TOPICAL REVIEW

Chronic Pain: Pathophysiology and Treatment Implications Stephen A. Greene, DVM, MS, DACVA An examination of the current understanding of the processes and related therapies aimed at treatment of chronic pain in animals is presented. Discussion focuses on mechanisms involved in the neural pathways of chronic pain, differences between acute and chronic pain, and pharmacologic options for chronic pain as they relate to inflammatory, neoplastic, and neuropathic processes. © 2010 Elsevier Inc. All rights reserved. Keywords: chronic pain, inflammatory pain, cancer pain, neuropathic pain, analgesia, pain pathway

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anagement of animal pain has become a significant ethical as well as economic component in the modern practice of veterinary medicine. To this end, the incorporation of analgesic protocols in the perioperative period has garnered attention and expertise of the practicing veterinarian. Evidence to support specific anesthetic and analgesic protocols effective in the treatment of operative pain continues to increase. Similarly, specific details underlying the physiology and pathophysiology of chronic pain syndromes have advanced our knowledge and rationale for treatments. Chronic pain differs in fundamental aspects when compared with those of acute pain. This article will examine current understanding of the processes and related therapies aimed at treatment of chronic pain in animals.

What Is Chronic Pain? Chronic pain has been defined as aberrant somatosensory processing in the peripheral or central nervous system (CNS) that is sustained beyond the normally expected time course relative to the stimulus. This definition, although helpful, provides only part of the story. Chronic pain is often insidious, vague, and difficult to pinpoint. Chronic pain may arise from a primary dysfunction within the nervous system. Chronic pain is difficult to diagnose by health care professionals, and its diagnosis may be especially elusive when the patient is nonverbal; obviously the situation veterinarians face every day. To appreciate the mechanistic differences in the physiology of chronic pain, it is useful to briefly review the pathway of normal (acute) or physiologic pain (see Lamont and coworkers1). Perception of pain is the culmination of transduction of spatially or temporally summated stimuli af-

From the Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA USA. Address reprint requests to: Stephen A. Greene, DVM, MS, DACVA, Professor of Veterinary Anesthesia, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA 99164-6610. E-mail: [email protected]. © 2010 Elsevier Inc. All rights reserved. 1527-3369/06/0604-0171\.00/0 doi:10.1053/j.tcam.2009.10.009

fecting peripheral nociceptors. Nociceptors may be specific for painful stimuli, or they may be generally responsive to a wide range of mechanical, thermal, chemical, or electrical stimuli. Nociceptive responses are transmitted from peripheral sites to the CNS via myelinated (type A-delta) or unmyelinated (type C) fibers. Neurotransmitters include substance P, neurokinin, neurotensin, glutamate, and N-methyl-Daspartate (NMDA) among others. Synapses in the dorsal horn laminae of the spinal cord may be modulated through a variety of mechanisms before decussation and ascension to higher dermatones and ultimately to brainstem and midbrain centers. Additional processing passes the pain signal through the thalamus before projection to the cerebral cortex. Basic differences from this scheme that occur in the pathophysiology of chronic pain arise from the sensitization of neurons along the path.2 Peripheral sensitization through chemical products of cell destruction (the “sensitizing soup”) or CNS sensitization via activation of glutamate or NMDA receptor– mediated pathways creates the setting for development of a chronic pain syndrome, a phenomenon also known as windup. A second feature associated with the pathophysiology of chronic pain is related to the plasticity of the nervous system. With prolonged activation of pain pathways, augmented by sensitization, neural plasticity results in degeneration and remodeling of synapses and ganglia with collateral sprouting among nerve cells. Changes in neuronal function may thus occur, resulting in production of pain transmitter substances by cells that previously did not. For example, the nerve fibers that normally carry proprioceptive information (type A-beta) may be altered to begin producing substance P, effectively converting these previously innocuous signals to pain transmissions (Fig 1). Sectioned nerves have been associated with induction of cholecystokinin (CCK) production in afferent nerve fibers.3 A direct antagonism of opioid-induced analgesia is mediated by CCK, potentially explaining the lack of opioid efficacy in some cases of neuropathic pain. These morphologic and functional changes in the nervous system can cause decreased pain threshold, exaggerated activation of the pain pathway, ectopic discharges, or loss of normal inhibitory processes. Chronic pain may elicit abnormal responses from the pain pathway that can be described as

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Figure 1. Morphologic changes in afferent fibers and the dorsal horn of the spinal cord typical of chronic pain syndromes. These changes are reflected by clinical symptoms of hyperalgesia or allodynia. (Color version of figure is available online.) hyperalgesia (exaggerated response to a normally painful stimulus) or allodynia (pain from a normally nonpainful stimulus). Chronic pain syndromes often involve sensitization of the pain pathway through the NMDA receptor in the dorsal horn of the spinal cord.4

Therapeutic Implications Better understanding of the pathophysiology associated with chronic pain will introduce the challenges to finding effective treatments and plant the seeds to nurture novel approaches in this quest. Drugs that are effective for acute pain may have little or no benefit when used for chronic pain syndromes. Conversely, drugs with little demonstrated benefit in treatment of operative pain may have significant efficacy in the treatment of chronic pain. The long-term therapies typically instituted for chronic pain syndromes may require unique routes of administration to achieve greater efficacy with fewer side effects. The use of oral, transdermal, and sustained-release formulations of analgesics has aided in the willingness of clients to comply with drug administration guidelines offered by the veterinarian. Species differences in absorption, metabolism, elimination, and therapeutic response dictate that the practitioner maintains vigilance in the

Figure 2. The pain pathway depicting sites of action for analgesics and adjuvants used in the treatment of chronic pain.

Figure 3. The World Health Organization (WHO) Analgesic Ladder: step one analgesics are used to control mild pain. When uncontrolled by step one analgesics (nonopioid analgesics ⫾ an analgesic adjuvant such as gabapentin), step two analgesics are used. When step two pain is uncontrolled, step three analgesics are administered.

expanding database of biomedical literature, particularly when treating with off-label or novel agents. Combinations of analgesics may offer optimal therapeutic approaches by attacking pain through different mechanisms (Fig 2). Recommendations for the treatment of chronic pain follow the established World Health Organization guidelines for pain management, sometimes referred to as the “WHO Ladder” (Fig 3). Pain of mild nature is initially treated with a nonopioid (e.g., nonsteroidal antiinflammatory analgesic). Nonsteroidal antiinflammatory analgesics available to the veterinarian include carprofen, etodolac, meloxicam, ketoprofen, deracoxib, tepoxalin, acetaminophen, and aspirin. Because of the differences in the spectrum of enzyme inhibition (e.g., cyclooxygenase [COX]-1 vs COX-2 vs lipoxygenase), efficacy may be variable among individuals, requiring the veterinarian to maintain stock of more than one agent. All are capable of side effects that include gastrointestinal ulceration and platelet dysfunction, so adherence to dosing guidelines is important. Appropriate washout periods for an initial treatment are suggested before beginning treatment with a different agent. Concurrent use of corticosteroids is not recommended beyond a single or short-term regimen. The nonsteroidal antiinflammatory analgesics have recently been implicated in the inhibition of nitric oxide radical generation and, rarely, in the promotion of immunosuppression.5 Although currently the mainstay of chronic pain therapy, clearly there is still much to learn about the specific

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Volume 25, Number 1, February 2010 Table 1. Classification of Analgesics Used in Chronic Pain Syndromes Drug

Drug Class

Analgesic Mechanism

Morphine Fentanyl Codeine Buprenorphine Butorphanol Amitriptyline Amantidine Gabapentin

Strong opioid: full ␮-agonist Strong opioid: full ␮-agonist Weak opioid: ␮-agonist Strong opioid: partial ␮-agonist Weak opioid: ␬-agonist Tricyclic antidepressant Antiviral Anticonvulsant

Opioid receptor modulation in the dorsal horn, primarily lamina 1 in the substantia gelatinosa

Lidocaine

Sodium channel blocker

Ketamine Tramadol

Dissociative anesthetic Non-opioid?: weak ␮-agonist

Dexmedetomidine

Alpha-2 adrenoceptor agonist

Bisphosphonate

Osteoclast inhibitor

Antagonist at NMDA receptors; inhibits norepinephrine reuptake Antagonist at NMDA receptors Inhibits release of excitatory neurotransmitters from primary afferent nerve fibers Local anesthetic via inhibition of nerve conduction; systemic analgesia possibly via modulation of the NMDA receptor activity through a glycine-like effect Antagonist at NMDA receptors Inhibits reuptake of serotonin and norepinephrine; has alpha-2 adrenoceptor activity Alpha-2 adrenoceptor agonist activity mediated by G-proteins in the dorsal horn of the spinal cord and the locus ceruleus of the brain stem; action may be linked with opioid receptor activity Inhibits bone resorption

Abbreviation: NMDA, N-methyl-D-aspartate.

advantages and disadvantages of nonsteroidal antiinflammatory analgesics in treatment of specific syndromes. Other options for a nonopioid analgesic are listed in Table 1. Tramadol is an agent with opioid receptor activity that is not strictly classified as an opioid and is not a controlled substance in the United States. Tramadol inhibits norepinephrine and serotonin uptake and inhibits activity at the NMDA receptor. High doses of tramadol may cause convulsions. Gabapentin also modifies NMDA receptor activity and has proven effective for treatment of neuropathic pain. Side effects of gabapentin include sedation, nausea, and vomiting. Amantidine, memantine, and acamprosate are antidepressants with low affinity but noticeable activity as NMDA receptor antagonists. In humans, side effects from this group of drugs include tachycardia, hypertension, gastrointestinal disturbances, renal dysfunction, and respiratory distress. The second step on the WHO ladder for treatment of moderate chronic pain involves concurrent administration of a nonopioid (usually a nonsteroidal antiinflammatory analgesic) and an opioid. Opioids commonly used for treatment of chronic pain in veterinary medicine include full ␮-agonists (morphine, codeine, and fentanyl), the partial ␮-agonist buprenorphine and the ␬-agonist butorphanol. Full ␮-agonist opioids are selected for patients with chronic conditions in the third step of the WHO ladder: those who experience more intense levels of pain. Opioid receptors are expressed in the periphery during inflammation. This activation may be a reflection of decreased CCK activity associated with inflammatory mediators.6 Further, the A-beta fibers pathologically recruited to carry pain information after sensitization in cases of allodynia (neuropathic pain) lack opioid receptors, which may explain poor responses to this class of analgesic in these

conditions.7 Human patients given opioids for long-term treatment of pain have demonstrated immune system dysfunction characterized by inhibition of natural killer immunocyte and T-cell activities and also by inhibition of phagocytic activity in the reticuloendothelial system, which may thereby promote increased incidence of infection.8 It should be recognized that some types of pain may respond better to a “weak opioid” compared with a “strong opioid” and a nonsteroidal antiinflammatory analgesic may yield a better response than an opioid for some types of pain, for example, when related to biliary or ureter spasm. Selection of drugs appropriate for treatment of chronic pain primarily depends on the type of syndrome being treated. However, the route of administration of the analgesic can offer advantages in specific circumstances. Oral medications offer a simple route of administration that may be associated with improved compliance. Analgesic patches (fentanyl, lidocaine) may also promote compliance, but variations in patch application can dramatically affect the plasma concentrations that are achieved. Appropriate patch application can result in long-term therapy (days) after a single treatment. Ointments (e.g., capsaicin) and pleuronic gels (e.g., ketamine) offer novel therapeutic approaches for nearly any desired analgesic agent. Direct topical application can ameliorate pain in the local region while minimizing systemic side effects. Nonpharmacologic therapies for chronic pain include massage, physical therapy, acupuncture, and transcutaneous electrical nerve stimulation. These modalities are associated with improved blood flow to affected sites and with the endogenous release of analgesic substances such as beta-endorphin and enkephalin. Endogenous opioids exert descending

8 inhibitory modulation on neuronal transmission of pain signals at the level of the dorsal horn. Suppression of sensitization in the CNS may also occur.

Chronic Inflammatory Pain Use of nonsteroidal antiinflammatory analgesics has become the hallmark of therapeutic interventions for mild to moderate chronic inflammatory pain in animals. By inhibiting production of COX enzymes, these agents decrease prostanoid production. Prostanoids are mediators of inflammation and amplify nociceptive input.9 Hyperalgesic responses to tissue injury are primarily ascribed to the effects of COX-2. Some drugs of this class, for example aspirin, may inhibit other significant promoters for inflammatory mediators such as nuclear factor kappa-B. One recent study suggests that carprofen may have actions without inhibition of either COX-1 or COX-2 enzymes, opening the possibility that some nonsteroidal antiinflammatory analgesics work through actions on other pathways.10 Dual inhibitors such as tepoxalin act through inhibition of both prostaglandins and leukotrienes. There is evidence to suggest that dual inhibitors have good analgesic efficacy with better gastrointestinal safety.11 Recent evidence about an old drug, acetaminophen, indicates that its mechanism of action may be through the peroxidase enzyme unit of prostaglandin H2 synthase, with COX inhibition occurring at specific sites in the CNS.12 This may explain acetaminophen’s relatively minimal effects on gastrointestinal mucosa, platelet function, and renal function.

Cancer Pain Pain in patients with cancer may be related to processes associated with the tumor itself or to the treatment of the disease. Nonsteroidal antiinflammatory analgesics aid in the reduction of inflammatory mediators that sensitize the pain pathways. Opioids constitute the backbone of treatment of moderate to severe cancer pain. Side effects associated with chronic administration of opioids include vomiting, dysphoria, diarrhea, or constipation. Dose-dependent analgesia from opioids is achieved with full ␮-agonists, whereas moderate pain relief is expected from the partial ␮-agonist buprenorphine. Buprenorphine appears to reach effective plasma levels in cats after buccal administration and mucosal absorption.13 Severe cancer pain is managed according to the step 3 guidelines of the WHO ladder and may include adjuncts to opioids and nonsteroidal antiinflammatory analgesics such as infusion of dexmedetomidine, ketamine, or lidocaine. Adjunctive agents for severe cancer pain may also include NMDA antagonists such as amantidine or tranquilizers such as acepromazine or diazepam for calming the dysphoric patient. For the patient with bone cancer, bisphosphonates have shown efficacy by inhibiting osteoclast activity and painful bone resorption.14

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Neuropathic Pain Neuropathic pain is pain originating in the nervous system. Traumatic damage to nervous tissue is a significant initiating factor in neuropathic pain. Additionally, ingredients in the “sensitizing soup” may activate macrophages at the site of nerve injury, resulting in production of tumor necrosis factor or interleukin-1␤, substances that promote neuropathic pain. Features of neuropathic pain include: 1) central sensitization; 2) central disinhibition (imbalance in excitatory and inhibitory inputs); and 3) phenotypic change of mechanoreceptive A-beta fibers to begin production of substance P.15 Diagnosis of neuropathic pain can be difficult in veterinary practice. It should be suspected when there are accompanying clinical signs such as vasomotor activity or sweating. Neuropathic pain is worsened during instances of sympathetic responses such as emotional outbursts or when startled. Pain relief from surgical destruction or pharmacologic blockade of sympathetic outflow to the affected area may be observed. Unfortunately, recurrence of pain after these procedures is not unusual. Common scenarios for the occurrence of neuropathic pain include accidental nerve ligation (inguinal hernia repair, pelvic fracture repair), amputation, spinal cord injury, polyradiculoneuritis, pancreatitis, inflammatory bowel disease, and diabetic neuropathy. Treatments for neuropathic pain may also follow the WHO pain ladder. Opioids are frequently included but not always effective. Methadone has been used in treatment of neuropathic pain syndromes because it is effective via both opioid and NMDA receptors. Other NMDA receptor antagonists used in neuropathic pain syndromes include ketamine and amantadine. Systemic lidocaine infusions have been used as well. The analgesic mechanism of systemic lidocaine may be related to inhibition of NMDA receptors via glycine-like activity in the dorsal horn neurons.16 Dexmedetomidine, gabapentin, tramadol, amantadine, and amitryptyline are other adjuncts to the treatment of neuropathic pain that are commonly used in veterinary medicine. Recently, the vanilloid receptor antagonists have received attention as the molecular site targeted for treatment of neuropathic pain. The transient receptor potential melastatin (TRPM8) receptor is one of a group of ion channels mediating thermosensation (cold). Increased inhibitory activity in the CNS metabotropic glutamate receptors by TRPM8 appears to produce analgesia in a neuropathic pain model.17 Perhaps this group of agents holds the key to future therapies for some chronic pain syndromes. Nonpharmacologic therapies such as acupuncture and electroacupuncture are also effective via prolonged inhibition of nociceptive stimuli processed in the dorsal horn of the spinal cord.18 The role of exercise, physical therapy, and nutrition in promoting optimal balance of chemical substrates to facilitate antinociception in the animal cannot be underestimated. In a holistic view of animal well-being, the successful treatment of chronic pain is predicated on the restoration of normal balance within the nervous system and among the myriad other functions of the body.

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References 1. Lamont LA, Tranquilli WJ, Grimm KA: Physiology of pain. Vet Clin North Am 30:703-728, 2000 2. Tranquilli WJ: Physiology of chronic pain, in Greene SA, (ed): Veterinary Anesthesia and Pain Management Secrets. Philadelphia, Elsevier, 2002, pp 345-348 3. Stanfa L, Ah D, Xu X, Wiesenfeld-Hallin Z: Cholecystokinin and morphine analgesia: variations on a theme. Trends Pharmacol Sci 15:65-66, 1994 4. Pozzi A, Muir WW, Traverso F: Prevention of central sensitization and pain by N-methyl-D-aspartate receptor antagonists. J Am Vet Med Assoc 228:53-60, 2006 5. Bizzarri C, Pagliei S, Brandolini L, et al: Selective inhibition of interleukin-8-induced neutrophil chemotaxis by ketoprofen isomers. Biochem Pharmacol 61:1429-1437, 2001 6. Wiertelek E, Maier S, Watkins L: Cholecystokinin antianalgesia: safety cues abolish morphine analgesia. Science 256:830833, 1992 7. Twycross RG: Opioids, in Wall PD, Melzak R (eds): Pain. Edinburgh, Churchill-Livingstone, 1999, pp 1187-1214 8. Kona-Boun J-J, Silim A, Troncy E: Immunologic aspects of veterinary anesthesia and analgesia. J Am Vet Med Assoc 226: 355-363, 2005 9. Malmberg AB, Yaksh TL: Antinociceptive actions of spinal nonsteroidal anti-inflammatory agents on the formalin test in the rat. J Pharmacol Exp Ther 263:136-146, 1992 10. Bryant CE, Farnfield BA, Janicke HJ: Evaluation of the ability

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of carprofen and flunixin meglumine to inhibit activation of nuclear factor kappa B. Am J Vet Res 64:211-215, 2003 Trang T, McNaull B, Quirion R, et al: Involvement of spinal lipoxygenase metabolites in hyperalgesia and opiate tolerance. Eur J Pharmacol 491:21-30, 2004 Aronoff DM, Oates JA, Boutaud O: New insights into the mechanism of action of acetaminophen: its clinical pharmacologic characteristics reflect its inhibition of the two prostaglandin H2 synthases. Clin Pharmacol Ther 79:9-19, 2005 Robertson SA, Taylor PM, Sear JW: Systemic uptake of buprenorphine by cats after oral mucosal administration. Vet Rec 152:675-678, 2003 Veri A, D’Andrea MR, Bonginelli P, et al: Clinical usefulness of bisphosphonates in oncology: treatment of bone metastases, antitumoral activity and effect on bone resorption markers. Int J Biol Markers 22:24-33, 2007 Matthews KA: Neuropathic pain in dogs and cats: if only they could tell us if they hurt. Vet Clin North Am 38:1365-1414, 2008 Muth-Selbach U, Hermanns H, Stegmann JU, et al: Antinociceptive effects of systemic lidocaine: involvement of the spinal glycinergic system. Eur J Pharmacol 613:68-73, 2009 Proudfoot CJ, Garry EM, Cottrell DF, et al: Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain. Current Biol 16:1591-1605, 2006 Karavis M: The neurophysiology of acupuncture: a viewpoint. Acupunct Med 15(1):33-42, 1997

ID 2401310

Title Chronic Pain: Pathophysiology and Treatment Implications

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