The Physiology of Pain and Principles for its Treatment

Why is the Control of Pain Important?

The alleviation of pain is important for physiologic and ethical reasons [1]. Briefly, pain can induce a stress response in patients that is associated with elevations in ACTH, cortisol, antidiuretic hormone (ADH), catecholamines, aldosterone, renin, angiotensin II, and glucose, along with decreases in insulin and testosterone. These changes can result in a general catabolic state with muscle protein catabolism and lipolysis, in addition to retention of water and sodium and excretion of potassium [2]. A prolonged stress response can decrease the rate of healing. In addition, the stress response can have adverse effects on the cardiovascular and pulmonary systems, fluid homeostasis, and gastrointestinal tract function [2,3].

Veterinarians have an ethical obligation to treat animal pain. Most under-treatment of animal pain is probably a result of lack of adequate knowledge and not a lack of concern. Outward show of concern for the pet and family is important to demonstrate a bond-centered approach to cancer therapy and pain management. Most owners who are willing to undergo the emotional stress and financial commitment to pet care have already shown they have a strong attachment to their pet. It is important for the veterinarian to foster good communication surrounding primary therapy and pain treatment and at the same time to demonstrate empathy for the owner. This fosters the doctor-client-patient relationship and will help build goodwill both within and outside of the practice.

Definitions

Having a working understanding of the terminology surrounding pain and analgesia is important. By knowing the terminology, practitioners can speak intelligently and accurately to one another when discussing their patients. Table 8-1 provides definitions, arranged alphabetically, that are commonly used when discussing pain.

Mechanisms of Pain

Textbook chapters and multiple review papers are dedicated to describing the mechanisms of nociception, transduction, modulations, and the perception of pain [4-7]. The following section provides an overview of what are considered the most important aspects of the mechanisms of pain. It is important to note that these concepts may change over time as we develop a better understanding on a basic science level and an improved interpretation of these aspects in the whole animal.

The detection of tissue damage by specialized receptors in the periphery is referred to as nociception. These peripheral receptors, nociceptors, can be found in the skin, mucosa, deep fascia, connective tissue of visceral organs, ligaments, muscles, tendons, articular capsules, periosteum, and arterial vessel walls. Nociceptors are the distal end of the axons of first order neurons in the pain pathway. They are responsible for detecting and transmitting the location, quality, and duration of the stimulus. Nociception occurs when the free nerve endings are activated on the distal terminals of A-delta and C nociceptors. The term nociception is used for the activity occurring from the periphery through the spinal cord to the brain. Pain, which is a conscious experience, requires integration with higher brain centers. Thermal, mechanical, chemical, and electrical stimuli may activate most nociceptors. Some, however, only respond to thermal or mechanical stimuli. The ability of a nociceptor to respond to a specific stimulus has been elucidated on a molecular basis. The cell bodies of the C fibers contain several unique molecules, which may be useful in the production of analgesic drugs in the future. These molecules include TTX-R, a tetrodotoxin-resistant Na+ channel; VR-1, the vanilloid receptor that is targeted by capsaicin; P2X3, a subtype of purinergic receptor; and DRASIC, an acid-sensing ion channel [8-18]. Once activated via the nociceptors, the nerve signal is propagated to the central nervous system via C fibers or A-delta fibers.

A-delta are small (1-6 μm) diameter myelinated fibers. They conduct at relatively high speeds, 5 to 25 m/sec. C fibers are smaller (< 1 μm) diameter unmyelinated nerves with slower conduction velocity, typically less than 2 m/sec. The primary afferent nociceptors contain a variety of neurotransmitters, including glutamate, substance P, and calcitonin gene-related peptide. Glutamate is an excitatory amino acid, which acts upon several receptor subtypes to mediate rapid depolarization of dorsal horn neurons via an influx of Na+ and an efflux of K+. Substance P also activates subpopulations of dorsal horn neurons. Substance P can contribute to some of the long-term changes produced by persistent injury, as can the N_Methyl_D_Asparte (NMDA) receptor. The NMDA receptor gates Ca++ in addition to Na+ and K+ and can alter long-term dorsal horn processing.

The propagated stimulus from the periphery enters the spinal cord via the dorsal roots of the spinal nerves where the first synapse takes place. The spinal nerves then innervate the different laminae of the gray matter of the dorsal horn of the spinal cord. The laminae are distinct layers of cells that form columns extending the length of the spinal cord. Laminae I, II, V, and VI are locations where incoming A-delta and C fibers typically synapse.

Local inhibitory interneurons and descending inhibitory pathways with origins in the brain stem, both in the dorsal horn, help regulate dorsal horn nociception. Most inhibitory interneurons use glycine or gaba (gamma-aminobutyric acid) as their neurotransmitters. These inhibit the firing of dorsal horn neurons. Enkephalin and dynorphin also have inhibitory effects in some interneurons by causing hyperpolarization via increased K+ conductance. Norepinephrine and serotonin have antinociceptive effects in the descending inhibitory pathways.

The second order neurons receive input from primary afferent fibers. These are located in the dorsal column nuclei and transmit signals to the higher centers of the brain via multiple parallel pathways including, but not restricted to, the spinothalamic, spinoreticular, spinocervicothalamic, neospinothalamic, and paleospinothalamic tracts. The importance of the various tracts is likely to have species-specific importance. The spinothalamic and spinocervicothalamic tracts seem to play an important role in conveying nociceptive input in domestic species.

The spinothalamic tract has neurons that originate in lamina I and ascend to the thalamus. The spinoreticular tract has origins deeper in the dorsal and ventral horns, with neurons coming from laminae VII and VIII. These axons project to reticular formations at all levels of the brainstem.

The sensation of pain is produced in the lateral thalamocortical system of the lateral thalamus and the primary and secondary somatosensory aspects of the cerebral cortex. Aversive reactions to noxious stimuli occur owing to projections to the medial thalamus, which sends projections to the limbic structures.

The gate control theory is a description of the physiologic mechanism of pain. Briefly, it states that sensory input is modulated by ascending and descending mechanisms in the central nervous system. In essence, the spinal cord acts like a gate, which increases or decreases the effect of the neural input before being processed by the brain, evoking pain perception and response [19].

Traditional Chinese Medicine Aspects of Pain and Acupuncture Therapy

From a traditional Chinese medicine (TCM) perspective, pain can be a result of an excess condition leading to the obstruction of the circulation of Qi and blood. Examples of excess conditions contributing to pain include invasion of exterior pathogenic factors, interior cold or heat, stagnation of Qi or blood, obstruction by phlegm, and retention of food. Pain can also be caused by deficiency conditions such as deficiency of Qi and blood and consumption of body fluids from Yin deficiency. These conditions cause malnourishment of the channels, and hence, pain. Stagnation of Qi causes distention with distending pain and no fixed location. Stasis of blood causes a severe boring pain in a small defined area [20].

The principles behind acupuncture therapy are the restoration of a balance in the body. Acupuncture needles placed in appropriate proximal, local, and distal locations can help resolve the underlying causes of pain. This ultimately restores Qi and blood circulation to normal. With no obstruction, there is no pain.

Acupuncture Pain Relief

Acupuncture can be used a pain relieving modality, often when conventional therapy does not work. It is also useful in conjunction with other therapy to allow lower doses of drugs that may have significant side effects. While some practitioners have difficulty accepting acupuncture because of traditional Chinese medical explanations, which may be scientifically untenable, it is important to remember that there exists well documented physiologic theory and evidence for its clinical effects [21,22]. In general acupuncture analgesia is extremely useful for pelvic, radius/ulna, and femoral bone pain as well as cutaneous discomfort secondary to radiation therapy. Acupuncture also helps alleviate nausea associated with chemotherapy and some analgesics, as well as promoting general well being.

Physiology of Acupuncture Pain Therapy

Placement of needles at specific acupuncture points can relieve pain through several different mechanisms. First, acupuncture may decrease muscle spasms when inserted into trigger points. Lack of spasms will increase comfort considerably. Acupuncture can also induce release of a variety of neurotransmitters, which can affect the processing of the pain impulse. This effect can be enhanced with specific types of electrical stimulation. Proper needle placement and low-frequency electrical stimulation (2 - 6 Hz) induces central release of endorphins and enkephalins, which may induce analgesia by inhibiting the transmission of nociceptive impulses from their origin to the brain and increasing the descending inhibition back to the periphery [23]. This type of stimulation usually produces analgesia in 10 to 20 minutes and is considered cumulative, meaning that subsequent treatments produce better and better analgesia. The analgesia produced by low-frequency stimulation can be abolished by the opioid antagonist naloxone [24-26]. High-frequency electrical stimulation (100 - 200 Hz) induces release of serotonin, epinephrine, and norepinephrine, inducing noncumulative analgesia [27-28]. As opposed to low-frequency-induced analgesia, analgesia from high-frequency stimulation is not affected by naloxone [29]. High-frequency-induced analgesia has its major effect by increasing descending inhibition of spinal tracts. For postoperative analgesia, low-frequency stimulation is most efficacious.

Approach to Pain Management in the Small Animal Patient

Drug treatment is the cornerstone of pain management. It is effective and affordable for most patients and owners. The general approach to pain management should follow the principles outlined further on. Individuals may suffer different side effects within the same category of drugs; therefore, if possible, it may be best to substitute drugs within a category before switching therapies. It is always best to try to keep dosage scheduling as simple as possible. The more complicated the regimen, the more likely that noncompliance will occur. Mild to moderate pain should be treated with a non-opioid such as a nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen. As pain increases, some type of opioid should be added to the regimen. As pain becomes more severe, increase the dose of the opioid. Drugs should be given on a regular basis, not just as needed, as pain becomes moderate to severe. Continuous analgesia will facilitate maintaining patient comfort. Additional doses of analgesics may then be administered as pain is intermittently more severe. Adjuvant drugs may be administered to help with specific types of pain and anxiety.

Principles of Pain Management

Three simple principles may be followed to avoid acute and chronic pain. The first principle is that pain control is good medicine. This follows from the earlier description of the physiologic importance of avoiding pain. Once again, prevention and alleviation of pain keep normal patients reasonably healthy, prevent sick patients from developing unnecessary complications, and can preempt catastrophic events in critically ill patients. In the simplest sense, pain control helps patients heal more quickly and more effectively.

The second principle of pain management is the concept of preventive analgesia. This concept implies the provision of pain control before a potentially nociceptive or painful stimulus is induced. Problem pain is frequently associated with pathophysiologic changes that occur at the level of the spinal cord and brain. These changes frequently involve the activation of NMDA receptors, resulting in central neuronal hypersensitization, commonly referred to as wind-up. As wind-up develops, the central neurons begin to exaggerate the stimulus, which enters the spinal cord, making the stimulus that eventually makes it to the higher centers of the brain of greater intensity than its peripheral origination, thus resulting in worsening pain. This can result in any of the NSAIDs or other analgesics having a tapering effect over time, even though the origin of the pain has not worsened.

The third principle of pain control is to use drugs in a multimodal manner. This is simply the implementation of drugs or techniques that work at different levels of the nociceptive pathways and via different mechanisms. This means using some combination of opioids, nonsteroidal anti-inflammatory drugs, alpha-2 agonists, NMDA-antagonists, and local anesthetics.

Assessment of Pain

Assessment of pain in animals can be difficult and frustrating. Understanding types of pain and their causes can be helpful. Often veterinarians need to rely on the experience in humans to help define the pain in animals. Technicians and other staff members are usually the ones who experience the postoperative period more than the doctors. Pain assessment typically is delegated to these staff members. Recognition and assessment of pain is the first and probably the most difficult step in providing analgesia to dogs and cats. It is often easiest to assume an animal is in pain if a person undergoing similar trauma or surgery would be in pain. A patient usually tolerates mild pain without a problem and does not exhibit any behavioral changes. Patients with mild pain often are not treated. Patients experiencing moderate pain usually exhibit changes in behavior, appetite, activity, positioning, or posture, at least in the absence of human interaction. These patients also tend to respond significantly to palpation of the painful area. Severe pain can be thought of as intolerable, and is often manifested as unprovoked crying, whimpering, or howling associated with violent thrashing. Nonspecific physiologic responses to pain include elevated heart rate and blood pressure, abnormal cardiac rhythm, panting, salivation, dilated pupils, and unhandleable behavior. It is important to remember that differences in variables will occur among individuals, breeds, and species.

Classification as to origin of pain is also important because some drugs have greater efficacy for different types of pain. Somatic pain originates from damage to bones, joints, muscles, or skin and is described in humans as localized, constant, sharp, aching, and throbbing. Visceral pain arises from stretching, distension, or inflammation of the viscera, and is described as deep, cramping, aching, or gnawing, without good localization. Neuropathic pain originates from injury or involvement of the peripheral or central nervous system and is described as burning or shooting, possibly associated with motor, sensory, or autonomic deficits.

Assessment of pain can be accomplished systematically with a pain scoring scale [30-31]. The objective of a pain scoring system is to place a quantitative value on a specific variable, add up the variables and compare the total to some predetermined assessment of pain. There are many different pain score scales and no one is perfect. Some investigators have also used a visual analog scale (VAS) in animals. A VAS would need to be validated for several people at each practice to assure consistent scoring.

Failure to assess pain initially and throughout the course of treatment is a leading factor of under-treatment. Pain should be assessed early with the goal of characterizing the pain as to location, intensity, and probable etiology. Client engagement in this process helps determine aggravating and relieving factors. After a good assessment is performed, goals for pain control can be set with the client.

Nonopioids

Nonopioid analgesics include drugs such as carprofen, meloxicam, tepoxalin, etodolac, deracoxib, firocoxib, acetaminophen, aspirin, ketoprofen, and etodolac (Table 8-2). All except acetaminophen are considered nonsteroidal anti-inflammatory drugs (NSAID). Despite the low anti-inflammatory activity of acetaminophen, it possesses beneficial analgesic effects, minimal risk of bleeding in thrombocytopenic patients, decreased gastrointestinal effects, and synergism with opioid analgesics, such as codeine. Acetaminophen should be avoided in cats because of their inadequate cytochrome P-450-dependent hydroxylation [32].

Mild to moderate pain, especially that arising from intrathoracic masses, intra-abdominal masses, minor fractures, mild soft tissue injuries, and bone metastases, can be relieved with NSAIDs. When pain increases, NSAIDs have an opioid-sparing effect so that better analgesia can be achieved with lower doses of opioids. NSAIDs have central analgesic and peripheral anti-inflammatory effects mediated via inhibition of cyclooxygenase. The choice of NSAID ultimately depends on available species information, clinical response, and tolerance of side effects. Most NSAIDs have been formally investigated only in dogs, leaving anecdotal information for use in cats. The most common side effect of NSAID administration in dogs is gastric irritation and bleeding owing to loss of gastric acid inhibition and of cytoprotective mucus production normally promoted by prostaglandins. Other side effects include renal failure and hepatic dysfunction that may lead to failure [33]. NSAIDs that are more selective for inhibition of cyclooxygenase-2 (COX-2) seem to have fewer gastrointestinal effects and potentially fewer renal effects [34,35]. Therefore, more selective COX-2 inhibitors, such as carprofen, meloxicam, deracoxib, tepoxalin, firocoxib and etodolac, should be considered priority NSAIDs in pain patients. A blood chemistry panel should be performed prior to initiating NSAID therapy. If evidence exists of liver or renal disease, dehydration or hypotension, another approach to therapy should be considered. Therapy with NSAIDs, which are non-specific cyclooxygenase inhibitors, may also inhibit platelet function, leading to bleeding and oozing. Therapy with these NSAIDs should be stopped if this occurs. If clinical effectiveness is not achieved with one NSAID, it should be discontinued and another started 4 to 7 days later to avoid additive or synergistic cyclooxygenase inhibition effects. Aspirin should be avoided in dogs because of the increased possibility of gastrointestinal bleeding, even with buffered formulations [36,37]. Administering misoprostol can help provide gastrointestinal protection during the switchover period.

Opioids

Opioids are the major class of analgesics used in the management of moderate to severe pain. They are reasonably effective, predictable, and have low risk associated with them. The most common parenteral opioids used in small animals are morphine, oxymorphone, fentanyl, codeine, meperidine, buprenorphine, and butorphanol (Table 8-3). Parenteral opioids should be used in the perioperative period and should be discontinued when a patient can be switched to oral medication. Common oral opioids include morphine and codeine with or without acetaminophen. An opioid-like oral drug that is becoming more commonly administered is tramadol.

As a patient's pain increases, the required dose of opioid also increases. Veterinarians may be reluctant to administer high doses of opioids for fear of adverse side effects. It is important to remember that veterinarians have an ethical obligation to benefit the patient by alleviating pain. Opioids can be administered while managing side effects to maximally help the patient. Side effects of opioid administration include diarrhea and vomiting initially, constipation with long-term use, sedation, and dysphoria. The initial gastrointestinal effects occur most frequently with the first injection in the perioperative period and usually do not occur with subsequent dosing. These effects usually do not occur with oral dosing. When sending a patient home with oral medications, it is important to discuss with the owner that dosing is highly individual. It is possible that a given dose may be perfect, or it does not provide enough analgesia, induces sedation, or induces dysphoria or excitement. Adjusting of the dose requires excellent doctor-client interaction. Bradycardia is also possible after opioid administration, but is most common if opioids are administered parenterally. If bradycardia occurs, an anticholinergic, such as atropine or glycopyrrolate, should be administered, rather than discontinuing the opioid.

Opioids are classified as full mu-receptor agonists, partial agonists, and kappa agonist--mu antagonists. Examples of the full mu-receptor agonists include morphine, oxymorphone, fentanyl, codeine, and meperidine. In normal, healthy animals, opioids may produce sedation, which is usually acceptable, or dysphoria, an exaggerated unrest, which usually is undesirable. Full mu agonists induce the best analgesia in a dose-dependent manner and are not limited by a ceiling effect. As pain increases, larger doses may be administered. Morphine should be the most commonly used opioid for severe pain. It is available in multiple injectable and oral formulations, including short-duration tablets and liquids and sustained release tablets. Oral morphine may be the most effective method for providing longer term analgesia to dogs with moderate to severe pain. Patients receiving analgesics at set dosing intervals should also be provided with some short-duration opioid for breakthrough pain. While the pharmacokinetics of oral morphine in dogs are variable, the clinical efficacy seems to be highly reliable [38,39].

Oxymorphone is only available as an injectable analgesic and may induce panting, by changing the temperature set point in the brain [40]. This usually is not an issue, except when attempting thoracic or abdominal radiography. Hydromorphone, like oxymorphone, is a pure mu-receptor agonist and can induce the same degree of analgesia as morphine. Meperidine is short acting in animals, limiting its use as an analgesic in patients with severe pain. Codeine is available alone or with acetaminophen, allowing some flexibility in choice of oral medications. Fentanyl is an injectable drug that is potent and equally effective as morphine. All of the previously mentioned parenteral opioids may be administered by intermittent intravenous, intramuscular, or subcutaneous routes. A problem with this type of intermittent dosing is that patients often develop pain before their subsequent dose, then are extremely sedate after dosing. An alternate dosing regimen would use continuous infusion of an opioid. Fentanyl, morphine, hydromorphone, and oxymorphone are appropriate drugs for continuous infusion. Fentanyl may be especially suited to continuous infusion therapy because it is short acting. This enables the practitioner to alter the dose as necessary from minute to minute to achieve good analgesia and potentially minimal sedation if desired.

Buprenorphine is an example of a partial mu agonist. It does not produce the same degree of analgesia as does morphine and has a ceiling effect. The advantage of buprenorphine is that it has a long duration of action, 6 to 12 hours. It also has a long time to onset, approximately 40 minutes, even when given intravenously. Buprenorphine is a unique drug in that larger doses may actually produce less analgesia owing to a bell-shaped dose-response curve. Tapering the dose to the individual may be difficult. If an animal does not have adequate analgesia after receiving buprenorphine, dosing with a morphine-like drug may not produce any results because of buprenorphine's strong affinity for mu-opioid receptors. Buprenorphine is not easily reversible. Experimentally, it takes 1000 times the normal dose of naloxone to reverse it in a normal dog [41-43]. Because of the inherent lack of maximal analgesia compared with morphine, buprenorphine should be used only for mild to moderate pain.

Buprenorphine can also be administered transmucosally in cats (Table 8-3). Owing to the pH of a cat's mouth, buccal buprenorphine has good uptake, resulting in pharmacokinetics that parallel intravenous administration [44-46]. Cats can usually tolerate 2 days of administration of buccal buprenorphine before developing unacceptable sedation.

Another group of opioids that are available are the kappa agonist--mu antagonists, of which butorphanol is an example. Butorphanol may reverse the effects of drugs like morphine, a pure mu agonist, but provides analgesia and sedation of its own. Butorphanol is also reversible with naloxone and nalmefene. Butorphanol cannot induce the same maximal analgesia as morphine, having a ceiling effect at moderate doses of pain. Even in large parenteral doses, butorphanol produces analgesia of short duration in dogs [47]. These last two properties may limit butorphanol's utility for treatment of severe pain.

Tramadol is an opioid-like drug that also inhibits serotonin reuptake [48]. Tramadol is a useful adjunct to NSAID therapy in patients with moderate pain. The pharmacokinetics seem to indicate the need for large doses administered frequently in dogs, although the clinical experience may indicate otherwise (Table 8-3).

An alternative to oral opioids for providing multiple-day analgesia is through transdermal fentanyl patches (Table 8-3). Fentanyl patches require 12 to 24 hours to take effect and last 2 to 4 days. Additional analgesia must be provided during the first 0.5 to 1 day after patch placement. One problem with transdermal fentanyl is related to unreliable plasma levels in dogs [49-51], probably related to failure of patch application or inappropriate dosing. Fentanyl patches may not provide enough analgesia for severe pain [52], but they allow lower doses of additional drugs. Fentanyl patches are expensive and should not be the first approach to chronic therapy. Transdermal fentanyl is most appropriate in those patients that do not tolerate oral medication.

Epidural opioids, especially morphine (Table 8-3), have been used as a method for perioperative analgesia. With placement of an epidural catheter, epidural opioids can be administered for days to weeks. Epidurals are discussed later in this chapter.

The appropriate dose of an opioid is that dose which produces analgesia with the fewest side effects. The need for increased doses often reflects progression of disease. Long-term use may produce opioid tolerance, increasing doses or frequency to achieve equivalent results. As previously mentioned, veterinarians should not be afraid of increasing doses in patients and should remember the need for analgesia. A distinct advantage of using opioids for pain control is that they are reversible with naloxone or nalmefene if unacceptable side effects occur. Prolonged use may produce constipation. Oral laxatives can help alleviate this problem.

Alpha-2 Agonists

Medetomidine and xylazine are two alpha-2 agonists approved for use in small animals in the United States (Table 8-4). They are non-controlled parenteral agents that provide excellent visceral analgesia, but only for 20 minutes to 2 hours [53]. Their effects can be nearly completely reversed with yohimbine or atipamezole, respectively. Xylazine and medetomidine should not be the first or sole choice in providing analgesia perioperatively to patients in moderate to severe pain because they greatly reduce cardiac function and, potentially, oxygenation [54-56]. Xylazine and medetomidine have synergistic effects with opioids. This effect,which can be achieved with microdoses, is useful postoperatively for inducing additional analgesia and alleviating dysphoria.

Ketamine

Ketamine has been used for many years as an induction agent to general anesthesia in normal and compromised patients (Table 8-4). It has been well established that ketamine provides reasonable somatic but poor visceral analgesia [57]. Recently, ketamine has been identified as a NMDA receptor antagonist. N-methyl-D-aspartate receptors are believed to play a role in the processes leading up to central sensitization and wind-up. As an NMDA receptor antagonist, ketamine reduces postoperative pain and cumulative opioid requirements for a variety of procedures in humans and dogs [58-59]. This is accomplished with doses that are much smaller than those for anesthesia. As such, it is uncommon for patients to develop behavioral or cardiovascular effects. Micro-dose ketamine appears to provide beneficial effects for a variety of surgical procedures, limb amputations, and major fracture repairs. When used in this manner, ketamine should be administered as a bolus (0.5 mg/kg IV) followed by an infusion (10 μg/kg/min) prior to and during surgical stimulation. A lower infusion rate (2 μg/kg/min) may be beneficial for the first 24 hours postoperatively and an even lower rate (1 μg/kg/min) for the next 24 hours. In the absence of an infusion pump, ketamine can be mixed in a bag of crystalloid solutions for administration during anesthesia. Using anesthesia fluid administration rates of 10 ml/kg/hr, 60 mg (0.6 ml) of ketamine should be added to a 1 liter bag of crystalloid fluids to deliver ketamine at 10 μg/kg/min.

Tranquilizers

A concern that frequently arises with pain management is concurrent tranquilization and sedation. Most of the drugs used by veterinarians usually produce concurrent sedation. As mentioned previously, opioids have the greatest potential of producing dysphoria, instead of sedation. Dysphoria becomes more likely when cats are administered higher than necessary doses of opioids and when a patient is already experiencing high anxiety in the hospital. Dysphoric patients can sometimes be treated simply by petting and soothing, or by helping the patient change positions. Low-dose acepromazine, both IV and/or IM is reasonable drug therapy for dysphoria (Table 8-4). While acepromazine does not treat pain, it calms anxious patients very well and also makes them care less about their pain. For patients in which acepromazine is contraindicated, those with bleeding and seizure disorders, the benzodiazepines, diazepam and midazolam, often calm patients (Table 8-4). Benzodiazepines should not be used by themselves in most alert patients as they frequently cause excitement. Combined with opioids, sedation usually results. In patients that are hemodynamically stable, a microdose of medetomidine, IV, also can decrease dysphoria and increase analgesia.

Patients that develop dysphoria after oral analgesic medications often respond well to oral acepromazine or diazepam. It is important to discern whether the opioid dose is effective before changing the analgesia regimen.

Tricyclic Antidepressants

Tricyclic antidepressants, such as amitriptyline, imipramine, and clomipramine block the re-uptake of serotonin and norepinephrine in the central nervous system. They also have antihistamine effects. These drugs have been used in humans for the treatment of chronic and neuropathic pain at doses considerably lower than those used to treat depression [60]. Veterinarians have not used tricyclic antidepressants in this manner for long, but they appear to induce similar analgesic properties and enhance opioid analgesia as they do in humans (Table 8-4).

Local Anesthetics

The use of local and regional anesthetic techniques in small animals was common in the early 20th century. Interest has increased in these techniques, probably owing to their ability to provide preemptive analgesia and decrease wind-up. Local anesthetic techniques can be used instead of general anesthesia in selected cases or, more commonly, in combination.

The most commonly used local anesthetics include lidocaine and bupivacaine (Table 8-5). Lidocaine has a short onset (< 1 min) and lasts approximately 60 to 90 minutes. Doses of 1.5 to 2.0 mg/kg are safe in dogs and cats. Signs of toxicity are manifested as neurologic changes, including seizures. Bupivacaine takes approximately 20 minutes to take effect, but may last for 5 to 8 hours. Whereas lidocaine has antidysrhythmic effects at low to moderate intravenous doses, bupivacaine has cardiotoxic effects when administered intravascularly. Inadvertent IV administration can result in death [61-64]. Epinephrine may be added to bupivacaine in a 1:200,000 dilution to cause local vasoconstriction and prolonged duration. Epinephrine should not be used for peripheral blocks because collateral circulation may not be available to provide adequate perfusion to distal tissues. Combinations of lidocaine and bupivacaine are often used to achieve quick onset and long duration. This is especially necessary when using local anesthetics interpleurally. Because of its long onset, bupivacaine causes stinging and discomfort. Lidocaine administered concurrently limits the discomfort to a period of seconds.

Local anesthetics have numerous uses. They are often used epidurally to produce either better analgesia in low doses or anesthesia for caudal procedures in higher doses. They may be used interpleurally for thoracic and cranial abdominal pain. Intercostal nerve blocks are easily performed for lateral thoracotomy pain. Brachial plexus infiltration provides anesthesia for procedures distal to the elbow. Maxillary, infraorbital, mandibular, and mental nerve blocks are commonly used for procedures involving the face and mouth. Local infiltration is common for procedures involving the ear. Ring blocks have also been used for distal limb and digit amputations. Many of these techniques have been well described [65].

Epidurals

Epidural administration of drugs requires additional skill and expertise that may not be available in all clinical settings. With epidural administration, a needle is placed on the dorsal midline and advanced at the lumbosacral junction through the ligamentum flavum until one encounters a loss of resistance. This technique has been well described [65,66]. Epidural morphine is commonly administered in the perioperative period to provide analgesia, but not anesthesia, for the abdomen or more caudally. In some instances, analgesia may be effective for the thorax and forelimb. This analgesia may last up to 24 hours [67]. Local anesthetics may also be administered epidurally as a low dose to augment epidural morphine-induce analgesia or at a higher dose to produce anesthesia.

A catheter can also be placed in the epidural space for severe pain that may be intractable in the caudal portion of the body. Maintenance of this catheter requires veterinarian and client vigilance to assure cleanliness and prevent infection migrating to the spinal cord. With proper care, an epidural catheter can remain in place for days to weeks.

Conclusion

The understanding of pain and its alleviation is a constantly evolving science. While we know more now than ever before, new information changes our approach to patients almost daily. Veterinarians have a physiologic and ethical obligation to treat pain to help assure optimal well being of their patients. The current understanding of pain medicine allows veterinarians to effectively treat the vast majority of patients with acute pain and a large number of patients with chronic pain. While chronic pain may be more of a challenge, no patient should be euthanized because of pain if the owners have the means to explore multiple modalities.