Managing Chronic Pain in Dogs & Cats

Peer Reviewed Managing Chronic Pain in Dogs & Cats Part 3: Management of Nonosteoarthritic Pain Conditions

Mark E. Epstein, DVM, Diplomate ABVP (Canine/Feline), CVPP Carolinas Animal Pain Management & TotalBond Animal Hospitals (Forestbrook), Gastonia, North Carolina

Parts 1 and 2—The Two Most hile osteoarthritis (OA) may be the most commonly Important Tools in the Management recognized cause of chronic pain in dogs and cats, Wother pain syndromes exist. The following scenarios, of Osteoarthritis and The Best of when evaluated together, may have a prevalence approaching the Rest in the Management of that of OA: Osteoarthritis (November/December 1. Chronic or chronic–active inflammatory pain 2. Maladaptive chronic pain 2013 and September/October 2014, 3. Cancer pain. respectively; available at tvpjournal Treatment of these pain phenomena has not been inves- .com)—of this 3-part series discussed tigated in depth, so therapeutic rationale must be inferred from disease pathophysiology and existing evidence regard- therapeutic options for its most common ing individual treatment modalities. manifestation in companion animals: osteoarthritis. CHRONIC OR CHRONIC–ACTIVE INFLAMMATORY PAIN A growing body of evidence suggests that peripheral and central sensitization not only exists in chronic inflammatory disease states (Table 1) but may actually advance pathologic abnormali- Table 1. Examples of Chronic & ties through proinflammatory neurogenic mechanisms. Chronic–Active Inflammatory Pain Few studies have assessed the management of nonOA chronic inflammatory conditions, and such studies may be Chronic periodontal disease difficult to perform. However, a treatment sequence for this Feline lymphocytic–plasmacytic stomatitis category of chronic pain can be inferred, in the following Idiopathic feline lower urinary tract disease* approximate order: Inflammatory bowel disease 1. Anti-inflammatory medications: nonsteroidal anti-inflam- Meningoencephalitides matory drug (NSAID) or corticosteroid Otitis externa 2. Treatment of underlying disease or aggravating comor- Pancreatitis bidities 3. Neuromodulatory analgesic drugs, such as gabapentin, * Feline interstitial cystitis is increasingly being consid- tramadol, and amitriptyline ered a somatic pain syndrome.1 4. Weight optimization.

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mend the following drugs: tricyclic antidepressants, gaba- Table 2. Examples of Potential or Existing pentin, and opioids.3 While these papers are drawn mainly Maladaptive Chronic Pain2 from trials involving diabetic neuropathy and postherpetic neuralgia—clinical conditions not identified in animals— Central nervous system lesions, including post- these drugs commonly play a more prominent role in trauma or vascular accidents, intracranial masses, managing maladaptive pain than NSAIDs. and congenital defects (eg, syringomyelia) • Gabapentin can be considered a relatively well-tolerat- Chronic intervertebral disk disease ed, inexpensive, easy-to-administer, and effective pain Diabetic neuropathy medication in dogs and cats, with efficacy supported by Feline hyperesthesia syndrome numerous case reports.4–7 Feline orofacial pain syndrome • Use of the tricyclic antidepressant amitriptyline for Postperipheral nerve injury (eg, trauma, amputation) pain has been described in canine and feline case Postsurgical conditions (eg, fractures, hernia repair) 7,8 9 Others reports and for feline interstitial cystitis. • Oral opioids may also have a role in treating these syn- dromes. MALADAPTIVE CHRONIC PAIN Additional medications that have been used in humans Maladaptive pain occurs through the process of peripheral for maladaptive pain states include: and central sensitization. Its features include pain that is • Other anticonvulsants (pregabalin, lamotrigine) protracted in duration, exaggerated in severity (hyperal- • Ion channel blockers (mexiletine, infusions of sys- gesia, allodynia), and expanded in field, and can occur in temic lidocaine, ketamine) the absence of obvious tissue pathology. These types of • Selective serotonin-norepinephrine reuptake inhib- disease states (Table 2) include many poorly understood itors (duloxetine, venlafaxine). pain syndromes. However, lack of experience with, and data on, these agents for pain in animals limits their use at this time. NSAIDs To the degree that inflammation is considered a compo- Additional Therapies nent of the underlying pathologic abnormality activating As adipose tissue is the body’s largest endocrine organ nociceptive pathways, NSAIDs can be considered a first- and secretes a witches brew of degradative enzymes and line drug. However, many maladaptive chronic pain states pro-inflammatory cytokines, weight optimization may have progressed to, or are intrinsically, a neuropathic have the same important role to play in managing nonOA state. In these cases, NSAIDs may contribute a less robust chronic pain as it does in OA. In elderly humans, central analgesic effect. obesity (abdominal fat) doubles the risk for chronic pain from any cause.10 Other Analgesic Therapies Table 3 outlines therapeutic options for maladaptive In humans, systematic reviews of neuropathic pain recom- chronic pain.

TABLE 3. Management of Maladaptive Pain: Therapies to Consider MODALITY COMMENTS 1. Neuromodulatory Agents Gabapentin • Anticonvulsants Pregabalin • Gabapentin preferred in dogs • Possible role for pregabalin Amitriptyline • Tricyclic antidepressant Tramadol • Pharmacokinetics of oral tramadol do not favor its use for pain in dogs11-15 • It may have better results in cats16 Amantadine • NMDA receptor antagonist Venlafaxine • Selective serotonin-norepinephrine reuptake inhibitor • Oral venlafaxine has approximately 50% bioavailability in dogs, with half-life of 3 H17 • Duloxetine has poor oral bioavailability in dogs18 Acetaminophen + • Consider judicious use, especially for breakthrough pain in dogs hydrocodone or codeine • The dog does not appear to demonstrate a special proclivity toward hepatotoxicity, but methemoglobinemia and anemia are reported with overdosage and long-term use. Complete blood count monitoring is recommended. • Pharmacokinetic, but not clinical, data support the utility of codeine and hydrocodone in the dog (Table continued on page 42) tvpjournal.com November/December 2014 Today’s Veterinary Practice 41 | Management of Nonosteoarthritic Pain Conditions

TABLE 3. Management of Maladaptive Pain: Therapies to Consider (continued) MODALITY COMMENTS 1. Neuromodulatory Agents (continued) IV CRI of ketamine • Have been used with success to treat refractory neuropathic pain states in 19,20 IV CRI of lidocaine humans • Have not yet been investigated for canine and feline neuropathic pain 2. Weight Optimization 3. NSAIDs (may play a role in managing maladaptive pain) 4. Physical Modalities (limited data-based studies available) • Acupuncture • Myofascial trigger point therapy • Physical therapy (prescribed therapeutic exercises, hydrotherapy) • energy-based modalities (therapeutic laser, extracorporeal shock wave therapy)

CANCER PAIN tin, pregabalin, and strong opioids as the most effective Any primary neoplasm or cancer metastasis to bone, and best-tolerated drugs, while amitriptyline, tramadol, including osteosarcoma (OSA), causes a chronic pain con- and NSAIDs elicited less effect or had a more unfavorable dition in dogs and cats; pain is due to many unique factors safety profile.21 to this disease (Table 4). See Medications for Cancer Pain in Dogs & Cats for further information.

Table 4. Factors That Cause CONCLUSION Chronic Cancer Pain The treatment of chronic pain in dogs and cats remains a vast and largely unexplored frontier, but provides enor- Action of osteoclasts mous opportunities for positive outcomes for patients, pet Local necrosis owners, veterinary teams, and practices themselves. With Lymphatic obstruction focus, continued learning, and leadership, this arena of Neurochemical blend of bi-active, proinflammatory cytokines, which distinctly sustain and enhance veterinary medicine is a means for personal and profes- nociceptive pathways sional growth and, ultimately, compassionate care of com- Upregulation of cyclooxygenase (COX) enzymes panion animal populations. n

COX = cyclooxygenase; CRI = constant rate infusion; NMDA = N-methyl-D-aspartate; NSAID = nonsteroidal Palliative Care anti-inflammatory drug; OA = osteoarthritis; OSA = For patients whose owners have opted for palliative care— osteosarcoma pain management and disease control versus amputation or References chemotherapy—inadequate pain control, rather than the 1. buffington CAT. Idiopathic cystitis in domestic cats—beyond the lower disease itself, will probably be the terminal event leading to urinary tract. J Vet Intern Med 2011; 25(4):784-796. euthanasia. Once a collaborative decision is made between 2. Mathews KA. Neuropathic pain in dogs and cats: If only they could tell us if they hurt. Vet Clin North Am Small Anim Pract 2008; 38(6):1365-1414. the veterinarian and pet owner that pain can no longer be 3. Finnerup NB, Otto M, McQuay HJ, et al. Algorithm for neuropathic pain sufficiently managed, humane euthanasia should quickly treatment: An evidence based proposal. Pain 2005; 118:289-305. follow. 4. rusbridge C, Heath S, Gunn-Moore DA, et al. Feline orofacial pain syndrome (FOPS): A retrospective study of 113 cases. J Feline Med Surg In these difficult cases, it is important to access the entire 2010; 12(6):498-508. pain management arsenal because undermanaging these 5. Plessas IN, Rusbridge C, Driver CJ, et al. Long-term outcome of cavalier patients’ pain is inhumane and results in death (euthana- King Charles spaniel dogs with clinical signs associated with Chiari-like malformation and syringomyelia. Vet Rec 2012; 171(20):501. sia). OSA and other bone cancers warrant a multimodal 6. Wolfe KC, Poma R. Syringomyelia in the cavalier King Charles spaniel polypharmacy approach to treatment, while paying atten- (CKCS) dog. Can Vet J 2010; 51(1):95-102. 7. Cashmore RG, Harcourt-Brown TR, Freeman PM, et al. Clinical diagnosis tion to the potential for adverse drug reactions and inter- and treatment of suspected neuropathic pain in three dogs. Aust Vet J actions. 2009; 87(1):45-50. 8. o’Hagan BJ. Neuropathic pain in a cat post-amputation. Aust Vet J 2006; 84(3):83-86. Therapeutic Approach 9. Chew DJ, Buffington CA, Kendall MS, et al. Amitriptyline treatment for A recent review in the human literature evaluated the severe recurrent idiopathic cystitis in cats. JAVMA 1998; 213(9):1282-1286. number needed to treat:number needed to harm ratio 10. ray L, Lipton RB, Zimmerman ME, et al. Mechanisms of association between obesity and chronic pain in the elderly. Pain 2011; 152(1):53-59. for treatment of cancer pain. The authors cited gabapen- 11. giorgi M, Saccomanni G, Lebkowska-Wieruszewska B, Kowalski C.

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Medications for Cancer Pain in Dogs & Cats 1. NSAIDs it worthy of consideration The antineoplastic effects of certain NSAIDs in • Acetaminophen: May be useful for breakthrough humans22 and dogs23 are well established, and appear pain in dogs but cannot be used in cats; a literature to be mediated through the upregulation and overex- search for toxicity in dogs revealed no special predis- pression of COX-2 enzymes by some neoplasms.24 position to adverse effects or toxicity. It remains a However, the spectrum of NSAIDs, species, and first-line therapy for acute and chronic pain in elderly neoplasms for which this effect might occur is humans.32 unknown. • IV CRI of ketamine, lidocaine, opioids, or combina- Most tumors evaluated in cats have little, if any, tion: Can be used for a 24- to 48-hour pain holiday, COX-2 expression.25 That said, the upregulation of and to reduce central sensitization; this approach has COX enzymes and presence of perineoplastic inflam- been anecdotally used for severe neuropathic pain mation warrant use of NSAIDs, whether or not they states in humans but has not yet been investigated in exhibit an antineoplastic effect. canine and feline OSA-related pain.

2. Opioids 4. Bisphosphonates While long-term use of oral opioids in animals with These compounds may palliate OSA related pain by cancer pain is limited, canine patients may benefit decreasing osteoclast activity and inhibiting calcium from codeine26 or hydrocodone27 as these drugs have and phosphorus dissolution, and appear most the most favorable pharmacokinetic profile in dogs. effective when administered as part of multimodal Transmucosal buprenorphine may be used in cats. therapy.33 In addition, a recent rat study suggested that bone Pamidronate is the bisphosphonate most cancer pain may respond better to delta-receptor commonly used in dogs.34,35 IV infusions are adminis- active opioids than to mu-receptor active opioids.28 tered Q 3 to 4 weeks in patients whose owners elect to Fentanyl patches in humans are labeled for use in forego surgery and chemotherapy. Anecdotally, 60% cancer breakthrough pain, as are some buprenorphine of dogs respond favorably, and the dosing cycle is patches, but their efficacy in animals is questionable. repeated until the drug is no longer effective for bone Newer extended-release oral and transmucosal pain. Nephrotoxicity is a dose-limiting adverse effect. opioids—combined with peripheral opioid-receptor antagonists (to minimize gastrointestinal side effects) 5. Lidocaine Patch and, in the future, glial inhibitors—may ultimately play a anecdotal experience suggests pain relief with use of greater role in palliative care and breakthrough cancer lidocaine patches applied to the skin over the site of pain in pets. the OSA. Patches are considered safe because they elicit very low plasma levels.36 However, they must be 3. Neuromodulatory Agents secured properly in order to prevent ingestion by the • Gabapentin or pregabalin: No studies yet exist patient. in the veterinary literature, but several systematic reviews in humans support the use of gabapentin for 6. Energy-Based Biophysical Modalities cancer related pain.29-31 These modalities (eg, therapeutic laser, shock wave • Tricyclic antidepressants: Such as amitriptyline therapy, electromagnetic field) are generally consid- • Tramadol: See Table 3 ered contraindicated in neoplasia due to possible • Amantadine: Although not used for human cancer adenosine triphosphate production and activation of pain, its NMDA receptor antagonist activity may make cell division.

Pharmacokinetic evaluation of tramadol and its major metabolites after 18. howell SR, Hicks DR, Scatina JA, Sisenwine SF. Pharmacokinetics of single oral sustained tablet administration in the dog: A pilot study. Vet J venlafaxine and O-desmethylvenlafaxine in laboratory animals. Xenobiotica 2009; 180(2):253-255. 1994; 24(4):315-327. 12. Kukanich B, Papich MG. Pharmacokinetics and antinociceptive effects of 19. goldberg ME, Domsky R, Scaringe D, et al. Multi-day low dose ketamine oral tramadol hydrochloride administration in greyhounds. Am J Vet Res infusion for the treatment of complex regional pain syndrome. Pain 2011; 72:256-262. Physician 2005; 8(2):175-179. 13. Matthiesen T, Wöhrmann T, Coogan TP, Uragg H. The experimental 20. tremont-Lukats IW, Challapalli V, McNicol ED, et al. Systemic toxicology of tramadol: An overview. Toxicol Lett 1998; 95(1):63-71. administration of local anesthetics to relieve neuropathic pain: A 14. Malek S, Sample SJ, Schwartz Z, et al. Effect of analgesic therapy on systematic review and meta-analysis. Anesth Analg 2005; 101(6):1738- clinical outcome measures in a randomized controlled trial using client- 1749. owned dogs with hip osteoarthritis. BMC Vet Res 2012; 8:185. 21. tassinari D, Drudi F, Carloni F, et al. Neuropathic pain in oncology. Novel 15. McMIllan CJ, Livingston A, Clark CR, et al. Pharmacokinetics of evidence for clinical practice. Recenti Prog Med 2011; 102(5):220-227. intravenous tramadol in dogs. Can J Vet Res 2008; 72(4):325-331. 22. gupta RA, DuBois RN. Colorectal cancer prevention and treatment by 16. Pypendop BH, Ilkiw JE. Pharmacokinetics of tramadol, and its metabolite inhibition of cyclooxygenase-2. Nature Rev Cancer 2001; 1(1):11-21. O-desmethyl-tramadol, in cats. J Vet Pharmacol Ther 2008; 31(1):52-59. 23. Knapp DW, Richardson RC, Chan TC, et al. Piroxicam therapy in 34 dogs 17. KuKanich B. Outpatient oral analgesics in dogs and cats beyond with transitional cell carcinoma of the urinary bladder. J Vet Intern Med nonsteroidal antiinflammatory drugs: An evidence-based approach. Vet 1994; 8(4):273-278. Clin North Am Small Anim Pract 2013; 43(5):1109-1125. 24. Mohammed SI, Kahn KN, Sellers RS, et al. Expression of tvpjournal.com November/December 2014 Today’s Veterinary Practice 43 | Nonosteoarthritic Pain

cyclooxygenase-1 and 2 in naturally occurring canine cancer. Prostaglandins Leukot Essent Fatty Acids 2004; 70(5):479-483. 25. beam SL, Rassnick KM, Moore AS, McDonough SP. An immunohistochemical study of cyclooxygenase-2 expression in various feline neoplasms. Vet Pathol 2003; 40(5):496-500. 26. KuKanich B. Pharmacokinetics of acetaminophen, codeine, and the codeine metabolites morphine and codeine-6-glucuronide in healthy greyhound dogs. J Vet Pharmacol Ther 2010; 33(1):15-21. 27. KuKanich B, Paul J. Pharmacokinetics of hydrocodone and its metabolite hydromorphone after oral hydrocodone administration to dogs. ACVIM Proc, 2010. 28. brainin-Mattos J, Smith ND, Malkmus S, et al. Cancer-related bone pain is attenuated by a systemically available gamma-opioid receptor agonist. Pain 2006; 122(1-2):174-181. 29. bar Ad V. Gabapentin for the treatment of cancer- related pain syndromes. Rev Recent Clin Trials 2010; 5(3):174-178. 30. Caraceni A, Zecca E, Bonezzi C, et al. Gabapentin for neuropathic cancer pain: A randomized controlled trial from the Gabapentin Cancer Pain Study Group. J Clin Oncol 2004; 22(14):2909- 2917. 31. ross JR, Goller K, Hardy J, et al. Gabapentin is effective in the treatment of cancer-related neuropathic pain: A prospective, open-label study. J Palliat Med 2005; 8(6):1118-1126. 32. british Geriatrics Society. Guidance on the management of pain in older people. Age Ageing 2013; 42:i1-i57. 33. Personal communication, Louis-Philippe de Lorimier, Hôpital Vétérinaire Rive-Sud, Brossard, Québec, September 2007. 34. Fan TM, de Lorimier LP, O’Dell-Anderson K, et al. Single-agent pamidronate for palliative therapy of canine appendicular osteosarcoma bone pain. J Vet Intern Med 2007; May-Jun; 21(3):431-439. 35. Fan TM, de Lorimier LP, Charney SC, Hintermeister JG. Evaluation of intravenous pamidronate administration in 33 cancer- bearing dogs with primary or secondary bone involvement. J Vet Intern Med 2005; 19(1):74-80. 36. Ko J, Weil A, Maxwell L, et al. Plasma concentrations of lidocaine in dogs following lidocaine patch application. JAAHA 2007; 43(5):280-283.

Mark Epstein, DVM, Diplomate ABVP (Canine/ Feline), CVPP, is the senior partner and medical director of Carolinas Animal Pain Management & TotalBond Animal Hospitals, a group of AAHA-accredited practices in the Charlotte and Gastonia, North Carolina, areas. He is a member of the American Academy of Pain Man- agement and International Veteri- nary Academy of Pain Management; a past president of the IVAPM and ABVP; and an author and lecturer on the recognition, prevention, and treat- ment of pain. Dr. Epstein received his DVM from University of Georgia.

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