Pathophysiology of cancer pain (Proceedings)

Pain ranges in prevalence from 15 to 90% among human cancer patients, with an incidence and severity that parallels disease progression. Cancer pain can be successfully treated in 70% to 90% of these same human patients when the WHO recommendations are followed and opioid-based regimens are used for severe pain. While studies evaluating the frequency or severity of cancer pain in pets are lacking, we can safely estimate that more than half of our patients suffer some degree of cancer-associated pain. With advancement in the understanding of pain physiology, the veterinary community has gained a greater appreciation for which types of cancers, paraneoplastic syndromes, or diagnostic and therapeutic procedures are most commonly associated with physical discomfort, and what type of pain is present. Pain negatively impacts quality of life as well as many important physiological functions, and controlling it in any patient is a priority. Novel therapeutics for the management of cancer pain are rapidly being developed, and will undoubtedly provide better treatment options for animals suffering from various neoplastic processes.

Pathophysiology of pain: Nomenclature and basics

Generally speaking, pain is an unpleasant sensory and emotional experience perceived following transmission to the CNS of nerve signals generated by stimulated nociceptors, usually following actual or potential tissue damage. The nociceptors are nerve endings of certain fibers, mainly the small myelinated Aδ fibers (intermediate conduction velocity) and the small unmyelinated C fibers (low velocity). Nociception is therefore the transduction, conduction and processing of the signals generated by stimulated nociceptors. The nerve endings of Aδ and C fibers are located in the skin, subcutaneous tissues, periosteum, joints, muscles, and viscera, and their neurons enter the spinal cord via the dorsal root ganglia, where they can synapse with second order neurons of the grey matter, but not before integration and modulation takes place, through interactions with excitatory and inhibitory interneurons. The large myelinated Aβ fibers (high velocity) usually transmit nerve signals generated by non-noxious stimuli such as touch, vibration, pressure, movement and proprioception, although the non-noxious input from this type of fibers may occasionally result in perception of pain, after incorrect processing by an altered CNS (see chronic pain below).

Many stimuli (thermal, mechanical, or chemical) can lead to activation or peripheral sensitization of the nociceptors. These include heat, protons (hydrogen ions), prostanoids, bradykinin, serotonin, histamine, adenosine, glutamate and aspartate (excitatory amino acids), ATP, substance P, calcitonin gene-related peptide (CGRP), cytokines, and nerve growth factor (NGF). Once activated, the nerve signals are conducted by action potentials, following the membrane depolarization generated by the inward flux of sodium ions, through the sodium channels located in the nerve membrane. Some sodium channels found on C fibers are unique in that they are closed until inflammation is present. These fibers are sometimes said to be "sleeping" and do not respond to basal stimulation until activated and sensitized by inflammation.

As previously mentioned, the nociceptive signals transmitted via Aδ and C fibers undergo significant modulation. It is known that transmission, modulation, and integration of noxious signals resulting in pain are complex processes where excitatory and inhibitory systems counteract each other at various levels of the CNS. Three of the main central inhibitory systems located primarily in the superficial dorsal horn include the opioid receptors, the α-2 adrenoreceptors, and the inhibitory transmitter GABA. A key excitatory transmission system is through the N-methyl-D-aspartate receptor (NMDA), which is activated after repetitive noxious inputs when a stimulus is maintained. There is substantial evidence for the involvement of NMDA receptors in neuropathic and chronic pain states.

Chronic pain

While it is clear that pain initially follows noxious stimuli, certain peripheral and central changes may on occasion result in increased sensitivity to non-noxious stimuli (hyperesthesia), in an amplified painful response to mildly noxious stimuli (hyperalgesia), or in an abnormal painful response to non-noxious stimuli (allodynia). Hyperalgesia and allodynia are most frequently observed in conditions of untreated or undertreated chronic pain, and stem from central and peripheral alterations in the transmission, modulation, and integration of nociceptive stimuli. A sudden pain flare-up during a state of chronic pain is termed breakthrough pain, and may occur even when baseline chronic pain is under control via the use of around-the-clock medication. Many factors might lead to prolonged pain, and consequently to allodynia, and hyperalgesia. These include peripheral sensitization and activation of C fibers by various substances such as prostaglandins, histamine, serotonin, bradykinin, and cytokines, central sensitization by yet other modulators including glutamate and substance P, decreased inhibitory modulation by central actors (GABA, opioid receptors, α-2 adrenoreceptors), and wind-up. The term wind-up denotes the temporal summation of painful stimuli in the cord, mediated chiefly via activation of NMDA receptors of the C fibers.

Changes observed in chronic cancer pain and resulting in peripheral or central sensitization and wind-up are very likely frequent with various veterinary cancer pain syndromes. Examples of chronic cancer pain states likely associated with sensitization in pets would include a destructive appendicular osteosarcoma simultaneously or not with degenerative joint disease in a dog; a large cutaneous mast cell tumor with waxing and waning degranulation resulting in histamine release in a dog; an oral squamous cell carcinoma with bone lysis and chronic suppurative inflammation in a cat; an injection-site sarcoma invading into the surrounding tissues, nerves and spinous processes in a cat; an advance stage nasal adenocarcinoma causing local bone lysis, invading into the orbit, and penetrating through the cribriform plate and into the cranial vault in a dog; an advanced pancreatic carcinoma with peritoneal carcinomatosis in a dog or cat (common source of neuropathic pain in people); a very large hepatic tumor causing capsular distension in a dog or cat; an inflammatory mammary carcinoma with lymphatic vessel invasion in a dog and associated lymphedema, etc.

Classification and causes of cancer pain

Pain can be difficult to describe accurately and various classification systems exist each based on different criteria, such as the temporal aspect, the intensity, the type of pain, or the underlying cause. Pain can be described as acute, chronic, or intermittent when considering the temporal aspect. Pain is said to be mild, moderate, severe, or excruciating when intensity is used as the criterion. Types of pain reported according to the origin of the noxious stimuli include somatic pain (skin, muscles, joints, bones), visceral pain (various viscera), and neuropathic pain (structural or functional damage to peripheral or central nervous system). It is important to know that these three types of pain can occur either alone or simultaneously in the same patient. Equally important is that the different types of pain will not respond uniformly to various classes of analgesics. For example, neuropathic pain typically involves multiple pathophysiological changes within the peripheral and central nervous systems. With neuropathic pain, certain drugs acting centrally (ex: gabapentin, amantadine, NSAIDs) will be helpful but typical opioids may not prove as efficient for this specific type of chronic pain.

Possibly the most useful classification of pain is the one separating physiologic pain (a.k.a. nociceptive or adaptive pain) from inflammatory pain (a.k.a. pathologic pain) from dysfunctional and neuropathic pain states (a.k.a. maladaptive pain). It can be said that physiologic pain plays a role in "educating" the individual and has a protective function: get away from the painful stimulus and the pain will stop! If the message has been understood but pain persists (chronic pain, neuropathic pain), it is considered maladaptive and serves no useful purpose to the individual suffering it. Chronic cancer pain is always maladaptive and serves no useful purpose.

When classified according to the underlying cause, cancer pain can result from the primary tumor itself (ex: primary bone sarcomas, sinonasal carcinomas, bladder/prostate carcinoma), from distant metastases (ex: bone or meningeal metastasis, carcinomatosis, skin metastasis), from paraneoplastic syndromes (ex: hypertrophic osteopathy, hyperhistaminemia), from diagnostic (ex: bone biopsy, transthoracic fine-needle aspirates) or therapeutic procedures (ex: radical surgical excision, extravasated vesicant chemotherapy, early or late side effects of radiation therapy), or can occur as a result of a condition unrelated to the cancer itself (ex: osteoarthritis, severe periodontal disease, chronic otitis externa) but present simultaneously.

Regarding pain from therapeutic procedures, it is well recognized in people that certain chronic neuropathies can be associated to chemotherapeutic agents (ex: vincristine, taxanes, platinum agents), aggressive surgeries, or irradiation of tissues even long after the treatment has been performed or completed. Chronic pain in cancer survivors can also be the result of residual tissue damage from the cancer. The same may apply to pets, and it is crucial to understand that even patients that are virtually cured of their cancer may suffer chronic pain that requires intervention.

Other causes of discomfort, pain, or decreased well-being of the cancer-bearing patient exist that should be treated symptomatically. Amongst those are opportunistic or secondary infections, most typically bacterial, that may require culture and sensitivity but may also be treated empirically on occasion. Similarly, any suspicion of nausea or evidence of vomiting should be treated aggressively. Nausea and vomiting could be caused by the tumor or certain paraneoplastic syndromes, the anticancer therapy, the analgesic therapy, or the severe pain itself. Finding the underlying cause is ideal, but treatment of these unpleasant symptoms and clinical signs should never be delayed. Finally, certain tumor-bearing patients that will benefit from symptomatic therapy may be suffering from liquid accumulation in body cavities (ex: centesis for thoracic fluid from thymoma or rib tumor), muscle spasms (ex: muscle relaxants for bladder or urethral tumor), sudden changes in blood pressure (ex: antihistamines or vasopressors if low blood pressure from mast cell tumor degranluation leading to hyperhistaminemia, alpha-blockers if high-blood pressure from cathecolamines produced by pheochromocytoma), etc.

Cox-2, prostaglandins, and cancer

In a discussion about cancer pain, certain facts concerning cyclooxygenase-2 (COX-2) are important to appreciate. An important role of prostanglandins in pain is through sensitization of certain nociceptors found at the nerve endings of small unmyelinated C fibers. Once tissue trauma and inflammation has occurred, these generally "silent" nociceptors become responsive, and excitable to pressure, temperature changes, and tissue acidosis, resulting in hyperalgesia and occasionally in allodynia. Prostanglandins may also facilitate the activation of certain sodium channels in dorsal root ganglion neurons, increasing the excitability of nociceptive nerve fibers. It is also thought that they may act in the CNS to produce hyperalgesia in the dorsal horn of the spinal cord, and it may be that COX-2 expression is increased following N-methyl-D-aspartate (NMDA) receptor activation. Peripheral and central sensitization are commonly associated with chronic cancer pain.

NSAIDs and COX-2 inhibitors are therefore important players in the therapy of cancer pain. While the WHO three step ladder recommends the use of nonopioid drugs only for the first and second step (mild and moderate pain, respectively), they are also useful, in a multimodal approach, for more severe pain. In people with cancer, studies support their use in the treatment of moderate and severe pain from bone metastases, distension of the peritoneum or pleura, compression of muscles and tendons. There is no reason to believe that the situation should be any different in companion animals with cancer pain, and this class of drugs should therefore be considered, alone for mild pain, or in combination with opioid drugs (mild or stronger) and adjuvant analgesics, for the effective treatment and relief of moderate to severe pain. When using an NSAID or COX inhibitor for cancer pain, the various commercially available veterinary-approved products appear equianalgesic. For a given patient, the clinical response and toxicity profile may vary, and cannot be predicted.

Commonly, the process of malignant transformation occurs through the gradual accumulation of genetic changes (termed multistep carcinogenesis), which result in deranged molecular events. A better understanding of the mechanisms of carcinogenesis would provide insights for designing and implementing effective preventative and therapeutic strategies, as well as the possibility to target specific alterations that are proper to the cancer cell. In humans, epidemiological and experimental evidence supports the use of NSAIDs to decrease the development of certain cancers (termed chemoprevention). This apparent chemopreventive effect may be partially mediated through the inhibition of COX-2 activity, blocking endogenous PGE2 production. Prostaglandin E2 exerts multiple pro-oncogenic effects including conversion or procarcinogens to carcinogens, activation of certain oncogenes and inactivation of certain tumor-suppressor genes, increased cell proliferation, suppression of the immune system, increased migration, evasion of apoptosis, and increased angiogenesis, in addition to its other physiologic functions.

In veterinary oncology, immunohistochemical and molecular studies have demonstrated that COX-2 protein expression or PGE2 is upregulated in many canine cancers including mammary carcinomas, sinonasal carcinomas, appendicular osteosarcoma, bladder transitional cell carcinoma, prostatic adenocarcinoma, squamous cell carcinoma, oral malignant melanoma, colorectal polyps, adenomas, and carcinomas, renal cell carcinoma, and ovarian carcinoma. There are fewer studies evaluating COX-2 protein expression in feline cancers, but COX-2 overexpression has been observed in bladder transitional cell carcinoma, oral squamous cell carcinoma, and mammary carcinomas. It becomes evident that COX-2 presents as an attractive target in cancer therapy.

Most studies evaluated the non specific COX inhibitor piroxicam and demonstrates clinical efficacy that approaches or surpasses equipotency with standard chemotherapy agents in canine transitional cell carcinoma, oral squamous cell carcinoma, prostatic carcinoma, rectal tubulopapillary polyps, and inflammatory mammary carcinoma. Combination with cytotoxic chemotherapy agents appears to improve the response rate in certain studies, but large prospective studies are still lacking. Certain studies have shown that COX-2 inhibition may selectively sensitize cancer cells to specific chemotherapy agents and to ionizing radiation, raising the hope that multimodality therapy incorporating NSAIDs or COX-inhibitors with traditional anticancer therapeutic options could benefit the cancer patient, and provide additive or supraadditive effects resulting in better clinical responses. However, it appears obvious that combining NSAIDs or COX inhibitors with other nephrotoxic agents, such as the chemotherapy agent cisplatin, appears to carry an unfavorable risk vs. benefit ratio.

Despite the apparent therapeutic utility of COX-2 inhibition in treating cancers in dogs, the actual mechanism for the observed in vivo anticancer effect remains poorly elucidated. Although some of the anticancer effects may be mediated via the inhibition of endogenous PGE2 production, there is evidence that NSAIDs anticancer effects are mediated independent of COX-2 inhibition and prostaglandin E2 levels. It is believed that piroxicam could exert some of its anticancer effect via immunomodulation. A study found no correlation between the pre-treatment COX-2 expression or PGE2 levels in the tumor and the clinical response to piroxicam monotherapy. Further research is needed and ongoing studies evaluating COX-2 in veterinary oncology are promising.

References available upon request