Understanding and recognizing cancer pain in dogs and cats

Pain is common in people with cancer, with the reported incidence varying between 30% and 90%; a higher frequency of pain is reported with more advanced disease.1-4 Pain negatively affects quality of life as well as many important physiological functions, so controlling it in all patients should be a top priority. It is said that more than 70% of human patients suffering from cancer pain can be relieved with an opioid-based regimen.1-4

Similar data on cancer pain and its treatment in companion animals do not exist, but a conservative estimate is that at least 50% of veterinary cancer patients experience some degree of pain. While certain veterinary patients with cancer pain may be relieved adequately by treating the underlying malignancy, other patients will require symptomatic therapy to improve their quality of life, the primary objective of veterinary oncology.

To adequately manage cancer pain in dogs and cats, it must be recognized early, and patients should be frequently assessed for pain by both the attending clinician and the pet owner. Many barriers remain for the appropriate treatment of cancer pain in animals, including its poor recognition with many neoplastic conditions, the difficulty of objectively assessing the degree of pain, inappropriate reassessment once therapy is implemented, fear of using or lack of knowledge about the analgesic arsenal, and poor communication with the client.5-12

PAIN TERMINOLOGY AND A BRIEF PHYSIOLOGY OVERVIEW

Pain can be described in many different ways, based on various criteria.1,2,5-7,10-12 When classified according to temporal aspects, pain is described as acute, chronic, or intermittent. When classified by intensity, pain can be mild, moderate, severe, or excruciating. Another classification is by origin or type of pain, with somatic, visceral, and neuropathic pain having different causes, associated symptoms (as described by human patients), and response to therapeutic intervention. These three types of pain may occur alone or in combination in the same patient.1 Finally, cancer pain can be a direct result of the primary tumor (e.g. invasion, tissue destruction, pressure), a result of distant metastases (e.g. bone, meninges, pleura), a result of painful paraneoplastic syndromes (e.g. hypertrophic osteopathy, peripheral neuropathies), or the result of either diagnostic (e.g. biopsies) or therapeutic procedures (e.g. aggressive surgery, chemotherapy, radiation therapy). Pain in patients with cancer may also be secondary to unrelated conditions common in older animals (e.g. osteoarthritis).

Nociception is the transduction, conduction, and processing of afferent nerve signals generated by stimulated nociceptors, resulting in the perception of pain.2,6,11 Signals from noxious stimuli (mechanical, thermal, or chemical) are transmitted mainly through two types of nerve fibers: the small myelinated A delta fibers and the small unmyelinated C fibers.2,6,11 Their nerve endings are located in the skin, subcutaneous tissues, periosteum, joints, muscles, and viscera.6 The larger myelinated A beta fibers normally transmit non-noxious stimuli, such as touch, vibration, pressure, movement, and proprioception.6 However, the non-noxious input from these fibers may be incorrectly processed in an altered central nervous system, resulting in the perception of pain (allodynia).2,6,11 The A delta and C fibers enter the dorsal horn of the spinal cord through the dorsal root ganglia, where they synapse with second-order neurons of the gray matter.2,6,11,12 Some integration and modulation may take place in the dorsal horn, through interactions with excitatory and inhibitory interneurons. The resulting nociceptive information is carried to the brain through the spinothalamic tracts, where it can be integrated, processed, and recognized in multiple areas of the brain.2,6

While pain will normally follow a noxious stimulus, certain alterations occasionally result in increased sensitivity to non-noxious stimuli (hyperesthesia), an exaggerated painful response to mildly noxious stimuli (hyperalgesia), or an abnormal painful response to non-noxious stimuli (allodynia).2,6,11 Allodynia and hyperalgesia are most commonly encountered in conditions of untreated or undertreated chronic pain and result from peripheral and central alterations in the transmission, modulation, and integration of nociceptive stimuli. Breakthrough pain occurs when controlled chronic pain suddenly becomes more severe (flare-up).2,6,10,11 Various factors may lead to prolonged and exaggerated pain (hyperalgesia or allodynia). Examples are peripheral sensitization by various substances including prostaglandins, histamine, serotonin, bradykinin, and cytokines (collectively termed the inflammatory soup by certain authors6); central sensitization by other modulators, including glutamate and substance P; and decreased inhibitory modulation.2,6 The term wind-up refers to the temporal summation of painful stimuli in the spinal cord. It arises when chronic pain is untreated or undertreated and is mediated by N-methyl-D-aspartate (NMDA) receptor activation of the C fibers.1,2,6,11,12

ANALGESIA PRINCIPLES AND THE WHO LADDER

An understanding of the principles of analgesia is fundamental to developing a pain control program. Preemptive analgesia is the administration of analgesic therapy before a patient is exposed to noxious stimuli. The goals are better pain control, lower anesthetic and analgesic needs, a smoother recovery, and a lower risk of establishing a chronic pain state.6,11,12 Another principle essential to pain control is multimodal analgesia. This concept takes into account the complexity of pain transmission and uses various methods or classes of drugs with different mechanisms of action to control pain.6,8,11,12 The goal is better pain control than if just a single analgesic agent was used. If we merge both concepts, it becomes obvious that preemptive analgesia is best achieved by combining drugs of various classes, such as a nonsteroidal anti-inflammatory drug (NSAID) with an opioid and an alpha2 agonist, in addition to the use of a local or regional block with a local anesthetic.

The World Health Organization (WHO) has proposed a three-step analgesic ladder for controlling mild, moderate, and severe pain in people.1-3,5-12 With that model, in which adjuvant therapy can be added at any level, mild pain is treated initially with nonopioid drugs, generally NSAIDs. If pain persists after treatment with a nonopioid or if the pain is moderate, a weak opioid (e.g. codeine or tramadol) can be added on the second step. If pain is not controlled with that combination or if the pain is severe, stronger opioids, preferably full mu agonists, are used for the third step of the ladder. It has recently been recommended that two more steps be added to the ladder for patients with advanced, difficult-to-control cancer pain.3 Techniques such as intrathecal administration of opioids, neurostimulation, and peripheral neuroablation can be introduced as a fourth step, and central neuroablative procedures can be added as a fifth step.3 Others have recommended using an analgesic reverse pyramid for certain veterinary patients.8,9 With this approach, when chronic pain is present and central sensitization is suspected, a multimodal approach to reverse such changes is used first, and then the doses of analgesics are gradually reduced or weaker classes of analgesics are given.8,9

RECOGNIZING PAIN

One of the biggest problems in controlling pain in veterinary patients is its recognition by clinicians. Since our patients do not communicate what they feel to us, at least not in words, we must use other means to adequately detect pain. One essential component of pain recognition is adequate communication with the owner.5,6,8-12 Owners know their pets better than anyone else and can recognize abnormal behavior, which is a common and reliable indicator that something is wrong.13 Always believing owners who think their pets may be in pain is an important first step, and involving them in periodic reassessment is equally crucial. In general, a simplistic rule applies when clinicians are faced with patients that may be in pain: If an animal seems to be in pain, then it most likely is. A clinically useful way to confirm the presence of pain is to treat the patient for pain and observe clinical improvement.

Certain physiological parameters, such as heart and respiratory rates, body temperature, pupil size, and blood pressure, have been used as surrogate measures of pain in veterinary patients, but they do not appear to provide adequate specificity because they are influenced by other psychologic factors and stressors.8,14 Clinically, behavior appears to provide a better estimate. Observing movement, posture, grooming, appetite and thirst, licking of the painful area, drooling or dysphagia, vocalization, and growling or hissing when approached may provide semiobjective information on the degree of pain a given patient is experiencing.5,6,8-10,13,15-17

Few objective methods of pain measurement exist. In veterinary studies, researchers have done force plate analysis, used a pressure-sensing floor mat (MatScan System—Tekscan Inc.) to detect gait abnormalities, or used pressure algometers, instruments that measure the pressure required to elicit pain. Investigators currently use these methods of measuring pain in a research setting. The clinical application and usefulness of such instruments for determining the degree of pain in a single patient with a given condition is uncertain and awaits further study.

Figure 1. An example of a numerical rating scale, with a gradation from 0 (no pain) to 10 (worst possible pain).

The American Animal Hospital Association (AAHA) has published standards that recommend pain be assessed in all animals, regardless of the presenting complaint. To comply, each practice team needs to adopt a system for measuring pain in a clinical setting. Various observer pain scales have been used to estimate pain in animals.5,6,10-12 The most common types are the visual analog scale (VAS) and the numerical rating scale (NRS) (Figure 1).16,17 Both scales are represented by a horizontal line, generally 100 mm long. The NRS has gradations from 1 to 10 (or from 1 to 100), with 1 equaling no pain and 10 (or 100) equaling the worst possible pain. With the VAS, the distance from the end to the mark is measured and recorded as the pain score. The VAS method has more subjectivity and interobserver variation than does the NRS, which often incorporates descriptive criteria in many numeric intervals (physiological and behavioral).6,11 Both systems have many weaknesses. A pain assessment system that is readily understood, is easily used, and produces repeatable results is more important than the type of scale used. The pain score should be recorded upon initial examination of all patients and regularly reassessed during therapy.

Table1. Examples of Tumors that Can Cause Pain in Veterinary Patients

WHICH VETERINARY CANCERS CAUSE PAIN?

It seems obvious that primary bone tumors, the most common being appendicular osteosarcoma, will cause a marked degree of pain (Figures 2A & 2B). However, it is important to understand that any tumor type can be associated with pain. Pain can be due to invasion and destruction of surrounding tissues, including nerves and bones. It can also result from regional or distant metastasis to sites such as bone, the body cavity (serosal surfaces), or the meninges.

Figure 2A. This 4-year-old Labrador retriever has obvious signs of pain, including a nonweightbearing lameness of the left hindlimb, associated with a large mass of the distal femur.

Additionally, tumors may cause pain by stretching the capsule of certain visceral organs or by causing flow obstruction (in the biliary, urinary, or gastrointestinal tract). Finally, a tumor can become painful because of inflammation or secondary infection. Table 1 lists examples of pain caused by various tumors in veterinary patients.

Figure 2B. A lateral radiograph confirms a destructive lesion of the distal left femoral metaphysis, with both lytic and blastic changes, suggestive of a primary bone tumor.

WHICH DIAGNOSTIC OR THERAPEUTIC PROCEDURES CAUSE PAIN?

Any mildly invasive diagnostic or therapeutic procedure can cause pain in veterinary patients with cancer. Some routinely performed staging procedures, such as soft tissue biopsies (Tru-Cut, punch, wedge), bone marrow aspiration or biopsy, and bone biopsies (Figure 3), predictably result in mild to moderate pain. This pain can be treated with analgesics and local blocks preemptively and a nonopioid analgesic postoperatively. More aggressive surgeries usually require more aggressive preemptive analgesia, such as regional blocks, epidural or interpleural analgesia, and the use of postoperative opioids, in addition to nonopioid drugs. Such surgeries include amputation, hemipelvectomy, thoracotomy, radical mastectomy, large en bloc tumor resection with dorsal spinous processes, mandibulectomy, and maxillectomy (Figure 4). These more aggressive pain control measures should be standard rather than be given on an as-needed basis. With a good pain control program, it is common to observe that patients appear more comfortable after radical surgeries to remove painful invasive tumors.

Figure 3. Obtaining a bone biopsy sample of a Rottweiler's distal tibia by using a Jamshidi biopsy needle. This procedure is moderately to severely painful, and a preemptive multimodal analgesic protocol should be used.

While chemotherapy is not thought to be painful per se, it occasionally results in painful side effects. Examples include colitis from doxorubicin, constipation from vincristine in cats, sterile hemorrhagic cystitis from cyclophosphamide, pancreatitis from various agents, and a burning sensation at the catheter site during dacarbazine infusion (low pH).7,12,18,19 In people, painful peripheral neuropathies are known to occur at a certain frequency with drugs such as vincristine, cisplatin, and the taxanes, but this has not been well-described in cats and dogs.1,2 Perivenous extravasation of certain chemotherapy agents, including vincristine, doxorubicin, vinblastine, mechlorethamine, and dactinomycin, causes painful tissue destruction, sometimes severe enough to necessitate surgical débridement.1,2,7,12,18 Such complications should be avoided by placing clean-stick catheters in undamaged veins immediately before administering these known vesicants.

Figure 4. Less than 24 hours after a segmental maxillectomy for an oral osteosarcoma, this German shepherd appears relatively pain-free, thanks to preemptive multimodal and postoperative analgesia.

Surgically implanted vascular access ports in the jugular veins of patients requiring repeated intravenous therapy over weeks to months are an attractive option to avoid pain from extravasation or unnecessary stress from multiple venipunctures and catheter placement (Figure 5). Vascular access ports are standard-of-care for people receiving chemotherapy. Their use in veterinary oncology is becoming more common, and now ports specifically designed for companion animals of various body sizes are available (Companion Port—Norfolk Vet Products).

Figure 5. A vascular access port (left) and the specifically designed right angle Huber infusion set.

Finally, radiation is a valuable therapeutic tool, but normal tissue toxicity may result in moderate to significant pain. Mucositis is an early radiation side effect that commonly occurs with curative-intent protocols that involve daily treatments over four weeks; it can be fairly painful.1,2,7,12,19,20 It typically develops toward the end of the treatment (in the third and fourth weeks) and may persist for a few weeks after radiation is discontinued. The most common sites of painful radiation-induced mucositis are the mouth (stomatitis, glossitis) when oral or sinonasal tumors are irradiated and the large intestine (colitis, proctitis) when pelvic irradiation is performed.7,20 Moist dermatitis is occasionally observed and can also be fairly painful (Figure 6).7,20 Computerized planning and precise analysis of dose distribution help prevent severe early radiation side effects to normal tissues. Occasionally, pain may result from late side effects of radiation therapy, including osteoradionecrosis causing pathologic fracture and peripheral neuropathies.20

Figure 6. This Boxer cross is recovering from radiation-induced acute moist dermatitis, two weeks after the end of a full course of radiation therapy for an incompletely excised infiltrative lipoma. At this stage, the therapy-induced lesion is no longer painful.

ACKNOWLEDGEMENTS

The authors thank Drs. Kurt A. Grimm and William J. Tranquilli for critically reviewing this manuscript.

Louis-Philippe de Lorimier, DVM

Timothy M. Fan, DVM, DACVIM (internal medicine, oncology)

Department of Veterinary Clinical Medicine

College of Veterinary Medicine

University of Illinois

Urbana, IL 61802

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