Pain issues and management in veterinary dentistry and oral surgery: Part 3 (Proceedings)

Continuous Rate Infusions (CRI)

Oral surgery in canine and feline patients often requires extended periods of anesthesia necessitating optimal anesthetic management. A safe and effective mode of pain management for the oral surgery patient is intravenous continuous rate infusion utilizing a multimodal approach to affect various levels of the nociceptive pathway.

The administration of opiates in various veterinary species has been studied and has been shown to be both safe and effective in decreasing MAC.1,2,3 Lidocainea acts to decrease central hypersensitivity in significant pain states and when given with opiates has a sparing effect on those agents.4 In a recent study dogs undergoing limb amputation that received ketamineb infusions had significantly lower pain scores 12 and 18 hours after surgery and were significantly more active on postoperative day 3 than dogs that did not.5 Furthermore the combination of morphinec , lidocainea and ketamineb delivered as a low dose CRI provides significant decreases in required isoflurane MAC in dogs.6 No adverse hemodynamic effects were experienced. Medetomidined has been used as a CRI in veterinary patients however a recent study warned of adverse hemodynamic effects of this drug when used in this manner noting that further investigation needs to be done before its use is advocated.7

Detailed spreadsheets are available for calculation of rates, volumes and loading doses for CRI in dogs and cats utilizing morphinec , lidocainea and ketamineb (Table 1) (1) (2). Weight/volume calculations for commonly used analgesics are particularly convenient resources and can be found at the Veterinary Anesthesia Support Group website.(2)

IV FLUID BAG BASED CRI INFUSIONS

Drug CRI Dose Range

MORPHINE - 0.12 to 0.36 mg/kg/hr (2 to 6 ug/kg/min).

LIDOCAINE - 0.6 to 1.5 mg/kg/hr (10 to 25 ug/kg/minute).

Dogs can be given a max. dose of 3.0 mg/kg/hr (50 mcg/kg/min)

Cats should be limited to a max. dose of 1.5 mg/kg/hr (25 mcg/kg/min)

KETAMINE - 0.12 to 1.2 mg/kg/hr (2 to 20 ug/kg/minute).

Loading Doses

MORPHINE - 0.5 mg/kg IM (or very slowly IV)

At 0.5 mg/kg this patients needs a loading dose of: 0.17 ml

LIDOCAINE - 0.5 to 1 mg/kg IV

At 0.25 mg/kg this patients needs a loading dose of: 0.06 ml

At 1.0 mg/kg this patients needs a loading dose of: 0.25 ml

CATS - Limit cats to 0.25 mg/kg loading dose

DOGS - 1.0 mg/kg is the normal loading dose

KETAMINE - 0.25 to 0.50 mg/kg IV bolus

At 0.25 mg/kg this patients needs a loading dose of: 0.01 ml

Drug Concentrations

MORPHINE - 15 mg/ml

LIDOCAINE - 20 mg/ml

KETAMINE - 100 mg/ml

Chronic Pain

The pathophysiology of chronic pain involves the complex mechanisms of peripheral and central sensitization. Significant pain states arise frequently in oral disease in that the pathology is hidden from casual owner observation and many patients that suffer from chronic pain do not become anorectic. Feline lymphocytic plasmacytic gingivostomatitis (LPGS), canine stomatitis, chronic ulcerative paradental stomatitis (CUPS), untreated oral trauma and some types of oral cancer are common examples of chronic oral pain states.

In the presence of persistent central and peripheral sensitization traditional perioperative and postoperative pain management fall considerably short of desirable. In order to effectively manage postoperative pain in chronic conditions more aggressive means must be employed. A novel approach to managing chronic pain states termed the "analgesic reverse pyramid" protocol shows considerable promise in effectively managing these patients.(1) With this approach immediate intense multimodal analgesic management is employed utilizing agents targeted to different portions of the nociceptive pathway. The chronic pain is targeted aggressively from the initiation of pain management and then tapered as desired based upon patient observation. This is in contrast to the traditional approach of adding analgesics from different classes if the initial response was less than desired.

Feline patients with LPGS are particularly painful. Utilizing multimodal, preemptive and analgesic reverse pyramid concepts the author initiates pain management for these patients 6-24 hours prior to initiation of the surgical stimulus for caudal mouth extractions. Meloxicamr is instituted to minimize the inflammatory peripheral sensitization experienced in these patients. Loading doses and a subsequent CRI of ketamineb and morphinec are commonly employed. Hydromorphonef and fentanylg are alternative opiods that are particularly effective as well.

CRI is continued in the intraoperative and postoperative period. Postoperative analgesics consisting of buprenorphineh (transmucosal or transdermal) or a fentanylg transdermal patch and meloxicamr are continued for up to 4 days. If a fentanylg patch is used it is placed such that the onset of therapeutic serum levels coincides with the anticipated culmination of the procedure. Regional nerve blocks are always employed preoperatively following achievement of a surgical plane of anesthesia. Table 1 provides an example of CRI protocol (2) and regional nerve block calculations for a feline patient undergoing four quadrant extractions.

Lidocainea as an additional CRI agent can be utilized in canine patients in the sample protocol from Table 2. A loading dose of 1.0 mg/kg IV is administered. 12.5 ml of lidocaine 2% is added to the morphinec /ketamineb CRI mixture previously described and is administered at the previously recommended rate of 2 ml/kg/hour. Lidocainea is also light sensitive. Due to the narrow spectrum between therapeutic and toxic doses of lidocainea in feline patients in addition to its routine inclusion in the regional nerve block lidocainea cannot be advocated as a CRI agent for oral surgery in this species.

Chronic pain may not always be eliminated by surgical means. Many cases of oral neoplasia remain undetected until feasible surgical margins for complete resection no longer exist. Management of patients with oral cancer involves a thorough historical and clinical evaluation utilizing knowledge of pain behaviors and incorporation of pain scoring. Excellent descriptions of pain evaluation in companion animals have been published.8,9

Table 2

Sample CRI protocol and nerve block calculations for a feline patient undergoing four quadrant extractions. Lidocaine can safely be added to CRI's at recommended doses in canine patients.

CRI

Loading Dose for morphine = 0.50 mg/kg IM

Loading dose for ketamine = 0.25 mg/kg IV

CRI formulation = 500 ml LRS + 30 mg ketamine + 30 mg morphine (Morphine will lose potency if exposed to light, therefore cover the fluid bag to protect it).

Run at 2 ml/kg/hour = 0.12 mg/kg/hour of each drug.

Intraoperative fluid rates of 10 ml/kg/hour are obtained by adding a second line of LRS at 8 ml/kg/hour.

Regional Nerve Block

Lidocaine + bupivicaine (refer to tables 2-6) + morphine at 0.5 mg/kg or a volume equal to the regional mixture whichever is less.

Example for a feline patient that weighs 4 kg:

Using table 6 for four anticipated sites = lidocaine 2% = 0.2 ml + bupivicaine 0.5% = 0.8 ml + morphine (15mg/ml) [5.0 mg/kg x 4 kg = 2.0 mg] = 0.13 ml

Cancer Pain

Pain from oral cancer pain is a distinct subset of chronic pain that characteristically is very difficult to manage. Understanding the pathophysiology of cancer pain has led to research that has produced analgesics that target specific mechanisms involved in this category of painful conditions. We too must familiarize ourselves with these mechanisms so that we may better choose analgesics based on pain severity, cancer location and individual patient response.

Compounds produced by tumor cells work in concert with our own macrophages, neutrophils and T-lymphocytes to increase the exitability of nociceptors.10 Compounds commonly secreted by tumors include prostaglandins, endothelins, interleukins and tumor necrosis factor alpha. The management of cancer pain involves the utilization of analgesic agents to block the actions of these substances.

Cox-2 enzyme expression and prostaglandin production are characteristics of many tumors and the macrophages associated with them.11,12 Cox-2 expression appears to play a role in angiogenesis which in turn acts to promote the growth of cancer.13,14 Cox-2 inhibitors therefore may not only control inflammatory pain in this instance but also may act to alter cancer growth. Endothelins are peptides that also possess properties that block angiogenesis15 and tumor proliferation.16 Plasma levels of endothelins have been shown to be directly correlated with the severity of pain in humans with prostate cancer.17 Drugs that block the production of prostaglandins and endothelin inhibitors have been approved for other disease states in humans. These drugs have promising potential for use in oral cancer pain management and to arrest development of some tumors.10 Protons are released during the normal turnover of cells as tumors expand and apoptosis results. These protons consequently render the immediate tissue environment acidic18 This corresponding decrease in tissue pH acts to induce bone destruction by osteoclasts.19 Acid-sensing ion channels (ASIC) expressed by nociceptors are stimulated within the acid environment and likely play a role in the generation of cancer pain. Some bisphosphonates and the substance osteoprotegerin that facilitate osteoclast apoptosis have been show to decrease osteoclast-induced cancer pain.10 ASIC blocking agents currently under development may prove viable as analgesics in cancer pain.

Neuropathic pain occurs when sensory and sympathetic nerve fibers are exposed to proteolytic enzymes produced by tumor cells10 Neuropathic pain is very difficult to treat in human medicine and is regarded as the most severe form of pain. Gabapentini , classically used as an anticonvulsant, is also used to treat neuropathic pain and may show promise in treating pain from oral and other cancer.20

Cancer pain physiology research suggests that central sensitization(windup) plays a role in the severity and maintenance of cancer pain.10 Ketamineb is an NMDA antagonist that is currently being employed to successfully manage human cancer pain.21 Studies show that two oral NMDA receptor antagonists, dextromethorphanj22,23 and amantidiner24 , are also successful at treating human cancer pain.

Knowledge of the pathophysiology of chronic and caner pain helps clinicians choose proper protocols for patients based on variables involved with individual case management. Pain management studies using companion animal models are scarce. Fortunately organizations like the and the Veterinary Anesthesia Support Group (2) and International Veterinary Academy of Pain Management (3) have developed techniques and protocols using available studies and practical experience helping clinicians better manage chronic and cancer pain in our veterinary patients. We must challenge ourselves to remain current with advances in pain management in order to continually provide comfort in to our patients with chronic and oral cancer pain.

Footnotes

(1) Lascelles BD. Interaction of Pain and Cancer, and Principles of Alleviation of Cancer Pain in Dogs and Cats. 21st Annual ACVIM Forum, 2003.

(2) Stein B, Thompson D. Veterinary Anesthesia Support Group. www.VASG.org Accessed February 11, 2006.

(3) International Veterinary Academy of Pain Management www.cvmbs.colostate.edu/ivapm/ Accessed February 11, 2006.

Products

a. Lidocaine Hydrochloride2%, Phoenix Scientific Corp, St Joseph, MP

b. Ketaset, Fort Dodge Animal Health, Fort Dodge, IA

c. Morphine sulfate 15mg/ml, Baxter Animal Health Care Corp, Deerfield, IL

d. Domitor, Orion Corp, Espoo, Finland

e. Metacam, Boehringer Ingelheim Vetmedica Inc, St. Joseph, MO

f. Hydromorphone, Baxter, Deerfield, IL

g. Duragesic, ALZA Corp, Mountain View, CA

h. Buprenex, Reckitt & Colman, Wayne, NJ

i. Gabapentin, Pfizer Inc., NY, NY

j. Vick's Forumula 44D Hygiene and Helathcare Limited , Maharashta, India

k. Amantidine, Alliance Pharmaceuticals, Wilshire, UK

References

Ilkiw JE, Pascoe PJ, Tripp LD Effects of morphine, butorphanol, buprenorphine, and U50488H on the minimum alveolar concentration of isoflurane in cats.Am J Vet Res. 2002; 63(8):1198-202.

Criado AB, Gomez e Segura IA et al Reduction of isoflurane MAC by fentanyl or remifentanil in rats. Vet Anaesth Analg. 2003; 30(4):250-6.

Criado AV, Gomez de Segura IA et al. Reduction of isoflurane MAC with buprenorphine and morphine in rats. Lab Anim. 2000; 34(3):252-9.

Koppert W, Weigand M, et al.Perioperative intravenous lidocaine has preventive effects on postoperative pain and morphine consumption after major abdominal surgery. Anesth Analg. 2004; 98(4):1050-5

Wagner AE, Walton JA et al. Use of low doses of ketamine administered by constant rate infusion as an adjunct for postoperative analgesia in dogs. J Am Vet Med Assoc 2002; 221(1):72-5.

Muir WW3rd, Wiese AJ, March PA Effects of morphine, lidocaine, ketamine, and morphine-lidocaine-ketamine drug combination on minimum alveolar concentration in dogs anesthetized with isoflurane. Am J Vet Res 2003; 64(9):1155-60.

Grimm KA, Tranquilli WJ Cardiopulmonary effects of fentanyl in conscious dogs and dogs sedated with a continuous rate infusion of medetomidine. Am J Vet Res 2005; 66(7):1222-6.

Muir WM 3rd , Gaynor JS. Pain Behaviors. In: Gaynor JS, Muir W W. Handbook of Veterinary Pain Management. St. Louis: Mosby, 2002; 65-81.

Hellyer PW Objective, Categoric Methods for Assessing Pain and Analgesia. In: Gaynor JS, Muir W W. Handbook of Veterinary Pain Management. St. Louis: Mosby, 2002; 82-107.

Mantyh PW. Cancer Pain: Causes, Consequences and Therapeutic Opportunities. In: McMahon SB, Koltzenburg M, eds. Wall and Melzack's Textbook of Pain, 5th ed. China: Elsevier, 2006; 1087-1097.

Dubois R N, Radhika A, Reddy B S et al Increased cyclooxygenase-2 levels in carcinogen-induced rat colonic tumors. 1996; Gastroenterology 110(4):1259-1262

Molina M A, Sitja-Arnau M, Lemoine M G et al Increased cyclooxygenase-2 expression in human pancreatic carcinomas and cell lines: growth inhibition by nonsteroidal anti-inflammatory drugs. 1999; Cancer Research 59(17):4356-4362

Masferrer J L, Leahy K M, Koki A T et al Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. 2000; Cancer Research 60(5):1306-1311

Moore B C, Simmons D L COX-2 inhibition, apoptosis, and chemoprevention by nonsteroidal anti-inflammatory drugs. Current Medicinal Chemistry 2000;7(11):1131-1144

Dawas K, Laizidou M, Shankar A et al Angiogenesis in cancer: the role of endothelin-1. Annals of the Royal College of Surgeons of England 81:306-310

Asham E H, Loizidou M, Taylor I 1998 Endothelin-1 and tumour development. European Journal of Surgical Oncology 1999; 24(1):57-60

Nelson J B, Hedican S P, George D J et al 1995 Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nature Medicine 1(9):944-999

Helmlinger G, Sckell A, Dellian M et al Acid production in glycolysis-impaired tumors provides new insights into tumor metabolism. Clinical Cancer Research 2002; 8(4):1284-1291

Delaisse J-M, Vaes G Mechanism of mineral solubilization and matrix degradation in osteoclastic bone resorption. In: Rifkin B R, Gay C V (eds) Biology and Physiology of the Osteoclast. CRC Press, Ann Arbor, 1992; 289-314

Ripamonti C, Dickerson E D Strategies for the treatment of cancer pain in the new millennium. Drugs 2001; 61(7):955-977

Lossignol, DA, Obioils-Portis M, Body JJ Successful use of ketamine for intractable cancer pain. Support Care Cancer 2005; 13(3):188-93.

Weinbroum AA, Bender B et al. Preoperative and postoperative dextromethorphan provides sustained reduction in postoperative pain and patient-controlled epidural analgesia requirement: a randomized, placebo-controlled, double-blind study in lower-body bone malignancy-operated patients. Cancer 2003; 97(9):2334-40.

Weinbroum AA, Gorodetzky A, et al. Dextromethorphan for the reduction of immediate and late postoperative pain and morphine consumption in orthopedic oncology patients: a randomized, placebo-controlled, double-blind study. Cancer 2002; 95(5):1164-70.

Pud D, Eisenberg E, et al. The NMDA receptor antagonist amantadine reduces surgical neuropathic pain in cancer patients: a double blind, randomized, placebo controlled trial. Pain 1998; 75(2-3):349-54.