An introduction to NSAIDs for cattle: recommendations for the veterinary surgeon

Non-steroidal anti-inflammatory drugs (NSAIDs) are increasingly being used in cattle driven by the increased recognition and awareness of pain in cattle by veterinarians and farmers, and also by increasing evidence that treatment with NSAIDs can significantly improve treatment response for key diseases.

As of February 2020, five NSAIDs are authorised for use in cattle in the UK (see Table 1).

Choosing which NSAID to use

The literature on the use of NSAIDs in cattle is growing — a quick search using Scopus with search terms ‘NSAID’ and ‘cattle’ identified 228 documents of which half had been published in the last 9 years. However, of those studies only eight had comparisons of NSAIDs, of which four were comparisons in clinical trials of NSAIDs registered for use in cattle in the UK.

Many comparison studies are small and underpowered. For example, the most recent study identified by the search evaluated carprofen and flunixin after calving, but only had 20 cows in each treatment group (Giammarco et al, 2018). Studies are also inconsistent in both results and method — the other three studies identified by the search all evaluated the use of NSAIDs in the treatment of pneumonia, but one study compared single doses of carprofen, flunixin and ketoprofen, one a single dose of carprofen with three of flunixin, and the third a single dose of meloxicam with (depending on response) up to three doses of flunixin. All studies found no difference, but the authors of the first study claimed that one dose of flunixin was as good as one of carprofen and the second that one dose of carprofen was as good as three of flunixin. None of the studies is large enough to provide conclusive evidence in regard to NSAID choice.

Provided recommended treatment regimens are followed, all of the NSAIDs authorised for treatment of cattle in the UK are effective analgesics, antipyretics and anti-endotoxic agents, there is no clinically-relevant evidence that any NSAID authorised for use in cattle in the UK is better than another. We need to look at other evidence when choosing NSAIDs.

NSAID classification

NSAIDs can be classified based on their chemical structure, with structure being related to activity and side effects. However there are no published data in cattle that compare the effect of NSAIDs based on their classification by chemical structure.

The most common classification of NSAIDs is COX1 vs. COX2, i.e. whether the NSAID affects principally the constitutive cyclooxygenase enzyme (COX1) or the inducible enzyme that mediates inflammation (COX2). The beneficial effects of NSAIDs are principally due to COX2 inhibition of and side effects to COX1 inhibition. However, data from humans have shown that not only are the benefits of COX2-selective NSAIDs not as high as expected, they also have their own specific side effects.

The NSAIDs in Table 1 vary in their selectivity — at least in rat and human studies. However, selectivity varies between species; for example meloxicam has an approximately 10:1 COX2:COX1 in humans but in cattle it appears to be non-selective. We have very few comparative studies of COX selectivity in cattle, so it is not a useful means of determining NSAID choice.

Side effects

Studies on side effects of NSAIDs in cattle are rare and inconclusive other than those showing the impact of flunixin (currently only available as a pour-on in food producing animals) on retention of the fetal membranes (Newby et al, 2017). Thus, other than avoiding the use of flunixin within 48 hours of calving, NSAID choice cannot be based on side effects.

Side effects of NSAIDs seem to be extremely rare in cattle. This may be due to an inherent resistance, but also because side effects and length of treatment are strongly correlated and cattle, unlike dogs and humans, do not generally get treated for long periods of time.

Pharmacokinetics

For animals where meat or milk withhold times are important, choosing the NSAID with the shortest withhold time is unlikely to have clinically important effects, especially when treatment is repeated as required following label recommendations.

Another useful difference is half-life. Of the five products in Table 1, two (carprofen and meloxicam) are long-acting (t½ >20 hours), two (ketoprofen and flunixin) are short acting (t½ <10 hours), and one (tolfenamic acid) is intermediate (~12 hours). This is reflected in the label recommendations — shorter half-life products have shorter intervals between repeated doses.

Half-life of NSAIDs is only a guide as protein-bound NSAIDs can persist in affected tissues and have effects that last longer than high plasma concentrations. A single dose of a short-acting NSAID such as flunixin could therefore have the same effect as a single dose of a longer acting NSAID such as meloxicam. Nevertheless, a good rule of thumb to follow is to use a long-acting product where only a single injection is likely to be used, and where monitoring and reassessment are important to use a shorter-acting product.

This rule needs modifying depending on the condition being treated. This is not just severe vs. mild but also what the principal reason for treatment is, for example, analgesia vs anti-endotoxin effects. In cattle, meloxicam has an anti-endotoxin effect that probably lasts at least 50 hours (Salamon et al, 2000), but post-surgical analgesia may not last longer than 24 hours (Offinger et al, 2013).

Condition to be treated

Under the cascade the first question is: ‘Is there a suitable veterinary medicine authorised for this indication in the country where the treatment should take place?’ Thus, for pneumonia and mastitis any of the NSAIDs available can be chosen, in contrast only meloxicam is authorised for use to control disbudding pain, and only ketoprofen is authorised for use in cows with white line disease. Nevertheless, the use of ‘suitable’ means that it is unlikely that using authorised NSAIDs for unauthorised diseases will be an issue, and thus the registered uses should be a guide rather than a straightjacket. Use of non-authorised NSAIDs in cattle is completely unjustifiable as the range of authorised products covers all the categories of NSAIDs that a veterinarian is likely to need.

When to use NSAIDs

Chronic vs acute pain

Chronic pain is very difficult to control even in species where repeated use of NSAIDs is feasible. Outside of breeding bulls or other pedigree cattle kept primarily for reproductive purposes, long-term NSAID treatment is not likely to be practicable. Thus, using a single dose of a NSAID in a cow with chronic pain is not likely to be effective, and is likely to be counter-productive, especially if the cause of the chronic pain is not treated.

In contrast, acute pain is effectively reduced by NSAIDs. This is most clear in calves undergoing painful procedures, especially disbudding. There is good published evidence for all of the UK authorised NSAIDs, bar tolfenamic acid, as analgesics post-disbudding. However, no studies have tested whether multiple doses are better than a single treatment. Similarly, we lack evidence showing that longer-acting NSAIDs produce longer-lasting benefits than shortacting ones, although this seems a plausible hypothesis. Nevertheless, if cost is an issue a single dose of ketoprofen will be better than no NSAID (Figure 1).

Similarly in adult cattle combining local anaesthesia and NSAIDs can significantly reduce surgery-related pain compared with local anaesthetic alone. Again if only a single dose is to be used the preference should be to use a long-acting product.

Mastitis

Most or even all mastitis cases would benefit in terms of animal wellbeing from NSAID treatment. For peracute mastitis, products that can be given intravenously are probably ideal, but there is no evidence that one product is better than another.

In milder cases, treatment with NSAIDs can reduce pain and inflammation more effectively than antibiotic alone. In mild cases meloxicam has been shown to reduce both somatic cell count and the impact of mastitis on fertility in large studies (McDougall et al, 2016). Similar effects have not been reported for other NSAIDs, but it is plausible that they would also produce similar effects. The use of meloxicam in mild cases is economically beneficial (van Soest, 2018), but the significant addition to the cost of treatment seems likely to be a barrier to more widespread use.

Lameness

Pain associated with lameness lasts for at least 28 days after successful treatment and probably starts at least 28 days before diagnosis. Lameness is a chronic pain issue — single one-off treatments with NSAIDs are not likely to make a sustained difference unless lameness is detected early. However, lameness treatment is acutely painful so NSAIDs should be standard in cows treated for lameness even if the lameness is chronic.

To minimise pain, lame cows should be treated as early as possible by trimming, blocking and NSAIDs. If treatment is delayed the same treatment regimen should be used to minimise the pain from lameness treatment. There are very limited data on which NSAID to use — ketoprofen has the most data with 3 days’ treatment being the recommended regimen, but in one study carprofen had a similar impact to ketoprofen so could be a potential alternative (Laven, 2018). If cost is an issue then, as with disbudding, a single shot of a short-acting NSAID will not be optimal but it will be better than no treatment (Figure 2).

Post-calving treatment

Dystocia, hypocalcaemia and metritis are all examples of conditions where routine use of anti-inflammatories can be beneficial. For the former two conditions NSAIDs are probably under-used as most cases are treated by farmers rather than veterinarians. The same choice rules apply — long-acting for cows that are only going to be treated once (Figure 3).

Calf pneumonia

The benefits of NSAIDs in pneumonia are clear. Some studies have suggested that NSAIDs alone combined with close monitoring is a useful alternative to antibiotic treatment in milder cases (Mahendran et al, 2017). Choice of NSAID should be guided by the monitoring and treatment regimen being used. With close monitoring and daily treatment, short-acting NSAIDs may be as effective and cheaper than longer-acting products and allow the treatment regimen to be more flexible. If long-acting antibiotics are being used along with less close monitoring, then long-acting NSAIDs can be used so that cattle are not being handled just to administer NSAIDs.

Calf diarrhoea

The use of NSAIDs as part of the treatment of mild diarrhoea has not been properly evaluated so in such cases NSAIDs should perhaps be used on an individual basis. However in more severe diarrhoea bacterial overgrowth by coliforms together with invasion across the gut is common. In such cases the use of NSAIDs should be routine. Concern is often expressed about using NSAIDs in dehydrated animals; however, provided they are used alongside intravenous fluids side effects are unlikely.

In these cases we tend to use repeated doses of long-acting NSAIDs, principally meloxicam, to ensure that the anti-inflammatory activity persists throughout the treatment period, which may not happen unless short-acting NSAIDs are used more often than the label recommendation of every 24 hours. Many calves only require a single dose of meloxicam, but in those where the condition requires more treatments we use up to five doses repeated every 24 hours. This regimen has not been compared with either a single meloxicam dose or with repeated doses of short-acting NSAIDs, but in calves where dehydration due to acidosis and diarrhoea is the underlying problem we get high success rates (>80% in collapsed calves) without clinically-apparent side effects.

Conclusions

In the UK we have a very good range of NSAIDs that are authorised for use in cattle. The choice of which of these NSAIDs to use cannot be based on data from comparative studies, because we do not have enough data from such studies. However, if we base our choice on pharmacokinetics and matching the disease and symptoms to the individual label claims, in cattle we can choose NSAIDs that are suitable for every situation in which we want to use them.

KEY POINTS

• Lameness and lameness treatment are painful. The use of non-steroidal anti-inflammatory drugs (NSAIDs) at the time of treatment can significantly reduce the pain response.
• NSAIDs are an essential part of treatment in calves with pneumonia — the choice of NSAID depends on the approach to treatment with longer acting NSAIDs being more useful when handling is minimised.
• NSAIDs are underused for mild mastitis treatment even though there is strong evidence that their use may improve reproductive performance in cattle with mild mastitis.