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NSAIDs have analgesic, antipyretic and anti-inflammatory properties, but are also associated with a number of side effects that may be serious in vulnerable individuals. Prescribers should be aware of the contraindications, interactions and adverse effects before initiating NSAIDs, and know how to manage their cardiovascular, renal and gastrointestinal risks.
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NSAIDs prescribing issues
WHAT ARE NSAIDs?
Nonsteroidal anti-inflammatory drugs (NSAIDs) have analgesic, antipyretic and, at higher doses, anti-inflammatory actions.
HOW DO NSAIDs WORK?
NSAIDs act peripherally and centrally, however the peripheral action predominates.
NSAIDs inhibit prostaglandin synthesis, which normally potentiates the pain caused by other inflammatory mediators (such as histamine and bradykinin).
NSAIDs work by reversibly inhibiting cyclo-oxygenase (COX) enzymes — the two main types are COX-1 and COX-2, which have different physiological functions.
COX-1 produces prostaglandins that help to maintain gastric mucosal integrity and platelet-initiated blood clotting.
Inhibition of COX-1 is thought to be responsible for GI toxicity.
COX-2 produces prostaglandins that mediate pain and inflammation.
Inhibition of COX-2 is thought to be responsible for the anti-inflammatory action of NSAIDs.
NSAIDs vary in how selective they are for COX-1 and COX-2 pathways.
There is no absolute selectivity for one or other COX enzyme — even highly selective COX-2 inhibitors will also inhibit COX-1 at high enough concentrations.
Aspirin is technically a standard NSAID (it inhibits COX enzymes). However, it is mainly used for antithrombotic effects, which is due to permanent inhibition of the COX-1 pathway in platelets.
HOW ARE NSAIDs CLASSIFIED?
NSAIDs can be classified as:
Diclofenac, etodolac, meloxicam, and nabumetone, are also nonselective NSAIDs, but are thought to have a preference for COX-2.
Coxibs are highly selective for COX-2, but they can interact with COX-1 in certain circumstances.
WHAT SHOULD I CONSIDER WHEN INITIATING NSAIDs?
Prescribe NSAIDs at the lowest effective dose for the shortest possible duration
When prescribing NSAIDs, take into account the person's individual risk factors for adverse effects and consider if an alternative to an NSAID may be suitable, for example:
WHAT ARE THE CONTRAINDICATIONS FOR NSAIDs?
Do not prescribe NSAIDs to people with:
Do not prescribe COX-2 inhibitors, diclofenac, aceclofenac or high dose ibuprofen (more than 2400 mg daily) to people with:
Do not prescribe etoricoxib or high dose ibuprofen to people with uncontrolled hypertension (persistently above 140/90 mmHg).
Prescribe NSAIDs with caution to people with:
WHAT ARE THE ADVERSE EFFECTS OF NSAIDs?
The risks of adverse effects varies among individual NSAIDs and is influenced by the dose and duration of use.
Adverse effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.
Dyspepsia and other upper GI complications are the most common adverse effects of NSAIDs — for example, ulcer, perforation, obstruction or bleeding.
People are at increased risk of serious NSAID–induced GI adverse events if they have one or more risk factor.
CV and renal complications are less common but serious NSAID adverse effects — for example, myocardial infarction, stroke, cardiac failure, hypertension, and renal failure.
All NSAID use is associated with a small increased risk of thrombotic events independent of baseline CV risk factors or duration of NSAID use. However, the greatest risk may be in those receiving high doses long-term.
People with certain risk factors have an increased risk of serious cardiac or renal adverse events.
Other adverse effects include:
Very rarely, NSAIDs can precipitate severe hepatic reactions (such as hepatitis, liver necrosis, or hepatic failure).
If there are symptoms or signs of liver damage (for example, nausea, vomiting, abdominal pain, and jaundice), or persistently abnormal liver enzymes, stop the NSAID.
WHAT ARE THE RISK FACTORS FOR CV AND RENAL ADVERSE EFFECTS?
Inhibition of COX-2 leads to suppression of prostacyclin (which normally protects endothelial cells, produces vasodilation and interacts with platelets to antagonize aggregation).
Inhibition of COX-1 inhibits conversion of arachidonic acid to thromboxane A2 (a potent platelet aggregator and vasoconstrictor).
Selective COX-2 inhibition presents a CV risk, as it shifts the prothrombotic/antithrombotic balance and favours thrombosis.
NSAIDs inhibit prostaglandins PGE2 and PGI2 synthesis which may result in sodium retention, reduced renal blood flow, and renal failure.
The risk for serious cardiac or renal adverse events (including myocardial infarction, heart failure, and hypertension) is increased in people with:
People with risk factors for CV disease (for example, hypertension, hyperlipidaemia, diabetes mellitus, smoking) and all elderly people (aged 65 years or over) are also at increased risk.
HOW SHOULD I MANAGE THE RISK OF CV AND RENAL ADVERSE EFFECTS?
For people with heart failure:
Severe heart failure — do not prescribe NSAIDs.
Mild to moderate heart failure — do not prescribe a COX-2 inhibitor, diclofenac, or high-dose ibuprofen (2400 mg or more daily). Prescribe a standard NSAID and monitor the person closely.
Ibuprofen up to 1200 mg daily, or naproxen up to 1000 mg per daily are first-line options.
For people with ischaemic heart disease, cerebrovascular disease, or peripheral arterial disease, prescribe:
Ibuprofen up to 1200 mg per day or naproxen up to 1000 mg daily are first-line options.
COX-2 inhibitors, diclofenac, and high-dose ibuprofen are contraindicated.
For people with severe renal impairment (estimated glomerular filtration rate [eGFR] less than 30 ml/minute/1.73 m2):
Ideally, avoid prescribing NSAIDs.
If an NSAID is used, monitor the person closely.
For people with risk factors for CV disease or the elderly, prescribe:
For people with hypertension:
WHAT ARE THE RISK FACTORS FOR GI ADVERSE EFFECTS?
NSAIDs inhibit cyclo-oxygenase-1 (COX-1) — this is thought to be responsible for GI toxicity.
COX-2 inhibitors (such as etoricoxib and celecoxib) selectively inhibit cyclo-oxygenase-2 and have a reduced risk for GI toxicity.
Risk factors for NSAID–induced GI adverse events include:
People are considered at:
High risk if they have a history of previously complicated ulcer, or multiple (more than two) risk factors.
Moderate risk if they have 1–2 risk factors.
Low risk if they have no risk factors.
Additional risk factors for NSAID-induced GI adverse events include:
HOW SHOULD I MANAGE THE RISK OF GI ADVERSE EFFECTS?
To prevent GI adverse effects associated with the use of an NSAID:
Avoid prescribing more than one NSAID at a time.
Avoid concomitant use of an NSAID with low-dose aspirin (if possible) – if this is essential, monitor closely.
Prescribe the lowest dose of NSAID for the shortest period of time.
Use a short-acting NSAID (such as ibuprofen) in preference to a long-acting NSAID (such as naproxen).
Consider an alternative analgesic if appropriate.
Consider gastroprotection when prescribing an NSAID. Co-prescribe a proton pump inhibitor (PPI) for people:
For people at:
High risk of GI adverse events — prescribe a COX-2 selective NSAID (for example, etoricoxib, or celecoxib) instead of a standard NSAID, and co-prescribe a PPI.
Moderate risk of GI adverse events — prescribe a COX-2 inhibitor alone, or an NSAID plus a PPI.
Low risk of GI events — prescribe a non-selective NSAID.
Managing GI adverse effects
The management of GI adverse effects in people using an NSAID depends on whether they have been investigated (for example, with endoscopy or a test for H. pylori) and whether 'alarm' symptoms are present.
What dose of PPI should be used for people who need gastroprotection?
Proton pump inhibitor Dose
Lansoprazole 15-30mg once daily
Omeprazole 20mg once daily
Esomeprazole 20mg once daily
Pantoprazole 20mg once daily
WHAT ARE THE IMPORTANT DRUG INTERACTIONS WITH NSAIDs?
Alendronate — concurrent use with NSAIDs may increase the risk of upper GI adverse effects. Monitor for signs of GI irritation.
Angiotensin-converting enzyme (ACE) inhibitors or an angiotensin-II receptor blocker (ARB) — concurrent use with NSAIDs may increase blood pressure, the risk of renal impairment and rarely hypokalaemia. Monitor blood pressure if an NSAID is started, and consider monitoring urea and electrolytes. Consider intermittent use of NSAIDs as a possible cause if erratic blood pressure control occurs.
Anticoagulants (for example, warfarin, dabigatran) — all NSAIDs can cause GI irritation and reduce platelet aggregation, which can worsen any bleeding event. Avoid concomitant use if possible.
If concurrent use is necessary be aware of the potential risks of bleeding. Consider giving gastroprotection (such as a PPI).
Antidepressants — increased risk of upper GI bleeding when some antidepressants (selective serotonin reuptake inhibitors, and serotonin noradrenaline reuptake inhibitors) and an NSAID are taken concomitantly. If an NSAID is considered necessary, weigh the risks and benefits of treatment and consider prescribing gastroprotection.
Antiplatelets (low dose aspirin, clopidogrel) — NSAIDs may antagonize the antiplatelet effects of aspirin, and increase the risk of GI bleeds when taken concurrently with other antiplatelets. If concomitant use is unavoidable consider prescribing gastroprotection with a PPI.
Beta blockers — NSAIDs may reduce the efficacy of beta blockers given for heart failure. Consider monitoring blood pressure if an NSAID is started or stopped.
Note: NSAIDs should generally be avoided in people with heart failure.
Corticosteroids — the incidence and/or severity of ulceration associated with NSAIDs, and the possibility of GI bleeding may be increased. Consider giving gastroprotection.
Ciclosporin — NSAIDs may reduce renal function, and lead to increased ciclosporin levels. If concurrent is necessary, monitor renal function and consider reducing the dose of the NSAID.
Fluconazole, voriconazole — the peak plasma level of some NSAIDs (for example, ibuprofen) may be increased. Monitor for NSAID adverse effects (for example, dyspepsia, nausea, dizziness). Consider using the lowest NSAID dose and titrate accordingly.
Lithium — NSAIDs can reduce lithium excretion, and increase the risk of lithium toxicity. Avoid concomitant use especially if risk factors for lithium toxicity (such as advanced age or renal impairment) are present, unless lithium levels can be closely monitored, and the dose adjusted accordingly. Advise people to report lithium adverse effects (tremor, dysarthria, ataxia, confusion).
Loop diuretics (for example, furosemide) — NSAIDs may reduce the antihypertensive effects of loop diuretics and exacerbate congestive heart failure. Consider an alternative non-NSAID analgesic, but if concurrent use is essential, monitor the diuretic effects, renal function and electrolytes closely, and increase the dose of the loop diuretic if required.
Methotrexate — NSAIDs may reduce the excretion of methotrexate and increase the risk of methotrexate toxicity. Advise people to report symptoms such as sore throat, dyspnoea or cough.
If high-dose methotrexate is given with an NSAID, monitor methotrexate levels and increase routine methotrexate monitoring (full blood count, liver function tests).
Nicorandil — there may be an increased risk of GI ulceration, perforation or haemorrhage if taken concurrently with an NSAIDs. Monitor for GI adverse effects.
Potassium-sparing diuretics (for example, spironolactone) — several cases of acute renal impairment have been reported with concurrent use with NSAIDs. Avoid concurrent use.
Probenecid — reduces excretion of NSAIDs. Avoid concurrent use.
If concurrent use is unavoidable, use a lower dose of NSAID. Ketorolac is specifically contraindicated in people taking probenecid.
Quinolones (for example, ciprofloxacin) — possible increased risk of convulsions if taken concurrently. This is rare, therefore in most cases, the concomitant use of a quinolone and an NSAID is acceptable. However, concurrent use should be avoided in people with epilepsy or people who are predisposed to convulsions.
Thiazide-type diuretics (for example, bendroflumethiazide) — some NSAIDS (for example, indometacin) may reduce the antihypertensive effect of thiazides.
If concurrent use is indicated monitor blood pressure regularly and increase the thiazide dose as necessary.
Zidovudine — the risk of haematological toxicity and risk of bleeding may be increased if given concurrently with NSAIDs.
Note: combined treatment with an NSAID, plus an ACE inhibitor or ARB and a diuretic (the so called 'triple whammy') significantly increases the risk of acute kidney injury (AKI) and should be avoided if possible.
WHAT MONITORING IS REQUIRED FOR PEOPLE TAKING NSAIDs?
Review the appropriateness of NSAID prescribing widely and on a routine basis, especially in people who are at higher risk of GI, renal and CV morbidity and mortality (for example, older people).
Consider the risks and the response to treatment, and use clinical judgement to decide what must be monitored and how frequently.
Enquire about, and manage, adverse effects.
Monitor blood pressure in the elderly and people:
Monitor renal function at least annually.
For people with renal impairment — monitor renal function 1–2 weeks after starting or increasing the dose of the NSAID, and then regularly thereafter.
Monitor liver function in people:
Monitor haemoglobin levels
In people at high risk of GI adverse effects 1–4 weeks after NSAID treatment has started.
Consider monitoring blood pressure, renal function, and features of heart failure 1–[blob]2 weeks after starting or increasing the dose of the NSAID, and then regularly thereafter, in the elderly and people with:
Also consider monitoring renal function in people who are taking additional drugs that can affect renal function (for example, ACE inhibitors, angiotensin-II receptor antagonists, or diuretics).
CAN NSAIDs BE TAKEN BY PEOPLE TRYING TO CONCEIVE?
Avoid NSAIDs during pre-conception.
Paracetamol is the analgesic and/or antipyretic of choice.
CAN NSAIDs BE TAKEN DURING PREGNANCY?
Paracetamol is the analgesic and/or antipyretic of choice during pregnancy.
However, if during the first or second trimester paracetamol is ineffective and an NSAID is clinically indicated:
As with all people who are prescribed an NSAID, use the lowest effective dose for the shortest duration possible.
If regular use is clinically indicated, such as in a woman with rheumatoid arthritis, seek specialist advice.
NSAIDs must not be used from 30 weeks of pregnancy onwards without specialist advice and regular fetal monitoring.
CAN NSAIDs BE TAKEN BY WOMEN WHO ARE BREASTFEEDING?
Paracetamol is the drug of choice for women who are breastfeeding. Seek expert advice if the:
If a NSAID is clinically indicated, ibuprofen is preferred.
Use the lowest effective dose for the shortest time possible.
If a COX-2 inhibitor is clinically indicated, celecoxib is preferred.
If a non-preferred NSAID is required, monitor the infant for GI adverse effects, and avoid repeated use of drugs with a long half-life (for example, naproxen) where possible, due to the potential risk of accumulation in the infant.
Single doses of non-preferred NSAIDs may be used if required without the need for monitoring.
WHAT ADVICE SHOULD I GIVE SOMEONE WHEN PRESCRIBING AN NSAID?
Advise the person about the adverse effects associated with NSAIDs including the CV and renal and GI adverse effects.
Explain that adverse effects may be minimized by:
Explain that they may need close monitoring to determine the response to treatment and manage any adverse effects.
Advise them to read the patient information leaflet that comes with their medicine.
Provide the person with a Medicine Sick Day Rules Card, and explain that they should:
During this module you have learned:
Clinical Knowledge Summaries. NSAID prescribing issues. 2018https://cks.nice.org.uk/nsaids-prescribing-issues
NICE CG184. Gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management, 2014 https://www.nice.org.uk/guidance/cg184
European Medicines Agency. European Medicines Agency updated advice on use of high-dose ibuprofen, 2015. https://www.ema.europa.eu/en/news/updated-advice-use-high-dose-ibuprofen
Schmidt M, Lamberts M, Schjerning Olsen A, et al. Cardiovascular safety of non-aspirin non-steroidal anti-inflammatory drugs. European Society of Cardiology. Eur Heart J 2016;37(13):1015-23
Health Improvement Scotland. Medicine Sick Day Rules Card. https://ihub.scot/improvement-programmes/scottish-patient-safety-programme-spsp/spsp-primary-care/medicines-sick-day-rules-card/