NSAIDs and cardiovascular events (BNF 66 September 2013)

• All NSAID use (including cyclo-oxygenase-2 selective inhibitors) can, to varying degrees, be associated with a small increased risk of thrombotic events (e.g. 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.
• Cyclo-oxygenase-2 selective inhibitors, diclofenac (150mg daily) and ibuprofen (2.4g daily) are associated with an increased risk of thrombotic events. The increased risk for diclofenac is similar to that of 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.
• The lowest effective dose of NSAID or COX-2 should be prescribed for the shortest period to control symptoms and that the need for long-term treatment should be reviewed periodically

NSAIDs and gastro-intestinal side-effects (BNF 66 September 2013)

• All NSAIDs associated with serious GI toxicity; the risk is higher in the elderly. Evidence on the relative safety of non-selective NSAIDs indicates the differences in the risks of serious upper GI side-effects.
• Recommendations are that NSAIDs associated with a low risk e.g. ibuprofen are generally preferred, to start at the lowest recommended dose, not to use more than one oral NSAID at a time, and to remember that all NSAIDs (including COX-2) are contra-indicated in patients with active peptic ulceration.
• Also contra-indicated are non-selective NSAIDs in patients with a history of peptic ulceration. The combination of an NSAID and low-dose aspirin can increase the risk of gastro-intestinal side effects; this combination should only be used if absolutely necessary and the patient monitored closely. Low dose aspirin alone does not significantly increase ulcer incidence. However addition of a COX-2 selective inhibitor to low dose aspirin increases ulcer incidence to a rate similar to NSAIDs alone.

Asthma (BNF 66 September 2013)

• Any degree of worsening of asthma may be related to the ingestion of NSAIDs, either prescribed or (in the case of ibuprofen and others) purchased over the counter.

Renal adverse effects of NSAIDs and COX-2 inhibitors

All NSAIDs and COX-ll inhibitors can have effects on the kidney, particularly at high doses, which increase the risk of fluid retention, high blood pressure and (rarely) heart failure in at-risk patients. In people with CKD the chronic use of NSAIDs may be associated with progression of kidney disease; acute use is associated with a reversible decrease in GFR. These drugs may rarely precipitate renal failure; the risk of renal failure is highest in those with existing renal impairment. Contributing factors include current administration of ACE inhibitors, ARBs and diuretics.

NSAIDs and COX-II inhibitors should be used in the lowest effective dose for the shortest possible duration in all patients.

• NSAIDs or COX II inhibitors should be avoided if possible in patients who have renal impairment and/or patients taking ACE inhibitors or ARBs.
• If these drugs are clinically essential in patients with renal impairment or those taking concomitant ACE inhibitors or ARBs, monitor renal function every week until the patient stops the drug or shows stability in renal function, in which case monitoring may become less frequent.
• Annual monitoring is recommended for patients without renal disease who take NSAIDs or COX II inhibitors on a continuous basis.

Patients taking NSAIDs and COX-ll inhibitors who develop diarrhoea and vomiting are at increased risk of becoming dehydrated leading to renal problems. At risk patients may be advised to stop their NSAIDs or COX-ll inhibitors if they become unwell.

1. Don't use them unless you have to
   1. The only way to avoid NSAID side-effects is not to use them
   2. Paracetamol works for many and is frequently underestimated in its effectiveness. If there is no inflammatory component, e.g. in osteoarthritis, many patients could achieve adequate control with simple analgesia alone
   3. Employ non-drug interventions routinely
   4. Consider short-term course (1-2 weeks) of topical NSAID
2. If you have to use them, use them wisely
   1. The balance of benefits and risks needs to be carefully assessed; think about CV, GI and renal issues routinely
   2. Use a safer drug (ibuprofen, then naproxen) in the lowest effective dose for the shortest period
   3. NSAID users should be a high priority for medication review: are NSAIDs effective or needed? Drug holidays? Don't issue repeat prescriptions without review
   4. Short acting NSAIDs are preferred for the majority of patients as they allow flexible dosing leading to better control of symptoms using lower daily doses
   5. Long acting NSAIDs may be required in patients with established rheumatoid arthritis and other conditions where morning stiffness is a major component of the disease
3. Consider gastro-protection in those at high risk (NICE definition)
   1. Options are PPIs, double-dose H2RAs (not ranitidine), Misoprostol. The European Medicines Agency has recommended a precautionary suspension of the licences for all ranitidine medicines (30 April 2020). See section 1.3.1 H2-receptor antagonists for further information
   2. COX-2 should be considered only in those at high GI risk, but also consider the CV risks.
   3. Systemic as well as local effects of NSAIDs contribute to gastrointestinal damage. This damage may not be prevented by the use of enteric-coated tablets or suppositories.

All of this particularly applies to those aged over 65

Osteoarthritis

• See NICE Guideline NG226 (Osteoarthritis in over 16s: diagnosis and management) (October 2022)
• Offer education and encourage exercise and weight loss
• Consider regular paracetamol and/or topical NSAIDs if patient remains symptomatic

Rheumatoid arthritis

• See NICE Guideline NG100 (Rheumatoid arthritis in adults: management) (February 2009)
• If symptom control is needed in addition to DMARDS/Biologicals add regular paracetamol plus the addition of codeine if necessary

Other indication where benefits of use deemed to outweigh risks

• Consider regular paracetamol
• For some acute indications (e.g. gout, dysmenorrhoea or migraine) an NSAID first line may be more effective

If patient remains symptomatic

• Prescribe oral NSAID at lowest effective dose for shortest possible time. Avoid is possible in patients with CVD, heart failure or renal disease

First line NSAIDs:

• Ibuprofen 400-800mg three times a day or
• Naproxen 250mg-500mg twice a day (if longer action required)

Is the patient at high risk of developing serious GI adverse events?

• If yes ....consider co-prescribing of PPI for gastro-protection (omeprazole 20mg daily, lansoprazole 15-30mg daily)
• NICE advises that the following groups as high risk:
  • 65 years of age and over
  • Previous clinical history of gastro-duodenal ulcer, gastrointestinal bleeding or gastro-duodenal perforations.
  • Using concomitant medications known to increase the likelihood of upper GI events, especially steroids, anticoagulants and other NSAIDs (including aspirin)
  • Serious co-morbidity such as cardiovascular disease, renal or hepatic impairment, diabetes and hypertension.
  • Requiring prolonged or long term use of maximum recommended dose NSAIDs.
  • Patients with osteoarthritis (NICE CG 59)
• In OA, NICE CG 59 advises co-prescribing of a PPI with both standard NSAIDS and COX-2 inhibitors. The use of a PPI with any NSAID significantly reduces the risk of GI side effects. There is as yet no good evidence that adding a PPI to a COX-2 is more beneficial, equivalent or worse than adding a PPI to a traditional NSAID.

Misoprostol is included as one option for NSAID prophylaxis. However, NSAIDs should be avoided in patients with dyspepsia wherever possible. Refer to 7.5 Obstetrics. Dose: 200 micrograms 4 times daily

Other formulary NSAIDs

• Etodolac
• Celecoxib
• Etoricoxib
• Diclofenac

There is no evidence that these drugs offer greater efficacy but variability between patients may occur

Patients with established IHD or CVD should be switched to alternative treatment: in addition, the existing contraindication for severe heart failure is now extended to include moderate heart failure NHYA class II-IV.

For all patients the balance of gastrointestinal and cardiovascular risk should be considered before prescribing a COX-2, particularly for those with risk factors for heart disease and those taking low dose aspirin, for whom gastrointestinal benefit has not been clearly demonstrated.

The lowest effective dose of COX-2 should be used for the shortest necessary period. Periodic re-evaluation is recommended, especially for osteoarthritis patients who may only require intermittent treatment.

Gastro-protective agents should be considered for patients switched to non-selective NSAIDs.

Serious thrombotic events: Rofecoxib was been withdrawn voluntarily as trial results showed an increased risk of confirmed serious thrombotic events (including myocardial infarction and stroke) compared to placebo, following long-term use. Caution should be used when using other COX-II selective agents in patients at risk of cardiovascular disease.

It should be noted that the SPCs for the COX-2 states that they are contra-indicated in patients with active peptic ulceration or gastro-intestinal bleeding.

Treatment of dysmenorrhoea

• Standard NSAIDs reduce restriction of daily activities, absence from work or school, and the need for additional analgesia compared with placebo. Ibuprofen and naproxen are indicated for the use of dysmenorrhoea; both are available OTC for treatment of dysmenorrhoea.
• Mefenamic acid has not been included in the formulary. Evidence from two systematic reviews supports the use of standard NSAIDs for the management of primary dysmenorrhoea. There is insufficient evidence to indicate whether any one NSAID is more effective than another for the treatment of dysmenorrhoea

Treatment of menorrhagia

• NSAIDs significantly reduce menstrual blood loss compared with placebo. There is no significant difference between mefenamic acid and naproxen, or between NSAIDs and oral progestogens given in the luteal phase