Steven C. Budsberg and Whitney D. Hinson Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA As small animal clinicians attempt to treat chronic pain and the associated dysfunction in their patients with osteoarthritis (OA), they face several challenges. First, pain is a complex experience involving not only transduction and transmission of noxious stimuli from the periphery to the central nervous system (CNS), but also processing of stimuli by higher centers in the brain [1,2]. Pain is the most clinically profound but least well‐studied component of OA [3,4]. Articular cartilage degeneration, inflammation, synovitis, and subchondral bone, and periarticular tissue changes are believed to be sources of pain associated with OA in companion animal patients [5–9]. OA is the most common joint disorder leading to significant disability and dysfunction encountered by clinicians. While considered a common problem in small animal medicine, OA is likely the most underdiagnosed and misunderstood rheumatic disease in dogs and cats. OA is a slow, progressive, and often insidious problem, and the wide range of clinical signs makes it a frequently misdiagnosed condition. In the dog, primary OA is uncommon, and the condition mainly develops secondary to another joint pathology (such as hip or stifle instability). OA has been estimated to affect 20% of the United States (US) canine population [10]. This widely referenced estimate, in practical terms, translates to over 15.6 million dogs based on an estimated US canine population of 78 million [11–13]. Estimates of cats affected with OA are between 60% and 90%, and with an estimated number of cats in the US of about 86 million, the number affected with OA is between 51 and 77 million [14–18]. Therefore, the identification and management of this disease is of utmost importance to the small animal clinician. While the terms “osteoarthritis” and “degenerative joint disease” (DJD) are considered nearly synonymous in dogs, this may not be the case in cats. Joint pathology in cats may differ in etiology, onset, clinical signs, and pathophysiology compared to dogs [19–21]. For the purposes of this chapter, when discussing the cat, the term “DJD/OA” will be used to highlight this potential difference [22]. The American Academy of Orthopaedic Surgeons has proposed the following definition of osteoarthritis: “Osteoarthritic diseases are a result of both mechanical and biological events that destabilize the normal coupling of degradation and synthesis of articular cartilage, extracellular matrix (primarily collagen and aggrecan), and subchondral bone. Although they may be initiated by multiple factors, including genetic, developmental, metabolic, and traumatic factors, osteoarthritic diseases involve all of the tissues of the diarthrodial joint” [23]. Ultimately, osteoarthritic diseases are manifested by morphologic, biochemical, molecular, and biomechanical changes of both cells and matrix, which lead to softening, fibrillation, ulceration, articular cartilage loss, sclerosis and subchondral bone eburnation, and osteophyte production [4–7,9]. When clinically evident, osteoarthritic diseases are characterized by joint pain, tenderness, limitation of mobility, crepitus, occasional effusion, and variable degrees of inflammation without systemic effects. From a pathophysiologic view, OA is characterized by articular cartilage degeneration and changes in the periarticular soft tissues (synovium and joint capsule) and subchondral bone. In essence, OA can be considered the end stage of organ failure of a joint [9,24]. Specifically, the pathologic changes of OA 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 and the inability of chondrocytes in injured articular cartilage to restore a functional matrix despite high metabolic activity remains a complex and challenging problem [4–7,9,24]. Clinical signs of OA occur 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. Painful mechanical stimuli are detected by nociceptors (Type III or Aδ and Type IV or C fibers), which are afferent nerve fibers located in the joint capsule, associated ligaments, periosteum, and subchondral bone. Joint movement induces mechano‐gated ion channels to open resulting in nerve firing [1–3,8]. When joint movement exceeds normal limits, nerve firing dramatically increases and the CNS interprets these signals as pain. Data from experimental models of OA suggest that peripheral mechanosensory fibers become sensitized resulting in increased afferent firing even in response to normal physiological joint motion [25]. Furthermore, sensitization via neuropathic and central pain mechanisms also contributes significantly to pain in a large portion of patients with OA [26–28]. In chronic pain states, these pathophysiologic changes profoundly alter nociceptive processing in both the periphery, by increasing excitability of nociceptors, and centrally, through upregulation in the dorsal root ganglia, spinal cord, and glial cells of the brain. Additionally, modifications and alterations of inhibitory pathways and descending modulation of pain perception can occur [27,28]. Regardless of the type of pain (nociceptive or neuropathic), the role of inflammation in both has been clearly demonstrated [26–28]. Currently, there are no proven methodologies to reverse the changes seen in the joint with OA. As stated earlier, the clinical signs of OA can vary from mild to severe and from vague to obvious, with pain as a hallmark. However, accurate assessment of pain and dysfunction can be very difficult in dogs and cats. Typically, the diagnosis of OA is based on history, clinical signs, physical examination, and radiographs of the affected joint(s). The goal in assessing a dog or cat with suspected OA is to identify the site of pain and discomfort and attempt to diagnose any initiating causes. While diagnosis of the inciting cause may be more important in younger patients, it is never too late to address conditions such as stifle instability. When dealing with a chronic end‐stage OA joint, initiating factors may be less relevant and management of associated pain may become the sole focus of therapy. Owner assessment of pain severity is an interesting paradox. While owners are most aware of a patient’s daily routine, they are not always aware of what pain looks like. Owners often need to see their pet on a successful pain management plan to better recognize pain and dysfunction. This is the rationale for using owner assessments in addition to veterinary examinations. Owner assessments should begin at the start of treatment to define the degree of disability, and thus help decide the level of treatment required. Going forward, they should be used to monitor treatment efficacy. The owner sees the patient daily and can assess multidimensional aspects of pain and associated functional disability. Using metrics like owner questionnaires is advantageous to combat bias associated with subjective evaluation of the patient. In one study, caregiver placebo effect was common when response to treatment was evaluated by both the owner (40% improvement noted on placebo) and the veterinarian (between 40% and 45%) [29]. While another study suggests a lower placebo effect, the potential for bias is significant and may impact assessment of the success or failure of a product or procedure [30]. To increase client awareness and involvement, and to begin to quantify the clinical signs, the use of client questionnaires or clinical metrology instruments is recommended. These instruments are discussed in more detail in Chapter 47. In brief, questionnaires that have been designed and validated in the dog include the Canine Brief Pain Inventory (CBPI), the Liverpool Osteoarthritis in Dogs (LOAD) scale, and the Helsinki Chronic Pain Index (HCPI) [31–36]. Use of a validated questionnaire may lead to improved outcomes as less biased and more accurate assessments will be available to the owner and the clinician. For cats, clinical manifestations of disease and pain are very different from dogs. Several validated instruments for cats are now available including the Feline Musculoskeletal Pain Index (FMPI) and the Montreal Instrument for Cat Arthritis Testing [37–41], and additional information is available in Chapter 47. Current therapy for OA focuses on palliative care with the goal of reducing pain and inflammation and maintaining or improving joint function without altering the pathologic process in the joint. As most OA in the dog, and perhaps in the cat, is secondary to some other pathologic state, the underlying cause must be identified to minimize the long‐term effects. While efforts to develop treatments that alter the course of the disease are ongoing, these therapies are still largely unproven. Management of OA involves a multimodal approach with four to five important components for both dogs and cats [19–21,42–47]. Relying on pharmacologic management alone (i.e., drugs administered singularly or in combination) is usually associated with limited success. Managing OA should be based on a well‐thought‐out comprehensive plan, which can be presented as “WEDDS”: Weight reduction and control; an Exercise and physical therapy program; Dietary modification; a Drug (pharmacologic) plan that may include biological therapy; and a discussion of potential Surgical interventions (Box 71.1). Thus, initiating a treatment plan for a patient with OA requires a lengthy discussion of all aspects of management with the client that addresses common false assumptions. Three of the most common misconceptions are presented in Box 71.2 and emphasize the need for a realistic and scientifically sound approach to pain management. Each case must be examined individually, assessing the age, normal activity levels, and, most importantly, the owner’s expectations for performance of their animal. Success largely depends on the accurate assessment of client expectations. During the discussion of each potential treatment modality, the justification and recommendation for a given therapy should be evidence‐based. Weight control is essential when dealing with OA. Most patients with clinical manifestations of OA are overweight or obese. While clinicians often recommend weight loss programs, success is not common. Several articles are available which discuss strategies for increasing the success of weight loss recommendations [48–52]. Available evidence supports weight loss in canine OA patients and, while little data are available to guide management of cats, it is reasonable to extend these recommendations to feline patients. Owner education and proper dietary management should be considered in every case. Several studies support improved quality of life and lameness in dogs with OA that undergo weight reduction [53–59]. On reviewing the available clinical data, the strength of evidence supports a moderate degree of confidence that weight loss positively impacts dogs with OA. There is significant interest in the use of exercise modification and physical therapy in dogs and cats suffering with OA/DJD. There are several programs providing extensive education (including various certifications) in this area, although the description of these is beyond the scope of this chapter. A recent review provides an excellent starting point [60]. There are also textbooks available to help guide the clinician [61]. While it is generally accepted that controlled exercise and physical therapy are helpful in OA patients, peer‐reviewed data to support specific programs for canine and feline patients are unfortunately limited. It is beyond the scope of this chapter to discuss the many recommendations about the use of exercise and physical therapy, though any interventions considered should be practical and pragmatic. While data to support physical therapy modalities are sparse, some reports are available, and more information on these therapies is available in Chapter 49. Treatment of OA with extracorporeal shockwave therapy has shown mixed results [62–64]. Two studies had mixed positive results and one study demonstrated minimal effects. Another prospective study found that a combination of caloric restriction and intense physiotherapy improved both weight loss and force plate kinetic data in overweight dogs with OA [54]. Finally, there are limited data to support the use of photobiomodulation (e.g., low‐level laser therapy) in the treatment of OA [65,66]. Overall, the strength and quality of the evidence from these published studies is consistent with a low to moderate degree of confidence that these therapies positively impact OA patients. Consequently, it is incumbent on those promoting, practicing, and financially benefiting from physical therapy and rehabilitation to perform clinical trials to critically evaluate these interventions. The introduction of diets formulated with high omega‐3 polyunsaturated fatty acids (PUFAs), specifically eicosopentanoic acid (EPA) and docosahexaenoic acid (DHA), has introduced a new dimension in the management of OA [67–69]. The omega‐3 (n‐3) family of PUFAs includes α‐linolenic acid (ALA), EPA, and DHA, while the omega‐6 (n‐6) family includes linoleic acid (LA) and arachidonic acid (AA) [70]. EPA and DHA are precursors for anti‐inflammatory lipid mediators, while AA is a precursor for proinflammatory lipid mediators. The current understanding of the mechanism of action of dietary omega‐3 PUFAs in OA is twofold. The first effect is indirect, whereby consumption dose‐dependently increases concentrations of EPA and DHA, which are less potent mediators of inflammation, and these increased proportions occur at the expense of AA concentrations [71–73]. In addition to forming more anti‐inflammatory lipid mediators, less substrate is also available for the formation of AA‐derived proinflammatory eicosanoids. The second effect results from direct actions of omega‐3 PUFAs on cartilage. Cartilage cell cultures treated with omega‐3 PUFAs inhibit the transcription of major enzymes and cytokines tied to matrix degradation [74]. Several clinical trials have looked at the effects of diets high in omega‐3 PUFAs on pain and dysfunction associated with OA in dogs [75–80]. All studies were prospective and randomized and adequately addressed issues of scientific quality relating to data collection, analysis, bias, and generalizability. While outcome measures varied between studies creating some challenges in assessing the overall strength of evidence, they uniformly identified positive effects. Thus, the strength and quality of the evidence is consistent with a high degree of confidence that diets high in omega‐3 PUFAs positively impact dogs with OA. Given this, it is recommended to switch patients with OA to one of these diets. The data are less clear on the effects of supplementing a diet with omega‐3 fatty acid products (e.g., fish oil capsules). In cats, one study has evaluated the effects of elevated omega‐3 PUFA diets, with largely inconclusive results. Thus, there are very little data to support or reject the use of these types of diets in cats [81]. Analgesic and anti‐inflammatory agents are the most common components in the management of OA. The efficacy of non‐steroidal anti‐inflammatory drugs (NSAIDs) in treating chronic pain associated with OA has been well documented in several systematic reviews in small animal medicine [47,82–84]. The strength and quality of the evidence is consistent with a high degree of confidence supporting the use of NSAIDs in the management of OA in dogs. There are growing data available in cats showing positive clinical effects, and this supports a moderate degree of confidence in the use of NSAIDs in the management of DJD/OA in cats [39,85]. It is not surprising that, as a class of drugs, NSAIDs are among the most prescribed in small animal medicine. There are more data on NSAID efficacy and potential complications than there are for any other aspect of the multimodal OA management plan. As stated previously, NSAIDs are one of the most common classes of drugs used to manage chronic pain in small animals. There are several reasons for the dramatic increase in NSAID use in companion animals, including the availability of NSAIDs with improved safety and efficacy that are approved specifically for small animals (primarily dogs) [83,86,87]. Generally, currently prescribed NSAIDs are very safe drugs, with only a small percentage of patients experiencing serious complications [86]. Detailed information regarding the pharmacology of NSAIDs is available in Chapter 24. Efficacy of NSAIDs is comparable to opioids in many instances of mild to moderate musculoskeletal and visceral pain. However, for severe pain associated with some fractures, data are not available to substantiate that claim [88]. NSAIDs can be used to alleviate acute pain, either traumatically or surgically induced, and for chronic pain such as OA. Efficacy and toxicity may vary among individuals, and monitoring of each patient is mandatory [86]. Selecting an efficacious NSAID and monitoring its usage is important, but definitive evidence‐based guidelines for this are not available. First, it is wise to use products with a history of extensive clinical use. Use only one NSAID at a time and ensure correct dosing. Review the treatment plan frequently and change to an alternative NSAID if there is a poor response to therapy. Observe for signs of potential toxicity as soon as administration begins with increased vigilance and monitoring of high‐risk patients. If indicated, establish the patient’s baseline renal and hepatic function prior to NSAID administration. Therapy should be adapted to suit the patient’s needs. In patients with chronic disease, begin with the recommended dose and, if efficacious, attempt to reduce the dose at regular intervals (e.g., weekly) until the lowest dose providing the maximum benefit is reached. Determining the lowest effective dose is challenging, and one study suggested that it is difficult to decrease by more than 50% of recommended (label) dose for most dogs [89]. Avoid NSAIDs in patients with known contraindications to their use. Contraindications for NSAID use can range from fairly obvious to quite subtle reasons. The following is a list of general guidelines on potential contraindications for NSAID usage. These recommendations may change with generation of more clinical data [90]. The most common problems associated with NSAID administration to dogs and cats involve the gastrointestinal (GI) tract [86]. Signs may range from vomiting and diarrhea, including hematemesis and melena, to a silent ulcer which results in perforation. The overall incidence of GI toxicity in dogs or cats treated with NSAIDS is unknown. 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. The effect that aging has on an individual patient’s ability to metabolize NSAIDs is likely to be quite variable. Hepatotoxicosis caused by NSAIDs is generally considered to be idiosyncratic [86,90]. Most dogs recover with cessation of treatment and supportive care. Renal dysfunction may occur with NSAID administration as a consequence of prostaglandin inhibition [91]. While renal prostaglandin synthesis is low under normovolemic conditions, this increases in the face of hypovolemia and prostaglandin synthesis becomes important for maintaining renal perfusion [92,93]. The use of NSAIDs must be considered very carefully in hypovolemic or hypotensive animals, and it is important to remember this in the context of perioperative NSAID administration where patients will be undergoing general anesthesia. A common clinical management question is whether a washout period is needed when switching from one NSAID to another. Several sources, including crowd sourcing websites, conference proceedings, pharmaceutical company promotional materials, and journal articles, have advocated a washout period of varying lengths (1–7 days) when changing NSAIDs due to presumed lack of efficacy [90,94–96]. These recommendations are not based on clinical data but rather are derived from extrapolations of pharmacokinetic data and conservative speculation. There are several different scenarios to consider when switching from one NSAID to another in a clinical patient. The first involves a switch after a single dose of a perioperative parenteral NSAID (e.g., meloxicam) to an oral NSAID the next day. The only data available in this situation are from a study involving normal healthy dogs that were given parenteral (subcutaneous) carprofen followed by deracoxib orally 24 h later and repeated for 4 days. This portion of the study compared subcutaneous carprofen/oral deracoxib, subcutaneous carprofen/oral carprofen, and placebo and found no differences in clinical findings or gastric lesions. Thus, these limited data appear to suggest that it may be safe to switch from a single injection of one drug to an oral formula the next day if using another product [94]. However, without testing all the possible combinations of injectable and oral NSAIDs, it is not possible to make definitive treatment recommendations. The second situation involves switching NSAIDs for perceived lack of a response by the patient. This is a difficult question for clinicians, and there is significant variation in recommendations. Many authors suggest waiting five half‐lives from administration of the first drug before initiating the second drug to reduce the plasma concentration of the first drug to near zero. The only clinical data that may shed light on this situation are from a report that described switching to firocoxib from another NSAID. This study showed no increase in documented side effects whether firocoxib was started the next day or up to 7 days after stopping the original drug [97]. These data would seem to suggest that a washout period is not necessary, but most clinicians follow the recommendation of discontinuing an NSAID for 1–7 days before initiating another drug. The final situation involves transitioning to or from aspirin. If aspirin is the initial drug, it has been recommended that a minimum 7‐day washout period be followed before starting another NSAID. The basis for this recommendation is to provide time for platelet regeneration due to aspirin’s irreversible effects on platelets [90,98]. However, there are limited clinical data to support this recommendation. If a dog is receiving a product that is COX‐1 sparing (i.e., a primary COX‐2 inhibitor) and is then changed to aspirin, a 7‐day washout period is recommended due to the gastric adaptation and production of aspirin‐triggered lipoxins (ATLs) [90,98]. Patients receiving aspirin produce ATLs, which have been shown to exert protective effects in the stomach by diminishing gastric injury, most likely via release of nitric oxide (NO) from the vascular endothelium. However, concurrent administration of COX‐1‐sparing drugs with aspirin results in the complete inhibition of ATLs and can potentially cause significant exacerbation of gastric mucosal injury. It is important to remember that the formation of ATLs has yet to be proven in the dog. The approved NSAIDs available to clinicians vary considerably around the world. It is very important for practitioners to remember that the clinical response of an individual to a particular drug is quite variable. Patients may respond favorably to one product and not another, so if a NSAID is indicated in a case and the first product used does not achieve a positive clinical response, NSAIDs should not be abandoned altogether but a different product tried. Carprofen is a member of the arylpropionic acid class of NSAIDs. In the US, it is approved, both in oral and injectable formulations, to treat pain and inflammation associated with OA in dogs. Carprofen improved limb function in clinical trials of dogs with naturally occurring OA [99–105]. Three long‐term studies (84 and 120 days) found that carprofen was well tolerated, and based on subjective assessments, dogs appeared to improve over the treatment period. The strength and quality of evidence supports a high degree of confidence in the use of carprofen to treat OA pain in dogs. Cimicoxib is a member of the coxib class of NSAIDs. It is approved by the European Union as an oral formulation in dogs for the treatment of postoperative pain and pain and inflammation associated with OA [106–108]. There is one study evaluating its use in OA and two studies evaluating perioperative pain treatment in comparison to other products, and the results were favorable [109–111]. One final study evaluated its use for palliative pain management in patients with osteosarcoma [112]. At the time of writing, the strength of evidence supports a low to moderate degree of confidence in the use of cimicoxib to treat OA pain in dogs. Deracoxib is a member of the coxib class of NSAIDs. It is approved for use in dogs as an oral formulation for the treatment of pain and inflammation associated with OA and postoperative pain associated with orthopedic surgery. It has been demonstrated to provide effective relief of pain in clinical OA trials in dogs in a study that has not been published in a peer‐reviewed journal but has been presented in abstract form [113]. As with OA, data regarding its efficacy for pain relief following orthopedic surgery are only available in abstract form [114]. There are two additional studies that evaluated postoperative pain in dental and soft tissue procedures [115,116]. Due to lack of information, it is not possible to rate confidence in the use of deracoxib to treat OA pain in dogs. Enflicoxib is a member of the coxib class of NSAIDs [117–119]. It is approved in the United Kingdom (UK) and Europe for the management of pain and inflammation associated with OA in dogs as a once‐a‐week therapy. Clinically, it has been shown to improve limb function in dogs with OA in one well‐controlled study [120]. Additionally, a second study showed noninferiority with mavacoxib [121]. The strength and quality of the evidence supports a moderate to high degree of confidence in the use of enflicoxib to treat OA pain in dogs. Firocoxib is a member of the coxib class of NSAIDs. It is approved as an oral formulation for the management of pain and inflammation associated with OA in dogs. Clinically, several studies have demonstrated improved limb function in dogs with OA [122–126]. Long‐term dosing of firocoxib showed continued improvements over the year of treatment. The strength and quality of evidence supports a high degree of confidence in the use of firocoxib to treat OA pain in dogs. Grapiprant is a member of the piprant class of drugs. It is a highly selective antagonist of the prostaglandin‐E2 receptor 4 (EP4) and is considered a novel NSAID due to its unique mechanism of action [127–129]. One well‐controlled study provides data showing clinical improvement in dogs with chronic OA [130]. Interestingly, there are conflicting data in grapiprant’s ability to modulate acute pain. One study found noninferiority of grapiprant compared to carprofen for perioperative analgesia in dogs undergoing ovariohysterectomy [127], while two canine acute experimental pain models found that grapiprant was not different than control treatment and was significantly less effective than firocoxib and carprofen, respectively [131,132]. At this time, the strength of evidence supports a moderate degree of confidence in the use of grapiprant to treat OA pain in dogs. Ketoprofen is a member of the arylpropionic acid class of NSAIDs. One limited study compared dosages of ketoprofen and the combination of ketoprofen with tramadol in a small group of dogs with OA [133]. Most data regarding clinical use of this product involve acute pain models or short‐term (mostly perioperative) pain management in both dogs and cats [134–137]. Due to lack of information, it is not possible to rate confidence in the use of ketoprofen to treat chronic OA pain. Mavacoxib is a member of the coxib class of NSAIDs. It is approved by the European Union as an oral formulation for the treatment of pain and inflammation associated with OA in dogs. Mavacoxib has published pharmacological data and four noninferiority studies showing clinical improvements in dogs with chronic OA [120,121,138–142]. Mavacoxib is a long‐acting agent with an approved dosing regimen consisting of a loading dose repeated at 14 days and thereafter at dosing intervals of 1 month. The strength and quality of evidence supports a high degree of confidence in the use of mavacoxib to treat OA pain in dogs. Meloxicam is a member of the oxicam family of NSAIDs. It is approved for use in dogs for the control of pain and inflammation associated with OA and is available in oral, transmucosal oral mist, and parenteral formulations. There are robust data evaluating meloxicam safety and efficacy for chronic OA pain management in dogs [141,143–145]. The strength and quality of evidence supports a high degree of confidence in the use of meloxicam to treat OA pain in dogs. Meloxicam is approved for use in cats but, in the US, that approval is limited to a single dose to control pain and inflammation associated with orthopedic surgery, ovariohysterectomy, and castration. In other countries, however, meloxicam is approved for long‐term management of musculoskeletal pain in cats. Administration to cats ranging from 5 days to indefinite dosing to manage pain for locomotor disorders including OA has been described with a range of dosing recommendations (0.01–0.05 PO mg/kg once daily) [146–151]. Clinical efficacy is primarily supported by data generated from studies using the 0.05 mg/kg dose PO every 24 h. At lower dosing regimens (0.01–0.03 mg/kg PO every 24 h), meloxicam has been shown to be well tolerated and safe in cats, including cats with chronic renal dysfunction [148–150,152]. The strength and quality of evidence supports a high degree of confidence in the use of meloxicam to treat DJD/OA pain in cats. Robenacoxib is a member of the coxib class of NSAIDs. Depending on the country, approval may be for dogs only, or for both dogs and cats. Indications in the dog are for the treatment of pain and inflammation associated with orthopedic or soft tissue surgery as well as the treatment of pain and inflammation associated with chronic OA [153–158]. The strength and quality of evidence supports a high degree of confidence in the use of robenacoxib to treat OA pain in dogs. In the cat, approved indications vary by country and include treatment of postoperative pain and inflammation associated with surgery as well as acute and chronic administration for pain and inflammation associated with musculoskeletal disorders [157–165]. The strength and quality of evidence supports a moderate to high degree of confidence in the use of robenacoxib to treat DJD/OA pain in cats. Tolfenamic acid is an anthranilic acid derivative and a member of the fenamates class of NSAIDs. It is approved in Canada and Europe in both oral and parenteral formulations for dogs and cats. While some clinical data are available to support use of tolfenamic acid in dogs and cats, all studies involve short‐term administration (3–7 days) only [166–168]. Given the lack of long‐term data, the strength of evidence supports a low degree of confidence in the use of tolfenamic acid to treat OA pain in dogs or cats. A significant breakthrough in the understanding of nociceptive processing came with the recognition that the nervous system was plastic, which is to say, inputs from the periphery could, via activation of a variety of receptors (principally the NMDA receptor), produce changes in processing of nociceptive signals in the spinal cord. The characteristics of the NMDA receptor are such that with repeated stimulation, a state of prolonged depolarization in dorsal horn neurons is produced. This long‐term potentiation is thought to produce the state known as “central sensitization” via activation of a variety of second messenger systems, and the production of NO, eicosanoids, and induction of immediate early genes. Central sensitization is thought to contribute to injury‐ or disease‐induced pain by causing amplification of afferent signals, and by altering processing of sensory information such that previously non‐noxious signals are now encoded as noxious. The NMDA receptor appears to be central to the induction and maintenance of central sensitization, and the use of NMDA receptor antagonists would appear to offer benefit in the treatment of pain where central sensitization has become established (especially chronic pain). Ketamine, tiletamine, dextromethorphan, and amantadine possess NMDA antagonist properties, among other actions [169–173]. Additional information about these drugs in available in Chapters 25 and 27. There is one publication evaluating amantadine combined with an NSAID that demonstrated improvements in the canine OA patients compared to the NSAID alone [174]. This study was a randomized, blinded, placebo‐controlled trial. The study indicated efficacy based on both objective and subjective outcome measures, and the evidence supports a moderate degree of confidence in the use of amantadine to impact the outcomes reported. The descending opioidergic system is one of the best described endogenous analgesic mechanisms [88]. For both pharmacologic and regulatory reasons, long‐term classic oral opioid therapy has not been a viable treatment methodology in veterinary patients. However, the use of tramadol (a synthetic derivative of codeine classified as an opioidergic/monoaminergic drug), which has actions at both μ‐opioid receptors and facilitates activity in the descending serotonergic system, has become commonplace in small animal practice. Tramadol use grew despite a lack of supporting clinical data and unfavorable pharmacologic data [175–177]. In a well‐controlled clinical trial, tramadol was found to be ineffective alone in treating chronic OA in dogs [178]. A second prospective clinical trial provides data showing limited improvements in both objective and subjective outcome measures in canine OA patients receiving tramadol [41]. Mixed results were found in two studies examining postoperative analgesia after tibial plateau leveling osteotomy (TPLO) surgery [179,180]. Additionally, a recent systematic review and meta‐analysis of tramadol for postoperative pain management in dogs found the certainty of evidence to be low to very low that the drug had any efficacy [181]. Thus, the strength and quality of evidence supports a very low level of confidence in the use of tramadol for chronic pain management in dogs. Interestingly, in cats, tramadol has very different pharmacokinetics, which may provide better analgesia when compared to dogs [182,183]. Two small well‐controlled studies found increased mobility and improved owner assessments of impairment in cats receiving tramadol [184,185]. Given these data, the evidence supports a moderate level of confidence in the use of tramadol for treatment of DJD/OA pain in cats. Further information on tramadol is available in Chapter 25. Gabapentin, a gabapentinoid, binds to the α2δ subunit of voltage‐gated calcium channels, causing a decrease in the release of neurotransmitters and reducing neuronal excitability [38,186]. Single small well‐controlled reports in both dogs (treating neuropathic pain) and cats (treating OA) documented improvement in outcome measurements when treated with gabapentin [187,188]. Given the limited data, the strength of evidence supports a low degree of confidence in the use of gabapentin for chronic DJD/OA pain in dogs and cats. Further information on gabapentin is available in Chapter 25. A variety of other drugs have been suggested for use in chronic pain in dogs and cats with no pharmacological information or clinical trials. As examples, there have been no clinical trials assessing pregabalin, venlafaxine, duloxetine, ketamine, intra‐articular steroids, or amitriptyline for the relief of painful symptoms associated with any type of chronic pain (such as OA) in dogs or cats. Thus, due to lack of information, it is not possible to rate confidence in the use of any of these drugs for treatment of chronic DJD/OA pain. The lack of high‐quality, peer‐reviewed literature makes it difficult to draw conclusions about any of these therapies. Studies commonly have limitations related to methods of participant recruitment and randomization, baseline characteristic data reporting, intervention standardization and concealment, blinding, participant retention, follow‐up procedures, and overall protocol. The following is a limited exploration of some of the data available to date. A recent systematic review and meta‐analysis of enriched diets and nutraceuticals concluded in part “a very marked non‐effect of chondroitin–glucosamine nutraceuticals, which leads us to recommend that the latter products should no longer be recommended for pain management in canine and feline OA” [189]. This conclusion was based in part on the evaluation of three trials [101,189,190]. One study subjectively (via a non‐validated tool) showed a limited positive effect at only one of three time points [190]. The other two studies showed no positive effects measured by force plate analysis [101,191]. The strength and quality of evidence supports a very low degree of confidence in the use of these products for the treatment of OA pain in dogs. Two studies have evaluated polysulfated glycosaminoglycan (PSGAG) efficacy on lameness due to OA. Both studies were limited by study design deficiencies (small sample size and non‐validated subjective scoring systems). One study was blinded, with a placebo control, and found no significant improvement in lameness scores between groups (three PSGAG doses and placebo) [192]. There was a trend toward improvements that may have been confirmed with a larger sample size. The second study demonstrated lameness improvement but was neither randomized nor blinded [193]. Interestingly, the product tested in both studies did gain approval by the US Food and Drug Administration for use. The strength and quality of evidence supports a low degree of confidence in the use of these compounds for treatment of OA pain in dogs. Four trials were identified using a compound whose main ingredient was green‐lipped mussel (Perna canaliculus) for the treatment of OA in dogs. The studies were prospective and randomized in design [194–197]. While all showed positive effects (subjectively and objectively), they all had small sample sizes. Additionally, there are some questions regarding the scientific quality in two of these studies. There was moderate consistency across the studies, and their conclusions suggest that the observed effect will be physiologically meaningful and achievable. Based on these data, the strength and quality of evidence supports a moderate degree of confidence in the use of these compounds for the treatment of OA pain in dogs. Two trials were identified using Zeel® for the treatment of OA in dogs. While both were prospective, only one was randomized and blinded [198,199]. Both studies showed subjective positive effects associated with the product; however, in one study, effects were less than those produced by carprofen. Given the small sample sizes and the study limitations, there are some questions regarding the scientific quality of the studies. There was a moderate level of consistency between the studies, and the overall strength and quality of evidence supports a low to moderate degree of confidence in the use of these compounds for the treatment of OA pain in dogs. Six studies including three randomized, blinded, placebo‐controlled clinical trials using type II collagen as a treatment for OA in dogs have been performed [109,200–204]. The more recent studies boost earlier positive findings that support the use of this compound. Given the study design limitations (small sample size, non‐validated subjective tools, limited follow‐up data points, etc.), there are still some questions regarding the scientific quality of these studies [189]. Based on these data, the strength and quality of evidence supports a moderate degree of confidence in the use of this compound for the treatment of OA pain in dogs. There are several single‐center clinical trials involving a variety of cannabidiol (CBD) products showing limited to no positive effects for the treatment of OA pain and dysfunction. Though difficult to evaluate, these products may have a place in OA therapy if additional studies show a positive effect with larger sample sizes and/or different study designs. Two recent reviews emphasized the limitations (low sample size) and conflicting data available to date [84,189]. Two studies comparing CBD oil treatment to placebo found a reduction of clinical signs by subjective measurements, while another randomized, blinded crossover study found no significant difference between CBD oil treatment and placebo over the course of 6 weeks based on clinical metrology instrument outcomes and objective pressure gait analysis [205–207]. Based on these data, the strength and quality of evidence supports a low degree of confidence in the use of these compounds for the treatment of OA pain in dogs. Nerve growth factor (NGF) has been shown to be an important driver of pain in OA due to its ability to facilitate peripheral and central sensitization in mature patients [208–211]. In dogs, two studies found significant pain relief with anti‐NGF monoclonal antibodies [212,213]. More recently, a large well‐controlled clinical trial evaluating the monoclonal antibody bedinvetmab found it to be efficacious in dogs with OA [214]. This product is now approved for dogs in the US, Canada, the UK, and the European Union. The strength and quality of evidence supports a high degree of confidence in the use of bedinvetmab to treat OA pain in dogs. A feline‐specific monoclonal antibody has also gone through a similar pathway of clinical testing. Initially, two small well‐controlled studies suggested efficacy in cats [215,216]. These findings were confirmed with two large well‐controlled clinical trials with the monoclonal antibody frunevetmab [217,218]. This product has been approved for cats in the US, Canada, the UK, the European Union, and several other countries. The strength and quality of evidence supports a high degree of confidence in the use of frunevetmab to treat OA pain in cats. Further information on anti‐NGF monoclonal antibodies is available in Chapter 48. Cell‐based therapies include many products, and it can be confusing to differentiate these therapies from each other. Blood‐derived products are often lumped together but include a range of varied therapies including autologous conditioned serum, autologous protein solution, platelet‐rich plasma, and certain preparations containing medicinal (or messenger or mesenchymal) stem cells [84,219–223]. Other stem cell‐based therapies are adipose‐derived stromal fraction and autologous, allogenic, or xenogeneic stem cells of varying origins (e.g., adipose, bone marrow, or umbilical tissue). To complicate things further, there is no uniformity in production of these products or methods to test for efficacy [221,224]. These factors make it difficult to assess efficacy in dogs and cats. The following is a limited discussion of the different products available at the time of writing. One pilot study and two small clinical trials evaluate intra‐articular autologous protein solution (APS) in dogs with OA [225–227]. While there are some data to support use in dogs, the small sample sizes and lack of a control group in one study limit the conclusions that can be drawn. No data are available in using APS for the treatment of OA/DJD in cats. Thus, the strength and quality of evidence supports a low degree of confidence in the use of this therapy in dogs. Limited clinical data are available to assess the efficacy of platelet‐rich plasma (PRP) in chronic OA pain. Again, the clinical studies suffer from limitations associated with study design (small numbers of patients, and lack of controls and standardization of product) [228–232]. No data are available for the treatment of OA/DJD in cats with PRP. While there is evidence of some positive efficacy in each study, the strength and quality of evidence supports a low degree of confidence in the use of this therapy. Medicinal stem cells (MSCs) can be autologous, allogenic, or xenogeneic [84,220,221,223]. The exact mechanism of how MSCs exert their effects is not completely understood. Current data suggest that MSCs are active primarily through their secretory factors [84,220,223,233]. These paracrine factors may produce immunomodulatory and anti‐inflammatory effects as well as other effects such as angiogenesis. Autologous and allogenic MSCs can be clinically delivered intra‐articularly. Additionally, allogenic and xenogeneic MSCs can be given intravenously. One xenogeneic product of equine umbilical cord MSC is approved for use in the UK and the European Union for the treatment of OA in dogs [234]. Clinical studies involving MSCs have been extensively reviewed [84,220,223,233,235]. The majority have limitations associated with study design (small numbers, lack of controls or blinding, non‐validated subjective outcome measures, and few measurement time points). While most studies show positive results, the strength and quality of evidence supports a moderate degree of confidence in the use of MSCs in dogs; however, this has the potential to improve with additional clinical data. There are currently no clinical data available evaluating the use of MSCs for the treatment of DJD/OA in cats. There is a continued desire to identify additional drugs and compounds to alleviate chronic pain in small animal patients. This is based upon the fact that current products are not always effective, and some result in more adverse events than some clinicians and clients are willing to accept. Given this set of circumstances, a discussion about non‐responders to current treatments is appropriate. After initiation of treatment, the veterinarian and client must decide whether the animal is responding to the prescribed pain management plan. Clinicians need to ask this question every time a product or therapy is prescribed. Without verbal patient communication, veterinarians are hampered in all phases of treating pain, including the diagnosis, accurate characterization and localization, and evaluation of therapeutic efficacy. While veterinary patients possess many of the same nociceptive pathways (including neurotransmitter receptors) and perhaps even similar perceptions of painful stimuli as other species (including humans), one cannot assume that the evaluation of responses should be similar for all patients. One needs to go no further than comparing cats, dogs, and pet birds to find striking examples of this conundrum. In recent years, strides have been made in evaluating the effects of different pain therapies in veterinary patients, but it is important to remember current limitations and proceed with caution when making claims about new treatments or therapeutic agents. In addition, the criteria for defining a “responder” as well as the outcome measures used to define the response require clarification. In the human literature, the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consortium defines outcome responses in clinical trials for human chronic pain, and these are summarized in Box 71.3. Given these guidelines, in many human studies, a 30% improvement in a patient makes that case a positive responder. In veterinary medicine, clinical trials to demonstrate efficacy for pain control are usually performed for regulatory purposes and outcomes are typically reported as statistical comparisons between treatment group population means. Thus, the results represent the “average” patient. These data are difficult to apply clinically because individual patients are being treated [238]. In human medicine, managing the pain and dysfunction of OA has been often described as the 80/20 rule [236]. That is, 80% of patients experience 20% pain relief, while only 20% of patients experience 80% pain relief. About 50% have their pain halved. An extensive review of data available in human medicine yields interesting and sobering results. Data clearly show that different NSAIDs show a range of responses for pain relief. This is compounded by the fact that the same NSAID, at different doses, shows the same gradation of responses. Generally, only about 15–30% of patients actually show extensive improvement, while over 60–70% show minimal improvement (i.e., a benefit) [239,240]. In veterinary medicine, outcome testing instruments cannot reliably differentiate this range of clinical responses, so there are no data supporting different doses of a given NSAID even though it has been observed that NSAID effects are dose dependent. Despite these limitations to detect clinical improvements, many (including the Food and Drug Administration Center for Veterinary Medicine) suggest that clinicians titrate the dose of NSAIDs to the lowest effective dose.
71
Osteoarthritis Patients
Introduction
Diagnosis of osteoarthritis
Treatment strategies for managing chronic osteoarthritis pain
Weight reduction and management
Exercise modification and physical therapy
Nutritional support and high omega‐3 diets
Pharmacologic management
Non‐steroidal anti‐inflammatory drugs
Contraindications for NSAID use
Adverse events associated with NSAID use
Washout period between NSAIDs
Specific NSAIDs
Carprofen
Cimicoxib
Deracoxib
Enflicoxib
Firocoxib
Grapiprant
Ketoprofen
Mavacoxib
Meloxicam
Robenacoxib
Tolfenamic acid
N‐methyl‐D‐aspartate (NMDA) receptor antagonists
Amantadine
Opioids
Gabapentin
Other pharmaceuticals
Alternative, complementary, and homeopathic compounds
Compounds based on chondroitin sulfate and glucosamine hydrochloride
Polysulfated glycosaminoglycan
Green‐lipped mussel preparation
Zeel® homeopathic preparation
Type II collagen
Cannabidiol products
Anti‐nerve growth factor monoclonal antibodies
Cell‐based therapies
Autologous protein solution
Platelet‐rich plasma
Medicinal (messenger or mesenchymal) stem cells
Dealing with non‐responders to standard treatment approaches
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