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10.1.1 Non-steroidal anti-inflammatory drugs (NSAIDs)

10.1.1 Non-steroidal anti-inflammatory drugs (NSAIDs)

Ibuprofen tablets, MR tablets, syrup (first choice); injection (for closure of patent ductus arteriosus - see BNFc)
Naproxen tablets; effervescent tablets (second choice)
Diclofenac Enteric Coated tablets, dispersible tablets, SR and Retard tablets, suppositories, injection

(but see note below re: diclofenac and CV/arterial thrombotic risk, as well as new contraindications & warnings in Drug Safety Update June 2013

Celecoxib capsules
Indometacin capsules, MR capsules, suppositories.
Mefenamic Acid capsules, tablets (gynaecological use only)
Meloxicam tablets
Nabumetone tablets

Notes:

1. Non-steroidal anti-inflammatory drugs (NSAIDs) have been responsible for 25% of all yellow card reports. They remain a class associated with frequent adverse events.

2. Evidence suggests that NSAIDs are commonly used in osteoarthritis although the condition is associated with only modest and patchy episodes of inflammation.

3. Paracetamol at full regular dose should be first choice in painful osteoarthritis. Evidence suggests that patients being considered for, or currently receiving, an NSAID may achieve adequate control with paracetamol This approach would represent a significant reduction in cost, morbidity and mortality. An NSAID should only be prescribed after a careful assessment of risk and the prescription should be regularly re-evaluated.

4. Efficacy

Most trials comparing different NSAIDs show equal efficacy. Patient response and tolerability is highly variable; only 60% of patients will respond to any given NSAID.

5. Side effects

NSAIDs and GI risk

NSAID use is associated with significant morbidity and mortality. All NSAIDs should generally be used at the lowest effective dose and for the shortest period of time necessary to control symptoms.

On average the risk of a serious adverse Gl event while taking an NSAID is three times that of a non user. The risk does not reduce over time. Further risk factors for Gl bleeding include:

1) Age over 65 years

2) Previous history of peptic ulcer disease

3) Concurrent gastro-toxic drugs e.g. aspirin, corticosteroids, SSRIs, anticoagulants.

3) Serious co-morbidities e.g. Cardiovascular disease, renal/hepatic impairment.

NSAIDs should ideally be avoided in patients at high risk. Evidence suggests that the risk of Gl toxicity varies between drugs. Ibuprofen, at low doses, is the least toxic but at higher doses ranks with other NSAIDs at intermediate risk, e.g. diclofenac and naproxen. Coxibs as a class are associated with a lower GI risk than traditional NSAIDs. However, this disadvantage is eliminated when they are co-administered with aspirin.

Patients at high risk of GI toxicity should be given a PPI as cover. NICE guidelines specifically recommend co-prescribing a PPI with NSAIDs for people who have osteoarthritis, rheumatoid arthritis, or for people over 45 years who have low back pain.

NSAIDs and thrombotic risk

Evidence continues to suggest that coxibs are associated with an increased thrombotic risk. The risk will vary according to underlying patient risk factors; however, an estimated risk across the whole population may be about three additional events (mainly myocardial infarction) per 1000 patients per year, compared to placebo.

A recent safety review of all NSAIDs suggests that some non-selective NSAIDs may also be associated with a small increased risk of thrombotic events when used at high doses for long-term treatment. Diclofenac, particularly at the 150mg daily dose, has a thrombotic risk profile similar to that of licensed doses of etoricoxib, and possibly other coxibs.

For ibuprofen at high doses (e.g. 2400mg a day), there may be a small thrombotic risk, but overall, at lower doses (e.g. 1200mg a day or below), data do not suggest an increased risk of MI. For naproxen, there is a lower thrombotic risk than for the coxibs, and overall, no evidence to suggest an increased risk of MI. For those reasons, D&T support the preferred use of low dose ibruprofen (1200 mg a day or less) or naproxen (1000 mg a day or less), particularly  for patients in whom cardiovascular risk is a significant consideration in decision making.

For all NSAIDs, including coxibs, thrombotic risk is likely to be greater when used at high doses and for long-term treatment. Therefore:

  • Prescribe the lowest effective dose for the shortest time necessary for control of symptoms. Review need for long-term treatment periodically.
  • Prescribe on the basis of the overall safety profiles of individual agents and individual patient risk profiles (e.g. underlying gastrointestinal, renal and cardiovascular disease).
  • Concomitant aspirin (and other antiplatelet agents) greatly increase the gastrointestinal risks of NSAIDs and severely reduce any potential gastrointestinal safety advantages of coxibs. Aspirin should only be co-prescribed if absolutely necessary.
  •  Long-term, daily use of ibuprofen may reduce the cardioprotective effects of low-dose aspirin; however, occasional ibuprofen use is unlikely to have a clinically meaningful effect on the benefits of low-dose aspirin.

 

Further evidence that the cardiovascular risk with diclofenac is higher thanwith other NSAIDs/coxibs is available in the Drug Safety Update June 2013.

High-dose ibuprofen (>2400mg/day) is associated with a small increase in cardiovascular risk – see: Drug Safety Update

NSAIDs and renal toxicity

Patients at risk of renal impairment or renal failure (particularly elderly people) should avoid NSAIDs if possible. If NSAID treatment is absolutely necessary, then the lowest effective dose for the shortest possible duration should be used to control symptoms. The renal function of such patients should be carefully monitored during NSAID treatment. It is important to consider other concomitant disease states, conditions, or medicines that may precipitate reduced renal function when prescribing NSAIDs.

Although rare, acute tubulointerstitial nephritis (TIN) has been reported in association with all proton-pump inhibitors (PPIs), occurring usually after about 10 weeks of treatment. A decline in renal function is usually noted over a period of days to weeks. There may be associated fatigue, malaise, weakness, nausea, vomiting, anorexia, and weight loss. Classic drug hypersensitivity signs and symptoms, such as the clinical triad of rash, fever and eosinophilia, are seen in less that 10% of patients. Abnormal urine analysis measurements have included haematuria, pyuria, proteinuria and eosinophiluria, although these findings may occur in less than half of patients.

Discontinuation of the PPI is the primary therapy, while corticosteroids are often used but efficacy has not been demonstrated in controlled clinical trials. The majority of patients regain renal function, although not always to pre-TIN levels. As NSAIDs are well known to cause acute TIN, the PPI might be overlooked as the causative agent. In patients showing deteriorating renal function on both an PPI & NSAID, the PPI should be stopped at the SAME time as the NSAID. If there is no improvement in renal function on stopping both drugs the patient should be referred for a nephrology opinion (which may include renal biopsy).

6. Treatment

In patients with an active NSAID- induced ulcer, a proton pump inhibitor is the most effective treatment. NSAIDs should be discontinued in these patients.

For link to BNF section: 10.1.1 Non-steroidal anti-inflammatory drugs