Tough Target: New Therapies for Cancer Pain Lagging

Jane de Lartigue, PhD
Published: Friday, Aug 05, 2016
Advances in the treatment of patients with cancer have not been matched in the management of pain associated with the disease, which remains a substantial and fearsome burden.

More than half of all patients with cancer experience pain, one of the most dreaded symptoms that can severely impact quality of life. In advanced or metastatic disease settings, that number can exceed three-quarters of patients, particularly when the cancer metastasizes to the bone.

Current treatment options center around the use of opioid drugs to block painful sensations, often combined with adjuvants that address some of the underlying causes of pain, but it is often poorly or undertreated.

Despite a leap forward in our understanding of the molecular mechanisms of cancer pain in the past several decades, clinical translation of targeted therapies has been slow.

Understanding Cancer Pain

The vast majority of cancer pain is moderate or severe in intensity and is related to the underlying cancer itself, although it can arise as a result of treatment or from comorbidities that are unrelated to the presence of the tumor. Around a third of patients will continue to experience cancer pain after curative treatment.

Thanks in large part to the development of more appropriate animal models, researchers have begun to unravel some of the molecular mechanisms underlying cancer pain. Although our understanding of many aspects of cancer pain remains limited, these studies have generated a clear picture of an extremely complex pathological condition that, like the tumor it is associated with, evolves over time.

Although pain can manifest in numerous different ways, there are two major types: nociceptive or inflammatory pain arising from chemical or mechanical stimuli that usually result from tissue damage, and neuropathic pain in which electrical stimuli result from direct damage to the nerves or nervous tissue.

The prevailing wisdom is that pain relating to cancer can incorporate aspects of both of these types of pain and results from a complex interaction between the tumor, its microenvironment, and the host’s immune system.

Between them, the composite cells of these 3 components secrete a “soup” of directly and indirectly pain-stimulating molecules that activate the nociceptors. The low pH of the tumor microenvironment further contributes to this effect, activating certain channels in cell membranes including those involved in acid-sensing nociception, such as transient receptor potential vanilloid-1 (TRPV1) and acid-sensing ion channel 3 (ASIC3).

Meanwhile, the neuropathic component of cancer pain, which is estimated to occur in up to 40% of patients over the course of their disease, results from direct damage to the nervous system as tumors invade the surrounding tissue. Neuropathic pain is often associated with abnormal sensations such as increased perception of painful stimuli (hyperalgesia), pain induced by nonpainful stimuli (allodynia), and an exaggerated pain response (hyperpathia). It has an even greater effect on patient quality of life than nociceptive pain and is particularly difficult to treat.

Both peripheral (at the sites of tumors) and central (within the spinal cord and brain) processes are involved in the generation of cancer pain. With acute pain, these processes are temporary and resolve once the painful stimuli are no longer present. Chronic pain ultimately results from continual stimulation at the periphery, which drives permanent morphological, neurochemical, and physiological changes to the peripheral nociceptors and to the central nervous system, resulting in a general state of overexcitability of the neurons that convey pain signals to the brain. This phenomenon, known as sensitization, lowers the patient’s pain threshold.

Bone Pain

Bone pain, the most significant cause of cancer pain, appears to be a unique type of pain with distinct neurochemical and cellular features from other types of pain and it responds poorly to traditional analgesic drugs.

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