While surgery, radiation therapy, or chemotherapy may be used alone for certain tumors, they are frequently combined to achieve
better and longer tumor control, translating into prolonged and more complete pain alleviation.19,24,26,27 Examples of cancer best treated with multimodality therapy include feline vaccine-associated soft tissue sarcomas, canine
apocrine gland anal sac adenocarcinoma, high-grade canine mast cell tumors and soft tissue sarcomas, and certain oral tumors.
The above treatments are directed at the tumor itself. In addition, many analgesic drugs can be administered to treat pain
in general in patients with cancer.
By far, NSAIDs are the drugs most veterinarians will initially use to control various types of pain in companion animals.
NSAIDs' main mechanism of action is through inhibiting cyclooxygenases (COXs). COX-2 is the main target of recently developed
selective inhibitors because of its role in inflammation and pain; it is an inducible enzyme that leads to the production
of prostaglandin E2 and other eicosanoids from arachidonic acid. COX-1 has often been referred to as the good COX since it is the isoform responsible for homeostasis (gastrointestinal mucosal protection, renal blood flow, platelet aggregation),
and COX-2 has been called the bad COX because of its involvement with pain, inflammation, fever, ischemia, and cancer. It is now apparent that COX-2 may also carry
important physiological functions, with basal expression levels demonstrated in tissues such as the ovaries, uterus, brain,
spinal cord, kidney, cartilage, bone, and gut.2
As a class, NSAIDs can be helpful in treating cancer pain for numerous reasons. Prostaglandins play an important role in peripheral
sensitization of certain nociceptors, leading to a state of hyperalgesia, an exaggerated response to a mildly noxious stimulus,
or allodynia, a painful response after a non-noxious stimulus.2,9 The prostaglandins can also activate certain sodium channels in the dorsal horn of the spinal cord and cause changes resulting
in central sensitization and establishment of a state of chronic pain. Peripheral and central sensitization are common in
chronic cancer pain.2,9 Hence, it seems rational to use NSAIDs, in combination with other drugs, to treat conditions of moderate to severe chronic
cancer pain. (For a three-step analgesic ladder for controlling mild, moderate, and severe pain proposed by the World Health Organization,
see the article "Understanding and recognizing cancer pain in dogs and cats".)
NSAIDs are effective to some degree in people for treating moderate to severe pain from bone metastases, compression of muscles
and tendons, and distention of the peritoneum or pleura.2 Veterinary patients with cancer pain also appear to benefit from the use of NSAIDs, and they are often used alone for mild
pain or in combination with opioid drugs and adjuvant analgesics for moderate and severe pain. When used for cancer pain,
the various veterinary-approved NSAIDs appear to be equianalgesic.11 The clinical response and toxicity profile may vary among patients receiving a given drug. If a patient fails to benefit
from a given NSAID for pain control or suffers untoward side effects, it is reasonable to try another drug, ideally after
a washout period of seven to 10 days, although no guidelines have been established.
Another rationale to use NSAIDs for cancer pain stems from information gathered in the last decade regarding the potential
anticancer and chemopreventive effects of these drugs in human and veterinary patients. Overexpression of COX-2 has been demonstrated
to occur in many human and canine tumors, including carcinomas of the bladder, prostate, mammary gland, intestine, kidney,
skin and oral cavity (squamous cell carcinoma), and nasal cavity, as well as in some malignant melanomas and osteosarcomas.28-38 This overexpression may lead to a decreased immune response against the cancer cells, decreased apoptosis (programmed cell
death), increased angiogenesis, and increased proliferation. Therefore, using NSAIDs could have both analgesic and antitumor
effects. Many studies in dogs have demonstrated tumor responses with NSAID monotherapy, and others have shown a possible additive
effect when combined with standard chemotherapy agents.35,39-44