Optimal pain indicators for field trial assessment of analgesic efficacy in piglets undergoing surgical castration

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Berliner und Münchener Tierärztliche Wochenschrift 2021 (134) 1 Open Access Animal Ethics Pty. Ltd., Yarra Glen, 3775, Victoria, Australia1 Department of Microbiology and Infectious Diseases, NSW Health Pathology, Nepean Hospital, Penrith, New South Wales, Australia2 Berl Münch Tierärztl Wochenschr (134) The University of Sydney Medical School, Nepean Clinical School, Faculty of Medi- 1–10 (2021) cine and Health, University of Sydney, Penrith, 2750, New South Wales, Australia3 DOI 10.2376/1439-0299-2020-38 © 2021 Schlütersche Fachmedien GmbH Optimal pain indicators for field trial Ein Unternehmen der Schlüterschen Mediengruppe assessment of analgesic efficacy in piglets ISSN 1439-0299 undergoing surgical castration Korrespondenzadresse: mlksheil@me.com Die geeignetsten Schmerz-Indikatoren zur Beurteilung der analgetischen Wirksamkeit bei der chirurgischen Kastration Eingegangen: 13.11.2020 von Ferkeln im Feldversuch Angenommen: 05.02.2020 Veröffentlicht: 15.03.2021 Meredith Sheil1, Adam Polkinghorne2,3 https://www.vetline.de/berliner-und- muenchener-tieraerztliche-wochen-schrift- open-access Summary There is a growing demand for pain mitigation strategies that improve the welfare of piglets undergoing surgical castration in commercial pig production systems. While a range of potential anaesthetic and/or analgesic interventions have been trialled, efforts to confirm efficacy in field use, are stymied by the absence of ‘gold-standard’ methods to measure pain experienced by piglets during and after surgical castration. A review of the available literature in this field reveals that many methods commonly utilised to measure piglet pain lack sensitivity and/or specificity and may be unreliable. Measurement of biomarkers of physiological responses to pain, for

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ed to measure piglet pain lack sensitivity and/or specificity and may be unreliable. Measurement of biomarkers of physiological responses to pain, for example, appear to be readily confounded by similar responses to handling and restraint and/or to tissue trauma, which may occur in the absence of piglet pain. Similarly, it is challenging to accurately document pain-related behaviours in neonatal piglets following castration, since such behavioural disturbances are subtle, variably expressed and short-lived as compared with those undergoing handling only. Of the methods reviewed, nociceptive motor responses and/or vocal responses during the procedure, and targeted direct observation of specific pain-related behaviours, along with mechanical sensory testing for sensory hyperalgesia following the procedure, appear to be the most reliable methods for detection of pain in neonatal piglets, with significant differences most consistently observed between castrated and non-castrated animals, and/or those receiving analgesia/anaesthesia versus those left untreated. Understanding the strengths and weaknesses of current methods of measuring perioperative pain in piglets is critical to ongoing efforts by stake- holders to develop effective pain mitigation strategies. Keywords: pain mitigation, anaesthesia, biomarker Zusammenfassung Es besteht eine wachsende Nachfrage verschiedener Interessengruppen nach Strategien zur Schmerzlinderung nach einer chirurgischen Kastration in kommer- ziellen Schweineproduktionssystemen, die das Wohlbefinden von Ferkeln ver- bessern. Während eine Reihe potenzieller anästhetischer und/oder analgetischer Eingriffe erprobt wurden, fehlen „Goldstandard“-Methoden zur Messung der Schmerzen während und nach der chirurgischen Kastration zur

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der analgetischer Eingriffe erprobt wurden, fehlen „Goldstandard“-Methoden zur Messung der Schmerzen während und nach der chirurgischen Kastration zur Bestätigungen der Wirksamkeit. Eine Übersicht der verfügbaren Literatur auf diesem Gebiet zeigt, dass viele Methoden, die üblicherweise zur Messung von Schmerzen verwendet werden, nicht genügend empfindlich und/oder spezifisch bzw. möglicherweise gar unzuverlässig sind. Die Messung von Biomarkern physiologischer Reaktionen auf Schmerzen kann beispielsweise leicht mit ähnlichen Reaktionen auf Gewe- betraumata verwechselt werden. In ähnlicher Weise ist es schwierig, schmerzbe- dingte Verhaltensweisen bei neugeborenen Ferkeln zu dokumentieren, da solche Verhaltensstörungen subtil und kurzlebig sind. Von den untersuchten Methoden CC BY-NC-ND 4.0 scheinen nozizeptive motorische Reaktionen, Stimmreaktionen während des 2 Berliner und Münchener Tierärztliche Wochenschrift 2021 (134) Verfahrens, die gezielte direkte Beobachtung spezifischer schmerzbedingter Ver- haltensweisen sowie mechanische sensorische Tests auf sensorische Hyperalgesie die zuverlässigsten Methoden zum Nachweis von Schmerzen bei neugeborenen Ferkeln zu sein. Dabei konnten signifikante Unterschiede gefunden werden, am häufigsten zwischen kastrierten und nicht kastrierten Tieren und/oder solchen, die Analgesie/Anästhesie erhalten hatten. Das Verständnis der Stärken und Schwächen der derzeitig verwendeten Methoden zur Messung perioperativer Schmerzen bei Ferkeln ist entscheidend, um wirksame Strategien zur Schmerzlin- derung zu entwickeln. Schlüsselwörter: Schmerzlinderung, Anästhesie, Biomarker Introduction operative pain (Gottardo et al. 2016, Lomax et al. 2017, Surgical castration is a painful procedure employed in Sheil et al. 2020,

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marker Introduction operative pain (Gottardo et al. 2016, Lomax et al. 2017, Surgical castration is a painful procedure employed in Sheil et al. 2020, Sutherland et al. 2012). commercial swine facilities to remove the risk of ‘boar While some of the options for pain mitigation in taint’, reduce undesirable behaviours and to prevent piglets undergoing surgical castration show potential, uncontrolled breeding. Concern exists over the welfare identifying options that are the most effective for pain of animals that undergo these procedures given that it mitigation while also being acceptable for use in a com- is reported to cause significant acute pain to the animal mercial swine facility (e.g. safe, practical, economically during the procedure, as well as post-operative pain sustainable) is a major challenge for stakeholders world- in the hours and days after the procedure (Borell et wide. Many or most of the anaesthetic/analgesic options al. 2009, Rault et al. 2011). Despite increasing efforts required skilled veterinary administration and prolonged to develop and implement pain-mitigation strategies, or double handling which may not be practically or a 2016 survey revealed that over half of the male pigs commercially viable. Furthermore, many or most of the undergoing castration in surveyed countries in Europe, medications are not registered for use for this indication still received no analgesia or anaesthesia (De Briyne and must therefore be used off-label under veterinary et al. 2016). Data prevalence for USA swine farms is prescription (Castrum Consortium 2016, De Briyne et al. lacking but is likely to have a similar prevalence of cas- 2016, Wagner et al. 2020). Obtaining regulatory approval trated pigs than in the European Union, with an even requires meeting

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ilar prevalence of cas- 2016, Wagner et al. 2020). Obtaining regulatory approval trated pigs than in the European Union, with an even requires meeting high standards of proof of safety and lower prevalence of analgesia/anaesthetic use (Rault efficacy, including in the field situation. et al. 2011, Wagner et al. 2020). The lack of effective, To gain desperately needed safety and efficacy data on commercially viable, practical and simple to administer the use of different pain medications, to date, research- methods of anaesthesia is a key barrier to the adoption ers have employed a variety of methods to assess pain in of on-farm pain mitigation (Wagner et al. 2020). piglets during and after castration. In general (Sheil and Pain-mitigation strategies must be targeted at miti- Polkinghorne 2020), these methods look to assess piglet gating both acute and post-operative pain. This gener- pain using measurement of (i) potential physiological ally involves the use of general or local anaesthesia markers of piglet pain, such plasma adrenaline, nor- for mitigation of acute procedural (neurally medi- adrenaline, cortisol, adrenalcorticotrophic hormone and ated) pain, and non-steroidal anti-inflammatory drugs β-endorphin; (ii) motor and vocal responses during the (NSAIDs) or other long-acting analgesics for mitiga- surgical procedure; (iii) the sensitivity of piglet wounds tion of post-operative (inflammatory mediated) pain. after the procedure; and (iv) changes to the behaviour A number of such medication options have been of piglets in the period of time immediately after castra- explored to reduce perioperative pain experienced by tion and in the following hours and days. Unfortunately, piglets undergoing surgical castration (Borell et al. there is both a wide variability in

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by tion and in the following hours and days. Unfortunately, piglets undergoing surgical castration (Borell et al. there is both a wide variability in methods employed and 2009, Dzikamunhenga et al. 2014, O’Connor et al. in results reported, and a complete lack of information 2014, Sheil and Polkinghorne 2020, Sutherland, 2015). regarding the consistency, specificity or reliability of dif- General anaesthesia options trialled include the use of ferent methods used (Dzikamunhenga et al. 2014, Sheil injectable agents or sedatives such as Ketamine, Azo- and Polkinghorne 2020). This poses a risk that the pain perone and/or Buprenorphine (McGlone and Hellman experienced by piglets and the efficacy of treatments 1988, Rintisch et al. 2012, Viscardi and Turner 2018a), may both be significantly misconstrued. as well as inhalable CO2, halothane and isoflurane To be valuable as indicators of pain mitigation, meas- (Kohler et al. 1998, Walker et al. 2004). Local anaes- ures must be capable of consistently detecting a signifi- thetics such as procaine or lignocaine can be injected cant difference in pain-associated responses during and/ subcutaneously as well as into the testis or infundibu- or following castration as compared with pre-operative lum, separately or in combination with NSAIDs (e.g. values, and/or as compared between castrated and non- meloxicam) prior to the procedure (Courboulay et al. castrated piglets. Secondly, variables must optimally be 2010, Hansson et al. 2011, Horn et al. 1999, Keita et physiologically and/or clinically relevant to the evalu- al. 2010, Kluivers-Poodt et al. 2012, Leidig et al. 2009, ation of the type of pain being measured e.g., intraop- Saller et al. 2020, Wavreille et al. 2012). More recently, erative pain or post-operative pain.

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tion of the type of pain being measured e.g., intraop- Saller et al. 2020, Wavreille et al. 2012). More recently, erative pain or post-operative pain. Ideally, these meas- topical local anaesthetics (applied pre-operatively or ures (i) must be practically measured within the study by direct wound instillation during or following the without being confounded by the assessment of other procedure) have also been trialled to mitigate peri- variables; and; (ii) have the ability to be measured using Berliner und Münchener Tierärztliche Wochenschrift 2021 (134) 3 TABLE 1: Summary of, and recommendations regarding, indicator methods used for field assessment of castration-associated pain in neonatal piglets Sensitivity (to detect change in Specificity Reproduci- Method Method Details Recommendation Comment piglets undergoing (to pain) bility castration) Markers of HPA axis/SNS High Low Moderate Not recommended Confounded by extra- activation (adrenalcortico- for assessment of neous factors such as trophic hormone/cortisol/ pain mitigation via duration of restraint/ adrenalin) general or local surgical stress response/ anaesthesia (blo- degree of bleeding or Markers of neuropeptide/ Moderate Low Moderate Physiological ckade of neural pain tissue trauma. inflammatory response (TNF- response transmission) α, IL-1β, C-reactive protein) May provide indica- tion of efficacy for NSAIDs (blockade of inflammatory- induced pain) Nociceptor motor Scored via NRS/VAS or ordi- High High High Recommended Optimally, scoring response nal scale restricted to time of acute pain generation. Nociceptive vocal Measured via peak dB, total High Moderate Moderate Recommended with Sensitivity/specificity responses vocal response (such as area (depending (depending qualification may be reduced in

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oderate Moderate Recommended with Sensitivity/specificity responses vocal response (such as area (depending (depending qualification may be reduced in non- under the dB/time wave- on assess- on assessment acoustically separated form), the frequency (Hz) of ment method) method) environment call with the highest inten- sity (dB (A)), rate of high frequency calls (>1000 Hz) or stress vocalisations using the STREMODO system Measured using von-Frey, High High (to High (von- Recommended (von- Optimally should be needlestick or pressure evoked pain/ Frey) Frey) used in combination Mechanical algometry hyperalgesia) with a method to assess wound sensory spontaneous pain testing Low (to Low (pressure Not recommended spontaneous algometry) (pressure algometry) pain) General postures and Moderate Low Low Not recommended Confounded by neona- behaviours (time spent lying, tal piglet response to standing sitting, nursing etc.) restraint, handling and separation from sow Specific pain associated Low (Evident in first High Moderate Recommended Continuous video Post-operative behaviours (Huddling up, minutes and hours fol- (depending recording techniques pain behaviour prostration, tremors/trem- lowing castration, when on assessment appear insensitive to bling, stiffness, scratching recorded by direct quiet method) acute pain related beha- abnormal gait) observation). viours, however, may be sensitive to subacute behavioural abnor- malities (scratching/ tail-wagging) Facial grimace Assessed via – orbital tighte- Moderate Low Low Further develop- May be impacted by score ning, ear position, cheek ment/evidence body weight or activity tightening/nose bulge required state Infra-red thermo- Reduction in skin surface High Low Low Not recommended Confounded by piglet graphy temperature

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tightening/nose bulge required state Infra-red thermo- Reduction in skin surface High Low Low Not recommended Confounded by piglet graphy temperature secondary to response to stress and pain-related activation of inflammatory response SNS to tissue trauma an analytical method or measurement device/subjective for assessing efficacy of anaesthesia/analgesia for peri- assessment tool that has sufficient validation (Ison et al. operative castration pain mitigation in neonatal piglets. 2016). To support the development of effective pain mitiga- tion strategies in neonatal piglets, we recently com- Identification of the optimal methods pleted and reported a comprehensive review of the for assessment of pain during castration strengths and weaknesses of these methods for in-field use to assess pain in piglets during and after castration A summary of the relative sensitivity, specificity and repro- (Sheil and Polkinghorne 2020). Here, we summarise the ducibility of different methods for assessing pain in piglets outcomes of this review and provide a series of recom- based on a comprehensive review of the available litera- mendations on the optimal methods currently available ture (Sheil and Polkinghorne 2020) is presented in Table 1. 4 Berliner und Münchener Tierärztliche Wochenschrift 2021 (134) Physiological responses to castration activation which means that biomarkers associated with Physiological responses to castration in piglets have the surgical stress response may be elevated even when been widely reported (Table 1, and as reviewed by Dzi- pain induced by them is blocked. A further confounder kamunhenga et al. 2014, O’Connor et al. 2014, Rault to the use of local anaesthetics comes from the com- et al. 2011, Sheil and Polkinghorne 2020, Sutherland mon

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et al. 2014, O’Connor et al. 2014, Rault to the use of local anaesthetics comes from the com- et al. 2011, Sheil and Polkinghorne 2020, Sutherland mon co-administration of adrenaline or nor-adrenaline 2015). Activation of the hypothalamus-pituitary-adrenal to enhance the effects of local anaesthetics and mini- axis (HPA-axis), sympathetic nervous system (SNS) and mise the risk of systemic absorption. This may clearly release of opiate neuropeptides occurs in response to confound their use as indicators of pain secondary to stress, pain and tissue trauma, which also initiates an activation of the SNS. Adrenaline and nor-adrenaline, inflammatory response. Although a relatively short-lived may have centrally and/or peripheral effects to stimu- (0–3 hr) physiological response can be detected follow- late corticotrophin releasing hormone and increase the ing castration in piglets, unfortunately however, due to breakdown of proopiomelanocortins into ACTH and the aforementioned confounders, these markers show β-endorphins (Labrie et al. 1984, Liu et al. 1991, Slomin- low specificity and cannot be relied upon to indicate ski et al. 2013). Adrenaline administered exogenously pain. Surgical incision under general anaesthetic (i.e. in may thus further confound the use of markers of endog- the absence of pain) increases stress hormone expres- enous HPA-axis and SNS activation and opiate-peptide sion, similar to the pain response (Lykkegaard et al. production in castrated piglets. 2005). Further, when duration of handling and restraint Based on our review (Sheil and Polkinghorne 2020), it is similar, sham-handled control piglets show similar is apparent that biomarkers of activation of the HPA axis, expression levels of cortisol and β-endorphin, as well SNS, opiate

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rol piglets show similar is apparent that biomarkers of activation of the HPA axis, expression levels of cortisol and β-endorphin, as well SNS, opiate neuropeptides and immune response, lack as markers of the inflammatory response to castrated specificity as indicators of pain associated with neonatal piglets following the procedure (Hay et al. 2003, March- piglet castration. Pain biomarkers may have some role in ant-Forde et al. 2009, Moya et al. 2008). For this reason, assessment of post-operative inflammatory pain mitiga- physiological responses may be unreliable indicators of tion following NSAID administration, however, are poor efficacy of pain-mitigation. This is particularly the case markers of efficacy of pain mitigation for local or general for assessment of the efficacy of anaesthetics (local or anaesthetics. general), which prevent pain via blockade of neural transmission without necessarily having impact on the Piglet motor response to castration physiological (humoral) response to surgical incision and Castration without anaesthesia induces a piglet’s noci- tissue trauma induced by cytokine- or other mediator ceptive withdrawal response to acute pain, involving release from damaged cells at the incision site (Desbor- protracted violent struggling and escape behaviour and ough 2000). Haemorrhage alone, for example, without a loud vocal response (Hansson et al. 2011, Leidig et al. pain, is known to result in an increase in ACTH, cortisol, 2009, Nyborg et al. 2000, Saller et al. 2020, Walker et al. β-endorphin concentration, as well as tissue content of 2004). The nociceptive motor response can be graded pro-inflammatory cytokines; (including tumour necro- using a range of validated methods (Dobromylskyj et sis factor-alpha (TNF-a) and interleukin-1alpha

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o-inflammatory cytokines; (including tumour necro- using a range of validated methods (Dobromylskyj et sis factor-alpha (TNF-a) and interleukin-1alpha (IL-1a), al. 2001) such as (i) ordinal scales (Leidig et al. 2009) (ii) IL-6 and IL10), and opiates have a proposed role in focal assessments (Keita et al. 2010, Nyborg et al. 2000), regulating the hemodynamic response to blood loss (iii) visual analogue scales (VAS) (Hansson et al. 2011), (Molina 2001). or; (iv) the use of numerical rating scales (NRS) (Lomax It should be noted that NSAIDs and local anaesthetics et al. 2017, Walker et al. 2004). Despite a range of dif- block pain by different mechanisms. This has important ferent methodologies used for assessment, studies have implications for the use of biomarkers of HPA axis, neu- consistently reported a significant increase in nocicep- roendocrine and/or inflammatory cascade activation as tive motor response in castrated versus sham-castrated indicators of pain and pain mitigation. NSAIDS block piglets and/or a reduction in these responses in castrated the conversion of arachidonic acid to prostaglandins by animals following the administration of general (Walker cyclooxygenase enzymes (COX), preventing activation et al. 2004), injected local anaesthesia (Hansson et al. of the inflammatory cascade and release of pain-induc- 2011, Horn et al. 1999, Leidig et al. 2009, Nyborg et al. ing inflammatory mediators which contribute to post- 2000, Saller et al. 2020) or topical anaesthesia applied operative (inflammatory) pain (Vane and Botting 1998). via wound instillation (Sheil et al. 2020). Good cor- Prostaglandins also directly stimulate ACTH and cortisol relation has been reported in piglets castrated under release, and thus directly mitigate the humoral aspect of

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o directly stimulate ACTH and cortisol relation has been reported in piglets castrated under release, and thus directly mitigate the humoral aspect of Ketamine-Azoperone general anaesthesia, between the surgical stress response to tissue trauma (Aloisi et thresholds for nociceptive flexor reflex amplitudes (ini- al. 2011, Zacharieva et al. 1992), separate from mitigat- tiated by electrical stimulation distal from the wound ing pain. Nevertheless, a reduction in cortisol following site and measured using electromyography), traditional NSAID administration may be anticipated to indicate a intra-operative controls of analgesia (interdigital reflex) collateral reduction in production of prostaglandins and and defence reactions initiated by surgical stimulation other associated pain-inducing inflammatory mediators, including; incisions in the scrotal skin, in the tunica and hence also an associated decrease in inflammatory- vaginalis and in the testis, pulling off the spermatic cord, induced pain in piglets post castration. In this setting, clamping and cutting off the spermatic cord and final therefore, cortisol or ACTH levels may provide an indi- wound disinfection (Rintisch et al. 2012). The nociceptive rect biomarker of pain mitigation in piglets following withdrawal response to clamping the interdigital space NSAID administration. of the hind claw (interdigital reflex) is also recommended Local anaesthetics, on the other hand, block nerve as a method of testing adequacy of general anaesthe- fibre conduction of pain signals. In doing so, local anaes- sia, prior to castration of piglets (Saller et al. 2020). In thetics do not primarily affect the cytokine/inflamma- review((Sheil and Polkinghorne 2020), assessment of tory response to tissue trauma or associated HPA-axis

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not primarily affect the cytokine/inflamma- review((Sheil and Polkinghorne 2020), assessment of tory response to tissue trauma or associated HPA-axis the nociceptive motor response is concluded to provide Berliner und Münchener Tierärztliche Wochenschrift 2021 (134) 5 a relatively consistent and sensitive method of assess- mitigation in neonatal piglets (Sheil and Polkinghorne ing acute procedural pain and pain-mitigating effects 2020). of anaesthetic/analgesic treatments in neonatal piglets undergoing castration. Identification of the optimal methods Piglet vocal response to castration for assessment of post-operative pain A number of studies have reported that piglets under- going castration squeal more often, more loudly and/ A variety of methods have been utilised to assess post- or at higher frequency than those undergoing sham- operative pain in piglets. Our review of these methods handling (Marchant-Forde et al. 2009, Taylor et al. 2001, (Sheil and Polkinghorne 2020) has revealed that post- Weary et al. 1998, Wemelsfelder and van Putten 1985). operative pain control is optimally evidenced by a reduc- Furthermore, the vocalisation sound parameters of the tion in peripheral afferent nerve sensitisation combined castration responses can be comprehensively distin- with an associated reduction in specific pain-related guished from that emitted by handling alone (Marx et behaviours. The key findings of this analysis are sum- al. 2003). Analysis of these parameters have revealed marised in Table 1. that a single event in a call, such as peak level or peak frequency are considered to provide more consistent Mechanical nociceptive sensory testing results than parameters that describe an average, such Afferent nerve sensitisation, resulting in hyperalgesic as weighted

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nociceptive sensory testing results than parameters that describe an average, such Afferent nerve sensitisation, resulting in hyperalgesic as weighted frequency and main frequency (Marx et al. responses to sensory stimuli, is considered to be a pri- 2003). mary underlying mechanism responsible for the devel- Most studies have shown local and general anaes- opment and persistence of post-operative pain (Amaya thetics mitigate the piglet vocal response to castration et al. 2013, Brennan et al. 1996, 2005). Post-operative (Hansson et al. 2011, Leidig et al. 2009, Marx et al. 2003, hyperalgesic responses can be most specifically and Sheil et al. 2020; Sutherland et al. 2012, White et al. sensitively identified using quantitative sensory testing 1995) while NSAID treatment has little impact (Hans- (QST) (Brennan et al. 1996, Curatolo et al. 2000, Ison son et al. 2011, Kluivers-Poodt et al. 2012, O’Connor et al. 2016), providing evidence of a lower threshold et al. 2014, Reiner et al. 2012, Sutherland et al. 2012). for nociceptive responses to a mechanical, thermal or This is not unexpected as NSAIDs do not block the chemical stimulus. Assessment of nociceptive responses nerve conduction of incisional pain signals occurring to von Frey mechanical stimulation at the wound site acutely at the time of tissue trauma (O’Connor et al. (primary mechanical hyperalgesia) is a well-established, 2014). NSAIDs are more likely to affect post-operative widely used method of assessment of post-incisional inflammatory pain stimuli that are transmitted as a pain, and efficacy of anaesthetics/analgesics (Whiteside consequence of the later production of cytokines and et al. 2004), including in neonatal rats and humans (De prostaglandins that occurs secondary to disruption of Lima et al.

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production of cytokines and et al. 2004), including in neonatal rats and humans (De prostaglandins that occurs secondary to disruption of Lima et al. 1999, Fitzgerald et al. 1989), with similar cell membranes (Coetzee 2013). It should nevertheless methods recently also developed in pigs (Castel et al. be noted that while there is consistency in the reported 2014, 2017, Janczak et al. 2012). Von Frey filaments or outcomes, it is difficult to combine these data or quan- ‘hairs’ are a set of calibrated filaments that bend when tify the effect of pain mitigation interventions, since the a certain pressure is reached, allowing a reproducible actual metrics reported are diverse (Dzikamunhenga et mechanical stimulus to be delivered, graduating from al. 2014, O’Connor et al. 2016). Another challenge with that inducing a light-touch sensation through to a pain- measurement of pig vocalisation is that regulatory safety weighted stimulation of skin or tissues. In non-verbal and efficacy trials require demonstration of the efficacy humans and animals, the reflex nociceptive response is of drugs in field situations. In most cases, studies of pig assessed using similar validated grading schemes (NRS, vocalisation response to castration have been recorded VAS, ordinal scale) as are used for measurement of in rooms acoustically isolated from farrowing pens the piglet nociceptive motor response during castration. where piglet castration usually takes place (Sheil and Studies in neonatal piglets post-castration (Lomax et al. Polkinghorne 2020). Measurement of vocal responses 2017, Sheil et al. 2020) using Von-Frey stimulation and in commercial farm settings must account for normal grading of the nociceptive motor response, have identi- background noise levels and the confounding

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n commercial farm settings must account for normal grading of the nociceptive motor response, have identi- background noise levels and the confounding effects fied a significant reduction in threshold for nociceptive of the sow and littermates on piglet vocal responses. In motor response (equating to an increase incidence and/ this respect, vocal response measurements may be less or grade of motor response to 300g von-Frey filament sensitive in regulatory field trial settings compared to and needlestick stimulation of the wound site) in cas- acoustically separated research environments. In review trated piglets as compared to sham handled controls however, it was concluded that with careful applica- (Lomax et al. 2017), and those treated with injected local tion to ensure targeting of the measurement period to (Lomax et al. 2017) or topical anaesthesia (Lomax et al. coincide with the time points of pain generation, and 2017, Sheil et al. 2020), and is concluded to provide a avoidance of confounding factors such as the duration relatively sensitive and specific method of assessment of restraint or recordings, several measures of piglet of incisional pain, and efficacy of pain mitigation post vocalisation in response to castration including the peak castration in neonatal piglets. decibel (dB), total vocal response (such as area under Pressure algometry is an alternative to Von Frey fila- the dB/time waveform), the frequency (Hz) of call with ments for mechanical nociceptive testing. This method the highest intensity (dB [A]), rate of high frequency is designed to indicate hyperalgesia through detecting calls (>1000 Hz) or stress vocalisations using automated a lowering of the threshold for a blunt stimulus applied software (e.g. STREMODO system) appear to provide with

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r stress vocalisations using automated a lowering of the threshold for a blunt stimulus applied software (e.g. STREMODO system) appear to provide with increasing pressure over time, rather than as brief a relatively consistent and sensitive method of assess- punctate touch stimulus at a predetermined pressure (as ing procedural pain associated with castration, and pain occurs with Von Frey assessment) (Curatolo et al. 2000). 6 Berliner und Münchener Tierärztliche Wochenschrift 2021 (134) Pressure algometry is generally applied using a hand- (3–6 hrs) following the procedure as compared with held device to hard surfaces such as the sternum, or uncastrated controls, effects that were ameliorated by pincer device to softer/movable tissues such as the ear use of lignocaine local anaesthesia prior to castration lobe. Although this method has been trialled for QST (McGlone and Hellman 1988, McGlone et al. 1993). in piglets following castration (Gottardo et al. 2016), A subsequent study (Taylor et al. 2001), however, issues with the algometry tip inducing significant reported differently, documenting decreased lying, skin indentation were noted. Furthermore, confound- increased sitting and increased nursing in piglets post ing factors such as a piglet’s age and weight affect castration as compared with uncastrated controls. In responses to pressure algometry, particularly in the all cases, however, the authors reported that effects, first week of life where responses were not repeatable although statistically significant, were marginal and/ (Janczak et al. 2012). On this basis, QST using von or of low magnitude (Table 1). Separate to the pain- Frey filaments and needlestick should be considered specific behaviours already mentioned, Hay et al. the most robust method for

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Separate to the pain- Frey filaments and needlestick should be considered specific behaviours already mentioned, Hay et al. the most robust method for measuring incisional pain recorded, but did not find significant differences in a and pain-mitigation in piglets following castration. It range of indices of piglet posture, position, and ‘non- should be noted, however, that QST methods examine specific’ behaviours (such as walking, running, sleep- evoked pain responses as compared with “sponta- ing, playing, exploring and aggression) in neonatal neous” or “at-rest” pain responses. This provides an piglets post-castration as compared with sham han- indication of mechanisms underlying post-incisional dled controls, and concluded that these were not reli- pain, however such elicited responses may be present able indicators of pain in piglets post-castration (Hay in the absence of spontaneous (at-rest) pain (Ison et et al. 2003). These data indicate that general postures al. 2016). For this reason, it is advised to combine such and behaviour, including nursing, may be affected assessments with assessment of post-operative pain- by a multitude of factors in addition to pain, in this related behaviour. setting, including stress of separation from the sow, and restraint and handling. Furthermore, responses Post-operative pain-related behaviour may vary considerably between piglets. With regard to In general, measures of behaviour have proven to be suckling, for example, inappetence or immobility may more reliable indicators of pain than physiological predispose to decrease suckling, however neonatal measures in animals following castration (Rault et animals may also increase suckling such as to “self- al. 2011, Sheil and Polkinghorne 2020). In other ani-

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s in animals following castration (Rault et animals may also increase suckling such as to “self- al. 2011, Sheil and Polkinghorne 2020). In other ani- medicate”, as suckling may activate natural pain- mal species, behaviours such as decreased or abnor- modulating mechanisms and have quite profound mal locomotion, turning the head towards the rump, analgesic action (Blass and Watt 1999, Shann 2007). abnormal postures including prostration (standing On review of available data (Sheil and Polking- or sitting with head below the shoulders), hunch- horne 2020), we concluded that acute pain-related ing (standing with kyphosis), stiffness (lying with behaviour post-castration in neonatal piglets appears legs tense and extended or walking with a stiff gait), to be transient, subtle and variably expressed. The increased or reduced movements of the tail are con- most consistent and reliable evidence for pain was a sidered indicators of pain resulting from castration statistically significant increase in total “pain-specific” (Almond et al. 2015, Crowe 2011, Lomax and Wind- behaviours including tremors/trembling, huddled-up, sor 2013, Mellor and Stafford 2000, Sheil et al. 2020). stiffness, prostration, kyphosis, scratching, and stiff/ More diffuse and variable responses may occur in abnormal gait, as compared with sham handled ani- neonatal animals due to immaturity of neuronal path- mals in the early minutes and up to 1–2 hours follow- ways involved with pain processing (Hatfield 2014). ing castration. Increased tail-wagging and scratch- Consistent with this, a similar range of individ- ing may be seen at later time points. Other general ual ‘pain-specific’ behaviours have been described in indices of piglet posture, position, and ‘non-specific’ neonatal

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ater time points. Other general ual ‘pain-specific’ behaviours have been described in indices of piglet posture, position, and ‘non-specific’ neonatal piglets following castration, however they behaviours are confounded by the piglet response to appear to be transient, subtle and variably expressed. handling and restraint and are not reliable indicators First detailed in an ethogram by Hay et al. (Hay et of pain in piglets post-castration. al. 2003), and subsequently examined by a number The majority of investigators that have identified a of investigators (using an ethogram with only minor significant increase in acute “pain-specific” behaviours variations) (Hansson et al. 2011, Keita et al. 2010, in piglets in the first minutes and 1–2 hours following Kluivers-Poodt et al. 2013, Moya et al. 2008), acute castration have employed direct observation methods, pain-specific behaviours have been evident in the first with trained observers using scan sampling and/or minutes and up to 1–2 hours post-procedure includ- focal assessments (Burkemper et al. 2020, Gottardo et ing; tremors/trembling, spasms, “huddled up” posture, al. 2016, Hansson et al. 2011, Keita et al. 2010, Moya et “prostration” and “stiffness”, as well as later identified al. 2008). Although there are no validated methods of “kyphosis” and gait abnormalities (Gottardo et al. behavioural assessment for use in piglets, continuous 2016, Lonardi et al. 2015). Additionally, increased tail recording, scan sampling and focal assessment are all wagging and/or scratching are reported in the later well described methodologies of behavioural assess- hours (from 2 hours and peaking at 24 hours) follow- ment (Lehner 1992). Whilst continuous sampling may ing the procedure (Hay et al. 2003,

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al assess- hours (from 2 hours and peaking at 24 hours) follow- ment (Lehner 1992). Whilst continuous sampling may ing the procedure (Hay et al. 2003, Viscardi and Turner be considered the gold standard, this method suffers 2018a). from the need to use video-tape recording with off- Earlier studies identified a number of behaviours line analysis, as opposed to live, or direct observation. thought to be indicative of pain in piglets, including Unfortunately, possibly due to the subtlety and nature changes in posture, position and nursing behaviour, of expression of acute pain in piglets, to date, methods with reduced standing and increased lying (away using video recording and off-line analysis have not from heat), and reduced nursing in the early hours proven sensitive enough to detect behavioural differ- Berliner und Münchener Tierärztliche Wochenschrift 2021 (134) 7 ences between castrated and non-castrated piglets in Recommendations and future directions the early minutes and hours following the procedure, when such pain is most acute. For example, using a Our review (Sheil and Polkinghorne 2020) has high- video-tape and off-line analysis method, Viscardi and lighted that there is considerable variability in the sensi- Turner (2018a) demonstrated a significant difference in tivity and specificity of different pain-indicators used for the proportion of time engaged in pain related behav- castration pain assessment in neonatal piglets (Table 1). iour when comparing piglets castrated without anaes- This poses significant challenges identifying methods thesia/analgesia versus sham controls across all study sufficiently reliable to assess the efficacy of pain-mitiga- timepoints, however, at individual time points this tion interventions to meet field-trial regulatory

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reliable to assess the efficacy of pain-mitiga- timepoints, however, at individual time points this tion interventions to meet field-trial regulatory require- difference was only significant at 24 hours following ments. In the absence of a gold-standard method, from the procedure, but not at earlier time points. Similar the body of available literature, our review found that findings were described in their separate study (Vis- the most reliable indicators of pain for in-field analgesic cardi and Turner 2018b) with a significant difference in efficacy assessment include; nociceptive motor and vocal proportion of time engaged in pain related behaviour responses during the procedure; and, for assessment of when analysing all time points together, but only seen post-operative pain, a combination of mechanical (von- at 2, 7 and 24 hours on individual time points (Fig. 2 Frey) sensory testing and direct observational assessment and 4 of publication). Furthermore, these differences and scoring of acute “pain-specific” behaviours. Under- pertained primarily to increased tail wagging and standing the need for flexibility to accommodate different scratching at the latter time points. These behaviours pain-mitigation methods and on-farm analysis scenarios, may indicate itch or irritation rather than pain, and there is nevertheless the need to better standardise thus may be less amenable to analgesic medications. methods of assessing these indicators. The use of such Video assessment therefore appears to be of greater methods for in-field assessments is anticipated to assist sensitivity for detecting subacute behavioural abnor- stakeholders in the development of pain mitigation strat- malities including tail-wagging and scratching, which egies that will improve the welfare of

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stakeholders in the development of pain mitigation strat- malities including tail-wagging and scratching, which egies that will improve the welfare of piglets undergoing are generally only increased from several hours fol- surgical castration in commercial pig facilities. lowing castration, peaking at 24 hours. Ethical approval Other pain indicators Not applicable. A number of alternative methods have been exam- ined as pain-indicators in piglets with variable results. Infra-red thermography measurement of skin tem- Conflict of Interest perature has been used to assess loss of heat from the This work was supported by Animal Ethics Pty Ltd, for body’s periphery. This is hypothesized to occur due to the development of methodologies for use in analgesic peripheral vasoconstriction, secondary to activation of efficacy trials to international VICH regulatory require- the SNS in response to pain (McCafferty 2007). Similar ments for the topical anaesthetic product, “Tri-Solfen”®. results have been observed for piglets undergoing cas- Dr Sheil is Founding Director, Chief Medical Officer and tration, with lidocaine and meloxicam treatment prior indirect shareholder of Animal Ethics Pty Ltd. to castration mitigating this effect somewhat (Bates et al. 2014, Bonastre et al. 2016), however conflicting results have been reported (Coetzee 2019, Lonardi et Funding al. 2015). There are a number of known confounders to temperature measurements which may affect studies This work was funded by Animal Ethics Pty Ltd. of the pain relief efficacy of different methods, how- ever, with (i) body temperature in piglets potentially affected by the stress response to restraint and han- Author Contributions dling, and/or the post-surgical inflammatory response (Lonardi et al. 2015); and (ii)

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y the stress response to restraint and han- Author Contributions dling, and/or the post-surgical inflammatory response (Lonardi et al. 2015); and (ii) NSAIDS having an anti- Conceptualization, methodology, supervision, project pyretic effect, and anaesthetics and adrenaline hav- administration, funding acquisition: MS. ing vaso-active effects, which could confound assess- Data collection, writing review and editing: MS, AP. ments of the efficacy of such treatments to reduce Writing original draft preparation: AP. piglet pain. Piglet facial grimace scores (PGS) have All authors have read and agreed to the published ver- also been used to assess castration related pain in pig- sion of the manuscript. lets. Piglet facial expressions, including the assessment of orbital tightening, ear position, cheek tightening/ nose bulging, can be captured and assessed at various References stages of surgical castration (Viscardi et al. 2017) with the initial study showing a strong correlation between Almond KL, Fainberg HP, Lomax MA, Bikker P, Symonds ME, piglet grimaces and piglet pain-related behaviours. A Mostyn A (2015): Substitution of starch for palm oil during ges- subsequent study, however, has raised questions about tation: impact on offspring survival and hepatic gene expression in the pig. Reprod Fertil Dev 27: 1057–1064. its specificity with evidence that facial grimacing may be confounded by piglet body weight and/or activ- Aloisi AM, Buonocore M, Merlo L, Galandra C, Sotgiu A, Bac- ity state (Viscardi and Turner 2018b). Inter-operator chella L, Ungaretti M, Demartini L, Bonezzi C (2011): Chronic reproducibility of the PGS amongst investigators is pain therapy and hypothalamic-pituitary-adrenal axis impair- also of concern (Gottardo et al. 2016). ment.

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