Pain pathophysiology and pharmacology of cattle: how improved understanding can enhance pain prevention, mitigation, and welfare

Abstract

Globally, humans rely on cattle for food production; however, there is rising societal concern surrounding the welfare of farm animals. From a young age, cattle raised for dairy and beef production experience pain caused by routine management procedures and common disease conditions. The fundamental mechanisms, nociceptive pathways, and central nervous system structures required for pain perception are highly conserved among mammalian species. However, there are limitations to a comparative approach to pain assessment due to interspecies differences in the expression of pain. The stoicism of prey species may impede pain identification and lead to the assumption that cattle lack pain sensitivity. This highlights the importance of establishing validated bovine-specific indicators of pain-a prerequisite for evidence-based pain assessment and mitigation. Our first objective is to provide an overview of pain pathophysiology to illustrate the importance of targeted analgesia in livestock medicine and the negative welfare outcomes associated with unmitigated pain. This is followed by a review of available analgesics, the regulations governing their use, and barriers to implementation of on-farm pain management. We then investigate the current research undertaken to evaluate the pain response in cattle-a critical aspect of the drug approval process. With an emphasis on emerging research in animal cognition and pain pathology, we conclude by discussing the significant influence that pain has on cattle welfare and areas where further research and modified practices are indicated.

Keywords: analgesia; animal welfare; cattle; cow; pain; pain management.

Figure 1

The four processes of nociception targeted by analgesia and the specific drugs available for on-farm use in cattle. Transduction (1) occurs when a noxious stimulus is converted into an action potential. This action potential then travels from the periphery to the central nervous system in the process of transmission (2). Modulation (3) results in enhancement or suppression of the nociceptive signal. Pain is experienced when the signal is perceived (4) in the higher centers of the brain. The nociceptive signal can also result in an immediate reflex response. Analgesics can target each of these processes: the NSAIDs flunixin meglumine, meloxicam, carprofen, and firocoxib inhibit transduction; the local anesthetic lidocaine inhibits transduction and transmission; the α₂ agonist xylazine inhibits transmission and, when combined with the NMDA receptor antagonist ketamine and the opioid butorphanol, affects modulation and perception to inhibit pain. Flunixin meglumine transdermal is the only FDA-approved drug for pain control in cattle, and it is labelled only for foot rot; all other NSAIDs must be used in an extra-label manner. Opioids cannot be dispensed on-farm. Figure adapted from (21). Created with BioRender.com.

Figure 2

The normal somatosensory pathway for pain and touch versus heightened and abnormal activation of the pain pathway associated with central sensitization resulting in hyperalgesia and allodynia. In an animal experiencing normal sensation, noxious stimuli activate nociceptors, leading to pain. Innocuous stimuli are detected by low-threshold mechanoreceptors, which do not communicate with the pain pathway and result in touch sensation. The pathways do not communicate. Hyperalgesia describes a heightened response to nociceptive input, whereas allodynia occurs when an innocuous stimulus results in pain due to low-threshold mechanoreceptor activation of pain pathways. Figure adapted from (40). Created with BioRender.com.

Figure 3

The hypothalamic-pituitary-adrenal axis and autonomic nervous system respond to noxious stimuli resulting in physiologic changes. A noxious stimulus activates the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic division of the autonomic nervous system (ANS). After processing the nociceptive signal (1), the hypothalamus releases corticotropin-releasing hormone (CRH) to the anterior pituitary (2), which then releases adrenocorticotropic hormone (ACTH) to the adrenal gland (3). Once stimulated, the adrenal cortex releases cortisol into the bloodstream (4), resulting in physiologic changes associated with the stress response. Nociception also stimulates sympathetic nerve fibers innervating the adrenal gland (A) causing catecholamine release from the adrenal medulla (B) Catecholamines, such as epinephrine and norepinephrine, are responsible for the “fight or flight” response. Figure adapted from (138). Created with BioRender.com.