Analgesia for feline arthritis (Proceedings)

Awareness of the possibility of pain is the first step to its alleviation and prevention. In some cases, pain is pre-existing and part of the condition for which the patient is presented to us however, thought and careful handling go a long way to reduce the stress, distress and discomfort of the hospital visit. The scope of this presentation is to feline arthritic pain but an introduction on pain, per se, is still warranted.

Understanding pain

Pain evolved as a protective mechanism. Certain types of pain, such as physiologic pain, are beneficial for survival. Conditions resulting in damage to tissues or nerves, on the other hand, are pathological and include visceral and neuropathic forms of pain. The nociceptive response begins with the free nerve endings signaling potential or actual tissue injury. This results from a combination of mechanical (crush), chemical (mediators) or thermal input being translated (transduced) into electric impulses. These impulses are transmitted via the primary afferent (1st order) neuron to the spinal cord where they are modulated in the dorsal horn. The impulse is further transmitted via 2nd order neurons in the spinal tract to the thalamus where the message is received by a 3rd order neuron to be projected to the somatosensory cortex. It is at this point that the impulse is experienced as pain and an appropriate response might be generated.

The implications are important; rather than addressing the alleviation of pain at one level, we have multiple points to target. Using a combination of agents in a multimodal approach is often more effective than using a single modality to treat and prevent pain. Pre-emptive plays a key role in patient care. By blocking the transduction and transmission of input, it is easier to keep patients comfortable.

Recognition of pain

The signs of pain are generally more subtle in cats than in dogs. Some objective clinical signs indicative of pain include

• Inability to rest/sleep

• Inappropriate activity level

• Sitting in the back of the kennel

• Mental attitude/demeanour (stupor or anxiety)

• Changes in attitude/personality

• Poor hair coat

• Lack of comfort when palpated

• Facial expression, staring, fixed gaze, dilated pupils

• Lack of appetite and thirst

• (Self-mutilation)

• Vocalizations

• Posture

• Tachycardia

• Tachypnea

Body temperature and blood pressure can be variable. The truest assessment of the presence of pain is response to analgesics resulting in return to normal behaviors.

If a procedure is to be performed or a patient is ill, given the similarities in pain perception between humans and cats, assume that the cat's experience is similar to that of a human and err on the side of humaneness. Through the process of central sensitization, chronic conditions are especially debilitating and interfere with quality of life. Concerns that analgesic agents may be harmful depend on the type of drug and the underlying status of the patient. Factors to be taken into consideration include the integrity of renal and hepatic function, state of hydration and intestinal health. The other side of this is that the cascade of catabolic and detrimental effects that occur as a result of uncontrolled pain may be a greater risk for the patient than the drugs are. Each case needs to be evaluated individually so that the safest protocol is used to blunt or eliminate pain.

Chronic osteoarthritic pain

Recognition of chronic pain and arthritic pain is a relatively recent event. The incidence of osteoarthritis or degenerative joint disease appears to be much more common that previously thought and is probably a major cause of discomfort in aging cats. Secondary osteoarthritis may be caused by joint trauma (i.e., fractures or ligamentous injuries), infectious or immune-mediated inflammation, compensation for congenital and developmental, as well as neoplastic, endocrine (diabetic) or metabolic conditions.. Osteoarthritis involves cascade of mechanical and biochemical events resulting in articular cartilage deterioration, synovial membrane inflammation, soft tissue changes and osteophyte formation, with bone remodeling.

In one study of the prevalence of degenerative joint disease (DJD) in cats3, Hardie et al reviewed 100 radiographs (taken as part of a diagnostic workup for multiple reasons) of cats over 12 years of age finding that 90% of these cats showed evidence of DJD. Interestingly, in only 4 of these patients' medical records was a concern noted for DJD. Does this mean that, as in dogs, the clinical signs of OA do not correlate well with radiographic findings or does this mean that we are very poor at recognizing the signs? Godfrey4 performed another retrospective radiographic study looking at cats of all ages. This study showed radiographic changes suggestive of OA in 22% of cats; in 33% of these cats' medical records, clinical signs were noted. In a third study 5, the prevalence of radiographic signs of DJD or OA in 218 cats was 33.9%, of clinical signs was 16.5% and most of these were in cats over 10 years of age.

Lameness is uncommonly a clinical sign of this problem. Rather, the signs are insidious or attributed to aging. Problems with movement include constipation, defecating outside of the litter box, falling when jumping onto or off of the bed, inability to climb stairs, inability to crouch to eat resulting in weight loss. Decreased grooming, objecting to being combed, reluctance to jump up or down, sleeping more, moving less, withdrawing from human interaction, and possibly even hiding are other signs of joint pain. When activity monitors have been attached to cats' collars6, activity counts increased with NSAID treatment suggesting alleviation of musculoskeletal discomfort.

Regular nail trimming helps by maintaining proper joint relationships. Ramps and steps onto favorite sleeping spots are thoughtful. Numerous websites (e.g.,www.cozycatfurniture.com) have steps and ramps for cats. Warm, soft, padded sleeping places for stiff, painful, possibly bony joints should be considered. Adding a litter box to reduce the distance between boxes may reduce accidents as well as encourage regular voiding and defecation. The rim of the box mustn't be too high, nor the opening into the box too small. It should be scooped several times a day.

Therapeutic options

The cat with joint pain is often an older patient with concurrent problems. Of most concern are the possible consequences of using NSAIDs in a patient predisposed to dehydration with resulting effects on their gastric mucosal health or their renal function. Additionally, some NSAIDs may negatively affect proteoglycans synthesis by cartilage. Some NSAIDs, including meloxicam and carprofen in in vitro studies, do not have this negative effect when used at recommended doses.

In one study, cats were treated for one month with meloxicam, clients felt that their cats were more willing to jump and the height of jumping increased during the study. Evaluation of the cats at the end of the month showed a significant reduction of gait stiffness. Pharmacokinetic data is lacking for long-term use of many NSAIDs in cats. Metacam 0.5 mg/ml oral suspension has been granted a license in the EU for the alleviation of inflammation and pain in chronic musculoskeletal disorders in cats. Pharmacokinetic studies as well as safety and efficacy studies have been performed to the satisfaction of the regulatory bodies. The registered dose is 0.1 mg/kg on the first day followed by 0.05 mg/kg orally once daily. This is the first NSAID licensed for long-term use in cats.

Carprofen half-life varies from nine to over 40 hours in cats. As most NSAIDs have long half-lives in cats when compared to other species, one necessary precaution to avoid toxicity is to reduce the frequency of administration. Individual patients respond differently to the same agent and dose; use the lowest effective dose and base it on lean, hydrated weight.

The key to safe chronic NSAID administration in cats is the use of the smallest effective dose and avoiding use, or using much lower doses, in cats with renal disease. In most cases, NSAIDs are most effective when used in conjunction with other treatment modalities.

Opioids are not a first drug of choice for cats with arthritic pain. This is not to suggest that they shouldn't be used for "break-through" pain or for comfort during diagnostic testing. They are best reserved for palliative hospice care if they produce adverse side effects (euphoria, constipation and inappetence) in an individual patient.

Disease modifying osteoarthritis agents

One approach that has received a lot of attention and research in the past ~15 years, has been looking for ways to slow the progression of cartilage degradation as well as to promote rebuilding of healthy matrix. Products have been developed that, in research on humans and dogs, have been shown to be beneficial in enhancing hyaluronic acid production, inhibiting catabolic enzymes in osteoarthritic joints, and encouraging normalization of the synovial fluid and joint cartilage matrix.

Studies using radiolabeled compounds have shown that 87% of orally administered glucosamine is absorbed and is incorporated into the cartilage matrix. Glucosamine provides raw materials for synthesis of glycosaminoglycans. Since chondrocytes obtain preformed glucosamine from the circulation (or synthesize it from glucose and amino acids), adequate glucosamine levels in the body are essential for synthesis of glycosaminoglycans in cartilage. Glucosamine is required for the production of hyaluronic acid by synoviocytes. In vitro studies indicate that administration of glucosamine may normalize cartilage metabolism and stimulates the synthesis of proteoglycans. In one study, glucosamine stimulated synthesis of glycosaminoglycans, prostaglandin and collagen by chondrocytes and fibroblasts, suggesting it may actually up-regulate their synthesis.

Chondroitin Sulfate (CS) is a long chain polymer of repeating disaccharide units. It is the predominant glycosaminoglycan found in articular cartilage and can be purified from bovine, whale, and shark cartilage sources. Bioavailability studies in rats, dogs and humans have shown that 70% of orally administered CS is absorbed, some of it intact. Studies in rats and humans using radiolabeled CS have shown that CS does reach synovial fluid and articular cartilage. Hyaluronate concentrations and viscosity were shown to be increased, and collagenolytic activity was decreased, in the synovial fluid of human osteoarthritis patients treated with CS for 10 days.

Both oral preparations (Cosequin) and parenterally injected preparations (Adequan) have been shown to have therapeutic benefit in in vivo studies. One factor of note is that a polysulfated glycosaminoglycan, such as Adequan, is a heparin analog, resulting in a transient prolonged partial thromboplastin time. Avoid using it in cats with bleeding disorders or pre-operatively and do not use it concurrently with NSAIDs that have potent anti-thromboxane activity.

Cartrofen Vet is a pentosan polysulfate that is approved in Canada and Europe. In osteoarthritic dogs clinical improvement was noted with its use. Like Adequan, it should not be used concurrently with NSAIDs with anti-thromboxane activity.

Diet

Weight loss should be encouraged in the obese, arthritic cat to reduce the pressure on joints. The addition of omega 3 fatty acids may be beneficial by blocking the production of prostaglandins from arachadonic acid in the inflammatory cascade. A therapeutic prescription diet for joint health (Hill's j/d) is available in the EU for cats.

References

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2. Mathews KA. Relieving Pain: Assessment and Management of Post-Operative Pain in Dogs and Cats.

3. Hardie EM, Roe SC, Martin FR. Radiographic evidence of degenerative joint disease in geriatric cats: 100 cases (1994-1997). J Am Vet Med Assoc 2002: 220(5): 628-32.

4. Godfrey DR Osteoarthritis in cats: a retrospective radiological study. J Small Anim Pract 2005: 46, 425-429.

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. Lascelles BD, Hansen BD, DePuy V, et al. Evaluation of client specific outcome measures and activity monitoring to measure pain relief in cats with osteoarthritis. In: 2nd World / 33rd Annual Veterinary Orthopedic Society Conference: Keystone, Colorado, 2006.

7. Clarke SP, Bennett D Feline osteoarthritis: a prospective study 28 cases. J Small Anim Pract 2006: 47, 439-445.

8. Taylor PM, Delatour P, Landoni FM, et al. Pharmacodynamics and enantioselective pharmacokinetics of carprofen in the cat. Res Vet Sci 1996:60, 144-151.

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