Abstract
Cancer pain, especially pain caused by metastasis to bone, is a severe type of pain, and unless the cause and consequences can be resolved, the pain will become chronic. As detection and survival among patients with cancer have improved, pain has become an increasing challenge, because traditional therapies are often only partially effective. Until recently, knowledge of cancer pain mechanisms was poor compared with understanding of neuropathic and inflammatory pain states. We now view cancer-induced bone pain as a complex pain state involving components of both inflammatory and neuropathic pain but also exhibiting elements that seem unique to cancer pain. In addition, the pain state is often unpredictable, and the intensity of the pain is highly variable, making it difficult to manage. The establishment of translational animal models has started to reveal some of the molecular components involved in cancer pain. We present the essential pharmacologic and neurobiologic mechanisms involved in the generation and continuance of cancer-induced bone pain and discuss these in the context of understanding and treating patients. We discuss changes in peripheral signaling in the area of tumor growth, examine spinal cord mechanisms of sensitization, and finally address central processing. Our aim is to provide a mechanistic background for the sensory characteristics of cancer-induced bone pain as a basis for better understanding and treating this condition.
Highlights
Pain is a multifaceted sensation involving the entire nervous system
Pain can be divided into inflammatory pain, where the pain arises from chemical or natural stimuli from damaged tissue, and neuropathic pain, caused by direct lesion or disease of the sensory nerves
Inflammatory pain is initiated by chemical mediators, and neuropathic pain is initiated by altered electrical events (Fig 1)
Summary
Pain is a multifaceted sensation involving the entire nervous system. Pain processes usually start in the periphery, where tissue or nerve damage arises as a consequence of trauma, disease, or lesion, including the growth of a tumor within tissue or nerves. Preclinical studies have suggested that the bases for this are descending noradrenergic, mostly inhibitory, and certain serotonergic controls that facilitate pain These monoamine descending controls regulate spinal neuronal activity bidirectionally and underlie the efficacy of antidepressants for the treatment of pain.[84] Little has been done regarding descending controls in cancer pain models, but blocking the 5HT3 receptor attenuates descending excitatory controls from the brain to the spinal cord and reduces the response of superficial dorsal horn WDR-like cells to thermal and mechanical stimuli.[73] This strongly suggests that part of the increased spinal excitability seen in the cancerinduced bone pain model is not peripheral or spinal but that abnormal descending controls contribute to the changes. Conception and design: All authors Manuscript writing: All authors Final approval of manuscript: All authors
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