An Overview written for Mrs Carole Smedley for use by the Rough Collie Community by Dr Lynda Boyle [Barrenclough Rough Collies], to whom queries should be addressed.

What are NSAIDs and why do we need them?

When tissue is damaged, chemicals are released that cause inflammation, attracting white blood cells to the area to fight any infection and remove debris. This inflammatory response causes swelling and pain, which can be severe and debilitating, for instance, in osteoarthritis. Steroids are the 'big guns' in reducing inflammation, but they are involved in many processes in the body and cause unpleasant side effects. Thus, we tend to use them only when we must in short bursts to get inflammation under control. For general and longer term use, we have the NSAIDS – Non Steroidal Anti Inflammatory Drugs.

Common NSAIDs include ibuprofen, diclofenac, naproxen, ketoprofen, indomethacin, mefanamic acid, celecoxib, etoricoxib, meloxicam but there are others. A few are available OTC [over the counter] in low dose tablets or as gels and creams. A prescription is required for the rest. You may see them under these generic names or under brand names, like Brufen for ibuprofen or Celebrex for celecoxib. Sometimes you will see branded generics, where the patent has expired, but the manufacturer is trying to differentiate his particular product and sometimes to imply added value – for instance Nurofen [ibuprofen]. Although the shape may be different and the packaging may be more expensive, 200mg of ibuprofen is 200mg of ibuprofen, no matter whether you pay under 2p or over 20p for it!!! [The makers of Nurofen were fined $1,7M for falsely claiming their products targeted particular types of pain, despite containing the same active ingredient!]

How do NSAIDs work?

NSAIDs work by reducing the production of prostaglandins, which cause inflammation, pain and fever. However, they also have a good side. They protect the stomach lining and intestines from stomach acid, they promote normal functioning of the kidneys and they activate platelets that allow blood to clot. Enzymes called cyclooxygenases [COX] promote production of prostaglandins. Inhibiting these enzymes thus reduces prostaglandin formation and, hence, inflammation, pain and fever. Unfortunately, the beneficial effects are also reversed, and even ibuprofen can have a negative effect on the stomach and gut., causing ulcers and increased risk of bleeding. There are, however, 2 types of COX enzymes, COX-1 and COX-2. Prostaglandins produced by COX-1 promote inflammation and protect the gut, but prostaglandins produced by COX-2 only promote inflammation. Thus, a truly selective COX-2 inhibitor will reduce inflammation without reducing protection of the gut.

What are the differences between NSAIDs?

NSAIDs differ in potency, duration of effect and potential to cause adverse events, such as ulcers and bleeding, because they have different relative abilities to inhibit COX-1 and COX-2. Generally, the stronger the stronger the anti-inflammatory effect, the worse the side effects. However, some people respond to certain NSAIDs better than others and some people tolerate them better. We cannot identify these people in advance. It really is a case of try it and see.

Celecoxib [Celebrex] inhibits COX-2 but has little effect on COX-1. It is the first licensed selective COX-2 inhibitor, causing fewer ulcers and less bleeding than non-selective NSAIDs. [although meloxicam also has some COX-2 effect.] Etoricoxib is much more highly specific for COX-2, with a ratio of 106 to 1 [vs 35 to 1 for rofecoxib and 1.78 to 1 for ibuprofen] and is as effective on arthritic pain as ibuprofen and naproxen.

Aspirin can be considered as an NSAID, and is the only one able to inhibit blood clotting over a period of time, say 4 to 7 days, and is effective in preventing blood clots leading to heart attacks and strokes.

So why do we not all take the COX-2 inhibitors?

One reason is cost – ibuprofen can cost under 2p a tablet, etoricoxib about £3, depending on dose. Another is availability – some NSAIDS are available to buy OTC, but most are prescription only. A major reason is tolerability – adverse events or side effects. Indeed, if you have a pain in one particular place, you will likely be advised to try an NSAID gel or cream first to try to avoid systemic side effects.

However, we will not mention every possible side effect of every known NSAID here. Everything officially recorded against any one particular drug can easily be found online via such reliable agencies as the BNF. What we will say is that is is important to get it all in context. Not everybody experiences every side effect and those that do will experience them to different extents. We are all individuals. Progress is already being made towards more specifically targeted therapies, which should reduce side effects, and eventually, as our knowledge of DNA develops, we should be able to target some therapies to the individual patient, thus reducing side effects even further. This will not come cheaply. For now, we must consider whether the benefits we get from the drug outweigh the negatives from taking it. All this, together with purchase and administration costs, is considered as actual numeric data by organisations such as NICE [National Institute for Clinical Excellence] to determine the cost effectiveness of a drug [and, hence, whether it will be available under the NHS], when quantities such as QALYs [Quality of Life Years] are discussed. And do bear in mind that, if aspirin was released on the market today as a new synthetic drug, it would probably be reserved for consultant use only because of its side effects.

So, back to the COX-2s. When rofecoxib [Vioxx] was released and out-performed celecoxib, it rapidly became a blockbuster drug, with many millions of users, generating massive revenue. Unfortunately, the more it was used, the more it became apparent that it had a dark side. It was voluntarily withdrawn by the manufacturers because it allegedly caused tens of thousands of deaths from cardiovascular events, It was the highest prescribed drug ever to be withdrawn – 80 million prescriptions at the time. Many devoted users were devastated. The following year, the similar valdecoxib was also withdrawn and the FDA issued a class warning about cardiovascular events associated with COX-2s. Nobody had done the equivalent studies with the older NSAIDs, like ibuprofen and diclofenac. The FDA investigated and found that the traditional NSAIDs acted in the same way. They are now all contraindicated in anyone with heart problems. They must all be treated with respect.

From 2017 to date, efforts have been made to bring back rofecoxib for cases where all else fails. We await the outcome.

Ibuprofen toxicity in dogs

Never be tempted to give a dog an ibuprofen or naproxen etc tablet. Canine physiology differs from ours in metabolising these drugs. Excretion is delayed, causing toxic effects. Small doses cause severe gastric effects within hours, higher doses cause kidney failure within 1 to 5 days. It may be impossible to reverse these effects. Dogs can die from ibuprofen poisoning.

What NSAIDs are used in dogs?

Meloxicam [Metacam] is commonly used in dogs. It has a little COX-2 specificity but still must be given with food to try to avoid gastric effects. [I have collies that cannot tolerate meloxicam because of GI effects.] Correct dosing is very important to avoid toxicity and depends on the size of the dog – hence the liquid formulation.

A newer drug, Previcox [frlocoxib], is available as a tablet and is more COX-2 specific than meloxicam, but should still be given with food to try to avoid GI effects. Again, dosing is important and the tablets may need to be split. Interestingly, it only has a licence for dogs. The European submission includes no human data.

NSAIDs approved by the FDA for dogs include:

• RIMADYL (carprofen)
• METACAM (meloxicam)
• DERAMAXX (deracoxib)
• PREVICOX (firocoxib)
• NOVOCOX (carprofen)
• VETPROFEN (carprofen)
• CARPRIEVE (carprofen)
• QUELLIN (carprofen)
• OROCAM (meloxicam)
• LOXICOM (meloxicam)
• MELOXIDYL (meloxicam)
• ONSIOR (robenacoxib) for a maximum of 3 day use
• GALLIPRANT (grapiprant)