• Prescribe nonsteroidal anti-inflammatory drugs (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:
    • A topical NSAID. 
    • Physiotherapy, or referral for consideration of surgery.
    • A different oral analgesic (such as paracetamol, or an opioid).
  • The person has any contraindications to oral NSAIDs.
  • There are any potentially hazardous drug interactions.
  • The person is already using an NSAID — for example, ibuprofen or aspirin purchased over-the-counter.
  • Gastroprotection is indicated. For example, because the person is:
    • At increased risk of gastrointestinal adverse effects (for example, people that require long-term treatment).
    • Experiencing dyspepsia from standard NSAIDs.
  • More frequent review and monitoring for adverse effects is required — for example, for people who are:
    • At risk of multiple adverse effects (for example, the elderly, people with comorbidities).
    • Taking drugs which may interact with an NSAID. 
    • At increased risk of gastrointestinal or cardiovascular or renal adverse effects.

• Do not prescribe nonsteroidal anti-inflammatory drugs (NSAIDs) to people with:
  • Active gastrointestinal (GI) bleeding, or active GI ulcer.
  • A history of GI bleeding related to previous NSAID therapy, or a history of GI perforation related to previous NSAID therapy. 
  • A history of recurrent GI haemorrhage (two or more distinct episodes), or history of recurrent GI ulceration (two or more distinct episodes).
  • A history of hypersensitivity/severe allergic reaction to an NSAID (including aspirin) — for example, asthma, rhinitis, angioedema or urticaria.
  • Severe heart failure.
  • Severe hepatic impairment — serum albumin less than 25 g/L or Child-Pugh score of 10 or more.
  • Severe renal impairment — estimated glomerular filtration rate (eGFR) less than 30 mL/minute/1.73 m².
• Do not prescribe COX-2 inhibitors, diclofenac, aceclofenac or high dose ibuprofen (more than 2400 mg daily) to people with:
  • Ischaemic heart disease.
  • Inflammatory bowel disease (COX-2 inhibitors only).
  • Peripheral arterial disease.
  • Cerebrovascular disease.
  • Congestive heart failure (New York Heart Association [NYHA] classification II–IV).
• 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:
  • A history of peptic ulceration (standard NSAIDs are contraindicated), or people at high risk of GI adverse effects (for example, the elderly).
  • Allergic disorders.  
  • Cardiac impairment, or heart failure — NSAIDs may impair renal function.
  • Cerebrovascular disease.
  • Coagulation disorders.
  • Connective-tissue disorders. 
  • Hypertension — NSAIDs may impair renal function.
  • Inflammatory bowel disease — NSAIDs may increase the risk of developing or cause exacerbations of ulcerative colitis or Crohn's disease.
  • Ischaemic heart disease. 
  • Peripheral arterial disease.
  • Risk factors for cardiovascular events — for example, hypertension, hyperlipidaemia, diabetes mellitus, smoking.
  • Hepatic impairment — dose reductions may be necessary.
  • Renal impairment (avoid if possible) — sodium and water retention may occur leading to a deterioration in renal function and, possibly renal failure. 
    • If the person cannot avoid using an NSAID and has impaired renal function, monitor creatinine clearance or eGFR. 
• Also prescribe NSAIDs with caution in: 
  • Women trying to conceive — NSAIDs may impair female fertility. 
  • The elderly — increased risk of cardiovascular, renal, and serious GI adverse effects (including GI bleeding and perforation, which may be fatal).
• For detailed information on specific medicines, see the summary of product characteristics, available at the electronic Medicines Compendium (eMC) (www.medicines.org.uk).

• The risks of adverse effects varies among individual nonsteroidal anti-inflammatory drugs (NSAIDs) and is influenced by the dose and duration of use.
  • Adverse effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.
• Dyspepsia and other upper gastrointestinal (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. 
• Cardiovascular 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 cardiovascular 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:
  • Prolonged bleeding (for example, after surgery) as a result of inhibition of platelet aggregation.
  • Bronchospasm — NSAIDs may exacerbate or precipitate asthma. Stop the NSAID if it is suspected to have precipitated bronchospasm.
  • Severe skin reactions and angioedema (for example, exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis) — stop the NSAID if these occur.
  • Anastomotic leakage. [ABPI, 2019]
  • 'Kounis syndrome' (allergic acute coronary syndrome). [ABPI, 2019]
• 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.
• For detailed information on specific medicines, see the summary of product characteristics, available at the electronic Medicines Compendium (eMC) (www.medicines.org.uk).

• Cardiovascular (CV) 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. 
• Renal effects 
  • 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:
  • Cerebrovascular disease. 
  • Heart failure.
  • Ischaemic heart disease.
  • Peripheral arterial disease.
  • Renal impairment.
• People with risk factors for cardiovascular disease (for example, hypertension, hyperlipidaemia, diabetes mellitus, smoking) and all elderly people (aged 65 years or over) are also at increased risk. For more information, see the CKS topic on CVD risk assessment and management.  

• Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclo-oxygenase-1 (COX-1) — this is thought to be responsible for gastrointestinal (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 gastrointestinal (GI) adverse events include:
  • Aged over 65 years.
  • A high dose of an NSAID.
  • A history of gastroduodenal ulcer, GI bleeding, or gastroduodenal perforation.
  • Concomitant use of medications that are known to increase the likelihood of upper GI adverse events (for example, anticoagulants, corticosteroids, selective serotonin reuptake inhibitors [SSRIs]).
  • A serious comorbidity, such as cardiovascular disease, hepatic or renal impairment (including dehydration), diabetes, or hypertension. 
  • Heavy smoking. 
  • Excessive alcohol consumption. 
  • Previous adverse reaction to NSAIDs.
  • Prolonged requirement for NSAIDs.
• 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:
  • The type of NSAID used.
  • The presence of Helicobacter pylori infection.
  • For more information on risk factors, see the CKS topic on Dyspepsia - proven GORD. 

• Alendronate — concurrent use with nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of upper gastrointestinal (GI) adverse effects. Monitor for signs of GI irritation.
• Angiotensin-converting enzyme (ACE) inhibitors or an angiotensin-II receptor antagonists (AIIRAs) — 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 proton pump inhibitor [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 — 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 AIIRA and a diuretic (the so called 'triple whammy') significantly increases the risk of acute kidney injury (AKI) and should be avoided if possible. For more information on people most at risk of AKI and how to manage them, see the CKS topic on Acute kidney injury.  

• Review the appropriateness of non-steroidal anti-inflammatory drug (NSAID) prescribing widely and on a routine basis, especially in people who are at higher risk of gastrointestinal, renal and cardiovascular 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:
  • Taking COX-2 inhibitors.
    • Before starting treatment. 
    • Two weeks after treatment for etoricoxib. 
    • Periodically during treatment.
  • With hypertension — for example, 1–4 weeks after starting long-term treatment, or increasing the dose of the NSAID. 
• 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:
  • With hepatic impairment.
  • On long-term NSAID therapy.
• Monitor haemoglobin levels in people at high risk of gastrointestinal adverse effects 1–4 weeks after NSAID treatment has started.
• Consider monitoring blood pressure, renal function, and features of heart failure 1–2 weeks after starting or increasing the dose of the NSAID, and then regularly thereafter, in the elderly and people with: 
  • Ischaemic heart disease.
  • Risk factors for cardiovascular disease.
  • Cerebrovascular disease. 
  • Peripheral vascular disease.
  • Heart failure.
• 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).
• For more specific advice check the drug's summary of product characteristics (SPC).

• Avoid nonsteroidal anti-inflammatory drugs (NSAIDs) during conception.
• Paracetamol is the analgesic and/or antipyretic of choice during conception.

• 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:
  • Ibuprofen is the preferred NSAID — however, it should only be used before 30 weeks of pregnancy.
    • COX-2 inhibitors are contraindicated.
  • 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.
  • Use after 30 weeks of pregnancy is associated with premature closure of the ductus arteriosus.
• For more information, contact the UK Teratology Information Service (UKTIS) on 0844 892 0909.

• Paracetamol is the drug of choice for women who are breastfeeding. Seek expert advice if the:
  • Infant is pre-term, or low birthweight.
  • Absorption, distribution, metabolism, or excretion of paracetamol may be affected by an underlying medical condition.
• If a nonsteroidal anti-inflammatory drug (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 gastrointestinal 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. 

• Advise the person about the adverse effects associated with NSAIDs including the cardiovascular and renal and gastrointestinal (GI) adverse effects. 
• Explain that adverse effects may be minimized by:
  • Using an alternative treatment to an oral NSAID (for example paracetamol, or a topical NSAID if appropriate).
  • Using an NSAID at the lowest effective dose and for no longer than is necessary.
  • Taking an NSAID with or after food.
  • Taking a proton pump inhibitor if they have an increased risk of GI adverse effects.
• 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: 
  • Stop the NSAID (and any of the other medicines mentioned on the card) when they are unwell with vomiting or diarrhoea (unless minor), or fever, sweats and shaking (unless minor).
  • Restart when they are well (after 24–48 hours of normal eating and drinking).

• NSAIDs are commonly used over the counter and prescribed by clinicians for people suffering symptoms resulting from acute respiratory infections (ARI). 
• The advice on prescribing NSAIDs to someone with proven or suspected COVID-19 infection is that this should be done with caution. For each person, the following should be taken into account: 
  • Comorbidities and medical history.
  • Risks in each person.
  • Contraindications.
  • Interactions.
  • Monitoring requirements.
• If NSAIDs are prescribed, then this should be at the lowest dose and for the shortest period. 
• The need for continued NSAIDs should be reviewed using clinical judgement. 
• Naproxen and low-dose ibuprofen (up to 1200 mg per day) are considered first-choice options. 
• For people who are taking NSAIDs long term for other indications, the advice is that there no need for them to stop their treatment.

• For acute gout:

  • Give 500 micrograms of colchicine, two to four times a day, until pain relief is achieved, or diarrhoea or vomiting occurs.
    • Do not exceed a total dose of 6 mg of colchicine (i.e. up to 6 days with colchicine 500 micrograms twice a day, or up to 3 days with colchicine 500 micrograms four times a day), and
    • Do not repeat treatment within three days.
  • In the elderly or people with an eGFR of 10-50 mL/minute/1.73m² use a reduced dose or increase the dosage interval. Colchicine is contraindicated in people with an eGFR less than 10 mL/minute/1.72m².
• For prophylaxis of gout (during urate-lowering treatment):

  • Give 500 micrograms of colchicine once or twice a day following initiation of long-term treatment with allopurinol or febuxostat. For more information, see the sections on Allopurinol and Febuxostat.
  • Use colchicine for prophylaxis of gout with caution in people with renal impairment. Limit the dose to:
    • 500 micrograms once a day for people with an eGFR of 30-60 mL/minute/1.72m².
    • 500 micrograms every 2-3 days in people with eGFR 10-30 mL/minute/1.72m².

Adverse effects of colchicine include:

• Gastrointestinal — nausea and vomiting, abdominal pain. Common, and can be severe enough to limit treatment.
• Alopecia
• Blood disorders
• Inhibition of spermatogenesis
• Myopathy and peripheral neuritis

The severity of adverse effects of colchicine is dose-dependent.

• A low-dose regime may produce fewer adverse effects.

Colchicine has a narrow therapeutic index and is extremely toxic in overdose.

• Refer for medical assessment in overdose even if the person has no symptoms.

• Consider febuxostat as an alternative second-line therapy if allopurinol is not tolerated or is contraindicated (for example if renal impairment prevents adequate allopurinol dose increases).
  • Prescribers should be aware that a prior history of hypersensitivity to allopurinol and/or renal disease may indicate potential hypersensitivity to febuxostat.
• Start febuxostat after the acute attack has resolved.
• Perform liver function tests (LFTs) before starting febuxostat treatment, as mild liver test abnormalities have been observed. Check LFTs periodically thereafter, based on clinical judgement.
• Prescribe febuxostat at a starting dose of 80 mg once daily. If the serum uric acid (SUA) level is greater than 300 micromol/L after 4 weeks, increase the dose of febuxostat to 120 mg once daily, aiming for a therapeutic target SUA level of below 300 micromol/L. 
  • In people with mild hepatic impairment, a maximum dose of 80 mg daily is recommended. There is limited information regarding the use of febuxostat in people with more severe hepatic impairment.
  • No dose adjustment is needed for the elderly, or those with mild or moderate renal impairment. Febuxostat has not been fully evaluated in people with severe renal impairment (creatinine clearance less than 30 ml/min).
• When starting or up-titrating febuxostat, flare prophylaxis using colchicine or an NSAID is recommended - see Gout prevention section.
• If a gout flare occurs during treatment with febuxostat:
  • Advise that febuxostat should not be discontinued.
  • Manage the flare as appropriate for the person.
  • Reassure the person that continuous treatment with febuxostat will decrease the frequency and intensity of further gout flares.
• Avoid febuxostat in people with ischaemic heart disease or heart failure.
• Information on prescribing febuxostat is based mainly on a guideline produced by expert representatives of the British Society for Rheumatology (BSR) [Hui, 2017], the Technology Appraisal: Febuxostat for the management of hyperuricaemia in people with gout, published by the National Institute for Health and Clinical Excellence [NICE, 2008b] and the Summary of Product Characteristics for Adenuric^® film-coated tablets [ABPI, 2017].
  • The BSR recommend The Summary of Product Characteristics for Adenuric^® film-coated tablets and the British National Formulary recommend that a prophylactic nonsteroidal anti-inflammatory drug (NSAID) or colchicine is co-prescribed for at least 6 months when starting febuxostat [ABPI, 2017; BNF 74, 2017].
    • The BSR advises that prophylaxis with colchicine can be given for up to 6 months [Hui, 2017].
• Hepatic impairment
  • The manufacturers recommend that a maximum dose of 80 mg once daily is prescribed to people with mild hepatic impairment [ABPI, 2017].

• There is a risk of precipitating acute attacks of gout after starting febuxostat.
  • Advise people who experience acute attacks of gout after initiation of treatment with febuxostat, or during established treatment, to continue taking febuxostat.
• The most commonly reported adverse effects in clinical trials of febuxostat have been mostly mild or moderate in severity. The most common adverse effects are liver abnormalities, diarrhoea, headache, nausea, and rash.
• There have been post-marketing reports of rare serious rashes, generalised skin rashes, and severe hypersensitivity reactions occurring mostly during the first month of treatment with febuxostat. Some of the people affected reported previous hypersensitivity to allopurinol. Following on from this, the Medicines and Healthcare products Regulatory Agency have advised that:
  • Febuxostat should be stopped immediately if signs or symptoms of serious hypersensitivity reactions occur; early withdrawal is associated with a better prognosis.
  • If a hypersensitivity reaction occurs with febuxostat, including Stevens-Johnson syndrome, febuxostat must not be re-started at any time.
  • Anyone taking febuxostat should be advised of the signs and symptoms of severe hypersensitivity reactions or Stevens-Johnson syndrome.
  • A prior history of hypersensitivity to allopurinol and/or renal disease may indicate potential hypersensitivity to febuxostat.
• Somnolence, dizziness, and paresthesia have been reported with febuxostat use.
  • Advise that when starting febuxostat, people should be cautious about driving or using machinery until they are reasonably certain that febuxostat does not adversely affect their performance.

[MHRA, 2012; ABPI, 2017]

• Mercaptopurine and azathioprine. Concomitant use with mercaptopurine or azathioprine is not recommended. The manufacturers SPC details that where this combination cannot be avoided the dose of mercaptopurine/azathioprine should be reduced to 20% or less of the previously prescribed dose.
• Inducers of glucuronidation. Potent inducers might possibly lead to increased metabolism and decreased efficacy of febuxostat. Monitoring of serum uric acid is therefore recommended 1-2 weeks after start of treatment with a potent inducer of glucuronidation. These drugs include rifampicin, phenytoin and phenobarbitone. Conversely, cessation of treatment of an inducer might lead to increased plasma levels of febuxostat.

[ABPI, 2018b]