SYMPOSIUM: A MULTIMODAL APPROACH TO TREATING OSTEOARTHRITIS

EOARTHRITIS • A MULT ING OST IMODAL TREAT APPRO H TO ACH T ROAC O TR APP EATIN DAL G O TIMO STE MUL OAR A THR ITIS • A MU LTIM ODA L AP AT PROA TRE CH TO TO TREATIN PROACH G OSTEOARTHRITIS • A MULTIMODAL AP

NSAIDs and nutraceuticals: What’s the evidence?

Multimodal management of osteoarthritis in dogs

Beyond NSAIDs for canine osteoarthritis patients: What other drug options exist?

Nutritional pain management: What is the evidence?

This symposium, sponsored by an educational grant from Novartis Animal Health US Inc., was presented at the 2007 Western Veterinary Conference.

NSAIDs and nutraceuticals: What’s the evidence? By Steven M. Fox, MS, DVM, MBA, PhD Director of Pain Management Novartis Animal Health Albuquerque, N.M.

Multimodal management of canine osteoarthritis is rapidly becoming the standard of care. This approach integrates nonmedical modalities (weight control and exercise, eicosapentaenoic acid [EPA]-rich diets, and physical rehabilitation) with medical modalities (nonsteroidal anti-inflammatory drugs [NSAIDs], chondroprotectants, and adjunct drugs). The founding tenet of this approach is to achieve the lowest effective pharmaceutical dose which will minimize the potential for adverse drug reactions yet provide an optimal quality of life.

The evidence base for these selected modalities can be taken gait, the velocity and acceleration of changes in joint angles, from the pyramid of evidence (Figure 1, page 3), in which the stride length, gait swing, and stance times. Kinematic evaluation most credible evidence is systematic (meta-analytic), well- is often combined with force platform gait analysis, providing designed, properly randomized, controlled, patient-centered a powerful method of detecting abnormalities and therapeutic clinical trials. These data provide the most reliable predictors response. While several manufacturers have generated compara- of results likely to be seen in clinical practice and can be tive efficacy data between one or two drugs or between a prod- ranked from 1 (highest) to 4. Based on the rules of evidence, uct and placebo, a noncommercially funded study compared NSAIDs, chondroprotectants, adjunct drugs, weight control, many contemporary NSAIDs given at the labeled dose in a EPA-rich diets, and physical rehabilitation are considered at canine osteoarthritis model where responses were assessed by the top of the pyramid.1* objective force plate analysis. Together with efficacy, safety is a determining criterion for NSAIDs most clinicians in selecting an NSAID. The gastrointestinal sys- By virtue of Food and Drug Administration (FDA) licensing, tem is most commonly documented as ill-tolerant of NSAIDs, contemporary NSAIDs show proven efficacy and safety. While followed by the renal and hepatic systems. Data regarding gas- some NSAIDs have greater potential for molecule-specific trointestinal adverse events observed during the developmental adverse effects, they are all relatively safe, and virtually no trials of all FDA-approved NSAIDs are available on package credible evidence differentiates the FDA-approved NSAIDs inserts. These data seem to suggest (as in people3) that COX-1- based on safety. However, research suggests that some sparing NSAIDs produce fewer gastrointestinal adverse events. NSAIDs may be more efficacious than others (Table 1, page Vomiting is particularly noteworthy; a recent investigation 4).2 In general, objective assessments are more credible and demonstrated that vomiting was the most common clinical sign repeatable than subjective assessments. A major shortcoming seen with NSAID-associated gastric perforation.4 of subjective assessment is the dependence on the observer’s Licensing data suggest what can be expected with broader skill in making and recording valid assessments and the ability use; however, only after a drug has been administered to a to accurately recall historical data and make meaningful com- large population of animals is its true profile apparent. Finding parisons over long periods of time, as well as capture subtle reliable data that can be used to compare the safety of currently changes over time or among different patients. used NSAIDs is virtually impossible, principally because not Measuring ground reaction forces is the most common way all adverse events are reported, not all reports are determined to objectively assess weight bearing in dogs. Using a force plate causal, and there is no accurate way to determine the frequency platform, investigators can compare with certainty the degree of use for any given NSAID. Nonetheless, adverse drug event of lameness over a period of time. Kinematic gait analysis, or databases strongly suggest that adverse responses could be motion analysis, is used less frequently than force platform reduced 75% to 80% simply by rigorous attention to responsi- analysis, but its use is increasing in research laboratories. ble use.5 This includes attention from veterinarians, staff mem- Kinematic evaluation measures changes in joint angles with bers, and pet owners.

2 ©2007 Novartis Animal Health US Inc. www.novartis.com All rights reserved. Cover art by Ryan Kramer. Nutraceuticals Figure 1: Systematic Next to NSAIDs, nutraceuticals are the fastest growing group Pyramid reviews of healthcare products in both human and animal health. A of evidence Randomized nutraceutical is defined as a food additive that is given orally controlled studies and, as such, is not regulated by the FDA. In contrast, chon- Epidemiologic studies droprotectants are FDA-regulated. Together, chondroprotec- (cohort, case control) tants and nutraceuticals are considered disease modifying Models of disease osteoarthritic agents, whereas nutraceuticals are not consid- ered disease modifying osteoarthritic drugs. More than 30 Case series nutraceutical products have been listed as potentially active in Case reports osteoarthritis.6 Avocado-soybean unsaponifiables are a recent Research in other species entry to the nutraceutical pool. These compounds may pro- Pathophysiologic rationale mote osteoarthritic cartilage repair by preventing the inhibito- Ideas, editorials, opinions ry effect of subchondral osteoblasts on aggrecan synthesis.7 Osteoarthritis is among the most frequent and sympto- In vitro research matic medical problems for middle-aged and older people, afflicting an estimated 12% of people ages 25 to 74 in the osteoarthritis-related joint pain, tenderness, and swelling.15 United States.8 NSAIDs are the foundation for treating osteo- The rationale for using nutraceuticals is that providing arthritis; however, ongoing controversy over conventional cartilage matrix precursors in excess quantities may favor medications has created fertile soil for the growth of alterna- matrix synthesis and repair of articular cartilage. Glucosamine tive remedies, particularly glucosamine and chondroitin. First is an amino monosaccharide that is proposed to act as a pre- popularized by the 1997 best-selling book The Arthritis Cure, cursor of the disaccharide units of glycosaminoglycans, such by Jason Theodosakis, MD, these supplements racked up com- as hyaluronan and keratin sulfate. Chondroitin sulfate is a bined sales of $640 million in 2000, according to the Nutri- glycosaminoglycan and a normal constituent of cartilage. To tion Business Journal. Estimated sales of glucosamine and date, there is no evidence that nutraceuticals modulate the chondroitin sulfate for use in people approached $730 million natural course of osteoarthritis. Their inclusion in foods is in 2004.9 It appears that the popularity of these supplements based on theoretical considerations. Therefore, although in people is driving veterinary use. The world market for pet nutraceuticals are often used in osteoarthritis cases, their nutraceuticals was $960 million in 2004. About 60% of this ability to prevent or slow the disease remains unproved.6 total was allocated to dogs, 25% to cats, and 10% to horses.10 The literature does support the use of glucosamine sulfate A meta-analysis of studies evaluating the efficacy of glu- as opposed to glucosamine hydrochloride in people with cosamine and chondroitin for osteoarthritis has suggested osteoarthritis of the knee.16 It is noteworthy that glucosamine potential benefits,11 but as is often the case with nutraceuti- sulfate is very hygroscopic and unstable, which is why cals, questions have been raised about the scientific quality varying amounts of potassium or sodium chloride are added of the studies. Therefore, the glucosamine-chondroitin arthri- during manufacturing. Researchers have reported that glu- tis intervention trial (GAIT), a 24-week, randomized, double- cosamine sulfate not only increases the expression of the blind, placebo- and celecoxib-controlled, multicenter, $14 mil- aggrecan core protein but also down-regulates the expression lion trial, was sponsored by the National Institutes of Health of matrix metalloproteinase-1 and -3 in a dose-dependent to rigorously evaluate the efficacy and safety of glucosamine manner.17 Some investigators have suggested that glucosa- hydrochloride, chondroitin sulfate, and the two in combination mine sulfate restores the adhesion of fibrillated cartilage for treating pain caused by knee osteoarthritis in people.12 The chondrocytes to fibronectin, thus improving the repair primary outcome measure was a 20% decrease in knee pain. process of osteoarthritic cartilage by allowing proliferated Analysis of the primary outcome measure did not show that cells to migrate to damaged areas.18 either supplement, alone or in combination, was efficacious. Pharmacokinetic studies in dogs reveal that glucosamine Discrepancies between this study and previous investigations hydrochloride is only 10% to 12% bioavailable from single suggesting efficacy may be explained, in part, by the rigors or multiple doses.19 At the current recommended intake, it is imposed by the National Institutes of Health and the use of extremely unlikely that a relevant concentration of glucosa- only pharmaceutical-grade supplements in the GAIT study. mine reaches the joint20 or is circulated after oral ingestion.21 Many nutraceuticals are least-cost formulations and quality Glucosamine is most likely metabolized rapidly by the liver assurance is often deficient or nonexistent.13,14 As a matter of or incorporated into glycoproteins; it is not ordinarily avail- record, in 2005 the FDA rejected 12 model claims related to able in circulation as a source of cartilage matrix substrate— glucosamine and chondroitin’s ability to reduce the risk of cartilage uses glucose for that purpose. osteoarthritis, joint degeneration, cartilage deterioration, and Charged molecules exceeding approximately 180 daltons

SPONSORED BY NOVARTIS 3 Table 1: Comparison of NSAID efficacy studies used for FDA approval

Drug Primary assessment method Ground reaction force assessment Carprofen Subjective owner and veterinary assessment No significant difference between indicated improvement more likely in treated dogs. placebo dogs and treated dogs. Etodolac Ground reaction forces Peak vertical force improved 0.4%, 2.3%, and 1.6% with placebo, low-dose, and high-dose treatments, respectively. Vertical impulse improved 0.4%, 0.13%, and 0.22%, respectively. Deracoxib Ground reaction forces Peak vertical force improved 7.4% with treatment vs. placebo. Vertical impulse improved 4.9% with treatment compared with placebo. Tepoxalin Subjective changes compared with Not measured carprofen; no placebo comparison. Subjective improvement similar to carprofen. Meloxicam Subjective assessment of lameness, weight-bearing, Not measured pain on palpation, and overall improvement compared with placebo. Significant improvement noted on Day 14 of one 14-day study. Significant improvement noted in the parameter of overall assessment on Day 7 by veterinary assessors and on Day 14 by owners in a second study. Firocoxib Subjective comparison to etodolac. Ground reaction forces were determined No comparison to placebo. Subjective in a subset of patients. Results were com- efficacy comparable to etodolac. parable between firocoxib and etodolac.

are not likely to be absorbed from the gastrointestinal tract un- ty in inflamed joints and enhance anabolic enzyme activi- less assisted by a carrier-mediated transport system; therefore, ty. Polysulfated glycosaminoglycans also have been shown it is also unlikely that chondroitin sulfate is absorbed intact. to significantly inhibit serine proteinases, which play a The gastric mucosa contains a number of glycosaminoglycan- role in the cartilage proteoglycan and collagen degrada- degrading enzymes, which should degrade chondroitin sulfate. tion. Polysulfated glycosaminoglycans have further been Controversy remains over the mechanisms by which nutra- reported to inhibit catabolic enzymes that degrade colla- ceuticals may help modulate disease symptoms and slow car- gen, proteoglycans, and hyaluronic acid. They are also tilage degradation in osteoarthritis, as well as which product is reported to inhibit prostaglandin E synthesis. Finally, preferred for treatment. Perhaps the scientific community lacks polysulfated glycosaminoglycans have shown a specific the expertise to identify how these products work. Neverthe- potentiating effect on hyaluronic acid synthesis by syn- less, as a class of agents, nutraceuticals fall short in evidence- ovial membrane cells in vitro.22 based efficacy, lack titration studies to validate appropriate doses, and show inconsistent quality. A sound recommen- Conclusion dation for consumers is “buyer beware.” For veterinarians, The evidence shows that, when used responsibly, all FDA- the most responsible way to recommend a nutraceutical may approved NSAIDs are safe and effective. It is the veteri- be as an adjunct to a science-based medicinal, with a clear narian’s responsibility to select the optimal NSAID for each explanation that the nutraceutical may—or may not—help. individual patient. The evidence base is also strong for poly- Recommending that the pet owner use a nutraceutical as a sulfated glycosaminoglycans. In contrast, although nutraceu- first-line treatment is without scientific underpinning. ticals appear to cause no harm, evidence-based support for their efficacy is weak. Nutraceuticals should be considered Polysulfated glycosaminoglycans adjuncts to an evidence-based osteoarthritis treatment. Experiments conducted in vitro have shown that polysul- *To view this publication and a complete reference fated glycosaminoglycans inhibit catabolic enzyme activi- list online, visit www.advanstarvhc.com/c1

4 SYMPOSIUM: A MULTIMODAL APPROACH TO TREATING OSTEOARTHRITIS NSAIDs and nutraceuticals: What’s the evidence? By Steven M. Fox, MS, DVM, MBA, PhD

References 1. Fox SM. The power of multimodal management for canine osteoarthri- tis. Novartis Animal Health, Greensboro, N.C., 2006:1-8. With Vet Med 101(6). Sponsored symposium proceedings. 2. Millis DL. Nonsteroidal anti-inflammatory drugs, disease-modifying drugs, and osteoarthritis. Novartis Animal Health, Greensboro, N.C., 2006: 9-19. With Vet Med 101(6). Sponsored symposium proceedings. 3. Singh G, Fort JG, Goldstein JL. Celecoxib versus naproxen and diclofenac in osteoarthritis patients: SUCCESS-I study. Am J Med 2006; 119:255-266. 4. Lascelles BD, Blikslager AT, Fox SM, et al. Gastrointestinal tract perfo- ration in dogs treated with a selective cyclooxygenase-2 inhibitor: 29 cases (2002-2003). J Am Vet Med Assoc 2005;227:1112-1117. 5. Pharmacovigilance summary: 3-year clinical experience with Deramaxx (deracoxib). Novartis Animal Health, Greensboro, N.C. Data on file, 2006. 6. Henrotin Y. Nutraceuticals in the management of osteoarthritis: an overview. J Vet Pharmacol Ther 2006;29(Suppl 1):201-210. 7. Henrotin YE, Deberg MA, Crielaard JM, et al. Avocado/soybean unsaponifiables prevent the inhibitory effect of osteoarthritic subchondral osteoblasts on aggrecan and type II collagen synthesis by chondrocytes. J Rheumatol 2006;33:1668-1678. 8. Lawrence RC, Helmick CG, Arnett FC, et al. Estimates of the preva- lence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 1998;41:778-799. 9. Annual nutrition industry overview. Nutr Bus J 2005;10:6-7. 10. Nutraceuticals in the animal health industry. Animal Pharm Report 2005 Oct. Available at: www.animalpharmreports.com. Accessed Nov 9, 2006. 11. McAlindon TE, LaValley MP, Gulin JP, et al. Glucosamine and chon- droitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA 2000;283:1469-1475. 12. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sul- fate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006;354:795-808. 13. Adebowale AO, Cox DS, Liang Z, et al. Analysis of glucosamine and chondroitin sulfate content in marketed products and the Caco-2 permeability of chondroitin sulfate raw materials. J Am Nutraceut Assoc 2000;3:37-44. 14. Russell AS, Aghazadeh-Habashi A, Jamali F. Active ingredient consis- tency of commercially available glucosamine sulfate products. J Rheumatol 2002;29:2407-2409. 15. Food and Drug Administration. Available at: www.fda.gov/ohrms/ dockets/dailys/04/oct04/101304/04p-0060/pdn0001-toc.htm. Accessed April 27, 2005. 16. Rovati LC. Clinical development of glucosamine sulfate as selective drug in osteoarthritis. Rheumatology in Europe 1997;26:70. 17. Dodge GR, Hawkins DF, Jimenez SA. Modulation of aggrecan, MMP1 and MMP3 productions by glucosamine sulfate in cultured human osteoarthritis articular chondrocytes. Arthritis Rheumatol 1999;42(suppl):253. 18. Piperno M, Reboul P, Hellio Le Graverand MP, et al. Glucosamine sul- fate modulates dysregulated activities of human osteoarthritis chondrocytes in vitro. Osteoarthritis Cartilage 2000;8:207-212. 19. Adebowale A, Du J, Liang Z, et al. The bioavailability and pharmaco- kinetics of glucosamine hydrochloride and low molecular weight chondroitin sulfate after single and multiple doses to beagle dogs. Biopharm Drug Dispos 2002;23:217-225. 20. Setnikar I, Palumbo R, Canali S, et al. Pharmacokinetics of glu- cosamine in man. Arzneimittelforschung 1993;43:1109-1113. 21. McAlindon T. Why are clinical trials of glucosamine no longer uni- formly positive? Rheum Dis Clin North Am 2003;29:789-801. 22. Adequan Canine product label and insert, Novartis Animal Health, Greensboro, N.C.

SPONSORED BY NOVARTIS Multimodal management of osteoarthritis in dogs By Denis Marcellin-Little, DEDV, DACVS, DECVS, CCRP Clinical Sciences Department College of Veterinary Medicine North Carolina State University Raleigh, N.C.

Osteoarthritis is a ubiquitous disease in dogs and cats. While comprehensive epidemiological studies are not available, estimates indicate that more than one quarter of dogs and cats have the disease in one or more joints.1-6*

Because osteoarthritis is a lifelong progressive disease and alpha-2 adrenoreceptor agonists, γ-aminobutyric acid impacts the daily life of affected animals, it is critical for (GABA) agonists, and anticonvulsants. Nonpharmacologic veterinarians to establish long-term, sustainable management options for central pain management include low-level heat- programs for their patients. These programs must also be ing, massage, and possibly acupuncture, acupressure, and multifaceted because managing osteoarthritis involves multi- electro-acupuncture. Consider these nonpharmacologic treat- ple objectives: decreasing pain, restoring or maintaining joint ments to manage pain: mobility, maintaining or increasing strength, and maintaining Cold. Icing is always a good consideration for osteo- proprioception. This article will describe the treatment options arthritic pets with a sudden increase in clinical signs, that compose such a plan and the anticipated benefits of these described in humans as a flare or flare-up. Flares are part of options to dogs. the normal course of osteoarthritis. Over time, they become more frequent and more severe and tend to last longer. Pain and osteoarthritis Clinically, flares appear to result from excessive activity in Without appropriate pain relief, strengthening and maintaining unfit dogs—the weekend warrior syndrome—or events that joint mobility is rarely achievable. Relief is achieved by inter- place excessive stress on arthritic joints, like stepping in a fering with the peripheral (tissue inflammation and damage) hole. Flares may last several hours to several weeks. I do not and central (neuropathic; involving the central nervous sys- recommend making irreversible decisions, such as surgery tem) aspects of pain. or euthanasia, during flares because patients may appear Managing the peripheral component of osteoarthritis pain severely affected and often demonstrate dramatically hinges on pharmacologic treatment, specifically nonsteroidal, decreased mobility. Instead, focus on comprehensive pain anti-inflammatory drugs that decrease the transduction and management and rest. transmission of noxious stimuli in affected tissues and periph- Icing may also help after a period of exercise or before eral nerves. Local anesthetics are rarely used to alleviate bedtime. Ice cubes or frozen vegetables are not recommended peripheral pain. Nonpharmacologic, anti-inflammatory options because they have large air pockets that decrease cold con- for peripheral pain management include icing and massage. duction. Ice bags (filled with ice chips or crushed ice) or Icing provides direct pain relief by decreasing nerve conduc- cold packs provide more effective cold delivery. Most cold tion velocity.7,8 It also provides secondary pain relief by packs get cold after two hours in a freezer. For longhaired decreasing edema (itself a source pain) and decreasing the patients, place and hold an ice bag or cold pack directly on overactivity of catabolic enzymes in osteoarthritic cartilage. the pet’s arthritic joint or joints and secure it with a self- The short- and long-term effects of massage in companion adhesive band. A thin towel may be used between the cold animals are not known. Massage may decrease myofascial pack or bag and the skin in patients with short or no hair. pain and muscle tension. Some cold packs (Elasto-Gel—Southwest Technologies Inc., Managing the central component of osteoarthritis pain Kansas City, MO) have a built-in self-adhesive band. A neo- revolves around several classes of pharmacologic treat- prene sleeve (DogLeggs LLC—Reston, VA) may also be used ments: opiates, N-methyl-D-aspartate (NMDA) inhibitors, to secure a cold pack or bag. Continue icing for 10 to 15

SPONSORED BY NOVARTIS 5 minutes. Most patients tolerate the treatment, but whoever Figure 1 is applying the ice should make sure the patient is not un- comfortable and that the skin surface feels cold to the touch after icing is complete. Heat. Heat is widely considered to positively impact painful osteoarthritis patients. The use of heat is two-fold. Low-level heat (elevation of tissue temperature by 1 C to 2 C) relieves pain through the stimulation of non-nociceptive

Aβ sensory fibers, as well as the vasodilation and normal- ization of blood flow.8 This low-level tissue relaxation may be achieved by keeping osteoarthritic patients in A hip joint is gently stretched after being heated with a relatively dry and warm temperatures throughout the day moist heat pack. Note the joint’s limited ability to flex. (e.g., sleeping in heated indoor environments or providing Figure 2 heated beds). More intense heat (elevation of tissue temperature by 3 C to 4 C) is used to increase the effectiveness of stretching while minimizing tissue damage. Intense heating is most often applied by a healthcare professional who uses a hot pack that is heated by a hydrocollator or microwave oven (Therabead—Duro-Med Industries, Shelton, CT). A dry towel is generally placed between the hot pack and the skin, and heat is generally applied for 15 to 20 minutes. Caution must be used when placing a hot pack on a dog because burns can occur. Initially, the packs may not The change in slope of a dogwalk promotes appear excessively hot to the touch, but they can induce back-to-front weight shifting. (Photo: Fiona Hulse, Agility Addicts) thermal damage after several minutes of contact. There- fore, it’s important to check for excessive redness, skin swelling, or blistering every few minutes during intense- Table 1: Therapeutic exercises included heat therapy. in canine osteoarthritis Nutritional changes. Osteoarthritis pain is also re- management programs duced through a decrease in cell membrane concentrations of the omega-6 fatty acids that are precursors of arachi- Possible donic acid, a key player in osteoarthritic inflammation. Purpose therapeutic exercises Increasing the nutritional intake of eicosapentaenoic acid Increasing limb strength Daily walk or trot longer than (EPA), an omega-3 fatty acid, has been shown to decrease 10 minutes; tunnel-walk osteoarthritic pain by decreasing arachidonic acid concen- repetitions; sit-to-stand and trations and increasing EPA concentrations in the cell stand-to-sit repetitions membranes of canine chondrocytes.9 Green-lipped mussel (pelvic limb strengthening) supplements also appear to alleviate the clinical signs of 10,11 Increasing core strength Daily walk or trot longer than osteoarthritis in dogs, although the reasons they are 10 minutes; swimming beneficial are unknown. Transcutaneous electrical nerve stimulation (TENS). Increasing cardiovascular Daily walk or trot longer than This purely sensory form of electrical stimulation has been fitness 10 minutes shown to provide pain relief in people with osteoarthritis,12 Stretching pelvic limbs Climbing up slopes, hills, and and it seems readily adaptable to dogs. The common treat- stairs; low jumps ment duration for dogs is 20 to 30 minutes per session. The main disadvantage of TENS is it requires clipping of the Stretching forelimbs Walking downhill; teeter-totter affected areas. or pole-weaving Home modifications and restrictions. Pain relief from Increasing proprioception Daily walk or trot longer than osteoarthritis may also be obtained through the enhance- 10 minutes; walk on soft ment of ergonomics (i.e., making all daily activities of surfaces: sand, mulch, gravel, osteoarthritic dogs easier and safer) and by modifying rest- leaves, grass; teeter-totter or ing and sleeping surfaces, avoiding unnecessary jumps, and pole-weaving exerting proper control over dogs during activity.

6 SYMPOSIUM: A MULTIMODAL APPROACH TO TREATING OSTEOARTHRITIS Restoring or maintaining mobility patients with joint injuries that have sensory deficits.13 In Osteoarthritis influences joint mobility in several ways. older people with decreased proprioception, balance exer- With chronic osteoarthritis, joint capsules become thicker cises readily improve proprioception. In dogs with osteo- and stiffer, and joint motion may be decreased. Some joints arthritis, it is logical to dedicate a small portion of thera- are more vulnerable to loss of motion than others. The loss peutic exercise programs to exercises requiring rapid and of motion associated with osteoarthritis in dogs has not unpredictable side-to-side weight shifts and, to a lesser been assessed scientifically. Clinically, flexion is often extent, front-to-back and back-to-front weight shifts. lacking in arthritic elbows and tarsi. Extension is often These exercises may include walking on soft or irregular lacking in arthritic hips. Near maximal joint motion surfaces and gentle agility exercises, including pole weav- (hyperflexion, hyperextension) is often the source of ing and walking on a teeter-totter, dogwalk, or over low severe acute pain. rails (Figure 2, page 6). Dogs learn to avoid placing their joints in painful posi- tions. For example, a dog with hip dysplasia may refuse to Putting it all together climb stairs. The fact that dogs with osteoarthritis modify Some osteoarthritic dogs have minor problems, such as their activities, gait, and joint motion during locomotion mild lumbar spondylosis. The main focus of osteoarthritis and rest creates a vicious circle: a joint hurts in flexion, the management for these patients is an exercise program that dog does not flex the joint, flexion is progressively lost be- will decrease pain, maintain limb and core strength, stretch cause of underuse, the pain increases because less flexion the joints, and stimulate proprioception. For pets with mild is available, and so on. Therefore, once an osteoarthritic osteoarthritis, pain management is generally achieved with dog’s pain is managed with rest and medications, it is logi- simple pharmacologic steps, rest, and exercise supervision cal to promote exercises that gently stretch arthritic joints and customization. Pharmacologic and other forms of pain (Figure 1, page 6), which helps maintain as much joint relief may be intermittent as long as pets adhere to a long- motion as possible. term exercise program. Because osteoarthritis screening is not done routinely in Maintaining or increasing strength dogs and cats, osteoarthritis is often discovered in its later Muscle strength decreases in arthritic limbs partly because stages. Losing mobility because of severe osteoarthritis is of disuse. When pets encounter joint pain, two responses common in large-breed dogs. In a lifelong study involving occur: neurogenic inhibition of muscle contractions and a seven litters of Labrador retrievers, the mobility loss caused decrease in mitochondrial performance in muscle fibers. by osteoarthritis was the most common reason for euthan- The latter leads to qualitative loss of strength beyond the asia.14 Similarly, osteoarthritis is a major reason for euthana- quantitative loss caused by the muscle mass decrease. The sia of military working dogs.15 lack of activity causes these pets to progressively lose car- For patients with severe osteoarthritis, it is critically diovascular fitness. important to implement all possible support strategies to Over time, even modest physical activity helps osteo- decrease the impact of the disease on pets’ well-being arthritic pets increase and maintain muscle strength, reduce and mobility. These may include multimodal pharmaco- the loss of muscle mass, and increase cardiovascular fitness. logic management, ice, heat, massage, acupuncture, acu- Table 1 (page 6) lists some exercises that are suitable for pressure, electroacupuncture, TENS, and rest. Once pain osteoarthritic dogs, such as walking and trotting. The is managed, it is important to begin an initially conserva- motion and speed of these activities should be controlled tive and subsequently progressive exercise program. using a step-in dog harness and 6-foot-long leash. Trotting Patients with severe osteoarthritis may need temporary is the most fundamental therapeutic exercise. It increases or permanent ambulation assistance. Slings (Walkabout limb and core strength and enhances a weight management Harnesses—Santa Cruz, CA) are the most common and program by boosting metabolism. cost-effective ambulation-assistance devices. Severely Initially, veterinarians should select a few exercises that impaired dogs may benefit from an ambulation cart are tailored to the needs of the patient, with consideration (Doggon’ Wheels—Bozeman, Mont. and Eddie’s Wheels given to the intensity, duration, frequency, and location. The for Pets—Shelburne Falls, Mass.). patient should be willing and able to perform these exercis- Overall, a management program for companion animals es before the owner is asked to oversee them without pro- with osteoarthritis should be simple and logical. Managing fessional supervision. pain is the first priority for all patients. The program must then address the most critical aspects of each patient’s Proprioception and osteoarthritis unique situation and, over time, improve the patient’s mobil- While little is known about the negative impact of naturally- ity, strength, proprioception—and above all—quality of life. occurring osteoarthritis on proprioception in dogs, there is *To view a complete reference clear evidence that osteoarthritis progresses rapidly in list online, visit www.advanstarvhc.com/c1

SPONSORED BY NOVARTIS 7

Multimodal management of osteoarthritis in dogs By Denis Marcellin-Little, DEDV, DACVS, DECVS, CCRP

References 1. Smith GK, Paster ER, Powers MY, et al. Lifelong diet restriction and radi- ographic evidence of osteoarthritis of the hip joint in dogs. J Am Vet Med Assoc 2006;229:690-693. 2. Banfield CM, Bartels JE, Hudson JA, et al. A retrospective study of canine hip dysplasia in 116 military working dogs. Part II: Clinical signs and perform- ance data. J Am Anim Hosp Assoc 1996;32:423-430. 3. Godfrey DR. Osteoarthritis in cats: a retrospective radiological study. J Small Anim Pract 2005;46:425-429. 4. Hardie EM. Management of osteoarthritis in cats. Vet Clin North Am Small Anim Pract 1997;27:945-953. 5. Clarke SP, Mellor D, Clements DN, et al. Prevalence of radiographic signs of degenerative joint disease in a hospital population of cats. Vet Rec 2005;157:793-799. 6. Lund EM, Armstrong PJ, Kirk CA, et al. Health status and population characteristics of dogs and cats examined at private veterinary practices in the United States. J Am Vet Med Assoc 1999;214:1336-1341. 7. Oosterveld FG, Rasker JJ. Treating arthritis with locally applied heat or cold. Semin Arthritis Rheum 1994;24:82-90. 8. Lehmann JF, Warren CG, Scham SM. Therapeutic heat and cold. Clin Orthop Relat Res 1974;Mar-Apr(99):207-245. 9. Innes J. Diet and disease: Exploring the link through nutrigenomics. Can Vet J 2006;47:68-70. 10. Bui LM, Bierer TL. Influence of green lipped mussels (Perna canaliculus) in alleviating signs of arthritis in dogs. Vet Ther 2003;4:397-407. 11. Servet E, Biourge V, Marniquet P. Dietary intervention can improve clini- cal signs in osteoarthritic dogs. J Nutr 2006;136(suppl 7):1995S-1997S. 12. Osiri M, Welch V, Brosseau L, et al. Transcutaneous electrical nerve stim- ulation for knee osteoarthritis. Cochrane Database Syst Rev 2000(4):CD002823. 13. Brandt KD. Neuromuscular aspects of osteoarthritis: A perspective. Novartis Found Symp 2004;260:49-58 (discussion 58-63, 100-104, 277-279). 14. Lawler DF, Evans RH, Larson BT, et al. Influence of lifetime food restric- tion on causes, time, and predictors of death in dogs. J Am Vet Med Assoc 2005;226:225-231. 15. Moore GE, Burkman KD, Carter MN, et al. Causes of death or reasons for euthanasia in military working dogs: 927 cases (1993-1996). J Am Vet Med Assoc 2001;219:209-214.

SYMPOSIUM: A MULTIMODAL APPROACH TO TREATING OSTEOARTHRITIS Beyond NSAIDs for canine osteoarthritis patients: What other drug options exist?

By B. Duncan X. Lascelles, BSc, BVSc, PhD, MRCVS, CertVA, DSAS (ST), DECVS, DACVS Comparative Pain Research Laboratory College of Veterinary Medicine North Carolina State University Raleigh, N.C.

Osteoarthritic disease is the most common cause of chronic pain in dogs, involving about 20% of the U.S. canine population, or up to 12 million dogs.1-3* Clinical experience4 and a review of experimental studies5-7 reveal that nonsteroidal anti-inflammatory drugs (NSAIDs) may not provide complete pain relief in all cases of canine osteoarthritis. In human medicine, a multimodal pharmacologic approach is used frequently for chronic pain associated with osteoarthritis.8-11 A multimodal approach has also been suggested for the alleviation of chronic pain in veterinary species.4

This suggestion stems from the recent understanding of cen- Integrating NSAID, adjunctive drug, tral nervous system changes that result from the constant and nondrug therapies input of noxious signals from the periphery. Pain transmission The benefit of nondrug therapies in osteoarthritis pain manage- involves multiple pathways, mechanisms, and transmitter ment is also relatively undefined in the veterinary literature. systems.12-14 Therefore, it is unlikely that a single class of anal- Clinically, the analgesic therapeutic effects of acupuncture,16-19 gesic, whatever the dose, will provide complete pain relief. electroacupuncture, acupressure, and transcutaneous electrical Clinical experience confirms this. The combination of two or nerve stimulation have not been fully investigated, nor has the more classes of analgesics (e.g., concurrent use of opioids, analgesic effect of physical therapy (cold and heat therapy; mas- NSAIDs, and local anesthetics) is more effective for perioper- sage therapy; passive physiotherapy; hydrotherapy; and active ative pain control.15 controlled exercise, including swimming) been fully evaluated.20 A similar multimodal approach is recommended for chron- However, despite the lack of experimental evidence for their ic pain management, such as that associated with cancer or efficacy, clinical experience supports the use of such modalities osteoarthritis.4 The analgesic effect from these drugs is often in conjunction with NSAID and adjunctive drug therapy as appro- synergistic. Therefore, smaller doses of the individual drugs priate. The desired clinical outcome is better control of patient can be used, thus decreasing the likelihood of side effects discomfort and an overall decrease in the amount of drugs needed. from any one drug. In 2002, the American Pain Society published the first However, there is no published scientific evidence that evidence-based, multidisciplinary arthritis pain management multimodal drug therapy is of benefit over monomodal thera- guideline.21 This document outlines the detrimental effects of py in veterinary patients suffering from osteoarthritis. Any untreated chronic pain, the need for comprehensive pain suggestions and recommendations are based on information assessment, and the evidence-based medicine recommenda- extrapolated from the human literature or clinical experience. tions for multimodal drug therapy and concurrent multimodal The effectiveness and toxicity of multimodal therapy is an nondrug therapy. The use of multiple classes of drugs and the area of active research in veterinary medicine, and recommen- integration of drug and nondrug therapies can be called inte- dations may change as data are generated. grated multimodal pain therapy.

8 SYMPOSIUM: A MULTIMODAL APPROACH TO TREATING OSTEOARTHRITIS Rationale for adjunctive drug use dogs is encouraging.37 Animals with chronic osteoarthritis Adjunctive drugs are used together with NSAIDs to provide were treated with a low dose of ketoprofen (0.25 mg/kg orally greater osteoarthritic pain relief. Adjunctive drug classes include once daily) or low dose ketoprofen plus tramadol (5 mg/kg of opioids, N-methyl-D-aspartate (NMDA) receptor antagonists, prolonged release form orally once daily) for 28 days. Dogs tricyclic antidepressants, anticonvulsants and calcium channel receiving both drugs had a significant improvement in pain blockers, sodium channel blockers, and polysulfated glycos- scores, and even after treatment was discontinued, they con- aminoglycans. The most commonly used drugs are amantadine, tinued to improve. The dogs in the ketoprofen-only group tramadol, gabapentin, amitriptyline, and Adequan (Luitpold remained static and had more incidences of acute flare-ups Pharmaceuticals—Shirley, N.Y.) (see Table 1, page 10). than the other dogs after the end of treatment. Opioids. Opioids act at all levels of the pain pathway— NMDA antagonists. The NMDA receptor plays a key peripherally and centrally at the spinal cord and at higher role in inducing and maintaining central sensitization,38,39 a centers. Four opioid receptors have been cloned: mu, delta, change that appears to be present in chronic pain states. The kappa, and ORL-1. Little progress has been made on the use of NMDA receptor antagonists appears to be of benefit in development of synthetic opioid drugs that will produce anal- arthritis models where central sensitization is present.40 Given gesia without the classic opioid side effects in dogs, such as that even a brief noxious input to the spinal cord can induce sedation and gastrointestinal ileus leading to constipation. In central changes, NMDA antagonists have been studied in the the next few years, most progress with opioids will probably treatment of most types of pain.41 NMDA receptors have also be made by defining their interactions with other systems. For been found on unmyelinated axons in the peripheral nervous example, there appears to be an interaction between the system, suggesting that they play a role in primary nocicep- NMDA receptor and the opioid receptor in the dorsal horn of tion. Memantine, amantadine, ketamine, and dextromethor- the spinal cord and a positive interaction between the alpha-2- phan are uncompetitive NMDA antagonists that have been receptor and opioid receptor. Harnessing these interactions by used clinically in people with neuropathic pain. However, using a multimodal analgesic approach should provide greater there are no reports of NMDA antagonists being used to treat therapeutic effects in the future. Recently, there has been osteoarthritis pain in people. Research indicates that dogs interest in redefining the role of opioids and opioid derivatives probably do not make the active metabolite from dex- in chronic pain states in people,22-25 and both the American tromethorphan necessary for NMDA blockade.42 and Canadian pain societies have endorsed the use of opioids In collaboration with James Gaynor, DVM, MS, DACVA, I for osteoarthritis as part of a multimodal approach.21,22 have been evaluating the NMDA antagonist amantadine (3 to Transdermal fentanyl can be used but is expensive for 5 mg/kg orally once daily) as an adjunct to NSAID use in long-term use, and recent concerns about its safety in people26 canine osteoarthritis and consider it to augment pain relief may lead manufacturers to pull fentanyl patches from the with a low incidence of side effects (agitation and diarrhea). market in the future. The recent advent of buprenorphine The dose of amantadine was decided upon on the basis of patches in human medicine hold promise for providing known kinetics,43 clinical observations, and pilot data. longer-term pain relief than with fentanyl patches.27-29 The Although I have not performed toxicity studies on amanta- buprenorphine patch has not been evaluated in dogs, but dine, others have.43,44 In repeated studies conducted over a research has been performed in cats.30 two-year period, a dose of 40 to 80 mg/kg resulted in deaths Oral opioid medications, such as codeine, codeine- after 30 weeks of administration, a dose of 40 mg/kg resulted combination drugs (such as acetaminophen with codeine), in one death (out of eight dogs) after 47 weeks of adminis- morphine, methadone, and butorphanol, can be administered tration, and a dose of 8 mg/kg was not associated with any to dogs, although very little is known about their efficacy in adverse signs. The deaths were attributed to vomiting and dogs. Oral opioids are subject to a high first-pass effect in the seizures. In my experience and based on the results of a liver, and recent work has demonstrated that oral morphine recently completed clinical trial in my laboratory, the oral and oral methadone are not well absorbed in dogs, casting NMDA antagonist amantadine appears to be effective in treat- doubt on their efficacy as canine analgesics.31,32 This area ing canine osteoarthritis when combined with an NSAID. The needs further research—both to define the potential overall development of more specific NMDA antagonists is an excit- usefulness of oral opioids in dogs and to evaluate other ing area being pursued by several manufacturers. However, specific oral opioids, such as codeine and butorphanol. the development of clinically useful and targeted NMDA Oral tramadol, however, was found to be absorbed suffi- antagonists is hampered because the NMDA receptor exists in ciently.33 Tramadol is an opioid derivative that also has actions numerous forms, the form changes rapidly after nociceptive on the serotoninergic and alpha-adrenergic systems. Trama- input, and the form and quantity may differ significantly from dol’s analgesic efficacy is a result of complex interactions one type of painful stimulus to another. between opiate, adrenergic, and serotonin receptor systems. It Tricyclic antidepressants. Tricyclic antidepressants have has been used successfully in osteoarthritis pain management been used for many years for the treatment of chronic pain in people and is now recommended as part of a multimodal syndromes in people and are becoming widely used for the drug therapy for osteoarthritis pain control.34-36 One report in modulation of behavior disorders in animals. Given that

SPONSORED BY NOVARTIS 9 Table 1: Adjunctive drugs used in canine osteoarthritis pain management*

Drug Dose for dogs Comments Amantadine 3 to 5 mg/kg • May take up to two weeks to see positive effects orally once daily • Side effects appear to be mild agitation in some dogs • Marketed as 100 mg capsules. Suggest one capsule for dogs weighing 20 to 37 kg, and two capsules for dogs weighing 37 to 65 kg.

Amitriptyline 0.5 to 2 mg/kg • Bitter taste orally once daily • Should not be used concurrently with tramadol

Gabapentin 5 to 10 mg/kg • Most common side effect appears to be sedation orally twice daily (up to 10 mg/kg three times daily)

Polysulfated 5 mg/kg intramuscularly • No noted side effects glycosaminoglycan twice weekly for four (Adequan) weeks, then once a month

Tramadol 4 to 5 mg/kg orally • Side effects appear to be sedation twice or three times daily and vomiting (likely opioidergic effects) • Should not be used concurrently with amitriptyline

* This table outlines the doses for some of the adjunctive oral drugs used by the author to help alleviate chronic osteoarthritis pain in dogs. Although all of these drugs are available in the United States, not all are approved for use in dogs. Most of the drugs have not had comprehensive efficacy, kinetic, or toxicity stud- ies carried out in dogs and are being used empirically based on extrapolation from human medicine and clinical experience. There has been no comprehensive evaluation of the toxicity when these drugs are administered simultaneously. Evaluation of these drugs is being undertaken by a number of investigators, and new information may result in changes in the recommended doses. These drugs are for use in combination with NSAIDs, steroids, or acetaminophen; howev- er, they can also be used on their own to provide pain relief in canine osteoarthritis.

many behavioral disorders are due to chronic pain, tricyclic analogue of gamma-aminobutyric acid, and the more recent- antidepressants may not directly affect behavior but rather the ly introduced pregabalin, appear to be the most effective of pain itself, which results in behavior modification. Antide- the anticonvulsants for neuropathic pain. Their mechanism pressants, such as amitriptyline, clomipramine, imipramine, of action appears to be binding to the alpha-2-delta subunit maprotiline, fluoxetine, and paroxetine primarily inhibit the of calcium channels, thereby modulating the activity of cal- reuptake of various monoamines (such as serotonin and norepi- cium channels. Calcium channels participate in the process nephrine). Many of these drugs have mixed actions, which may of nociceptive transmission at the level of the neuronal be an added benefit (e.g., amitriptyline has some effect on the synapse in the central nervous system. Calcium channel norepinephrine system and on histidine and cholinergic recep- modulators have been demonstrated to reduce pain, allody- tors). These drugs have been used in people for the treatment of nia, and hyperalgesia. The indications for their use are chronic and neuropathic pain at doses considerably lower than unclear for veterinary patients, but they may be useful as an those used to treat depression. Amitriptyline has been used adjunct to other analgesics, especially for neurogenic pain, successfully for feline interstitial cystitis,45 a syndrome associ- neuropathic pain, and pain from certain cancers, such as ated with chronic pain, but as of yet, the use of these drugs in bone tumors. Although there is considerable information on animals has not been systematically evaluated. Tricyclic anti- gabapentin as an anticonvulsant in dogs, there is no peer- depressants should probably not be used concurrently with reviewed information on its use for osteoarthritis pain, drugs that modify the serotoninergic system, such as tramadol. although recent studies in rats suggest it may play a role in Anticonvulsants and calcium channel blockers. Many the management of osteoarthritis pain.46 I use gabapentin for anticonvulsants, such as carbamazepine, phenytoin, baclo- neuropathic, neurogenic, and osteoarthritic pain at relatively fen, and gabapentin, have been used for chronic pain, includ- low doses of 5 to 10 mg/kg twice daily. ing neuropathic pain, in people. Gabapentin, a structural Sodium channel blockers. Alterations in the level of

10 SYMPOSIUM: A MULTIMODAL APPROACH TO TREATING OSTEOARTHRITIS expression, cellular localization, and distribution of sodium improvement in orthopedic scores, whereas dogs in the channels are strongly associated with neuropathic pain.47 placebo group showed the smallest improvement. However, Although not convenient for most patients, intravenous lido- the differences in clinical improvement among the four treat- caine has proven effective for neuropathic pain in people. I ment groups were not statistically significant.51 Overall, it have used it as part of an intravenous cocktail for the treat- appears that Adequan can have a mild analgesic effect and ment of neurogenic pain, such as nerve root entrapment pain, is compatible with other therapies mentioned and devoid of lumbosacral pain, and severe osteoarthritis pain. There is side effects. increasing interest in transdermal lidocaine patches for osteoarthritis in people.48 Currently no information exists on Neurobiologic signature of osteoarthritis how to use these agents safely and effectively in animals, In recent years, researchers have noted that chronic pain re- although one study has evaluated the kinetics of lidocaine sults in a unique set of changes in the peripheral and central absorbed from patches applied to dogs. Mexiletine, pheny- nervous system, and these changes vary depending on the toin, carbamazepine, oxcarbazepine, and lamotrigine have all disease. These changes have been referred to as the neurobi- demonstrated sodium channel blocking properties, but their ologic signature of the disease. Understanding the neurobio- use in people has been limited by logic signatures for different disease inconsistent efficacy, drug-drug processes should lead to the develop- interactions, and side effects. “Adjunctive drugs ment of novel, targeted, and more Polysulfated glycosaminogly- effective treatments.52 Currently, details cans. In the United States, one are drugs used of pain neurobiology associated with polysulfated glycosaminoglycan naturally occurring osteoarthritis are is approved by the Food and scant. Further research should allow for Drug Administration for dogs— together with more informed choices regarding effi- Adequan. It is used for the cacy of the currently available drugs. potential modification (decrease) NSAIDs to of osteoarthritis progression. Multimodal use of Theoretically, it modifies the adjunctive drugs disease cycle by reducing pro- provide greater Despite the scarcity of clinical evidence teoglycan degradation and inhi- to guide practitioners, the following biting cytokine synthesis and osteoarthritic points summarize a currently suitable activity. Adequan also stimulates approach to multimodal osteoarthritis glycosaminoglycan synthesis and pain management: results in an increased concentra- pain relief.” 1. NSAIDs, acetaminophen, or tion of hyaluronan. Adequan is a steroids usually form the analgesic base semisynthetic heparinoid, the major component of which when treating osteoarthritis pain, and all of the above-men- is chondroitin sulfate. The extra sulfate groups that are tioned drugs can be administered safely with them. synthetically added to chondroitin sulfate to produce 2. Generally, the above-mentioned drugs are most effec- polysulfated glycosaminoglycan appear to increase the tive when used with NSAIDs. But in dogs that are intolerant efficacy of this molecule in inhibiting enzyme activity. of NSAIDs, steroids, or acetaminophen (or where they are Presumably the extra sulfate groups increase the available contraindicated), these drugs can be used alone or in combi- charge area for interaction of polysulfated glycosamino- nation with each other. Amitriptyline and tramadol, however, glycan with active enzymes. should probably not be used concurrently. A number of studies have evaluated Adequan in a vari- 3. It appears that NSAIDs and the above-mentioned drugs ety of scenarios. One study has shown a beneficial effect in can be used in combination for many months. reducing the progression of hip dysplasia in puppies.49 Other 4. A suitable order in which to add adjunctive drugs to studies have shown positive effects on the metabolism of NSAID therapy would be Adequan, tramadol, amantadine, cartilage explants.50 A study evaluating the effects of and then gabapentin. Tramadol will probably provide the Adequan on pain and lameness in adult dogs with hip fastest analgesic result; the others take a variable amount of osteoarthritis found a benefit (although not statistically time to have a measurable effect. significant) to the administration of Adequan.51 The drug 5. The drugs should probably be added one by one, was administered intramuscularly to 84 dogs every three to allowing five to seven days to assess the potential for drug five days for a total of eight injections. Treatment response intolerance (sedation, vomiting, or agitation) and the need for was analyzed based on changes in lameness, range of dosage adjustments before adding the next one. motion, and pain on manipulation of the hip joints. Dogs *To view a complete reference that were given 4.4 mg/kg of Adequan showed the greatest list online, visit www.advanstarvhc.com/c1

SPONSORED BY NOVARTIS 11

26. U.S. Food and Drug Administration. 2005 safety alerts for drugs, bio- Beyond NSAIDs for canine logics, medical devices, and dietary supplements. Available at: www.fda.gov/ osteoarthritis patients: medwatch/SAFETY/2005/safety05.htm#Fentanyl. Accessed Nov 21, 2006. 27. Likar R, Kayser H, Sittl R. Long-term management of chronic pain What other drug options exist? with transdermal buprenorphine: a multicenter, open-label, follow-up study in By B. Duncan X. Lascelles, BSc, BVSc, PhD, MRCVS, CertVA, patients from three short-term clinical trials. Clin Ther 2006;28:943-952. DSAS (ST), DECVS, DACVS 28. Sittl R. Transdermal buprenorphine in the treatment of chronic pain. Expert Rev Neurother 2005;5:315-323. 29. Sorge J, Sittl R. Transdermal buprenorphine in the treatment of chronic References pain: results of a phase III, multicenter, randomized, double-blind, placebo- 1. Hedhammar A, Olsson SE, Andersson SA, et al. Canine hip dysplasia: controlled study. 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Pain mechanisms and management: a central 40. Sluka KA, Westlund KN. Spinal cord amino acid release and content perspective. Clin J Pain 2000;16(Suppl 3):S144-156. in an arthritis model: the effects of pretreatment with non-NMDA, NMDA, and 13. Muir WW 3rd, Woolf CJ. Mechanisms of pain and their therapeutic NK1 receptor antagonists. Brain Res 1993;627:89-103. implications. J Am Vet Med Assoc 2001;219:1346-1356. 41. Fisher K, Coderre TJ, Hagen NA. Targeting the N-methyl-D-aspartate 14. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. receptor for chronic pain management. Preclinical animal studies, recent clini- Science 2000;288:1765-1769. cal experience and future research directions. J Pain Symptom Manage 15. Slingsby LS, Waterman-Pearson AE. Analgesic effects in dogs of 2000;20:358-373. carprofen and pethidine together compared with the effects of either drug 42. Kukanich B, Papich MG. Plasma profile and pharmacokinetics of dex- alone. Vet Rec 2001;148:441-444. tromethorphan after intravenous and oral administration in healthy dogs. J Vet 16. Habacher G, Pittler MH, Ernst E. Effectiveness of acupuncture in vet- Pharmacol Ther 2004;27:337-341. erinary medicine: systematic review. J Vet Intern Med 2006;20:480-488. 43. Bleidner WE, Harmon JB, Hewes WE, et al. Absorption, distribution and 17. Hielm-Bjorkman A, Raekallio M, Kuusela E, et al. Double-blind eval- excretion of amantadine hydrochloride. J Pharmacol Exp Ther 1965;150:484-490. uation of implants of gold wire at acupuncture points in the dog as a treatment 44. Vernier VG, Harmon JB, Stump JM, et al. The toxicologic and phar- for osteoarthritis induced by hip dysplasia. Vet Rec 2001;149:452-456. macologic properties of amantadine hydrochloride. Toxicol Appl Pharmacol 18. Jaeger GT, Larsen S, Soli N, et al. Double-blind, placebo-controlled 1969;15:642-665. trial of the pain-relieving effects of the implantation of gold beads into dogs 45. Chew DJ, Buffington CA, Kendall MS, et al. Amitriptyline treatment with hip dysplasia. Vet Rec 2006;158:722-726. for severe recurrent idiopathic cystitis in cats. J Am Vet Med Assoc 1998; 19. Kapatkin AS, Tomasic M, Beech J, et al. Effects of electrostimulated 213:1282-1286. acupuncture on ground reaction forces and pain scores in dogs with chronic 46. Fernihough J, Gentry C, Malcangio M, et al. Pain related behaviour in elbow joint arthritis. J Am Vet Med Assoc 2006;228:1350-1354. two models of osteoarthritis in the rat knee. Pain 2004;112:83-93. 20. Millis DL, Levine D. The role of exercise and physical modalities in the 47. Devor M, Govrin-Lippmann R, Angelides K. Na+ channel immunolo- treatment of osteoarthritis. Vet Clin North Am Small Anim Pract 1997;27:913-930. calization in peripheral mammalian axons and changes following nerve injury 21. Guideline for the management of pain in osteoarthritis, rheumatoid arth- and neuroma formation. J Neurosci 1993;13:1976-1992. ritis, and juvenile chronic arthritis. Glenview, IL: American Pain Society, 2002. 48. Galer BS, Sheldon E, Patel N, et al. Topical lidocaine patch 5% may 22. Jovey RD, Ennis J, Gardner-Nix J, et al. Use of opioid analgesics for the target a novel underlying pain mechanism in osteoarthritis. Curr Med Res Opin treatment of chronic noncancer pain—a consensus statement and guidelines from 2004;20:1455-1458. the Canadian Pain Society, 2002. Pain Res Manag 2003;8(Suppl A):3A-28A. 49. Lust G, Williams AJ, Burton-Wurster N, et al. Effects of intramuscular 23. Katz WA. Pharmacology and clinical experience with tramadol in administration of glycosaminoglycan polysulfates on signs of incipient hip osteoarthritis. Drugs 1996;52(Suppl 3):39-47. dysplasia in growing pups. Am J Vet Res 1992;53:1836-1843. 24. Rowbotham MC, Twilling L, Davies PS, et al. Oral opioid therapy 50. Sevalla K, Todhunter RJ, Vernier-Singer M, et al. 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SYMPOSIUM: A MULTIMODAL APPROACH TO TREATING OSTEOARTHRITIS Nutritional pain management: What is the evidence?

By Todd L. Towell, DVM, MS, DACVIM Hill’s Pet Nutrition Topeka, Kan.

Canine osteoarthritis, or degenerative joint disease, is a chronic, progressive disease characterized by pathologic joint changes, pain, and limited mobility. Osteoarthritis involves an inflammatory response, articular cartilage degeneration, loss of proteoglycans and collagen, and proliferation of new bone. Risk factors for developing osteoarthritis include age, breed, genetics, obesity, trauma, and a history of devel- opmental orthopedic diseases. The breeds of dogs at highest risk tend to be large and fast-growing with a genetic predisposition for develop- mental orthopedic disease. Treating osteoarthritis requires multimodal management: nutritional intervention, control of inflammation, and slowing of cartilage degradation.

Evidence-based management dations. Applying evidence-based medicine does not always The goals of managing osteoarthritis include: lead to a definitive answer, but it does provide a framework 1. preventing and managing risk factors for making diagnostic and treatment decisions and understand- 2. slowing disease progression ing the risk-benefit relationship of various therapeutic or 3. controlling clinical signs. preventive plans. Nonsurgical options for managing osteoarthritis include activi- ty modification, medications and supplements, and nutritional Nutritional management management. Using an individualized combination of these Restricted calcium and energy levels options for each patient will enhance quality of life, which is Developmental orthopedic diseases are a diverse group of mus- the ultimate therapeutic goal. Deciding which options to use culoskeletal disorders that occur in growing dogs and are some- for individual patients can be challenging, but applying the times related to nutrition. Canine hip dysplasia, osteochondrosis, principles of evidence-based veterinary medicine to this deci- elbow dysplasia, fragmented medial coronoid process, and sion can improve outcomes. ununited anconeal process are common developmental diseases Practicing evidence-based medicine involves integrating that can lead to osteoarthritis. The radiographic prevalence of the best available research evidence with clinical expertise canine hip dysplasia has been reported to be as high as 70% in and individual client or patient values. One of the most chal- golden retrievers and rottweilers.1* However, the expression of a lenging aspects of this approach is evaluating the strength of genetic predisposition for hip dysplasia can be influenced by the evidence. environmental factors.2 Nutritional intervention is an important The grading scale found in Table 1 (page 13) may be part of influencing environmental factors and can help control useful for establishing guidelines for therapeutic recommen- inflammation and slow cartilage degradation.

12 SYMPOSIUM: A MULTIMODAL APPROACH TO TREATING OSTEOARTHRITIS Current evidence suggests that the manifestation of Addition of eicosapentaenoic acid developmental orthopedic disease is affected by growth Therapeutic foods designed for dogs with osteoarthritis rate, specific nutrients, volume of food consumption, and need to supply age-appropriate nutrition and specific nutri- feeding methods. Appropriate nutrition during growth in ents that help reduce inflammation and pain, enhance carti- large- and giant-breed dogs requires providing nutrients in lage repair, slow the degradative process, complement pre- appropriate amounts and balances for optimal bone devel- scribed medications, and provide tangible improvement in opment. Excess calcium and energy together with rapid the clinical signs of osteoarthritis. Recent discoveries in growth have been demonstrated to exacerbate underlying fatty acid production and function have provided evidence genetic predispositions for developmental orthopedic dis- that canine osteoarthritis may be very responsive to dietary eases in a variety of experimental models of developmen- additions of specific fatty acids. tal orthopedic diseases in laboratory dogs (Grades 2 to Arachidonic acid, an omega-6 fatty acid, and eicos- 3).3-5 One long-term study (Grade 2) has documented that apentaenoic acid (EPA), an omega-3 fatty acid, act as pre- the prevalence and severity of osteoarthritis is greater in cursors for the synthesis of eicosanoids, a significant group dogs with body condition scores above normal.6 Over the of immunoregulatory molecules that function as local hor- dogs’ life spans, the mean age at mones and mediators of inflam- which 50% required long-term mation. The amounts and types treatment for osteoarthritis was “Studies in people of eicosanoids synthesized are significantly earlier in the over- determined by the availability of weight dogs (10.3 years) than in the polyunsaturated fatty acid the dogs with normal body condi- suggest that as precursor and by the activities of tion scores (13.3 years).7 the enzyme system to synthesize an isolated factor, them. In most conditions, the Weight control principal precursor for these It is generally accepted that obese compounds is arachidonic acid, dogs are at increased risk for obesity may although EPA competes with osteoarthritis. However, the role arachidonic acid for the same of obesity in the etiology of contribute to enzyme systems. Because EPA osteoarthritis is not clear. Studies in replaces arachidonic acid in the people suggest that as an isolated substrate pool, ingesting foods factor, obesity may contribute to osteoarthritis that contain high levels of EPA osteoarthritis of the knee. Increased results in decreased membrane mechanical forces across the joint, arachidonic acid levels and an which lead to cartilage matrix dam- of the knee.” accompanying decrease in the age, may be one contributing factor. capacity to synthesize Weight reduction can help decrease abnormal forces placed eicosanoids from arachidonic acid.10 The eicosanoids pro- on joints and help alleviate clinical signs. In two nonblinded, duced from arachidonic acid appear to be more proinflam- prospective clinical trials (Grade 3), dogs with hip dysplasia matory than those formed from eicosapentaenoic acid, and and rear limb lameness that were as little as 11% to 29% when produced in excess amounts, they may result in above their ideal body weight had improved clinical scores pathologic conditions. Therefore, the addition of omega-3 or force plate measurements once they reached their opti- fatty acids, particularly EPA, to therapeutic foods should mum weight.8,9 Therefore, an individualized weight manage- reduce inflammation and slow the progression of ment program that includes a diet specifically designed for osteoarthritis. A variety of studies document the effects of weight loss should be recommended for even mildly over- omega-3 fatty acids. weight dogs. Restricting the volume of a maintenance food In vitro studies. Mechanisms of cartilage metabolism in to reduce calories will similarly restrict the availability of canine osteoarthritis and the potential role of omega-3 fatty other essential nutrients and is not recommended. acids to ameliorate early events in the disease process were Although calorie restriction is important, successful investigated recently with in vitro models (Grade 4). Stimu- weight loss generally requires participation in an appro- lated aggrecan (chondroitin sulfate proteoglycan) loss was priate exercise program. Frequent, mild, weight-bearing associated with increased cleavage by aggrecanases, and exercise over an extended period has been shown to help EPA was the only omega-3 fatty acid found to significantly patients reduce body weight, increase joint mobility, reduce decrease the loss of aggrecan in the canine cartilage in vitro joint pain, and strengthen supporting muscles. Remember model (Caterson B. Cardiff University, Wales, UK: Unpub- that weight reduction alone may result in substantial clinical lished data, 2004).11-12 improvement and should be a fundamental part of osteo- Clinical studies. Four clinical studies (randomized, arthritis management. double-blinded, and controlled; Grade 1) were completed

SPONSORED BY NOVARTIS 13 study and at set time intervals after the study’s onset. Vet- erinary clinical evaluations consisted of an orthopedic examination with a specific emphasis on lameness, pain, limitation in weight-bearing ability, range of motion of the Table 1: Study grades in affected joint, and willingness to bear weight on the affect- evidence-based medicine* ed limb when the contralateral limb was elevated. In the three veterinary hospital studies, veterinarians Well-designed, properly randomized and controlled reported a significant improvement in range of motion and Grade clinical trial that utilizes patients with naturally occur- ability to bear weight along with a decrease in pain upon I ring disease: palpation of the affected joint and lameness in animals that • prospective studies were fed the EPA-supplemented therapeutic food. In addi- tion, pet owners observed improvements in multiple clinical Well-designed and controlled laboratory studies in signs associated with osteoarthritis, such as rising from rest, Grade the target species with naturally occurring disease. II running, walking, and playing. In the academic specialty practice study, variables were assessed at the beginning of the study and at 45 and Evidence obtained from one of the following: 90 days. Gait analyses using a computerized biomechani- Grade • well-designed nonrandomized clinical trial cal force plate were conducted at the same time intervals. III • cohort or case-controlled epidemiologic studies For each dog, five valid force plate trials were obtained • studies using an acceptable disease model during each test period for the most severely affected and • case series ipsilateral limb. • dramatic results from uncontrolled studies. On clinical orthopedic examination, a significantly Evidence obtained from one of the following: greater percentage of dogs consuming the test food had Grade • bench-top in vitro laboratory studies improved vs. those consuming the control food. In addition, IV • opinions based on clinical experience more dogs in the test group had a reduction in pain at the • descriptive studies end of the 90-day trial when the affected joint was palpated. • studies conducted in another species Vertical peak force was the key parameter measured to • pathophysiologic justification determine weight bearing of affected limbs. There was no • reports of expert committees. significant change in mean peak force over the duration of the 90-day feeding trial for the control group, while the mean vertical peak force increased significantly (p=0.04) * Quality of evidence guidelines are adapted from the U.S. Preventative Services Task Force. for the test group over the same time interval, indicating that the test group increased weight bearing on the affected limb over the course of the study. recently on arthritic dogs fed either a control food or thera- These clinical studies indicate that nutritional manage- peutic food designed to manage canine osteoarthritis ment using a therapeutic food with high levels of omega-3 (Prescription Diet® j/d™ Canine—Hill’s Pet Nutrition).13-16 fatty acids, and in particular EPA, helped improve the clini- Three studies were conducted in veterinary hospitals and the cal signs of osteoarthritis in dogs as measured by pet own- fourth was conducted in two academic specialty practices. ers, clinical orthopedic examination, and gait analysis of In all studies, osteoarthritis was diagnosed based on ground reaction forces. compatible history, clinical signs, and radiographic evidence of arthritis in one or more joints on the clinically affected Summary limb. To be eligible for inclusion, dogs also had to be Therapeutic nutrition is an integral part of a multidiscipli- greater than or equal to 1 year old, weigh greater than or nary approach to osteoarthritis management. Good clinical equal to 12.5 kg, and be free of systemic disease as deter- evidence suggests that feeding diets designed for large-breed mined by history, physical examination, complete blood dogs during growth and maintaining a healthy body weight count, serum biochemistry analysis, and urinalysis. Exclu- throughout life will minimize the manifestation of develop- sion criteria included acute traumatic injuries, complicating mental orthopedic diseases. Grade 3 clinical trials demon- disease conditions, preexisting conditions for which correc- strate that returning overweight dogs to an ideal body condi- tive surgery was anticipated during the feeding period, and tion will improve clinical signs of osteoarthritis, and Grade 1 recent intra-articular injection or arthrocentesis. evidence supports the use of Prescription Diet® j/d™ Canine Change in arthritic condition was based on owner for control of pain in dogs diagnosed with osteoarthritis. observations of clinical signs and veterinary clinical evalua- *To view a complete reference tions. These variables were assessed at the beginning of the list online, visit www.advanstarvhc.com/c1

14 SYMPOSIUM: A MULTIMODAL APPROACH TO TREATING OSTEOARTHRITIS Nutritional pain management: What is the evidence? By Todd L. Towell, DVM, MS, DACVIM

References 1. Paster ER, LaFond E, Biery DN, et al. Estimates of prevalence of hip dysplasia in Golden Retrievers and Rottweilers and the influence of bias on published prevalence figures. J Am Vet Med Assoc 2005;226:387-392. 2. Smith GK, Paster ER, Powers MY, et al. Lifelong diet restriction and radiographic evidence of osteoarthritis of the hip joint in dogs. J Am Vet Med Assoc 2006;229:690-693. 3. Richardson DC, Schoenherr WD, Zicker SC. Nutritional management of osteoarthritis. Vet Clin North Am Small Anim Pract 1997;27:883-911. 4. Hedhammar A, Wu FM, Krook L, et al. Overnutrition and skeletal dis- ease. An experimental study in growing Great Dane dogs. Cornell Vet 1974;64 (Suppl 5):5-160. 5. Meyer H, Zentek J. Energy requirements of growing Great Danes. J Nutr 1991;121 (11 Suppl):S35-S36. 6. Kealy RD, Lawler DF, Ballam JM, et al. Evaluation of the effect of lim- ited food consumption on radiographic evidence of osteoarthritis in dogs. J Am Vet med Assoc 2000;217:1678-1680. 7. Kealy RD, Lawler DF, Ballam JM, et al. Effects of diet restriction on life span and age-related changes in dogs. J Am Vet Med Assoc 2002;220:1315-1320. 8. Impellizeri JA, Tetrick MA, Muir P. Effect of weight reduction on clini- cal signs of lameness in dogs with hip osteoarthritis. J Am Vet Med Assoc 2000;216:1089-1091. 9. Burkholder WJ, Taylor L, Hulse DA. Weight loss to optimal body condition increases ground reactive force in dogs with osteoarthritis, in Proceedings. Purina Nutrition Forum 2000;74. 10. Wander RC, Hall JA, Gradin JL, et al. The ratio of dietary (omega-6) to (omega-3) fatty acids influences immune system function, eicosanoid metabolism, lipid peroxidation and vitamin E status in aged dogs. J Nutr 1997;127:1198-1205. 11. Caterson B, Flannery CR, Hughes CE, et al. Mechanisms involved in cartilage proteoglycan catabolism. Matrix Biol 2000;19:333-344. 12. Curtis CL, Rees SG, Cramp J, et al. Effects of omega-3 fatty acids on cartilage metabolism. Proc Nutr Soc 2002;61:381-389. 13. Allen T. Effects of feeding omega-3 fatty acids on force plate gait analysis in dogs with osteoarthritis, 3-month feeding study. Hill’s Pet Nutrition, Topeka, Kan: Data on file, 2003. 14. Allen T. Dose titration effects of omega-3 fatty acids fed to osteo- arthritic dogs, 3-month feeding study. Hill’s Pet Nutrition, Topeka, Kan: Data on file, 2004. 15. Allen T. A multicenter practice-based study of a therapeutic food and drug in dogs with osteoarthritis, 3-month feeding study. Hill’s Pet Nutrition, Topeka, Kan: Data on file, 2004. 16. Dodd CE, Fritsch FD, Allen TA. Omega-3 fatty acids in canine osteoarthritis: A randomized, double-masked, practice-based study, 6-month feeding study. Hill’s Pet Nutrition, Topeka, Kan: Data on file, 2004.

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