Elements of Oncology:Strategies for Managing Cancer Pain in Dogs & CatsPart1: Pathophysiology & Assessment of Cancer Pain
Nicholas Rancilio, DVM, Diplomate ACVR (Radiation Oncology); Jean Poulson, DVM, PhD, Diplomate ACVR (Radiation Oncology); and Jeff Ko, DVM, MS, Diplomate ACVAA
Welcome to Elements of Oncology—a column that will address the many components of diagnosing, managing, treating, and monitoring veterinary cancer patients. This column begins with a series of two articles that describe strategies for cancer pain management in dogs and cats, with an overall goal of raising awareness among the veterinary community about treating cancer pain early and recognizing that cancer pain can be quite different from other types of acute or chronic pain.
Cancer pain is one of the most common, overlooked, and undertreated comorbidities in human patients. In a recent retrospective study of more than 1000 patients presenting to a radiation oncology service for palliative treatment of bone metastasis, over 25% had pain that was inadequately managed before initiation of radiation therapy.1
Other surveys and systematic reviews of the human literature estimate that the prevalence of inadequate pain management among all humans with cancer approaches 50%.2-4 Although the incidence of untreated or undertreated cancer pain among veterinary patients is unknown, it is most likely similar or even higher.
Unrecognized or undertreated pain that progresses from acute to chronic in oncology patients can lead to treatment failure, death,5 or premature euthanasia despite treatment of the cancer itself. The longer a cancer patient’s pain is ongoing, the more difficult it becomes to successfully treat both the underlying cancer and the pain.
CHALLENGES OF PAIN MANAGMENT
No published statistical data specify why veterinary patients are undertreated for cancer pain, but clinical experience suggests several reasons:
- Cancer pain generally progresses slowly until the patient’s physiologic function is severely affected.
- As the cancer progresses and becomes more advanced, pain may go undetected for some time before owners notice deficits in function or daily routine.
- Over time, factors that contribute to the progression of acute pain result in chronic pain (Table 1), which becomes more difficult to treat if no intervention occurs.
The insidious onset of cancer pain is further complicated by the fact that veterinary patients cannot verbally communicate their levels of pain. Attending veterinarians and pet owners must evaluate the patient and categorize the level of pain when, and even before, the patient shows clinical signs because, by the time discomfort is recognized, the animal may already be in severe pain that is difficult or impossible to treat.
Further challenges to managing cancer pain in veterinary patients include the:
- Wide variability in training, experience, and comfort among practitioners for assessing veterinary oncology patients and treating their disease
- Limited pharmacologic options for managing cancer pain
- Hesitation many practitioners face when considering whether to add pain medications to therapy that already includes multiple drugs
- Lack of a universally agreed-upon standard of care—among general practitioners and even oncology specialty groups—for active management of cancer pain in veterinary medicine.
KEYS TO SUCCESSFUL MANAGEMENT
Successful management of cancer pain in veterinary oncology requires knowledge of the following 3 key areas:
- Basic understanding of the pathophysiology of cancer pain
- Early recognition of the clinical signs of cancer pain and understanding of the importance of preventing or delaying chronic pain development
- Proper concurrent pharmacologic pain management during appropriate treatments for the underlying cancer.
Successful cancer pain management also requires a clear strategy of regular (set intervals during treatment) evaluation of the animal’s pain and quality of life by the veterinarian and client.
PATHOPHYSIOLOGY OF CANCER PAIN
In the early stages of cancer, nerve fibers and nociceptors involved in cancer pain are similar to those involved in acute pain and other types of chronic pain. As the cancer progresses, however, the extent of nerve involvement and the pain mechanisms in abnormal tissues can be quite different from those seen with other types of pain.
Cancer pain can be classified into 2 general categories:
- Endogenous chemical irritation in the tumor microenvironment6,7
- Compression and inflammation resulting from direct tumor invasion of normal tissues.8
The pain inflicted by abnormal cellular proliferation is very different from chronic pain induced by other conditions, such as osteoarthritis. Table 2 summarizes the origin of the sensory nerves associated with certain tumor types, together with levels of pain in dogs and cats.
The Behavior of Cancer
Cancer begins as a single abnormal cell, with driving mutations that cause the cell to divide in an unregulated manner. These driving mutations are generally loss-of-function mutations of the critical pathways in the cell cycle that regulate growth, division, and secretion of growth-inhibiting factors.
Cancer cells as a group share several characteristics, including:9,10
- Ability to invade normal tissues and metastasize to distant organs
- Unlimited capability to divide
- Resistance to the normal mechanisms of cell death
- Evasion of the body’s normal immunologic defenses
- Ability to secrete growth factors and hormones that stimulate cellular proliferation.
Endogenous Chemical Irritation
Microenvironment Irritation. In cancer cells, driving mutations that cause unrestrained cellular growth may result in the release of neurotropic growth factors, such as nerve growth factor (NGF). NGF regulates the growth and sensitivity of neurons important for the sensation of pain.11 Overabundance of peripheral sensory neurons within, and adjacent to, the tumor may result in:
- Increased pain sensitivity
- Decreased pain threshold
- Development of long-lasting chronic pain.
Experimental models of cancer-induced bone pain in animals have found that antibody blocking of NGF results in decreased metastatic bone pain,12 and a monoclonal anti-NGF antibody developed for dogs is under clinical investigation.13 Use of canine anti-NGF monoclonal antibody in an experimental model of pain showed significantly reduced lameness scores compared with a placebo.13 These studies provide evidence that large tumors with rapid rates of growth can also induce pain as a result of abnormal chemical mediators secreted by the tumor into the microenvironment.
Tissue Hypoxia. In addition to chemical mediators in the microenvironment, cancer cells with limitless replicative potential have abnormally rapid growth rates that result in abnormal tissue expansion, innervation, and disorganized tumor vasculature. Disorganized tumor tissues and vasculature result in tissue hypoxia and nutritional deprivation, which trigger further release of various harmful chemicals and chemotactic factors that can lead to peripheral and central pain sensitization.11,12
A tumor need not be large in order to cause regional tissue hypoxia because the maximum distance oxygen can diffuse is limited to 70 micrometers. This short diffusion distance prevents effective oxygen delivery beyond this radius from often sparse capillaries in the tumor microenvironment. Abnormal tumor vasculature lacks normal physiologic mechanisms of autoregulation; capillaries and arterioles within the tumor vasculature cannot constrict or dilate in response to lowered or altered blood flow, furthering the cycle of localized hypoxia.14
Localized hypoxia of the tumor microenvironment leads to tissue acidosis, which:
- Lowers the sensitivity threshold of peripheral sensory afferents and
- Can lead to allodynia and hyperalgesia.
Increased expression of acid-sensing ion channels in the acidic tumor microenvironment may result in:7
- Peripheral pain sensitization and
- Lower pain threshold.
Examples of Endogenous Chemical Irritation
Mast Cell Tumors
A common canine cancer that releases growth factors, hormones, and cytokines into the tumor microenvironment, which then contribute significantly to localized pain pathology, is the mast cell tumor (MCT).
These tumors are the most common cutaneous cancers in dogs and may secrete serotonin, histamine, and collagenase, all of which contribute to upregulation of pain stimuli locally and systemically.15 Serotonin, in particular, results in sensitization of peripheral pain fibers, while histamine and collagenase cause localized damage and inflammation in tissues.16 For these reasons, treatment of canine MCT should routinely include pain management.
When an MCT degranulates (Figure 1), the affected areas become red and edematous circumferential to the primary lesion—this is called Darier’s sign. A red, edematous, and pruritic MCT is evidence of histamine and serotonin release from the MCT into the local microenvironment, which may occur in both low- and high-grade lesions.
Feline MCTs may also release these chemotactic agents into the tumor microenvironment, but the incidence of high-grade tumors that cause significant morbidity is lower in cats than dogs.
Squamous Cell Carcinoma
Oral squamous cell carcinoma (OSCC) is the most common oral tumor in cats. Significant areas of hypoxia have been demonstrated in feline OSCCs through use of multiple hypoxia detection methods.17 Due to the highly invasive nature of this tumor and its characteristically rapid growth, mechanisms of hypoxic pain sensitization are likely.
Feline OSCCs are highly invasive tumors that can affect the bone and soft tissues of the mouth. This localized destruction of bone and soft tissues directly causes severe pain due to the rich peripheral innervation of periosteal and endosteal surfaces in bone (Figure 2).
Direct Tumor Invasion
Tumors act as space-occupying lesions that cause substantial pressure and compression, leading to mechanical and pressure-induced pain. Large tumors are common in veterinary oncology patients because these animals are usually presented when their tumors have reached a noticeable size and advanced stage.
Pain Signal Cycling. Large tumor masses may cause stretching of mechanoreceptors in the skin and muscles, as well as compress nerves in the surrounding tissues. If left untreated, a large tumor mass may result in a vicious cycle of pain signaling. For example, a very large soft tissue sarcoma in a dog (Figure 3) can cause significant pain from the mass protruding outward into the integument and inward toward the abdomen.
Such compressive pressure results in constant stimulation of the sensory receptors due to mechanical stretching and distortion. Chronically distorted mechanoreceptors send continuous pain signals to the dorsal horn of the spinal cord, resulting in chronic pain and central sensitization.
Treatment for this type of pain may include surgical removal of the mass or, if removal is not possible, palliative treatment. Such treatment may include palliative radiation therapy or, in limited situations such as airway obstruction, debulking surgery and must include concurrent pain medications.
Inflammation. Inflammation is an integral part of the uncontrolled proliferation of abnormal cells during the direct invasion of these abnormal cells into normal tissues. Cancer cells may destroy normal tissue surrounding the tumor and trigger the patient’s inflammatory response. Inflammatory cytokines and chemokines are released at the site of inflammation, resulting in upregulation of inducible cyclooxygenase-2 and recruitment of more inflammation.
From this perspective, inflammatory cancer pain resembles osteoarthritic pain, although the mechanism is slightly different. Local inflammation around tumors adds an inflammatory component to the patient’s pain, beginning with vasodilation, fluid extrusion, and recruitment of neutrophils to the tumor site. Tumors in various locations may also become infected, furthering the cycle of inflammation (Figure 4).
Because inflammatory cancer pain is similar in nature to osteoarthritic inflammation, tumors with such lesions can respond favorably to nonsteroidal anti-inflammatory drugs for pain relief during cancer treatment.
ASSESSMENT OF CANCER PAIN
An ideal cancer pain scoring system should include both:
- An objective in-hospital/clinic pain measurement score
- A score based on the owner’s impression of the animal’s level of pain and quality of life at home.
The veterinarian can use the in-hospital/clinic pain score system upon admission and at follow-up visits to score the patient’s pain initially and evaluate the effectiveness of therapeutic interventions. To achieve this goal, we developed the Purdue Integrated Cancer Pain Score System, which includes the Canine/Feline Brief Pain Inventory for pet owners and an in-hospital cancer pain score system for the veterinary team (Table 3).
Modified Canine/Feline Brief Pain Inventory
In humans, a rapid and objective pain inventory system called the Brief Pain Inventory (BPI) was developed to validate large, multi-institutional clinical trials.18 In 2006 researchers at the University of Pennsylvania modified the BPI for use in dogs and called it the Canine BPI (cBPI).19 At Purdue University, we modified the cBPI (mCBPI) with the intention to designate this system specifically for oncology patients (dogs, cats, and potentially other species) and to exclude patients with osteoarthritis.
Our in-home pain inventory system consists of 3 scored sections, with a total of 10 questions catalogued by dog or cat owners. The first 2 sections are objective and ask owners to score the patient’s pain and function, respectively. The scores can be averaged to help the practitioner gauge the patient’s progress over time. The final question is an overall subjective impression of the client’s perception of the patient’s quality of life.
In-Hospital Cancer Pain Score System
To assess the progress of cancer treatment with pain management, we use the in-hospital cancer pain score system. This modified scoring system was developed previously by one of the authors.20 The in-hospital cancer pain score system is a 5-point scale on which a pain score is assigned to the dog or cat upon examination when admitted for care. The patient is assessed daily, and the pain score is assigned and recorded.
While the in-home pain inventory score provides a baseline from the perspective of the owner, the in-hospital pain score system provides a progress report for both cancer treatment and concurrent pain management. The clients are asked to continue the in-home pain inventory system when the animal is discharged.
Pain medication is adjusted as required based on the whole Purdue Integrated Pain Score System. The goal of this system is to provide a user-friendly tool that:
- Can be adapted as needed when treating cancer patients
- Tracks the status of pain relief, restoration of function, and quality of life over time.
We hope that this article, and the next article, raise awareness about the all-too-often overlooked problem of cancer pain and help practitioners provide a sound, objective assessment and treatment strategy when managing cancer pain in dogs and cats.
BPI = Brief Pain Inventory; cBPI = Canine Brief Pain Inventory; mCBPI = Modified Canine Brief Pain Inventory; MCT = mast cell tumor; NGF = nerve growth factor; OSCC = oral squamous cell carcinoma
- Mitera G, Zeiadin N, Kirou-Mauro A, et al. Retrospective assessment of cancer pain management in an outpatient palliative radiotherapy clinic using the pain management index. J Pain Symptom Manage 2010; 39:259-267.
- Kirou-Mauro AM, Hird A, Wong J, et al. Has pain management in cancer patients with bone metastases improved? A seven-year review at an outpatient palliative radiotherapy clinic. J Pain Symptom Manage 2009; 37:77-84.
- Deandrea S, Montanari M, Moja L, et al. Prevalence of undertreatment in cancer pain. A review of published literature. Ann Oncol 2008; 19:1985-1991.
- Oldenmenger WH, Sillevis Smitt PAE, van Dooren S, et al. A systematic review on barriers hindering adequate cancer pain management and interventions to reduce them: A critical appraisal. Eur J Cancer 2009; 45:1370-1380.
- Lee YJ, Yang J-H, Lee J-W, et al. Association between the duration of palliative care service and survival in terminal cancer patients. Support Care Cancer 2015; 23:1057-1062.
- Franceschini A, Adinolfi E. P2X receptors: New players in cancer pain. World J Biol Chem 2014; 5:429-436.
- Yoneda T, Hata K, Nakanishi M, et al. Involvement of acidic microenvironment in the pathophysiology of cancer-associated bone pain. Bone 2011; 48:100-105.
- Withrow SJ, Vail DM, Page RL (eds). Withrow & MacEwen’s Small Animal Clinical Oncology, 5th ed. St Louis: Elsevier/Saunders, 2013.
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- Lewin GR, Lechner SG, Smith ESJ. Nerve growth factor and nociception: From experimental embryology to new analgesic therapy. Handb Exp Pharmacol 2014; 220:251-282.
- McCaffrey G, Thompson ML, Majuta L, et al. NGF blockade at early times during bone cancer development attenuates bone destruction and increases limb use. Cancer Res 2014; 74:7014-7023.
- Gearing DP, Virtue ER, Gearing RP, et al. A fully caninised anti-NGF monoclonal antibody for pain relief in dogs. BMC Vet Res 2013; 9:226.
- Hall EJ. Radiobiology for the Radiologist, 7th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2012.
- Fröberg GK, Lindberg R, Ritter M, et al. Expression of serotonin and its 5-HT1A receptor in canine cutaneous mast cell tumours. J Comp Pathol 2009; 141:89-97.
- Sommer C. Serotonin in pain and analgesia. Mol Neurobiol 2004; 30:117-125.
- Ballegeer EA, Madrill NJ, Berger KL, et al. Evaluation of hypoxia in a feline model of head and neck cancer using 64Cu-ATSM positron emission tomography/computed tomography. BMC Cancer 2013; 13:218.
- Cleeland CS, Ryan KM. Pain assessment: Global use of the Brief Pain Inventory. Ann Acad Med Singapore 1994; 23:129-138.
- Brown DC, Boston RC, Coyne JC, et al. Development and psychometric testing of an instrument designed to measure chronic pain in dogs with osteoarthritis. Am J Vet Res 2007; 68:631-637.
- Ko JC, Mandsager RE, Lange DN, et al. Cardiorespiratory responses and plasma cortisol concentrations in dogs treated with medetomidine before undergoing ovariohysterectomy. JAVMA 2000; 217:509-514.