Reviewed by Shameer Deen, ST5 Urology Registrar
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medicines in the world, available both over the counter and by prescription. Their analgesic, antipyretic, and anti-inflammatory properties make them valuable across a broad range of conditions. However, their gastrointestinal, cardiovascular, and renal toxicity profiles mean they must be prescribed thoughtfully, particularly in patients with pre-existing risk factors [1].
Mechanism of Action and COX Selectivity
NSAIDs exert their effects by inhibiting cyclo-oxygenase (COX) enzymes — specifically COX-1 and COX-2 — which are responsible for prostaglandin synthesis [2]. COX-1 is constitutively expressed and produces cytoprotective prostaglandins in the gastric mucosa and thromboxane A2 in platelets. COX-2 is inducible, expressed predominantly at sites of inflammation. Traditional non-selective NSAIDs (ibuprofen, naproxen, diclofenac) inhibit both isoforms. Selective COX-2 inhibitors (celecoxib, etoricoxib) were developed to preserve gastric cytoprotection while maintaining anti-inflammatory activity.
Gastrointestinal Risk
Inhibition of COX-1-derived prostaglandins reduces gastric mucosal protection, impairing mucus secretion and bicarbonate production while increasing gastric acid secretion. This leads to a spectrum of gastrointestinal harm ranging from dyspepsia to peptic ulceration and life-threatening upper GI haemorrhage [1].
A major meta-analysis of over 750,000 patients across 754 trials demonstrated that all NSAIDs increase the risk of upper GI complications compared to placebo, with diclofenac and ibuprofen conferring lower GI risk than naproxen and indomethacin, and selective COX-2 inhibitors showing the most favourable GI profile among NSAIDs [1].
Gastroprotection with a proton pump inhibitor (PPI) substantially reduces the risk of peptic ulceration in NSAID users. Concurrent PPI should be prescribed for patients with additional risk factors including age over 65, prior peptic ulceration, anticoagulant or corticosteroid use, or high NSAID doses.
Cardiovascular Risk
The cardiovascular risk of NSAIDs was firmly established following withdrawal of rofecoxib (Vioxx) from the market in 2004 after trial data demonstrated a doubling of myocardial infarction risk [2]. Subsequent analysis has shown that the cardiovascular risk is a class effect of COX-2 inhibition, not unique to rofecoxib.
Selective COX-2 inhibitors reduce prostacyclin (PGI2) synthesis — a vasodilatory and platelet-inhibitory prostanoid — while sparing thromboxane A2 production, creating a pro-thrombotic imbalance. Non-selective NSAIDs inhibit both, producing a more balanced effect [2]. In practice, all NSAIDs should be avoided where possible in patients with established cardiovascular disease, and used at the lowest effective dose for the shortest duration when they are necessary.
Renal Effects
In patients with normal renal perfusion, prostaglandins play a minor role in maintaining GFR. However, in states of reduced effective circulating volume — heart failure, hypovolaemia, CKD, advanced cirrhosis — prostaglandins become critical vasodilators that maintain renal perfusion [1]. NSAID-induced prostaglandin inhibition in these patients can precipitate acute kidney injury, electrolyte disturbances (hyperkalaemia, hyponatraemia), and fluid retention.
NSAIDs should be avoided in patients with CKD (eGFR <60 mL/min/1.73m²), established heart failure, or decompensated cirrhosis. They should be used with particular caution in patients on diuretics, ACE inhibitors, or ARBs — the "triple whammy" combination increases AKI risk many-fold.
Choosing the Right NSAID
When an NSAID is genuinely needed, the choice should be guided by the patient's risk profile. For patients with predominantly GI risk, a selective COX-2 inhibitor with gastroprotective PPI cover is appropriate. For patients with predominantly cardiovascular risk, naproxen has the most favourable cardiovascular profile among non-selective NSAIDs and is preferred where an NSAID cannot be avoided. MedNext Formulary contains detailed safety profiles for all NSAID agents within the MedNext Audited Proprietary Dataset to support these individualised prescribing decisions.
References
- Bhala N, Emberson J, Merhi A, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382(9894):769-779.
- FitzGerald GA. Coxibs and cardiovascular disease. N Engl J Med. 2004;351(17):1709-1711.