Cancer pain physiology

Abstract

Mechanisms of inflammatory and neuropathic pains have been elucidated and translated to patient care by the use of animal models of these pain states. Cancer pain has lagged behind since early animal models of cancer-induced bone pain were based on the systemic injection of carcinoma cells. This precluded systematic investigation of specific neuronal and pharmacological alterations that occur in cancer-induced bone pain. In 1999, Schwei et al. described a murine model of cancer-induced bone pain that paralleled the clinical condition in terms of pain development and bone destruction, confined to the mouse femur. This model prompted related approaches, and we can now state that cancer pain may include elements of inflammatory and neuropathic pains but also unique changes in sensory processing. Cancer-induced bone pain results in progressive bone destruction, elevated osteoclast activity and distinctive nocifensive behaviours (indicating the triad of ongoing, spontaneous and movement-induced hyperalgesia). In addition, cancer cells induce an inflammatory infiltrate and release growth factors, cytokines, interleukins, chemokines, prostanoids and endothelins, resulting in a reduction of pH to below 5 and direct deformation of primary afferents within bone. These peripheral changes, in turn, drive hypersensitivity of spinal cord sensory neurons, many of which project to the parts of the brain involved in the emotional response to pain. Within the spinal cord, a unique neuronal function reorganization within segments of the dorsal horn of the spinal cord receiving nociceptive input from the bone are discussed. Changes in certain neurotransmitters implicated in brain modulation of spinal function are also altered with implications for the affective components of cancer pain. Treatments are described in terms of mechanistic insights and in the case of opioids, which modulate pain transmission at spinal and supraspinal sites, their use can be compromised by opioid-induced hyperalgesia. We discuss evidence for how this comes about and how it may be treated.

Bone Pain and Muscle Weakness in Cancer Patients

“…The most common cause of cancer-induced pain arises from bone metastases. [1] Of advanced cancer suffers, 60–84% are estimated to experience varying degrees of bone pain. [2] Cancer-induced bone pain (CIBP) involves both neuropathic and inflammatory pain pathways, associated with tumor, stroma, and adjacent tissues, including peripheral and central nerves.…”

“…[2] Cancer-induced bone pain (CIBP) involves both neuropathic and inflammatory pain pathways, associated with tumor, stroma, and adjacent tissues, including peripheral and central nerves. [1]…”

Mechanisms Underlying Bone and Joint Pain

“…In addition to the development of inflammation, neuropathic changes have also been reported in animal models of bone and joint pain [67, 68, 47, 69, 70]. Studies in rat and mouse models of cancer-induced bone pain and chemical-induced osteoarthritis joint pain have demonstrated expression of ATF3, a neural marker of nerve damage, in cell bodies within the dorsal root ganglion innervating the bone or joint [71–73, 69].…”

“…Many animal and clinical studies have demonstrated that sensitization of peripheral and central neurons develops in the context of chronic bone or joint pain [5, 67, 78]. The international association for the study of pain (IASP) defines sensitization as “Increased responsiveness of nociceptive neurons to their normal input, and/or recruitment of a response to normally subthreshold inputs”.…”

“…There are many well written overviews of mechanisms contributing to development of peripheral sensitization [80, 58] and central sensitization [67, 68, 80, 81]. Much has been learned about the impact of many of the factors that are released by local tissues, such as ATP, ADP, endothelins, bradykinin, and growth factors [7, 12, 47, 58, 80].…”