A rational approach to osteoarthritis management (Proceedings)

Osteoarthritis (OA) is a common problem in small animal medicine. It is estimated to affect 20% of the United States' canine population, translating to over 10 million dogs. However, it remains widely underdiagnosed and misunderstood. Unlike in humans, canine osteoarthritis is rarely primary. It is virtually always secondary to other joint pathology. Its insidious onset, slow progression, and wide range of clinical signs make osteoarthritis a challenge to diagnose.

Terminology

The nomenclature surrounding the discussion of osteoarthritis and degenerative joint disease (DJD) can be confusing, as these terms are often interchanged. Further confusion arises when considering the term of an "itis, (i.e., inflammatory,) and sometimes an "osis", (i.e., degeneration without inflammation). While degenerative joint disease is the more technically more correct term, due to the literature and definitions promoted in humans it is easier to refer to the disease as osteoarthritis.

Pathophysiology

Osteoarthritis is characterized by articular cartilage degeneration and changes in the periarticular soft tissues (synovium and joint capsule) and subchondral bone. Specifically, the pathologic changes of osteoarthritis encompass articular cartilage degeneration, which includes matrix fibrillation, fissure appearance, gross ulceration, and full-thickness loss of the cartilage matrix. This pathology is accompanied by hypertrophic bone changes with osteophyte formation and subchondral bone plate thickening. Failure to repair the damage affecting the surface cartilage is a distinctive condition of OA. Failure of chondrocytes in injured articular cartilage to restore a functional matrix in spite of high metabolic activity remains a complex and challenging problem. Currently, there is no treatment regimen proven to arrest or reverse the cartilage degeneration.

Clinical Signs

Osteoarthritis is a syndrome affecting synovial joints that is characterized by pain and dysfunction, associated with degeneration of the articular cartilage and changes in the periarticular soft tissues. It occurs with varying degrees of severity, ranging from a mild, intermittent condition that causes mild discomfort and minimal disability, to a disease state characterized by constant pain along with severe functional disability. As such, it is often difficult to describe any single treatment that will cover the entire spectrum of change that may be present.

Treatment Goal

Current therapy is primarily palliative, aiming to reduce pain and inflammation and maintain or improve joint function without altering the pathologic process in the tissue. Remember, most OA in the dog and cat is secondary to some other pathologic state, and thus the underlying cause must be identified in an attempt to minimize the long-term effects. Certainly efforts are being made to provide treatments which may alter the course of the disease but these therapies are still to a large part unproven.

Treatment Plan

Management Components

1. Weight Reduction: Weight control is a must when dealing with OA. The vast majority of our patients seen with clinical manifestations of OA are obese. Owner education and proper dietary management must be considered in every case. In many cases, the implementation of weight reduction with rest and exercise modification diminishes or completely alleviates the clinical signs of OA.

2. Nutritional Support: The recent influx of diets on the market with a high N3:N6 fatty acid ratio is adding a whole new area of intervention. It is important to understand that there is an increase in N3 fatty acids in the diet and that specific N3 fatty acids are elevated (EPA and DHA).

3. Exercise modification/Physical Therapy: Protecting the osteoarthritic joint from excessive mechanical stress may limit clinical signs. Use of the joint in a manner that consistently results in discomfort is generally believed to lead to acceleration of cartilage destruction. Most patients with OA are comfortable with light to moderate exercise regimens that do not vary significantly. Enforced rest and exercise modification is different for each animal, but exercise extremes tend to exacerbate clinical signs. Swimming is a wonderful minimal load exercise, and in many parts of the country is available nearly year round to our patients.

4. Pharmacologic Management: Analgesic and antiinflammatory agents are the most common final component in the management of OA. However, these agents are not used without risk of side effects. The application of analgesic nonsteroidal antiinflammatory drugs (NSAIDs) reduces inflammation responsible for joint damage. It also reduces physiologic pain signals which limit activity, and thus can indirectly cause overuse. This is precisely why part of our whole treatment protocol specifically involves exercise modification.

Disease-modifying osteoarthritis drugs (DMOAD) or structure modifying osteoarthritis drugs (STMOAD) are an expanding area of interest in osteoarthritis management. These products are directed at preventing, reducing, or reversing the cartilaginous lesions of OA. Agents that have been previously called chondroprotective are now considered DMOADs or STMOADs. These drugs can have both effects on the inflammatory cascade and release of mediators and also direct effects on the target tissues (cartilage, bone, synovium).

NSAIDs

New discoveries regarding inflammatory mediators and biochemical mediators associated with osteoarthritis have led to an increased understanding and use of NSAIDs in veterinary osteoarthritis management. It is now recognized that there are at least three different cyclooxygenase (COX) enzymes (COX-1, COX-2, and a COX-1 variant called COX-3) which are active in the metabolism of arachadonic acid. Certain NSAIDs may have selectivity in their actions against these isoenzymes. Furthermore, there is data to support that the ratio of COX and lipoxygenase (LOX) inhibition may be important in the improved gastrointestinal safety seen in dogs, and a dual COX/LOX inhibitor has been introduced to the market.

Pharmacokinetics and Mechanisms of Action

NSAIDs produce analgesia and toxic side-effects primarily by inhibiting COX, a key enzyme in the arachadonic acid (AA) pathway, and ceasing the production of prostaglandins, most notably prostaglandin E2 (PGE2). Two isoforms of the COX enzyme have been intensely investigated: a constitutive COX-1, responsible for normal physiologic functions; and an inducible COX-2, associated with inflammation and pain. Theoretically, an NSAID that selectively inhibits COX-2 without affecting COX-1 will allow analgesia without the common side effects of COX-1 inhibition, which include altered gastrointestinal and thrombocyte function.

An NSAID's ability to inhibit each COX enzyme is often reported as a ratio, which defines enzyme selectivity based on in vitro testing. While some drugs are now marketed as COX-2 preferential, bottom line is all NSAIDs are COX-2 inhibitors. What is different is how the newer compounds do not concomitantly inhibit COX-1. Thus it is probably better to consider these products as COX-1 sparing. Coxibs are a subclass of NSAIDs with a specific molecular structure that confers high specificity, saturability, and reversibility in binding. Coxibs, like all NSAIDs, inhibit COX-2, but their important feature is their sparing effect on COX-1.

In addition, extensive data exists which indicate that many of the anti-inflammatory effects of NSAIDs are unrelated to the inhibition of arachadonic acid metabolism. NSAIDs have been shown to inhibit a variety of neutrophil functions, and there is strong evidence to support that NSAIDs act directly in the spinal cord and higher centers.

Indications

NSAIDs can be used to treat acute pain, either traumatic or surgically induced, as well as chronic pain such as in osteoarthritis. There is evidence that NSAIDs are effective in treating certain neoplasias and potentially certain central nervous system disorders. It is wise to use products with a history of extensive clinical experience and good safety profiles. Always use only one NSAID at a time and ensure adequate dosing. Review therapy frequently, and change to alternative NSAIDs if there is a poor response to therapy. Observe for potential toxicity as soon as administration is begun with increased vigilance and monitoring required for at-risk patients. If indicated, establish renal and hepatic status of the patient prior to NSAID administration. Remember, efficacy and toxicity is often individualistic and individual monitoring is mandatory.

Contraindications

One must adapt therapy to suit the patient's requirements. In patients with chronic disease, begin with the recommended dose, and if efficacious, attempt to reduce dose at regular intervals (ex. weekly) until you have the lowest dose providing the maximum benefit. In patients with the following conditions, NSAIDS should be avoided or given judiciously and under close supervision: renal or hepatic insufficiency, decreased in the circulating blood volume (e.g. shock, dehydration, hypotension, or ascites), confirmed or suspected coagulopathy (this may be less important with COX-1 sparing drugs), active GI disease, traumatic injury with known or suspected significant active hemorrhage or blood loss, pregnancy, and significant pulmonary disease (this may be less important with COX-1 sparing drugs).

Adverse Events

The most common problems associated with NSAID administration to dogs and cats involve the gastrointestinal (GI) tract. Signs may range from vomiting and diarrhea, including hematemesis and melena, to a silent ulcer which results in perforation. Concurrent administration of other medications (especially other NSAIDs or corticosteroids), previous GI bleeding, or the presence of other systemic diseases may contribute to adverse reactions. Hepatotoxicosis can occur, and is generally considered to be idiosyncratic. Most dogs recover with cessation of treatment and supportive care. Renal dysfunction may occur with NSAID administration as a consequence of prostaglandin inhibition. In hypovolemic animals prostaglandin synthesis is increased to maintain renal perfusion; NSAID use in these patients must be considered very carefully.

Multimodal Therapy

There is a move towards greater use of a multimodal therapeutic approach to treat chronic pain in human medicine, and a multimodal approach has been suggested for the alleviation of chronic pain in veterinary species. One goal of multimodal therapy is to avoid the 'cellular windup' and heightened sensitivity of the central nervous system to pain sensation seen in response to repetitive noxious stimulus. A key player in this nociceptive processing is the N-methyl-D-aspartate (NMDA) receptor, and NMDA receptor antagonists may offer a benefit, especially in the treatment of chronic pain. Ketamine, tiletamine, dextromethorphan and amantadine possess NMDA antagonist properties, among other actions. Opioid receptors are well known to be involved in pain states, and the descending serotinergic system is known to be one of the body's endogenous 'analgesic' mechanisms. Opioid agonists and opioidergic/monoaminergic drug such as Tramadol have been found to be effective alleviating osteoarthritis pain in humans, as part of a multimodal approach.

Steroidal Antiinflammatory Agents

Corticosteroids: These drugs should be limited in use to those dogs in which no other treatment has worked. There is considerable evidence that steroid therapy speeds up progression of OA, and any positive short-term results are negated by long-term loss of the remaining cartilage. Whenever steroids are used, owners must be aware of the probable detrimental side effects. Remember along with iatrogenic induction of Cushing's syndrome, corticosteroids have been shown to inhibit healing and initiate damage to articular cartilage.

Chondromodulating Agents

These agents are collectively defined as slow-acting drugs in osteoarthritis (SADOA), and are subdivided into symptomatic slow acting drugs (SYSADOA) and disease-modifying osteoarthritis drugs (DMOAD). SYSADOA are agents that claim to improve pain or function with a delay (weeks to months) but may have persistent benefits after treatment discontinuation. DMOADs are products that claim to prevent, reduce or reverse the cartilaginous lesions of OA. These products include compounds such as glucosamine, chondroitin sulfate, polysulfated glycosaminoglycans (PSGAG), Pentosan Polysulfate (PPS), hyaluronan (HA), and different forms of tetracycline analogs.There is little information available verifying treatments that successfully alter the course of pathologic change.

Nutraceuticals

These supplements include Cosequin (glucosamine and purified chondroitin sulfate) and Glycoflex (extract from Perna Canaliculus mussel and sea cucumber), among many others. Many anecdotal reports proclaim high success rates using these products to treat OA, however remember as nutritional supplements these products avoid FDA scrutiny and do not require data to support label claims. There is no current scientific data available that these products are clinically effective in the dog. There is some evidence being generated in vitro which is interesting but it is not directly applicable to the clinical setting. To date, most of the evidence of efficacy used by manufacturers to support their products comes from human clinical trials performed overseas. Several studies involving individual components of Cosequin have demonstrated no significant toxic or detrimental side effects. The product appears to be safe, at least in the short term.