KNOWLEDGE SUMMARY

Keywords: BEHAVIOUR; COWS; HEIFERS; NSAIDS; PAIN; PAIN-RELIEF; PARTURITION; WELFARE

Nonsteroidal anti-inflammatory drug administration to periparturient cows to reduce postpartum pain-related behaviours

Amelia Cannadine, BVB DVM^1*

¹ The University of Sydney, Australia
* Corresponding author email: amelia.cannadine13@gmail.com

Vol 9, Issue 3 (2024)
Submitted: 22 Jul 2023; published: 18 Oct 2024; next review: 31 Jan 2026
DOI: https://doi.org/10.18849/ve.v9i4.692

PICO question

In periparturient cows does the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) aid in reducing pain-related behaviours after parturition when compared to cows not administered NSAIDs?

Clinical bottom line

Category of research

Treatment.

Number and type of study designs reviewed

Four randomised control trials.

Strength of evidence

Moderate.

Outcomes reported

The evidence suggests that NSAIDs can reduce some pain-related behaviours and increase resting behaviours in postpartum cows, with the effect being most consistently observed when administered between 6 and 48 hours before calving or within 3 hours after calving. This effect was most consistently observed in individuals that had experienced uncomplicated calving events and primiparous animals. Primiparous animals administered meloxicam prior to natural calving displayed significantly more lying bouts on the day of calving when compared to primiparous control animals and primiparous animals administered meloxicam postpartum. A separate study reported that cows administered ketoprofen spent less time in lateral recumbency than cows in the placebo group, irrespective of whether calving was assisted. Additionally, when treatment cows were in sternal recumbency, they spent more time with their head in a rested position than the placebo group. There was no significant difference in feeding behaviours postpartum between treatment and placebo animals. There were conflicting results between papers assessing activity levels.

Conclusion

In some cows, in particular cows with an uncomplicated parturition, NSAIDs can reduce some pain-related behaviours and increase some resting behaviours postpartum. The NSAID should be administered between 6 and 48 hours before calving or within 3 hours after calving.

How to apply this evidence in practice

The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources.

Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.

Clinical scenario

In recent decades, awareness around the importance of nonsteroidal anti-inflammatory drugs (NSAIDs) in animals has increased dramatically (Edwards, 2021). NSAIDs have been reported to be efficacious at reducing pain inflicted on cattle during husbandry procedures, such as castration, dehorning, and disbudding (Steagall et al., 2021). However, it is not only these procedures that have proved to induce pain in cattle. The literature has demonstrated the presence of an inflammatory state in postpartum cows from the tissue trauma associated with calving, even in healthy individuals (Humblet et al., 2006; Trimboli et al., 2020).

To date, the effects of postpartum analgesia on production parameters has been the focus in existing literature (Carpenter et al., 2016). However, very few studies include measures more typically considered to be sensitive indicators of welfare status, such as behaviour. Lying, for example, is a biologically important behaviour associated with sleeping and ruminating which can be reduced if an animal is experiencing stress, and potentially pain can have a similar effect (Gladden et al., 2021; Ruckebusch, 1975; Tucker et al., 2021). Given that pain is a primary welfare concern, determining whether the provision of immediate postpartum analgesia provides welfare benefits is essential, particularly in primiparous cows or in cows experiencing, or expected to experience, varying severities of dystocia (Gladden et al., 2021). Thus, evaluation of the evidence that measures behavioural parameters in periparturient cows administered NSAIDs is required to inform veterinarians and producers whether such a protocol can optimise welfare in the breeding herd.

The evidence

The evidence consists only of randomised control trials, which are ranked as high-level evidence due to their unbiased design and minimal risk of systematic errors (Burns et al., 2011; Sargeant et al., 2022). The evidence is weakened by those studies that omitted evidence of sample size calculations or 95% confidence, which would have evaluated whether sample size was sufficient, thus we cannot confirm whether there were enough study subjects to reduce type two errors (Jones et al., 2003; Mainau et al., 2014; Swartz et al., 2018). Furthermore, the variation in methodology between the papers limits the ability to compare them. Three NSAID types were utilised amongst the studies, namely, meloxicam (Mainau et al., 2014; Swartz et al., 2018), ketoprofen (Gladden et al., 2021), and acetylsalicylic acid (Barragan et al., 2020). Only one study included administration of an NSAID prior to calving as part of their protocol (Swartz et al., 2018), whilst administration post-calving was conducted in four of the studies (Barragan et al., 2020; Gladden et al., 2021; Mainau et al., 2014; Swartz et al., 2018). The studies containing the greatest number of significant findings for the reduction in pain-related behaviours and the promotion of resting behaviours came from those cows that were administered an NSAID prior to or promptly after parturition.

Summary of the evidence

Barragan et al. (2020)

 

Gladden et al. (2021)

 

Mainau et al. (2014)

 

Swartz et al. (2018)

 

Appraisal, application and reflection

Five randomised control trials were included in the analysis. Two of the studies did not state whether there was blinding of study personnel (Barragan et al., 2020; Gladden et al., 2021) as the element of observer bias may influence the outcome. Studies by Swartz et al. (2018) and Mainau et al. (2014) omitted calculations to determine the sample size required to deliver sufficient study power and there was no evidence of 95% confidence intervals to evaluate whether their chosen sample size was sufficient. Consequently, some of the non-significant results may be an artefact of low power, limiting the reliability of each study’s conclusions. This may stand for those studies that utilised a small subset of the study animals for the behavioural analysis component, without a sample size calculation to justify the number of individuals within these smaller subsets, the reliability of the results is questionable (Barragan et al., 2020; Gladden et al., 2021). It is important to address that these analyses are of a subjective nature and must be interpreted with caution. Nevertheless, all of the studies had at least one significant finding relating to pain-related behaviour in postpartum cows.

There were no reports of retained placenta or stillbirths associated with NSAID administration in any of these studies. The papers that utilised meloxicam all reported that there was no association between the incidence of adverse outcome post-calving and NSAID administration (Mainau et al., 2014; Swartz et al., 2018). However, the paper that utilised ketoprofen did measure the incidence of these undesirable side-effects, but the outcome was not reported (Gladden et al., 2021).

Studies using flunixin meglumine were excluded from this analysis as cows treated with Flunixin post-calving had an increased risk of retained placentas, still births and metritis (Duffield et al., 2009; Newby et al., 2017). This is due to its propensity to preferentially inhibit cyclooxygenase 1 (COX-1), in contrast to meloxicam which is predominately a cyclooxygenase 2 (COX-2) inhibitor (Trimboli et al., 2020). Thus, it has been recommended that flunixin should not be administered to cattle within 24 hours of parturition (Newby et al., 2017). Ketoprofen’s COX selectivity in cows has not been reported, but it has been reported to lower incidence of retained foetal membranes (Richards et al., 2009). Acetylsalicylic acid has been reported to be a weak inhibitor of both COX isoforms (Barragan et al., 2020). However, the paper that utilised acetylsalicylic acid did not report on the incidence of any of the aforementioned undesirable effects (Barragan et al., 2020).

Lying was reported in all of the papers included in the analysis. When primiparous animals were administered meloxicam prior to natural calving, they displayed significantly more lying bouts on the day of calving when compared to primiparous control animals and primiparous animals that were administered meloxicam postpartum (Swartz et al., 2018). Interestingly, the number of lying bouts in the pre-calving meloxicam group on the day of calving was more similar to the multiparous cows (Swartz et al., 2018). Furthermore, primiparous controls and primiparous animals that received meloxicam postpartum had significantly fewer bouts of lying on the day of calving than all treatment groups of multiparous cows (Swartz et al., 2018). Multiparous animals typically deliver more easily than primiparous animals, but this data suggests that the anti-inflammatory effects of pre-calving meloxicam in primiparous animals allows for an easier calving, or a calving comparable to that of multiparous cows (Swartz et al., 2018). Although these conclusions are not measuring the reduction in a pain-related behaviour and thus are not directly aligned with the research question, the presence of a behaviour associated with the reduction in pain is important to report. The study that administered meloxicam to their treatment animals’ postpartum concluded insignificant lying results (Mainau, 2014). However, significant lying results were also reported in a study by Barrier et al., 2014 which stated that when cows undergoing a caesarean were administered meloxicam prior to the first incision, they spent more time lying and had more bouts of lying within the first 16 hours and 24 hours respectively, when compared to the placebo group (Barrier et al., 2014).

The study by Swartz et al. (2018) relied on the drop in rectal temperature that occurs prior to parturition to aid in calving detection. This method of detection has moderate accuracy (at best) and resulted in 43 cows being removed from the study as they did not receive the pre-calving treatment within the specified timeframe. This demonstrates that the application of administering meloxicam before calving is challenging. Advances in identifying the onset of calving through technology that measures rumination, lying and activity provides promising potential in this space (Borchers et al., 2017; Fadul et al., 2017).

To support the theory that NSAID administration reduces pain postpartum, the Gladden et al. (2021) study   analysed specific lying postures found that all cows administered ketoprofen spent less time in lateral recumbency than cows treated with saline, irrespective of whether calving was assisted. Lateral recumbency in adult cattle is considered an abnormal lying posture exhibited when animals are in pain or are unwell (Hudson et al., 2008; Petherick et al., 2014). Therefore, this suggests that pain is experienced after parturition in all cows and ketoprofen administration improves comfort irrespective of parturition experience (Gladden et al., 2021). It is important to recognise that this conclusion is drawn based on the theory that lateral recumbency in cattle is an indicator of pain. Additionally, when treatment cows were in sternal recumbency, they spent more time with their head in a rested position than the placebo group (Gladden et al., 2021). Such posture is usually adopted when in a deep sleep (i.e., rapid eye movement sleep) (Ruckebusch, 1975). It is possible that pain reduced the duration of the placebo group’s sleep, explaining why the placebo group spent less time with their head rested (Gladden et al., 2021; Ruckebusch, 1975). The Gladden et al., 2021 study only included parturition events that produced live dairy female Holstein calves (Gladden et al., 2021). Considering that male dairy calves consistently weigh more than females the selection of only female associated calving events limits the usefulness  of this data and its ability to be extrapolated to all calving events (Dhakal et al., 2013; Olson et al., 2009).

Activity measures of the study animals were taken either via the use of accelerometers or pedometers (Barragan et al., 2020; Mainau et al., 2014; Swartz et al., 2018). One study found no significant effects in eutocic animals (Swartz et al., 2018). However, dystocic animals in this study that received meloxicam prior to or after calving were less active than the dystocic control animals postpartum (Swartz et al., 2018). The administration of meloxicam may have reduced activity by alleviating inflammation, allowing cows to rest more easily postpartum (Swartz et al., 2018). Conversely, studies also concluded that cows or heifers treated with NSAID postpartum had increased activity when compared to the control animals and that postpartum administration does lead to a reduction in inflammatory mediators, ameliorating behaviours associated with pain, and allowing these individuals to exhibit their normal behaviours (Barragan et al., 2020; and Mainau et al., 2014). Consequently, activity as a behavioural measure was difficult to analyse due to the conflicting findings presented.

Two of the studies assessed the differences in feeding behaviour postpartum (Gladden et al., 2021; Mainau et al., 2014) . These studies did not find a significant result regarding feeding behaviour. These insignificant results could have been explained by the adoption of scan methodology whereby feeding was measured in 10- or 20-minute intervals. Feeding behaviours are better represented by shorter sample intervals (Gladden et al., 2021; Mainau et al., 2014; Mitlöhner et al., 2001). Thus, it is possible that the proportion of time spent feeding was underestimated as the chosen interval was not sensitive enough to detect a change in feeding behaviour (Gladden et al., 2021; Mainau et al., 2014). Due to the discrepancy in the results reported and the potential that the scan methodology adopted could have had an influence, the need for further exploration into NSAID effect on feeding behaviour postpartum is validated.

Upon critical analysis, NSAID proved to reduce pain-related behaviours or increase resting behaviours in postpartum cows most consistently when they were administered 48 hours prior to but no less than 6 hours before calving, or within three hours of calving  (Gladden et al., 2021; Swartz et al., 2018). This conclusion proved to be most consistent in individuals that had experienced uncomplicated calving events, primiparous animals and potentially those that experienced dystocia; however, due to the conflicting analysis of activity between studies, this should be interpreted with caution (Gladden et al., 2021; Swartz et al., 2018). This analysis has revealed that the inflammatory state that has been identified and reported on in postpartum cows which experienced uneventful calving could be dampened down by NSAID administration (Gladden et al., 2021). Additionally, multiparous animals typically deliver calves more easily than primiparous cows, but the literature suggests NSAID administration to primiparous cows in the recommended time frame could allow for a calving experience similar to that of a multiparous cow (Swartz et al., 2018). As a result, if NSAID are introduced into primiparous calving protocols to improve calving ease, not only could the culling rates of animals who experienced calving difficulties be reduced, but animal welfare could be improved (MLA, 2019; Swartz et al., 2018). To explore this further, and due to the low numbers of studies which focuses on NSAID administration to cows that experienced uncomplicated calving events, are primiparous or that experienced dystocia more research is warranted.

Interestingly, two included studies measured milk yield postpartum and found that milk-yield was greater in the cows administered NSAID when compared to those that received a placebo (Barragan et al., 2020; Swartz et al., 2018). It cannot be denied that administration of NSAID to cows is laborious for producers but the increase in milk-yield may provide them with some incentive to consider administering NSAID to cows approaching parturition or promptly post-parturition.

Methodology

Search strategy

 

Exclusion / inclusion criteria

 

Search outcome

 

ORCiD

Amelia Cannadine: https://orcid.org/0000-0003-0147-6601

Conflict of interest

The author declares no conflicts of interest.

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