1. The Inflammatory Nature of Cancer Pain Pawandeep Brar Palliative Care Physician Temmy Latner Centre for Palliative Care Mount Sinai Hospital

2.  Mechanisms of Cancer Pain  Inflammatory Markers Role in Cancer Pain

3.  Clinical questions do arise though when one considers the mechanisms of cancer pain: ◦ Why are only 25% of bone metastases painful? ◦ Why do patients with similar disease present with very different pain? ◦ Why doesn’t every patient respond to opioids?

4.  Need to think of mechanisms of: ◦ Inflammation-local, CNS ◦ Neuropathy, CNS changes ◦ Visceral/Somatic  Also need to think of: ◦ Cancer treatment related pain particularly CIPN ◦ Co-morbidities ◦ Psychosocial Factors ◦ Genetic factors

5.  Progression of cancer  variety of local changes, including chemotaxis of immune cells (e.g. macrophages, T cells, dendritic cells) & production of pro-inflammatory agents ◦ Several of these agents play major roles in cell proliferation, angiogenesis, invasion & metastases

6.  Included are pro-inflammatory cytokine gene products that can be pro-nociceptive as well ◦ Tumour necrosis factor ◦ Interleukins ◦ metalloproteases

7.  TNFα ◦ Considerable evidence of its role in pain ◦ Initiates cascade of inflammatory responses ◦ Produced by tumours  hyperalgesia & nocioceptor sensitization  neuronal discharge in DRG & adjacent neurons

8.  Increased Levels of TNF play a role in bony mets pain and neuropathic pain ◦ Activates channels that stimulate an acidic environment of bone mets ◦ Increase TNF levels associated with overall neuronal hyperexcitability and increase neuropathic pain

9.  Interleukin-1β ◦ Produced by macrophages, glial cells, sympathetic & sensory neurons ◦ Also produced by tumour cells  Increased Interleukin 1B levels ◦ Increase dorsal horn excitablility ◦ Inhibition of tonic neurons ◦ Contribute to central sensitization associated with chronic pain

10.  IL 6 ◦ Involved in generation of neuropathic pain ◦ Directly regulates sensitivity of nocioceptors

11.  Metalloproteases ◦ roles in neuroinflammation and are involved in a wide range of CNS diseases ◦ Matrix metalloproteases (MMP) family of enzymes expressed by malignant cells  Facilitate tumour invasion, metastasis, angiogenesis ◦ MMPs implicated in neuropathic pain particularly CINP

12.  Reality that we have no specific treatments to target cytokines in pain  What all this tells us is that cancer pain is complex & mostly an inflammatory event  Specific drugs being developed to counter effects of cytokines on pain & tumor growth