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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.
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.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, 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.
The Analgesic Ladder
The presence of tumor metastases leads to severe disruption of normal bone metabolism. A number of the molecules in the soup secreted by tumor cells, their microenvironment, and the immune system drive the proliferation and activation of the osteoclasts, the cells that break down bone tissue. Since the mineralized bone tissue acts as a reservoir for various minerals and growth factors, as it is eroded inflammatory mediators and other factors that activate the nociceptors are produced. Osteoclasts can also contribute to the acidic environment as they produce protons to degrade the bone, thus stimulating the acid-sensing nociceptors.Despite an improved understanding of the mechanisms of cancer pain, treatment continues to center on the opioid class of drugs, which act by modulating the incoming pain information, often by antagonizing opioid receptors, in the central nervous system to produce temporary relief from pain. These are administered according to the World Health Organization’s analgesic ladder, a 3-step program that is applied according to the severity of the pain (Figure).
New opioid formulations continue to be developed in efforts to treat different kinds of pain and to treat it more effectively. In July, the FDA approved transmucosal immediate-release fentanyl (Lazanda), which is delivered as a nasal spray, in a 300 mcg dose for the treatment of breakthrough pain. Although opioids are the most effective clinically available pain relievers, their effects are highly variable in cancer patients and up to 80% will experience significant unwanted side effects, including sedation, constipation, confusion, nausea, and vomiting.In the hope of better controlling pain, opioids can also be given in conjunction with adjuvant treatments with drugs that are typically marketed for other conditions but are potentially useful for relieving certain types of pain when added to opioid therapy. Some are even beginning to find a place as monotherapy. These adjuvants have grown dramatcially in number and type over the past decade (Figure). The options include glucocorticoids, alpha-2 adrenergic agonists, cannabis and cannabinoids, and the anesthetic lidocaine.
Anticonvulsants, particularly gabapentin and pregabalin, are often used as adjuvant therapy for neuropathic pain. Anticholinergic drugs such as scopolamine and glycopyrrolate can offer effective analgesic adjuvants in the treatment of patients with bowel obstruction, a common complication of advanced intra-abdominal or pelvic tumors.The most significant advances in adjuvant therapy have been achieved for the treatment of bone pain. Since osteoclast-mediated bone resorption appears to have a critical function in the generation of bone pain, a group of antiresorptive compounds, bisphosphonates, were developed. These drugs have a high affinity for binding to calcium and, as such, are incorporated into the calcium-rich structure of the mineralized bone. They are subsequently then taken up by active osteoclasts, wherein they block their activity through inhibition of a key enzyme.
Pamidronate (Aredia) was approved by the FDA in 1991 for hypercalcemia of malignancy, followed by an indication for multiple myeloma in 1995 and for osteolytic bone metastases from breast cancer the following year.
The only other FDA-approved bisphosphonate is zoledronic acid (Zometa), which first came to market in 2001 for the treatment of hypercalcemia of malignancy, followed by an expanded indication for treating bone metastases in patients with multiple myeloma, breast cancer, prostate cancer, lung cancer, and other solid tumors in 2002.Mechanistic insights into the causes of bone pain have also revealed that the receptor activator of nuclear factor kappa β (RANK) signaling pathway plays a critical role in tumor-induced effects on osteoclasts.
Denosumab (Xgeva) is a fully human monoclonal antibody that binds to the RANK ligand (RANKL) and offers more specific inhibition of osteoclast activity than the bisphosphonates. It received regulatory approval in 2010 for the prevention of skeletal-related events in patients with bone metastases from solid tumors and in 2011 for increasing bone mass in patients with cancer at high risk for fracture.
There is evidence that inhibiting osteoclastic bone resorption can also limit tumor growth within the bone in addition to helping reduce cancer pain. Indeed, denosumab was also approved in 2013 for the treatment of patients with unresectable giant cell tumor of the bone following the demonstration of durable objective responses in a quarter of the 304 patients who received denosumab.
Taking Aim at New TargetsNerve Growth Factor
Unfortunately, the inhibition of osteoclast activity can produce severe adverse events, which has limited the use of the drugs somewhat. These include atrial fibrillation, osteomyelitis, and osteonecrosis of the jaw. Ongoing studies are evaluating how to reduce or overcome these effects.In search of novel, more effective cancer pain treatments with fewer adverse events and buoyed by the success of the bisphosphonates and denosumab, researchers have made several other attempts to develop drugs that target some of the mechanisms underlying cancer pain.
Significant research efforts have focused on pursuing the tumor-secreted factors that drive cancer pain as potential drug targets; however, success has been limited thus far.
Most notable has been the development of monoclonal antibodies designed to inhibit nerve growth factor (NGF), a protein that is vital to the development and survival of certain sensory neurons. NGF can directly stimulate nociceptors that bear either of the 2 receptors that mediate its effects: tropomyosin receptor tyrosine kinase A (TrkA) and the low-affinity neurotrophin receptor p75.
At one point, NGF inhibitors were hailed as the new blockbuster drugs for the treatment of pain, but the emergence of severe side effects led the FDA to put a hold on their development in 2012, prompting many exploratory agents to be dropped from clinical trials. Exploration of this pathway has since resumed.
The most advanced NGF-targeting drug currently in development is the monoclonal antibody tanezumab. It is being explored in a phase III trial for patients experiencing cancer pain due to bone metastasis while already taking opioid therapy (NCT02609828).
Vasoconstrictive Peptide Endothelin-1 Another potentially promising drug target is the potent vasoconstrictive peptide endothelin-1. Through its 2 receptors, it mediates a range of physiological activities and has been shown to play a role in inflammatory pain and in particular in bone pain through its effects on the osteoblast cells that build bone. Selective endothelin receptor antagonists have been evaluated in clinical trials following promising preclinical results but were mostly unsuccessful in treating pain.
As a result of its effects on osteoblast cells, endothelin plays a part in the development of osteoblastic lesions, which are frequently seen in patients with metastatic prostate cancer. The endothelin receptor antagonist, atrasentan, was evaluated as an anticancer therapy in this setting and, although no effect on patient survival was observed, a recent meta-analysis suggested that atrasentan improved cancer-related bone pain and skeletal events in prostate cancer patients.