Advertisement

Invited Review: On-farm pain management of food production animals

      ABSTRACT

      Purpose

      The purpose of this review was to describe the current options and unmet needs for on-farm pain control in food production animals.

      Sources

      Peer-reviewed literature was the primary source of data and information for this review.

      Synthesis

      There are millions of farm animals that experience painful livestock management procedures each year. Moreover, disease conditions such as lameness require on-farm analgesic treatment. Consumer concerns about the welfare of food animals experiencing painful procedures have increased the requirement for producers to implement pain management protocols on farms. However, objective pain evaluation methods are lacking, making it difficult to identify animals in pain and to secure regulatory approval of analgesics for livestock. Flunixin, meloxicam, and ketoprofen are nonsteroidal anti-inflammatory drugs with supporting research for on-farm analgesia. An understanding of their pharmacological properties and effects in animals, regulatory restrictions such as meat withholds, costs, and dosing requirements are needed to make the most prudent drug choice.

      Conclusions and Applications

      Options for on-farm analgesia are limited, and further research is needed on simple and objective ways to measure pain in food animals. The use of local anesthetics and nonsteroidal anti-inflammatory drugs such as flunixin or meloxicam are currently the best options for on-farm analgesia.

      Key words

      INTRODUCTION

      It is well established that farm animals are capable of experiencing pain. The pain experienced by food animals may be the result of animal management procedures, such as castration, dehorning, and tail docking, or medical conditions, such as lameness and dystocia. Many of these procedures are performed on farm without the use of analgesics or anesthetics for pain management. The American Veterinary Medical Association, American Association of Bovine Practitioners, and American Association of Swine Veterinarians have all developed position statements recommending analgesic use in food animals following painful procedures. Furthermore, consumers are becoming more aware and concerned about the welfare and well-being of animals raised for food. This has increased pressure on suppliers to ensure animals entering their systems are treated humanely.
      Unfortunately, a challenge with on-farm pain management in the United States is the lack of approved therapeutics. To date, in the United States, there is only one drug approved for control of pain associated with interdigital phlegmon (foot rot) in nonlactating cattle. Therefore, use of drugs for pain management during elective procedures such as dehorning and castration in cattle, or to provide analgesia in lactating dairy cows and swine, is considered extra-label drug use and is regulated in accordance with the Animal Medicinal Drug Use Clarification Act. In other countries, there are approved analgesics, but they are not always used at the time of the painful procedure or event (
      • Moggy M.A.
      • Pajor E.A.
      • Thurston W.E.
      • Parker S.
      • Greter A.M.
      • Schwartzkopf-Genswein K.S.
      • Campbell J.R.
      • Windeyer M.C.
      Management practices associated with stress in cattle on western Canadian cow-calf operations: A mixed methods study..
      ). The use of alternative and preventive strategies has been explored, but few strategies have gained widespread acceptance.
      The objectives of this review were to briefly describe pain assessment and challenges in providing pain mitigation to food production animals and to describe on-farm pain mitigation strategies with a focus on pharmacologic interventions.

      PAIN ASSESSMENT IN FOOD ANIMALS

      Pain assessment in cattle and swine is difficult as they are stoic by nature and conceal pain behaviors. For the approval of analgesics in cattle and swine, the US Food and Drug Administration (US FDA) has provided guidance recommending that validated methods of pain assessment be used in the target species (

      US FDA (United States Food and Drug Administration). 2006. Guidance for Industry #123 Development of data supporting approval of NSAIDs for use in animals. Accessed Aug. 23, 2020. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cvm-gfi-123-development-data-supporting-approval-nsaids-use-animals.

      ). Outcome measures for pain assessment must be (1) objective, (2) repeatable, and (3) clearly defined (

      US FDA (United States Food and Drug Administration). 2006. Guidance for Industry #123 Development of data supporting approval of NSAIDs for use in animals. Accessed Aug. 23, 2020. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cvm-gfi-123-development-data-supporting-approval-nsaids-use-animals.

      ). In previous research, markers for the evaluation of pain and distress associated with noxious animal husbandry procedures have focused on assessing behavioral, physiological, and neuroendocrine changes. Changes in animal behavior have been assessed using visual pen behavior scoring, videography, facial grimace scoring, accelerometers, mechanical nociception threshold testing, condition place aversion, and gait analysis through the use of pressure mats (
      • Coetzee J.F.
      Assessment and management of pain associated with castration in cattle..
      ;
      • Kleinhenz M.D.
      • Van Engen N.K.
      • Smith J.S.
      • Gorden P.J.
      • Ji J.
      • Wang C.
      • Perkins S.C.B.
      • Coetzee J.F.
      The impact of transdermal flunixin meglumine on biomarkers of pain in calves when administered at the time of surgical castration without local anesthesia..
      ;
      • Ede T.
      • von Keyserlingk M.A.G.
      • Weary D.M.
      Assessing the affective component of pain, and the efficacy of pain control, using conditioned place aversion in calves..
      ). Physiological changes have been assessed using serum cortisol measurement, heart rate determination, feed intake and ADG. Neuroendocrine changes have been assessed through measurement of the neuropeptide substance P, infrared thermography, heart rate variability, and electroencephalography (
      • Coetzee J.F.
      A review of pain assessment techniques and pharmacological approaches to pain relief after bovine castration: Practical implications for cattle production within the United States..
      ). Of these outcomes, behavioral scoring, pressure mats for gait analysis, and cranial thermography have shown the greatest promise for field applications.
      To date, the combination of behavioral scoring with pressure mat gait analysis has proven to be the optimal pain assessment outcomes for FDA approval. Pressure mat gait analysis uses a floor-based mat that records and analyzes the contact force, contact area, and stance time for each limb as an animal walks. Pressure mat gait analysis was employed to support the approval of transdermal flunixin for control of pain associated with foot rot (

      US FDA (United States Food and Drug Administration). 2017. Freedom of information summary original new animal drug application Banamine Transdermal. Accessed Nov. 30, 2020. https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/1944.

      ). Cattle treated with transdermal flunixin placed increased total contact force and had greater contact area for the limbs with experimentally induced foot rot. The pressure mat gait analysis has also been deployed to assess pain associated with lameness in cattle and swine, castration in cattle, and parturition in cattle. Following surgical castration, cattle place more force on their front limbs, indicating a shift in weigh distribution (
      • Kleinhenz M.D.
      • Van Engen N.K.
      • Smith J.S.
      • Gorden P.J.
      • Ji J.
      • Wang C.
      • Perkins S.C.B.
      • Coetzee J.F.
      The impact of transdermal flunixin meglumine on biomarkers of pain in calves when administered at the time of surgical castration without local anesthesia..
      ). A similar shift in weight distribution is seen in dairy cows following unassisted calving. Cows treated with oral meloxicam placed more weight on the rear limb compared with placebo-treated cows (
      • Kleinhenz M.D.
      • Gorden P.J.
      • Burchard M.
      • Ydstie J.A.
      • Coetzee J.F.
      Rapid Communication: Use of pressure mat gait analysis in measuring pain following normal parturition in dairy cows..
      ). Meloxicam-treated cows had shorter stride lengths measured by video camera compared with placebo-treated cows. The authors attributed this to meloxicam reducing the pain associated with udder edema similar to cows with mastitis (
      • Fitzpatrick C.E.
      • Chapinal N.
      • Petersson-Wolfe C.S.
      • DeVries T.J.
      • Kelton D.F.
      • Duffield T.F.
      • Leslie K.E.
      The effect of meloxicam on pain sensitivity, rumination time, and clinical signs in dairy cows with endotoxin-induced clinical mastitis..
      ).

      CHALLENGES IN FOOD ANIMAL ANALGESIA

      There are numerous challenges associated with providing analgesia to food production animals. These challenges include the lack of approved medications, regulatory concerns, delayed onset of action, short duration of action, the need to handle animals repeatedly and the cost of the analgesic, and the associated meat and milk withhold periods. With the exception of the use of transdermal flunixin for the control of pain associated with interdigital phlegmon in cattle, medications dispensed for pain control are used in an extra-label manner under the Animal Medicinal Drug Use Clarification Act of 1994 (

      US FDA (United States Food and Drug Administration). 1994. Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA). Accessed Sep. 6, 2020. http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/AnimalMedicinalDrugUseClarificationActAMDUCAof1994/default.htm.

      ). To use drugs in an extra-label manner, specific conditions must be met. These conditions include the following: (1) the extra-label drug use (ELDU) must be under a veterinary-client-patient relationship; (2) ELDU is only allowed for FDA-approved animal and human drugs; (3) ELDU is only permitted when the health or well-being of the animal is threatened and not for production purposes; (4) ELDU in feed is prohibited; and (5) the ELDU cannot result in a violative drug residue in food intended for human consumption.
      There is a delay in onset for most analgesic drugs, and their duration of action is relatively short with effects lasting only hours. This presents a challenge to producers and veterinarians as it may result in the need for additional doses as it has been documented that animals may be experiencing pain for days following the painful procedure (
      • Adcock S.J.
      • Cruz D.M.
      • Tucker C.B.
      Behavioral changes in calves 11 days after cautery disbudding: Effect of local anesthesia..
      ). These characteristics will be discussed in more depth later in the review, but it should be noted that local anesthetics require 5 to 10 min to reach full effect and last for less than 4 h. The time for nonsteroidal anti-inflammatory drugs (NSAID) to take effect is longer compared with local anesthetics, but their duration of action is longer. However, each NSAID has individual properties. For example, meloxicam takes up to 12 h to reach full effect but lasts up to 48 h. This is in contrast to flunixin, which acts rapidly but has a duration of action of under 24 h.
      Producers must account for the time required to perform the procedure, the time required to administer the analgesic drug(s), and the time required for onset of analgesic action. These delays may require animals to be handled longer, be handled additional times, or undergo the procedure without full benefit of the analgesia. The additional costs of drugs and labor must also be considered for on-farm pain management. Additional labor costs have been cited as a barrier to implementation of on-farm analgesic protocols (
      • Moggy M.A.
      • Pajor E.A.
      • Thurston W.E.
      • Parker S.
      • Greter A.M.
      • Schwartzkopf-Genswein K.S.
      • Campbell J.R.
      • Windeyer M.C.
      Management practices associated with stress in cattle on western Canadian cow-calf operations: A mixed methods study..
      ). Finally, the route of administration may require technical training or, in the case of i.m. and s.c. injections, result in pain and tissue damage (
      • Pyorala S.
      • Laurila T.
      • Lehtonen S.
      • Leppa S.
      • Kaartinen L.
      Local tissue damage in cows after intramuscular administration of preparations containing phenylbutazone, flunixin, ketoprofen and metamizole..
      ).

      PAIN MANAGEMENT FOR ON-FARM PROCEDURES

      Dehorning

      Dehorning is a common husbandry practice that occurs on the majority of dairy farms and, to a lesser extent, beef farms. Although there is widespread interest in selecting for polled genetics to reduce the need for dehorning in dairy operations, current strategies to increase the percentage of polled Holstein calves may decrease the herd genetic merit (
      • Spurlock D.M.
      • Stock M.L.
      • Coetzee J.F.
      The impact of 3 strategies for incorporating polled genetics into a dairy cattle breeding program on the overall herd genetic merit..
      ). Dehorning is performed to reduce the risk of injury to livestock caregivers and pen mates and to decrease carcass bruising. Dehorned animals also require less bunk space. Regardless of the method used, dehorning has been shown to be painful (
      • Adcock S.J.
      • Tucker C.B.
      The effect of disbudding age on healing pain and sensitivity in diary calves..
      ). Calves have been shown to positively respond to lidocaine administered 11 d after dehorning. This indicates the pain associated with dehorning may last for weeks beyond the procedure (
      • Adcock S.J.
      • Cruz D.M.
      • Tucker C.B.
      Behavioral changes in calves 11 days after cautery disbudding: Effect of local anesthesia..
      ). The American Veterinary Medical Association and American Association of Bovine Practitioners recommend that dehorning take place at the earliest age practicable, and the National Dairy FARM Program 4.0 requires calves to be dehorned by 8 wk of age (

      National Dairy FARM Program. 2020. Animal Care Reference Manual. Accessed Sep. 26, 2020. https://nationaldairyfarm.com/wp-content/uploads/2020/02/Animal-Care-V4-Manual-Print-Friendly.pdf.

      ). Additionally, the National Dairy FARM Program 4.0 requires the use of analgesia at the time of dehorning or disbudding regardless of the method used and age of calf (

      National Dairy FARM Program. 2020. Animal Care Reference Manual. Accessed Sep. 26, 2020. https://nationaldairyfarm.com/wp-content/uploads/2020/02/Animal-Care-V4-Manual-Print-Friendly.pdf.

      ). The same recommendations can be made for goats and sheep that require dehorning or disbudding.
      For dehorning, a multimodal analgesic strategy, where a local anesthetic such as lidocaine is used in combination with an NSAID, is recommended (
      • Winder C.B.
      • Miltenburg C.L.
      • Sargeant J.M.
      • LeBlanc S.J.
      • Haley D.B.
      • Lissemore K.D.
      • Godkin M.A.
      • Duffield T.F.
      Effects of local anesthetic or systemic analgesia on pain associated with cautery disbudding in calves: A systematic review and meta-analysis..
      ). This allows for acute pain relief at the time of the procedure as well as decreased inflammation for hours afterward. Lidocaine is a commonly used local anesthetic drug used to manage acute pain due to its rapid onset of action (minutes) and relatively low cost. Blockade of nerve impulses transmitted by the cornual nerve, which innervates the horn area, is easily accomplished by local infiltration of lidocaine or similar agent (Figure 1). Local anesthetics alone have been shown to attenuate acute pain (
      • Winder C.B.
      • Miltenburg C.L.
      • Sargeant J.M.
      • LeBlanc S.J.
      • Haley D.B.
      • Lissemore K.D.
      • Godkin M.A.
      • Duffield T.F.
      Effects of local anesthetic or systemic analgesia on pain associated with cautery disbudding in calves: A systematic review and meta-analysis..
      ), but their action lasts less than 4 h after administration. When local anesthetics are administered as the sole analgesic, cortisol levels increased over time compared with controls, indicating a rebound effect as the pharmacological effects diminish (
      • Allen K.A.
      • Coetzee J.F.
      • Edwards-Callaway L.N.
      • Glynn H.
      • Dockweiler J.
      • KuKanich B.
      • Lin H.
      • Wang C.
      • Fraccaro E.
      • Jones M.
      • Bergamasco L.
      The effect of timing of oral meloxicam administration on physiological responses in calves after cautery dehorning with local anesthesia..
      ;
      • Winder C.B.
      • Miltenburg C.L.
      • Sargeant J.M.
      • LeBlanc S.J.
      • Haley D.B.
      • Lissemore K.D.
      • Godkin M.A.
      • Duffield T.F.
      Effects of local anesthetic or systemic analgesia on pain associated with cautery disbudding in calves: A systematic review and meta-analysis..
      ). A potential negative side effect of lidocaine administration is the risk of increased hemorrhage due to the drug causing vasodilation.
      Figure 1
      Figure 1(A) Anatomic location of the cornual nerve (red line) with the landmarks for identifying the correct injection site: the eye, horn bud, and frontal ridge (blue line). (B) Infiltration of 2% lidocaine for local anesthesia of the horn.
      Nonsteroidal anti-inflammatory drugs are commonly used to provide analgesia and reduce inflammation associated with dehorning. Flunixin meglumine has US FDA approval for reduction of fever, inflammation, and pain associated with foot rot in cattle. Flunixin meglumine provides up to 6 h of analgesia when used with a local anesthetic nerve block. When used at the time of dehorning, transdermal flunixin provides for decreased cortisol levels compared with controls and improvement in mechanical nociception threshold tests at control sites, indicating reduction in central sensitization (
      • Kleinhenz M.D.
      • Van Engen N.K.
      • Gorden P.J.
      • Ji J.
      • Walsh P.
      • Coetzee J.F.
      Effects of transdermal flunixin meglumine on pain biomarkers at dehorning in calves..
      ).
      An injectable formulation of meloxicam is approved in Canada for pain control after dehorning. In the United States, human generic meloxicam tablets can be administered in an extra-label manner. There are several studies supporting the use of meloxicam for dehorning pain control. Meloxicam has been shown to improve mechanical nociception threshold tests 24 h after dehorning (
      • Heinrich A.
      • Duffield T.F.
      • Lissemore K.D.
      • Millman S.T.
      The effect of meloxicam on behavior and pain sensitivity of dairy calves following cautery dehorning with a local anesthetic..
      ). Meloxicam has also been shown to lower cortisol and substance P in calves 8 to 10 wk of age (
      • Glynn H.D.
      • Coetzee J.F.
      • Edwards-Callaway L.N.
      • Dockweiler J.C.
      • Allen K.A.
      • Lubbers B.
      • Jones M.
      • Fraccaro E.
      • Bergamasco L.L.
      • KuKanich B.
      The pharmacokinetics and effects of meloxicam, gabapentin, and flunixin in postweaning dairy calves following dehorning with local anesthesia..
      ). In calves undergoing amputation dehorning at 6 mo of age, meloxicam-treated calves had improved ADG over 10 d after the procedure (
      • Allen K.A.
      • Coetzee J.F.
      • Edwards-Callaway L.N.
      • Glynn H.
      • Dockweiler J.
      • KuKanich B.
      • Lin H.
      • Wang C.
      • Fraccaro E.
      • Jones M.
      • Bergamasco L.
      The effect of timing of oral meloxicam administration on physiological responses in calves after cautery dehorning with local anesthesia..
      ). Recent data have revealed meloxicam-treated calves were less averse to spending time in the pen in which they were disbudded compared with pens they were not disbudded (
      • Ede T.
      • von Keyserlingk M.A.G.
      • Weary D.M.
      Assessing the affective component of pain, and the efficacy of pain control, using conditioned place aversion in calves..
      ).
      Ketoprofen is approved in Canada for pain control associated with a variety of conditions but not dehorning. It has been evaluated for dehorning analgesia. When administered in combination with a local anesthetic, ketoprofen ameliorated the acute cortisol response (
      • McMeekan C.M.
      • Stafford K.J.
      • Mellor D.J.
      • Bruce R.A.
      • Ward R.N.
      • Gregory N.G.
      Effects of regional analgesia and/or a non-steroidal anti-inflammatory analgesic on the acute cortisol response to dehorning in calves..
      ;
      • Sutherland M.A.
      • Mellor D.J.
      • Stafford K.J.
      • Gregory N.G.
      • Bruce R.A.
      • Ward R.N.
      Cortisol responses to dehorning of calves given a 5-h local anaesthetic regimen plus phenylbutazone, ketoprofen, or adrenocorticotropic hormone prior to dehorning..
      ;
      • Milligan B.N.
      • Duffield T.
      • Lissemore K.
      The utility of ketoprofen for alleviating pain following dehorning in young dairy calves..
      ;
      • Duffield T.F.
      • Heinrich A.
      • Millman S.T.
      • DeHaan A.
      • James S.
      • Lissemore K.
      Reduction in pain response by combined use of local lidocaine anesthesia and systemic ketoprofen in dairy calves dehorned by heat cauterization..
      ). Ketoprofen improved mechanical nociception threshold measures when given at 3 mg/kg by i.m. injections in conjunction with a topical local anesthetic (
      • Espinoza C.A.
      • McCarthy D.
      • White P.J.
      • Windsor P.A.
      • Lomax S.H.
      Evaluating the efficacy of a topical anaesthetic formulation and ketoprofen, alone and in combination, on the pain sensitivity of dehorning wounds in Holstein-Friesian calves..
      ). A negative attribute of ketoprofen is its short duration of action, and thus, it is not a suitable choice for dehorning pain (
      • Ede T.
      • von Keyserlingk M.A.G.
      • Weary D.M.
      Assessing the affective component of pain, and the efficacy of pain control, using conditioned place aversion in calves..
      ).
      Carprofen and firocoxib have both been evaluated for dehorning pain control. Carprofen is approved in the European Union for pain. A study investigating oral carprofen did not show analgesic benefit (
      • Stock M.L.
      • Barth L.A.
      • Van Engen N.K.
      • Millman S.T.
      • Gehring R.
      • Wang C.
      • Voris E.A.
      • Wulf L.W.
      • Labeur L.
      • Hsu W.H.
      • Coetzee J.F.
      Impact of carprofen administration on stress and nociception responses of calves to cautery dehorning..
      ). Similarly,
      • Stock M.L.
      • Millman S.T.
      • Barth L.A.
      • Van Engen N.K.
      • Hsu W.H.
      • Wang C.
      • Gehring R.
      • Parsons R.L.
      • Coetzee J.F.
      The effects of firocoxib on cautery disbudding pain and stress responses in preweaned dairy calves..
      observed firocoxib given at 1 mg/kg orally did not provide analgesia despite evidence of anti-inflammatory action based on lower prostaglandin E2 production. Studies comparing NSAID side by side are lacking in the literature.

      Branding

      Branding is a common management practice on beef operations especially in the western part of Canada and the United States (

      USDA, Animal and Plant Health Inspection Service. 2008. Beef 2007–08, Part I: Reference of Beef Cow-calf Management Practices in the United States, 2007–08 USDA-APHIS-VS, CEAH, Fort Collins, CO #N512–10080. Accessed Sep. 10, 2020. https://www.aphis.usda.gov/animal_health/nahms/beefcowcalf/downloads/beef0708/Beef0708_dr_PartI_rev_1.pdf.

      ;
      • Moggy M.A.
      • Pajor E.A.
      • Thurston W.E.
      • Parker S.
      • Greter A.M.
      • Schwartzkopf-Genswein K.S.
      • Campbell J.R.
      • Windeyer M.C.
      Management practices associated with stress in cattle on western Canadian cow-calf operations: A mixed methods study..
      ). In a Canadian survey, branding was practiced on half of the farms, but analgesia was provided on less than 5% (
      • Moggy M.A.
      • Pajor E.A.
      • Thurston W.E.
      • Parker S.
      • Greter A.M.
      • Schwartzkopf-Genswein K.S.
      • Campbell J.R.
      • Windeyer M.C.
      Management practices associated with stress in cattle on western Canadian cow-calf operations: A mixed methods study..
      ). Both hot-iron and freeze branding have been shown to induce pain that lasts for extended periods of time (
      • Lay Jr., D.C.
      • Friend T.H.
      • Bowers C.L.
      • Grissom K.K.
      • Jenkins O.C.
      A comparative physiological and behavioral study of freeze and hot-iron branding using dairy cows..
      ;
      • Schwartzkopf-Genswein K.
      • Stookey J.
      • Passillé A.D.
      • Rushen J.
      Comparison of hot-iron and freeze branding on cortisol levels and pain sensitivity in beef cattle..
      ;
      • Tucker C.B.
      • Mintline E.M.
      • Banuelos J.
      • Walker K.A.
      • Hoar B.
      • Drake D.
      • Weary D.M.
      Effect of a cooling gel on pain sensitivity and healing of hot-iron cattle brands..
      ). Despite the evidence that branding is painful, there are few studies in the published literature regarding analgesic strategies at the time of branding. Of those, a single dose of flunixin at 1.1 mg/kg did not provide adequate analgesia (
      • Tucker C.B.
      • Mintline E.M.
      • Banuelos J.
      • Walker K.A.
      • Hoar B.
      • Varga A.
      • Drake D.
      • Weary D.M.
      Pain sensitivity and healing of hot-iron cattle brands..
      ). This is not surprising as flunixin, given at the high end of the label dose of 2.2 mg/kg by i.v. administration, has a relatively short half-life. Meloxicam given at 0.5 mg/kg subcutaneously at the time of concurrent surgical castration provided analgesia based on improved pain behaviors of increased lying time, decreased tail flicks, and less head turning (
      • Melendez D.M.
      • Marti S.
      • Pajor E.A.
      • Sidhu P.K.
      • Gellatly D.
      • Moya D.
      • Janzen E.D.
      • Coetzee J.F.
      • Schwartzkopf-Genswein K.S.
      Effect of meloxicam and lidocaine administered alone or in combination on indicators of pain and distress during and after knife castration in weaned beef calves..
      ).

      Bovine Castration

      Castration is performed on male food animals to minimize male aggressive behaviors, improve carcass quality, and eliminate the risk of unwanted pregnancies in the feeding period. Regardless of the animal’s age and technique used, castration causes pain, distress, and other behavioral and neuroendocrine changes (
      • Coetzee J.F.
      • Shearer J.K.
      • Stock M.L.
      • Kleinhenz M.D.
      • van Amstel S.R.
      An update on the assessment and management of pain associated with lameness in cattle..
      ). Alternatives such as immunocastration have been demonstrated to be effective (
      • Hirsbrunner G.
      • Rigert A.
      • Janett F.
      • Hüsler J.
      • Schnydrig P.
      • Lopez E.
      • Amatayakul-Chantler S.A.
      • Steiner A.
      Immunization against GnRF in adult cattle: A prospective field study..
      ). However, this technique has not gained wide-spread adoption due to lack of product approvals, the need for repeated injection, and risk of human health implications due to vaccine exposure.
      Similar to dehorning, a multimodal analgesic strategy has been shown to be the most beneficial to reduce pain during castration. Local anesthetics on their own reduced cortisol compared with controls undergoing castration but had little effect on ADG, feed intake, or inflammatory mediators (
      • Earley B.
      • Crowe M.A.
      Effects of ketoprofen alone or in combination with local anesthesia during the castration of bull calves on plasma cortisol, immunological, and inflammatory responses..
      ;
      • Ting S.T.
      • Earley B.
      • Crowe M.A.
      Effect of repeated ketoprofen administration during surgical castration of bulls on cortisol, immunological function, feed intake, growth, and behavior..
      ,
      • Ting S.T.
      • Earley B.
      • Hughes J.M.
      • Crowe M.A.
      Effect of ketoprofen, lidocaine local anesthesia, and combined xylazine and lidocaine caudal epidural anesthesia during castration of beef cattle on stress responses, immunity, growth, and behavior..
      ;
      • Webster H.B.
      • Morin D.
      • Jarrell V.
      • Shipley C.
      • Brown L.
      • Green A.
      • Wallace R.
      • Constable P.D.
      Effects of local anesthesia and flunixin meglumine on the acute cortisol response, behavior, and performance of young dairy calves undergoing surgical castration..
      ). Local anesthetic action is potentiated by co-administration of an NSAID (
      • Nordi W.M.
      • Marti S.
      • Gellatly D.
      • Meléndez D.M.
      • González L.A.
      • McAllister T.A.
      • Fierheller E.E.
      • Caulkett N.A.
      • Janzen E.
      • Schwartzkopf-Genswein K.S.
      Effect of preemptive flunixin meglumine and lidocaine on behavioral and physiological indicators of pain post-band and knife castration in 6-mo-old beef calves..
      ).
      Calves administered flunixin and lidocaine also had lower salivary cortisol and pain scores compared with placebo controls (
      • Nordi W.M.
      • Marti S.
      • Gellatly D.
      • Meléndez D.M.
      • González L.A.
      • McAllister T.A.
      • Fierheller E.E.
      • Caulkett N.A.
      • Janzen E.
      • Schwartzkopf-Genswein K.S.
      Effect of preemptive flunixin meglumine and lidocaine on behavioral and physiological indicators of pain post-band and knife castration in 6-mo-old beef calves..
      ). Calves treated with flunixin and given lidocaine as a local anesthetic at the time of castration had greater DMI compared with flunixin only–treated calves (
      • Coetzee J.F.
      Assessment and management of pain associated with castration in cattle..
      ;
      • Nordi W.M.
      • Marti S.
      • Gellatly D.
      • Meléndez D.M.
      • González L.A.
      • McAllister T.A.
      • Fierheller E.E.
      • Caulkett N.A.
      • Janzen E.
      • Schwartzkopf-Genswein K.S.
      Effect of preemptive flunixin meglumine and lidocaine on behavioral and physiological indicators of pain post-band and knife castration in 6-mo-old beef calves..
      ). Flunixin-treated calves also had longer stride lengths following surgical castration compared with controls, suggesting flunixin reduced pain at the castration cite, allowing for longer distances between steps (
      • Currah J.M.
      • Hendrick S.H.
      • Stookey J.M.
      The behavioral assessment and alleviation of pain associated with castration in beef calves treated with flunixin meglumine and caudal lidocaine epidural anesthesia with epinephrine..
      ). The transdermal flunixin formulation, without a local anesthetic, reduced plasma cortisol up to 8 h after the procedure compared with placebo controls but provided negligible evidence of analgesia based on substance P and pressure mat gait analysis (
      • Kleinhenz M.D.
      • Van Engen N.K.
      • Smith J.S.
      • Gorden P.J.
      • Ji J.
      • Wang C.
      • Perkins S.C.B.
      • Coetzee J.F.
      The impact of transdermal flunixin meglumine on biomarkers of pain in calves when administered at the time of surgical castration without local anesthesia..
      ).
      Meloxicam has been evaluated for pain control from surgical and nonsurgical (band) castration. Additionally, meloxicam is approved for the control of pain following castration in Canada. Meloxicam-treated calves had a reduced inflammatory response compared with placebo controls based on lower salivary cortisol levels, white blood cell counts, and reduced acute phase protein responses when administered meloxicam (
      • Melendez D.M.
      • Marti S.
      • Pajor E.A.
      • Moya D.
      • Gellatly D.
      • Janzen E.D.
      • Schwartzkopf-Genswein K.S.
      Effect of subcutaneous meloxicam on indicators of acute pain and distress after castration and branding in 2-mo-old beef calves..
      ). Interestingly, no additional benefit was observed when meloxicam was administered with lidocaine (
      • Melendez D.M.
      • Marti S.
      • Pajor E.A.
      • Moya D.
      • Gellatly D.
      • Janzen E.D.
      • Schwartzkopf-Genswein K.S.
      Effect of subcutaneous meloxicam on indicators of acute pain and distress after castration and branding in 2-mo-old beef calves..
      ).

      Processing Procedures on Pig Farms

      Piglets undergo several processing procedures during their first week of life, including surgical castration, tail docking, teeth clipping, and ear tagging or notching for identification. Surgical castration eliminates boar taint (i.e., improves meat quality) and reduces aggression (
      • Hay M.
      • Vulin A.
      • Genin S.
      • Sales P.
      • Prunier A.
      Assessment of pain induced by castration in piglets: Behavior and physiological responses over the subsequent 5 days..
      ). Tail docking reduces the occurrence and severity of injury associated with tail biting (
      • Sutherland M.A.
      • Bryer P.J.
      • Krebs N.
      • McGlone J.J.
      Tail docking in pigs: Acute physiological and behavioural responses..
      ). Teeth clipping, or removal of the piglet’s third incisors and canine teeth, is done to reduce tissue damage associated with interpig aggression and to decrease lacerations to the sow’s udder (
      • Sutherland M.A.
      Welfare implications of invasive piglet husbandry procedures, methods of alleviation and alternatives: A review..
      ). However, previous work has challenged this, finding minimal association between teeth clipping and lesion incidence or severity on sows and piglets (
      • Holyoake P.K.
      • Broek D.J.
      • Callinan A.P.L.
      The effects of reducing the length of canine teeth in suckling pigs by clipping or grinding..
      ;
      • Fu L.
      • Zhou B.
      • Li H.
      • Liang T.
      • Chu Q.
      • Schinckel A.P.
      • Li Y.
      • Xu F.
      Effects of tail docking and/or teeth clipping on behavior, lesions, and physiological indicators of sows and their piglets..
      ). The implications of teeth clipping on pig welfare (e.g., increased stress; pain; and risk of gum damage, abscesses, and infection) and production appear to outweigh the benefits (
      • Sutherland M.A.
      Welfare implications of invasive piglet husbandry procedures, methods of alleviation and alternatives: A review..
      ), and many pig producers in North America are electing to leave needle teeth intact, clipping only when necessary (

      American Veterinary Medical Association. 2010. Welfare policies revised and adopted. Accessed Sep. 15, 2020. https://www.avma.org/javma-news/2010-06-01/welfare-policies-revised-and-adopted.

      ;

      National Farm Animal Care Council. 2014. Code of practice for the care and handling of pigs. Accessed Sep. 20, 2020. https://www.nfacc.ca/pdfs/codes/pig_code_of_practice.pdf

      ).
      Alternatives to traditional surgical castration have been reported. A gonadotropin-releasing factor analog vaccine has been approved by the FDA for the temporary immunocastration of boars (

      US FDA (United States Food and Drug Administration). 2011. Freedom of information summary original new animal drug application Improvest. Accessed Aug. 30, 2020. https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/880.

      ). Although approved for use in swine, the need for repeated vaccination and the risk of human health implications due to vaccine exposure have slowed its adoption. Recently, a pilot study using a CO2 laser scalpel was reported as an alternative to traditional surgical castration (
      • Viscardi A.V.
      • Cull C.A.
      • Kleinhenz M.D.
      • Montgomery S.
      • Curtis A.
      • Lechtenberg K.
      • Coetzee J.F.
      Evaluating the utility of a CO2 surgical laser for piglet castration to reduce pain and improve wound healing: A pilot study..
      ). There were no observed differences in wound healing or pain biomarkers. The authors report thermal damage of the laser-castrated piglets as a possible factor in the lack of differences (
      • Viscardi A.V.
      • Cull C.A.
      • Kleinhenz M.D.
      • Montgomery S.
      • Curtis A.
      • Lechtenberg K.
      • Coetzee J.F.
      Evaluating the utility of a CO2 surgical laser for piglet castration to reduce pain and improve wound healing: A pilot study..
      ).
      Piglet processing procedures are known to be painful; however, without approved analgesia options in the United States, pain management is not routinely provided. In Canada and countries in the European Union, analgesia administration is required for postoperative pain management of piglets undergoing surgical castration and tail docking (

      European Commission. 2010. European declaration on alternatives to surgical castration of pigs. Accessed Sep. 15, 2020. https://ec.europa.eu/food/sites/food/files/animals/docs/aw_prac_farm_pigs_cast-alt_declaration_en.pdf.

      ;

      National Farm Animal Care Council. 2014. Code of practice for the care and handling of pigs. Accessed Sep. 20, 2020. https://www.nfacc.ca/pdfs/codes/pig_code_of_practice.pdf

      ). As with all food animals, the most common class of analgesics given to pigs to alleviate pain are NSAID.
      Meloxicam (0.4 mg/kg) is the only NSAID labeled for swine to relieve pain associated with minor soft tissue surgery in Canada. Meloxicam can be administered to pigs on farm orally or via an i.m. injection. Previous studies have reported that an i.m. injection of meloxicam was successful in providing pain relief to piglets after surgical castration, noting a reduction in blood cortisol concentration and decreased pain-related behaviors postoperatively (0.4 mg/kg;
      • Keita A.
      • Pagot E.
      • Prunier A.
      • Guidarini C.
      Pre-emptive meloxicam for postoperative analgesia in piglets undergoing surgical castration..
      ;
      • Kluivers-Poodt M.
      • Zonderland J.J.
      • Verbraak J.
      • Lambooij E.
      • Hellebrekers L.J.
      Pain behaviour after castration of piglets; effect of pain relief with lidocaine and/or meloxicam..
      ; 0.06 mL/piglet:
      • Gottardo F.
      • Scollo A.
      • Contiero B.
      • Ravagnani A.
      • Tavella G.
      • Bernardini D.
      • De Benedictis G.M.
      • Edwards S.A.
      Pain alleviation during castration of piglets: A comparative study of different farm options..
      ). Oral meloxicam (30 mg/kg) administered to the sow and delivered transmammary to her nursing piglets also provided analgesia after surgical castration and tail docking, as evidenced by a decrease in blood cortisol and prostaglandin E2 concentration, and maintenance of cranial skin temperature (
      • Bates J.L.
      • Karriker L.A.
      • Stock M.L.
      • Pertzborn K.M.
      • Baldwin L.G.
      • Wulf L.W.
      • Lee C.J.
      • Wang C.
      • Coetzee J.F.
      Impact of transmammary-delivered meloxicam on biomarkers of pain and distress in piglets after castration and tail docking..
      ). However, these results have been contradicted by other studies, which have indicated that an i.m. injection of meloxicam (0.4–1.0 mg/kg) was ineffective at alleviating pain associated with piglet processing procedures (castration:
      • Kluivers-Poodt M.
      • Houx B.B.
      • Robben S.R.
      • Koop G.
      • Lambooij E.
      • Hellebrekers L.J.
      Effects of a local anaesthetic and NSAID in castration of piglets, on the acute pain responses, growth and mortality..
      ;
      • Viscardi A.V.
      • Turner P.V.
      Use of meloxicam or ketoprofen for piglet pain control following surgical castration..
      ;
      • Yun J.
      • Ollila A.
      • Valros A.
      • Larenza-Menzies P.
      • Heinonen M.
      • Oliviero C.
      • Peltoniemi O.
      Behavioural alterations in piglets after surgical castration: Effects of analgesia and anaesthesia..
      ; tail docking:
      • Herskin M.S.
      • Di Giminiani P.
      • Thodberg K.
      Effects of administration of a local anaesthetic and/or an NSAID and of docking length on the behaviour of piglets during 5 h after tail docking..
      ;
      • Viscardi A.V.
      • Turner P.V.
      Use of meloxicam, buprenorphine, and Maxilene® to assess a multimodal approach for piglet pain management, part 2: Tail-docking..
      ). The inconsistent results following meloxicam use to alleviate piglet pain suggests more work may be needed to optimize drug dose, route and time of administration, as well as study design and outcome measures to ensure drug efficacy before making recommendations.
      Ketoprofen (approved in Canada only) and flunixin meglumine (approved in Canada and the United States) are NSAID labeled to treat fever and respiratory disease in swine; however, there is limited research on their ability to reduce postprocedural pain in piglets.
      • Cassar G.
      • Amezcua R.
      • Tenbergen R.
      • Friendship R.M.
      Preoperative ketoprofen administration to piglets undergoing castration does not affect subsequent growth performance..
      found 3.0 mg/kg ketoprofen, administered intramuscularly, reduced blood cortisol levels of piglets up to 4 h after castration. In another study, piglets given the same dose of ketoprofen intramuscularly before surgical castration were able to navigate a chute faster than castrated piglets not given an NSAID (
      • Reynolds K.
      • Johnson R.
      • Brown J.
      • Friendship R.
      • O’Sullivan T.L.
      Assessing pain control efficacy of meloxicam and ketoprofen when compounded with iron dextran in nursing piglets using a navigation chute..
      ). However,
      • Viscardi A.V.
      • Turner P.V.
      Use of meloxicam or ketoprofen for piglet pain control following surgical castration..
      found that administration of ketoprofen (6.0 mg/kg i.m.) did not significantly reduce piglet pain behaviors or facial grimacing after castration. Similarly, flunixin meglumine (no dose noted), administered intramuscularly, did not reduce castration-associated vocalizations, pain behaviors, or the cortisol response after the procedure (
      • Sutherland M.A.
      • Davis B.L.
      • Brooks T.A.
      • Coetzee J.F.
      The physiological and behavioral response of pigs castrated with and without anesthesia or analgesia..
      ). A recent pharmacokinetic study in preweaned piglets found flunixin meglumine (3.3 mg/kg, oral and i.m.) achieved therapeutic concentration ranges that have provided appropriate pain management to adult pigs; however, a transdermal application of flunixin resulted in very low plasma drug concentrations, unlikely to effectively alleviate postoperative pain (
      • Kittrell H.C.
      • Mochel J.P.
      • Brown J.T.
      • Forseth A.M.K.
      • Hayman K.P.
      • Rajewski S.M.
      • Coetzee J.F.
      • Schneider B.K.
      • Ratliffe B.
      • Skoland K.J.
      • Karriker L.A.
      Pharmacokinetics of intravenous, intramuscular, oral, and transdermal administration of flunixin meglumine in pre-wean piglets..
      ). Future work should determine whether 3.3 mg/kg (oral or i.m.) of flunixin can reduce behavioral and physiological signs of pain in piglets after processing.
      Lidocaine, a local anesthetic, decreased procedure-associated vocalizations and defense behavior and reduced plasma cortisol levels of piglets after castration when pre-emptively injected into each testicle (0.5–1.0 mL;
      • Marx G.
      • Horn T.
      • Thielebein J.
      • Knubel B.
      • von Borell E.
      Analysis of pain-related vocalizations in young pigs..
      ;
      • Hansson M.
      • Lundeheim N.
      • Nyman G.
      • Johansson G.
      Effect of local anaesthesia and/or analgesia on pain responses induced by piglet castration..
      ;
      • Kluivers-Poodt M.
      • Houx B.B.
      • Robben S.R.
      • Koop G.
      • Lambooij E.
      • Hellebrekers L.J.
      Effects of a local anaesthetic and NSAID in castration of piglets, on the acute pain responses, growth and mortality..
      ). Similarly, a s.c. injection of 0.3 mL of lidocaine into the base of the tail reduced vocalizations and defensive movements of piglets at the time of tail docking but did not reduce postprocedural pain behaviors (
      • Herskin M.S.
      • Di Giminiani P.
      • Thodberg K.
      Effects of administration of a local anaesthetic and/or an NSAID and of docking length on the behaviour of piglets during 5 h after tail docking..
      ). The routes of administration described (subcutaneous and intratesticular) are much more technical than those described for NSAID, which reduces the practicality of lidocaine use on farm. The route of administration may also cause more distress to piglets, due to prolonged handling and increased pain, while providing limited postoperative pain relief (
      • Leidig M.S.
      • Hertrampf B.
      • Failing K.
      • Schumann A.
      • Reiner G.
      Pain and discomfort in male piglets during surgical castration with and without local anaesthesia as determined by vocalization and defence behaviour..
      ;
      • Hansson M.
      • Lundeheim N.
      • Nyman G.
      • Johansson G.
      Effect of local anaesthesia and/or analgesia on pain responses induced by piglet castration..
      ). Topical anesthetics have been used to reduce processing procedure–associated pain in piglets, with limited efficacy. Cetacaine (14% benzaine, 2% butamben, and 2% tetracaine hydrochloride; Cetylite Inc., Pennsauken, NJ) or Tri-Solfen (40.6 g/L lignocaine, 4.5 g/L bupivacaine, 24.8 mg/L adrenaline, and 5.0 g/L cetrimide; Bayer Australia Ltd., Pymble, NSW, Australia) were administered topically onto the spermatic cords before they were cut during piglet surgical castration in a study conducted by
      • Sutherland M.A.
      • Davis B.L.
      • Brooks T.A.
      • McGlone J.J.
      Physiology and behavior of pigs before and after castration: Effects of two topical anesthetics..
      . Neither treatment significantly reduced plasma cortisol concentrations, stress vocalizations, or pain behaviors after castration (
      • Sutherland M.A.
      • Davis B.L.
      • Brooks T.A.
      • McGlone J.J.
      Physiology and behavior of pigs before and after castration: Effects of two topical anesthetics..
      ). Recent contradictory studies found Tri-Solfen was effective at mitigating acute peri-operative castration pain in piglets (
      • Lomax S.
      • Harris C.
      • Windsor P.A.
      • White P.J.
      Topical anaesthesia reduces sensitivity of castration wounds in neonatal piglets..
      ;
      • Sheil M.L.
      • Chambers M.
      • Sharpe B.
      Topical wound anaesthesia: Efficacy to mitigate piglet castration pain..
      ). It appears more work is needed to verify Tri-Solfen anesthesia efficacy (this product is currently unavailable in North America). EMLA (a eutectic mixture of 2.5% lidocaine and 2.5% prilocaine; APP Pharmaceuticals LLC, Schaumburg, IL) cream or Maxilene (4% lidocaine; RGR Pharma Ltd., LaSalle, Ontario, Canada) applied topically to the scrotum or tail of piglets before surgical castration or tail docking, respectively, were not able to reduce procedure-associated vocalizations or postoperative pain behavior and facial grimacing (
      • Viscardi A.V.
      • Hunniford M.
      • Lawlis P.
      • Leach M.
      • Turner P.V.
      Development of a Piglet Grimace Scale to evaluate piglet pain using facial expressions following castration and tail docking: A pilot study..
      ;
      • Viscardi A.V.
      • Turner P.V.
      Use of meloxicam or ketoprofen for piglet pain control following surgical castration..
      ,
      • Viscardi A.V.
      • Turner P.V.
      Efficacy of buprenorphine for management of surgical castration pain in piglets..
      ). Based on their short duration of action and minimal analgesic effects, it is unlikely that a topical anesthetic alone will be able to provide sufficient pain management for piglets undergoing processing procedures.
      A multimodal approach to piglet pain management, with a local anesthetic and an NSAID, may be the most effective option to alleviate processing-procedure pain.
      • Bonastre C.
      • Mitjana O.
      • Tejedor M.T.
      • Calavia M.
      • Yuste A.G.
      • Úbeda J.L.
      • Falceto M.V.
      Acute physiological responses to castration-related pain in piglets: The effect of two local anesthetics with or without meloxicam..
      found lidocaine (0.4 mL, intratesticular) and meloxicam (0.4 mg/kg i.m.) significantly decreased cortisol concentrations of piglets after castration. Similar results were found by
      • Hansson M.
      • Lundeheim N.
      • Nyman G.
      • Johansson G.
      Effect of local anaesthesia and/or analgesia on pain responses induced by piglet castration..
      , using 0.5 mL intratesticular injection of lidocaine (10 mg/mL) combined with epinephrine (5.0 µg/mL), and meloxicam (0.2 mL/piglet, i.m.) before surgical castration; piglets had reduced procedure-associated vocalizations and less observed pain behaviors. Unfortunately, these are not practical options for on-farm use, primary because of the cost, time, and effort needed to administer both an anesthetic and analgesic at the time of processing. Buprenorphine (an opioid) alone was found to effectively reduce postcastration pain behaviors and facial grimacing in piglets (
      • Viscardi A.V.
      • Turner P.V.
      Efficacy of buprenorphine for management of surgical castration pain in piglets..
      ); however, this is an even less practical on-farm option, due to restrictions associated with obtaining and administering a controlled substance.
      Authors of a systematic review of the pain management literature for piglets undergoing routine processing procedures were not able to make strong recommendations due to the low-quality evidence in the literature (
      • O’Connor A.
      • Anthony R.
      • Bergamasco L.
      • Coetzee J.
      • Gould S.
      • Johnson A.K.
      • Karriker L.A.
      • Marchant-Forde J.N.
      • Martineau G.S.
      • McKean J.
      • Millman S.T.
      • Niekamp S.
      • Pajor E.A.
      • Rutherford K.
      • Sprague M.
      • Sutherland M.
      • von Borell E.
      • Dzikamunhenga R.S.
      Pain management in the neonatal piglet during routine management procedures. Part 2: Grading the quality of evidence and the strength of recommendations..
      ). It was evident that more work is needed to determine effective pain management strategies for neonatal pigs. Recently, our group described administering firocoxib to sows for pain mitigation in piglets undergoing routine neonatal processing. Barrows nursing sows administered firocoxib at 2 mg/kg by i.m. injection had lower cortisol concentrations compared with controls and sows receiving a lower dose of firocoxib (
      • Coetzee J.F.
      • Sidhu P.K.
      • Seagen J.
      • Schieber T.
      • Kleinhenz K.
      • Kleinhenz M.D.
      • Wulf L.W.
      • Cooper V.L.
      • Mazloom R.
      • Jaberi-Douraki M.
      • Lechtenberg K.
      Transmammary delivery of firocoxib to piglets reduces stress and improves average daily gain after castration, tail docking, and teeth clipping..
      ). Additionally, piglets nursing from sows receiving 2 mg/kg firocoxib by i.m. injection had improved weight gains. These findings suggest that firocoxib, passed from the sow to piglets in the milk, may safely reduce stress and enhance production by increased weight gains.

      Lameness

      Lameness is a relatively common disease condition of cattle and swine. Unlike the painful procedures discussed previously in this review; the onset of lameness associated pain is typically unknown. Lameness rates vary by farm with reported prevalence ranging from 6.9 to 54.8% (
      • von Keyserlingk M.A.
      • Barrientos A.
      • Ito K.
      • Galo E.
      • Weary D.M.
      Benchmarking cow comfort on North American freestall dairies: Lameness, leg injuries, lying time, facility design, and management for high-producing Holstein dairy cows..
      ;
      • Adams A.E.
      • Lombard J.E.
      • Fossler C.P.
      • Roman-Muniz I.N.
      • Kopral C.A.
      Associations between housing and management practices and the prevalence of lameness, hock lesions, and thin cows on US dairy operations..
      ). Furthermore, lameness has been observed to be under-reported by producers when compared with independent observers (
      • Wells S.J.
      • Trent A.M.
      • Marsh W.E.
      • Robinson R.A.
      Prevalence and severity of lameness in lactating dairy cows in a sample of Minnesota and Wisconsin herds..
      ;
      • Whay H.R.
      • Main D.C.J.
      • Green L.E.
      • Webster A.J.F.
      Assessment of the welfare of dairy cattle using animal-based measurements: Direct observations and investigation of farm records..
      ). There are known economic and production losses seen with lameness in addition to pain and distress. Lameness in the United States has been estimated to cost between $120 and $216 per case (
      • Cha E.
      • Hertl J.A.
      • Bar D.
      • Grohn Y.T.
      The cost of different types of lameness in dairy cows calculated by dynamic programming..
      ). Due to the visible changes in animal movement, the evaluation of lameness prevalence is included in third party animal welfare audits (

      National Dairy FARM Program. 2020. Animal Care Reference Manual. Accessed Sep. 26, 2020. https://nationaldairyfarm.com/wp-content/uploads/2020/02/Animal-Care-V4-Manual-Print-Friendly.pdf.

      ).
      Causes of lameness include both infectious and noninfectious etiologies. It is important to note that infectious and noninfectious etiologies may both be present in cases of lameness. Common infectious etiologies are foot rot (interdigital phlegmon) and digital dermatitis in cattle and Streptococcus suis in swine. Noninfectious causes include laminitis, defects in the horny tissue, such as sole ulcers or white line disease, and fractures of any bones of the limb. Due to the nature of lameness, treatment recommendations include a multimodal approach. These approaches include trimming of the diseased hoof, application of hoof blocks to sound toes, systemic or local antibiotics, and analgesics (
      • Coetzee J.F.
      • Shearer J.K.
      • Stock M.L.
      • Kleinhenz M.D.
      • van Amstel S.R.
      An update on the assessment and management of pain associated with lameness in cattle..
      ).
      Early lameness detection is ideal for the obvious animal welfare implications but also for prevention of central sensitization. Central sensitization can lead to increased sensitivity of pain (hyperalgesia) or pain from nonpainful stimuli (allodynia;
      • Anderson D.E.
      • Muir W.M.
      Pain management in cattle..
      ). Unlike dehorning or castration, pre-emptive analgesia, that has the potential to block central sensitization, is not possible with lameness.
      Transdermal flunixin is approved for the control of pain associated with lameness and is the only FDA-approved pain medication for food animals in the United States. In the United States, the label claim is specific for the control of pain associated with foot rot. According to documentation supporting the approval of transdermal flunixin, calves treated at the dose of 3.3 mg/kg had improved lameness scores and increased contact force when walking across a pressure mat (

      US FDA (United States Food and Drug Administration). 2017. Freedom of information summary original new animal drug application Banamine Transdermal. Accessed Nov. 30, 2020. https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/1944.

      ). A study investigating transdermal flunixin at the label dose of 3.3 mg/kg administered to lactating dairy cattle for 3 treatments using an amphotericin B arthritis/synovitis lameness model reported flunixin-treated cows had lower joint temperatures as measured by infrared thermography and improved mechanical nociception threshold measures (
      • Kleinhenz M.D.
      • Gorden P.J.
      • Smith J.S.
      • Schleining J.A.
      • Kleinhenz K.E.
      • Juarez J.R.
      • Rea D.
      • Coetzee J.F.
      Effects of transdermal flunixin meglumine on experimentally induced lameness in adult dairy cattle..
      ). However, these improvements were not seen until after the second dose was administered. No differences in pressure mat gait outcomes such as contact force or stride length were noted in this study. These results indicate that multiple administrations of transdermal flunixin may be required to provide analgesia to cattle with lameness.
      Flunixin meglumine administered by i.v. injection has also been investigated in lameness models and clinical field trials (
      • Schulz K.L.
      • Anderson D.E.
      • Coetzee J.F.
      • White B.J.
      • Miesner M.D.
      Effect of flunixin meglumine on the amelioration of lameness in dairy steers with amphotericin B-induced transient synovitis-arthritis..
      ;
      • Chapinal N.
      • Fitzpatrick C.E.
      • Leslie K.E.
      • Wagner S.A.
      Short Communication: Automated assessment of the effect of flunixin meglumine on rumination in dairy cows with endotoxin-induced mastitis..
      ;
      • Wagner S.A.
      • Young J.M.
      • Tena J.K.
      • Manning B.H.
      Short Communication: Behavioral evaluation of the analgesic effect of flunixin meglumine in lame dairy cows..
      ). Calves receiving i.v. flunixin following lameness induction using amphotericin B had improved lameness scores compared with controls (
      • Schulz K.L.
      • Anderson D.E.
      • Coetzee J.F.
      • White B.J.
      • Miesner M.D.
      Effect of flunixin meglumine on the amelioration of lameness in dairy steers with amphotericin B-induced transient synovitis-arthritis..
      ). Additionally, flunixin-treated cattle had an increase in contact pressure and surface area of the affected limb on pressure mat gait analysis. Flunixin-treated cattle spent less time lying compared with placebo cows for the first day. This is likely due to the short half-life of flunixin given intravenously (
      • Gorden P.J.
      • Kleinhenz M.D.
      • Wulf L.W.
      • Rajewski S.J.
      • Wang C.
      • Gehring R.
      • Coetzee J.F.
      Comparative plasma and interstitial fluid pharmacokinetics of flunixin meglumine and ceftiofur hydrochloride following individual and co-administration in dairy cows..
      ).
      In a clinical trial, cattle were given flunixin meglumine before corrective hoof trimming and 24 h later. No differences in weight distribution or lameness scores were observed (
      • Chapinal N.
      • de Passillé A.M.
      • Rushen J.
      • Wagner S.A.
      Effect of analgesia during hoof trimming on gait, weight distribution, and activity of dairy cattle..
      ). This study did include nonlame cows in each treatment group and inclusion of these sound cows may have diluted treatment effects. A follow-up by the same research group revealed flunixin-treated cows had decreased weight shifting compared with saline controls. The group then followed only lame cows following a hoof trim and found that flunixin-treated cows had decreased amounts of weight shifting of the rear legs (
      • Wagner S.A.
      • Young J.M.
      • Tena J.K.
      • Manning B.H.
      Short Communication: Behavioral evaluation of the analgesic effect of flunixin meglumine in lame dairy cows..
      ). The authors attribute this change to pain alleviation of lame cows by flunixin.
      Meloxicam has been shown to improve lameness when given at 0.5 or 1.0 mg/kg orally (
      • Offinger J.
      • Herdtweck S.
      • Rizk A.
      • Starke A.
      • Heppelmann M.
      • Meyer H.
      • Janssen S.
      • Beyerbach M.
      • Rehage J.
      Postoperative analgesic efficacy of meloxicam in lame dairy cows undergoing resection of the distal interphalangeal joint..
      ;
      • Nagel D.
      • Wieringa R.
      • Ireland J.
      • Olson M.E.
      The use of meloxicam oral suspension to treat musculoskeletal lameness in cattle..
      ).
      • Coetzee J.F.
      • Mosher R.A.
      • Anderson D.E.
      • Robert B.
      • Kohake L.E.
      • Gehring R.
      • White B.J.
      • Kukanich B.
      • Wang C.
      Impact of oral meloxicam administered alone or in combination with gabapentin on experimentally induced lameness in beef calves..
      found meloxicam reduced lameness in cattle with experimentally induced lameness based on meloxicam-treated cattle having increased step counts in lame limbs. In that same study, plasma meloxicam concentrations were inversely associated with lameness scores and positively associated with contact pressure on gait analysis. Additionally, meloxicam has been shown to work synergistically with gabapentin (
      • Coetzee J.F.
      • Mosher R.A.
      • Anderson D.E.
      • Robert B.
      • Kohake L.E.
      • Gehring R.
      • White B.J.
      • Kukanich B.
      • Wang C.
      Impact of oral meloxicam administered alone or in combination with gabapentin on experimentally induced lameness in beef calves..
      ). Cattle treated with oral meloxicam and gabapentin had increased stride lengths and applied more force on pressure mat gait analysis compared with placebo-treated controls (
      • Coetzee J.F.
      • Mosher R.A.
      • Anderson D.E.
      • Robert B.
      • Kohake L.E.
      • Gehring R.
      • White B.J.
      • Kukanich B.
      • Wang C.
      Impact of oral meloxicam administered alone or in combination with gabapentin on experimentally induced lameness in beef calves..
      ).
      • Glynn H.D.
      • Coetzee J.F.
      • Edwards-Callaway L.N.
      • Dockweiler J.C.
      • Allen K.A.
      • Lubbers B.
      • Jones M.
      • Fraccaro E.
      • Bergamasco L.L.
      • KuKanich B.
      The pharmacokinetics and effects of meloxicam, gabapentin, and flunixin in postweaning dairy calves following dehorning with local anesthesia..
      found that co-administration of meloxicam and gabapentin do not alter either drug’s pharmacokinetics.
      Ketoprofen has been evaluated for its analgesic benefits in cattle with lameness (
      • Whay H.R.
      • Webster A.J.F.
      • Waterman-Pearson A.E.
      Role of ketoprofen in the modulation of hyperalgesia associated with lameness in dairy cattle..
      ;
      • Flower F.C.
      • Sedlbauer M.
      • Carter E.
      • von Keyserlingk M.A.G.
      • Sanderson D.J.
      • Weary D.M.
      Analgesics improve the gait of lame dairy cattle..
      ;
      • Chapinal N.
      • de Passillé A.M.
      • Rushen J.
      • Wagner S.A.
      Effect of analgesia during hoof trimming on gait, weight distribution, and activity of dairy cattle..
      ). Cattle receiving ketoprofen at 3 mg/kg had improved gait symmetry and weight distribution (
      • Flower F.C.
      • Sedlbauer M.
      • Carter E.
      • von Keyserlingk M.A.G.
      • Sanderson D.J.
      • Weary D.M.
      Analgesics improve the gait of lame dairy cattle..
      ).
      • Chapinal N.
      • Fitzpatrick C.E.
      • Leslie K.E.
      • Wagner S.A.
      Short Communication: Automated assessment of the effect of flunixin meglumine on rumination in dairy cows with endotoxin-induced mastitis..
      demonstrated a reduced variation in weight distribution in cattle administered ketoprofen. Furthermore, when included as part of a trim and block treatment regimen, ketoprofen cows had a greater proportion of nonlame cows 35 d later (
      • Thomas H.J.
      • Miguel-Pacheco G.G.
      • Bollard N.J.
      • Archer S.C.
      • Bell N.J.
      • Mason C.
      • Maxwell O.J.R.
      • Remnant J.G.
      • Sleeman P.
      • Whay H.R.
      • Huxley J.N.
      Evaluation of treatments for claw horn lesions in dairy cows in a randomized controlled trial..
      ). Ketoprofen given intramuscularly for 3 consecutive days prevented the development of hyperalgesia (
      • Whay H.R.
      • Webster A.J.F.
      • Waterman-Pearson A.E.
      Role of ketoprofen in the modulation of hyperalgesia associated with lameness in dairy cattle..
      ).

      APPLICATIONS

      Objective pain assessment in food producing animals remains challenging and is needed to support regulatory approval of analgesic drugs in the United States. In the absence of drugs specifically labeled for pain relief, extra-label drug use will be necessary to address animal welfare concerns related to pain in livestock. This places a regulatory burden on the prescribing veterinarian. Multimodal analgesia, combining an NSAID and local anesthetic, has been the most beneficial for reducing pain associated with on-farm husbandry practices. For cattle undergoing castration, dehorning, or both, meloxicam administered orally (1 mg/kg of BW) or subcutaneously (0.5 mg/kg of BW), in combination with local anesthesia, is currently the preferred analgesic approach based on available scientific evidence. Similar multimodal analgesic approaches have been described in pigs. However, optimizing the timing of drug administration relative to the procedure remains difficult. Transmammary delivery of firocoxib may be a viable option for piglet analgesia at the time of processing. Flunixin, ketoprofen, and meloxicam have been shown to provide temporary pain relief associated with lameness but the addition of gabapentin may be necessary to address chronic pain. Future research needed to better understand the duration of pain, multi-day pain mitigation strategies, and dosing regimens that are economical and practical.

      ACKNOWLEDGMENTS

      The authors were supported by the Agriculture and Food Research Initiative Competitive Grants no. 2017-67015-27124, 2020-67030-31479, 2020-67015-31540, and 2020-67015-31546 from the USDA National Institute of Food and Agriculture.

      LITERATURE CITED

        • Adams A.E.
        • Lombard J.E.
        • Fossler C.P.
        • Roman-Muniz I.N.
        • Kopral C.A.
        Associations between housing and management practices and the prevalence of lameness, hock lesions, and thin cows on US dairy operations..
        J. Dairy Sci. 2017; 100: 2119-2136
        • Adcock S.J.
        • Cruz D.M.
        • Tucker C.B.
        Behavioral changes in calves 11 days after cautery disbudding: Effect of local anesthesia..
        J. Dairy Sci. 2020; 103: 8518-8525
        • Adcock S.J.
        • Tucker C.B.
        The effect of disbudding age on healing pain and sensitivity in diary calves..
        J. Dairy Sci. 2018; 101: 10361-10373
        • Allen K.A.
        • Coetzee J.F.
        • Edwards-Callaway L.N.
        • Glynn H.
        • Dockweiler J.
        • KuKanich B.
        • Lin H.
        • Wang C.
        • Fraccaro E.
        • Jones M.
        • Bergamasco L.
        The effect of timing of oral meloxicam administration on physiological responses in calves after cautery dehorning with local anesthesia..
        J. Dairy Sci. 2013; 96: 5194-5205
      1. American Veterinary Medical Association. 2010. Welfare policies revised and adopted. Accessed Sep. 15, 2020. https://www.avma.org/javma-news/2010-06-01/welfare-policies-revised-and-adopted.

        • Anderson D.E.
        • Muir W.M.
        Pain management in cattle..
        Vet. Clin. North Am. Food Anim. Pract. 2005; 21: 623-635
        • Bates J.L.
        • Karriker L.A.
        • Stock M.L.
        • Pertzborn K.M.
        • Baldwin L.G.
        • Wulf L.W.
        • Lee C.J.
        • Wang C.
        • Coetzee J.F.
        Impact of transmammary-delivered meloxicam on biomarkers of pain and distress in piglets after castration and tail docking..
        PLoS One. 2014; 9
        • Bonastre C.
        • Mitjana O.
        • Tejedor M.T.
        • Calavia M.
        • Yuste A.G.
        • Úbeda J.L.
        • Falceto M.V.
        Acute physiological responses to castration-related pain in piglets: The effect of two local anesthetics with or without meloxicam..
        Animal. 2016; 10: 1474-1481
        • Cassar G.
        • Amezcua R.
        • Tenbergen R.
        • Friendship R.M.
        Preoperative ketoprofen administration to piglets undergoing castration does not affect subsequent growth performance..
        Can. Vet. J. 2014; 55: 1250-1252
        • Cha E.
        • Hertl J.A.
        • Bar D.
        • Grohn Y.T.
        The cost of different types of lameness in dairy cows calculated by dynamic programming..
        Prev. Vet. Med. 2010; 97: 1-8
        • Chapinal N.
        • de Passillé A.M.
        • Rushen J.
        • Wagner S.A.
        Effect of analgesia during hoof trimming on gait, weight distribution, and activity of dairy cattle..
        J. Dairy Sci. 2010; 93: 3039-3046
        • Chapinal N.
        • Fitzpatrick C.E.
        • Leslie K.E.
        • Wagner S.A.
        Short Communication: Automated assessment of the effect of flunixin meglumine on rumination in dairy cows with endotoxin-induced mastitis..
        Can. J. Anim. Sci. 2014; 94: 21-25
        • Coetzee J.F.
        A review of pain assessment techniques and pharmacological approaches to pain relief after bovine castration: Practical implications for cattle production within the United States..
        Appl. Anim. Behav. Sci. 2011; 135: 192-213
        • Coetzee J.F.
        Assessment and management of pain associated with castration in cattle..
        Vet. Clin. North Am. Food Anim. Pract. 2013; 29: 75-101
        • Coetzee J.F.
        • Mosher R.A.
        • Anderson D.E.
        • Robert B.
        • Kohake L.E.
        • Gehring R.
        • White B.J.
        • Kukanich B.
        • Wang C.
        Impact of oral meloxicam administered alone or in combination with gabapentin on experimentally induced lameness in beef calves..
        J. Anim. Sci. 2014; 92: 816-829
        • Coetzee J.F.
        • Shearer J.K.
        • Stock M.L.
        • Kleinhenz M.D.
        • van Amstel S.R.
        An update on the assessment and management of pain associated with lameness in cattle..
        Vet. Clin. North Am. Food Anim. Pract. 2017; 33: 389-411
        • Coetzee J.F.
        • Sidhu P.K.
        • Seagen J.
        • Schieber T.
        • Kleinhenz K.
        • Kleinhenz M.D.
        • Wulf L.W.
        • Cooper V.L.
        • Mazloom R.
        • Jaberi-Douraki M.
        • Lechtenberg K.
        Transmammary delivery of firocoxib to piglets reduces stress and improves average daily gain after castration, tail docking, and teeth clipping..
        J. Anim. Sci. 2019; 97: 2750-2768
        • Currah J.M.
        • Hendrick S.H.
        • Stookey J.M.
        The behavioral assessment and alleviation of pain associated with castration in beef calves treated with flunixin meglumine and caudal lidocaine epidural anesthesia with epinephrine..
        Can. Vet. J. 2009; 50: 375-382
        • Duffield T.F.
        • Heinrich A.
        • Millman S.T.
        • DeHaan A.
        • James S.
        • Lissemore K.
        Reduction in pain response by combined use of local lidocaine anesthesia and systemic ketoprofen in dairy calves dehorned by heat cauterization..
        Can. Vet. J. 2010; 51: 283-288
        • Earley B.
        • Crowe M.A.
        Effects of ketoprofen alone or in combination with local anesthesia during the castration of bull calves on plasma cortisol, immunological, and inflammatory responses..
        J. Anim. Sci. 2002; 80: 1044-1052
        • Ede T.
        • von Keyserlingk M.A.G.
        • Weary D.M.
        Assessing the affective component of pain, and the efficacy of pain control, using conditioned place aversion in calves..
        Biol. Lett. 2019; 15
        • Espinoza C.A.
        • McCarthy D.
        • White P.J.
        • Windsor P.A.
        • Lomax S.H.
        Evaluating the efficacy of a topical anaesthetic formulation and ketoprofen, alone and in combination, on the pain sensitivity of dehorning wounds in Holstein-Friesian calves..
        Anim. Prod. Sci. 2015; 56: 1512-1519
      2. European Commission. 2010. European declaration on alternatives to surgical castration of pigs. Accessed Sep. 15, 2020. https://ec.europa.eu/food/sites/food/files/animals/docs/aw_prac_farm_pigs_cast-alt_declaration_en.pdf.

        • Fitzpatrick C.E.
        • Chapinal N.
        • Petersson-Wolfe C.S.
        • DeVries T.J.
        • Kelton D.F.
        • Duffield T.F.
        • Leslie K.E.
        The effect of meloxicam on pain sensitivity, rumination time, and clinical signs in dairy cows with endotoxin-induced clinical mastitis..
        J. Dairy Sci. 2013; 96: 2847-2856
        • Flower F.C.
        • Sedlbauer M.
        • Carter E.
        • von Keyserlingk M.A.G.
        • Sanderson D.J.
        • Weary D.M.
        Analgesics improve the gait of lame dairy cattle..
        J. Dairy Sci. 2008; 91: 3010-3014
        • Fu L.
        • Zhou B.
        • Li H.
        • Liang T.
        • Chu Q.
        • Schinckel A.P.
        • Li Y.
        • Xu F.
        Effects of tail docking and/or teeth clipping on behavior, lesions, and physiological indicators of sows and their piglets..
        Anim. Sci. J. 2019; 90: 1320-1332
        • Glynn H.D.
        • Coetzee J.F.
        • Edwards-Callaway L.N.
        • Dockweiler J.C.
        • Allen K.A.
        • Lubbers B.
        • Jones M.
        • Fraccaro E.
        • Bergamasco L.L.
        • KuKanich B.
        The pharmacokinetics and effects of meloxicam, gabapentin, and flunixin in postweaning dairy calves following dehorning with local anesthesia..
        J. Vet. Pharmacol. Ther. 2013; 36: 550-561
        • Gorden P.J.
        • Kleinhenz M.D.
        • Wulf L.W.
        • Rajewski S.J.
        • Wang C.
        • Gehring R.
        • Coetzee J.F.
        Comparative plasma and interstitial fluid pharmacokinetics of flunixin meglumine and ceftiofur hydrochloride following individual and co-administration in dairy cows..
        J. Vet. Pharmacol. Ther. 2018; 41: 76-82
        • Gottardo F.
        • Scollo A.
        • Contiero B.
        • Ravagnani A.
        • Tavella G.
        • Bernardini D.
        • De Benedictis G.M.
        • Edwards S.A.
        Pain alleviation during castration of piglets: A comparative study of different farm options..
        J. Anim. Sci. 2016; 94: 5077-5088
        • Hansson M.
        • Lundeheim N.
        • Nyman G.
        • Johansson G.
        Effect of local anaesthesia and/or analgesia on pain responses induced by piglet castration..
        Acta Vet. Scand. 2011; 53: 34
        • Hay M.
        • Vulin A.
        • Genin S.
        • Sales P.
        • Prunier A.
        Assessment of pain induced by castration in piglets: Behavior and physiological responses over the subsequent 5 days..
        Appl. Anim. Behav. Sci. 2003; 82 (10.1016/S0168–1591(03)00059–5): 201-218
        • Heinrich A.
        • Duffield T.F.
        • Lissemore K.D.
        • Millman S.T.
        The effect of meloxicam on behavior and pain sensitivity of dairy calves following cautery dehorning with a local anesthetic..
        J. Dairy Sci. 2010; 93: 2450-2457
        • Herskin M.S.
        • Di Giminiani P.
        • Thodberg K.
        Effects of administration of a local anaesthetic and/or an NSAID and of docking length on the behaviour of piglets during 5 h after tail docking..
        Res. Vet. Sci. 2016; 108: 60-67
        • Hirsbrunner G.
        • Rigert A.
        • Janett F.
        • Hüsler J.
        • Schnydrig P.
        • Lopez E.
        • Amatayakul-Chantler S.A.
        • Steiner A.
        Immunization against GnRF in adult cattle: A prospective field study..
        BMC Vet. Res. 2017; 13: 208
        • Holyoake P.K.
        • Broek D.J.
        • Callinan A.P.L.
        The effects of reducing the length of canine teeth in suckling pigs by clipping or grinding..
        Aust. Vet. J. 2004; 82: 574-576
        • Keita A.
        • Pagot E.
        • Prunier A.
        • Guidarini C.
        Pre-emptive meloxicam for postoperative analgesia in piglets undergoing surgical castration..
        Vet. Anaesth. Analg. 2010; 37: 367-374
        • Kittrell H.C.
        • Mochel J.P.
        • Brown J.T.
        • Forseth A.M.K.
        • Hayman K.P.
        • Rajewski S.M.
        • Coetzee J.F.
        • Schneider B.K.
        • Ratliffe B.
        • Skoland K.J.
        • Karriker L.A.
        Pharmacokinetics of intravenous, intramuscular, oral, and transdermal administration of flunixin meglumine in pre-wean piglets..
        Front. Vet. Sci. 2020; 7: 586
        • Kleinhenz M.D.
        • Gorden P.J.
        • Burchard M.
        • Ydstie J.A.
        • Coetzee J.F.
        Rapid Communication: Use of pressure mat gait analysis in measuring pain following normal parturition in dairy cows..
        J. Anim. Sci. 2019; 97 (a): 846-850
        • Kleinhenz M.D.
        • Gorden P.J.
        • Smith J.S.
        • Schleining J.A.
        • Kleinhenz K.E.
        • Juarez J.R.
        • Rea D.
        • Coetzee J.F.
        Effects of transdermal flunixin meglumine on experimentally induced lameness in adult dairy cattle..
        J. Dairy Sci. 2019; 102 (b): 6418-6430
        • Kleinhenz M.D.
        • Van Engen N.K.
        • Gorden P.J.
        • Ji J.
        • Walsh P.
        • Coetzee J.F.
        Effects of transdermal flunixin meglumine on pain biomarkers at dehorning in calves..
        J. Anim. Sci. 2017; 95: 1993-2000
        • Kleinhenz M.D.
        • Van Engen N.K.
        • Smith J.S.
        • Gorden P.J.
        • Ji J.
        • Wang C.
        • Perkins S.C.B.
        • Coetzee J.F.
        The impact of transdermal flunixin meglumine on biomarkers of pain in calves when administered at the time of surgical castration without local anesthesia..
        Livest. Sci. 2018; 212: 1-6
        • Kluivers-Poodt M.
        • Houx B.B.
        • Robben S.R.
        • Koop G.
        • Lambooij E.
        • Hellebrekers L.J.
        Effects of a local anaesthetic and NSAID in castration of piglets, on the acute pain responses, growth and mortality..
        Animal. 2012; 6: 1469-1475
        • Kluivers-Poodt M.
        • Zonderland J.J.
        • Verbraak J.
        • Lambooij E.
        • Hellebrekers L.J.
        Pain behaviour after castration of piglets; effect of pain relief with lidocaine and/or meloxicam..
        Animal. 2013; 7: 1158-1162
        • Lay Jr., D.C.
        • Friend T.H.
        • Bowers C.L.
        • Grissom K.K.
        • Jenkins O.C.
        A comparative physiological and behavioral study of freeze and hot-iron branding using dairy cows..
        J. Anim. Sci. 1992; 70: 1121-1125
        • Leidig M.S.
        • Hertrampf B.
        • Failing K.
        • Schumann A.
        • Reiner G.
        Pain and discomfort in male piglets during surgical castration with and without local anaesthesia as determined by vocalization and defence behaviour..
        Appl. Anim. Behav. Sci. 2009; 116: 174-178
        • Lomax S.
        • Harris C.
        • Windsor P.A.
        • White P.J.
        Topical anaesthesia reduces sensitivity of castration wounds in neonatal piglets..
        PLoS One. 2017; 12
        • Marx G.
        • Horn T.
        • Thielebein J.
        • Knubel B.
        • von Borell E.
        Analysis of pain-related vocalizations in young pigs..
        J. Sound Vibrat. 2003; 266: 687-698
        • McMeekan C.M.
        • Stafford K.J.
        • Mellor D.J.
        • Bruce R.A.
        • Ward R.N.
        • Gregory N.G.
        Effects of regional analgesia and/or a non-steroidal anti-inflammatory analgesic on the acute cortisol response to dehorning in calves..
        Res. Vet. Sci. 1998; 64: 147-150
        • Melendez D.M.
        • Marti S.
        • Pajor E.A.
        • Moya D.
        • Gellatly D.
        • Janzen E.D.
        • Schwartzkopf-Genswein K.S.
        Effect of subcutaneous meloxicam on indicators of acute pain and distress after castration and branding in 2-mo-old beef calves..
        J. Anim. Sci. 2018; 96 (a): 3606-3621
        • Melendez D.M.
        • Marti S.
        • Pajor E.A.
        • Sidhu P.K.
        • Gellatly D.
        • Moya D.
        • Janzen E.D.
        • Coetzee J.F.
        • Schwartzkopf-Genswein K.S.
        Effect of meloxicam and lidocaine administered alone or in combination on indicators of pain and distress during and after knife castration in weaned beef calves..
        PLoS One. 2018; 13 (b)
        • Milligan B.N.
        • Duffield T.
        • Lissemore K.
        The utility of ketoprofen for alleviating pain following dehorning in young dairy calves..
        Can. Vet. J. 2004; 45: 140-143
        • Moggy M.A.
        • Pajor E.A.
        • Thurston W.E.
        • Parker S.
        • Greter A.M.
        • Schwartzkopf-Genswein K.S.
        • Campbell J.R.
        • Windeyer M.C.
        Management practices associated with stress in cattle on western Canadian cow-calf operations: A mixed methods study..
        J. Anim. Sci. 2017; 95: 1836-1844
        • Nagel D.
        • Wieringa R.
        • Ireland J.
        • Olson M.E.
        The use of meloxicam oral suspension to treat musculoskeletal lameness in cattle..
        Vet. Med. (Auckl.). 2016; 7: 149-155
      3. National Dairy FARM Program. 2020. Animal Care Reference Manual. Accessed Sep. 26, 2020. https://nationaldairyfarm.com/wp-content/uploads/2020/02/Animal-Care-V4-Manual-Print-Friendly.pdf.

      4. National Farm Animal Care Council. 2014. Code of practice for the care and handling of pigs. Accessed Sep. 20, 2020. https://www.nfacc.ca/pdfs/codes/pig_code_of_practice.pdf

        • Nordi W.M.
        • Marti S.
        • Gellatly D.
        • Meléndez D.M.
        • González L.A.
        • McAllister T.A.
        • Fierheller E.E.
        • Caulkett N.A.
        • Janzen E.
        • Schwartzkopf-Genswein K.S.
        Effect of preemptive flunixin meglumine and lidocaine on behavioral and physiological indicators of pain post-band and knife castration in 6-mo-old beef calves..
        Livest. Sci. 2019; 230
        • O’Connor A.
        • Anthony R.
        • Bergamasco L.
        • Coetzee J.
        • Gould S.
        • Johnson A.K.
        • Karriker L.A.
        • Marchant-Forde J.N.
        • Martineau G.S.
        • McKean J.
        • Millman S.T.
        • Niekamp S.
        • Pajor E.A.
        • Rutherford K.
        • Sprague M.
        • Sutherland M.
        • von Borell E.
        • Dzikamunhenga R.S.
        Pain management in the neonatal piglet during routine management procedures. Part 2: Grading the quality of evidence and the strength of recommendations..
        Anim. Health Res. Rev. 2014; 15: 39-62
        • Offinger J.
        • Herdtweck S.
        • Rizk A.
        • Starke A.
        • Heppelmann M.
        • Meyer H.
        • Janssen S.
        • Beyerbach M.
        • Rehage J.
        Postoperative analgesic efficacy of meloxicam in lame dairy cows undergoing resection of the distal interphalangeal joint..
        J. Dairy Sci. 2013; 96: 866-876
        • Pyorala S.
        • Laurila T.
        • Lehtonen S.
        • Leppa S.
        • Kaartinen L.
        Local tissue damage in cows after intramuscular administration of preparations containing phenylbutazone, flunixin, ketoprofen and metamizole..
        Acta Vet. Scand. 1999; 40: 145-150
        • Reynolds K.
        • Johnson R.
        • Brown J.
        • Friendship R.
        • O’Sullivan T.L.
        Assessing pain control efficacy of meloxicam and ketoprofen when compounded with iron dextran in nursing piglets using a navigation chute..
        Animals (Basel). 2020; 10: 1237
        • Schulz K.L.
        • Anderson D.E.
        • Coetzee J.F.
        • White B.J.
        • Miesner M.D.
        Effect of flunixin meglumine on the amelioration of lameness in dairy steers with amphotericin B-induced transient synovitis-arthritis..
        Am. J. Vet. Res. 2011; 72: 1431-1438
        • Schwartzkopf-Genswein K.
        • Stookey J.
        • Passillé A.D.
        • Rushen J.
        Comparison of hot-iron and freeze branding on cortisol levels and pain sensitivity in beef cattle..
        Can. J. Anim. Sci. 1997; 77: 369-374
        • Sheil M.L.
        • Chambers M.
        • Sharpe B.
        Topical wound anaesthesia: Efficacy to mitigate piglet castration pain..
        Aust. Vet. J. 2020; 98: 256-263
        • Spurlock D.M.
        • Stock M.L.
        • Coetzee J.F.
        The impact of 3 strategies for incorporating polled genetics into a dairy cattle breeding program on the overall herd genetic merit..
        J. Dairy Sci. 2014; 97: 5265-5274
        • Stock M.L.
        • Barth L.A.
        • Van Engen N.K.
        • Millman S.T.
        • Gehring R.
        • Wang C.
        • Voris E.A.
        • Wulf L.W.
        • Labeur L.
        • Hsu W.H.
        • Coetzee J.F.
        Impact of carprofen administration on stress and nociception responses of calves to cautery dehorning..
        J. Anim. Sci. 2016; 94: 542-555
        • Stock M.L.
        • Millman S.T.
        • Barth L.A.
        • Van Engen N.K.
        • Hsu W.H.
        • Wang C.
        • Gehring R.
        • Parsons R.L.
        • Coetzee J.F.
        The effects of firocoxib on cautery disbudding pain and stress responses in preweaned dairy calves..
        J. Dairy Sci. 2015; 98: 6058-6069
        • Sutherland M.A.
        Welfare implications of invasive piglet husbandry procedures, methods of alleviation and alternatives: A review..
        N. Z. Vet. J. 2015; 63: 52-57
        • Sutherland M.A.
        • Bryer P.J.
        • Krebs N.
        • McGlone J.J.
        Tail docking in pigs: Acute physiological and behavioural responses..
        Animal. 2008; 2: 292-297
        • Sutherland M.A.
        • Davis B.L.
        • Brooks T.A.
        • Coetzee J.F.
        The physiological and behavioral response of pigs castrated with and without anesthesia or analgesia..
        J. Anim. Sci. 2012; 90: 2211-2221
        • Sutherland M.A.
        • Davis B.L.
        • Brooks T.A.
        • McGlone J.J.
        Physiology and behavior of pigs before and after castration: Effects of two topical anesthetics..
        Animal. 2010; 4: 2071-2079
        • Sutherland M.A.
        • Mellor D.J.
        • Stafford K.J.
        • Gregory N.G.
        • Bruce R.A.
        • Ward R.N.
        Cortisol responses to dehorning of calves given a 5-h local anaesthetic regimen plus phenylbutazone, ketoprofen, or adrenocorticotropic hormone prior to dehorning..
        Res. Vet. Sci. 2002; 73: 115-123
        • Thomas H.J.
        • Miguel-Pacheco G.G.
        • Bollard N.J.
        • Archer S.C.
        • Bell N.J.
        • Mason C.
        • Maxwell O.J.R.
        • Remnant J.G.
        • Sleeman P.
        • Whay H.R.
        • Huxley J.N.
        Evaluation of treatments for claw horn lesions in dairy cows in a randomized controlled trial..
        J. Dairy Sci. 2015; 98: 4477-4486
        • Ting S.T.
        • Earley B.
        • Crowe M.A.
        Effect of repeated ketoprofen administration during surgical castration of bulls on cortisol, immunological function, feed intake, growth, and behavior..
        J. Anim. Sci. 2003; 81 (a): 1253-1264
        • Ting S.T.
        • Earley B.
        • Hughes J.M.
        • Crowe M.A.
        Effect of ketoprofen, lidocaine local anesthesia, and combined xylazine and lidocaine caudal epidural anesthesia during castration of beef cattle on stress responses, immunity, growth, and behavior..
        J. Anim. Sci. 2003; 81 (b): 1281-1293
        • Tucker C.B.
        • Mintline E.M.
        • Banuelos J.
        • Walker K.A.
        • Hoar B.
        • Drake D.
        • Weary D.M.
        Effect of a cooling gel on pain sensitivity and healing of hot-iron cattle brands..
        J. Anim. Sci. 2014; 92 (a): 5666-5673
        • Tucker C.B.
        • Mintline E.M.
        • Banuelos J.
        • Walker K.A.
        • Hoar B.
        • Varga A.
        • Drake D.
        • Weary D.M.
        Pain sensitivity and healing of hot-iron cattle brands..
        J. Anim. Sci. 2014; 92 (b): 5674-5682
      5. US FDA (United States Food and Drug Administration). 1994. Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA). Accessed Sep. 6, 2020. http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/AnimalMedicinalDrugUseClarificationActAMDUCAof1994/default.htm.

      6. US FDA (United States Food and Drug Administration). 2006. Guidance for Industry #123 Development of data supporting approval of NSAIDs for use in animals. Accessed Aug. 23, 2020. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cvm-gfi-123-development-data-supporting-approval-nsaids-use-animals.

      7. US FDA (United States Food and Drug Administration). 2011. Freedom of information summary original new animal drug application Improvest. Accessed Aug. 30, 2020. https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/880.

      8. US FDA (United States Food and Drug Administration). 2017. Freedom of information summary original new animal drug application Banamine Transdermal. Accessed Nov. 30, 2020. https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/1944.

      9. USDA, Animal and Plant Health Inspection Service. 2008. Beef 2007–08, Part I: Reference of Beef Cow-calf Management Practices in the United States, 2007–08 USDA-APHIS-VS, CEAH, Fort Collins, CO #N512–10080. Accessed Sep. 10, 2020. https://www.aphis.usda.gov/animal_health/nahms/beefcowcalf/downloads/beef0708/Beef0708_dr_PartI_rev_1.pdf.

        • Viscardi A.V.
        • Cull C.A.
        • Kleinhenz M.D.
        • Montgomery S.
        • Curtis A.
        • Lechtenberg K.
        • Coetzee J.F.
        Evaluating the utility of a CO2 surgical laser for piglet castration to reduce pain and improve wound healing: A pilot study..
        J. Anim. Sci. 2020; 98: 1-11
        • Viscardi A.V.
        • Hunniford M.
        • Lawlis P.
        • Leach M.
        • Turner P.V.
        Development of a Piglet Grimace Scale to evaluate piglet pain using facial expressions following castration and tail docking: A pilot study..
        Front. Vet. Sci. 2017; 4: 51
        • Viscardi A.V.
        • Turner P.V.
        Use of meloxicam or ketoprofen for piglet pain control following surgical castration..
        Front. Vet. Sci. 2018; 5 (a): 299
        • Viscardi A.V.
        • Turner P.V.
        Efficacy of buprenorphine for management of surgical castration pain in piglets..
        BMC Vet. Res. 2018; 14 (b): 318
        • Viscardi A.V.
        • Turner P.V.
        Use of meloxicam, buprenorphine, and Maxilene® to assess a multimodal approach for piglet pain management, part 2: Tail-docking..
        Anim. Welf. 2019; 28 (a): 499-510
        • Viscardi A.V.
        • Turner P.V.
        Use of meloxicam, buprenorphine, and Maxilene® to assess a multimodal approach for piglet pain management, Part 1: Surgical castration..
        Anim. Welf. 2019; 28 (b): 487-498
        • von Keyserlingk M.A.
        • Barrientos A.
        • Ito K.
        • Galo E.
        • Weary D.M.
        Benchmarking cow comfort on North American freestall dairies: Lameness, leg injuries, lying time, facility design, and management for high-producing Holstein dairy cows..
        J. Dairy Sci. 2012; 95: 7399-7408
        • Wagner S.A.
        • Young J.M.
        • Tena J.K.
        • Manning B.H.
        Short Communication: Behavioral evaluation of the analgesic effect of flunixin meglumine in lame dairy cows..
        J. Dairy Sci. 2017; 100: 6562-6566
        • Webster H.B.
        • Morin D.
        • Jarrell V.
        • Shipley C.
        • Brown L.
        • Green A.
        • Wallace R.
        • Constable P.D.
        Effects of local anesthesia and flunixin meglumine on the acute cortisol response, behavior, and performance of young dairy calves undergoing surgical castration..
        J. Dairy Sci. 2013; 96: 6285-6300
        • Wells S.J.
        • Trent A.M.
        • Marsh W.E.
        • Robinson R.A.
        Prevalence and severity of lameness in lactating dairy cows in a sample of Minnesota and Wisconsin herds..
        J. Am. Vet. Med. Assoc. 1993; 202: 78-82
        • Whay H.R.
        • Main D.C.J.
        • Green L.E.
        • Webster A.J.F.
        Assessment of the welfare of dairy cattle using animal-based measurements: Direct observations and investigation of farm records..
        Vet. Rec. 2003; 153: 197-202
        • Whay H.R.
        • Webster A.J.F.
        • Waterman-Pearson A.E.
        Role of ketoprofen in the modulation of hyperalgesia associated with lameness in dairy cattle..
        Vet. Rec. 2005; 157: 729-733
        • Winder C.B.
        • Miltenburg C.L.
        • Sargeant J.M.
        • LeBlanc S.J.
        • Haley D.B.
        • Lissemore K.D.
        • Godkin M.A.
        • Duffield T.F.
        Effects of local anesthetic or systemic analgesia on pain associated with cautery disbudding in calves: A systematic review and meta-analysis..
        J. Dairy Sci. 2018; 101: 5411-5427
        • Yun J.
        • Ollila A.
        • Valros A.
        • Larenza-Menzies P.
        • Heinonen M.
        • Oliviero C.
        • Peltoniemi O.
        Behavioural alterations in piglets after surgical castration: Effects of analgesia and anaesthesia..
        Res. Vet. Sci. 2019; 125: 36-42