patency. | Indomethacin/ibuprofen may close PDA under neonatal protocol; late-pregnancy exposure can close it prematurely. |
4. Classification: learn by COX selectivity and by chemical family
| Group | Examples | High-yield point |
|---|---|---|
| Salicylate | Aspirin | Unique irreversible COX inhibition; antiplatelet use and salicylate toxicity/Reye syndrome. |
| Propionic-acid derivatives | Ibuprofen, naproxen, ketoprofen, flurbiprofen | Common oral agents; ibuprofen short acting, naproxen longer acting. |
| Acetic-acid/indole derivatives | Diclofenac, aceclofenac, indomethacin, sulindac, ketorolac | Diclofenac widely used but CV risk matters; indomethacin potent but CNS/GI toxicity; ketorolac short-term only. |
| Fenamate | Mefenamic acid | Often taught for dysmenorrhoea; GI upset/diarrhoea prominent. |
| Oxicam | Piroxicam, tenoxicam, meloxicam | Long half-life; prolonged exposure also prolongs adverse effects. |
| Preferential COX-2 | Meloxicam, etodolac; diclofenac has relative COX-2 preference | Not equivalent to complete GI or CV safety. |
| Selective COX-2 (coxibs) | Celecoxib, etoricoxib, parecoxib | Less endoscopic GI injury/platelet effect, but CV, BP, fluid and renal risks remain. |
5. Individual-drug profiles
Aspirin (acetylsalicylic acid)
The prototype NSAID and the only commonly used irreversible COX inhibitor. At low dose it preferentially blocks platelet TXA2 and is used for antiplatelet indications; at analgesic/anti-inflammatory dose it has the familiar NSAID actions and risks. Do not confuse low-dose cardiovascular aspirin with analgesic aspirin.
- Uses: antiplatelet secondary prevention/ACS where indicated; pain/fever and inflammatory conditions are now less common uses because safer alternatives are often available.
- Do not give for viral illness in children/adolescents: association with Reye syndrome (acute hepatic encephalopathy).
- Adverse effects: dyspepsia, ulcer/bleeding, bronchospasm in susceptible asthma, hypersensitivity, renal fluid retention, salicylism and overdose.
- Salicylism: tinnitus, reduced hearing, dizziness, nausea/vomiting, sweating and hyperventilation.
- Acute salicylate poisoning: early respiratory alkalosis, then high-anion-gap metabolic acidosis in severe toxicity; assess urgently and manage with toxicology/emergency protocol (including alkalinisation and dialysis when indicated).
Ibuprofen, naproxen and mefenamic acid
- Ibuprofen: short-acting propionic-acid NSAID; common for brief musculoskeletal/dental pain, dysmenorrhoea and fever. Still carries GI/renal/CV risk and can interfere with aspirin’s antiplatelet action depending on timing.
- Naproxen: longer half-life and good anti-inflammatory effect; often used for inflammatory arthropathy, acute gout or dysmenorrhoea. Its risk profile must still be individualised.
- Mefenamic acid: fenamate used in some settings for dysmenorrhoea/short-term pain; diarrhoea and GI intolerance are notable. Avoid casual repeated courses without diagnosis of abnormal uterine bleeding.
Diclofenac, indomethacin, ketorolac and piroxicam
- Diclofenac: potent analgesic/anti-inflammatory with good synovial penetration; used for acute musculoskeletal, dental, postoperative and rheumatic pain. Review CV risk carefully.
- Indomethacin: potent anti-inflammatory; useful in selected acute gout, spondyloarthropathy and PDA protocols. Headache, dizziness, confusion and GI toxicity make it a poor casual choice, especially in older people.
- Ketorolac: potent short-term analgesic for acute moderate pain; its GI/renal/bleeding toxicity limits duration. It is not a chronic-pain medicine and must not be combined with other NSAIDs.
- Piroxicam: long acting; may help adherence in chronic inflammatory disease but prolonged half-life and GI/skin toxicity require caution.
Celecoxib, etoricoxib and other coxibs
COX-2 selective drugs cause less platelet inhibition and may reduce GI injury compared with non-selective NSAIDs, especially when the patient is not also taking aspirin. They can still cause ulceration, kidney injury, oedema and BP elevation. By reducing endothelial PGI2 without suppressing platelet TXA2, they may increase thrombotic risk; avoid or use only after careful assessment in established cardiovascular disease, stroke risk, heart failure or uncontrolled hypertension.
6. Indications: select the diagnosis, not the brand
| Indication | Role | Important caveat |
|---|---|---|
| Sprain, strain, soft-tissue injury, dental/inflammatory postoperative pain | Short course can be effective. | Consider topical NSAID where pain is local; review renal/GI/bleeding risk. |
| Primary dysmenorrhoea | Reduces endometrial prostaglandin-mediated cramps. | Exclude pregnancy/secondary pathology if symptoms are atypical, severe or changing. |
| Osteoarthritis | Symptomatic pain relief; topical agents often useful for local peripheral joints. | Pair with exercise, weight/function plan; do not leave systemic NSAID indefinitely without review. |
| RA/ankylosing spondylitis | Relieves symptoms and stiffness. | Does not replace disease-modifying therapy or rheumatology review. |
| Acute gout | NSAID may control inflammation if no contraindication. | Check renal, GI/CV and anticoagulant status; do not confuse treatment of flare with urate-lowering plan. |
| Fever | May relieve discomfort. | Investigate cause; paracetamol is often preferable in children or bleeding-risk patients. |
| PDA closure | Indomethacin/ibuprofen in specialist neonatal pathways. | Not an outpatient use; monitor renal, GI and platelet effects. |
7. Adverse effects: explain each from physiology
| System | Mechanism | Clinical picture and prevention |
|---|---|---|
| GI | COX-1/COX-2 prostaglandin loss reduces mucus, bicarbonate, blood flow and repair; topical mucosal irritation also contributes. | Dyspepsia, gastritis, ulcer, perforation and occult/overt bleed. Risks: older age, ulcer/bleed history, high dose/long duration, H. pylori, steroids, anticoagulants, antiplatelets, SSRIs, alcohol/smoking. Use lowest dose; consider PPI gastroprotection in at-risk patients. |
| Renal/fluid | Loss of afferent arteriolar prostaglandin vasodilation and natriuresis. | AKI, sodium-water retention, oedema, hyperkalaemia, raised BP and papillary injury with chronic exposure. High risk: CKD, dehydration, cirrhosis, heart failure, sepsis and older age. |
| Cardiovascular | Fluid retention/BP increase; altered PGI2-TXA2 balance, especially COX-2 selectivity. | Hypertension, worsening heart failure, MI/stroke risk. Avoid or carefully justify in heart failure/CVD; monitor BP and oedema. |
| Respiratory/allergic | COX blockade may shift arachidonic acid toward leukotrienes in susceptible people. | Urticaria, angioedema, rhinitis, bronchospasm/NSAID-exacerbated respiratory disease. Stop and urgently manage severe reaction. |
| Haematological/skin/hepatic | Platelet inhibition; idiosyncratic immune/toxic reactions. | Bleeding; rare severe skin reaction, hepatitis or marrow effects. New rash, blistering, jaundice or unexplained bruising requires urgent review. |
| Pregnancy/fetus | Reduced fetal/renal prostaglandins and ductal prostaglandins. | Avoid routine NSAID use in pregnancy, especially later pregnancy; possible oligohydramnios and premature ductus closure. Follow obstetric protocol. |
8. Interactions and the “triple whammy”
The triple whammy: NSAID + ACE inhibitor/ARB + diuretic
ACE inhibitor/ARB reduces efferent arteriolar tone, diuretic reduces circulating volume and NSAID constricts the afferent side by removing prostaglandin support. Together they can precipitate AKI—especially during vomiting, diarrhoea, fever, dehydration or sepsis.
- Anticoagulants/DOACs/warfarin, antiplatelets and SSRIs/SNRIs: increased bleeding risk; avoid when possible, document rationale and consider gastroprotection/monitoring when unavoidable.
- Corticosteroids: substantially increase GI ulcer/bleed risk.
- Other NSAIDs including OTC cold/flu or topical/oral combinations: no extra analgesic benefit worth the extra toxicity; avoid duplication.
- Antihypertensives/diuretics: NSAIDs may blunt BP and diuretic response and worsen fluid retention.
- Lithium and methotrexate: renal effects can increase toxicity; seek medicine-specific advice.
- Aspirin: do not stop prescribed low-dose aspirin without the responsible team; additional NSAID creates GI/bleeding risk and some schedules affect aspirin antiplatelet action.
9. Safe prescribing algorithm and monitoring
- Is an NSAID needed? Confirm inflammatory/nociceptive pain and non-drug/local options; choose paracetamol or another class if NSAID benefit is low.
- Screen risk: GI, renal, CV, respiratory allergy, pregnancy and interactions.
- Choose route and duration: topical for local pain where appropriate; lowest effective systemic dose, shortest duration; do not create open-ended repeats.
- Protect the gut when indicated: use PPI strategy in high GI-risk patients according to local guidance; COX-2 selection alone is not a guarantee of safety.
- Baseline checks for higher-risk/longer-term use: BP, creatinine/eGFR, electrolytes, FBC and medication list.
- Reassess: pain/function response, adherence and OTC duplication; BP, renal function, anaemia/melaena and oedema. Stop if harms outweigh benefit.
10. Special populations
Higher GI, renal, CV and polypharmacy risk. Prefer topical/local measures; if systemic, use short course with gastroprotection/monitoring where indicated.
Avoid NSAIDs in severe renal impairment where possible; never overlook vomiting, diarrhoea, sepsis, diuretics or ACEi/ARB.
NSAIDs may worsen BP, oedema and cardiac failure. Select only with clear need and review.
Ask specifically about past wheeze/rhinitis/urticaria after aspirin or NSAIDs; avoid culprit class and use emergency care for reaction.
Do not routinely recommend NSAIDs; follow obstetric guidance, particularly in later pregnancy.
No aspirin for viral fever because of Reye syndrome; use age- and weight-appropriate protocolled medicines.
11. High-yield cases, traps and OSCE questions
Case 1: the ACEi–diuretic patient with gastroenteritis
A hypertensive patient taking lisinopril and furosemide asks for diclofenac while vomiting and passing little urine. This is a high AKI-risk situation: assess volume status, renal function and alternatives; do not simply add an NSAID.
Case 2: knee OA with prior melaena
Start with non-drug measures and consider topical therapy. If systemic NSAID is unavoidable, identify ulcer/bleed risk, review aspirin/anticoagulants/steroids and apply gastroprotection/local protocol—then set a review date.
Case 3: menstrual cramps in a student with sudden worse pain
NSAID may help primary dysmenorrhoea, but new severe pain, pregnancy risk, fever, dyspareunia or abnormal bleeding requires assessment for secondary pathology rather than repeat medication alone.
- Why do NSAIDs cause ulcers? Loss of protective prostaglandins and mucosal defence—not simply “acid excess.”
- Why do NSAIDs cause AKI? They remove prostaglandin-dependent afferent vasodilation when renal perfusion is threatened.
- Why is aspirin different? It irreversibly inhibits platelet COX-1, so its antiplatelet effect persists for the platelet lifespan.
- Why are coxibs not universally safer? Less platelet/GI effect does not remove renal, BP, fluid-retention or thrombotic risk.
- What must every patient be told? Avoid duplicate OTC NSAIDs and seek help for black stool/vomiting blood, reduced urine, swelling/breathlessness, severe abdominal pain, rash/blistering or asthma symptoms.
Further study and source trail
Supplied course sources: NSAIDs—SlideShare and Non-steroidal Anti-inflammatory Drugs Pharmacology—SlideShare. Expand with current NICE NSAID prescribing guidance, BNF/NICE NSAID treatment summary, and ibuprofen safety information. Use current local protocol for all doses, pregnancy care, paediatrics, acute poisoning and emergency management.
