Choosing a nonsteroidal anti-inflammatory drug for pain

SUMMARY

Nonsteroidal anti-inflammatory drugs (NSAIDs) are useful for many conditions, frequently in preference to other therapies such as opioids. They play an important role in osteoarthritis, headache disorders, acute musculoskeletal injury, dysmenorrhoea and dental pain. In axial spondyloarthritis, they can modify disease and represent first-line therapy.

Most NSAIDs have comparable efficacy for most conditions, despite their different pharmacodynamic effects. The pharmacokinetic profile of different NSAIDs might confer varying risks and advantages for acute or chronic conditions that influence their selection.

NSAIDs have well-recognised adverse effects, including cardiovascular, renal and gastrointestinal risks. While these risks vary between NSAIDs, all of them confer some increased risk. Proton pump inhibitors reduce upper gastrointestinal complications but not lower gastrointestinal ones. Other important precautions relate to pregnancy and hypersensitivity reactions.

 

Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used medicines worldwide. They are effective for a wide variety of indications given their broad analgesic, anti-inflammatory and antipyretic effects. NSAIDs are underutilised in some situations and play a role in reducing the burden of acute and chronic opioid use.^1,2 Nonetheless, the appropriate prescribing of NSAIDs poses a significant challenge to clinical decision-making, balancing variable benefit and risk in the context of individual patients. NSAIDs have a well-recognised spectrum of adverse effects, particularly involving the cardiovascular, renal and gastrointestinal systems. Safe and appropriate selection of an NSAID must therefore be guided by both patient factors and the relative toxicity profile of the NSAID. This article only relates to NSAIDs for pain and excludes low-dose aspirin. It also focuses exclusively on adults; children are outside the scope of this review.

 

Pharmacology of NSAIDs

NSAIDs inhibit the activity of cyclooxygenase (COX) enzymes, which metabolise arachidonic acid into prostaglandin H2, the precursor to prostaglandins and thromboxanes.³ Prostaglandins are signalling molecules which modulate pain, inflammation, fever and vasodilation, among other effects, while thromboxanes are primarily involved in platelet function and haemostasis.

NSAIDs are effective at reducing mild to moderate pain where there is an inflammatory component, for example, in rheumatic and musculoskeletal conditions or in the postoperative setting. Their efficacy is likely limited when pain is not primarily mediated by prostaglandins, such as in neuropathic pain.⁴

COX selectivity

In the 1990s, 2 distinct COX isoforms, COX-1 and COX-2, were discovered.³ COX-1 was recognised as a constitutive enzyme important for producing prostaglandins with physiological functions, such as mucosal protection in the gastrointestinal tract and maintaining normal renal function. In contrast, COX-2 was found to be an inducible enzyme expressed in the setting of inflammation, which leads to pain, fever and swelling.⁵

NSAIDs can be classified by their selectivity for COX-1 and COX-2 (Table 1). Nonselective NSAIDs, such as ibuprofen, indometacin and naproxen, inhibit both COX-1 and COX-2, while COX-2 selective NSAIDs, such as celecoxib and meloxicam, were developed to target COX-2 and maintain gastric mucosal integrity mediated by COX-1.⁶ Many of the theoretical safety advantages of COX-2 selective NSAIDs over COX-1 are minimal in practice, and both have similar considerations in clinical use.^7-9

Table 1 Comparison of nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAID	COX selectivity	Route of administration	Dose frequency
Aspirin	nonselective	oral	every 4 to 6 hours (when used as an anti-inflammatory)
Celecoxib	COX-2 selective	oral	1 to 2 times daily
Diclofenac	COX-2 preferential	oral, topical, rectal	2 to 3 times daily
Etoricoxib	COX-2 selective	oral	once daily
Ibuprofen	nonselective	oral, topical	every 4 to 6 hours
Indometacin	nonselective	oral, rectal	2 to 3 times daily
Ketorolac	nonselective	intramuscular, intravenous, oral	every 4 to 6 hours
Mefenamic acid	nonselective	oral	3 times daily
Meloxicam	COX-2 selective	oral	once daily
Naproxen	nonselective	oral	2 times daily
Parecoxib	COX-2 selective	intravenous, intramuscular	every 6 to 12 hours
Piroxicam	nonselective	oral	once daily

 

Clinical utility of NSAIDs

Osteoarthritis has been a common but often inappropriate indication for opioid prescriptions in Australia,¹⁰ and is usually better treated with NSAIDs. Most NSAIDs meaningfully reduce knee and hip osteoarthritis pain, greater than either paracetamol or opioids.¹¹ Similarly, oral NSAIDs demonstrate benefits for pain, function, patient global assessment and grip strength in hand osteoarthritis.¹²

Axial spondyloarthritis (including ankylosing spondylitis) is a chronic inflammatory disease characterised by lower back pain with sacroiliitis. NSAIDs in combination with physical therapy are considered first-line management for this condition as they slow disease progression and improve symptoms.^13,14 While all NSAIDs are effective, an indirect comparison meta-analysis found that etoricoxib may be superior to other NSAIDs for this condition.¹⁵

NSAIDs also provide effective symptom relief in rheumatoid arthritis, and may be useful prior to the full effect of disease-modifying antirheumatic drugs,¹⁶ and acute gout, although effective rapid-acting anti-inflammatory alternatives exist for both conditions (glucocorticoids, and colchicine in gout).

In addition to these chronic conditions, NSAIDs play a significant role in the management of acute pain. Most notably, they are widely recognised to be effective in the treatment of headache disorders, acute musculoskeletal injury, dysmenorrhoea, and most dental pain.

NSAIDs are not considered effective for nociplastic or neuropathic pain.

 

Precautions and adverse effects

Gastrointestinal risks

NSAIDs can cause mucosal damage in the upper, mid or lower gastrointestinal tract. These adverse effects include dyspepsia, gastrointestinal ulceration, bleeding or perforation.¹⁷ Although selective COX-2 inhibitors were developed to have little or no effect on COX-1 at therapeutic doses and hence reduce the incidence of gastrointestinal complications (approximately halved compared with ibuprofen and naproxen), these adverse effects can still occur.¹⁸ Celecoxib has the lowest gastrointestinal risk of all NSAIDs, followed by ibuprofen (Table 2).^19,20

Table 2 Relative gastrointestinal and cardiovascular risk from individual nonsteroidal anti-inflammatory drugs (NSAIDs)

	Gastrointestinal risk21,22	Cardiovascular risk18,20,23-26
High risk	piroxicam ketorolac high-dose aspirin (when used as an anti-inflammatory)	etoricoxib ketorolac
Moderate risk	naproxen indometacin mefenamic acid	ibuprofen diclofenac meloxicam indometacin mefenamic acid high-dose aspirin (when used as an anti-inflammatory)
Low risk	meloxicam diclofenac parecoxib etoricoxib	parecoxib piroxicam
Very low risk	ibuprofen celecoxib (lowest)	celecoxib naproxen (lowest)

Cardiovascular risk

All NSAIDs, particularly COX-2 inhibitors, are associated with an increased risk of cardiovascular events, particularly hypertension, heart failure and myocardial infarction.^27,28 Increased baseline cardiovascular risk should lead to increased caution in NSAID use, based on risk–benefit considerations. Naproxen and low-dose celecoxib may have lower cardiovascular risk than other NSAIDs (Table 2).¹⁸ For all NSAIDs, a higher daily dose increases overall cardiovascular risk.²⁸

NSAIDs may exacerbate existing heart failure with reduced ejection fraction (HFrEF) and should be avoided in patients with moderate to severe HFrEF.

Cardiovascular and gastrointestinal risk for individual patients may be outweighed by benefits of NSAID use, including avoiding harm from therapies such as opioids.¹⁸

Renal impairment

As COX enzymes are important for regulating homeostasis in the kidney,²⁹ inhibition by NSAIDs can cause adverse renal effects, especially in the setting of pre-existing renal impairment. Risk factors for acute kidney injury should also be considered, including volume depletion, older age and concurrent use of nephrotoxins. In chronic kidney disease, especially in older patients, NSAID dose should only be started at a low dose and incrementally increased, with monitoring for acute kidney injury. NSAIDs should be avoided altogether in patients with a glomerular filtration rate (GFR) less than 30 mL/min. In patients with a GFR between 30 and 60 mL/min, long-term NSAID use should only be considered if there are no other risk factors for acute kidney injury. Patients receiving an NSAID concomitantly with a diuretic and an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker are at increased risk of renal impairment due to the combination known colloquially as the ‘triple whammy’.^30,31

Hepatic impairment

NSAIDs should be avoided in patients with hepatic cirrhosis. As most NSAIDs undergo metabolism in the liver, the production of reactive intermediaries can cause liver damage. Diclofenac has the best defined risk of liver injury,³² with a 3% risk of meaningful transaminase elevation, although this injury is rarely severe.³³ NSAIDs may also precipitate other problems in patients with cirrhosis, including hepatorenal syndrome, other acute kidney injury, gastrointestinal bleeding, worsened platelet function, sodium retention and oedema.³⁴

Bleeding and thrombosis

Inhibiting COX-1 (but not COX-2) has a dose-dependent antiplatelet effect, and therefore not all NSAIDs have the same antiplatelet effects that aspirin does. NSAIDs may, however, contribute to clinically significant bleeding due to gastrointestinal ulceration, and combining NSAIDs with anticoagulants has been shown to double the risk of significant bleeding.³⁵ NSAIDs alone do not increase postoperative bleeding risk³⁶ or pose increased risk in patients with haemophilia.³⁷

NSAIDs have also been associated with increased thrombosis risk, including a doubling of risk of venous thromboembolism.^38,39 This may be due to thromboxane–prostacyclin imbalance from COX-2 inhibition.

Hypersensitivity reactions

NSAIDs can cause non-allergic hypersensitivity reactions (sometimes known as anaphylactoid reactions or pseudoallergy), thought to occur due to COX-1 inhibition and downstream overproduction of leukotrienes which can lead to urticaria or angioedema.^40,41 NSAIDs can also worsen asthma (known as NSAID-exacerbated airways disease), but this does not affect all patients with asthma. Individual NSAIDs can also cause allergic hypersensitivity reactions, including anaphylaxis and Stevens–Johnson syndrome.

Non-allergic reactions are known to demonstrate some cross-reactivity, where patients may experience reactions to chemically similar COX-1 inhibitors, while selective COX-2 inhibitors are less likely to cause cross-reactive hypersensitivity.⁴² Allergic reactions to NSAIDs are not thought to be subject to cross-reactivity.

The development of angioedema-like symptoms in the event of an NSAID hypersensitivity reaction can mimic a flare of hereditary angioedema. Hereditary angioedema is a rare genetic disorder characterised by recurrent episodes of angioedema caused by a deficiency or dysfunction of C1 esterase, mediated by excessive production of bradykinin.⁴³

Use in pregnancy and breastfeeding

In pregnancy, NSAIDs should be avoided in the first trimester due to an increased risk of miscarriage,⁴⁴ but may be considered in specific situations where the potential benefits outweigh the harms. Exposure in the third trimester is contraindicated, particularly after 30 weeks gestation, as there is an increased risk of oligohydramnios and early closure of the fetal ductus arteriosus. Apart from high-dose aspirin, short-acting NSAIDs are considered safe to use in breastfeeding.⁴⁴

 

Selection of NSAIDs

Few head-to-head randomised controlled trials have assessed comparative NSAID efficacy. However, systematic analyses suggest there is no clinically significant difference in analgesic potency between most NSAIDs for most indications.^45-47 The choice of drug is therefore often dictated by the adverse effect profile and patient preference.

In the setting of acute pain, NSAIDs with short half-lives, such as ibuprofen or diclofenac, may be easier to titrate, with ibuprofen preferred in people with a high risk of gastrointestinal toxicity.⁴⁸ In some settings, NSAIDs are used synergistically with paracetamol.⁴⁹ This combination has been found to be more effective than paracetamol and opioids.⁵⁰ Evidence suggests that the risk of myocardial infarction is highest within the first 7 days of therapy, and so the cardiovascular risk of NSAIDs must be considered even with short-term use.²⁸

Longer acting NSAIDs, such as celecoxib, meloxicam or naproxen, are often more convenient for those with chronic inflammatory conditions. A COX-2 selective NSAID is generally recommended for individuals with higher gastrointestinal risk, especially those older than 65 years, those with peptic ulcer disease, or those concurrently using an antiplatelet, anticoagulant or systemic glucocorticoid.¹⁹

In some situations, a specific NSAID is required. For example, paroxysmal hemicrania and hemicrania continua, 2 primary headache syndromes, only respond to indometacin.⁵¹ In situations where a short-term NSAID is required to be administered intravenously or intramuscularly, ketorolac is the primary NSAID used.

High-dose aspirin was historically used for its anti-inflammatory properties but, due to increased gastrointestinal toxicity, its use for musculoskeletal purposes has been superseded by newer NSAIDs. Lower doses of aspirin (e.g. 75 to 100 mg per day), used for secondary prevention following atherosclerotic cardiovascular events, confer a different safety profile.⁵²

Topical NSAIDs are better tolerated than systemic NSAIDs. Their main adverse effect is local skin irritation and, unless used in high amounts, there is minimal systemic absorption. However, they typically only result in limited local benefit.⁵³ They may modestly reduce pain and functional impairment from sprains, strains, and hand and knee osteoarthritis, and could be considered in these conditions, usually as adjunct therapy.⁵⁴

 

Practice points and common misconceptions

Most NSAIDs are metabolised by cytochrome P450 (CYP) 2C9, particularly celecoxib, ibuprofen, meloxicam and piroxicam. Impaired CYP2C9 (either from poor metaboliser polymorphisms or co-administration with inhibitors) may lead to higher NSAID concentrations and increased toxicity.⁵⁵

Proton pump inhibitor (PPI) therapy does not need to be routinely co-prescribed for all NSAID users, but should be considered in patients with conventional upper gastrointestinal risk factors (e.g. older age, history of peptic ulcer disease, concurrent systemic glucocorticoid therapy) and longer intended NSAID duration. PPI co-administration lowers the risk of NSAID-associated upper gastrointestinal complications,⁵⁶ but does not protect the mucosa of the lower gastrointestinal tract from injury such as ulceration or perforation.⁶ Patients with existing lower gastrointestinal pathology, including mucosal ulceration, increased gut permeability, inflammatory conditions and malabsorption, require clinical monitoring if starting an NSAID.

The need to take NSAIDs with food remains controversial. Impact on gastrointestinal damage has only been studied in animal models; fasting resulted in greater gastric adverse effects, while administration with food increased small bowel damage.⁵⁷ Time to maximum plasma concentrations of NSAIDs are reached more rapidly when taken with just water rather than food.⁵⁸ For acute pain, faster onset may improve overall pain control and reduce the total NSAID dose required. This may be less significant in long-term NSAID use, where steady state has been reached.

The risk of impaired bone healing from NSAIDs remains controversial.⁵⁹ While it remains plausible, shorter term use and lower doses appear to confer minimal risk.

 

Conclusion

NSAIDs have an important place in the pain management of many patients and are frequently more appropriate than opioids. While NSAIDs are largely comparable, the adverse effect profile and pharmacokinetic properties of individual NSAIDs may be useful in selecting the ideal medicine for any given scenario.

This article was finalised on 30 June 2025.

Conflicts of interest:  David Liew is a member of the Pharmaceutical Benefits Advisory Committee Drug Utilisation Subcommittee and a podcast host for Australian Prescriber.

Stephanie Hopkins and Victor Yang have no conflicts of interest to declare.

This article is peer reviewed.

 

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