Abstract

Pain is a very personal experience. This reality and the fact that we cannot communicate with animals about their pain experience has led to controversy about whether animals do or do not perceive pain. My assumption is that animals do experience pain but that many confounding factors make it difficult for us to assess pain in animals. Given these realities I am optimistic that new methods for assessing pain in animals (such as fecal steroids or species-specific pain scales) will help us identify the animal in pain. Furthermore, as we gain a better understanding of the biochemical and cellular mechanisms involved in pain, so too will we gain a better perspective on how to treat pain.

“Dying is nothing, but pain is a very serious matter.” —Henry Jacob Bigelow, 1871

What is pain?

Pain is defined as an unpleasant sensory experience associated with actual or potential tissue damage, or it is described in terms of such damage.¹⁰ It is often further defined in temporal terms—acute vs. chronic. Acute pain, although unpleasant, is usually transient and does not have long-term detrimental effects on an animal. Chronic pain can have long-term effects on the well-being of the animal: food consumption may be significantly reduced, social interaction with conspecifics may be affected and adversely affect the social status of the animal, and hormonal responses to pain may adversely affect healing processes and the body’s immune responses.

What are the mechanisms of pain and the implications for therapy?

The pain an animal experiences when exposed to a noxious stimulus typically has a high threshold, is well localized and transient, and has a stimulus–response relationship similar to that of other somatosensations. This pain has protective value, and it is often referred to as physiologic pain.³³ Clinical pain is associated with peripheral tissue damage such that occurs for example during surgery. This pain has three characteristics: it is spontaneous and human patients describe it as dull, burning or stabbing; it is exaggerated in response to an applied stimulus (hyperalgesia); and it can be produced by stimuli that normally would not produce pain (allodynia).³² Hyperalgesia and hypersensitivity are due to inflammatory mediators and other endogenous substances that are produced at the time of injury or in response to injury. They include hydrogen and potassium ions, bradykinins, prostaglandins, cytokines, norepinephrine, and various tissue growth factors to mention just a few.^2,21,32 These substances cause normally high-threshold primary sensory neurons to become hypersensitized (i.e., their threshold for transmitting noxious stimuli is reduced). In addition to this peripheral response, there is a central response where neurons in the spinal cord have an increase in excitability that is triggered by the nociceptive afferent inputs from the periphery as well as the central action of endogenous substances such as Substance P, NMDA, and nerve growth factor.^1,21,32 This central sensitization can outlast noxious sensory inputs from the periphery.^1,33

The realization that clinical pain is a reflection of peripheral input as well as an expression of changes produced in the CNS has lead researchers to direct their investigations at treating both the disease/injury process in the periphery and the changes induced or triggered in the CNS.³¹ An interesting and promising approach for treating pain that takes into account the fact that both peripheral and central neural sensitization play key roles in pain perception is preemptive analgesia.³³ The underlying theory of preemptive analgesia is to use drugs and techniques that block the hypersensitizing processes before, during and after surgical trauma. Therefore, it is reasoned that if a patient is treated preoperatively with an opioid, a nonsteroidal anti-inflammatory drug (NSAID), and a local anesthetic, then intraoperatively with an analgesic, and finally postoperatively with an opioid and NSAID, then theoretically the patient should be more comfortable in the postoperative period than if treated in a conventional manner. Some studies suggest that preemptive analgesia is effective,³³ but two studies specifically designed to investigate this issue did not demonstrate a benefit of preemptive analgesia in surgical patients.^5,11 This should not be a surprise given the number of endogenous substances that play key roles in sensitizing peripherally and centrally located neurons and receptors. One should not expect that a single drug, or combination of drugs such as opioids, local anesthetics and NSAID could block the effects of all of these various substances. Preemptive analgesia is limited at this time by the fact that the fundamental molecular processes involved in pain signaling are not completely understood. Furthermore, there is some question as to whether general inhalant anesthetics block preemptive analgesia.⁵ A study that investigated the genetic expression of an immediate early gene “c-fos” (a molecule that may produce molecular memory for painful stimuli) within the spinal cord after painful peripheral stimulation, demonstrated that general anesthesia failed to prevent expression of the gene.¹⁶ However, low concentrations of lidocaine have been shown to have a selective action on nociceptive transmission in the spinal cord that is different and more potent than its local anesthetic conduction blockade in the periphery, an indication that this class of sodium channel blockers may be potentially useful as analgesic agents.¹⁷ The concept of preemptive analgesia has merit and there is a great deal of current research into the biochemical mechanisms involved in central neural hypersensitivity.

Do animals perceive pain?

The definition of pain contains elements of communication that have made it difficult to assess pain in animals and has led to controversy as to whether animals do in fact perceive pain as do humans. This controversy has been further complicated by the fact that the way animals respond to pain is not always what we humans expect. Assessing pain in animals is further complicated by large confounding factors such as the differences between acute pain and chronic pain,^2,31 behavioral differences between domestic and wild animals, the response of the individual as compared to the species as a whole, and prey species versus predator species behaviors. An animal’s behavioral response to pain is the outward manifestation of a number of complex physiologic and emotional interactions. Fear or aggression can affect an animal’s perception of pain,¹⁴ or how an animal responds to pain. The fact that certain emotional states can affect an animal’s sensitivity to noxious stimuli may partially explain the difficulty of assessing pain in animals. For example, an animal’s fear response may cause immobilization that could be misinterpreted as evidence that the animal is not experiencing pain. Many veterinarians recognize that there is no advantage for a wild animal—either hunted or hunter—to show signs of “disease,” including pain, for to do so attracts unwanted attention. This has been amply demonstrated in birds,^8,9 and highlights another species-related phenomenon that complicates our ability to assess pain in animals.

All animals do not respond to drugs in a similar manner. Some reasons for this are quite obvious. Analgesic drugs administered orally to a ruminant are not likely to achieve blood concentrations that are pharmacologically effective because of poor absorption from the rumen, rumen pH effects, and the action of rumen microbes. We are also familiar with the so called “morphine mania” associated with doses of morphine and morphine-like drugs in cats that are more appropriate for use in dogs. We recognize now that this response is dose related due to differences in receptor numbers and that appropriate doses of opioids can be used quite effectively in cats both as preanesthetics and as analgesics. It also appears that there are species differences in terms of types of opioid receptors. Pharmacodynamic studies in pigeons have demonstrated that these birds have more kappa opioid receptors than mu opioid receptors.¹⁵ This may explain why birds do not respond to mu agonists like morphine in the same manner as mammals and lends support to the argument that kappa opioids such as butorphanol may be more efficacious as analgesics in birds than mu agonists.

The process of “thinking” about pain is another confounding factor of pain perception in animals.¹⁴ It is certainly true that humans can and do think about pain; but what about animals? If animals don’t “think” about pain does that mean there is no pain?¹⁴ An observer’s interpretation of a behavioral response to pain is often based on the observer’s own responses to pain. The manner in which we respond to pain is how we expect others to respond, including animals. These anthropocentric perspectives of pain are misleading when applied to animals.

These issues are interesting and serve to point out how difficult it is to assess pain in animals, but in my mind, there is no question that animals do perceive pain. Extensive research has clearly shown that animals possess the same neural circuitry, neuroreceptors, and neurotransmitters for the sensory component of pain as do people.⁶ So the task for us is not to discuss whether animals feel pain, but to focus on the dilemma of how we can determine when an animal is in pain, how to treat the pain, and what the future holds in terms of new analgesic drugs and therapeutic techniques.

What can we do to determine that an animal is in pain?

There are a number of approaches being pursued to try to determine when an animal is in pain. There is increasing interest in assaying blood, urine or feces for hormonal indicators of stress due to any number of causative factors including pain.^7,26,28,30 Assaying feces for cortisol, or corticosterone in the case of birds, is appealing because specimen collection can be done without stressing the animal. My own preliminary work in this area suggests that this technique may only be effective if one has sufficient baseline data for an individual animal or group of animals that take into account diurnal, seasonal and reproductive fluctuations.

Another technique that is increasingly being applied to assess pain in animals is the development of pain scales, especially ones that are specifically designed for a given animal species. These pain scales take time and effort to design. Terms must be clearly defined to reduce interobserver variability and to make the scoring process as objective as possible. The people using the scale must have a good understanding of normal and pain-related behavior for a given animal species.

Some Therapeutic Options for Treating Pain

Of real interest to all of us is how to treat pain in the diverse species that are presented to us for care. Realizing that clinical pain involves both peripheral and central mechanisms means that there is no one single silver bullet for treating pain. The best guide for treating pain is that the right drugs should be used at the right time and at the right dose. But what drugs should we use and what techniques? In the last few years we have seen “old” drugs used in “new” ways. Opioids have long been a standard of care for treating pain in a variety of animal species, but their use has not always been practical in zoo settings and certainly not in the wild except for capture purposes. However, the development of fentanyl-impregnated patches that, when applied to the skin, produce sufficient plasma concentrations of fentanyl and analgesia of several days’ duration have been used in a number of animal species for treating surgical and chronic pain. These patches have been used to treat pain in cats,²⁴ dogs,^4,12 and a Southeast Asian pig at the Bronx Zoo.²²

EMLA® cream is a eutectic mixture of lidocaine and prilocaine that, when applied to the skin, provides superficial, local analgesia. Although this product may reduce the pain associated with catheterization, the requirement that it be applied 45 minutes or more prior to a superficially painful procedure limits its usefulness in many animals.

The epidural administration of local anesthetics such as lidocaine and bupivacaine, is a well-recognized and time-honored technique for providing regional anesthesia extending caudally from the thoracolumbar region. But it was the discovery of opioid and alpha-2 adrenergic receptors in the spinal cord that has led to novel methods for providing pain relief. Veterinarians have injected a variety of opioids and alpha-2 adrenergic agonists into the epidural space of animal patients to provide postoperative analgesia. Although most of the reports concerning the epidural injection of morphine concern dogs that have had stifle arthrotomies or thoracotomies,^19,20 this technique has been used in a cheetah following total hip replacement.¹⁸ Interestingly, morphine injected into the lumbosacral epidural space appears to provide analgesia for patients after thoracotomy,¹⁹ and serves to demonstrate the complex interconnected neural circuitry in the dorsal horn of the spinal cord. Alpha-2 adrenergic drugs also have been injected epidurally in a variety of animals including dogs²⁹ and horses.^13,25,27

Local anesthetics and opioids, primarily preservative-free morphine, have been injected into the intra-articular space following surgery of the stifle.^3,23 While it is the local anesthetics, especially bupivacaine, that provide a great deal of pain relief in the immediate postoperative period, it is the opioids that appear to provide analgesia that lasts as long as 24 hours.

When do we stop treating pain?

A difficult question to answer is when to stop treating an animal for a painful condition? The cutoff point may be after resolution of the condition for which the animal is being treated, and there are often clear medical guidelines to help us. What about the animal with a chronic painful condition for which therapy does not provide a cure and only provides marginal relief from the pain associated with the condition? When do we consider euthanasia to be the more humane answer to the animal’s condition? These situations often do not have easy answers. For example, other considerations such as the breeding value of the animal or its genetic value to the species as a whole may influence the decision to keep an animal alive, albeit as comfortable as possible. In these situations, my own opinion is that if the decision is repeatedly made to keep an animal alive for reasons unrelated to the well-being of the animal itself and the condition cannot be medically corrected, then it is time to consider euthanasia as the better solution for the animal.

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