Title: The Potential to Treat Osteoarthritis Pain in Canine Stifles with Cryoanalgesia

Author: Sruti Raman, Mentor: Dr. Preciado

Osteoarthritis (OA) or degenerative joint disease is defined as the loss of smooth cartilage that covers and protects the ends of the bones in a movable (synovial) joint that results in thinning cartilage, bony outgrowths around the affected joint, or fluid buildup. (Refer to Fig. 1 for a visual representation of the [a] affected cartilage in a healthy human knee model and [b] bony growths that develop as a consequence of the cartilage loss.) Osteoarthritis can be classified into two subtypes—primary osteoarthritis and secondary osteoarthritis. While primary osteoarthritis develops as one ages, secondary osteoarthritis has a more specific cause. Possible causes include repeated trauma or stress on a particular joint, obesity, or as a direct result of a genetic disorder involving an underlying anatomical issue. Humans can be subject to either subtype but canines are rarely affected by primary OA 1 although old age is a risk factor for canines. 2

Understanding the pathophysiology of canine osteoarthritis is the next important step in understanding how the joint disease can potentially be treated with cryoanalgesia. Any excessive stress applied on the stifle joint initiates the development of OA pain but prior to the neuropathic sensation of the pain, there are multiple processes that take place in the space between the tibia and femur primarily occupied by articular cartilage. The chondrocytes are first damaged as a result of joint stress since they are the cells that make up the tissue content of the articular cartilage. These cells produce an essential protein of the cartilage, collagen, a gelatin-like substance that when bound to elastin, a stretchy protein (as the name suggests), provides the cushioning layer between the tibia and femur. Hyaluronic acid (HA) is a substance that collagen and elastin require to bind. (They are used in the form of injections, often times, to treat osteoarthritis in humans.) 3 Simultaneously, as chondrocytes are being damaged and collagen is lost, there is the release of nitric oxide which is an aggravator of inflammatory mediators--any molecules that mediate nociceptive pathways—an inhibitor of collagen and proteoglycan synthesis and the compound’s release has detrimental effects on chondrocyte function. 5 This instigation of inflammation

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FIGURE 1. Human Knee [a] articular cartilage and [b] bone spurs 4

a b

paired with degeneration of the articular cartilage causes the synovial fluid—an oil-like substance in the joint space between the tibia and femur that provides lubrication for smooth knee movement and contains HA (Fig. 2a)—to become less viscous 3 and this fluid characteristic change is logical since the release of nitric oxide has inhibited production of primary components contained in the tibiofemoral joint space such as chondrocytes and collagen. 5 As the synovial fluid thins and the cartilage continues to degenerate (Fig. 2b) exposing the bone surfaces of the tibia and femur, the bones come into contact and with every movement, friction is induced between the bones causing the creation of bony outgrowths (bone spurs) and pain sensation in the stifle joint. (Pain is experienced only once the bone surfaces are exposed since cartilage does not contain any innervation while bone does.)

There are many factors that could cause stress on joints for dogs. The most prominent risk factors being—obesity and hereditary disorders, in particular, hip dysplasia 9—along with any repeated exercise strain, trauma, or injury to a specific joint, 8 and the increased vulnerability to OA that dogs develop as a result of being spayed or neutered or as they get older. (Dogs that are older or have been spayed or neutered generally require fewer calories but more exercise to maintain a healthy weight.) 2

According to American Pet Product Association’s (APPA) 2015-2016 survey, approximately 68% of US households own at least one pet, 6 42% of those

households own a dog, and about 53% of US dogs are either overweight or obese 7; an estimated 40% are overweight. 8 What is most alarming is only 30-40% of dog owners are aware of their dog being overweight. 2 Hip dysplasia, another highly

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FIGURE 2. [a] Healthy human knee synovial fluid [b] degenerated cartilage surface 4

ba

common genetic disorder among many dog breeds—some such as the bulldog and pug being predisposed to this disorder 10—is another major risk factor for certain dogs to develop OA. This condition (Fig. 3) results in the dog’s hip socket being too shallow which in turn causes the femur to apply more pressure on the dog’s stifle

joint since it is the only form of support the femur has.

While being overweight or obese is a major risk factor for dogs to develop OA, similar to humans, dogs that tend to have an average weight at least over 50 pounds still have a quite high risk of developing OA as well. German Shepherds, Rottweilers, and Great Danes are among the most preferred dog breeds with also the largest average weights (Refer to Table 1).

Symptoms pets exhibit if experiencing OA pain should be identifiable for all pet owners. Some common symptoms include being relatively inactive, limping, having a depressed expression, and reluctance to go up or down stairs. 3

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FIGURE 3. Canine Hip Dysplasia

DOG BREED MALE WEIGHT (lbs.) FEMALE WEIGHT (lbs.) 2015 2014 2013

Retrievers (Labrador) 65-80 55-70 1 1 1

German Shepherd Dogs 75-95 75-95 2 2 2

Retrievers (Golden) 65-75 55-65 3 3 3

Bulldogs 50 40 4 4 5

Beagles 18-30 18-30 5 5 4

French Bulldogs 21-28 21-28 6 9 11

Yorkshire Terriers 5-7 5-7 7 6 6

Poodles

12-18 12-18

8 7 8

45-65 45-65

5-8 5-8

Rottweilers 85-135 80-100 9 10 9

Boxers 65-80 50-65 10 8 7

Pointers (German Shorthaired) 55-75 45-65 11 12 13

Siberian Huskies 45-60 35-50 12 13 14

Dachshunds

6-11 6-11

13 11 1011-32 11-32

Doberman Pinschers 65-90 65-90 14 14 12

Great Danes 130-180 100-150 15 15 16

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TABLE 1. Most Popular Dog Breeds and Avg. Weight (2013-15) 11, 12

While extensive research exists regarding the treatment of human OA pain through nerve studies (sciatic, 15 peroneal/common fibular, 16 and infrapatellar branch of saphenous 13), not enough research exists that has asserted particular nerves responsible for OA pain in canine stifles with some studies pointing at the femoral, sciatic, saphenous, common peroneal, and tibial nerves in canines. 17, 18, 19 The existing research regarding human OA neuropathic pain may aid us, regardless, in treating such pain in the canine stifle. A better understanding of analogous anatomical structures between canines and humans and the knowledge that dogs with knee or stifle arthritis almost always have a cranial cruciate ligament (CCL-analogous to human ACL) tear or patellar luxation 20 is important to carry through with such research. Some studies regarding this ligament do exist and must be reviewed carefully as well prior to deciding which nerves innervating the canine stifle must be tested with nerve blocks. 23, 24, 25, 26

Referring to Figure 4, much of the general anatomic structure is quite similar except for the size and shape of structure such as the tibial attachments and menisci. As I mentioned before, a difference to note is that analogous to the human ACL, canines possess a CCL which is a stifle ligament structure shared across most domestic animals.

Other anatomical differences to note (Fig. 5) are the popliteal sesamoid bones present in the canine stifle but not in the human knee. Humans possess a single sesamoid bone in the knee which is the patella whereas canines have a patella as well as three other sesamoid bones in the knee. (A commonly known location of sesamoid bones in humans are the metatarsals.) Other structures canines possess in

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FIGURE 4. Comparison of human knee and canine stifle anatomy 21

the stifle that humans do not have in their knee are a long digital extensor tendon (Fig. 5) and the lateral and medial heads of the gastrocnemius. 22

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FIGURE 5. Anatomical structures that exist in canine stifle; popliteal sesamoid bones (L), long digital extensor tendon (R)

FIGURE 6. [a] Bird’s eye view of dog leg cross section; saphenous nerve (red arrow)[b] Saphenous nerve (red arrow), femoral nerve (blue arrow) 27

a

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b

FIGURE 7. [a] blue=sciatic nerve [b] yellow=lateralcutaneous sural nerve, red=common fibular nerve, black=tibial nerve, green = caudal cutaneous sural nerve, blue = sciatic nerve [c] red=common fibular nerve [d] red=common fibular nerve, orange=superficial fibular nerve, pink = deep fibular nerve 27

a

b

The above images (Fig. 6 & 7) are images of dissection of the canine leg and the arrows help identify important nerves that research studies have mentioned as potential “culprit nerves” hat cause OA pain in canines. These nerves must be identified and tested with nerve blocks before we can assert the treatment of canine stifle OA pain with cryoanalgesia.

Current treatments available to dogs with OA pain include antibiotics, NSAIDs (nonsteroidal anti-inflammatory drugs), chondroprotective agents, MSM (natural dietary sulfur), antioxidant vitamins, and fatty acid supplements, cortisone, 3 and a few clinical studies that have administered hyaluronic acid injections, 28, 29 but the majority of these treatments although aimed at relieving pain, are not identifying the root cause of the pain which could often times be related to some form of nerve damage. Therefore, I conclude that in order to successfully assert the application of cryoanalgesia for canine stifle OA pain, extensive research testing nerve blocks on nerves that innervate the stifle and other supporting anatomical structures compared to placebo treatments is required.

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c

d

1. Suszynski, M. (2016, February 10). Understanding Primary and Secondary Osteoarthritis. Retrieved July 27, 2016, from http://www.everydayhealth.com/arthritis/osteoarthritis/index.aspx

2. Keith, C. (2012, April 9). The Big Fat Truth About Canine Obesity. Retrieved July 27, 2016, from http://thebark.com/content/big-fat-truth-about-canine-obesity

3. Grill, J. (2016). Treating Arthritis in Dogs: Video and Brochures. Retrieved July 27, 2016, from http://www.dog-health-guide.org/treatingarthritisindogs.html

4. What Causes Osteoarthritis Joint Disease? - Manipal Hospital. (2015, May 20). Retrieved July 27, 2016, from https://www.youtube.com/watch?v=rp1z9GjCUjo

5. Kidd, B. L., Photiou, A., & Inglis, J. J. (2004). The role of inflammatory mediators on nociception and pain in arthritis. Retrieved July 27, 2016, from http://www.ncbi.nlm.nih.gov/pubmed/15283447

6. U.S. Pet Industry Spending Figures & Future Outlook. (2015). Retrieved July 28, 2016, from http://www.americanpetproducts.org/press_industrytrends.asp

7. Obesity Facts & Risks. (2010, May 11). Retrieved July 28, 2016, from http://www.petobesityprevention.org/pet-obesity-fact-risks/

8. Arthritis and Pets [Audio blog interview]. (2012, June 22). Retrieved July 28, 2016, from http://www.avmamedia.org/manage/mediaimg/s108-arthritis1.mp3

9. Foster, Dr., & Smith, Dr. (n.d.). Hip Dysplasia in Dogs: Diagnosis, Treatment, and Prevention. Retrieved July 28, 2016, from http://www.peteducation.com/article.cfm?c=2 2084&aid=444

10. Hip Dysplasia by Breed. (2016). Retrieved July 28, 2016, from http://www.ofa.org/stats_hip.html

11. Smith, S. (2016, February 22). Most Popular Dog Breeds in America. Retrieved July 28, 2016, from http://www.akc.org/news/the-most-popular-dog-breeds-in-america/

12. Breed Weight Chart. (2016). Retrieved July 28, 2016, from http://modernpuppies.com/breedweightchart.aspx

13. Makovitch, S., Chu S., Stulberg D., Brander V. (2014, September). Successful Treatment of Painful Stiffness Following Total Knee Arthroplasty Using Cryoablation of the Infrapatellar Branch of the Saphenous Nerve: a case report. PM&R, 6(9), S353-0. Retrieved July 27, 2016, from http://www.pmrjournal.org/

14. Dasa V., Bliss R., Lensing ., Parsons M., Harris J., Volaufova, J. (2016, June). Percutaneous freezing of sensory nerves prior to total knee arthroplasty. The Knee, 23(3), 523 – 528. Retrieved July 27, 2016, from http://www.thekneejournal.com/

15. Ma, B. C. (2014, September 8). Sciatic nerve damage: MedlinePlus Medical Encyclopedia Image. Retrieved July 28, 2016, from https://medlineplus.gov/ency/imagepages/9765.htm

16. Baima, J., & Krivickas, L. (2008, March 11). Evaluation and treatment of peroneal neuropathy. Retrieved July 28, 2016, from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2684217/

17. Rasmussen, L. M. (2006, January). Controlled, clinical trial assessing saphenous, tibial and common peroneal nerve blocks for the control of perioperative pain following femoro-tibial joint surgery in the nonchondrodystrophoid dog. Retrieved July 28, 2016, from http://www.ncbi.nlm.nih.gov/pubmed/16412132

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References

18. Doyle, T., Lopez, M., & McNulty, M. (2015, April). Morphological Analysis of the Saphenous Nerve in the Dog. Retrieved July 28, 2016, from http://www.fasebj.org/content/29/1_Supplement/543.1

19. Campoy, L., Martin-Flores, M., Ludders, J. W., Erb, H. N., & Gleed, R. D. (2012, January). Comparison of bupivacaine femoral and sciatic nerve block versus bupivacaine and morphine epidural for stifle surgery in dogs. Retrieved July 28, 2016, from http://www.ncbi.nlm.nih.gov/pubmed/22117792

20. Anatomy of Canine Arthritis. (2015). Retrieved July 28, 2016, from http://www.canineortho.com/index.php/anatomy-of-canine-arthritis

21. Proffen, B. L., McElfresh, M., Fleming, B. C., & Murray, M. M. (2012, August). A COMPARATIVE ANATOMICAL STUDY OF THE HUMAN KNEE AND SIX ANIMAL SPECIES. Retrieved July 28, 2016, from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236814/

22. Martin H. Gregory, Nicholas Capito, Keiichi Kuroki, Aaron M. Stoker, James L. Cook, and Seth L. Sherman, “A Review of Translational Animal Models for Knee Osteoarthritis,” Arthritis, vol. 2012, Article ID 764621, 14 pages, 2012. doi:10.1155/2012/764621

23. Venable, R. O., Stoker, A. M., Cook, C. R., Cockrell, M. K., & Cook, J. L. (2008, December). Examination of synovial fluid hyaluronan quantity and quality in stifle joints of dogs with osteoarthritis. Retrieved July 28, 2016, from http://avmajournals.avma.org/doi/pdf/10.2460/ajvr.69.12.1569

24. Barkowski, V. J., & Embleton, N. A. (2016, July 11). Surgical Technique and Initial Clinical Experience with a Novel Extracapsular Articulating Implant for Treatment of the Canine Cruciate Ligament Deficient Stifle Joint. Retrieved July 28, 2016, from http://www.ncbi.nlm.nih.gov/pubmed/27398949

25. "Cranial Cruciate Ligament Rupture (CCL) in Dogs." Pet Health Orthopedics. Willows Veterinary Centre & Referral Service, n.d. Web. 28 July 2016.

26. De Rooster, H., T. De Bruin, and Bree H. Van. "Morphologic and Functional Features of the Canine Cruciate Ligaments." National Center for Biotechnology Information. U.S. National Library of Medicine, Dec. 2006. Web. 28 July 2016.

27. Clarkson, C., A. Brown, K. Ekenstedt, and T. F. Fletcher. "LAB 21 Introduction." Carnivore Anatomy Lab 21 Introduction. University of Minnesota College of Veterinary Medicine, 2015. Web. 28 July 2016.

28. Smith, G. N., Jr., S. L. Myers, K. D. Brandt, and E. A. Mickler. "Effect of Intraarticular Hyaluronan Injection in Experimental Canine Osteoarthritis." National Center for Biotechnology Information. U.S. National Library of Medicine, June 1998. Web. 28 July 2016.

29. Nganvongpanit, Korakot, Burin Boonsri, Thatdanai Sripratak, and Patsanan Markmee. "Effects of One-time and Two-time Intra-articular Injection of Hyaluronic Acid Sodium Salt after Joint Surgery in Dogs." Journal of Veterinary Science. The Korean Society of Veterinary Science, 21 June 2013. Web. 28 July 2016.

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