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  • Review Article
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Cancer pain and its impact on diagnosis, survival and quality of life

Key Points

  • Advances in cancer detection and therapy have dramatically increased the survival rates of patients with most cancers. For many patients, pain is the first sign of cancer and the majority of individuals will experience moderate to severe pain and/or neuropathy during the course of their disease and into survivorship.

  • Cancer pain has a considerable effect on the diagnosis, quality of life and survival of patients with cancer. During the past decade, preclinical and clinical data has begun to provide insight into the mechanisms that drive and mask cancer pain, and the mechanisms by which anti-neoplastic agents induce peripheral neuropathy.

  • Cancer pain seems to be modulated in the CNS by opioid-dependent mechanisms and, at least in an animal model of pancreatic cancer, endogenous opioid mechanisms seem to mask early- and mid-stage pancreatic cancer-related pain behaviours, which may contribute to the late diagnosis and lethality of this disease. Understanding the CNS mechanisms involved in masking and driving cancer pain might allow earlier detection of cancer and more effective therapies for controlling late-stage cancer pain.

  • Common anti-neoplastic agents such as the vinca alkaloids, taxanes and platinum-based compounds frequently induce a chemotherapy-induced peripheral neuropathy (CIPN) in which both large and small primary afferent sensory neurons are injured. As CIPN can affect both the quality of life, and in some cases the full delivery of the anti-neoplastic agent, the development of pre-emptive therapies to block or attenuate CIPN has the potential to improve both the quality of life and, in some cases, the survival of patients with cancer.

  • Tumour-induced cancer pain tends to increase with advancing disease, and can be driven by tumour-released products, acidosis and direct injury to sensory nerve fibres present at the site of the primary tumour or at the site of tumour metastasis.

  • An increase in our understanding of the thermal, chemical and mechanical transducers expressed by nociceptors, coupled with an increase in our knowledge of the interactions that occur at the nociceptor–tumour interface, have provided insights that could lead to the development of novel mechanism-based therapies to treat cancer pain.

  • In addition to reducing pain and/or neuropathy, commonly used analgesics such as the non-steroidal anti-inflammatory drugs (NSAIDS), cyclooxygenase 2 inhibitors and opiates may influence cancer disease progression. As patients with cancer continue to survive longer, it will be important to develop a mechanism-based understanding of the influence analgesics might have on the growth, vascularization and metastasis of tumours and their associated stromal cells.

  • By incorporating cancer pain research into mainstream cancer research it is possible that analgesic and cancer therapies can be simultaneously assessed with regard to how they affect the survival, overall health and quality of life of both patients with cancer and survivors.

Abstract

Cancer pain significantly affects the diagnosis, quality of life and survival of patients with cancer. During the past decade, preclinical and clinical data has begun to provide insight into the mechanisms that drive and mask cancer pain and the mechanisms by which anti-neoplastic agents induce peripheral neuropathy. Developing a mechanism-based understanding and mechanism-based therapies to treat cancer-associated pain and sensory neuropathy, and incorporating these into mainstream cancer research and therapy, will be crucial to improving the quality of life and survival of patients with cancer.

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Figure 1: Primary afferent sensory nerve fibres involved in generating the pain and/or neuropathy induced by tumours and anti-tumour therapies.
Figure 2: Neuronal circuits involved in the transmission and modulation of somatosensory information.
Figure 3: Endogenous opioids induce disparity between disease progression and pain-related behaviours in a mouse model of pancreatic cancer.
Figure 4: Pathological features present in sensory neurons and their supporting cells as a result of paclitaxel-induced peripheral neuropathy.
Figure 5: Detection of noxious chemical, thermal and mechanical stimuli by a terminal of a nociceptor in a tumour-bearing bone.

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Acknowledgements

This work is supported by the National Institute of Neurological Disorders and Stroke, and a Veterans Administration Merit Review. The author would like to thank J. R. Ghilardi, K. G. Halvorson, J. M. Jimenez-Andrade and C. M. Peters for their invaluable comments and suggestions to this review.

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Glossary

Neuropathy

Dysfunction of the cranial or spinal nerves.

Nociceptor

A primary afferent sensory neuron that is activated by stimuli related to tissue damage. Nociceptors terminate in free nerve endings with peripheral terminals that are devoid of specialized cell types.

Peripheral sensitization

An altered state of nociceptor function that is characterized by a lowered threshold of activation and an increased response to suprathreshold stimuli.

Hyperalgesia

An increased response to a stimulus that is normally painful.

Allodynia

Pain due to a stimulus that does not normally provoke pain.

Myalgia

Aching of the muscles and joints.

Paresthesia

An abnormal sensation such as burning, pricking or tingling that can be spontaneous or evoked.

Dysesthesia

Impairment of sensation and/or a condition in which an unpleasant sensation is produced by ordinary stimuli.

Central sensitization

Increased responsiveness to pain transmission by neurons in the spinal cord. This is usually caused by neurochemical changes in the spinal cord, brainstem or forebrain.

Disease-free survival from cancer

Length of time after treatment during which no cancer is found.

Sickness behaviour

Constellation of physiological and behavioural responses observed in animals after the administration of inflammatory agents or specific proinflammatory cytokines. These symptoms observed in animals are similar to those observed in cancer patients, and include pain, diarrhoea, nausea, cachexia, fatigue, anxiety and depression.

Cold block

The interruption of spinal cord neuron action potential propagation that results from decreasing the temperature of the spinal cord by 7–10°C.

Glove and stocking distribution

A pattern of sensory abnormalities that occurs with peripheral neuropathies in which the distal extremities (hands and feet) exhibit the most severe symptoms.

Neuropathic pain

Pain initiated or caused by a primary lesion or dysfunction in the nervous system.

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Mantyh, P. Cancer pain and its impact on diagnosis, survival and quality of life. Nat Rev Neurosci 7, 797–809 (2006). https://doi.org/10.1038/nrn1914

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