Non Steroidal Anti-inflammatory Drugs

Synonyms: NSAIDs, Cyclo-oxygenase (COX) inhibitors

NSAIDs are widely used drugs, both prescribed and over-the-counter. However they also cause serious side-effects, most notably gastric perforation and haemorrhage. Over the last few years, concern has mounted regarding the cardiovascular safety, initially of coxibs and then of all NSAIDs, leading to alterations in prescribing advice and behaviour. Within the NHS, total NSAID prescribing decreased by 2% (from 1.47 to 1.44 million items) between 2007-8, with prescribing of diclofenac falling, naproxen rising and no overall change with ibuprofen.¹

• Aspirin is the longest established of the anti-inflammatory drugs but is often considered separately to other NSAIDs. Its predominant use is in low dose for cardiovascular disease prevention, based on its potent and irreversible inhibition of COX-1 activity. It also has some COX-2 activity which increases with high dose. Anti-inflammatory activity is only present at very high dosage (over 3 g daily).
• Standard non-selective NSAIDs inhibit both COX-1 and COX-2 but do vary in their relative pathway selectivity. COX-1 activity promotes prostaglandins necessary to maintaining a healthy gastric mucosa and platelet initiated clotting. COX-2 activity promotes prostaglandins mediating pain and inflammation.
• COX-2 selective NSAIDs fall into 2 categories: older NSAIDs which display COX-2 preference (etodolac, meloxicam) and the newer coxibs, sometimes known as COX-2 specific NSAIDs (celecoxib, etoricoxib, rofecoxib and valdecoxib (both withdrawn)).

Therapeutic uses of NSAIDs are wide - drawing on their anti-inflammatory, analgesic and antipyretic properties:

• Acute pain relief following injury or surgery.
• Mild to moderate pain relief including dysmenorrhoea and migraine.
• Pain relief in acute renal colic - NSAID users were more likely to need rescue analgesia but experienced less side-effects than those treated with pethidine.⁵
• Fever and pain in children - although current NICE guidelines stress that we should not use antipyretics solely to reduce fever in children who are otherwise well or to prevent febrile convulsions (since they are ineffective).⁶
• Post-childhood immunisation induced pyrexia.
• Acute inflammatory disorders e.g. gout.
• Chronic inflammatory disorders including rheumatoid arthritis, osteoarthritis⁷ and chronic back pain.⁸
• NSAIDs are commonly used in the treatment of acute pericarditis.⁹
• Palliative pain relief for bony metastases, soft-tissue tumour infiltration and pleural pain. A Cochrane review found them superior to placebo for the treatment of cancer pain, but failed to demonstrate the superiority of any particular member of the class over another and mixed results looking at their efficacy in combination with opioids.¹⁰
• Specialist use in neonatology to aid closure of patent ductus arteriosus.¹¹

Include:

• Allergy or previous hypersensitivity reaction (including asthma, angioedema, severe skin reaction or urticaria, and rhinitis)
• Current treatment for GI bleeding, symptomatic peptic ulcer, GI perforation or obstruction
• Renal failure (eGFR<30, creatinine clearance<20 mL/min, acute dehydration)
• Severe hepatic impairment
• Severe heart failure (NSAIDs), moderate heart failure (coxibs)
• Ischaemic heart disease, cerebrovascular disease, peripheral arterial disease (coxibs)
• Pregnancy (risk of miscarriage associated with NSAID use suggested but not confirmed,¹² and fetal and neonatal pulmonary hypertension caused by premature closure of the ductus arteriosus)
• Coagulation defects

• Asthma
• Renal insufficiency
• CV disease or risk factors
• Hepatic and cardiac failure
• Past history of PUD or GI bleeding
• Hypertension
• The elderly (>65 years)
• The acutely unwell or debilitated
• Concurrent use of drugs that increase risk of bleeding (e.g. aspirin, warfarin, corticosteroids)
• Women trying to conceive due to reversible impairment of fertility
• Breast feeding (but some NSAIDs e.g. ibuprofen, diclofenac, are felt to be relatively safe as secreted in very small quantities)

• Differences between NSAIDs' anti-inflammatory activities are small - systematic reviews have found no important differences in their efficacy for the symptoms of musculo-skeletal disorders.¹³
• Individuals vary in their response to a NSAID - where they fail to respond to one NSAID, a switch to an alternative may produce a good response.
• Differences in NSAIDs' tolerability are large. Non-selective NSAIDs vary in their risk of GI toxicity.
  

  Risk of serious upper GI side-effects with non-selective NSAIDs14 High risk - azapropazone Intermediate risk - diclofenac, indometacin, naproxen, ketoprofen, piroxicam Low risk - ibuprofen

• Coxibs appear to have a lower risk of GI bleeding compared with older, unselective NSAIDs used without a PPI. Use of etoricoxib reduced the risk of upper GI events and dyspepsia compared to diclofenac, although the reduction was only seen in the more common but less serious events and not the complicated events (perforation, obstruction, witnessed ulcer bleeding, or significant bleeding).¹⁵ It is not known whether these GI advantages to the use of a coxib persist when compared to a traditional NSAID co-prescribed with a PPI.
• Assess an individual's risk for CV disease prior to prescribing any NSAID. NSAIDs are now considered to pose some thrombotic risk:^16,17
  • Diclofenac 150 mg daily has a CV risk profile equivalent to that of etoricoxib and possibly other coxibs. At current prescribing levels, this translates to 2000 extra or premature CV events in England per year, compared to no treatment.
  • Naproxen 1000 mg daily has a lower CV risk than coxibs, and data thus far does not suggest an increased risk of MI.
  • High dose ibuprofen (e.g. 2400 mg daily) appears to carry a small thrombotic risk but at lower dose (e.g. 1200 mg daily) does not.
  • There is less evidence available for other NSAIDs but these may also have some associated thrombotic risk, particularly if taken over the longer term and in high dose.

  Low dose ibuprofen and naproxen with a PPI are better choices than diclofenac for patients requiring a NSAID where CV risk is a concern.1,16 However, all NSAIDs may inhibit the cardioprotection offered by aspirin, so that when patients requiring CVD prophylaxis are likely to require longer term pain relief, such as in the management of osteoarthritis, other analgesics should be considered before the use of a NSAID.7

• Start at the lowest recommended dose as side-effects are proportional to dose. Benefits of NSAIDs increase towards a maximum value at high dose but side-effects increase linearly with dose without an apparent ceiling.¹³
• Pain relief should commence soon after the first dose with full analgesic benefit within a week but anti-inflammatory effect can take up to 3 weeks.
• Use any NSAID for the shortest possible time.

Enteric coating

Enteric-coating has not been shown to reduce clinically significant complications of NSAID induced peptic ulceration, but may reduce the incidence/severity of dyspeptic symptoms and endoscopic lesions.¹⁸

Modified release forms

Certain NSAIDs (e.g. ibuprofen, diclofenac, flurbiprofen, indometacin) are available in slow-release preparations. This can provide relief from night pain where day-time NSAID use has been successful in controlling pain. However it should not be assumed to lessen risk of GI toxicity - patients receiving slow release NSAIDs (regardless of prior risk factors) were more likely to require gastroprotection and GI investigations than those receiving standard forms and were more likely to switch away from SR formulations than to them¹⁹ suggesting poorer tolerability.

Slow release preparations are classed as premium-priced products - only to be used where there is a potential for improvement in compliance, effectiveness or side effects.

Topical preparations

Reviews suggest that topical NSAIDs are effective and well tolerated, reduce symptoms and improve function and have a reduced incidence of GI side-effects compared to oral routes.^20,21 The use of topical rather than oral NSAIDs for knee or small joint disorder as a strategy to avoid the severe adverse events has been suggested.¹⁴ Often studies have limited themselves to looking at short-term use so questions of longer term efficacy remain.²² Use of topical NSAIDs does avoid many of the interactions associated with systemic NSAIDs although side-effects (hypersensitivity, asthma, renal disease) have been reported when large doses are used topically. Ensure that patients are not using oral and topical NSAIDs concurrently.

• Routine monitoring is not normally required for NSAIDs. However, it is advisable where there is greater risk of side-effects or where side-effects could be more serious in view of co-morbidity.
• All patients on NSAIDs should have regular medication reviews considering:
  • The need for continuing treatment
  • Drug efficacy
  • Side-effects
  • The need for gastroprotection
  • Possible alternative treatment
• Renal Impairment - check renal function prior to treatment if anticipating longer term NSAID treatment:
  • With mild renal impairment (GFR 20-50 mL/minute, serum creatinine 150-300 micromol/litre), use NSAID in its lowest effective dose and monitor regularly for deteriorating renal function. If renal function deteriorates, the drug should be stopped.
  • With moderate to severe renal impairment (GFR > 50 mL/minute, serum creatinine > 300 micromol/litre), NSAIDs should be avoided where possible. Advice from renal physicians would be appropriate where options are limited. Beware the development of acute-on-chronic renal failure in those with concurrent acute illness.
• Hypertension/cardiac failure - consider stopping NSAID if treatment causes clinical deterioration.
• In the elderly, check for GI symptoms particularly at the outset of treatment, although the risk of complications exists throughout the course of treatment. Consider the impact of NSAID treatment on co-morbidities. Have a low index of suspicion for checking FBC and iron studies, differentiating between iron-deficiency anaemia (with NSAID related blood loss) and anaemia of chronic disease.

Gastrointestinal adverse effects

NSAIDs' most well-known and feared association is with serious GI adverse effects. The risk of serious ulcer disease requiring hospitalisation is 1 per 100 patient years of NSAID use in unselected patients.²³ In those not considered to be at high risk of GI bleeding, use of NSAIDs for musculoskeletal pain increases the risk of GI bleeding five-fold²³ but morbidity associated with over-the-counter use of ibuprofen is low.²⁴

Strategies for reducing the risk of GI adverse effects¹⁴

• Avoid prescribing NSAIDs or substitute with an alternative e.g. paracetamol ± codeine for pain, colchicine for gout. Paracetamol has similar analgesic efficacy to NSAIDs but lacks anti-inflammatory action. Consider non-drug options e.g. physiotherapy, exercise, weight reduction where appropriate, surgery in the management of osteoarthritis.⁷
• Use only one NSAID at a time. Avoid co-prescribing with aspirin. The need for low dose aspirin should take precedence over NSAID use.
• Use the lowest dose of NSAID compatible with symptom relief for the shortest time necessary.
• Never take NSAIDs on an empty stomach.
• Use gastroprotection with a standard NSAID where individuals are at higher risk of GI complications of NSAID use:
  • PPIs are generally the preferred choice as they are effective and well tolerated. Using a PPI appears to significantly reduce the bleeding risk of conventional NSAIDs.²⁵ Some have advocated the use of a coxib+PPI in individuals at very high risk of GI bleeding²⁶ but there is no substantial evidence to demonstrate an advantage of this over conventional NSAID+PPI.¹
  • Misoprostol is the only drug proven to reduce clinically important ulcer complications but needs to be used at higher (800 micrograms daily) dose and this is frequently poorly tolerated with diarrhoea a common side-effect.
  • H2RAs at standard dose do not appear to reduce the risk of gastric ulceration.
• NSAID use and H.Pylori are said to be independent risk factors for GI bleeding and ulceration. In a patient already on NSAIDs, H.Pylori eradication is not recommended as it is unlikely to reduce the risk of NSAID-induced bleeding. In those about to start long-term NSAID treatment and who suffer from dyspepsia or have a history of gastric or duodenal ulceration, future risk of ulceration can be reduced. Eradicating H.Pylori in those with NSAID induced ulcers does not increase the rate of healing compared to acid suppressants.²³
• Where patients develop dyspepsia whilst on a NSAID (not previously investigated and without alarm symptoms) stop the NSAID where possible. Opt to test and treat for H. Pylori or undertake one month's treatment with full dose PPI.²³
• Where patients develop a proven NSAID-associated ulcer, always stop NSAID and treat with full dose PPI for 2 months.²³ If H.Pylori is present subsequently, offer eradication therapy.²³ Once the ulcer has healed:
  • Review the need for continued use of NSAIDs since they are at significantly high risk of future GI adverse events.
  • Where treatment is deemed unavoidable, try gastroprotection.
  • If symptoms persist, stop the NSAID, repeat endoscopy to confirm healing, ensure other causes of PUD are excluded and refer for specialist review.

NSAID induced asthma

Aspirin-induced asthma is reasonably common and potentially life-threatening. A systematic review²⁷ estimated its prevalence (from oral provocation testing) as 21% in adults with asthma and 5% in children with asthma. The incidence of cross-sensitivity to NSAIDs was high (98% for ibuprofen, 100% for naproxen, 93% for diclofenac) but low for paracetamol (7%). Based on this:

• Approximately 80% of asthmatics can take aspirin safely but always ask asthmatic patients about previous experiences with aspirin and other NSAIDs and warn them to stop taking them if their asthma deteriorates.
• Paracetamol should be the analgesic and antipyretic of first choice for asthmatic patients and those with high risk features for developing aspirin-induced asthma (severe asthma symptoms, nasal polyps, urticaria, and rhinitis) should be advised to avoid all products containing NSAIDs.

It is worth noting that NSAIDs are not contraindicated in those with COPD.

Cardiovascular and renal adverse effects

• NSAIDs have multiple complex effects on the kidney but are generally considered nephrotoxic.
• COX enzymes are expressed in the kidney and are thought to be important in protecting the kidney from hypovolaemia.²⁸ Consequently, those on NSAIDs are more at risk of developing acute renal failure when haemodynamically challenged and the most vulnerable are those who have existing renal/hepatic or cardiac impairment and the elderly. Interstitial nephritis is a rare side-effect of some NSAIDs and is not dose-related.
• Fluid retention is associated with NSAID use and can be sufficient to precipitate congestive cardiac failure in the elderly. Avoid their use in those with severe heart failure.
• Hypertension can be exacerbated amongst NSAID users, with ibuprofen and naproxen showing the greatest effects and celecoxib and diclofenac showing the least. The effect of antihypertensive drugs is attenuated in those taking NSAIDS.²⁹ The CSM advised against the use of etoricoxib in uncontrolled hypertensives.³⁰
• Cox-2 selective inhibitors were shown to be associated with an increased thrombotic risk (account for an additional 3 events per 1000 people per year compared to non-users)¹⁴ and subsequently an increased risk has also been demonstrated to be the case for some non-selective NSAIDs (see above).

• All NSAIDs have adverse effects but some individuals are more at risk and some NSAIDs more risky in terms of particular side effects.
• Whether or not treatment should be initiated or continued, depends on an individual's chance of benefit versus risk and their ability to tolerate the medication.
• Patients should be aware of the main side-effects, their possible manifestations and when to seek help. Frequently those most at risk, such as the elderly, are ignorant of possible side-effects.²¹
• Strategies for minimising side effects should be discussed.
• The need for monitoring, particularly for those at higher risk, should be explained clearly.
• Patients should be warned not to use multiple NSAIDs concurrently, whether prescribed or bought over-the-counter or via different routes of administration.