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.