Lameness is a painful condition that affects cattle globally (Randall et al, 2019; Ranjbar et al, 2020). The pathogenic mechanisms driving the lesions causing this pain are poorly understood relative to other painful conditions affecting the dairy cow (e.g. mastitis) (Randall et al, 2018a). Evidence is indicative that the routine use of non-steroidal anti-inflammatory drugs (NSAIDs) has a role to play in lameness treatment (Whay et al, 2005; Thomas et al, 2015, 2016; Wilson et al, 2022) and prevention (Wilson et al, 2022). However, despite this evidence, NSAID administration as part of even a routine lameness treatment protocol is still not present in many herds across the UK. It is commonplace for very lame animals with chronic and progressed disease to receive pain relief in the form of a short course of NSAIDs which is arguably too late and largely ineffective for long-term pain management. The evidence that exists indicates that the efficacy of NSAID administration is diminished when used in late-stage disease treatment (although it is recognised that analgesia has welfare benefits) (Thomas et al, 2016). Understanding the mechanisms through which NSAIDs may function, and the regimens in which they have merit, is of the utmost importance for clinicians to be able to recommend their usage in a more diverse and efficacious range of situations.
Understanding the aetiology of lameness caused by claw horn disease is important when advocating NSAID usage in a management regimen. The pathogenic mechanisms driving lameness caused by claw horn lesions (CHLs) are centred around inflammation sourced from different pathways (Newsome et al, 2016; Wilson et al, 2022). Around the time of parturition, inflammatory processes are upregulated systemically (Bradford et al, 2015) and changes to the functional anatomy of the foot occur (Tarlton et al, 2002; Knott et al, 2007). Evidence is emerging to suggest that this inflammation is impacting on the functionality of the foot (Newsome et al, 2016; Wilson et al, 2021). This compromise of the functional anatomy may impact an animal's tolerance to forces exerted on the foot, thereby predisposing the cow to CHLs. Furthermore, the development of a CHL itself is an inflammatory process (Newsome et al, 2017), with the corium of the sole or dorsal wall becoming inflamed as a result of trauma within the largely closed hoof. The consequences of inflammation derived from CHLs (scarring of soft tissues, new bone formation) is understood to predispose the animal to future lameness for the remainder of her life (Newsome et al, 2016; Randall et al, 2018b; Wilson et al, 2021, 2022). With this context, NSAID usage is likely pivotal in both preventing new cases of lameness emerging by controlling inflammation around parturition and minimising the risk of animals becoming recurrently lame following CHL development.
Evidence for non-steroidal anti-inflammatory drug usage
Several randomised controlled trials have investigated the efficacy of NSAIDs as part of different treatment regimens using a range of outcome measures. A systematic literature review has recently appraised studies published between 2010 and 2021 regarding NSAID usage and the potential benefits derived therefrom (mobility score, nociceptive threshold, and lying time outcomes) (Mason et al, 2022). Mason et al (2022) identified that the evidence supporting NSAID usage was not yet substantial, and that the studies examined could be confounded by bias, and results could therefore be inconclusive. A recent study has now conclusively identified various benefits associated with routine NSAID administration as part of a lameness management protocol (Wilson et al, 2022).
It has been identified that NSAID administration as part of a lameness management regimen is likely to have a positive impact on the experience of the animal in the medium (Thomas et al, 2015), and longer terms (Wilson et al, 2022). Several studies have examined NSAIDs as a lameness treatment (Whay et al, 2005; Thomas et al, 2015; Wilson et al, 2022) and prophylaxis (Wilson et al, 2022). Whay et al (2005) reported that animals receiving NSAIDs as part of a treatment for a CHL, had a significantly reduced nociceptive (pain) threshold at 3-, 8-, and 28-days post-treatment in comparison to those animals that did not receive NSAID. However, Mason et al (2022) identified challenges with the design and analysis with this study which invalidate the results, meaning that there is a lack of evidence to further support this hypothesis. The authors, however, do not wish to diminish the importance of the administration of pain relief when managing a painful condition. NSAIDs have been shown to improve the ‘cure rates’ of lameness treatments (typically defined as return to a non-lame mobility score). Thomas et al (2015) identified that NSAID usage in conjunction with a therapeutic hoof trim and an orthopaedic block significantly improved the chance of recovering to a non-lame mobility score 35-days post treatment when compared with therapeutic trimming and applying a block alone. It is important to note that within the same randomised controlled trial, a separate dataset of animals was analysed that had been lame for more than 2 weeks. Animals exposed to the same treatments in that dataset (i.e. therapeutic trim, orthopaedic block, and course of NSAID) were at a 16% chance of recovery at 42-days (Thomas et al, 2016) in comparison to the 85% described in the original dataset (Thomas et al, 2015). This finding clearly demonstrates the importance of intervention in early-stage disease to ensure optimal recovery rates. Laven et al (2008) identified no benefit from the use of tolfenamic acid (NSAID) in the treatment of lameness at assessment points up to 100 days post lameness treatment. In that study, the authors recruited animals that were found to be lame by the farm staff on their respective unit, meaning that later stage lameness/CHL was identified (Leach et al, 2010; Alawneh et al, 2012; Ranjbar et al, 2020). As has already been described, animals experiencing later stage disease, are understood to have a greater degree of pathological change to anatomy, which is likely to hinder their recovery (see below; Newsome et al, 2016; Wilson et al, 2021, 2022). In the Laven study, it would be a logical hypothesis to suggest that the effects of NSAID could be diminished because of this pathological change being present. The process of trimming and blocking to alleviate weight from pathological change may be the only potential means of managing cows in late-stage disease. This would mean that no benefit of NSAIDs would be observed from a cure rates perspective, leading to no observable difference between the treatment groups described by Laven et al (2008). Indeed, this hypothesis is supported by the findings of Thomas et al (2016) in which they identified a reduced efficacy of NSAID usage in animals experiencing ‘chronic’ cases of lameness in comparison to ‘new cases’.
The long-term benefit of routine NSAID administration has recently been demonstrated by a 34-month randomised controlled trial, again conducted by a team based at the University of Nottingham. Wilson et al (2022) identified that heifers receiving NSAID at their first and subsequent calvings and at lameness events (irrespective of the cause) were at a significantly reduced risk of becoming lame in the first and future lactations when compared with animals just receiving a therapeutic trim and orthopaedic block when lame. This work highlights the importance of managing inflammation around the transition period and lameness. Further to this, Wilson et al (2022) hypothesised that the pathways associated with the sensation of pain could be downregulated, reducing the risk of the animal having a lowered nociceptive threshold (less likely to feel pain with mild stimulus). The benefit derived from NSAID usage as part of a lameness control programme is now suggested to manage pain, minimise change to distal limb anatomy, and act prophylactically in the case of administration at calving.
Evidence now also exists to support the use of NSAIDs in the treatment of digital dermatitis. A study recently conducted by Kasiora et al (2022) demonstrated that animals with active digital dermatitis lesions had an improved chance of being non-lame at a 7-day assessment point if a course of ketoprofen was included in the treatment protocol. Although statistical significance was not identified within this study, its conclusions present an opportunity to further develop research around NSAID usage in lameness management. Within that study, an increased average daily milk yield of 10.5 kg was described in animals that were freshly calved, but lame, adding to the benefit derived from NSAID usage (albeit in a high yielding herd).
A substantial raft of evidence exists that is indicative of a positive response to NSAID usage in the treatment and prevention of lameness. Although several of these studies have challenges in study design and analysis (Mason et al, 2022), they are all suggestive at least of NSAIDs playing a positive role in the management of lame animals. The most substantial and observable benefits appear to occur only when it is used in line with the early detection and prompt effective treatment (EDPET) protocol (Leach et al, 2012; Groenevelt et al, 2014; Pedersen and Wilson, 2021). The EDPET protocol describes how early disease stage must be intervened in quickly using best-practice evidence-based veterinary medicine to treat disease to prevent challenges from re-occurring (Pedersen and Wilson, 2021). A key part of EDPET is ensuring that NSAID usage is implemented following the evidence-base and demonstrates the responsible use of a veterinary medicine. Substantial progress has been made to reduce antibiotic use as a lameness treatment, with digital dermatitis, foul-in-the-foot and deep sepsis cases being the primary causes of lameness requiring antibiotics. In all the studies described in the current article, ketoprofen was the NSAID used as part of the treatment regimens (except for Laven et al (2008) in which tolfenamic acid was used), and at present is the only NSAID for which there is evidence supporting its use to manage lameness in the dairy herd.
Prescribing responsibilities
Recent publications (Bell et al, 2022; Kasiora et al, 2022; Wilson et al, 2022) when taken in combination lead to the recommendation that NSAID administration is a critical component of a lameness treatment protocol (irrespective of the causes). When prescribing NSAIDs the authors recommend that clinicians focus on animal welfare outcomes as the primary driver underpinning decision making on farm. Currently ketoprofen is the only NSAID that is licensed and has improved lameness outcomes (both as a treatment and prophylactic) and reduced the risk of an animal being culled (Wilson et al, 2022). Within the previously described studies a course and dose rate appropriate for the product was used (as listed in the product datasheet). It is important to note that the efficacy of ketoprofen when not used at an appropriate dose rate daily for 3 consecutive days is unknown. Although the authors recognise that some form of ketoprofen administration is likely to be better than none, it is the prescriber's responsibility to ensure the client has the appropriate information to make an informed choice about usage, especially regarding use off-licence. The same principle applies to NSAID use as a treatment for transition period inflammation as described by Wilson et al (2022). Gladden et al (2022) have recently reviewed some of the literature describing NSAID use at calving to provide a comprehensive description to aid practitioners. Previously, retained fetal membranes have arisen with flunixin use immediately post-partum (Waelchli et al, 1999). Because of these challenges, the authors do not recommend using NSAIDs other than ketoprofen post-partum at the label dose rate for the purposes of managing lameness, although evidence exists describing safe use of other NSAIDs (Stilwell et al, 2014; Kunz et al, 2019). Evidence does exist to support the safe use of ketoprofen immediately post-partum with Gladden et al (2018, 2021) identifying increased lying times in dairy cattle that received ketoprofen immediately post-partum.
Barriers to non-steroidal anti-inflammatory drugs use
It is important when prescribing NSAIDs that client motivation is fully understood alongside the potential barriers that exist with NSAID use. In one study looking into the barriers to use, veterinarians were found to place more importance on the cost of NSAID use than farmers (Browne et al, 2022). In that same study, it was described that generally, the farmers' understanding and perception of pain could be improved. Overcoming psychological barriers to change should not be overlooked and facilitation skills are part of the methodology embedded within the Agriculture and Horticulture Development Board (AHDB) Healthy Feet Programme (AHDB, 2022).
Ensuring that animals are being treated at early disease stage, with an appropriate trimming and blocking regimen is critical in preventing client demotivation regarding NSAID usage. Each stage of the EDPET principle is critical. For a full description of EDPET see Pedersen and Wilson (2021). If this is not properly implemented, then the NSAID may not present any form of tangible benefit (such as the results described in Laven et al (2008) and Thomas et al (2016)).
Another likely barrier is the cost of NSAID purchase, and the time associated with administering doses on 3 consecutive days. As stated previously, the current evidence gives no understanding of the impact that shorter courses of NSAID may have on lameness and other health parameters. The same applies for longer-acting NSAIDs, where a single dose may be more convenient, but efficacy is unknown. Finding mechanisms on farm whereby animals can be quickly and easily identified (Figure 1) (e.g., Velcro™ leg bands), and NSAID can be administered in a stress-free manner is vital to ensuring sustained uptake of its usage.
The cost associated with the purchase of NSAID and associated equipment (e.g. needles, syringes, and staff time) cannot be overlooked. The protocols described by Wilson et al (2022) describe how targeting heifers with NSAID is critical in deriving maximum benefit from NSAID use. This mechanism of introducing NSAID use to the dairy herd is more economically acceptable for the farm business and allows for the farm team to optimise mechanisms of protocol delivery. From a cost-benefit analysis perspective, in a recent roundtable discussion (Bell et al, 2022), a return on investment of £1.66 for every £1 invested was identified for the study farm from the results described by Wilson et al (2022). This cost-benefit examined the numbers of lameness cases and culling described by Wilson et al (2022) with the assumption that the benefit was derived from the combination of NSAID administration at lameness and calving. In essence, administering NSAIDs at first and subsequent calvings, and at lameness events is likely to be a cost-effective tool for managing lameness across a large range of dairy systems.
Further to the above, ensuring that the focus of the protocol is on first calving heifers is of the utmost importance to its success. The evidence suggests that a history of lameness may nullify the effects of NSAID administration (Newsome et al, 2016; Randall et al, 2018b; Wilson et al, 2021). Ensuring that heifers receive three days of ketoprofen at first and subsequent calvings, and at lameness events ensures that those animals from which the most benefit will be derived are targeted.
Conclusions
A key cornerstone of lameness treatment should be the utilisation of NSAIDs as part of the EDPET protocol. Further utilisation should be at first and subsequent calvings alongside all lameness events to ensure that animal welfare is optimised and the maximum benefit from the administration of NSAID is derived. The authors encourage clinicians to remain up to date with the fast-moving evidence-base to ensure that optimal benefit is derived from NSAID use on farm. Ensuring client motivation in its uptake can present challenges, however targeting the use of NSAID may alleviate farmer ambivalence towards NSAID use.
KEY POINTS
- The use of early detection and prompt effective treatment (EDPET) is essential to derive maximum benefit from non-steroidal anti-inflammatory drug (NSAID) usage.
- NSAIDs are important in managing the pain around lameness and reducing the risk of lameness recurrence.
- The authors recommend clinicians use products that have an evidence-base in the management of lameness and use them as part of a course made up of a dose rate appropriate for the product.
- Communication to motivate change is an important part of facilitating NSAID usage on farm.
- Administering NSAIDs appropriately around the animal's first and subsequent calving, alongside lameness events, is likely to provide a cost-effective intervention across many dairy systems.