Does UK licensed NSAID administration reduce signs of postoperative pain in calves castrated without local anaesthesia?

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Appraisal, application and reflection

All 20 studies appraised were controlled trials, of which 17 were randomised, indicating a relatively high level of evidence. No relevant meta-analyses were found and narrative reviews were excluded due to being widely focused and not showing reproducible search strategies. All studies appraised compared NSAID administration to a control calf castrated without NSAIDs; several studies also included non-castrated or sham-castrated calves to provide a baseline against which pain indicators could be compared. Some studies further improved this protocol by including both medicated and unmedicated sham groups, allowing more accurate differentiation between behavioural and physiological indicators of handling stress versus pain and reducing over-interpretation. Of the studies appraised, 15 included the use of a placebo (saline or lactated Ringer’s solution) in approximately equal volume to the NSAID in unmedicated calves to quantify and control for discomfort associated with drug administration. Eleven studies involved blinding, either of personnel recording behavioural observations or measuring physiological pain indicators or both. This was particularly important in behavioural observation to reduce bias as far as possible. However, due to the experimental nature it was sometimes difficult to blind observers, as e.g. surgically castrated calves can be visually differentiated from band castrated calves in the period immediately following castration; Petherick et al. (2014a; and 2014b) also reported that some surgically castrated calves had blood on their hindlimbs, making them easy to identify. Several studies also analysed behavioural parameters using video footage rather than via direct contact with the calves, reducing the likelihood of observer effects on behaviour.

The studies appraised showed mixed results for the efficacy of NSAIDs alone at reducing signs of postcastration pain, although overall 13 out of the 20 studies showed some improvement in pain indicators following NSAID administration. It is important to note that pain is inherently subjective and is therefore difficult to assess objectively; physiological indicators of pain can be measured but some lack specificity to pain alone and can be affected by other factors, e.g. cortisol may increase due to handling stress (Grandin, 1997). Similarly, APPs e.g. SAA and haptoglobin, are indirectly associated with pain through their inflammatory role; as NSAIDs reduce pain associated with inflammation, APP concentrations can be used as a measure of NSAID efficacy but they are not pain-specific. Substance P is involved in nociception, and has been shown to decrease with meloxicam administration following dehorning (Coetzee et al., 2012; and Allen et al., 2013). Substance P concentrations were measured in five studies, of which only two (Meléndez et al., 2018b; and Olson et al., 2016) found a significant decrease following NSAID administration. However, the three studies which found no effect on plasma substance P (Kleinhenz et al., 2018; Meléndez et al., 2018a; and Repenning et al., 2013) used sampling intervals which may have been too wide to detect any changes.

Behaviours such as lesion-licking, foot-stamping, tail flicking and changes in standing and lying behaviour may be more pain-specific (Millman, 2013) than physiological markers, but are more difficult to objectively assess. Several studies used a visual analogue scale to make subjective assessment of pain-related behaviours more repeatable, however in several cases the visual analogue scale was only used to assess intra-castration pain which was beyond the scope of this Knowledge Summary. Objective measurement of behavioural parameters can be obtained using devices e.g. pedometers, accelerometers and pressure mats, which was done by 11 studies. However, these devices generally only collect walking, standing and lying data and not discrete and more pain-specific behaviours such as those described above. Other behavioural changes measured objectively include exit velocity as calves leave the chute and feed intake, however again these are not very pain-specific.

Pain-associated behaviours vary between reports; some authors suggest cattle in pain take fewer steps and show more lying behaviour (Currah et al., 2009; and Laurence et al., 2018), whereas Ting et al. (2003) found that the incidence of combined lying postures in castrated calves was significantly lower than uncastrated calves. This is further confounded by different castration methods causing different behavioural changes: surgical castration may increase standing time and band castration may increase lying time (Roberts et al., 2018). Behavioural indicators of pain may also be difficult to detect as cattle are prey animals and therefore mask pain signs (Laurence et al., 2018), especially in older calves unused to human contact. Due to the limitations in both physiological and behavioural pain assessment methods, it is therefore preferable to use both together to obtain the most accurate results; of the studies appraised, all included both physiological and behavioural parameters in their analysis except Roberts et al., (2015) who only investigated physiological parameters and Sutherland et al., (2018) who only investigated behavioural parameters. Roberts et al. (2015) reported reduced plasma cortisol and haptoglobin concentrations following meloxicam administration so it would have been interesting to see if this coincided with behavioural changes as well. Conversely, Sutherland et al. (2018) reported no improvement in pain behaviours following meloxicam administration. However, meloxicam was under-dosed; the datasheet states a dose of 0.5 mg/kg and each calf was administered 5 ml (at 10 mg/ml), but as mean calf weight was 111.7 kg the mean dose should have been 5.6 ml. Behaviour was also only observed for 3 hours postcastration, so improvements may have been seen with a higher dose and a longer observation period, especially as band castration as used in this study may cause more chronic than acute pain (Petherick et al., 2014a; and 2014b).

Castration method may also affect the type of pain experienced and therefore the analgesic ability of NSAIDs. Within the same method the exact way castration is carried out may differ, e.g. differences in blunt dissection in surgical castration between individual veterinary surgeons and individual calves depending on anatomic variations and personal technique. Different individual calves may also have different pain tolerances (Stafford & Mellor, 2005); these differences in both pain tolerance and infliction make it difficult to accurately compare the studies appraised. Of the five studies which showed improvement in both physiological and behavioural pain indicators, three investigated surgical castration (Laurence et al., 2018; Meléndez et al., 2018a; and Ting et al., 2003) and two investigated surgical and band castration together (Meléndez et al., 2018b; and Olson et al., 2016). Conversely, of the seven studies which showed no significant improvement in pain, four only investigated band castration (Daniel et al., 2020; Paull et al., 2015; Repenning et al., 2013; and Sutherland et al., 2018). It is worth noting that of all the studies appraised, only these four studies investigated band castration alone. This could suggest that band castration is less amenable to pain relief through NSAIDs than surgical methods, although further work would be required to investigate this. Meléndez et al. (2018b) reported that knife castration was associated with the most behavioural pain indicators, in contrast with Petherick et al. (2014a; and 2014b) who reported more longer-term pain behaviours and less NSAID efficacy in band castration; this may be related to the age of calf used as band castration is thought to be less painful in younger calves than older calves due to smaller testicular size. Olson et al. (2016) and Roberts et al. (2018) found that meloxicam treated band castrated calves spent less time lying than their control counterparts, while meloxicam treated surgically castrated calves spent more time lying than their control counterparts, supporting the idea that different castration methods induce different types of pain and suggesting that meloxicam has some effective analgesic ability for both castration methods.

Pain perception in calves may be influenced by age. Bretschneider (2005) reported that castration closely following birth reduces weight loss associated with castration compared to calves castrated later in life; however weight changes are not specific to pain, as reduced weight gain can be influenced by both inappetence caused by pain and reduced testosterone secretion reducing muscle mass, and pain can also motivate calves to suckle more (Meléndez et al., 2018b), increasing weight gain. Bretschneider (2005) also reported that the cortisol response of calves castrated at 6 months or younger tended to be lower than that of older calves and hypothesised that this was related to increased trauma and discomfort due to increased testicular size. However, Stafford & Mellor (2005) reported relatively similar peaks in plasma cortisol concentration for calves aged 6, 21, 42 days, 2–4 months and 5.5 months by castration method used. Despite these possible differences in pain response depending on age, studies investigating calves of all ages up to 1 year were included in the evidence appraisal, as differences in pain response are likely not so significant that they make these studies completely inapplicable to UK practice. Only one study (Meléndez et al., 2018b) investigated a cohort where all calves were below the UK legal age limit for castration without anaesthesia and found meloxicam administration reduced both physiological and behavioural pain signs. Three other studies used calf cohorts where some individuals may have been within the legal age limit (Gellatly et al., 2021; Marti et al., 2018; and Paull et al., 2015) (2 months, 2 months and 7–9 weeks old respectively) and found no improvement in pain indicators following NSAID administration, suggesting that calf age is not the most important factor in NSAID efficacy.

The time at which NSAIDs are administered relative to castration is also likely to affect analgesic efficacy. 12 studies involved NSAID administration before castration and of these, four showed reduced physiological and behavioural indicators of pain and a further four resulted in improvements in either physiological or behavioural indicators. NSAID administration concurrently with castration (Kleinhenz et al., 2018; Repenning et al., 2013; Roberts et al., 2015; Roberts et al., 2018; and Ting et al., 2003) reduced both physiological and behavioural signs in one study (Ting et al., 2003) and one of physiological or behavioural indicators in a further three. Postoperative NSAID administration (Daniel et al., 2020; Laurence et al., 2018; Paull et al., 2015; Repenning et al., 2013; and Ting et al., 2003) appears to be the least effective, with only two studies reporting improvement in pain signs (Laurence et al., 2018; and Ting et al., 2003); however, it is important to note that these studies both incorporated NSAID administration at several different time points. This could be related to NSAID mechanism of action, as analgesia is provided through COX inhibition reducing prostaglandin synthesis (Day et al., 1987); administration before a painful stimulus may reduce total prostaglandins further than administration after the stimulus when prostaglandin synthesis has already occurred. Ting et al. (2003) reported that calves given either 3 mg/kg ketoprofen 20 minutes before castration or 1.5 mg/kg 20 minutes before followed by 1.5 mg/kg concurrent to castration had reduced mean plasma haptoglobin concentration relative to castrated control calves on day 3, but this was the main significant difference between ketoprofen treated calves, suggesting that time of administration is not the main factor in analgesic effect. Similarly, Laurence et al. (2018) reported that calves administered 0.5 mg/kg meloxicam 30 minutes before castration were more active after castration than unmedicated controls, and that postoperative meloxicam administration at the same dose resulted in calves resting less than controls. These behavioural changes are similar and both meloxicam treated calves had significantly lower plasma cortisol concentrations postcastration than control calves, suggesting both pre- and postoperative meloxicam have some analgesic effect. Repenning et al. (2013) also investigated the effect of several meloxicam doses (1.0, 0.5 and 0.5 mg/kg on days –1, 0 (concurrent with castration) and 1 respectively) and found no significant improvement in pain. This may be because band castration was used, which is thought to cause more chronic pain than the surgical castration used by Laurence et al. (2018) and Ting et al. (2003).

Several different NSAIDs were used in the studies appraised. Only NSAIDs licenced for use in cattle in the UK at the time of writing (meloxicam, ketoprofen, carprofen and flunixin) (Veterinary Medicines Directorate, 2020) were included; of these, 13 studies investigated meloxicam (of which eight reported some benefit), four investigated ketoprofen (of which one, Ting et al. (2003), reported improvements in physiological and behavioural parameters and two, Petherick et al. (2014a; and 2014b), reported behavioural improvements) and three investigated flunixin (of which two, Kleinhenz et al. (2018) and Webster et al. (2013) reported reduced cortisol concentrations). Paull et al. (2015) reported that calves treated with 200 mg flunixin showed significantly more pain avoidance behaviours than both calves castrated without flunixin and uncastrated calves. This was the only study which found increased pain following NSAID administration and is thought to be due to tissue irritation due to subcutaneous injection of flunixin into the scrotum. No studies investigating carprofen or directly comparing different NSAIDs were found. Based on the studies appraised, it appears that meloxicam has the best analgesic efficacy for postcastration pain. Ketoprofen has been reported to undergo variable chiral inversion in cattle depending on age and physiological status and these changes are thought to alter its ability to inhibit prostaglandin production (Moya et al., 2014); these changes are not currently well understood, making the efficacy of ketoprofen quite variable. Flunixin does not appear to reliably significantly reduce postcastration pain; Kleinhenz et al. (2018) and Webster et al. (2013) both reported reduced cortisol responses following flunixin administration, but no studies found any improvement in behavioural indicators of pain. However, these results must be taken with caution due to the small number of studies appraised.

The final confounding factor affecting NSAID efficacy is dose and administration. The most common dose for meloxicam was 0.5 mg/kg (seven out of 13 papers investigating meloxicam), and of these five papers found some improvement in pain signs following meloxicam administration. Interestingly, Daniel et al. (2020) used a dose of 2.0 mg/kg meloxicam but found no significant improvement in pain, however this study investigated band castration, which according to the appraised evidence was less amenable to pain relief via NSAIDs. Additionally, limited physiological indicators were assessed and behavioural changes were not clearly interpreted; meloxicam treated calves took fewer steps than unmedicated calves on days 7 and 15 which is reported to possibly suggest pain amelioration as the behavioural change occurred the day after meloxicam administration. However other authors (Olson et al., 2016; and Laurence et al., 2018) report that cattle in pain take fewer steps and the uncastrated controls in the Daniel et al. (2020) study took more steps, suggesting that the absence of pain increases step count. Ketoprofen was generally administered at a total dose of 3 mg/kg and flunixin was administered at variable doses of 3.33 mg/kg (Kleinhenz et al., 2018), 200 mg (Paull et al., 2015) and 1.1 mg/kg (Webster et al., 2013). It is also worth noting that in on-farm situations calf weight may be estimated, resulting in incorrect dose calculations and therefore ineffective analgesia, as in Sutherland et al. (2018).

It is also possible that NSAIDs generally do not provide adequate analgesia for invasive, painful procedures such as castration as NSAID analgesia displays a ceiling effect (Ong et al., 2007). Combinations of lidocaine and meloxicam or ketoprofen have been reported to be very efficacious in reducing signs of postoperative pain, including the initial acute spike in cortisol associated with castration (Meléndez et al., 2018c; and Webster et al., 2013). However, injection of local anaesthetic into the testes can be painful in itself (Stafford & Mellor, 2005) so more research into this area may be required.

Although not all of the studies appraised are in agreement about the efficacy of NSAIDs in reducing signs of pain postcastration, 13 out of the 20 studies found some benefit to NSAID use and only seven found no benefit, suggesting that on balance NSAID administration is likely to reduce postcastration pain by some degree. Of the NSAIDs investigated, meloxicam appears to be the most effective, although further work in this area is required. Further work is also required to investigate the effect of NSAIDs along with local anaesthetic administered 10–15 minutes prior to castration, as this appears to be the most effective way to mitigate both acute and more chronic pain associated with castration.

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