Advances in veterinary oncology and increased

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1 128 Vol. 22, No. 3 March 2001 Peer-Reviewed CE Article #2 Managing Pain in the Canine Cancer Patient Deneen Cordell, CVT Constantrate infusion is recommended when severe postoperative pain is likely (see Figure 1). Advances in veterinary oncology and increased interest from practitioners have led many pet owners to seek treatment for their dogs with cancer. The veterinary health care team must be ready to provide sound advice, current information, and the necessary expertise regarding cancer to allow owners to make informed decisions about their pets well-being. Depending on individual circumstances, some owners may decide to euthanize a pet with cancer, whereas others may elect to pursue heroic treatment. Veterinary staff must remember the importance of treating the patient not only medically but also ethically and humanely. Whatever the owners decision, they need to understand that their pets quality of life rather than longevity should be the primary concern. Noted humanitarian Albert Schweitzer once said, We all must die but that I can save him from days of torture that is what KEY POINTS The World Health Organization guidelines for managing pain in humans can be applied to canine and feline cancer patients. Preemptive sedation and analgesia can help relieve anxiety and stress in cancer patients. When performing surgical procedures in oncology patients, regional nerve blocks should be incorporated into anesthetic protocols whenever possible. I feel is my great and ever new privilege. Pain is a more terrible lord of mankind than even death itself. 1 Cancer can be a painful disease. To provide an acceptable quality of life, pain must be recognized, acknowledged, and treated. Standard protocols for pain management are useful, but all patients will not benefit similarly from a cookbook method of managing pain. The treatment plan should be individualized and alternate strategies prepared if it is ineffective. Each patient should be reevaluated frequently to ensure that pain is being controlled adequately. Types of Pain Acute Acute pain usually results from the inflammatory process that accompanies a traumatic, surgical, or infectious event. By definition, acute pain is abrupt in onset and relatively short in duration. 2 Pain is a normal adaptive reaction to cell injury or disease and is generally considered a protective mechanism that warns the animal of actual or potential tissue trauma. Acute pain often decreases with the healing process and therefore is self-limiting. Physiologic signs of acute pain include tachycardia, tachypnea, hypertension, and miosis (see the Glossary). These responses are usually accompanied by behavioral changes (e.g., vocalization, licking the area, anorexia, restlessness, and guarding). 3 Because acute pain is anticipated after surgery, clinicians and technicians are more likely to recognize it. Conversely, in patients that are presented with a chronic medical condition such

2 Managing Canine Cancer Pain Veterinary Technician March Glossary α 2 -Agonists Sedative/analgesics; medetomidine is an α 2 - agonist licensed for use in dogs; α 2 -agonists bind to α 2 - adrenergic receptors, causing sedation, muscle relaxation, and analgesia Allodynia Pain response caused by a stimulus that normally does not provoke pain Analgesia Absence of pain in the presence of a stimulus that is normally painful Miosis Constriction of the pupil Neuropathic Pathologic change or disturbance in nervous system function Nociception Reception, conduction, and central nervous system processing of nerve signals produced by the stimulation of nociceptors; a physiologic process resulting in the conscious perception of pain Nociceptor Receptor that is sensitive to a noxious stimulus or stimulus that would become noxious if prolonged Phantom pain Pain associated with an amputated limb or appendage; damaged or transected nerves continue to send information to the brain Somatic pain Pain in the tissues of the body Tachycardia Excessively rapid heart rate Tachypnea Excessively rapid breathing Visceral pain Pain in any large internal organ as cancer, acute pain is often treated too conservatively or not at all. In addition to its association with the disease process, acute pain can be linked with many diagnostic and therapeutic medical procedures in cancer patients. Diagnostic procedures such as fine-needle aspiration and biopsy may be mildly painful, and others (e.g., rhinoscopy, bone biopsy, exploratory laparotomy) can be moderately to severely painful. Severe acute pain can be associated with cancerrelated pathologic fractures and such surgical interventions as thoracotomies, amputations, and mandibulectomies. Chronic Chronic pain is pain that persists beyond the usual course of an acute disease or reasonable time for an injury to heal. 2 It is a neuropathologic process that can persist or recur for months to years after the original injury. 2 Unlike acute pain, chronic pain may respond poorly to traditional analgesic drugs. Often, creative alternatives must be sought. Chronic pain is less well characterized than is acute pain; therefore it may be more difficult to diagnose. Chronic pain often produces nonspecific signs (e.g., depression, anorexia, anxiety) and may be one of the major factors causing cachexia in some cancer patients. 4 There is no scientific proof that cancer-related pain in animals feels exactly the same as that in humans. However, some generalizations may be useful when discussing cancer pain in animals. In humans, the initial and most common cause of pain is tumor invasion into such structures as bone and viscera. The second most common source of pain follows such palliative and curative procedures as surgery, chemotherapy, and radiation therapy. Chemotherapy and radiation therapy can be considered palliative and pain relieving in some cancer patients but can also be mildly to moderately painful. A few canine cancer patients may suffer from concurrent disease. Cancer becomes the primary focus in these patients, and concurrent problems may be overlooked. For example, some patients may suffer from both degenerative joint disease and cancer. In these patients, any pain associated with arthritis and cancer should be individually assessed and treated. Pain can originate directly from somatic or visceral tissue or have a neuropathic origin. Somatic pain originates in the superficial or deep layers of skin and muscle. Visceral pain originates from the stimulation of nociceptors in such organs as the lungs, liver, bladder, and gastrointestinal tract. Tissue stretching, compression, or ischemia caused by cancer progression can cause pain. Neuropathic pain results from central or peripheral nervous system damage or altered nervous system processing. This may occur through invasion or compression of nerves by cancerous tissue growth, which is common with nerve sheath tumors and sarcomas of the spinal column. Neuropathic pain can also be secondary to nerve damage caused by chemotherapy or radiation therapy. Phantom pain may result from transection of nerves during limb amputation. 5 Although transected during surgical removal of cancer tissue, nerves may still send information to the brain. Allodynia results from altered neuroprocessing and is characterized by pain resulting from a stimulus that does not normally evoke a pain response. 2 For example, a light skin stroke may cause severe pain in patients with chronic inflammation caused by a swollen cancerous joint. Neuropathic pain can be excruciating and extremely difficult to treat. Pharmacologic Options The World Health Organization (WHO) has developed a three-step ladder for treating pain in human cancer patients. 6 These guidelines can be applied to canine and feline cancer patients once pain level has been assessed. This is objective because there is no single universally accepted grading scale for pain. The first step in the WHO ladder (for patients in mild pain) is administration of an NSAID. The second step is coadministration of an opioid (agonist antagonist or par-

3 130 Veterinary Technician March 2001 Managing Canine Cancer Pain TABLE I Oral Nonsteroidal Antiinflammatory Drugs for Dogs Drug Aspirin (65- and 325-mg tablets) Acetaminophen (235- and 500-mg tablets; 160 mg/5 ml elixir) Carprofen (25-, 75-, and 100-mg tablets; 25-, 75-, and 100-mg chewables) Etodolac (150- and 300-mg tablets) Meloxicam (1.5 mg/ml oral suspension) Ketoprofen (25-, 50-, and 75-mg capsules; 5- and 20-mg tablets in Canada) Dose mg/kg every 12 hr 15 mg/kg every 8 hr 2 mg/kg every 12 hr mg/kg/day 0.2 mg/kg (loading dose), then 0.1 mg/kg/day 2 mg/kg (loading dose), then 1 mg/kg/day (5-day maximum) TABLE II Oral Opioids for Dogs Drug Butorphanol (1-, 5-, and 10-mg tablets) Codeine (30- and 60-mg tablets) Morphine (15-, 30-, 60-, and 100-mg sustained-release tablets) Morphine (10-, 15-, and 30-mg tablets) Dose mg/kg every 1 4 hr 1 2 mg/kg every 6 8 hr mg/kg every 4 8 hr mg/kg every 4 8 hr tial agonist) with an NSAID. The third step is administration of opioids, which are available as tablets, syrups, transdermal patches, suppositories, and injections (intravenous [IV], intramuscular, epidural). Dissociative anesthetics, antidepressants, and acupuncture may be combined with standard analgesic protocols to improve the comfort of patients suffering with neuropathic pain. 6 Nonsteroidal Antiinflammatory Drugs In recent years, the NSAID armamentarium has expanded in veterinary medicine. This category of drugs includes aspirin, acetaminophen, phenylbutazone, ketoprofen, etodolac, meloxicam, piroxicam, and carprofen. Improved safety profiles of the newer NSAIDs make them the first choice of many practitioners for controlling minor pain. NSAIDs approved for veterinary use in the United States are phenylbutazone, meclofenamic acid, carprofen, and etodolac. However, many other NSAIDs (e.g., flunixin, ketorolac, ketoprofen, meloxicam, tolfenamic acid) have been used to manage cancer pain. NSAIDs produce analgesic, antipyretic, and antiinflammatory effects and are formulated as injectables, tablets, and chewables (Table I). Many NSAIDs can produce adverse side effects (including gastritis, gastric ulceration, and liver or kidney damage). 3 The occurrence of these side effects may be related to accidental overdose, concurrent steroid use, and other factors that reduce gastrointestinal or renal blood flow (e.g., hypotension, shock, or anesthesia). Some veterinarians have recommended that a complete blood cell count and chemistry profile be conducted on each patient before administering NSAIDs and that these parameters be rechecked periodically every 3 to 6 months. 7 This will provide a normal blood work baseline and help detect any early signs of potential problems or adverse effects of NSAID usage. Multiple types of NSAIDs should not be administered simultaneously. If the first NSAID does not provide adequate pain relief after a short washout period, a second one can be tried on a short-term basis before moving to the next step of the WHO ladder in which an NSAID is combined with a weak opioid analgesic. As mentioned, the use of NSAIDs in combination with an agonist antagonist or partial-agonist opioid is the second level of analgesic therapy recommended for cancer pain. 6 For example, a patient may be coadministered an NSAID with codeine or butorphanol (Table II). The most commonly used commercially available formulation is aspirin with codeine, but other proprietary combinations (e.g., acetaminophen with a weak opioid) can be used in canine cancer patients (Table III). Practices that do not stock controlled substances can prescribe them through human pharmacies. If one NSAID combined with a partial-agonist or agonist antagonist does not provide adequate pain relief, other NSAID opioid combinations can

4 Managing Canine Cancer Pain Veterinary Technician March TABLE III Oral Opioid Acetaminophen Combinations for Dogs Drug Codeine (60 mg) + acetaminophen (300 mg) Oxycodone (5 mg) + acetaminophen (325 mg) Codeine (2.4 mg/ml) + acetaminophen (24 mg/ml elixir) Dose Based on codeine at 1 2 mg/kg every 6 8 hr Based on acetaminophen at mg/kg every 8 12 hr Based on codeine at 1 2 mg/kg every 6 8 hr be tried in order to enhance analgesia before moving up the WHO analgesia ladder. When agonist antagonist or partial-agonist NSAID combinations are no longer providing pain relief, full agonist opioids can be given. They are the most potent and highly effective analgesics and are relatively safe when given in appropriate dosages. For moderate to severe cancer pain, full agonist opioids are the drugs of choice. Side effects of full opioid agonists in dogs may include constipation and sedation. 8 Although respiratory depression is the most severe and life-threatening adverse effect, clinically significant impairment is not normally a concern with oral administration at recommended dosages. 9 However, because of the biologic variability, narcotics administered at any dose and by any route can cause respiratory depression. Technicians must be aware of this potential, and monitoring with pulse oximetry is advisable for hospitalized patients, especially those on parenteral narcotics. Dosages vary significantly between patients and can be gradually increased as the level of pain increases. Tolerance may also develop, requiring an increase in the effective dosage. Opioids The weaker opioids include codeine, butorphanol, buprenorphine, hydrocodone, oxycodone, and dihydrocodeine. Severe pain requires the use of full opioid agonists. The most common full opioid agonists used in veterinary medicine are morphine, hydromorphone, oxymorphone, and fentanyl. Morphine has a duration of effect of approximately 4 hours after intramuscular injection and 1 hour after IV injection and is available in tablet, capsule, syrup, injectable, suppository, and timedrelease capsule formulations (Table II). 3 Oxymorphone, a semisynthetic opioid, is approximately 10 times more potent than is morphine. 10 Increased potency does not mean it is more efficacious but that similar analgesic effects occur at a lower dosage. In dogs, oxymorphone appears to cause more sedation than does morphine at equianalgesic dosages and is significantly more expensive than morphine. Hydromorphone is a related drug that has many properties similar to those of oxymorphone but is less expensive. Both morphine and oxymorphone can be given epidurally to provide several hours of analgesia for caudal-orthopedic and soft-tissue procedures. Fentanyl is a short-acting, full opioid agonist with only a 0.5-hour duration of effect when given intramuscularly. It is often administered IV during surgery to supplement inhalant anesthesia. 8 A more recent and popular method of administering fentanyl is through a transdermal patch. 3 The adhesive patch consists of a reservoir of fentanyl and a slow-release membrane system. Dogs are usually clipped over the shoulder blade, and the patch is applied to the skin and covered with a bandage to protect it from dislodgment or inadvertent contact with humans. Adequate blood levels are usually not achieved for 12 to 24 hours. Because of the delay in achieving a therapeutic plasma concentration, administering a parenteral opioid (e.g., morphine) may be required for the first 12 to 24 hours. If possible, the patch should be applied 12 to 24 hours before an anticipated painful procedure. Fentanyl patches may provide up to 72 hours of pain relief in some canine patients. Side effects may include excitement, sedation, and miosis. Because fentanyl has a rapid clearance, these side effects are usually short lived once the patch is removed. The disadvantages of patches are variable absorption and difficulty with proper placement because they are designed for human use. There is also a potential for human abuse. Because small children could accidentally ingest or handle dislodged patches, caution should be used when contemplating the use of patches on pets owned by families with small children. 11 Because opioids are controlled substances, their use requires veterinarians to possess a Drug Enforcement Administration license and storage facilities and follow record-keeping requirements. Although this seems to be a major stumbling block for the use of opioids in some practices, effectively managing severe cancer pain without opioids is often difficult or impossible. Pain Management Strategies Strategies for managing pain are based on the concept of interfering with nociceptive processes. Nociception can be divided into transduction, transmission, and central nervous system processing of signals (modulation). When carried to

5 134 Veterinary Technician March 2001 Managing Canine Cancer Pain TABLE IV Local Anesthetics for Dogs Type of Block Drug Dose Brachial plexus Lidocaine a (2%) 1 ml/4.5 kg Bupivacaine b (0.5%) 1 ml/4.5 kg Infraorbital dental Lidocaine (2%), bupivacaine (0.5%) ml/site, depending on size of animal; Mandibular dental toxic dose should not be exceeded Infiltrative Lidocaine (2%), bupivacaine (0.5%) Total dose should be less than the toxic dose Intercostal Lidocaine (2%), bupivacaine (0.5%) ml/site; dose depends on site on animal; if blocking multiple sites, total dose should be kept below toxic dose Radial/ulnar/median Lidocaine (2%), bupivacaine (0.5%) Proximal block: ml/injection site; toxic dose should not be exceeded; distal block; ml/injection site a The toxic dose is 6.0 mg/kg. The toxic dose is 2.0 mg/kg. TABLE V Intravenous Constant-Rate Infusions for Dogs Drug Loading Dose Constant-Rate Infusion Morphine (15 mg/ml) mg/kg mg/kg/hr Fentanyl (50 µg/ml) 2 10 µg/kg 1 5 µg/kg/hr Ketamine (100 mg/ml) mg/kg mg/kg/hr Medetomidine (1000 µg/ml) 2 5 µg/kg 1 4 µg/kg/hr completion, this process leads to the conscious perception of pain. Administering analgesic drugs or techniques before painful stimuli initiate nociception is called preemptive analgesia and should be employed whenever possible because the body may respond to untreated pain by altering nociceptive processing, causing wind up or central-sensitization phenomena. 2 These processes are often present with such ongoing chronic pain syndromes as cancer. Because some cancer patients are already in a state of chronic pain of peripheral, central, or neuropathic origin (central sensitization), preemptive analgesia before a surgical procedure may help to prevent any further progression of this pain as well as acute pain associated with surgical trauma. In addition, because many cancer patients undergo numerous procedures during the course of their therapy, anxiety and fear can become a large part of the pain experience. Preemptive sedation and analgesia can also help to relieve some of the anxiety and stress for these patients. Consequently, premedication with sedatives and/or opioids is recommended before surgical or diagnostic procedures. Regional Nerve Blocks When performing surgical procedures in oncology patients, regional nerve blocks should be incorporated into anesthetic protocols whenever possible (Table IV). Patients undergoing a hindlimb amputation often benefit greatly from an opioid and/or local anesthetic lumbosacral epidural block after general anesthesia has been induced. Epidural administration is a safe and effective way to provide long periods of analgesia. To prevent muscle weakness anterior to the umbilicus, opioid epidurals can be used alone for analgesia when performing thoracotomies or forelimb amputations. Epidurals are typically administered after anesthesia has been induced but before surgery. Local or regional nerve blocks can also be employed when performing thoracotomies (intercostal block), maxillectomies (infraorbital block), mandibulectomies (mandibular nerve block), forelimb amputations (brachial plexus block), and lumpectomies (infiltration block). A brachial plexus block can be effective for patients undergoing digit amputation or a forelimb bone biopsy. Depending on the length of the procedure and the duration of action of the specific local anesthesia, a regional nerve block can be repeated when necessary. Severely painful procedures (e.g., medial sternotomies, amputations, rhinotomies, maxillectomies) may also require

6 136 Veterinary Technician March 2001 Managing Canine Cancer Pain Figure 1 Analgesia administration via constant-rate infusion using a syringe pump after a surgical procedure. Figure 2 Analgesia administration via constant-rate infusion using fluids after an amputation. intraoperative analgesic supplementation. IV morphine, fentanyl, oxymorphone, or hydromorphone can be given intraoperatively. 12 The use of IV opioids often lowers the amount of inhalant needed to complete the surgery while helping to control postoperative emergent pain. 13 When administering IV opioids, pulse oximetry should be monitored. After surgery, constant-rate infusions (CRIs) can be used with the help of a syringe pump (Figure 1) or by placing analgesic drugs in fluids (Figure 2) administered at an appropriate rate (Table V). Whatever the method of administration, the need for postoperative analgesic therapy should be anticipated. Analgesics Analgesics delivered by CRI are recommended for patients with anticipated severe postoperative pain (Table V). CRI is preferred because it can be fine-tuned to achieve the desired level of pain control. Patients with mild to moderate postoperative pain can often be treated effectively with intermittent IV, intramuscular, or subcutaneous injection. The key to using intermittent injections is to anticipate the need for more analgesic before the effect of the previous dose has completely worn off. 13 Conclusion Veterinary technicians can help implement a more aggressive and humane method of treating canine cancer patients. Understanding and recognizing cancer pain will help in categorizing and identifying the level of analgesic therapy needed. The WHO three-step ladder can be used to initiate the proper level of analgesic intervention. Providing preemptive analgesia and being aggressive in managing pain in canine cancer patients will greatly improve their overall care and disease outcome. The goal of providing compassionate care is both a noble cause and a rewarding experience that all veterinary technicians can readily embrace. References 1. Schweitzer A: On the Edge of the Primeval Forest. New York, Macmillan, 1931, p Thurmon JC, Tranquilli WJ, Benson GJ: Perioperative pain and distress, in Lumb and Jones Veterinary Anesthesia, ed 3. Baltimore, Lippincott Williams & Wilkins, 1996, pp McKelvey D, Hollingshead KW: Analgesia, in Small Animal Anesthesia and Analgesia, ed 2. St. Louis, Mosby, 2000, pp Biebuyck JF: The metabolic response to stress: An overview and update. Anesthesiology 73: , Kanner R: Cancer pain syndromes, in Pain Management Secrets. Philadelphia, Hanley and Belfus, 1997, pp Tranquilli WJ, Grimm KA, Lamont LA: Managing chronic pain in dogs and cats, in Pain Management for the Small Animal Practitioner. Jackson, WY, Teton NewMedia, 2000, pp Tranquilli WJ, Grimm KA, Lamont LA: Nonsteroidal antiinflammatory drugs, in Pain Management for the Small Animal Practitioner. Jackson, WY, Teton NewMedia, 2000, pp Thurmon JC, Tranquilli WJ, Benson GJ: Pharmacology, in Essentials of Small Animal Anesthesia and Analgesia. Baltimore, Lippincott Williams & Wilkins, 1999, pp Papich MG: Pharmacologic considerations for opiate analgesic and nonsteroidal antiinflammatory drugs. Vet Clin North Am Small Anim Pract, Management of Pain. Philadelphia, WB Saunders Co, 2000, pp Thurmon JC, Tranquilli WJ, Benson GJ: Preanesthetics and anesthetic adjuncts, in Lumb and Jones Veterinary Anesthesia, ed 3. Baltimore, Lippincott Williams & Wilkins, 1996, pp Carroll GL: Analgesics and associated drugs and supplements, in Small Animal Pain Management. Lakewood, CO, AAHA Press, 1998, pp Pascoe PJ: Opioid analgesics. Vet Clin North Am Small Anim Pract, Management of Pain. Philadelphia, WB Saunders Co, 2000, pp Pascoe PJ: Perioperative pain management. Vet Clin North

7 Managing Canine Cancer Pain Veterinary Technician March Am Small Anim Pract, Management of Pain. Philadelphia, WB Saunders Co, 2000, pp About the Author Ms. Cordell is affiliated with the University of Illinois Companion Animal Pain Management Center, Urbana, and is featured on this month s cover (see more about her on p. 160).