Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guidelines Osteoarthritis in over 16s: diagnosis and management [NICE, 2022], Low back pain and sciatica in over 16s: assessment and management [NICE, 2020a], Rheumatoid arthritis in adults: management [NICE, 2020b], the European Medicines Agency (EMA) document Questions and answers on the review of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) and cardiovascular risk [EMA, 2012], the European Society of Cardiology (ESC) review and position paper Cardiovascular safety of non-aspirin non-steroidal anti-inflammatory drugs [Schmidt, 2016], expert opinion in narrative reviews Reducing the risk of NSAID related gastrointestinal problems: an update [Bradley, 2020] and Non-steroidal anti-inflammatory drugs (NSAIDs), pain and aging: Adjusting prescription to patient features [Ribeiro, 2022], and what CKS considers good clinical practice.

Considering baseline blood tests prior to initiating NSAIDs

• The recommendation to consider baseline blood tests prior to initiating an NSAID in people with a history of renal impairment, congestive heart failure, hypertension and/or type 2 diabetes mellitus, or the presence of unexplained anaemia, is from an Asian primary care practice advisory paper presenting consensus statements and guidance regarding appropriate NSAID use Practice Advisory on the Appropriate Use of NSAIDs in Primary Care [Ho, 2020]. 
  

Basis for recommendation

These recommendations are based on the Medicines and Healthcare products Regulatory Agency (MHRA) drug safety updates Diclofenac: new contraindications and warnings [MHRA, 2014], Non-steroidal anti-inflammatory drugs (NSAIDs): reminder on renal failure and impairment [MHRA, 2009], Aceclofenac (Preservex): updated cardiovascular advice in line with diclofenac and COX-2 inhibitors [MHRA, 2015a], and Non-steroidal anti-inflammatory drugs (NSAIDs): potential risks following prolonged use after 20 weeks of pregnancy [MHRA, 2023], the British National Formulary [BNF, 2023], and the manufacturers' Summaries of Product Characteristics for Diclomax retard [EMC, 2023a], ibuprofen [EMC, 2022a], naproxen [EMC, 2023b], ketoprofen [EMC, 2023c], mefenamic acid [EMC, 2022b], piroxicam [EMC, 2021], celecoxib [EMC, 2023d], etoricoxib [EMC, 2020], and tiaprofenic acid[MHRA, 2021]. 

NSAIDs and renal impairment or failure

• The adverse renal effects associated with NSAIDs are mainly mediated via inhibition of prostaglandin-induced vasodilation which can result in reduced renal blood flow. NSAID use may also result in direct renal toxicity. The main mechanisms for acute renal failure include acute tubular necrosis and acute interstitial nephritis [MHRA, 2009].
• The MHRA recommends that people at risk of renal impairment or renal failure (particularly older people) should avoid NSAIDs if possible, as NSAIDs may rarely precipitate renal failure [MHRA, 2009].
• In cases where NSAID treatment is considered necessary in people at risk of renal impairment or renal failure, then the lowest effective dose for the shortest possible duration should be used, with regular monitoring of renal function [MHRA, 2009].

Avoiding NSAID use in women experiencing difficulties conceiving or who are under investigation for infertility

• There is conflicting evidence as to whether NSAID use in early pregnancy may be associated with an increased risk of miscarriage [UKTIS, 2019].
• Although the available evidence is likely confounded, and a causal association between NSAID use in early pregnancy and miscarriage has not yet been fully determined, women experiencing difficulties conceiving or who are under investigation for infertility may benefit from avoiding NSAIDs.

A pregnancy that has reached 20 weeks or beyond

• Prolonged use of NSAIDs from 20 weeks of pregnancy onwards may be associated with an increased risk of oligohydramnios (as a result of impaired fetal renal function) and constriction of the ductus arteriosus [Dathe, 2019; Dathe, 2022].
• There is limited evidence to indicate the duration of use which may present a risk to the fetus, but NSAID use limited to a few days is not expected to pose a relevant risk [Dathe, 2022].
• The MHRA advises that [MHRA, 2023]:
  • Systemic NSAIDs should not be prescribed from week 20 of pregnancy onwards unless clinically required.
  • When required, NSAIDs should be prescribed at the lowest dose for the shortest time.
  • Where use exceeds several days, antenatal monitoring should be considered.
    • Oligohydramnios may occur shortly after initiation, although it is usually reversible upon discontinuation.
    • Constriction of the ductus arteriosus may also occur at this stage of pregnancy, but may resolve after treatment cessation.
  • Should oligohydramnios or ductal constriction occur, or if the NSAID is no longer clinically necessary, the NSAID should be discontinued.

Basis for recommendation

This information is based on the U.S. Food and Drug Administration (FDA) drug safety communication FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes [FDA, 2015], the European Society of Cardiology (ESC) review and position paper Cardiovascular safety of non-aspirin non-steroidal anti-inflammatory drugs [Schmidt, 2016], a literature review and analysis of the French pharmacovigilance database [Krabansky, 2018], guidance from the Royal College of Physicians Non-steroidal anti-inflammatory drugs and the gastrointestinal tract [Tai, 2021], expert opinion in a narrative review Reducing the risk of NSAID related gastrointestinal problems: an update [Bradley, 2020], the manufacturers' Summaries of Product Characteristics for Diclomax retard [EMC, 2023a], ibuprofen [EMC, 2022a], naproxen [EMC, 2023b], celecoxib [EMC, 2023d], and etoricoxib [EMC, 2020], and the British National Formulary [BNF, 2023]. 

NSAIDs and cardiovascular adverse effects

• NSAIDs can increase the risk of heart attack or stroke in people with or without heart disease or risk factors for heart disease [FDA, 2015].  
  • However, in general, people with heart disease or risk factors for it have a greater likelihood of heart attack or stroke following NSAID use than people without these risk factors because they have a higher risk at baseline.
• All non-aspirin NSAIDs roughly double the risk of heart failure, and increase the risk of adverse effects in people with heart failure, including recurrent admission for myocardial infarction and dose-related excess mortality risk [Schmidt, 2016].
  • Naproxen appears to have the least harmful cardiovascular risk profile, including in people with myocardial infarction or heart failure.

NSAIDs and gastrointestinal adverse effects

• Symptomatic upper gastrointestinal (GI) peptic ulcer disease and bleeding are the most commonly recognised adverse events related to NSAIDs, and complications can occur with or without symptoms, in the presence or absence of mucosal injury, and in the upper, mid and lower gastrointestinal tract [Tai, 2021].
• Approximately one-third of NSAID users will develop symptoms of dyspepsia (epigastric discomfort, bloating, post-prandial nausea, early satiety and belching) and gastroesophageal reflux (heartburn and regurgitation). However, these symptoms poorly predict the presence of NSAID-induced gastrointestinal adverse effects, as 20% of people with these symptoms will have a normal oesophagogastroduodenoscopy [Tai, 2021].
• Endoscopic evidence of mucosal injury in the upper GI tract is common with chronic use of NSAIDs, affecting as many as 70% of chronic users compared with 10% of people not taking NSAIDs [Ho, 2020; Tai, 2021].

How should I manage the risk of cardiovascular and renal adverse effects?

• For people with heart failure:
  • Severe heart failure — do not prescribe nonsteroidal anti-inflammatory drugs (NSAIDs).
  • Mild to moderate heart failure — do not prescribe a COX-2 inhibitor, aceclofenac, 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 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, consider the need for monitoring.
    • COX-2 inhibitors, aceclofenac, 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 cardiovascular (CV) disease or the elderly, prescribe:
  • Ibuprofen up to 1200 mg per day or naproxen up to 1000 mg daily.
    • Diclofenac should only be initiated after careful consideration of the associated risks in people with risk factors for CV disease.
  • If a COX-2 inhibitor is required (for example in those with risk factors for gastrointestinal adverse effects), where not otherwise contraindicated, use of celecoxib 100 mg twice daily may be considered when the benefits are expected to outweigh the risks.
    • There are insufficient CV safety data to permit the use of higher doses of celecoxib.
    • Regularly re-evaluate the ongoing need for, and response to therapy, and monitor the person closely.
• For people with hypertension:
  • Avoid prescribing etoricoxib or high-dose ibuprofen in people with uncontrolled hypertension (blood pressure persistently above 140/90 mmHg). 
  • Consider whether monitoring is needed.

Basis for recommendation

These recommendations are based on the Medicines and Healthcare products Regulatory Agency (MHRA) drug safety updates Diclofenac: new contraindications and warnings [MHRA, 2014], High-dose ibuprofen (≥2400mg/day): small increase in cardiovascular risk [MHRA, 2015b], Cox-2 selective inhibitors and non-steroidal anti- inflammatory drugs (NSAIDs): Cardiovascular safety [MHRA, 2015c], and Non-steroidal anti-inflammatory drugs (NSAIDs): reminder on renal failure and impairment [MHRA, 2009], the European Society of Cardiology (ESC) review and position paper Cardiovascular safety of non-aspirin non-steroidal anti-inflammatory drugs [Schmidt, 2016], joint recommendations from six Asian Pacific medical societies/associations Non-steroidal anti-inflammatory drug (NSAID) therapy in patients with hypertension, cardiovascular, renal or gastrointestinal comorbidities [Szeto, 2020], an Asian primary care practice advisory paper presenting consensus statements and guidance regarding appropriate NSAID use Practice Advisory on the Appropriate Use of NSAIDs in Primary Care [Ho, 2020], expert opinion in narrative reviews Reducing the risk of NSAID related gastrointestinal problems: an update [Bradley, 2020] and Non-steroidal anti-inflammatory drugs (NSAIDs), pain and aging: Adjusting prescription to patient features [Ribeiro, 2022], the British National Formulary [BNF, 2023], the European Medicines Agency (EMA) review Updated advice on the use of high-dose ibuprofen [EMA, 2015], a U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) statement FDA Approves labeling supplement for Celebrex (celecoxib) [FDA, 2018], the FDA drug safety communication FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes [FDA, 2015], and the manufacturers' Summaries of Product Characteristics for Diclomax retard [EMC, 2023a], ibuprofen [EMC, 2022a], naproxen [EMC, 2023b], celecoxib [EMC, 2023d], and etoricoxib [EMC, 2020], and expert opinion in a medical textbook Medical Pharmacology at a glance [Neal, 2015].

People at increased risk of cardiovascular events

• Nonsteroidal anti-inflammatory drugs (NSAIDs) can increase the risk of heart attack or stroke in people with or without heart disease, or risk factors for heart disease [FDA, 2015]. 
  • However, in general, people with heart disease or risk factors for it have a greater likelihood of heart attack or stroke following NSAID use than people without these risk factors, because they have a higher risk at baseline. 
• All non-aspirin NSAIDs roughly double the risk of heart failure, and increase the risk of adverse effects in people with heart failure, including recurrent admission for myocardial infarction and dose-related excess mortality risk [Schmidt, 2016].

Increased risk of renal adverse effects

• NSAIDs, including COX-2 inhibitors, may rarely precipitate renal failure, and vulnerable (particularly elderly) people may be at increased risk [MHRA, 2009]. 
• Risk factors include older age, renal impairment, heart failure, liver disease, diabetes mellitus, and concurrent prescription with antihypertensive drugs (for example diuretics and renin-angiotensin system inhibitors) [Ho, 2020].
• A nested case-control study of standard NSAIDs using a nationally representative UK primary care records dataset described a 3-fold increased risk of acute renal failure following NSAID use (with both short and long-term therapy) — ibuprofen was associated with a lower risk than diclofenac in this study [Huerta, 2005].
• Four systematic reviews found increased risks of hypertension and elevated blood pressure (particularly systolic blood pressure) with NSAIDs [Aw, 2005; Zhang, 2006; Morrison, 2007; Chan, 2009].
• A matched case-control study described an association between conventional NSAID use and nephrotic syndrome with NSAID exposure from at least 2 weeks, and following recent (discontinuation 1-2 months prior to the diagnosis of nephrotic syndrome) and past exposure (discontinuation up to 2 years prior). These associations appeared mainly attributable to acetic acid (indomethacin, diclofenac etc.) and propionic acid (ibuprofen, naproxen etc.) NSAID derivatives [Bakhriansyah, 2019].
• Etoricoxib, particularly at high doses, may be associated with more frequent and severe effects on blood pressure than other selective COX-2 inhibitors and standard NSAIDs [EMC, 2020].
• A Cochrane systematic review investigating the effect of NSAIDs used in the peri‐operative period on post‐operative kidney function in patients with normal kidney function (26 studies, 8835 participants) did not identify any clear effect on post-operative Acute Kidney Injury (AKI) risks, serum creatinine (SCr), urine output, requirement for renal replacement therapy (RRT), death (all causes) or length of hospital stay [Bell, 2018].

NSAIDS and cardiovascular (CV) risk profile

• COX-2 inhibitors may be associated with an increased risk of cardiovascular problems such as heart attacks and strokes [MHRA, 2015c].
  • The MHRA have stated that it is not possible to measure the increased risk precisely from the available evidence [MHRA, 2015c].
  • A 2006 meta-analysis indicated that COX-2 inhibitor use may be associated with about 3 additional thrombotic events per 1000 patients per year, which was mainly attributable to an approximate 2-fold increased risk of myocardial infarction [Kearney, 2006].
• People taking 2400 mg or more of ibuprofen daily are at a higher risk of arterial thrombotic events (heart attack, stroke) than people taking placebo. This higher risk is similar to that seen with COX-2 inhibitors and diclofenac [MHRA, 2015b]. 
  • No increased risk of arterial thrombotic events is seen with ibuprofen at doses up to 1200 mg daily compared with not taking ibuprofen. There are limited data on the risk with ibuprofen at doses between 1200 mg and 2400 mg per day. It is uncertain whether such doses are associated with an increased cardiovascular risk compared with not taking ibuprofen.
• An EMA review also advised that data from meta-analyses and epidemiological studies confirmed a small increased risk of cardiovascular problems in people taking high doses of ibuprofen, and confirmed that there was no increased risk with ibuprofen doses up to 1200 mg daily [EMA, 2015].
• Naproxen or low-dose ibuprofen are considered to have the most favourable thrombotic cardiovascular safety profiles of all non-selective NSAIDs [MHRA, 2014].  
• A non-inferiority trial, the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) trial (n = 24,081), which assessed CV outcomes with long-term use, concluded that celecoxib was non-inferior to naproxen and ibuprofen in terms of CV safety [Nissen, 2016].  
• However, the design and study of the PRECISION trial has been questioned as [FitzGerald, 2016; ]: 
  • 68.8% of patients stopped taking the treatment drug and 27.4% discontinued follow‐up, which may have introduced bias and confounding.
  • The study mostly included people with osteoarthritis at low CV risk.  
  • Due to the low number of events, the statistical power for non-inferiority was relaxed during the trial from 1.3 to 1.4.
  • The dose of celecoxib was restricted to just over 209 mg, while doses of ibuprofen and naproxen were allowed to be increased to attain efficacy — the mean daily doses of ibuprofen and naproxen were 2045 mg and 852 mg respectively.
  • The trial did not take into account use of aspirin in people taking naproxen or ibuprofen, which may reduce the cardioprotective effect, while this interaction does not happen with celecoxib.
• The FDA concluded that the results of the PRECISION trial demonstrated that celecoxib, at the lowest approved dose of 100 mg twice daily, is non-inferior to ibuprofen 600–800 mg three times daily, or naproxen 375–500 mg twice daily on a composite cardiovascular endpoint consisting of CV death, nonfatal myocardial infarction, and nonfatal stroke [FDA, 2018]. 
  • Too few people received higher doses of celecoxib to evaluate the risk of CV events or the effect on blood pressure for doses greater than 100 mg twice daily, so this result cannot be extrapolated to higher doses (200 mg or 400 mg).
• A Bayesian meta-analysis of individual patient data from four studies (involving 61,640 acute myocardial infarctions, across a population of 446,763 individuals) [Bally, 2017], compared the risk of acute myocardial infarction in NSAID users (COX-2 inhibitors and traditional NSAIDs) with non-users, concluded that:   
  • All NSAIDs, including naproxen, were associated with an increased risk of acute myocardial infarction (MI). 
  • The risk of MI with celecoxib was comparable to that of traditional NSAIDS and was lower than for rofecoxib.
  • The risk was greatest during the first month of NSAID use and with higher doses.
  • The risk for longer than one month was no greater than for short term use.
• The recommendation to cautiously consider the use of low dose celecoxib in people with risk factors for cardiovascular disease or the elderly was provided in an Asian primary care practice advisory paper which presents consensus statements and guidance regarding appropriate NSAID use [Ho, 2020]. This specific guidance appears to be mainly based on results from the PRECISION trial.
• Nonsteroidal anti-inflammatory drugs (NSAIDs) should be prescribed at the lowest effective dose for the shortest possible duration [Schmidt, 2016]. 
  • However, while use of NSAIDs in people with myocardial infarction and heart failure was thought to be risk-neutral in short treatment periods and in low doses, cumulating evidence suggests that there is no safe-treatment window.

How should I manage the risk of GI adverse effects?

• To prevent gastrointestinal (GI) adverse effects associated with the use of a nonsteroidal anti-inflammatory drug (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.
• For people:
  • With osteoarthritis and rheumatoid arthritis — co-prescribe a proton pump inhibitor (PPI) with an NSAID (see Table 1 for licensed doses of PPIs for gastroprotection).
  • Who are elderly — co-prescribe a PPI with an NSAID. 
  • With low back pain, axial spondyloarthritis, psoriatic arthritis, and other peripheral spondyloarthritides — consider gastroprotection when prescribing an NSAID.
  • For further prescribing information, see the CKS topic on Dyspepsia - proven GORD.
• 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 the range of previous investigations (for example with endoscopy or a test for Helicobacter pylori) and whether 'alarm' symptoms are present. For full details, see the CKS topics on:
    • Dyspepsia - pregnancy-associated
    • Dyspepsia - proven functional
    • Dyspepsia - proven peptic ulcer
    • Dyspepsia - unidentified cause
• For detailed information on the use of low-dose aspirin, including advice on how to minimize the risk of GI adverse events, see the CKS topic on Antiplatelet treatment.

Licensed doses of proton pump inhibitors used for gastroprotection for people who require continued NSAID treatment

Table 1. Licensed doses of proton pump inhibitors used for gastroprotection for people who require continued NSAID treatment.

For further prescribing information, see the CKS topic on Dyspepsia - proven GORD.

Basis for recommendation

These recommendations are based on the American College of Gastroenterology (ACG) guideline Guidelines for Prevention of NSAID-Related Ulcer Complications [Lanza, 2009], the National Institute for Health and Care Excellence (NICE) guidelines Osteoarthritis in over 16s: diagnosis and management [NICE, 2022], Gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management [NICE, 2019], Low back pain and sciatica in over 16s: assessment and management [NICE, 2020a], Rheumatoid arthritis in adults: management [NICE, 2020b], the European Society of Cardiology (ESC) review and position paper Cardiovascular safety of non-aspirin non-steroidal anti-inflammatory drugs [Schmidt, 2016], the British Pain Society (BPS) Guidance on the management of pain in older people [Abdulla, 2013], guidance from the Royal College of Physicians Non-steroidal anti-inflammatory drugs and the gastrointestinal tract [Tai, 2021], joint recommendations from six Asian Pacific medical societies/associations Non-steroidal anti-inflammatory drug (NSAID) therapy in patients with hypertension, cardiovascular, renal or gastrointestinal comorbidities [Szeto, 2020], an Asian primary care practice advisory paper presenting consensus statements and guidance regarding appropriate NSAID use Practice Advisory on the Appropriate Use of NSAIDs in Primary Care [Ho, 2020], systematic reviews Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS project) [Castellsague, 2012], and Comparative effectiveness and safety of strategies for preventing NSAID-associated gastrointestinal toxicity [Yuan, 2016], expert opinion in a medical textbook Medical Pharmacology at a glance [Neal, 2015], expert opinion in narrative reviews Non-steroidal anti-inflammatory drugs (NSAIDs) [O'Day, 2013], Non-steroidal anti-inflammatory drugs (NSAIDs): making safer treatment choices [BPJ, 2013], Reducing the risk of NSAID related gastrointestinal problems: an update [Bradley, 2020]and Non-steroidal anti-inflammatory drugs (NSAIDs), pain and aging: Adjusting prescription to patient features [Ribeiro, 2022], and a consensus report Management of Helicobacter pylori infection—the Maastricht V/Florence Consensus Report [Malfertheiner, 2017]. 

Risk stratification and NSAID treatment choice

• NICE considers that people with a previous peptic ulcer are at high risk of GI adverse effects and should be prescribed a COX-2 inhibitor plus a PPI, or if a standard NSAID is preferred, a PPI should be co-prescribed [NICE, 2019].
• NICE recommends that clinicians should be aware of the limited evidence of benefits of NSAIDs in people with sciatica [NICE, 2020a].
  • When NSAIDs are being considered in people with sciatica, potential differences in gastrointestinal, liver and cardio-renal toxicity profiles alongside the person's risk factors, including age, should be used to determine the most appropriate treatment option.
  • When NSAIDs are used for sciatica, regular monitoring of clinical features of, and risk factors for, adverse events, and the use of gastroprotective treatment is recommended. NSAID use should also be at the lowest effective dose for the shortest possible period of time.
• The ACG guideline states that people with a previous uncomplicated ulcer (and no other risk factors) are at moderate risk, while people with a previous complicated ulcer are at high risk of GI adverse events [Lanza, 2009]. 
• CKS recommends using clinical judgement to determine the individual risk of GI adverse effects for people starting NSAIDs and when deciding if gastroprotection is required. 

Managing GI risk

• Coxibs are associated with a reduction in the risk of GI symptoms and complications compared with standard NSAIDs, but they do not eliminate the risk of GI adverse effects [Rostom, 2007]. 
  • Selectivity for COX-2 represents a continuum, and COX-2 inhibitors can therefore be ranked based on their relative COX-2 vs COX-1 selectivity, with etoricoxib more selective than celecoxib [Schmidt, 2016].
• Proton pump inhibitors (PPIs) are well tolerated and effective at reducing the GI risks associated with NSAIDs and reduce the risks to a similar level as using a coxib alone [Chan, 2002; Ho, 2020].
• The combination of selective COX-2 inhibitors plus PPIs provides the best gastrointestinal protection, followed by selective COX-2 inhibitors alone, and thirdly by nonselective NSAIDs plus PPIs [Yuan, 2016].
  • Health economic analysis found that it was cost-effective to routinely prescribe a PPI to people taking NSAIDs or COX-2 inhibitors [Bradley, 2020].
• Options for gastroprotective drugs to prescribe with standard NSAIDs also include misoprostol or a histamine₂–receptor antagonist, but a PPI is the preferred choice [Ho, 2020; BNF, 2023].
• Although long-term PPI use is associated with an increased risk of fracture (particularly when used at high doses for over a year in the elderly) and osteoporosis, and may increase the risk of GI infections (including Clostridioides difficile), mask symptoms of gastric cancer and reduce absorption of vitamin B12 [Bradley, 2020].
• H. pylori eradication may also help to prevent NSAID induced GI complications, but may be inferior to the gastroprotective effect provided by PPI use [Ho, 2020].
• Chronic and concomitant use of NSAIDs and PPIs, particularly with exposure lasting between 4 and 12 months, increases the risk of microscopic colitis [Tai, 2021].
  • People using NSAIDs who develop a chronic non-bloody watery diarrhoea should discontinue NSAIDs where possible [Tai, 2021].

Basis for recommendation

These recommendations are based on the medical textbook Stockley's drug interactions [Preston, 2016], the British National Formulary [BNF, 2023], expert opinion in a narrative review Non-steroidal anti-inflammatory drugs (NSAIDs): making safer treatment choices [BPJ, 2013], expert opinion in a narrative review Practice Advisory on the Appropriate Use of NSAIDs in Primary Care [Ho, 2020], a retrospective cohort study Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study [Lapi, 2013], and the manufacturers' Summaries of Product Characteristics for Diclomax retard [EMC, 2023a], ibuprofen [EMC, 2022a], naproxen [EMC, 2023b], celecoxib [EMC, 2023d], and etoricoxib [EMC, 2020].

Triple therapy interactions

• Triple therapy with a nonsteroidal anti-inflammatory drug (NSAID), an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-II receptor antagonist (AIIRAs) and diuretic is associated with an increased risk of acute kidney injury [BPJ, 2013].   
• A nested case-control study of people using antihypertensive drugs (n = 487,372) which identified 2215 cases of acute kidney injury found that current use of triple therapy (ACE inhibitor/AIIRAs, a diuretic and an NSAID) was associated with an increased rate of acute kidney injury (Rate Ratio 1.31, 95% CI 1.12–1.53) compared to double therapy (diuretic plus ACE inhibitor/AIIRA). The greatest risk was observed in the first 30 days of use (Rate Ratio 1.82, 95% CI 1.35-2.46) [Lapi, 2013].

Cisplatin-induced nephrotoxicity

• Cisplatin is a highly potent cytotoxic medication used to treat several types of cancers, but causes kidney disorder in approximately 30% of treated people. As cisplatin-induced nephrotoxicity is a dose-limiting adverse event, prevention is therapeutically beneficial [Okamoto, 2020].
• A meta-analysis of seven retrospective studies (n=1282 participants) described a statistically significant association between NSAID use and cisplatin-induced nephrotoxicity [Okamoto, 2020].

Basis for recommendation

These recommendations are pragmatic and largely based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease in adults: assessment and management [NICE, 2021], joint recommendations from six Asian Pacific medical societies/associations Non-steroidal anti-inflammatory drug (NSAID) therapy in patients with hypertension, cardiovascular, renal or gastrointestinal comorbidities [Szeto, 2020], the Medicines and Healthcare products Regulatory Agency (MHRA) drug safety update Non-steroidal anti-inflammatory drugs (NSAIDs): potential risks following prolonged use after 20 weeks of pregnancy [MHRA, 2023], expert opinion in narrative reviews Non-steroidal anti-inflammatory drugs (NSAIDs): making safer treatment choices [BPJ, 2013], and Non-steroidal anti-inflammatory drugs (NSAIDs) [O'Day, 2013], the manufacturers' Summaries of Product Characteristics for Diclomax retard [EMC, 2023a], ibuprofen [EMC, 2022a], naproxen [EMC, 2023b], celecoxib [EMC, 2023d], and etoricoxib [EMC, 2020], and the British National Formulary [BNF, 2023].

• Fluid retention and oedema are associated with NSAID therapy, so particular caution is required in people with impaired cardiac or renal function, history of hypertension, the elderly, and people receiving concomitant treatment with diuretics or medicinal products that can significantly impact renal function [EMC, 2023a].
• The suggested monitoring intervals in people starting nonsteroidal anti-inflammatory drugs (NSAIDS) who also have heart failure, hypertension, or renal impairment, are extrapolated from the monitoring advice for people starting ACE inhibitors. See the CKS topics on Chronic kidney disease, Hypertension, and Heart failure - chronic for further information.

Basis for recommendation

These recommendations are based on the British National Formulary [BNF, 2023], the manufacturers' Summaries of Product Characteristics for Diclomax retard [EMC, 2023a], ibuprofen [EMC, 2022a], naproxen [EMC, 2023b], celecoxib [EMC, 2023d], and etoricoxib [EMC, 2020], expert opinion in a medical textbook Drugs during pregnancy and Lactation: treatment options and risk assessment [Schaefer, 2015], and a prospective cohort study Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population based cohort study [Li, 2003]. 

• Long-term use of some NSAIDs is associated with reduced female fertility, which is reversible on stopping treatment [BNF, 2023].
• NSAID use around conception has been associated with an increased risk of miscarriage. In a prospectively conducted study which recruited more than 1000 women with a positive pregnancy test, 53 (5%) of whom reported NSAID use, there was a nearly 2-fold risk for miscarriage in those who had used naproxen or ibuprofen compared to non-users [Schaefer, 2015; Li, 2003].
  • Suppression of prostaglandin synthesis could lead to abnormal implantation resulting in miscarriage. However, conclusive evidence on causal association is lacking [Schaefer, 2015]. 
  • The associated risk was particularly high when NSAIDs were used around the time of conception, and the risk was also higher when NSAIDs were used for longer than a week [Li, 2003]. 
  • Use of paracetamol during pregnancy was not associated with risk of miscarriage regardless of the timing or duration of use [Li, 2003]. 
• Paracetamol is the analgesic and antipyretic of first choice during pregnancy, and can be used in any trimester when indicated [Schaefer, 2015]. 

Basis for recommendation

These recommendations are based on the Medicines and Healthcare products Regulatory Agency (MHRA) drug safety update Non-steroidal anti-inflammatory drugs (NSAIDs): potential risks following prolonged use after 20 weeks of pregnancy [MHRA, 2023], UK Teratology Information Service (UKTIS) articles Use of nonsteroidal anti-inflammatory drugs (NSAIDs) in pregnancy [UKTIS, 2019], Therapeutic use of paracetamol in pregnancy [UKTIS, 2017], expert opinion in a medical textbook Drugs during pregnancy and Lactation: treatment options and risk assessment [Schaefer, 2015] and a literature review Medication Use and Pain Management in Pregnancy: A Critical Review [Black, 2019], the British National Formulary [BNF, 2023], and the manufacturers' Summaries of Product Characteristics for Diclomax retard [EMC, 2023a], ibuprofen [EMC, 2022a], naproxen [EMC, 2023b], celecoxib [EMC, 2023d], and etoricoxib [EMC, 2020].

Use of NSAIDs in pregnancy

• NSAIDs should only be used in the first 6 months of pregnancy if clearly necessary [EMC, 2022a].
  • All NSAIDs should be avoided in the third trimester [Black, 2019; UKTIS, 2019; MHRA, 2023].
  • Exposure to NSAIDs after 28 weeks gestation has been associated with an increased risk of premature closure of the ductus arteriosus and oligohydramnios [MHRA, 2023].
  • Repeated use of NSAIDs should be avoided after 28 weeks of pregnancy as oligohydramnios can occur as a result of fetal renal impairment, and inhibition of prostaglandin synthesis may lead to premature closure of the ductus arteriosus (DA) [Schaefer, 2015].
  • Premature closure of the DA increases the risk of persistent pulmonary hypertension in the newborn (PPHN). There are conflicting results from observational studies as to whether NSAID use in pregnancy is associated with PPHN [UKTIS, 2019].
• Prolonged use of NSAIDs from 20 weeks of pregnancy onwards may be associated with an increased risk of oligohydramnios and constriction of the ductus arteriosus [Dathe, 2019; Dathe, 2022].
  • Evidence is limited as to the length of use which may present a risk to the fetus, but NSAID use limited to a few days is not expected to pose a relevant risk [Dathe, 2022].
  • The MHRA advises that [MHRA, 2023]:
    • Systemic NSAIDs should not be prescribed from week 20 of pregnancy onwards unless clinically required.
    • When required, NSAIDs should be prescribed at the lowest dose for the shortest time.
    • Where use exceeds several days, antenatal monitoring should be considered — oligohydramnios may occur shortly after initiation, although it is usually reversible upon discontinuation, and constriction of the ductus arteriosus may also occur at this stage of pregnancy, but may resolve after treatment cessation.
    • Should oligohydramnios or ductal constriction occur, or if the NSAID is no longer clinically necessary, the NSAID should be discontinued.
• Ibuprofen is the analgesic of choice after paracetamol. Use of diclofenac is also possible [Schaefer, 2015].
• COX-2 inhibitors are contraindicated at any stage of pregnancy [Schaefer, 2015].

Use of paracetamol during pregnancy

• Paracetamol is the analgesic/antipyretic of first choice in pregnancy and can be used in any trimester when indicated [Schaefer, 2015; Black, 2019].
• Paracetamol use in pregnancy has been associated with an increased incidence of [Black, 2019; UKTIS, 2017]:
  • Cryptorchidism in male offspring following paracetamol use during pregnancy, although findings are conflicting.
  • Wheezing or childhood asthma with frequent paracetamol use during late pregnancy (20–32 weeks).
  • Poorer gross motor development, communication skills, externalising and internalising behaviours, and to have higher activity levels in children exposed to paracetamol in utero.
  • Behaviour subtypes that may be indicative of ADHD.
  • Symptoms of autism spectrum disorder (ASD) in boys (but not girls), and an increased risk of ASD with hyperkinetic symptoms in children but no increased risk of ASD without hyperkinetic symptoms.
• However, several important methodological limitations have been highlighted for the observational studies which have described associations between paracetamol use in pregnancy and neurodevelopmental impairments (ADHD/ASD) [Damkier, 2022]. A causal association with an increased risk of any adverse fetal outcome following therapeutic paracetamol use (500–1000 mg up to four times a day, with a maximum dose of 4g within a 24 hour period) in pregnancy therefore remains to be proven [UKTIS, 2017].

Basis for recommendation

These recommendations are based on expert opinion in a medical textbook Drugs during pregnancy and Lactation: treatment options and risk assessment [Schaefer, 2015], the UK Medicines Information (UKMI) document Can breastfeeding mothers take paracetamol or combination paracetamol products? [UKMI, 2020] the Specialist Pharmacy Service (SPS) articles Safety in lactation: nonsteroidal anti-inflammatory drugs [SPS, 2020a] and Safety in Lactation: Drugs for the relief of soft-tissue inflammation and topical pain relief [SPS, 2020b], the British National Formulary [BNF, 2023], ​​​and the manufacturers' Summaries of Product Characteristics for Diclomax retard [EMC, 2023a], ibuprofen [EMC, 2022a], naproxen [EMC, 2023b], celecoxib [EMC, 2023d], and etoricoxib [EMC, 2020].

Basis for recommendation

These recommendations are pragmatic and what CKS consider good clinical practice. 

Basis for recommendation

These recommendations are based on NICE COVID-19 rapid evidence summary: acute use of non-steroidal anti-inflammatory drugs (NSAIDs) for people with or at risk of COVID-19 [NICE, 2020c], the Centre for Evidence Based Medicine (CEBM) review on NSAIDs in acute respiratory infection (not including COVID-19) [CEBM, 2020], a World Health Organization (WHO) rapid systematic review The use of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with COVID-19 also located no studies investigating the safety of NSAID use in people with COVID-19 [WHO, 2020], the European Medicines Agency (EMA) guidance on the use of non-steroidal anti-inflammatories for COVID-19 [EMA, 2020] and general guidance from the Medicines and Healthcare products Regulatory Authority (MHRA) Non-steroidal anti-inflammatory drugs (NSAIDs): cardiovascular risks [MHRA, 2012] and Cox-2 selective inhibitors and non-steroidal anti-inflammatory drugs’ (NSAIDs): Cardiovascular safety [MHRA, 2015c].

Prescribe NSAIDs with caution to people with COVID-19

• Guidance from NICE and the CEBM recommends that NSAIDs ‘do not significantly reduce total symptoms or duration of respiratory infections (ARI) [NICE, 2020c; CEBM, 2020].
• The CEBM also concludes that because several publications suggest the possibility of poorer outcomes for people with ARI who are also prescribed NSAIDs, there is a need for caution when using NSAIDs for acute respiratory infections [CEBM, 2020].
• A rapid systematic review published by the WHO located no studies investigating the safety of NSAID use in people with COVID-19 [WHO, 2020].
  • The review also found limited evidence regarding the safety of NSAID use in people with acute viral respiratory infections.
  • No evidence was located regarding the effects of NSAID use on acute health care utilization, explicit quality of life measures, or long-term survival.
  • The only evidence of moderate to high certainty from this review was the little or no difference in risk of death from all causes, hospitalization for any cause, acute renal failure, and acute gastrointestinal bleeding between children with fever who were treated with ibuprofen in comparison to those treated with paracetamol.

Consider individual risk factors before prescribing NSAIDs to people with COVID-19

• The basis for considering individual risk factors for adverse effects before prescribing NSAIDs to people with COVID-19, including any contraindications, drug interactions, pre-existing conditions and medical history and any monitoring requirements, is based on the CEBM review [CEBM, 2020] and NICE guidance [NICE, 2020c].

Prescribing advice regarding use of NSAIDs in people with COVID-19

• The CEBM advise that clinicians prescribe the lowest effective dose of an NSAID for the shortest period required to control symptoms, and the need for long-term treatment should be reviewed periodically [CEBM, 2020].
• The European Medicines Agency (EMA) [EMA, 2020] advises that, when starting treatment for fever or pain in COVID-19, patients and healthcare professionals should consider all available treatment options, including paracetamol and NSAIDs.

Naproxen and low-dose ibuprofen as first-choice options

• The Medicines and Healthcare products Regulatory Authority (MHRA) advises that naproxen and low-dose ibuprofen (up to 1200 mg per day) are considered to have the most favourable thrombotic cardiovascular safety profiles of all NSAIDs [MHRA, 2012; MHRA, 2015c].

Do not interrupt treatment in people with COVID-19 who are using NSAIDs long-term

• The EMA [EMA, 2020] and NICE [NICE, 2020c] advise that there is currently no reason for patients taking ibuprofen to interrupt their treatment, and these sources stress that this is particularly important for patients taking ibuprofen or other NSAIDs for chronic diseases.