pain management in cancer

Management of pain comprises an integral part of successful treatment for a wide variety of human diseases. This is particularly true for patients with malignancies, where the physiologic and psychological effects of pain may have much greater impact. While advances in the understanding and treatment of pain in animals have lagged some years behind similar progress in the human field, it is now widely and increasingly accepted that appropriate therapy for pain must accompany primary treatment of many animal diseases including cancer.

Incidence

Approximately 50-80% of human patients with advanced cancer experience pain during the course of their disease. The majority of these patients will not obtain satisfactory relief. This fact constitutes a major problem in the medical field, because unrelieved pain can significantly diminish the patient's quality of life. Among the factors that may contribute to inadequate pain management are the overriding fears of addiction, health care professionals' lack of knowledge about pain medication and new pharmacological interventions, and the lack of confidence in the efficacy of behavior techniques. Similar factors are known to exist in the veterinary medical community and are not limited in application to pets with cancer.

Cancer pain can be acute or chronic. Acute pain generally results from tissue damage and is of limited duration. The physiological effects (e.g. tachycardia) observed result from stimulation of the autonomic nervous system. Once the cause of pain has been identified, it can be successfully treated and is often completely eradicated. Chronic pain, on the other hand, is persistent, usually greater than 3 months in duration. Because the pathology or cause of the pain cannot be altered, the nervous system eventually adapts and ceases to be hyperactive; the pain may then manifest itself as depression or anxiety.

Causes

The severity and prevalence of pain that cancer pets experience depends on many factors, including the site and stage of the disease and the location of metastases. Cancer-related pain can result from the disease process or cancer therapy. The most common causes pain from direct tumor involvement are metastatic bone disease, nerve compression or infiltration, and hollow viscus (e.g. bowel) involvement resulting in obstruction. All of the major treatment modalities may also cause pain syndromes. Additionally, pets may have pre-existing chronic pain that is not associated with either the disease or its treatment.

Pain affects each pet differently, depending upon factors such as age, perception, pain threshold, and past experiences with pain. Insomnia, fatigue, and anxiety can lower the pain threshold, while rest, sleep and diversion can raise it.

Pain Assessment

An accurate assessment of the pet's pain experience provides a basis for an evaluation of various pain management techniques. A comprehensive assessment includes information about the following dimensions of pain: location, intensity, factors influencing it occurrence, observed behaviors during pain, psychosocial variables (i.e., attitudes, situational factors), effects of pain, effects of therapy, and patterns of coping. A variety of pain assessment tools have been developed for use in humans, ranging from simple self-reports about pain intensity to detailed descriptive information. In veterinary medicine, assessment of chronic pain may be enhanced through the pet owner's use of a pain diary, in which descriptions of the characteristics of the pain and the effectiveness of management techniques can be recorded.

Pain Management

The goal of pain management is not only relief from pain, but also the maintenance of the pet's normal quality of life. All methods of pain management attempt to either control the cause of the pain or alter the pet's perception of it.

Although pain management techniques are many and varied, therapeutic approaches can be classified as either pharmacologic or nonpharmacologic. Pharmacologic pain control involves the use of analgesics, as well as other medications that potentiate the analgesics' effects or modify the pet's mood or pain perception. Nonpharmacologic approaches include behavioral techniques, radiation, surgery, neurological and neurosurgical interventions, and tradition nursing and psychosocial interventions, the latter measures attempting to promote comfort and evaluate the effectiveness of the therapy. Because of the complex nature of cancer-related pain, successful management usually involves a combination of techniques.

Cancer pain management in the geriatric pet calls for special considerations. Aging pets are at an increased risk for drug reactions, because drug adsorption, distribution, metabolism, and elimination change with age, disease status, and medication interactions.

Pharmacologic Management

Veterinary care personnel must aggressively manage acute pain in the cancer pet with medication to return the pet to a pain-free state as soon as possible. Once the pain is relieved, the pain medication is decreased to the lowest dosage or mildest analgesic that will maintain the pain-free state. When the pain cycle is broken, pets can be sustained on minimal amounts of pain information.

Chronic pain, however, requires very different medication management. For example, a pet with chronic pain is usually started on a non-narcotic analgesic and moves to a narcotic as more effective pain control is needed.

The World Health Organization (1987) states that "analgesic drugs are the mainstay of cancer pain management" and advocates a three-step "analgesic ladder" for decision-making. This schema is appropriate for use in veterinary medicine. Step one includes the use of a non-opiod drug with or without an adjuvant drug (e.g. aspirin, carprofen + misoprostil). If pain persists or increases, pain management moves to step two, a weak opioid plus a non-opioid, with or without an adjuvant drug (e.g. acetaminophen, codeine +/- carbamazepine). If pain persists or increases, pain management moves to step three, a strong opioid, with or without a non-opioid, with or without an adjuvant drug (e.g. morphine +/- acetaminophen +/- dexamethasone).

Non-narcotic pain agents are best used for mild cancer pain. This category includes aspirin, acetaminophen, and non-steroidal anti-inflammatory drugs (NSAIDS). Non-narcotic agents may also be used to potentiate the effect of narcotic analgesics in pets with severe pain. However, these agents have a ceiling effect: increasing the dosage beyond a certain point doesn't produce additional pain relief. NSAIDS reduce the production of prostaglandin by inhibiting cyclooxygenase (COX). Their analgesic properties are primarily due to their anti-inflammatory effects. Common side effects of these compounds include gastrointestinal and renal toxicity. The newer agents in this class include carprofen and etodolac. These compounds have a favorable COX1:COX2, which in theory will reduce the possible side effects associated with this class. Piroxicam is also included in this class. Other NSAID’s that may be useful in the small animal patient include ketoprofen and ketorolac.

Narcotic analgesics (opioids) are used for the treatment of moderate to severe cancer pain. They are categorized as either narcotic agonist or narcotic agonist-antagonist drugs. This is the largest and perhaps most valuable class of analgesic agents. These agents interact with specific receptors in the brain and spinal cord and are very efficacious. The side effects associated with this class are usually minimal with respiratory depression, bradycardia and hypotension being the most concerning. Using opiate antagonists can alleviate life threatening side effects. The opioid agents most commonly used include morphine, butorphanol, fentanyl and buprenorphine. Innovative modes for administration include continuous rate infusion, epidural administration and the transdermal fentanyl delivery system (patch).

One model explaining the actions and effects of the opioids, the Multiple Opioid Receptor Theory, proposes that narcotic agonist drugs, such as morphine and codeine, bind with specific opiate receptor sites. There are three kinds of receptor sites, or portions of the nerve cell to which a drug can bind: the mu receptor associated with analgesia and respiratory depression; the kappa receptor with sedative effects; and the sigma receptor with psychomimetic effects.

Although the Multiple Opioid Receptor Theory is still evolving and does not yet completely explain narcotic analgesia, pure narcotic agonists such as morphine and codeine are thought to occupy the mu receptor without antagonizing activity at the other receptor sites. Narcotic agonists-antagonists occupy the kappa receptor for pain relief which also antagonizing the effects of pure agonists at the mu receptor. Three agonist-antagonists are butorphanol, nalbuphine, and pentazocine.

Adjuvant analgesic drugs are also used to treat cancer pain. This group includes amphetamines, anticonvulsant agents, phenothiazines, tricyclic antidepressants, steroids, antihistamines, and levodopa. Although their exact mechanisms of action for pain relief are not well understood, these drugs relieve pain when used alone or in combination with other non-narcotics or narcotics.

Pain medication may be given by the following routes: orally, rectally, subcutaneously, intramuscularly, intravenously, intrathecally, and epidurally. Conditions such as thrombocytopenia, neutropenia, and duration of a medication's effect must be taken into account when selecting the route. The peak of a drug's effect is largely dependent on the route of administration. Oral medications usually peak in 2 hours, intramuscular drugs in 1 hour, and intravenous drugs in 15-30 minutes. Duration of effect varies widely and should be carefully considered.

The schedule for administering analgesics appears to be an important factor in their effectiveness. Research shows that around-the-clock (ATC) rather than as needed (PRN) administration of analgesics is more effective in the control of chronic pain. In many cases, doses of analgesics may be decreased with ATC scheduling because the pain intensity is consistently less.

Pets with cancer may be under medicated for their pain because veterinary care personnel may believe that cancer pets usually develop a tolerance to the effects of opioids rather than an addiction. Tolerance to narcotics can occur at anytime and requires increasing doses to produce the same level of analgesia. Pets also develop tolerance to the serious side effects of narcotics (e.g. sedation, respiratory depression) at the same rate as tolerance to analgesia, so they can accept larger doses of narcotics without overdosing.

Analgesics and Dosages Available for Use in Dogs and Cats.

Narcotic Analgesics in Dogs

Morphine, 0.25 to 5.0 mg/kg IM or SQ every 4 hours

Oxymorphone, 0.2 mg/kg IM, SQ or IV every 6 hours

Butorphanol, 0.4 to 0.6 mg/kg PO, IM, SQ or IV every 4-8 hours

Nonsteroidal Anti-inflammatory Drugs in Dogs

Aspirin, 10 to 25 mg/kg PO every 8 hours

Phenylbutazone, 10 to 25 mg/kg PO every 8-12 hours

Carprofen, 1mg/lb, PO every 24 hours

Piroxicam, 0.3 mg/kg PO every 24 hours

Narcotic Analgesics in Cats

Morphine, 0.1 mg/kg IM, SQ or IV every 4 hours

Oxymorphone, 2 to 4 mg/kg IM every 2 hours

Butorphanol, 0.4 to 0.8 mg/kg PO, IM or IV every 3-8 hours

Nonsteroidal Anti-inflammatory Drugs in Cats

Aspirin, 10 to 20 mg/kg PO every 48-72 hours

Piroxicam, 0.3 mg/kg PO every 72 hours

Other Analgesic Methods

Like insulin, pain medications can be administered on a continuous basis into subcutaneous tissue through a small-gauge butterfly needle taped in place.

Narcotics can also be continuously infused epidurally or intrathecally with the placement of an indwelling intrathecal catheter. This technique is associated with fewer central nervous system effects than systemic administration of narcotics. The major problem observed with intraspinal delivery of narcotics is respiratory depression.

Fentanyl patches are labeled for managing chronic cancer pain in humans, specifically people who cannot tolerate oral medications. The efficacy and convenience of this delivery system have generated interest in the use of this treatment for postoperative pain in both human and veterinary medicine. Fentanyl is not approved for use as a single agent in dogs and cats. The patch consists of a gel matrix containing fentanyl, a lipid-soluble opiod that diffuses through the skin and achieves blood concentrations high enough to produce analgesia. A variety of sizes deliver 25, 50, 75, and 100 m g/hr, with the delivery rate a function of the surface area of the patch. Patches are designed to provide continual release for about 72 hours. In dogs, there appears to be a 6 to 12 hour latency to achieve plasma concentrations associated with analgesia and up to 24 hours for plasma concentrations to reach a plateau. The principle advantage of fentanyl patches is provision of "hands-off" analgesia. One disadvantage is body temperature, fever or other causes of elevated body temperature (laying on a heating pad) can increase drug delivery substantially. To circumvent this, many apply the patch to the dorsal neck and secured with a light wrap. For cats and small dogs, a 25 m g patch is used. For medium-sized dogs (5 to 20 kg) a 50 m g patch is used. Larger dogs (20 to 30 kg) may require a 75 m g patch and giant dogs (> 30 kg) may require the 100 m g patch. Side effects may include euphoria (in cats) and increased appetite. Deleterious side effects may include agitation, dementia, heightened response to the environment and mild sedation or ataxia. However, side effects, when used properly, are uncommon.

Nonpharmacologic Management

Nonpharmacologic pain management approaches include surgery, radiation, neurological and neurosurgical interventions, behavioral techniques, and nursing interventions.

Both radiation therapy and surgery may be used for cancer pets with enlarging tumors or advanced disease to decrease the tumor mass and reduce painful compression of adjacent structures. These procedures are conducted for palliative purposes only.

Neurosurgical interventions are generally reserved for pets that cannot obtain adequate relief with analgesics, palliative radiotherapy or surgery. Most neurosurgical procedures involve interruption or destruction of the pain pathway at some point along the route to the brain or in the brain itself. The risks and benefits of these techniques must be discussed thoroughly with pet owners because, in many cases, the pet will have residual motor or sensory deficits.

Neurostimulation techniques are base on the "gate-control" theory of pain. Some research indicates the pathways in the spinal cord can accommodate only a certain amount of stimulation before sensory overload occurs. With neurostimulation, competitive non painful (e.g. vibratory) impulses are used to block the transmission of painful impulses along nerve pathways. Neurostimulation can be applied transcutaneously (as occurs with transcutaneous electrical nerve stimulation, or TENS) or via surgically implanted electrodes in the spinal cord.

Behavioral techniques such as relaxation, distraction, biofeedback, imagery, and hypnosis are now widely used to manage cancer-related pain in people. In general, behavioral techniques are designed to alter the response to pain by fostering a deep relaxation and a shifting of attention to something other than the pain. These approaches, although controversial and likely ineffective for use on most pets, should be used in combination with, and not as a substitute for, appropriate medications. Care must be taken not to misinterpret the efficacy of these techniques as an indication that the pet is not really experiencing pain.

Pets with Cancer

by Kevin A. Hahn, D.V.M., Ph.D., D.A.C.V.I.M. (Oncology)