NSAIDs (non-steroidal anti-inflammatory drugs)

• What are NSAIDs?
• How do NSAIDs work?
• What are the different types of NSAIDs?
  • Non-selective NSAIDs
  • Selective NSAIDs
• What are NSAIDs used for?
• When shouldn’t an NSAID be used?
• Precautions with using NSAIDs
• NSAIDs and gastric ulcers
• NSAIDs and heart attack risk
• What are the possible adverse reactions to NSAIDs?

What are NSAIDs?

Non-steroidal anti-inflammatory drugs (NSAIDs) are a very commonly prescribed type of drug (many of which are available over the counter without prescription) that can reduce pain, inflammation and also lower the body’s temperature during a fever.

They also have some, less desirable, effects such as reducing the production of substances that protect the stomach, stopping platelets (the cells that are vital in the formation of clots to stop bleeding) from working as effectively, and mildly reducing the amount of blood that flows to the kidneys by making the arteries that supply them constrict.

How do NSAIDs work?

NSAIDs work is by inhibiting an enzyme (a chemical that causes other chemical reactions to occur) called cyclooxygenase (sometimes referred to as COX). This enzyme is crucial for the production of chemicals called prostaglandins, which are substances that have a few different roles, one of which is to cause inflammation. So by stopping the enzyme, fewer prostaglandins are produced leading to less inflammation and pain.

What are the different types of NSAIDs?

The two classes of NSAIDs are ‘non-selective‘ and ‘selective‘. To understand the differences between them however, requires some more explanation about how they work.

The cyclooxygenase (COX) enzyme is actually present in two different forms, COX-1 and COX-2, each with a similar but distinct set of actions. COX-2 is the enzyme responsible for inflammation and fever, whereas COX-1 actually performs other functions such as protecting the gastric mucosa (the lining of the stomach) from the acid that the stomach naturally produces. COX-1 also plays a role in making platelets stick together to form clots. Both reduce blood flow to the kidneys, though.

One of the problems with NSAIDs is that they block both types of the COX enzyme, so while inflammation and pain were reduced, so were some of the good effects of prostaglandins such as protection of the stomach lining. That is why recently there has been the advent of what are known as ‘Selective NSAIDs’. These are drugs that only target the COX-2 enzyme that is responsible for pain and inflammation, without impacting the production of protective factors for the stomach.

Non-selective NSAIDs

Non-selective NSAIDs are drugs that inhibit both types of the COX enzyme and thus are associated with an increased risk of gastric ulceration, presumed to be both through the reduction in gastric protection that is provided by prostaglandins, as well as direct irritation of the gastric lining. Examples of non-selective NSAIDS include:

• Aspirin;
• Diclofenac;
• Ibuprofen;
• Naproxen;
• Mefenamic acid;
• Indomethacin;
• Ketoprofen;
• Piroxicam.

These are sold under lots of different brand names, so many that it is impractical to list them here.

Selective NSAIDs

Selective NSAIDs inhibit only the COX-2 enzyme, allowing for the production of the prostaglandins that protect the stomach, while still relieving fever, pain and inflammation. They do no have the anti-platelet effects associated with nonselective NSAIDs and so do not alter clotting. The selective NSAIDs are:

• Celebrex (celecoxib); and
• Mobic (meloxicam) (at doses of 7.5 mg per day or less).

What are NSAIDs used for?

NSAIDs can play a role in the treatment of many different conditions that involve inflammation, pain or both. NSAIDs can be used in the treatment of:

• Rheumatoid arthritis;
• Ankylosing spondylitis;
• Psoriatic arthritis;
• Reactive arthritis;
• Acute gout;
• Period pain;
• Metastatic bone pain;
• Osteoarthritis;
• Headache and migraine;
• Post-operative pain;
• Mild-to-moderate pain due to inflammation and tissue injury;
• Fever;
• Renal colic;
• The anti-platelet properties of NSAIDs (most commonly aspirin) are used to protect the heart by stopping the formation of clots.

When shouldn’t an NSAID be used?

Conditions were NSAIDs are generally avoided include:

• NSAID-sensitive asthma;
• Rhinitis;
• Urticaria (allergy in response to NSAIDs);
• Active gastrointestinal bleeding;
• A gastric or duodenal ulcer;
• Pregnancy: If given in the late stages of pregnancy, NSAIDs can cause closure of a the fetal ductus arteriosus (a small connecting vessel that allows fetal blood to bypass the lungs and usually closes after birth). They can also cause fetal renal impairment, inhibition of platelet aggregation and can delay labour and birth. Despite this, they can still be used in pregnancy under a doctor’s supervision if they feel the benefits will outweigh the risks;
• Lactation: While not recommended for breastfeeding mothers, ibuprofen appears safe. There is less data about selective COX-2 inhibitors, though they also appear to be safe.

It should be noted that each individual agent may have a different profile of contraindications, and if you are concerned you should consult the product information or, preferably, your doctor.

Precautions with using NSAIDs

NSAIDs should be used with caution in patients with the following conditions:

• Asthma: NSAIDs have been known, rarely, to cause constriction of the airways which can make asthma flare temporarily;
• Crohn’s disease;
• Previous gastrointestinal bleeding;
• Coagulation disorders: most nonselective agents increase the risk of bleeding whereas selective NSAIDs, and possibly diclofenac, can increase the risk of clotting;
• Bruising (may be made worse);
• Heart failure or hypertension: may be made a little worse following sodium and fluid retention, secondary to reduced blood flow to the kidneys;
• Renal impairment;
• Hepatic impairment;
• Patients at increased cardiovascular risk: NSAIDs may not be appropriate for treatment with certain selective COX-2 inhibitors or diclofenac;
• Patients on low-dose aspirin: these patients have increased cardiovascular risk with the use of COX-2 selective agents and the use of aspirin negates any benefits they may have in reducing ulcer risk.

NSAIDs and gastric ulceration

The lowering of protective prostaglandins by old-style NSAIDS causes the lining of the stomach to become irritated, causing nausea, difficulty swallowing and, most severely, gastric ulcers. These can occasionally burst causing large amounts of bleeding. The gastrointestinal symptoms could be very severe, with a 5 to 6 times higher risk of hospitalization than a non-NSAID user. In Australia this leads to up to 4,500 hospital admissions and up to 400 deaths each year.

The use of a selective COX-2 inhibitor can be very useful in patients who are on long term NSAIDs and thus are at a high risk of gastric ulceration. A selective NSAID such as celecoxib (Celebrex) has been shown to lower the risk of gastric ulceration, with some studies showing that it reduced the amount of ulcers to that of taking a placebo (which is basically a sugar pill with no active ingredients). This was an impressive 87.5% lower than in patients taking a traditional NSAID.

It should be noted however, that the use of a nonselective NSAID does certainly not mean that you will develop a gastric ulcer, nor does it mean that selective agents are perfect. Some other studies have shown that celebrex certainly does lower the rate of gastric ulcers compared to a drug such as Naproxen, but only to a rate that is comparable to another non-selective NSAID, diclofenac.

NSAIDs and heart attack risk

The cardiac risk for NSAIDs has received a lot of attention both in the media and within the medical profession; and rightly so, as they are very frequently prescribed medicines and any adverse effects can impact lots of people. The initial concerns was raised in 2004 when studies showed that Vioxx (rofecoxib), a type of selective NSAID that has since been taken off the market, increased the risk of having a ‘cardiac event’ (usually a heart attack). Since then, there has been a lot of research looking into whether or not it was something that only happened with Vioxx, or is associated with many (or even all) NSAIDs.

One study published in the Journal of the American Medical Association looked at over 233 articles, and pooled the results from the 23 that they thought met a high enough standard to be re-examined. They combined the results from all of these trials so that they could have a detailed look at all different NSAIDs. This gave them 86,193 cases of cardiovascular events, and more than 528,000 ‘controls’ (people without heart problems or who did not take NSAIDs) to give a high quality of data. They found the following results:

• Rofecoxib (Vioxx) definitely did cause an increase in cardiovascular events, and the higher the dosage the higher the likelihood of an event. This is why it was removed from the market;
• Some other non-selective agents still on the market also increased the risk of cardiovascular events if taken at normal doses;
• Increases in cardiovascular events were not universal for selective COX-2 inhibitors at normal doses, and some are still available that seem not to increase risk.

A trial conducted in Europe attempted to finally demystify the comparisons between NSAIDs and selective COX-2 inhibitors. Researchers pooled data from several previous clinical trials to compare the incidence of serious gastrointestinal and cardiovascular events. Researchers found on a whole, the COX-2 inhinitors caused less serious gastrointestinal effects without causing a significant increase in heart attacks and strokes. This was for five different coxibs, namely celecoxib, valdecoxib, etoricoxib, rofecoxib and lumiracoxib. Surprisingly the former two agents actually caused less cardiovascular events when directly compared to traditional NSAID treatments.

These results can be some comfort to patients who are taking long term anti-inflammatory treatments at normal doses, as they seem to show that not all are associated with an increased cardiovascular risk. However, this does not mean that at higher doses there is no long-term danger, and this should always be discussed with a doctor, weighing up the risks of being on long term NSAID or COX-2 treatment with the benefits of lowered pain and inflammation.

What are the possible adverse reactions to NSAIDs?

Some fairly common reactions (occuring in more than 1 in 20 people)to NSAIDs include:

• Nausea;
• Dyspepsia (discomfort with digestion);
• GI ulceration or bleeding;
• Raised liver enzymes;
• Diarrhoea;
• Headache;
• Dry eyes;
• Dizziness;
• Salt and fluid retention;
• Hypertension.

Less frequent reactions (occuring in between 1 in 20 and 1 in 100 people) include:

• Oesophageal ulceration;
• Heart failure;
• Renal impairment;
• Confusion;
• Bronchospasm (constriction of the airways);
• Rash.

Very rare reactions (occuring in less than 1 in 100 people) include:

• Inflammation of the bladder;
• Nephrotic syndrome;
• Acute renal failure;
• Photosensitivity;
• Hepatitis (inflammation of the liver);
• Aseptic meningitis;
• Blurred vision;
• Tinnitus.

References

1. Australian Medicines Handbook. [online]. NSAIDs. January, 2007. Available at URL: http://www.amh.net.au (last accessed 15/03/07)
2. McGettigan P, Henry D. A Systematic Review of the Observational Studies of Selective and Nonselective Inhibitors of Cyclooxygenase 2. JAMA. 2006;296(13):1633-44.
3. MIMS Australia. [online] Brufen. 2006. Available at URL: http://www.mims.com.au (last accessed 31/04/07)
4. MIMS Australia. [online] Celebrex. 2007. Available at URL: http://www.mims.com.au (last accessed 31/04/07)
5. Moore R, Derry S, McQuay H. Cyclo-oxygenase-2 selective inhibitors and nonsteroidal anti-inflammatory drugs: balancing gastrointestinal and cardiovascular risk, BMC Musculoskeletal Disorders 2007; 8 (73): 1-11.
6. Murtagh, J. General Practice (Third Edition), Sydney: McGraw-Hill 2005.

Drugs used in this treatment:

• Celebrex (Celecoxib)
• Diclofenac-BC (Diclofenac)
• Feldene (Piroxicam)
• Mobic (Meloxicam)
• Naprogesic (Naproxen sodium)
• Nurofen (Ibuprofen)
• Vioxx (no longer available) (Rofecoxib)
• Voltaren Rapid 12.5/ 25/ 50 (Diclofenac potassium)

This treatment is used for the following conditions:

• Ankylosing spondylitis
• Dysmenorrhoea
• Gout (crystal deposition disorders)
• Headache
• Migraine
• Osteoarthritis
• Reactive arthritis
• Rheumatoid arthritis