Lydia Love and Dave Thompson
Nontraditional analgesic agents are pain-relieving drugs other than opiates, nonsteroidal anti-inflammatory drugs (NSAIDs), and local anesthetics. The pharmacological mechanisms of nontraditional analgesic agents are diverse and are the focus of much current research activity. Many of these drugs are classified as adjuvant analgesics, used to potentiate the effect of traditional analgesics. As such, they may be employed in ambulatory surgical settings in order to decrease the dose of opioid, opioid-associated adverse effects, and time to discharge. Depending on the type of pain involved, some of the drugs in this group can be used as primary analgesic agents in the multimodal treatment of chronic pain.
The management of pain must be directed by the underlying mechanisms. Acute inflammatory pain is driven by cellular bio-chemical pathways that intersect with, but are distinct from, those of chronic neuropathic pain states. In addition, neuropathic pain can be divided into several different types, originating centrally or peripherally, and analgesic efficacy of adjunctive analgesics can vary accordingly. Most clinical studies of neuropathic pain have focused on humans with either peripheral diabetic neuropathy or postherpetic neuralgia. The diversity of underlying pain pathophys-iology and dearth of veterinary-specific studies may delay under-standing of the appropriate uses of adjunctive analgesics in the clinical veterinary setting.
The following review of nontraditional analgesics is arranged according to currently accepted pharmacological mechanisms, as opposed to susceptible pain states. In addition, certain drugs that could be considered nontraditional analgesics (e.g.,␣-2 agonists, tramadol) and novel applications of traditional agents (intravenous lidocaine) are considered in other chapters in this book. Finally, experimental evidence exists for the use of many different classes of drugs as analgesics, especially in neuropathic pain states. This review will focus on the classes of drugs currently used in clini-cal practice. Much of the information herein is extrapolated from human or experimental studies. When possible, veterinary stud-ies are cited, but much work remains to be done to document the efficacy of these drugs in animal species.
ANTIEPILEPTIC DRUGS Mechanism of Action
Since the 1960s, antiepileptic drugs (AEDs), including carba-mazepine, gabapentin, and pregabalin, have been used to manage
neuropathic pain in human patients (Alarc´on-Segovia & Lazcono, 1968; Segal & Rordof, 1996; Hill et al., 2001). These AEDs act through various mechanisms to suppress seizure activity, and the same cellular processes are thought to be responsible for their anal-gesic efficacy.
Carbamazepine, a first-line treatment for trigeminal neuropathy (Zakrzewska, 2010), prevents activation of synaptosomal voltage-gated sodium channels (Sheets et al., 2008), thereby preventing con-duction of neuronal action potentials and subsequent neurotrans-mitter release. Gabapentin and pregabalin (gabapentinoids) bind to the␣2␦subunit of voltage-gated calcium channels (VGCC) (Field et al., 2000; Stahl, 2004) and appear to disrupt intracellular traffick-ing of these subunits (Tran-Van-Minh & Dolphin, 2010). Calcium influx activates multiple cellular processes, including release of neurotransmitters, regulation of gene expression, and alterations in cellular excitability (Cao, 2006). By binding to VGCC, gabapenti-noids may interrupt some or all of these processes. Other cellular mechanisms may be important in the analgesia produced by the gabapentinoids, including upregulation of descending noradrener-gic inhibition (Hayashida et al., 2008). Although many of the AEDs have been studied in human neuropathic pain states, gabapentin has received the most attention as a nontraditional analgesic in veterinary medicine, and the rest of this section will focus on the gabapentinoids.
Efficacy of Gabapentinoids in Acute Pain
The effectiveness of gabapentin has been established most strongly for neuropathic pain syndromes; however, several small random-ized clinical human trials demonstrated efficacy in acute periopera-tive pain states, including arthroscopy (Bang et al., 2010), pediatric spinal fusion (Rusy et al., 2010), and after cesarean section (Moore et al., 2011). An interesting comparative study of oral gabapentin, ketamine infusion, or placebo demonstrated a decrease in pain scores and morphine consumption in the first 24 hours post hys-terectomy in both the ketamine and gabapentin groups (Sen et al., 2009). Moreover, the gabapentin group reported a lower incidence of chronic pain and chronic incisional pain. Results of clinical trials are mixed, and although a recent Cochrane review (Straube et al., 2010) did identify an effective dose of gabapentin for established acute postoperative pain in adults, the number needed to treat (NNT) to have an effect in one person was 11; the authors concluded that this was too large to be clinically relevant.
Pain Management in Veterinary Practice, First Edition. Edited by Christine M. Egger, Lydia Love and Tom Doherty.
C2014 John Wiley & Sons, Inc. Published 2014 by John Wiley & Sons, Inc.
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106 Section 2 / Pharmacology of Analgesic Drugs Pregabalin is the structurally related successor to gabapentin,
and is marketed in the United States as a Class V controlled drug, LyricaR. Results of studies investigating the efficacy of pregabalin in acute pain settings are mixed, with some studies demonstrating a decrease in pain scores and/or opioid consumption (Hill et al., 2001; Kim et al., 2010; Durkin et al., 2010), while others have been unable to establish that pregabalin lessens acute perioperative pain (Paech et al., 2007).
Veterinary studies of gabapentin are limited in scope and nature, and the veterinary literature has been unable to demonstrate effec-tiveness of gabapentin in acute pain states. In experimental studies in awake cats, gabapentin at 5, 10, or 30 mg/kg did not affect ther-mal threshold (Pypendop et al., 2010), and plasma concentrations up to 20g/mL (equivalent to 13 mg/kg orally (Siao et al., 2010)) did not reduce the minimum alveolar concentration of isoflurane (Reid et al., 2010). Moreover, administration of oral gabapentin at 10 mg/kg prior to forelimb amputation in dogs followed by 5 mg/kg PO every 12 hours for three additional days, did not decrease pain scores during hospitalization or at home (Wagner et al., 2010). The authors concluded that gabapentin, at the given dose and frequency, did not provide a significant reduction in acute perioperative pain as part of a multimodal analgesic plan. More veterinary studies are needed to evaluate efficacy in different dosing scenarios and species, and to investigate the potential for decreasing chronic pain following acute nociceptive insults.
Efficacy of Gabapentinoids in Chronic Pain
In neuropathic pain states in humans, the gabapentinoids are widely accepted as a first-line treatment (Dworkin et al., 2010), with effec-tiveness demonstrated especially in peripheral diabetic neuropathy and post-herpetic neuralgia (Segal & Rordof, 1996; Ko et al., 2010).
The efficacy of the gabapentinoids in neuropathic pain states is so well established that they are now used in comparative studies to investigate promising new pharmacotherapeutics (Sen et al., 2009;
Amr, 2010). Some evidence exists that pregabalin may provide analgesic efficacy superior to that of gabapentin in peripheral neu-ropathies of humans (Toth, 2010).
Use of gabapentin in the treatment of neuropathic pain in veteri-nary species has been suggested (Robertson, 2005), but published studies are limited to case reports and case series. The first vet-erinary case report of the use of gabapentin for analgesia involved the treatment of a 24-year-old pregnant draft horse with signs of pain due to suspected femoral neuropathy after recovery from colic surgery (Davis et al., 2007). In 2009, a case series involving three dogs with chronic pain disorders, unresponsive to traditional anal-gesic agents, reported resolution of clinical signs in one of the dogs with gabapentin therapy (Cashmore et al., 2009). Also in 2009, a case report regarding the use of gabapentin in a prairie falcon, as part of a multimodal approach to suspected neuropathic pain, was published (Shaver et al., 2009). The authors are unaware of veteri-nary studies investigating gabapentin in comparison to placebo or traditional analgesics in neuropathic pain states.
Pharmacokinetics
In humans, gabapentin is slowly absorbed after oral administra-tion and displays zero-order pharmacokinetics, that is, a constant amount of drug is eliminated per unit of time. In contrast, pregabalin is rapidly absorbed after oral dosing and is metabolized via first-order (or linear) processes (Bockbrader et al., 2010), wherein a fixed
fraction of drug in the body is eliminated over time. Gabapentin and pregabalin are excreted intact via renal mechanisms, are not metabolized by hepatic microsomes, and are not highly protein bound; therefore, few clinically significant drug interactions occur.
The most common side effects of short-term administration of the gabapentinoids are sedation and dizziness (Tiippana et al., 2007).
Pharmacokinetic (PK) data for gabapentin exists for dogs (Radulovic et al., 1995), greyhound dogs (KuKanich & Cohen, 2011), cattle (Coetzee et al., 2010), horses (Dirikolu et al., 2008;
Terry et al., 2010), and cats (Siao et al., 2010). Rapid absorption and disposition of oral gabapentin occurs in dogs, with moderate hepatic transformation to N-methyl-gabapentin prior to renal elim-ination (Radulovic et al., 1995). Bioavailability is high in cats, and gabapentin exhibits a small volume of distribution with a moder-ately long half-life (Siao et al., 2010). Cattle demonstrate a long half-life after oral administration of gabapentin, leading the authors of one study to conclude that further evaluation of oral gabapentin for analgesia in cattle is warranted (Coetzee et al., 2010). In contrast to other species, bioavailability of oral gabapentin in horses is low but the half-life is long (Dirikolu et al., 2008). In addition, behav-ioral effects such as sedation and increased frequency of drinking were observed after oral administration of 20 mg/kg gabapentin to horses (Terry et al., 2010). Pregabalin studies in veterinary species are currently limited. A PK study in dogs demonstrated that 4 mg/kg orally resulted in plasma concentrations associated with analgesic efficacy in humans (Salazar et al., 2009). Similar results were reported for cats administered pregabalin at 4 mg/kg (Cautela et al., 2010).
Recommendations for Clinical Use
Of the currently available AEDs, gabapentin has the most experi-mental and anecdotal support for its use in veterinary species. In acute pain states, it is the authors’ opinion that gabapentin may be useful as an adjunctive agent in multimodal analgesic protocols. In addition, the sedative and anxiolytic properties may be beneficial perioperatively. Finally, perioperative use may decrease the devel-opment of chronic pain, which can be very difficult to diagnose and treat in veterinary species. In neuropathic pain, it is quite likely that gabapentin and pregabalin may have beneficial effects, and can be used as first-line therapy or in addition to other analgesic agents. A suggested starting dose for gabapentin is 5–10 mg/kg every 8–12 hours. Because sedation can occur, especially in geri-atric patients, owner compliance may be improved by beginning with once-daily dosing at night for a few days to allow acclima-tization. In some instances the side effect of sedation is beneficial in painful patients with disrupted sleep patterns. When gabapentin is added to an analgesic regimen for patients with chronic pain the dose can be increased by 25–50% every week until an acceptable response occurs. One of the authors (DT) has used doses as high as 50–60 mg/kg every 8 hours in dogs with severe cancer pain, without adverse effect.
The use of pregabalin for neuropathic pain in veterinary species is limited to anecdotal reports and dosing is based on extrapolation from PK studies. For dogs, the suggested dose range is 2–4 mg/kg every 12 hours and for cats 1–2 mg/kg every 12 hours.
Gabapentin is currently available in 100 mg, 300 mg, and 400 mg capsules as well as 600 mg and 800 mg tablets. Liquid for-mulations can be compounded to specification by a licensed com-pounding pharmacy. The 50 mg/mL name brand liquid formulation,
8 / Nontraditional Analgesic Agents 107 Neurontin, contains 300 mg/mL xylitol, which can cause
hypo-glycemia in dogs at doses as low as 100 mg/kg and hepatotoxicity, and potentially death, at 500 mg/kg (Piscitelli et al., 2010). The toxic dose of xylitol in cats is unknown; to the authors’ knowledge, no reports of feline xylitol toxicity exist. Pregabalin is available in a wide variety of capsules, ranging from 25 mg to 300 mg, and a 20 mg/mL oral solution.
NMDA RECEPTOR ANTAGONISTS Mechanism of Action
The N-methyl-D-aspartate (NMDA) receptor is a nonselective cation channel that is located both pre- and postsynaptically throughout the CNS (Corlew et al., 2008). These receptors are widely distributed in the brain and spinal cord and are involved in many physiological functions (Corlew et al., 2008). Activation of the NMDA receptor contributes to development of hyperalgesia and chronic pain and is the basis of windup, long-term potentiation, and central sensitization (Zhuo, 2009; Tao, 2010). Interestingly, the NMDA receptor is implicated in conscious memory formation as well as central sensitization, which is essentially a “memory of pain.”
The NMDA receptor is a molecular coincidence detector in that it is both ligand- and voltage-gated (Zhuo, 2009). Activation of the NMDA receptor is prevented under conditions of minimal noci-ceptive input by a magnesium (Mg2+) ion block. High-frequency depolarization of the cell membrane causes expulsion of the Mg2+ ion. Concurrent binding of glutamate and glycine allows the NMDA receptor to conduct strong cation currents, including Na+, K+, and Ca2+. The number and strength of postsynaptic currents increase, upregulating numerous protein kinases and causing adjustments in cellular enzyme products via transcriptional and posttrans-lational alterations (Zhuo, 2009). The result is both stimulus-independent firing of the second-order neuron and increased pro-duction and trafficking of excitatory glutamate receptors. These are the underlying cellular mechanisms of windup and central sensitization.
Antagonists of the NMDA receptor, such as the dissociative anes-thetics ketamine and tiletamine, have traditionally been used in vet-erinary medicine as general anesthetics (Kaplan, 1972). However, there is a renewed interest in human and veterinary medicine in the use of NMDA antagonists as adjunctive analgesics in acute and chronic pain states. There are many drugs in current use that have antagonist activity at the NMDA receptor, including ketamine and tiletamine, amantadine, dextromethorphan, nitrous oxide, xenon, and some opioids, including methadone. This section will focus on ketamine and the oral NMDA antagonist amantadine, due to the large body of research available as well as ease of use in clinical veterinary medicine.
Efficacy in Acute Pain
Ketamine has been extensively researched for its analgesic and anti-hyperalgesic effects in the perioperative period (Figure 8.1). At sub-anesthetic doses ketamine is, by itself, a weak analgesic (Bergadano et al., 2009); however, low-dose perioperative ketamine improves opioid efficacy (Suzuki et al., 1999), decreases postoperative opi-oid requirements and side effects (Javery et al., 1996; Zakine et al., 2008), and decreases opioid-induced hyperalgesia (Minville et al.,
Figure 8.1. A continuous rate infusion of ketamine at a subanesthetic dose can be a useful adjunct to volatile anesthesia by providing additional analgesia.
2010). A Cochrane review established the efficacy and acceptabil-ity of perioperative ketamine in order to reduce opioid consumption in humans, although dosing strategies varied too widely to make a dose recommendation (Bell et al., 2006). Evidence exists that the development of chronic pain can be diminished by perioperative ketamine use (Rem´erand et al., 2009).
Perioperative ketamine infusions have been documented to decrease perioperative pain scores and increase activity in dogs undergoing forelimb amputation (Wagner et al., 2002). However, a similar small study in dogs demonstrated no decrease in opioid requirements in dogs postmastectomy (Sarrau et al., 2007). The latter study did find a significant increase in calorie consumption 2 days postoperatively in dogs given the highest ketamine infu-sion rates. Ketamine infuinfu-sions are often used clinically to reduce perioperative or laminitic pain in horses, but published studies are limited to laboratory-based investigations. Ketamine reduces the withdrawal response to an electrical nociceptive stimulus in con-scious horses (Peterbauer et al., 2008), whereas similar infusion rates do not decrease response to mechanical pain induced by hoof testers (Fielding et al., 2006).
The use of oral NMDA antagonists, such as amantadine, to decrease acute perioperative pain is not as well defined as adminis-tration of intravenous ketamine. A limited amount of data in humans indicates that multiple doses of amantadine before and after surgical intervention reduce pain scores and opioid consumption (Snijdelaar et al., 2004), whereas isolated preoperative administration does not (Gottschalk et al., 2001). To the authors’ knowledge, no veterinary studies of perioperative amantadine use exist.
Efficacy in Chronic Pain
Ketamine may play a role in mitigating chronic pain states, especially that of neuropathic origin (Elsewaisy et al., 2010;
Goldberg et al., 2010). Multi-day subanesthetic infusions of
108 Section 2 / Pharmacology of Analgesic Drugs ketamine in humans with complex regional pain syndrome (CRPS)
resulted in decreased pain scores (Sigtermans et al., 2009a; Dahan et al., 2011), although refractory CRPS may require a much higher dose (Kiefer et al., 2008). Oral NMDA antagonists have been dis-appointing in the treatment of established neuropathic pain, such as phantom limb pain (Maier et al., 2003). Conversely, some evidence exists that early or preventative treatment with oral NMDA antago-nists may prevent development of chronic pain states (Schley et al., 2007; Hackworth et al., 2008). One study indicates that perioper-ative administration of amantadine decreases the development of postoperative chronic pain (Eisenberg et al., 2007).
Due to the lack of high-level evidence and potential psy-chotomimetic effects of ketamine, the use of NMDA antagonists for neuropathic pain in humans is not currently recommended as a first-line treatment, but can be considered in refractory cases.
The veterinary literature concerning the use of NMDA antagonists for chronic pain states is limited. A case report of a cow tenta-tively diagnosed with CRPS reported successful treatment with a combination of extradural infusions of ketamine, detomidine, bupi-vacaine, and methadone (Bergadano et al., 2009). A randomized, masked, placebo-controlled trial of 31 client-owned dogs with signs of pelvic limb osteoarthritis (OA) pain despite NSAID therapy doc-umented an increase in owner-scored activity with the addition of amantadine (Lascelles et al., 2008). Further research is necessary to define the role of NMDA antagonists in the treatment of chronic pain states in veterinary species.
Pharmacokinetics
A wide variety of PK data exists for ketamine, though most studies involve anesthetic doses. Analgesic effects may not correlate with plasma ketamine concentrations (Goldberg et al., 2010), and this may be due to effect site concentrations or downstream metabo-lites. In humans with CRPS, ketamine produced analgesia to acute experimental pain that correlated with detectable plasma concen-trations; moreover, the study detected a decrease in pre-existing pain that persisted at least 5 hours beyond the ketamine infusion (Sigtermans et al., 2010). Although the racemic version is currently the only formulation available in the United States, the S(+) enan-tiomer is marketed in Europe and may be more a potent analgesic (Sigtermans et al., 2009b).
Human and canine PK data for amantadine indicate that it is highly absorbed after oral administration (Bleidner et al., 1965;
Aoki & Sitar, 1988). In horses, bioavailability after oral adminis-tration is about 50% (Rees et al., 1997). One human study docu-mented a decrease in morphine clearance in the group receiving oral amantadine, suggesting that PK mechanisms could be responsible for the reduction in opioid requirements (Snijdelaar et al., 2004).
Amantadine is cleared by the kidneys in dogs and humans, with minimal hepatic transformation (Bleidner et al., 1965), and dose reductions should be considered in patients with renal disease.
Recommendations for Clinical Use
In acute pain states, including traumatic injury and surgical inter-ventions, ketamine may be used as a constant rate infusion (CRI) to augment analgesia provided by traditional analgesics, decrease windup and central sensitization, and potentially decrease the devel-opment of chronic pain states. A dosing range of 2–20g/kg/min should provide NMDA receptor antagonism with minimal disso-ciative effects. For chronic pain, especially neuropathic pain states, ketamine CRIs may be useful in veterinary patients, though they
do require hospitalization. The authors have used this strategy most commonly in dogs with pain of neoplastic origin that may include a neuropathic component, often in combination with intravenous lidocaine and opioids. Amantadine may be most helpful in chronic and neuropathic pain states, and can be added to analgesic regi-mens at 3–5 mg/kg PO once daily. Rare side effects of amantadine include diarrhea and mild agitation. Amantadine is available in 100 mg capsules and a 10 mg/mL oral solution.
SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITORS
Mechanism of Action
The neurotransmitters serotonin and norepinephrine (NE) are fun-damental to many central nervous system activities, including vig-ilance, hunger, mood, and nociception (Arnold et al., 2008). Tri-cyclic antidepressants (TCAs) inhibit the reuptake transporters of serotonin and NE, thereby increasing concentrations in the CNS.
TCAs have varying degrees of antagonist activity at histamine,␣ -adrenergic, muscarinic cholinergic, and serotonin receptors (Gill-man, 2007). In addition, TCAs block voltage-gated sodium chan-nels, which may contribute to their analgesic efficacy (Dick et al., 2007). Newer generation drugs that prevent the reuptake of sero-tonin and NE are known as dual reuptake inhibitors (SNRIs).
Both TCAs and SNRIs are classified as antidepressants due to their mood elevating effects. However, analgesia provided by these drugs in chronic pain states appears to be independent of the mood-modulating effects (Bajwa et al., 2009). Mounting evidence indi-cates that NE systems may influence analgesia to a greater degree than serotonin pathways (Hall et al., 2011). Other analgesics also affect serotonin and NE reuptake, including tramadol and tapenta-dol. This section will focus on the TCA amitriptyline because of its widespread use in veterinary medicine. Clomipramine is another TCA that is used in veterinary medicine in the treatment of behav-ioral disorders, and there are reports in the human literature of its use in neuropathic pain syndromes. However, a high incidence of unpleasant side effects makes its use less attractive than amitripty-line or SNRIs. Because much attention has centered on the SNRI duloxetine for the management of chronic pain, relevant research will be reviewed. Tramadol and tapentadol are covered elsewhere in this book (see Chapter 4).
Efficacy in Acute Pain
Data for the efficacy of TCAs and SNRIs in acute pain states are very limited. Experimental evidence suggests that thermal nociception and hyperalgesia may be decreased by antidepressants that have strong NE reuptake inhibition (Bomholt et al., 2005; Jones et al., 2005). One recent placebo-controlled clinical trial demonstrated duloxetine decreased the requirement for opioids after total knee replacement, but no differences in pain scores or adverse events were detected (Ho et al., 2010).
Efficacy in Chronic Pain
TCAs have been used in the treatment of neuropathic pain states since the late 1950s (Bajwa et al., 2009), and are currently con-sidered first-line therapy for neuropathic pain in humans (Dworkin et al., 2010). Amitriptyline is used in veterinary species for behav-ioral disorders, and has been investigated for treatment of pain associated with feline idiopathic cystitis. Short-term treatment with
8 / Nontraditional Analgesic Agents 109 amitriptyline has not been effective in reducing signs or recurrence
of idiopathic cystitis in cats (Kraijer et al., 2003; Kruger et al., 2003), but long-term therapy has been promising (Chew et al., 1998). A case series involving suspected neuropathic pain condi-tions in three dogs reported response to treatment with amitriptyline in two of the dogs (Cashmore et al., 2009).
The SNRIs, such as duloxetine, have garnered much interest in the treatment of chronic neuropathic pain because of the adverse effects associated with TCA therapy, including dry mouth and tachycardia due to antimuscarinic activity. A meta-analysis indi-cates that duloxetine is effective for the treatment of diabetic periph-eral neuropathy and fibromyalgia in humans (Lunn et al., 2009).
Duloxetine also appears to be effective in decreasing pain scores in humans with OA of the knee (Chappell et al., 2009). No veterinary studies concerning the efficacy of SNRIs in chronic or neuropathic pain were identified.
Pharmacokinetics
Amitriptyline is well absorbed from the gastrointestinal tract and undergoes moderate first-pass hepatic extraction, resulting in bioavailability ranging from 33% to 62% in man (Schulz et al., 1983). Bioavailability is similar in dogs (Kukes et al., 2009). Dulox-etine is highly absorbed when administered orally to humans (Lantz et al., 2003). Both TCAs and SNRIs depend heavily on hepatic func-tion for metabolism (Schulz et al., 1983; Lantz et al., 2003). PK studies of duloxetine in veterinary species are lacking.
Recommendations for Clinical Use
Amitriptyline may be most effective in the treatment of neuropathic pain states, and is administered at 0.5–3 mg/kg every 12–24 hours.
Due to side effects, dose escalation should be gradual. Amitriptyline is available in a variety of tablet sizes, ranging from 10 mg to 150 mg. An effective and safe dose of duloxetine for veterinary species is unknown at this time.
Serotonin syndrome is reported in the veterinary literature and can involve changes in mentation, autonomic imbalance, includ-ing potentially fatal hyperthermia, and neuromuscular signs such as tremor (Crowell-Davis & Poggiagliolmi, 2008). Caution should be used when combining drugs that affect the serotonin system, including TCAs, SNRIs, tramadol, dextromethorphan, monoamine oxidase inhibitors (e.g., selegiline), certain opioids (e.g., meperi-dine and fentanyl), and selective serotonin reuptake inhibitors (e.g., fluoxetine).
DISEASE MODIFYING OSTEOARTHRITIS DRUGS Mechanism of Action
Degenerative OA is a major cause of morbidity in aging veteri-nary populations, and can result in euthanasia due to poor quality of life. Disease modifying osteoarthritis drugs (DMOADs) are a diverse group of agents utilized in an attempt to modulate the pathological processes of OA. Alterations in the cartilage, syn-ovial membrane, and subchondral bone are the result of the chronic and progressive nature of OA, and are driven by enzymatic and inflammatory mechanisms (Abramson & Attur, 2009). Existing research implicates matrix metalloproteinases (MMP) and inflam-matory cytokines, including IL-1B, in the destruction of cartilage as well as the synovial membrane (Pelletier & Martel-Pelletier,
2007). Various DMOADs, including polysulfated glycosaminogly-cans (PSGAGs), glucosamine, chondroitin sulfate, hyaluronic acid (HA), and omega-3 fatty acids, are utilized to counter the events of this degenerative cellular cascade.
PSGAGs, such as AdequanR and CartrophenR, and oral chon-droprotectives, including glucosamine and chondroitin, appear to inhibit degradation of cartilage (Fujiki et al., 2007; Scarpellini et al., 2008), decrease oxidative stress and inflammatory mediators (Tung et al., 2002; Calamia et al., 2010), and have been hypothesized to enhance chondrogenesis (Caron, 2005). HA is a nonsulfated glycosaminoglycan, which, like PSGAGs, appears to exert both anti-inflammatory activity and a direct chondroprotective effect (Greenberg et al., 2006; Kaplan et al., 2009). In addition, HA is theorized to improve the viscoelastic properties of synovial fluid.
Resolution of inflammation is an active process that is mediated by products of lipid metabolism. The omega-3 polyunsaturated fatty acids (PUFAs), docosahexenoic acid (DHA), and eicosapen-tanoic acid (EPA) offer an alternative substrate for cyclooxy-genase and lipoxycyclooxy-genase enzymes, generating bioactive lipid mediators, including protectins and resolvins, that exert a direct anti-inflammatory effect (Serhan & Chiang, 2008), and reduce the production of MMP and other inflammatory mediators (Zainal et al., 2009; Wann et al., 2010). Additionally, resolvins may modulate synaptic plasticity at the level of the spinal cord (Xu et al., 2010).
Efficacy in Osteoarthritic Pain
Most evidence for the use of DMOADs in osteoarthritic pain is anecdotal or experimental in nature. In one small prospective study, lameness improved in 75% of dogs treated with intramuscular PSGAGs (Fujiki et al., 2007). In horses with induced OA, PSGAGs decreased joint effusion and histological markers of disease pro-gression (Frisbie et al., 2009). Oral chondroprotectives are common in over-the-counter preparations for human OA pain, and several meta-analyses of their use have demonstrated modest effects that may not be clinically relevant, although this is debated intensely (Wandel et al., 2010). In canine OA patients, the combination of glucosamine and chondroitin sulfate (G/CS) has resulted in sta-tistically significant improvements in pain scores and lameness, when compared with carprofen as a positive control (McCarthy et al., 2007). However, G/CS in combination with manganese did not improve force plate analysis scores or subjective assessment, when compared with carprofen or meloxicam in a separate canine study (Moreau et al., 2003). Reviews of the veterinary literature regarding glucosamine-based products in canine (Aragon et al., 2007) and equine (Pearson & Lindinger, 2009) patients indicate that the quality of evidence for the use of these nutraceuticals is questionable.
HA is used widely to treat horses with lameness due to OA. In experimentally induced OA, histological markers of disease pro-gression were decreased by the intra-articular administration of HA, but no clinical improvement was noted (Frisbie et al., 2009).
Intravenous HA also improved histological scores as well as clini-cal evaluation of lameness in experimentally induced OA of horses (Kawcak et al., 1997). As with horses, HA administered intra-venously or intra-articularly has resulted in improvement in his-tological markers of canine OA, but has not consistently resulted in clinical improvement in either experimental or clinical models (Brandt et al., 2004; Canapp et al., 2005; Echigo et al., 2006).
Omega-3 fatty acid supplementation has been investigated in dogs with OA, and several small studies have documented
110 Section 2 / Pharmacology of Analgesic Drugs improvements in owner evaluated clinical signs and weight bearing
(Roush et al., 2010a, 2010b) as well as a reduction in carprofen dosage (Fritsch et al., 2010).
Recommendations for Clinical Use
Injectable PSGAGs are used widely in canine and equine OA. These products have an excellent safety profile and, although efficacy is debatable, may have some positive effects in specific patient populations and as a part of multimodal protocols. In the United States, AdequanR Canine is available as a 100 mg/mL solution, and is labeled for intramuscular use in dogs at 4 mg/kg twice weekly for 4 weeks. Anecdotal evidence indicates that the subcutaneous route may also be used, and owners can often be taught to give injections at home. Ongoing treatment at monthly, or more frequent intervals, is often recommended off-label for dogs and cats. An equine version of AdequanR is available in a dose pack of seven preservative-free vials, each containing 5 mL of 100 mg/mL solution. The labeled dose for horses is one 5 mL injection every 4 days for 28 days, although dosing is often extended in an off-label manner similar to dogs and cats.
Many oral OTC chondroprotectives are available, and dose rec-ommendations are varied. The glucosamine dose in dogs ranges from 20 mg/kg to 100 mg/kg. Care should be taken to select a reputable manufacturer, as glucosamine/chondroitin content and quality may not correlate with label claims.
LegendR is a 10 mg/mL HA product that is labeled for intra-venous use in horses, and is supplied in a box of six 4 mL vials.
A 40 mg (4 mL) dose can be repeated weekly for three treatments.
In an off-label manner, this product is also injected intra-articularly in horses, and intravenously or intra-articularly in dogs. Hylartin V (10 mg/mL) is marketed in the US for intra-articular injection in horses. In Canada and Europe, HY-50 (17 mg/mL) is approved for intra-articular or intravenous use in horses.
Many omega-3 fatty acid products are available and dosing is empirical and diverse. A common recommendation is to administer EPA at 36 mg/kg and DHA at 24 mg/kg.
BISPHOSPHONATES Mechanism of Action
Bisphosphonates prevent resorption of bone by disrupting osteo-clast function. These drugs localize to areas of active osteolysis by binding to Ca2+and other divalent metal ions and cause apop-tosis of osteoclasts (Roelofs et al., 2006). In addition, bisphos-phonates have direct anti-inflammatory (Bianchi et al., 2008) and antineoplastic effects (Aft, 2011). Bisphosphonates are divided into nitrogen-containing and non-nitrogen-containing groups. Amino-bisphosphonates contain nitrogen and are more potent. The amino-bisphosphonates are commonly used in humans with metastatic bone disease to help manage pain as well as skeletal complications such as pathological fractures. In dogs with osteosarcoma undergo-ing palliative therapies, aminobisphosphonates reduce pain associ-ated with skeletal neoplasia (Fan et al., 2007; Fan et al., 2009). For palliation of malignant bone pain, bisphosphonates are covered in more detail elsewhere in this book (see Chapter 27).
Efficacy in Osteoarthritic Pain
Because of their effects on bone remodeling, bisphosphonates have been investigated for the treatment of pain associated with OA in rats (Strassle et al., 2010), humans (Fujita et al., 2009), horses (Gough et al., 2010), and dogs (Moreau et al., 2011). In horses, tiludronate reduces lameness in navicular disease (Denoix et al., 2003), thoracolumbar OA (Coudry et al., 2007), and distal tarsal OA (Gough et al., 2010). Tiludronate is approved in Europe for the treatment of navicular disease and distal tarsal OA (or bone spavin).
Recommendations for Clinical Use
Tiludronate is available in Europe under the brand name Tildren.
Formulated at a concentration of 5 mg/mL, the manufacturer rec-ommends slow intravenous administration of 0.1 mg/kg every day for 10 days. Off-label uses include the administration of the total dose (1 mg/kg) over about 1 hour (Delguste et al., 2008), and as a regional limb perfusion. Tiludronate should not be used in horses under 3 years of age or those that are pregnant or lactating. Mild hypocalcemia can occur during injection and transient colic is occa-sionally reported.
It should be noted that long-term or high-dose bisphosphonate therapy has been linked to increased risk of osteonecrosis of the jaw in humans (Marx et al., 2007), and atypical femoral and pelvic fractures (Yli-Kyyny, 2011). Bisphosphonate-related osteonecrosis of the jaw has been experimentally reproduced in rats and dogs (Burr & Allen, 2009), and develops most commonly after oral surgery in humans. It is unknown if these conditions will occur in clinical veterinary patients.
EMERGING TREATMENTS
Many different classes of drugs hold promise for the treatment of pain and are currently being investigated. Among the most exciting are capsaicin and resiniferatoxin, which are agonists at transient receptor potential vanilloid type 1 (TRPV1) receptors. These are ligand-gated cation channels, expressed both centrally and periph-erally, which respond to mechanical, thermal, and chemical stimuli, initiating action potentials along sensory neurons and ascending spinal tracts (Palazzo et al., 2010). Prolonged activation leads to downregulation of receptors and cytotoxicity of sensory neurons expressing TRPV1 channels. In one unblinded and uncontrolled study of dogs with naturally occurring bone cancers, significantly improved comfort levels were noted after intrathecal administration of resiniferatoxin (Brown et al., 2005). Other compounds of inter-est include VGCC blockers such as ziconotide. An FDA-approved treatment for refractory pain, ziconotide is derived from the venom of a predatory marine snail, genus Conus (Schmidtko et al., 2010).
Limitations include side effects such as changes in mentation and nausea, and that it must be delivered intrathecally. Ongoing research is defining the analgesic profiles of many other classes of drugs, including cannabinoids, dopamine antagonists, novel anticonvul-sants, astrocyte inhibitors, and immune-modulating drugs.
SUMMARY
Management of pain, acute or chronic, inflammatory or neuro-pathic, can be challenging. Often, pain is incompletely or ineffec-tively managed, and in veterinary species, pain that is not adequately controlled may affect quality of life to the extent that the patient