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Is the most suitable NSAID being used?

A case study from the BNF highlights issues to consider when prescribing or supplying non-steroidal anti-inflammatory drugs

Knee pain (Clearvista/

A 59-year-old man continues to complain of bilateral knee pain despite applying diclofenac gel and taking regular paracetamol and codeine for the past month. Although the diclofenac and paracetamol have reduced his pain, he still has moderate pain when walking or carrying out strenuous activities such as gardening. The codeine has provided no additional benefit.

He is concerned that the pain is restricting his mobility and he has not been able to carry out the exercises that he has been advised to do to increase his general aerobic fitness and muscle strength. He has previously tried topical capsaicin to no avail.

Two years ago he had a non-ST segment elevation myocardial infarction. His medication includes:

  • Paracetamol 1g qds
  • Diclofenac gel qds
  • Codeine 60mg qds
  • Senna ii on
  • Atenolol 100mg od
  • Aspirin 75mg od
  • Simvastatin 40mg on

He has normal renal and liver function.

What alterations would you recommend to this patient’s prescription for analgesia? The prescribing notes on osteoarthritis and soft-tissue disorders (section 10.1) recommend that if pain relief further to paracetamol and a topical NSAID or topical capsaicin is required, an oral non-steroidal anti-inflammatory drug can be substituted for, or used in addition to paracetamol. But the notes also recommend that, an opioid analgesic should be considered before an oral NSAID for patients taking low-dose aspirin, because of the risk of gastro-intestinal or thrombotic effects (see later).

Because this patient is deriving no benefit from using codeine, it should be discontinued. The senna should be stopped if it was prescribed to prevent opioid-induced constipation.

If an oral NSAID is added to this patient’s therapy the topical diclofenac should be stopped to reduce the likelihood of side effects.

Which oral NSAIDs are associated with the lowest risk of thrombotic events? The prescribing notes for NSAIDs (section 10.1.1) state that all NSAID use can, to varying degrees, be associated with a small increased risk of thrombotic events (eg, myocardial infarction and stroke) independent of baseline cardiovascular risk factors or duration of NSAID use. However, the greatest risk may be in those receiving high doses long-term.

The Panel contains a reminder of some of the mechanisms behind thrombosis involved in this respect.

Thrombosis mechanisms

  • Within the endovascular lumen, activated platelets produce cyclo-oxygenase-1 dependent thromboxane A2. Thromboxane A2 has a prothrombotic effect.
  • The endothelium produces cyclo-oxygenase-2 dependent prostacyclin. Prostacyclin has an antithrombotic effect. 
  • Selective inhibitors of cyclo-oxygenase-2 impair synthesis of prostacyclin, but lack antiplatelet effects, tipping the scales in favour of thrombogenesis. 
  • Different non-selective NSAIDs inhibit cyclo-oxygenase-1 and cyclo-oxygenase-2  to varying degrees; inhibition of cyclo-oxygenase-1 is reversible and dependent on the half-life of the NSAID. Aspirin irreversibly inhibits cyclo-oxygenase-1 mediated synthesis of thromboxane A2.

Cyclo-oxygenase-2 selective inhibitors (eg, celecoxib, etoricoxib) are associated with an increased risk of thrombotic events but so are diclofenac (at a total dose of 150mg daily) and ibuprofen (at a total dose of 2.4g daily). The increased risk for diclofenac is similar to that for licensed doses of etoricoxib. Naproxen (1g daily) is associated with a lower thrombotic risk, and low doses of ibuprofen (1.2g daily or less) have not been associated with an increased risk of myocardial infarction.

For this reason, diclofenac and the selective inhibitors of cyclo-oxygenase-2 are contraindicated in patients with ischaemic heart disease, but the contraindication does not apply to topical formulations of diclofenac. Other non-selective NSAIDs should be used with caution in patients with ischaemic heart disease.

Note also that for patients with cardiac impairment, NSAIDs may impair renal function.

Which oral NSAIDs are associated with the lowest risk of gastrointestinal events? The prescribing notes for NSAIDs state that all NSAIDs are associated with serious gastrointestinal toxicity. Evidence on the relative safety of non-selective NSAIDs indicates differences in the risks of serious upper gastrointestinal side effects — piroxicam, ketoprofen and ketorolac are associated with the highest risk; indometacin, diclofenac, and naproxen are associated with intermediate risk, and ibuprofen with the lowest risk (although high doses have been associated with intermediate risk). Selective inhibitors of COX-2 are associated with a lower risk of serious upper gastrointestinal side effects than non-selective NSAIDs.

Recommendations are that NSAIDs associated with a low risk (eg, ibuprofen) should generally be preferred. They should be started at the lowest recommended dose and no more than one oral NSAID should be used at one time. The combination of an NSAID and low-dose aspirin should be used only if absolutely necessary and the patient should be monitored closely.

Which oral NSAID should be prescribed for this patient?
Differences in anti-inflammatory activity between NSAIDs is small, but there is considerable variation in individual response and tolerance. Because this patient has a history of ischaemic heart disease, an NSAID with a low risk of thrombotic events,  such as ibuprofen (1.2g daily or less) or naproxen (1g daily), should be prescribed. Low-dose ibuprofen would be preferred because it also has the lowest risk of serious gastrointestinal side effects.

The patient is to be prescribed ibuprofen 400mg tds by mouth. What further measures can be taken to protect the patient against gastrointestinal side effects? Systemic, as well as local, effects of NSAIDS contribute to gastrointestinal damage; taking oral formulations with milk or food, or using enteric-coated formulations may only partially reduce symptoms such as dyspepsia.

According to the prescribing notes on NSAID-associated ulcers (section 1.3), this patient is at high risk of developing gastrointestinal complications with an NSAID because he is taking another medicine that increases the risk of gastrointestinal side effects (ie, low-dose aspirin) and he has a serious co-morbidity (ie, cardiovascular disease).

In those at risk of ulceration, a proton pump inhibitor can be considered for protection against gastric and duodenal ulcers associated with non-selective NSAIDs; an H2-receptor antagonist, such as ranitidine given at twice the usual dose, or misoprostol are alternatives. Colic and diarrhoea may limit the dose of misoprostol. You could recommend that this patient is also prescribed omeprazole 20mg od.

The patient has read in a newspaper that simvastatin can cause diabetes. Should he stop taking it? According to the prescribing notes on Statins (section 2.12), these drugs may cause hyperglycaemia, and may be associated with the development of diabetes mellitus, particularly in those already at risk of the condition. However, the cardiovascular benefits of statins outweigh this small increased risk. He should be encouraged to continue taking the statin and monitored for symptoms and signs of diabetes.

Key points

  • All NSAID use can, to varying degrees, be associated with a small inceased risk of thrombotic events as well as with as a risk of gastrointestinal bleeds.
  • When choosing an NSAID, factors to consider include the presence of heart disease, renal function, gastrointestinal risk and other medicines, such as aspirin. 


Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2014.11133211

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