NSAIDs: risks & gastroprotection

NSAIDs: risks and gastroprotection

Non-steroidal anti-inflammatory drugs (NSAIDs) can be very effective for inflammatory pain, but their familiar names and over-the-counter availability can hide clinically important gastrointestinal, renal and cardiovascular harm. Safe prescribing is not simply choosing ibuprofen or naproxen: it requires a clear indication, individual risk assessment, the lowest effective exposure and a review plan.

Quick answer: prefer non-drug measures and topical treatment where appropriate. If an oral NSAID is necessary, use the lowest effective dose for the shortest possible time, assess GI, renal and cardiovascular risk, check interacting medicines, and provide gastroprotection when indicated.

How NSAIDs work—and why that creates risk

NSAIDs inhibit cyclo-oxygenase enzymes and reduce prostaglandin synthesis. This decreases pain and inflammation, but prostaglandins also protect the gastric mucosa, support renal perfusion and influence platelet and vascular function.

System	Mechanism and consequence
Gastrointestinal	Reduced protective prostaglandins increase dyspepsia, ulceration, bleeding and perforation. Serious injury can occur without warning symptoms.
Renal	Constriction of the afferent arteriole reduces glomerular perfusion, particularly during dehydration or reduced effective circulating volume. AKI, sodium retention, oedema, hypertension and hyperkalaemia can follow.
Cardiovascular	Fluid retention and altered thrombotic balance can worsen hypertension or heart failure and increase myocardial infarction or stroke risk. Risk differs between drugs and rises with dose and duration.
Respiratory	In susceptible people, COX-1 inhibition can provoke bronchospasm or other reactions associated with NSAID-exacerbated respiratory disease.
Haematological	Most non-selective NSAIDs reversibly impair platelet function and can compound bleeding caused by other medicines.

NSAID groups

• Non-selective oral NSAIDs: ibuprofen, naproxen and diclofenac are common examples.
• COX-2 selective inhibitors: celecoxib and etoricoxib cause less endoscopic GI ulceration than many non-selective agents but do not remove GI risk and can have important cardiovascular and renal effects.
• Topical NSAIDs: gels or preparations such as topical diclofenac or ibuprofen produce lower systemic exposure and are useful for localised musculoskeletal pain, although contraindications and adverse effects still matter.

NICE recommends a topical NSAID for knee osteoarthritis and says it can be considered for osteoarthritis affecting other joints. Oral therapy should follow only when topical treatment is ineffective or unsuitable and after toxicity and patient-specific risk have been considered.

Pre-prescribing safety screen

Before supplying or prescribing an NSAID, establish:

Indication and alternatives

• Is there an inflammatory or acute pain indication likely to benefit?
• Have exercise, physical measures or topical treatment been considered?
• Is the person using another NSAID from a prescription, supermarket product or combination cold remedy?

GI risk

• previous peptic ulcer, GI bleed or perforation;
• older age or frailty;
• high dose, prolonged use or more than one NSAID;
• Helicobacter pylori where relevant; and
• anticoagulant, antiplatelet, corticosteroid or SSRI/SNRI use.

Renal and fluid risk

• CKD, previous AKI or abnormal renal function;
• dehydration, vomiting, diarrhoea or poor oral intake;
• heart failure, cirrhosis or nephrotic syndrome;
• diabetes, older age or frailty; and
• ACE inhibitor/ARB, diuretic, SGLT2 inhibitor or other medicine affecting renal haemodynamics or volume.

Cardiovascular risk

• established ischaemic heart disease, cerebrovascular disease or peripheral arterial disease;
• heart failure or uncontrolled hypertension; and
• diabetes, smoking, hyperlipidaemia or other major risk factors.

Also check pregnancy, asthma or previous NSAID hypersensitivity, hepatic disease and the full medicines list.

The renal “triple whammy”

The classic high-risk combination is:

1. an ACE inhibitor or ARB, which dilates the efferent arteriole;
2. a diuretic, which reduces circulating volume; and
3. an NSAID, which constricts the afferent arteriole.

Together they can sharply reduce glomerular filtration, especially during intercurrent illness or dehydration. The practical response is to avoid unnecessary NSAIDs, check baseline renal function and potassium when clinically appropriate, counsel about hydration and illness, and reassess soon after initiation in higher-risk patients.

Do not treat “take with food” as renal protection. Food may reduce dyspepsia but does not prevent AKI, ulceration or cardiovascular events.

Choosing an NSAID

There is no universally safest oral NSAID. Choice depends on the person's risk profile.

• Naproxen and low-dose ibuprofen have comparatively favourable thrombotic cardiovascular profiles among non-selective NSAIDs, but both retain GI and renal risk.
• Diclofenac has an arterial thrombotic risk similar to selective COX-2 inhibitors. Systemic diclofenac is contraindicated in established ischaemic heart disease, peripheral arterial disease, cerebrovascular disease and NYHA class II–IV heart failure.
• A COX-2 inhibitor may reduce some GI harm compared with a non-selective NSAID, but it is not a solution for high cardiovascular or renal risk.
• Topical treatment is preferable when pain is localised and it can provide adequate benefit.

Whatever the agent, use one NSAID only, at the lowest effective dose, for the shortest duration. Set a review point rather than allowing an acute prescription to become an indefinite repeat.

Gastroprotection

For osteoarthritis, NICE advises offering gastroprotective treatment such as a PPI while an oral NSAID is being taken. In other settings, a PPI is particularly important when GI risk is raised by age, previous ulcer or bleed, higher NSAID exposure, or interacting medicines.

A PPI reduces upper-GI ulcer and bleeding risk but does not protect the kidneys, heart or lower GI tract. It must not be used to make an otherwise unsafe NSAID appropriate.

If there is a history of ulcer bleeding or very high GI risk, first reconsider whether the NSAID is necessary at all. H. pylori assessment, specialist advice or a different analgesic strategy may be appropriate depending on the clinical context.

Important interactions

Combination	Main concern
NSAID + anticoagulant or antiplatelet	Major GI and other bleeding; verify necessity and gastroprotection.
NSAID + ACE inhibitor/ARB + diuretic	AKI and hyperkalaemia—the triple whammy.
NSAID + corticosteroid or SSRI/SNRI	Additive GI bleeding risk.
NSAID + lithium	Reduced lithium clearance and toxicity; avoid or manage with specialist monitoring.
NSAID + methotrexate	Reduced methotrexate elimination and toxicity risk, influenced by dose and renal function.
Two NSAIDs	More toxicity without a rational additive analgesic benefit.

Ibuprofen can also interfere with aspirin's antiplatelet effect depending on timing and repeated use. A patient taking low-dose aspirin for secondary prevention should seek professional advice before using ibuprofen rather than self-treating repeatedly.

Pregnancy

Systemic NSAIDs are contraindicated after 28 weeks of pregnancy. MHRA also advises avoiding systemic NSAIDs from 20 weeks unless clinically necessary because prolonged exposure can cause fetal renal dysfunction, oligohydramnios and ductus arteriosus constriction. If use after 20 weeks is necessary, prescribe the lowest dose for the shortest time and consider antenatal monitoring when exposure lasts more than several days.

Do not assume an over-the-counter product is safe during pregnancy. Paracetamol remains the usual first-choice analgesic when appropriate, used at the lowest effective dose for the shortest duration.

Monitoring and review

Monitoring should match risk, duration and clinical context. For a higher-risk person or a longer course, consider:

• blood pressure and signs of oedema or heart-failure deterioration;
• serum creatinine/eGFR and electrolytes, particularly potassium;
• full blood count if bleeding or anaemia is suspected; and
• symptom benefit—stop treatment if there is no meaningful functional improvement.

Renal function may need checking shortly after initiation or dose escalation when risk is high. Always interpret a creatinine result against baseline and the person's hydration and medicines.

Counselling and safety-netting

Advise the patient to:

• take only the agreed NSAID and avoid duplicate OTC ibuprofen, naproxen or aspirin-containing products;
• use the smallest dose that controls symptoms and stop when no longer needed;
• seek urgent help for black tarry stools, vomiting blood, severe abdominal pain, chest pain, new neurological symptoms, severe breathlessness or markedly reduced urine output;
• stop and seek advice for wheeze, facial swelling or a suspected allergic reaction; and
• contact a clinician during significant vomiting, diarrhoea or dehydration rather than continuing a high-risk combination without review.

A structured OSCE approach

1. Clarify the pain: cause, severity, inflammation, duration and red flags.
2. Check what has been tried: non-drug options, topical therapy and current analgesics.
3. Screen four domains: GI, renal, cardiovascular and respiratory risk.
4. Reconcile interactions: especially anticoagulants, antiplatelets, steroids, SSRIs, ACE inhibitor/ARB and diuretic.
5. Choose the least harmful effective option: route, drug, dose, duration and PPI.
6. Create a review and safety-net plan: define success, monitoring and reasons to stop or seek urgent help.

Common mistakes

• Prescribing an NSAID because pain is present without considering whether it is inflammatory.
• Failing to identify OTC duplication.
• Adding a PPI but ignoring renal or cardiovascular contraindications.
• Missing the ACE inhibitor/ARB–diuretic–NSAID combination.
• Describing diclofenac as harmless in established cardiovascular disease.
• Saying only “avoid in the third trimester” and missing the MHRA warning from week 20.
• Leaving an acute NSAID on repeat without a benefit and safety review.

Active recall

1. What are the three major organ-system risks of an NSAID?
2. Which three medicine groups create the renal triple whammy?
3. Why does a PPI not make every NSAID prescription safe?
4. Which cardiovascular diseases contraindicate systemic diclofenac?
5. What changes at 20 and 28 weeks of pregnancy?

Authoritative sources

• NICE NG226: Osteoarthritis in over 16s
• MHRA: NSAIDs and cardiovascular risk
• MHRA: Diclofenac contraindications and warnings
• MHRA: NSAIDs and renal failure
• MHRA: NSAIDs after 20 weeks of pregnancy

Educational material for UK pharmacy learners. Apply the current BNF, product information and local formulary to individual prescribing decisions.