Carolyn M. McKune Mythos Veterinary, LLC, Gainesville, Florida, USA According to the International Association for the Study of Pain (IASP), pain is “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” [1]. This definition has been subtly but critically altered from its previous 1979 definition, which implied through words such as “described” instead of “associated,” that the ability to speak was a prerequisite for pain. The current definition includes the accompanying note: “verbal description is only one of several behaviors to express pain; inability to communicate does not negate the possibility that a human or a nonhuman animal experiences pain.” It is beyond the scope of a single chapter to address the clinical management and pharmacologic treatment of pain in its entirety. As such, this chapter focuses on initiatives to “anticipate, assess, and alleviate pain” [2]. The goals of the chapter are to: The concept of proactive pain management begins with acknowledging that pain is a sequela to many invasive and even some minimally invasive procedures. It is now accepted that proactivity is essential to effectively advocate for the patient. Harnessing the power of proactivity allows the clinician to engage in a plan to address pain before it occurs, rather than simply reacting to its presence. Education of the entire veterinary team is a key component in this strategy and different approaches are required depending on the type of pain being addressed. Foundational understanding of acute (adaptive) versus chronic (maladaptive) pain management allows us to employ an approach that is suitable for each patient. For example, acute pain is best managed as early as possible in the process. For elective procedures, such as castration or ovariohysterectomy, pain management is instituted prior to the start of surgery. However, in other situations, proactivity includes identifying diseases, such as osteoarthritis (OA) or laminitis, which are likely to cause long‐term pain and implementing a pain mitigation strategy as early as possible, with a focus on improving quality of life. Each member of the pain management team has a different role to play in the educational continuum with contributions from researchers, clinicians, and educators leading to enhanced standards of care for veterinary patients. While experts publish evidence‐based information to validate pain assessment and alleviation strategies, everyone must be well‐informed regarding current developments and continually update themselves so information can be disseminated to those directly responsible for patient care. This requires good communication skills, a structured approach, and a foundation of evidence‐based information. Suggestions for providing a coordinated pain management framework include having a case coordinator, for example, a trained technician or nurse, who is responsible for reaching out to follow‐up on a patient’s progress and facilitate additional re‐checks as necessary [3]. Successful pain management also includes education of the owner about the characteristics of their animal that may predispose them to chronic pain (e.g., breed, diet, body weight, body condition score, and age), the behavioral indicators of pain they should look for, and the importance of administering prescribed pain medications. Assessment of pain is critically important and this is covered in detail in Chapter 47. Pain assessment using validated tools is an essential outcome measure of any pain management protocol. Unfortunately, validated pain assessment tools are not available for all species, including most captive species in zoos, wildlife, fish, and amphibians. In the absence of a validated pain assessment tool, the practitioner must use their familiarity with these animals, including their natural behaviors, to make an educated assessment. The practitioner should prepare analgesic plans with a realistic goal in mind. In many cases, reduction of pain so that quality of life is improved is achievable, whereas complete absence of pain is not. The plan is deemed effective if reassessment of pain, using a chosen outcome measure, confirms this goal. Analgesic plans for acute pain are often successful because the animal usually has a diagnosis, a planned procedure, or known trauma, which allows targeted interventions. Inflammation is a core component of acute pain, and this is amenable to preventive or preemptive therapy. Preventive and preemptive analgesia, while often used interchangeably, are not the same. Preemptive analgesia alludes to the timing of analgesic administration – usually prior to noxious stimuli occurring [4]. Katz et al. [5] describe preventive analgesia as “minimizing the deleterious immediate and long‐term effects of noxious perioperative afferent input.” The key to this concept is preventing peripheral and central sensitization, which will reduce pain and analgesic requirements. Analgesic plans should match the degree (intensity) of anticipated or existing pain and its duration. Patients are assessed and reassessed for pain while in the clinic and after discharge by hospital staff (preferably the case coordinator) and owners, respectively. Treatment plans should also address patient anxiety. Children may experience significant anxiety related to painful medical procedures resulting in a greater perception of pain with subsequent procedures [6]. To reduce procedural pain and anxiety both pharmacologic (analgesics, anxiolytics, and sedatives) and non‐pharmacologic (distraction and play) interventions are used, many of which could be adapted for veterinary patients. Chronic pain is challenging in that it must start with an acknowledgment that it may be present, and it should be assessed or screened for during physical examinations. For example, older dogs and cats should be screened for OA and owners educated that changes in behavior can be due to pain and not the pet slowing down with age. Managing chronic pain can be challenging due to its complex etiology, lack of efficacious therapies, and potential limitations related to the owner’s ability to care for the animal due to financial, time, and physical constraints. As with acute pain, anxiety should be addressed. Fig. 48.1 demonstrates the challenges owners may face when caring for pets with chronic pain and other comorbidities. Figure 48.1 This image shows the medication box for a single canine patient with chronic otitis externa. Not pictured are the refrigerated medications, such as the allergy injections. In the background, there are also pills for the other household pets with osteoarthritis. The owner of this patient hired a separate care giver just to assist with the mid‐day routine and basic care of the patient. Not all owners have this financial freedom. Source: Dr. Carolyn McKune, with permission. Gruen et al. [3] have proposed an evidence‐based “decision‐making tree” for the treatment of acute and chronic pain in dogs and cats (Fig. 48.2). While Fig. 48.2 focuses on canine and feline patients, a similar approach can be used in other species based on species‐specific evidence (treatments in the first tier have robust evidence supporting use in that species, treatments in the second tier have moderate evidence, and those in the third tier have limited evidence). Additional information on pain management in particular species is available in species‐specific chapters elsewhere in this book. When acute pain is present, but a definitive diagnosis is not confirmed, the clinician most often relies on first‐tier drugs, which will provide reliable analgesia with minimal side effects. For small companion animal species (e.g., dogs, cats, and some pocket pets), opioids are a logical choice (see Chapter 23). For large animal species, non‐steroidal anti‐inflammatory drugs (NSAIDs) (see Chapter 24) and α2‐adrenergic receptor agonists (Chapter 22) are commonly used; opioids are administered by both systemic and epidural routes [7–9]. For acute pain of a known cause, the first tier of therapy often includes analgesia that targets the source of pain. For example, acute pain that is inflammatory in nature (e.g., a skin incision) will respond well to an NSAID. There are very few patients that do not benefit from a local anesthetic block and many techniques are applicable to surgical procedures. Please refer to other chapters dedicated to local anesthetic techniques in specific species for more information on these techniques. Supportive and nursing care, including nutrition, keeping patients warm and dry, and ensuring dressings are comfortable and clean are also important components of patient care. The International Society of Feline Medicine and the American Association of Feline Practitioners have created nursing care guidelines specific to the needs of cats [10]. Certain modalities, such as cold therapy, are also appropriate in many species [11–13]. Further information on non‐pharmacologic management of pain is available in Chapter 49. Figure 48.2 Decision tree for prioritizing pain management therapies. This figure outlines a tiered approach to pain management in cats and dogs for acute and chronic pain. Tiers are presented from highest recommendation (most evidence for effectiveness) to lowest, although all therapies presented have some evidence to support their use. Physical modalities include laser therapy, pulsed electromagnetic field therapy, acupuncture, and transcutaneous electrical nerve stimulation. Surgical procedures for chronic pain include top‐tier treatments such as dental procedures, removal of painful lesions, joint stabilization and replacement, and amputation; lower‐tier (salvage) procedures include arthrodesis, denervation, and excision arthroplasty. NSAIDs, non‐steroidal anti‐inflammatories; antiNGF mAbs, anti‐nerve growth factor monoclonal antibodies; α2s, α2‐adrenergic receptor agonists; PSGAGs, polysulfated glycosaminoglycans; TCAs, tricyclic antidepressants; IA; intra‐articular; PRP, platelet‐rich plasma. Source: Gruen et al. [3], with permission of the American Animal Hospital Association. NSAIDs have traditionally been used as first‐line drugs for chronic pain such as OA in many species. Chapter 24 provides information on the pharmacology of NSAIDs, and Chapter 71 is dedicated specifically to management of canine and feline OA patients. There is evidence to support the use of omega‐3‐fatty acids, which contain alpha‐linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), for some types of chronic pain, with their mode of action presumed to be via reducing oxidative stress [14]. Cats with degenerative joint disease that were fed a diet high in EPA and DHA (which also included glucosamine–chondroitin sulfate and green‐lipped mussel extract) demonstrated significant improvement in activity compared to a control group [15,16], as did dogs in a similar study [17]. Omega‐3 fatty acid‐supplemented diets have been shown to improve weight bearing in dogs with OA [18]. A range of omega‐3‐fatty acid dosages are reported in the literature, and it is important to follow recommended doses [19]. Evidence for the benefits of omega‐3 fatty acids is strong and, in some studies, they have allowed a reduction in NSAID dosage [20]. A comprehensive meta‐analysis reviewing the quality and efficacy of omega‐3 fatty acid supplementation supported its use for both canine and feline OA [16]. Omega‐3 fatty acids may also be beneficial in horses. In vitro studies suggest equine synoviocytes readily incorporate omega‐3 fatty acids to modulate inflammatory responses [21]. Locally administered corticosteroids have been used in horses with chronic joint pain for many years for their anti‐inflammatory effects [22,23]. In horses, evidence suggests that steroids may help them to return to normal function [24–26]. However, the specific steroid used was a significant factor, with horses administered methylprednisolone in the sacroiliac joint more likely to return to work than those administered triamcinolone [24]. Conversely, methylprednisolone leads to more cartilage damage in articular joints than triamcinolone [27]. There is less evidence supporting this intervention in other species and this class of drug is considered “second tier” in dogs and cats. Anti‐nerve growth factor monoclonal antibodies (anti‐NGF mAbs) are a breakthrough therapy for the control of OA pain in dogs and cats. Nerve growth factor (NGF), which is essential during development of the nervous system, appears to alter neuronal plasticity in conditions of chronic pain after the nervous system has matured [28]. In response to noxious stimuli, peripheral NGF protein is produced and released to facilitate binding to tropomyosin‐receptor kinase A (TrkA) receptors, which are present in nerve endings in subchondral bone [29]. Once this binding occurs, the complex becomes internalized and is transported to the dorsal root ganglion where, through binding to a multitude of different receptors, it ultimately leads to central sensitization. Peripherally, the binding of NGF to the TrkA receptor results in inflammatory mediator release, including histamine from mast cells and serotonin, as well as other pro‐inflammatory effects [30]. Synovial fluid from dogs with OA demonstrates increased NGF concentrations [31]. Pharmacotherapies, in the form of biological agents, target this growth factor peripherally. Anti‐NGF monoclonal antibodies are not chemically synthesized, but rather derived from natural sources. Specifically, monoclonal antibodies are produced through recombinant engineering or single B‐lymphocyte clones in laboratory animals [30] and, as they are species‐specific, they are recognized as native. A proposed benefit and important feature of anti‐NGF mAbs is that they do not block endogenous signaling as is seen with traditional analgesics [32]. NGF controls various endogenous ion channels, receptors, and signaling molecules and if anti‐NGF mAbs were to block these pathways, undesirable side effects could result [33]. In clinical trials, some human patients receiving anti‐NGF mAbs developed rapidly progressing OA, characterized by increased pain and radiographic changes. This adverse effect was linked to high doses of anti‐NGF mAbs or their combination with NSAIDs [34]; as a result, anti‐NGF mAbs are not currently approved for use in humans. These adverse effects have not been reported in animals. Bedinvetmab is a commercially available anti‐NGF mAb formulation for use in dogs. It is administered subcutaneously at a dose of 1 mg/kg and has a terminal elimination half‐life of 9.5 ± 1.8 days, primarily due to antibody recycling at the FcRn receptor [35]. It is intended as a once‐a‐month therapeutic and this duration of action is corroborated by a study evaluating another anti‐NGF mAb (ranevetmab) where owners used a clinical metrology instrument (the Canine Brief Pain Inventory) to score pain in their dogs for a period of four weeks following an injection of the anti‐NGF mAb versus saline [36]. Another study involving 26 dogs included an objective measurement of function (accelerometry) in addition to clinical metrology instruments. Compared to the placebo group, dogs administered ranevetmab showed significant improvement versus pretreatment based on pain scores as well as activity measured by an accelerometer [37]. Previous anti‐NGF mAbs were associated with a reduction in inflammatory pain in a canine kaolin model [38]. In studies looking at the safety of bedinvetmab, the drug was well tolerated in Beagle dogs over a period of 6 months. Clinical evaluations, including neurologic, ophthalmic, and joint evaluations found no adverse effects, nor were there any concerns with a two‐week concurrent administration of NSAIDs [35]. Treatment‐related immunogenicity has not been reported [35]. Frunevetmab is a felinized anti‐NGF mAb labeled for the control of OA‐related pain in cats. Minimum dosage is 1 mg/kg, administered subcutaneously, although significantly higher doses (up to 28 mg/kg) are well tolerated [39]. In a multicenter, randomized, placebo‐controlled, double‐blinded study of 275 cats, significant improvement was noted in client‐specific outcome measures as well as owner‐assessed global treatment response with frunevetmab versus placebo. Three doses were given 28 days apart and cats were assessed on days 28 and 56. Veterinarians assessed joint pain as improved, although this was not significant until later in the evaluation process at days 56 and 84 [40]. These improvements were consistent with reports from pilot studies looking at frunevetmab [41,42]. In the same study, evaluating 275 cats, adverse events did not differ between placebo and treatment groups, except for a variety of dermatologic issues, including dermatitis, alopecia, pruritis, and scabbing, which occurred significantly more frequently in cats that received frunevetmab [40]. This was also noted in the pilot study [42]. At the time of writing, areas in need of further research include the degree and duration of analgesic effect a patient may have from frunevetmab, as well as the necessary time to determine possible adverse events and/or immunogenicity, which may occur [30]. Future studies may expand the list of painful conditions that respond to anti‐NGF mAbs. Non‐pharmacologic tier‐one strategies for the management of chronic pain include encouraging activity, environmental modification, and weight management (Fig. 48.2). The approach to chronic pain management is integrative; therefore, the reader is encouraged to combine treatment strategies from this chapter with those described in Chapter 49. Second‐tier pain management treatments are best used in addition to tier‐one modalities or when first‐tier modalities do not meet the needs of the patient. It is appropriate that a more definitive diagnosis of the origin of pain is confirmed before these methods are employed. Suggestions for second‐tier modalities have less robust data to support their use and this section will review the information that is available. Evidence for second‐tier drugs used for chronic pain is particularly difficult to evaluate because chronic pain is complex and has many unique clinical presentations. For example, chronic pain can originate from multiple different organs, have a variety of stages, involve multiple pathways, and create varying degrees of emotional distress and reduction in quality of life. More than one chronic condition can exist at one time, so it is unlikely we will ever find a single “silver bullet” to use in these patients. We have an ethical obligation to use agents, which we currently have access to, and which have potential benefits with limited adverse effects when administered appropriately [43]. Ketamine, a N‐methyl‐D‐aspartate (NMDA) receptor antagonist, is a versatile drug with a place in anesthesia and pain management. In people, ketamine has been used to manage acute and chronic pain, in burn and cancer patients, and for alleviation of neuropathic pain [44–48]. Ketamine is often regarded as a more effective analgesic for somatic rather than visceral pain [49], especially when pain is inflammatory in origin. In people, the dose of ketamine required for analgesia is much lower than that required for anesthesia, especially when it is combined with an opioid [50]. These low doses do not appear effective in the cat or dog when assessed by mechanical and thermal threshold testing in non‐painful animals [51,52]. This may reflect the pain model used as, in the absence of clinical pain, it is unlikely that NMDA receptors were activated. Ketamine has been disappointing as a sole analgesic agent when administered as a constant rate infusion (CRI) [51,53], with only a single study in the dog [54] and cat [55] showing benefit, and several studies showing none. However, with the difficulty in recent years of accessing opioids reliably in some countries, ketamine infusions combined with lidocaine and/or opioids and/or α2‐adrenergic receptor agonists, have become commonplace in veterinary anesthesia, providing perioperative analgesia for a variety of procedures [56–61]. Clinical studies suggest that ketamine in combination with lidocaine is superior to tramadol alone [62]. However, when compared to a local anesthetic nerve block for patients undergoing cranial cruciate repair, the combination of an opioid, ketamine, and lidocaine was not as effective as the block for postoperative analgesia [63], thus reinforcing the importance of first‐tier analgesic choices (e.g., local blocks). This theory is also supported in one study in cats, where the addition of targeted local blocks to an anesthesia protocol that included ketamine showed benefits [64]. In addition to analgesic benefits, low‐dose infusions of ketamine appear to have few adverse cardiopulmonary effects in dogs [65,66]. No data exists on the cardiac effects of ketamine when used as a CRI in cats, leaving some clinicians unsure of its role in this species given the prevalence of subclinical cardiac disease [67,68]. However, when ketamine was administered at 23 μg/kg/min after a 2 mg/kg loading dose, to reduce propofol CRI requirements in a small number of cats, cardiovascular variables were not changed [69]. In the cat, ketamine is a component of various popular injectable drug combinations used to produce general anesthesia (e.g., “kitty magic”) [70], and likely contributes a degree of analgesia to these protocols [71]. Non‐traditional routes of administration of ketamine have been studied including its use as a regional and topical analgesic [72,73], or given in the epidural space [74–77]; however, these techniques are not common in clinical practice. In the horse, subanesthetic doses of ketamine combined with tramadol provided analgesia in cases of chronic laminitis [78], although caution is warranted when gastrointestinal transit time is a concern [79]. A large meta‐analysis of human studies concluded that magnesium, likely through its antagonism at NDMA receptors and calcium channels, reduced postoperative opioid use and resulted in lower pain scores [80]; however, the evidence supporting this is modest at best [81]. It is therefore not surprising that there is little work to support the use of magnesium as an analgesic strategy in animals. Two oral NMDA receptor antagonists, amantadine and memantine (an amantadine derivative), have been studied for their potential analgesic properties. Further information about these drugs is available in Chapter 25. In addition to targeted administration, systemic administration of local anesthetics for provision of analgesia has been studied with varying results. In conscious dogs, there was no change in nociceptive threshold using electrical cutaneous stimulation over a range of doses of systemically administered lidocaine [82]; however, this may reflect the model used in the study. Investigators using a thermal threshold model reported that systemically administered lidocaine had variable and species‐specific effects [83]. Clinical procedures, which may serve as better models, yield different results with systemic lidocaine administration [84]. Similarly, work done by Tsai et al. suggests that systemic administration of lidocaine provided comparable analgesia to meloxicam in dogs undergoing ovariohysterectomy [85]. In a meta‐analysis of human patients who received systemic lidocaine, the evidence was weak to moderate for pain reduction, and the studies that reported an effect found this only during early time points; however, the same meta‐analysis suggested that gastrointestinal recovery from anesthesia was positively impacted by use of systemic lidocaine [86]. Some veterinary patients (particularly those at risk for decreased gastrointestinal transit time or ileus, such as horses) may benefit from the prokinetic effects of systemic lidocaine [87]. By minimizing development of ileus, which is painful, lidocaine may have indirect analgesic effects. Unfortunately, the use of lidocaine did not translate into improved survival for horses with small intestinal lesions [88], and may indeed negatively impact their recovery from anesthesia [89–91]. Therefore, careful patient selection and judicious use of lidocaine in horses is advised. At the dose necessary for reduction of inhalant requirements in cats, significant cardiovascular depression occurs [92], and although there may be analgesic benefits [55], the risks of lidocaine infusions in cats may outweigh the benefits. Topical administration of eutectic mixtures of local anesthetics produces analgesia and reduces inflammation, with minimal systemic uptake [93–96]. Novel formulations of bupivacaine, including liposome‐encapsulated bupivacaine, which is released over 72 h, may be useful in multiple species [97–99]. The utility of this formulation is limited to infiltrative techniques using a moving‐needle injection technique in order to infiltrate deep and superficial layers of the surgical site. The product license in the United States is limited to regional analgesia for feline onychectomy and infiltration for canine stifle surgery [98], but continued research may expand its clinical application. Targeted nerve blocks, such as the transversus abdominis plane (TAP) block, showed no additional benefit of using liposome‐encapsulated bupivacaine compared to a dexmedetomidine–bupivacaine infiltration, although both techniques resulted in lower pain scores compared to the control group which did not receive a TAP block [100]. Caution is advised with incorporation of liposome‐encapsulated bupivacaine into targeted blocks that may impact critical neurologic pathways, as prolonged effects may occur [101]. For example, a brachial plexus block performed bilaterally with liposome‐encapsulated bupivacaine could last up to 72 h. If the drug diffused rostrally and desensitized cervical spinal nerves C3–C5, blockade of the phrenic nerve could necessitate the use of mechanical ventilation. In addition to patient side effects, client communication is equally important. For example, owners may perceive a reduction in motor function as detrimental, when in fact the extended effect of the block may contribute to better pain relief. There are case reports of side effects when blocks were performed with unencapsulated bupivacaine, such as Horner’s syndrome secondary to a brachial plexus block [102]. α2‐Adrenergic receptor agonists are discussed in greater detail in Chapter 22. Xylazine, detomidine, romifidine, medetomidine, and dexmedetomidine are commercially available veterinary α2‐adrenergic receptor agonists that provide analgesia in a variety of species [103–107]. A relatively new agent is a combination of the α2‐adrenergic receptor agonist, medetomidine, and a peripheral antagonist, vatinoxan, with the aim of eliminating the unwanted effects of medetomidine, such as vasoconstriction and bradycardia. Further work is necessary to assess this combination as an analgesic since α2‐adrenergic receptor agonists mediate analgesia both peripherally and centrally [108–112]. Benefit versus risk must be assessed before including any drugs in a pain management plan. In certain patients, the benefits of α2‐adrenergic receptor agonists are significant. In horses, xylazine provides significant relief of visceral and somatic pain, perhaps even more so than opioids or NSAIDs [113,114]. This species difference may be the result of α2‐adrenergic receptor distribution in the central nervous system [115]. Calves undergoing castration had a reduction in serum cortisol (one physiologic marker of pain) and improved behavior when a combination of low‐dose xylazine and ketamine was administered prior to the procedure [116]. Antinociception was improved in llamas receiving tiletamine–zolazepam when xylazine was concurrently administered [117]. Alternative routes of administration may provide varied benefits, such as the caudal epidural administration of detomidine in horses [118]. Regurgitant cardiac disease, which is prevalent in older dogs, is an example of a situation where there may be more risk than benefit to using α2‐adrenergic receptor agonists. Likewise, in a critically ill patient who is already obtunded, the use of systemic α2‐adrenergic receptor agonists may not be appropriate. When used as a component of an analgesic plan, this class of drug is more suited to healthy patients. The medetomidine–vatinoxan combination may help to ameliorate these concerns; however, as stated previously, the analgesic properties of this combination have not been studied. Gel oromucosal formulations of α2‐adrenergic receptor agonists (e.g., dexmedetomidine and detomidine) are available and labeled for use in several species for noise aversion in dogs and sedation in horses, respectively. At the time of writing, the use of these agents as analgesic adjuvants has not been reported. In human patients, topical clonidine has undergone a Cochrane review and was found to have limited efficacy [119]; therefore, it warrants little attention as an analgesic in veterinary medicine. Acetaminophen (paracetamol) is used in dogs and horses as a primary or adjunct analgesic. Unlike traditional NSAIDs, acetaminophen may target a COX‐1 splice variant (COX‐3). In equine patients [120], acetaminophen has a high oral bioavailability [121,122], with clinical reports suggesting it provides analgesia. Inhibitors of soluble epoxide hydrolase are a new class of non‐NSAID anti‐inflammatory and analgesic drugs, which increase endogenous concentrations of epoxy fatty acids by blocking their hydrolysis [123]. Epoxy fatty acids are analgesic and anti‐inflammatory signaling molecules, thus applicable to inflammatory diseases such as OA. The inhibitor with the most stability and potency across species seems to be trans‐4‐{4‐[3‐(4‐trifluromethoxy‐phenyl)‐ureido]‐cyclohexyloxy}‐benzoic acid (t‐TUCB) [123]. In horses, reduced lameness after intravenous injection of t‐TUCB has been demonstrated [124,125]. Pharmacokinetic work in the horse suggests that a dose of 1 mg/kg is most suitable to achieve an anti‐inflammatory effect [126], although in a small study, a dose of 0.1 mg/kg resulted in statistically significant improvement in pain scores for horses with chronic and severe laminitis [127]. The drug is relatively well tolerated, but gas colic was reported in a single horse [127]. There can be large species variations in drug bioavailability and metabolism, and inhibitors of soluble epoxide hydrolase are no exception [128]. Studies suggest a high oral bioavailability in dogs [129] and, when administered orally, they appear to reduce pain in dogs with naturally occurring arthritis [130]. While this work is preliminary, further investigation is warranted. Little to no clinical data is available regarding these agents in cats. Bisphosphonates decrease osteoclast activity by reducing development of osteoclast progenitors as well as by increasing osteoclast apoptosis [131]. This limits bone resorption and may have positive effects in horses with arthritis, lumbar spinal pain from cauda equina syndrome, and navicular disease [132–135]. Bisphosphonates also resulted in improved lameness scores in horses with bone fragility disease [136]. However, because of the effects on osteoclast activity, bisphosphonates can also perpetuate or exacerbate microfractures, and have detrimental effects in juvenile horses [131]. Dogs appear to tolerate the bisphosphonate zoledronic acid used for bone pain [137], although a small number developed azotemia [138,139]. Other bisphosphonates, such as tiludronate, also appear to improve bone pain in dogs [140,141]. This is an improvement over the historic use of pamidronate, which provided modest to no improvement for pain in dogs associated with diseases such as osteosarcoma [142–144]. Zoledronate was well tolerated in cats [145]; however, at the time of writing, there is no clinical data evaluating the drug’s efficacy in cancer‐associated pain. A comprehensive review and species comparison is available [146]. Canine patients may benefit from intra‐articular injections of steroids or other agents [147,148]. Small‐scale studies evaluating slow‐release triamcinolone acetonide show encouraging results in dogs [149]. Comprehensive reviews on this topic are available [150], and additional reading is imperative because novel therapies with promise receive approval intermittently and may offer effective pain relief for challenging conditions. One such intervention is 117mSn radiocolloid, which appears effective for debilitating conditions such as low to intermediate‐grade elbow OA in dogs [151,152].
48
Clinical Management and Pharmacologic Treatment of Pain
Introduction
Anticipation of pain
Assessment of pain
Alleviation of pain
Decision‐making tools
Tiers of the decision‐making tree
First‐tier, acute pain
First‐tier, chronic pain
Second tier
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