Managing Canine Pain

The Mechanics of Osteoarthritis

OA is a complex syndrome that results in irreversible damage to affected joints (7). While some authors refer to OA as an inflammatory syndrome (7), others categorize it as a degenerative disease in which inflammatory mediators play a role (16). Researchers continue to study the nuances of osteoarthritis, and though the etiology can be unknown in some cases (7), OA is typically caused by repeated microtrauma to articular cartilage (16). This can take the form of abnormal stresses placed on normal cartilage or normal stresses placed on abnormal cartilage (17). The resulting cascade of mechanical and biochemical events includes, but is not limited to, destruction of cartilage and inflammation of the synovial membrane (synovitis) (18). Inflammation of the synovial membrane can occur early in the disease process and allows leukocytes to invade the joint space. Synovial cells and leukocytes release destructive enzymes, free radicals, cytokines, and prostaglandins, which further incites inflammation, modulate cartilage metabolism, and damage the cartilage matrix. Much of the pain associated with OA has been attributed to this synovitis. Synovial fluid becomes less viscous and its ability to serve as a joint lubricant is diminished. Fibrillation (striations) of the superficial cartilage layers also occurs, exposing the underlying cartilage to abnormal stress and leading to fissures in the deeper cartilage layers. Ultimately, the supportive function of the cartilage matrix is reduced. As degeneration continues, the inflammatory response is exacerbated. The cartilage eventually loses its ability to resist compressive forces, and as the mechanical injury to the cartilage continues, the subchondral bone may become exposed (18). Once cartilage is damaged, the body is unable to maintain a balance within the naturally occurring process of cartilage breakdown and regeneration. Ultimately, breakdown exceeds regeneration (8). Pain and inflammation arise as the tissues involved in maintaining joint flexibility respond to degradation of cartilage (5). One author summarizes very simply what this means to affected animals: "Each step in the cycle of cartilage breakdown and inadequate repair produces pain." (5)

Sites and Signs of Canine Osteoarthritis

Common OA sites in dogs include hips (e.g., hip dysplasia, Legg-Calvé-Perthes disease), stifle (e.g., patellar luxation), shoulder (e.g., osteochondrosis dessicans) and elbow (e.g., osteochondrosis, elbow dysplasia). OA pain may begin as occasional soreness or stiffness following brisk activity, and then progress to daily discomfort that begins to affect the animal's quality of life (3). Signs vary according to the pattern and severity of the disease. For instance, if a dog's OA is "symmetrical," its gait may be "short-stepping" or "doddery." A dog with bilateral pain in the hind limbs will arch its spine and transfer weight to the front limbs. Thoracolumbar (thoracic and lumbar areas of the vertebral column) or lumbar spinal pain can produce the same types of changes in gait (19). The common clinical signs of OA are summarized in Table 1. Table 1: Common Clinical Signs of Osteoarthritis in Dogs (20)

Severity	Signs
Mild OA	Stiffness (but may "limber up"), decreased activity, limping
Moderate OA	Limping, pain, muscle atrophy, stiffness, difficulty rising
Severe OA	Limping, loss of range of motion, muscle atrophy, vocalization, pain, difficulty rising, crepitus (cracking sensations during joint movement that may indicate degenerative osteoarthritis), lethargy

Canine Hip Dysplasia (CHD or HD) CHD is a multifactorial, abnormal development of the coxofemoral joint in dogs that is characterized by joint laxity and subsequent degenerative joint disease [aka osteoarthritis]. The pathophysiologic basis for CHD is a disparity between hip joint muscle mass and rapid bone development. It is interesting to note that clinical signs vary and do not always correlate to radiographic evidence. (21) According to one author (22), "no single canine disease has been the focus of more controversy, debate, and scientific publications than HD. There are few points of consensus regarding this disease... we do know that all affected puppies are born with normal hips, but by 2 weeks of age changes have already occurred that predispose to excessive joint laxity and to changes in the shape of the femoral and pelvic components of the joint. Dogs with HD may be presented at a young age (6 to 12 months) due to hip laxity causing gait abnormality or pain associated with joint injury. Alternatively, they may be presented after maturity and into middle age due to secondary OA with its associated pain and lameness."

Elbow Dysplasia (23, 24) The Orthopedic Foundation for Animals explains that elbow dysplasia is a general term used to identify an inherited polygenic (multiple genetic influences) disease in the elbows of dogs. Three specific etiologies make up this disease and they can occur independently or in conjunction with one another. They include:

• Pathology involving the medial coronoid of the ulna (fragmented coronoid process).

• Osteochondritis of the medial humeral condyle in the elbow joint. (Osteochondritis is a condition in which a fragment of bone in a joint is deprived of blood and separates from the rest of the bone, causing soreness and making the joint less stable).

• Ununited anconeal process. The anconeal process is a bony protrusion that forms part of the ulna bone at the back of the elbow joint. In very young animals, this part of the ulna is still cartilage and bone is laid down from within its own ossification center. Sometimes, the anconeal process does not fuse onto the main body of the ulna, in which case it forms a separate bone and is called an ununited anconeal process. Ununited anconeal process typically affects large and giant breeds of dog, such as Afghans, Bullmastiffs, French Bulldogs, Great Danes, Irish Wolfhounds, Labrador Retrievers, Pointers, Pyrenean Mountain Dogs, St Bernards and Weimeraners. It has also been reported in Bassett Hounds and Dachshunds. The breed most often affected by UAP is the German Shepherd.

Studies have shown the causative inherited traits are independent of one another. Clinical signs involve lameness, which may remain subtle for long periods of time. No one can predict at what age lameness will occur due to a large number of genetic and environmental factors such as degree of severity of changes, rate of weight gain, amount of exercise, etc. Subtle changes in gait may be characterized by excessive inward deviation of the affected paw which raises the outside of the paw so that it receives less weight and distributes more mechanical weight on the outside (lateral) aspect of the elbow joint away from the lesions located on the inside of the joint. Range of motion in the elbow is also decreased.

Patellar Luxation (23) The patella (kneecap) is part of the stifle joint. In patellar luxation, the kneecap luxates, or pops out of place, in either a medial or lateral position. Bilateral involvement is most common, but unilateral patellar luxation is not uncommon. Animals can be affected by the time they are 8 weeks of age. The most notable finding is a "knock-knee" stance, and the foot can be seen to twist laterally as weight is placed on the limb. Patellar luxation can occur in dogs of any size and breed.

Legg-Calvé-Perthes Disease (LCP) (23) LCP is a disorder of hip joint conformation that occurs in humans as well as dogs. In dogs, it is most often seen in miniature and toy breeds between the ages of 4 months to one year. LCP results when the blood supply to the femoral head is interrupted, causing avascular necrosis, or the death of the bone cells. Followed by a period of revascularization, the femoral head is subject to remodeling and/or collapse creating an irregular fit in the acetabulum, or socket. This process of bone cells dying and fracturing followed by new bone growth and remodeling of the femoral head and neck can lead to stiffness and pain. LCP is believed to be an inherited disease, although the mode of inheritance is not known. Because there is a genetic component, it is recommended that dogs affected with LCP not be used in breeding programs.

Did You Know? There is an Orthopedic Foundation for Animals The Orthopedic Foundation for Animals was founded in 1966 to:

• Collate and disseminate information concerning orthopedic and genetic diseases of animals

• Advise, encourage and establish control programs to lower the incidence of orthopedic and genetic diseases

• Encourage and finance research in orthopedic and genetic disease in animals

• Receive funds and make grants to carry out these objectives

As part of its mission to support development of diagnostic criteria and databases for a number of genetic diseases, OFA maintains statistics on the incidence of CHD, elbow dysplasia, patellar luxation, and Legg-Calvé-Perthes disease in dogs. Much of the information in this sidebar is based on OFA's website (www.offa.org).

Cancer

A 1998 survey by the Morris Animal Foundation found that cancer is the predominant health concern of dog owners. Respondents reported that 45% of the dogs that had died at the age of 10 or older had died of cancer. Overall, cancer was responsible for the deaths of almost 25% of the pets that were the subject of the survey. (25) In dogs with cancer, pain can be difficult to assess and easy to ignore because animals generally tend to hide or under-exhibit their pain. In addition, tumors grow gradually and changes in the level of pain an animal is experiencing can be subtle. (3, 26) Cancer pain in dogs can result from the disease itself or from the treatment for the disease (26). The veterinary practice team should assume that some degree of pain is associated with the part of the body affected by the cancer. In patients whose cancer has reached a point at which the disease cannot be ameliorated, quality of life should be the primary concern of the team and the pet owner (3). It is expected that as the life spans of companion animals increase, the number of cancer cases treated in a typical companion animal practice will increase as well. According to one estimate, small animal veterinarians may already derive 15-20% of their practice income from services related to treating cancer (25). An extensive discussion of cancer in dogs is beyond the scope of this course. However, Table 2 summarizes common types of canine cancer. Table 2. Summary of common types of canine cancer (25).

Type	Comments
Tumors of the skin and subcutaneous tissue.	Common. Account for ~1/3 of cancers in dogs.
Oral tumors	Account for 6% of canine cancer; the fourth most common cancer overall.
Mammary tumors	Most common tumors of female dogs. The risk of developing mammary tumors in dogs spayed before the first estrus is reported to be 0.05%; the risk is 8% after the first estrus, and 26% after the second estrus. About half of mammary tumors in dogs are malignant.
Testicular tumors	Common in intact male dogs.
Lymphoma	Incidence estimated at 1.5/100,000 in dogs <1 year old to 84/100,000 dogs 10-11 years old.
Osteosarcoma	The major skeletal neoplasm in dogs. Most occur in large-breed dogs. Median age at diagnosis is 7 years.
Hemangiosarcomas (tumors arising from cells that line blood vessels)	The most common tumors of the spleen; seen primarily in German Shepherd dogs; also seen in Golden Retrievers and Labrador Retrievers.
Nasal tumors	Account for up to 2.5% of canine tumors; most commonly malignant.

Central Neuropathic Pain (3) This type of pain is chronic neck or back pain that may be caused by a variety of conditions, including intervertebral disk disease, nerve root entrapment, neoplasia, infection, and/or inflammation. Note that many animals with lesions in and around nervous tissue may experience intense pain in response to mild noxious stimuli and/or stimuli that do not normally elicit a pain response. In cases in which neck or back surgery is indicated, pain relief is not a substitute for the surgical procedure.

Otitis Media Otitis media refers to inflammation of the structures in the middle ear. The condition is typically associated with infection in external ear canal or penetration of the tympanic membrane by some type of foreign object. Though otitis media can occur in all species, it is most common in dogs, cats, and rabbits. Untreated otitis media can lead to infection of the auditory tube, inflammation of other structures in the ear, loss of balance, and/or deafness. Note that infection of the auditory tube is most common in dogs, cats, and pigs (21). An animal with otitis media may scratch, paw, or guard the head or ears, shake its head or turn the head towards the affected side of the head or rub the ear on the floor. These signs indicate pain and discomfort (3, 21). Discharge and inflammatory changes in the ear canal may be seen. Since several types of nerves course through the middle ear, facial nerve paralysis and/or Horner's Syndrome (a syndrome characterized by a sunken eye with a small pupil, droopy upper eyelid, and prominent third eyelid) may occur on the affected side (21). Note that because of the mechanics of pain response (see Chapter 1), chronic otitis media may increase sensitivity and response to stimuli that would otherwise not be painful (e.g., ear cleaning). It may be that wind-up or neuropathic pain is associated with otitis media (3).

Chapter 4 - Assessing Chronic Canine Pain   "... the greatest welfare issue in terms of pain suffered by dogs and cats lies in unrecognized, untreated, and poorly understood pain associated with chronic conditions. This ignorance allows us to feel comfortable about the situation but it may be beyond the comfort level of our patients, our companions." (1) Assessing and Managing Chronic Canine Pain in Clinical Practice The greatest value offered by systematic attention to pain management is derived from focusing the attention of the veterinary practice team and the client on patient pain and distress (2). Ideally, a companion animal practice would have a procedure in place to assess and manage pain in its patients. Such a procedure might include the following steps (2, 3):

• Assess patients for the presence and intensity of pain or distress.

• Record results in a way that facilitates regular reassessment and follow-up.

• Focus on staff competency in pain assessment and management and include pain assessment and management as part of the orientation program for new members of the veterinary practice team.

• Develop protocols for different case types encountered in daily practice and incorporate them into the practice's standard of care for patients. Evidence-based protocols should be adopted when available. Since individual responses to therapies can vary widely, protocols will typically need to be individualized.

• Establish policies and procedures that support appropriate dispensing of effective pain medications.

• Ensure that pain does not interfere with patient recovery and rehabilitation.

• Educate owners about pain assessment and management.

• Use consent forms and client education literature to emphasize the practice's commitment to pain management.

• Ask for the owner's perceptions of the degree of pain present and the ways in which it may be compromising the animal's quality of life.

• Believe the owner. The owner sees the pet every day in its own environment and knows when alterations in behavior are occurring.

• Document effectiveness of pain interventions in in-patients and out-patients.

• Explain potential side effects to the client and anticipate related patient needs.

• Include the client in ongoing management by asking for feedback and updates on how pain management is working.

• Revise pain management protocols periodically to reflect advances in veterinary pain management.

• Adopt a standardized assessment tool (such as the visual analog scale or numerical rating scale) that can be used by all team members on a routine basis, but remember that it is difficult to apply these scales, particularly in instances of chronic pain (see discussion below).

While these guidelines may seem simple and intuitive, some of the steps are easier said than done, particularly those relating to assessment. There is no "gold standard" for evaluating chronic pain in dogs (4) but several types of scales have been used to try to do so, including simple descriptive scales (SDS), visual analog scales (VAS), numerical rating scales (NRS) and multifactorial or variable pain scales (MFPS) (4, 5). When applied to animals, the scales rely on subjective observation rather than client input.

• Researchers (5) explain the use of these types of pain scales in domestic animals: "In the VAS method, the clinician assessing the animal places a mark on a 100-mm line with 'no pain' on one end and 'excruciating or unbearable pain' at the other end to indicate the amount of pain the observer believes the animal is suffering. The distance from the 'no pain' end of the line (in mm) is the pain score. Numerical rating scales (NRS) are similar, but the observer assigns a numerical score on a 0 to 10 scale for pain intensity rather than placing a mark on a line. The SDS consists of 4 or 5 expressions used to describe various levels of pain intensity (e.g., no pain, mild pain, moderate pain, or severe pain). Each expression is assigned an index value, which becomes the pain score for the animal. The MFPS is usually a composite of a number of SDS values relating to particular aspects of behavior that may be associated with pain... Good agreement has been found between VAS and the NRS system... Although VAS is liable to have a higher amount of observer variation, it is often considered to be more sensitive than NRS or SDS, because defined categories are not used... The NRS-based scales have been used to assess chronic pain in veterinary medicine."

All these scales are characterized by issues related to variability, accuracy, and ease of use (2). Research continues into methods of assessing chronic pain in dogs. See the sidebar Studies Suggest Approaches to Assessing Chronic Canine Pain (on the following page) for a summary of recent studies involving assessment of osteoarthritis-related pain and cancer-related pain in dogs.

Other Obstacles to Assessing Chronic Pain As discussed earlier in this course, the precise way in which chronic pain develops in individual animals is not well understood. Dogs with similar conditions may or may not develop signs of chronic pain (2). These are among the factors that make assessing chronic pain difficult. Other factors include but are not limited to (5):

• Anthropomorphism and empathy.

• Difficulty in deciding how far a given animal's behavioral and physiological state differs from what is considered "normal" and how much change is tolerable.

• Breed, gender, physiologic, and individual differences in pain sensitivity and pain-response behaviors and/or human expectations regarding those behaviors.

• Age of the animal and the animal's previous history of exposure to pain.

• Environmental effects on physiologic measurements (e.g., unfamiliar environment of the clinic, presence or absence of the owner).

Signs of chronic pain in dogs are included in Chapter 3.

Sidebar: Studies Suggest Approaches to Assessing Chronic Canine Pain One of the limitations of behavior as an indicator of pain in animals is its injury- and species-specific nature (5) but two recent studies have attempted to validate various methods of assessing canine pain in specific situations. One study focused on osteoarthritis (canine hip dysplasia); the other on canine cancer pain.

• Hielm-Bjorkman et al (4) reported on a Finnish study in which researchers sought to identify indicators of canine pain that could be assessed easily in a clinical setting and incorporated into some type of pain assessment index for use by veterinarians and their clients. Forty-one dogs with canine hip dysplasia (CHD) and 24 apparently healthy dogs with no history of pain were enrolled in the study. The team chose CHD because it is an orthopedic disease characterized by chronic pain. Two veterinarians evaluated the dogs' locomotion and signs of pain. Owners of dogs with CHD and owners of control dogs answered a questionnaire regarding their dogs' demeanor, behavior, and locomotion (descriptive scales) and assessed pain and locomotion. The owner questionnaire contained 25 questions, which owners answered by means of a descriptive numerical scale of 0-4. Demeanor, behavior, and locomotion parameters were included. Results indicated that "chronic pain could be assessed in dogs with CHD through completion of the study questionnaire by a person familiar with the pet (e.g., owner) after receiving appropriate education in its use. Eleven variables were identified as being potentially useful in assessment of chronic pain in dogs." Relevant variables were: mood, willingness to take part in play or games, vocalization (audible complaining), walking, trotting, galloping, jumping, laying down, getting up, difficulty moving after rest, and difficulty moving after major activity. In comparing veterinarian assessment of locomotion and pain with owner assessment via the study questionnaire, researchers found that some variables are easier for the dog owner to assess while others are easier for a veterinarian to assess. The authors recommend that for optimal pain assessment, the owner and veterinarian should work together, with the veterinarian evaluating walking, trotting, and galloping, and the owner evaluating the remaining variables. Owners who have received training in recognizing gait abnormalities could also evaluate gait in the home setting. Study data also indicated that radiographs and physiologic measurements such as plasma hormone concentrations "did not seem to provide much additional information regarding pain in individual dogs."

• Yazbek and Fantoni (6) reported on a Brazilian study intended to develop and validate a quality-of-life (QOL) scale for dogs with pain secondary to cancer. Owners of 40 healthy dogs with no history or signs of pain, 20 dogs with dermatologic disease but no signs of pain other than mild pruritis, and 20 dogs with cancer completed a 12-question questionnaire. Owners chose one of four possible answers for each question. The questionnaire included four questions related to the emotional behavior of the dog, seven related to the physical state of the dog, and one related to the animal's interactions with its owner. Questions related to physical condition included evaluations of pain, appetite, fatigue, sleep patterns, gastric and intestinal problems, and urination and defecation patterns (0-3 rating scale). Owners of animals with cancer were asked to assign a severity rating (0-10) to their dogs' pain. Scores for healthy dogs were significantly different from scores for dogs with cancer and scores for dogs with dermatologic disease. Scores for dogs with dermatologic disease were significantly different from scores for dogs with cancer. The authors believe that since the difference in scores between dogs with cancer and healthy dogs was considerable, the results suggest that a simple questionnaire may be useful in assessing health-related QOL in dogs with pain secondary to cancer. Dogs with cancer had a mean pain score that indicated a moderate level of pain; the health-related QOL score for these dogs suggested a decreased QOL compared with healthy dogs.

Instituting a Pain Management Program The commitment of a given practice to pain management must be communicated clearly to the veterinary practice team and to clients. Both groups need to understand pain management concepts and strategies. Integrating pain management is a stepwise process: "Once the veterinarian and support staff become familiar with and gain confidence in the use of one or two agents, the pain management armamentarium can be expanded to include other agents and classes of drugs.... Veterinarians in any practice environment, large or small, willing to take the first step of learning basic pain management concepts can improve overall patient care by incorporating these strategies into the services they provide." (7)

Chapter 5 - Overview of Managing Chronic Canine Pain   "Chances are some of your patients suffer from chronic pain, and the chances become even greater as they age... Treating chronic pain may be approached systematically, in conjunction with the owner, to alleviate the animal's suffering and improve its quality of life." (1) This chapter provides an overview of some of the options available to companion animal veterinarians to manage chronic pain in dogs, with a focus on nonsteroidal anti-inflammatory drugs (NSAIDs). Other types of analgesics and strategies are discussed only briefly, although the ongoing debate about complementary and alternative therapies is also addressed. In some instances, opinions among veterinarians and professional organizations vary. Please note that inclusion of a given type of pain-management strategy, drug, and/or method is for educational purposes only and should not be construed as an endorsement, recommendation or judgment. Overview of Analgesics Used in Managing Chronic Pain Different types of analgesia can inhibit pain at different points in the nociceptive pathway (2). Recall from Chapter 1 that there are four distinct physiological processes involved in nociception: transduction, transmission, modulation, and perception. Table 3 indicates the types of pharmacologic intervention that can be used to inhibit these processes. Table 3. Pharmacologic intervention of pain processing. (Note that some of these analgesics do not play a significant role in managing chronic pain).

Process	Purpose of Analgesia	Analgesic Drugs
Transduction	Inhibit peripheral sensitization of nociceptors	·Local anesthetics ·Opioids ·NSAIDs ·Corticosteroids
Transmission	Inhibit conduction of impulses	·Local anesthetics ·Alpha-2 agonists
Modulation	Inhibit central sensitization	·Local anesthetics ·Opioids ·Alpha-2 agonists ·Tricyclic antidepressants ·Cholinesterase inhibitors ·NMDA antagonists ·NSAIDs ·Anticonvulsants
Perception	Inhibit perception	·Anesthetics ·Opioids ·Alpha-2 agonists ·Benzodiazepines ·Phenothiazines

Table 4 summarizes the principal analgesic drugs in terms of their relative effectiveness in managing chronic and acute pain (3). Table 4. Principal analgesic drugs and their relative effectiveness against chronic and acute pain.

Drug Type	Relative Efficacy		Practical Issues
	Chronic Use	Acute Use
Opiods	+/-	++	Tolerance
NSAIDs	++	+/-	Efficacy, toxicity
Alpha-2 agonists	-	+	Sedation
Local anesthetics	-	+++	Loss of motor control; toxicity

            + indicates efficacious             - indicates minimal efficacy As you can see from Table 4, alpha-2 agonists and local anesthetics are not generally considered useful in managing chronic pain in dogs because they are intended for short-term use. These classes of drugs are beyond the scope of this course. Opioids are natural or synthetic drugs that produce "morphine-like" effects (3). There are several types of opioids, but they have similar modes of action (2). Opioids are known to act on three different types of receptors (4) in the central nervous system and periphery (4). A given opioid may be active on one, two or all of these receptors (4). Opioids vary in their analgesic potency and clinical efficacy when used to treat different types of pain (3). Differences in drug receptor selectivity among the opiods "confer discrete properties on individual drugs and will help predict the pharmacological properties of a given drug in an individual animal species." (4) Opioids are also classified on the basis of their ability to induce a response once they're bound to a receptor (3, 4):

• Agonists are able to induce a maximal response.

• Partial agonists are unable to induce a maximal response irrespective of the dose administered. They produce "morphine-like" effects but are generally less toxic and less effective.

• Antagonists do not produce a response, though they do bind to receptors. They are used to reverse opioid effects.

Note that an opioid drug can be an agonist at one type of opioid receptor and an antagonist or partial agonist at another type of opioid receptor (4). Because opioids are controlled substances, their use entails strict procedures related to ordering, storage, and record keeping. This status can make the opioids unattractive to some veterinarians (5).

Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Nonsteroidal anti-inflammatories (NSAIDs) reduce the signs of inflammation but do not eliminate or affect the clinical course of the underlying cause of the inflammation. NSAIDs also don't protect against tissue or joint injury (6). While individual NSAIDs do not share uniform chemical properties with one another, they are all characterized by analgesic (pain-reducing), anti-inflammatory and antipyretic (fever-reducing) properties and the potential for similar side effects (7) (e.g., gastrointestinal, renal, hepatic), though in varying degrees. In the 1970s, researcher and Nobel Prize winner Dr. John Vane demonstrated that "the anti-inflammatory action of nonsteroidal anti-inflammatory drugs rests in their ability to inhibit the activity of the cyclooxygenase (COX) enzyme... This action is considered to be not the sole but a major factor of the mode of action of NSAIDS." (8). In the early 1990s, two distinct COX forms were identified: COX-1 and COX-2 (8).

• COX-1 is primarily responsible for producing prostaglandins involved in maintaining physiological functions (gastric cytoprotection, renal homeostasis, and normal platelet function). (9) It has been called the "housekeeping" enzyme.

• COX-2 is primarily responsible for production of prostaglandins associated with inflammatory conditions (9).

How NSAIDs Work

The arachidonic acid (AA) cascade (Figure 2) is the pathway by which fatty acids known as eicosanoids (prostaglandins, thromboxanes, leukotrienes) are produced. Eicosanoids play important roles in inflammation.

Figure 2.

Anti-inflammatories inhibit enzymes in the AA cascade at different points. Corticosteroids, which are not NSAIDs, act very early in the cascade. Lipoxygenase catalyzes the reaction that produces leukotrienes, which are inflammatory mediators. To date, there is no veterinary anti-inflammatory on the market that inhibits this segment of the AA cascade for longer than 3 - 5 hours (10). Nonsteroidal anti-inflammatory drugs (NSAIDs) exert their action on cyclooxygenase (COX). As described above, there are two basic types of COX: COX-1, which is essential to protecting important physiological functions (e.g., gastric protection), and COX-2, which is associated predominantly with inflammation and pain. All NSAIDs have some impact on both COX-1 and COX-2, but to varying degrees. Lascelles, McFarland, and Swann (2005) (11) explain: "The COX-1 isoform, which is constitutively present in virtually all cells, synthesizes prostaglandins that regulate normal homeostasis, including cytoprotection of the gastric mucosa. The COX-2 isoform is induced by proinflammatory stimuli. It has been shown that COX-2 is also constitutively expressed in a narrow range of tissues and organs (neural, reproductive, and renal), where it has an apparent homeostatic function. Also, COX-1 has been shown to be involved in pain and inflammation."

• The so-called "classic" NSAIDs such as aspirin and ibuprofen, are considered "nonselective," that is, they are characterized as inhibiting the conversion of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes, which is believed to account for the gastrointestinal and renal side effects that can be associated with NSAIDs.

• When used at therapeutic levels, NSAIDs introduced in the 1990s (e.g., carprofen, meloxicam) exhibit some degree of selectivity for the inducible COX enzyme (COX-2) largely responsible for redness, swelling, fever and pain. However, there is also some inhibition of the constitutive COX enzyme (COX-1) responsible for certain normal physiological functions.

• Coxibs are defined by the World Health Organization as compounds that target the inhibition of the COX-2 while sparing the activity of COX-1 (12). They inhibit COX-2 production while allowing COX-1 production to continue to some degree ("sparing" COX-1). Coxibs are therefore believed to be more selective than the classic NSAIDs. Coxibs are not all alike. There are significant differences in their degree of COX-2 selectivity. In other words, at therapeutic doses, all coxibs inhibit COX-2 but vary in their ability to spare COX-1. A simple way to visualize NSAID selectivity is by creating inhibition curves. In a published study using the canine whole-blood assay, the percent of COX-1 and COX-2 inhibition was measured for each of three NSAIDS (carprofen, deracoxib, and firocoxib). To create the inhibition curves shown in Figure 3, the following steps were taken:

  • For each NSAID, the canine whole-blood assay was conducted over a range of drug concentrations (x-axis).

  • At each drug concentration, the percent inhibition (y-axis) of COX-2 and COX-1 were determined and plotted.

  • The graph points were connected, generating a "curve" for COX-2 inhibition and COX-1 inhibition.

  • At a given percent inhibition of COX-2, a vertical line drawn down to the COX-1 curve demonstrates the corresponding level of COX-1 inhibition.

Figure 3. Carprofen, deracoxib and firocoxib inhibition curves (9).

Figure 3 inhibition curve interpretation ·The greater the separation between the COX-1 and COX-2 curves, the more selective the NSAID is for COX-2 and the more sparing of COX-1. ·COX-2 selective NSAIDs vary significantly in their ability to spare COX-1 at drug concentrations required for pain relief. ·The COX-1 sparing nature of an NSAID may diminish at higher drug concentrations. ·In this study, firocoxib spares COX-1 even at drug concentrations that result in 100% inhibition of COX-2. Although the clinical relevance of COX-2 selectivity has not been demonstrated, the inhibition curves derived from whole-blood assays are valuable tools for evaluating and comparing the in vitro COX-2 and COX-1 inhibition effects of NSAIDs. Even though a given NSAID may be classified as COX-2 selective, the inhibition curves clearly demonstrate that there is a significant variation in the ability of different drugs to spare the COX-1 enzyme at drug concentrations required for pain relief.

PREVICOX As a class, cyclooxygenase inhibitory NSAIDs may be associated with gastrointestinal, kidney or liver side effects. These are usually mild, but may be serious. Pet owners should discontinue therapy and contact their veterinarian immediately if side effects occur. Evaluation for pre-existing conditions and regular monitoring are recommended for pets on any medication, including PREVICOX. Use with other NSAIDs, corticosteroids or nephrotoxic medication should be avoided. Refer to the prescribing information for complete details or visit www.previcox.com.

Managing the Chronically Painful Dog with NSAIDs Benefits NSAIDs reduce clinical signs associated with inflammation, primarily through inhibition of the cyclooxygenase enzymes. Clinical benefits include analgesia, antipyretic, and anti-inflammatory effects. It is important to note that NSAIDs do not eliminate or affect the course of the underlying cause of inflammation, nor do they protect against further tissue or joint injury. As such, it is not realistic to expect a "cure" of the underlying pathology due to NSAIDs. NSAIDs are an effective tool for managing the inflammation and pain associated with chronically painful conditions, such as osteoarthritis. While the underlying pathology may be chronic and progressive, reduction of the associated pain and inflammation through the use of NSAIDs can be of enormous clinical benefit to the patient. Consistent use of NSAIDs for chronic conditions can help to maintain function and increase comfort for the long term. Potential Adverse Events As a class, NSAIDs have been associated with a number of adverse events. The most common of these are characteristic of the entire class and include gastrointestinal effect, such as vomiting and/or diarrhea. Other potential adverse events are thought to be related to the degree of COX-1 inhibition, and may include GI ulceration or coagulation abnormalities. Idiosyncratic toxicities have also been reported for individual NSAIDs. Monitoring In the case of NSAIDs used for chronic conditions, such as osteoarthritis in dogs, labeling approved by the FDA Center for Veterinary Medicine states: "All dogs should undergo a thorough history and physical examination before initiation of NSAID therapy. Appropriate laboratory tests to establish hematological and serum biochemical baseline data prior to, and periodically during, administration of any NSAID should be considered. Owners should be advised to observe for signs of potential drug toxicity." The appropriate level and frequency of monitoring should be determined by the veterinarian based on the age and clinical condition of each patient. Post-marketing Reporting As with any drug, post-marketing reporting plays an important role in gathering data concerning clinical efficacy and safety relevant to real-world use. Suspected adverse events should be reported to the manufacturer as well as to the FDA. Post-marketing studies can also be a valuable source of information providing results of clinical experiences in a large number of patients. Efficacy and safety data beyond those generated in prelicensing studies can be obtained, which may assist practitioners in choosing appropriate medications for their patients. One such example is the 2005 40-day study of firocoxib in 1002 dogs at 106 US veterinary practices (16).

Other Management Options for Chronic Pain (4) Under certain circumstances, corticosteroids or mood-altering drugs may be useful in managing chronic pain:

• Corticosteroids can be effective tools when the need to ameliorate chronic pain or pain associated with terminal conditions outweighs the risk of corticosteroid side effects (i.e., hyperadrenocorticism).

• Mood altering drugs such as tricyclic antidepressants and monoamine oxidase inhibitors, may have an analgesic effect apart from their antidepressant effects, but this has not been documented in cases of chronic pain in the veterinary clinical setting. Benzodiazepines can be helpful in treating pain related to muscle spasms, such as chronic back pain.

Certain physical techniques may be applied in cases of chronic pain. These include (4):

• Sensory neurectomy, which is sectioning of sensory nerves to eliminate sensation in a specific area in instances of intractable pain. Potential problems with this approach include subsequent accidental injury and tissue damage to the desensitized area and development of painful swelling at the surgical site.

• Removal of the pain-causing stimulus, for example, intervertebral disc material or a tumor. (Note that in humans, "phantom pain" has been documented in limbs that have been surgically removed. Although it is not known for certain whether animals experience this as well, "some animals, following amputation of a limb, will compulsively lick or otherwise interfere with the site of the amputation long after wound healing is complete, suggesting that they are experiencing a sensation from the site of the amputation.... No concerted attempt has been made to treat this phenomenon in animals." (4)

• Physiotherapy, such as application of heat and/or cold, and use of massage, exercise, ultrasound, and laser therapy. These techniques may be useful in treating pain related to orthopedic problems.

• Stimulation-induced analgesia, including transcutaneous electrical nerve stimulation and acupuncture.

A detailed discussion of these types of options is outside the scope of this course.

Alternative and/or Complementary Treatments: A Place in the Pain-Management Toolbox? The use of alternative or complementary methods of treating pain and other conditions is a much discussed but generally unresolved issue in veterinary medicine. For example:

• The Colorado State University College of Veterinary Medicine and Biomedical Sciences acknowledges that "Interest in Complementary and Alternative Veterinary Medicine (CAVM) among veterinary professionals and clients continues to strengthen and grow. The need for solid and scientifically supported information is evident. To meet this need, [we]... offer educational training programs in CAVM modalities (specifically, acupuncture and manual therapy) to veterinarians, as well as learning opportunities throughout the professional veterinary medical curriculum that address issues related to CAVM. In addition... The mission of [our] Shipley Natural Healing Center is to teach students, scientists, physicians and veterinarians about the importance of enhancing health and wellness using proven complementary therapies, and to perform well designed, scientifically valid, prospective, clinical and basic research to develop, authenticate, and document natural healing methodologies." (17)

• In their 2002 Handbook of Veterinary Pain Management, Drs. James S. Gaynor and William W. Muir (eds.) include a chapter on Complementary and Alternative (Integrative) Pain Therapy, which states that six "nonpharmocologic neuromodulation therapies... are safe techniques for providing pain relief in humans and animals, either as a supplement to conventional pain therapy or alone... All six modalities produce an analgesic effect. Acupuncture and related techniques are effective therapies for acute and particularly for chronic pain in animals." The six therapies are: acupuncture, electroacupunture or percutaneous acupoint electrical stimulation, transcutaneous electrical nerve stimulation, percutaneous electrical nerve stimulation, laser therapy, and pulsed magnetic field therapy. The chapter notes that "no regulation... exists to ensure the competence of a licensed veterinarian to practice acupuncture and related techniques on animal patients." The book also provides an appendix listing publications by authors who challenge the utility of these types of therapies (3).

• In his paper Relief of Chronic Pain in Cats and Dogs: Multimodal Drug Therapy, Dr. B. Duncan X. Lascelles states "pain therapy should not just revolve around drugs; therapies such as surgery, physical therapy and rehabilitation (cold therapy, massage, hydrotherapy, controlled exercise, swimming, passive physiotherapy) and acupuncture all have an important role to play in providing effective pain relief." Lascelles acknowledges that "Relatively undefined in the veterinary literature is the benefit of non-drug therapies in the management of pain associated with conditions such as osteoarthritis and cancer. Clinically, the analgesic effect of therapies such as acupuncture and electroacupuncture, acupressure and transcutaneous electrical nerve stimulation are undefined, as is the analgesic effect of physical therapy... However, despite the lack of experimental evidence for their efficacy, clinical experience recommends the use of such modalities in conjunction with drug therapy as appropriate." (18)

• In their 2004 book Pain Management for the Small Animal Practitioner, Drs. William J. Tranquilli, Kurt A. Grimm, and Leigh A. Lamont state: "veterinarians have an increasing variety of nonpharmacologic options available for the prevention and treatment of both acute and chronic pain... Alternative analgesic therapies should undergo rigorous clinical testing to validate their role in the future of pain management." (2)

• In the April 15, 2005 issue of the Journal of the American Veterinary Medical Association (JAVMA), Editor-in-Chief Dr. Janis H. Audin acknowledges that "during the past 10 years, there has been heightened interest in the practice of alternative and complementary veterinary medicine" but "the decade-long debate on CAVM... has not contributed sufficient evidence to refute or substantiate the scientific merits of CAVM." (19)