Cancer remains a devastating disease, to be sure. But while many people still lose their lives to cancer, many more survive than at any other time in history, thanks to advances in the understanding and treatment of cancer. With increased survival rates, though, patients are spending many more years living with the symptoms of cancer—including pain.
Historically, very little research was done to investigate cancer-related pain—in part because outcomes were dire, and patients with severe pain often did not live long. But today, as people recover and live longer, researchers have realized the tremendous need for better treatments for pain associated with cancer—and with cancer therapies. Toward that effort, they have made tremendous strides toward understanding the roots of cancer pain.
How does cancer cause pain?
At its core, cancer pain arises like all pain: when a potentially damaging stimulus activates pain-sensing nerves that spread throughout the skin, muscles, organs and bones, they send signals to the brain that culminate in the experience of pain. To understand how cancer causes pain, it’s important to consider three main types of pain. Nociceptive pain serves as a warning signal to protect the tissues of the body—like when you stub your toe, or when your hand grazes a hot oven. Inflammatory pain results from immune cell activity—at the site of an infection, for example. And neuropathic pain occurs following nerve damage due to injury, toxins or disease. Researchers agree: cancer and its treatment can cause all three of these types of pain.
Brian Schmidt, an oral and maxillofacial surgeon and pain researcher at New York University, New York City, US, believes that cancer pain is chiefly nociceptive—that is, that nerves fire in response to cancer cells. Indeed, pain can actually be the initial symptom of cancer that first sends a patient to a physician.
Cancer can invade different tissues of the body; once established, cancerous tumors transform the cellular environment. “Our primary hypothesis is that cancer cells produce molecular mediators to activate and sensitize nerves that come into contact with the cancer,” Schmidt says. Nerve activation causes transmission of a pain signal, and nerve sensitization makes nerves more likely to fire, which can lead to spontaneous nerve activity and pain. Although the potential mediators released by cancer cells remain unknown, “it probably depends on the type of cancer,” Schmidt says.
In addition to nociceptive pain, once the immune system detects cancer, immune cells flock to the site of a tumor, making conditions ripe for inflammatory pain too.
“The body is trying to fight and kill the cancer, so it brings inflammatory and immune cells to bear,” says Patrick Mantyh, a pain researcher at the University of Arizona Cancer Center, Tucson, US. “When tumors invade an area, there are almost always ten times more inflammatory and immune cells around than cancer cells themselves.” Immune cells release chemicals that activate pain-sensing neurons. In addition, when cancer cells invade bone, they promote growth of cells called osteoclasts that break down bone by releasing acid; this also promotes pain signaling.
Cancer also causes neuropathic pain, particularly at later stages of the disease; when tumors become very large, they compress organs and nerves and break bones. Neuropathic pain can also arise from nerve damage caused by surgery, radiation or chemotherapy.
“Either the tumor injures nerve fibers, or it causes them to undergo sprouting,” a process whereby pain-sensing nerves grow additional sensory endings, making them far more sensitive and active than normal, Mantyh says. “That’s probably true of every type of cancer, particularly when a tumor invades the spine, where sensory nerves converge and send signals up to the brain.” Cancer treatments—including surgery, radiation and chemotherapy—can also damage nerves, often bringing on neuropathic pain that lasts even after the cancer is cured or in remission.
The pain that stems from cancer and its treatment can take many forms, depending on the type, severity, and location of cancer, as well as the course of treatment. To complicate matters, not everyone experiences these conditions the same way.
“Pain doesn’t necessarily track with the level of tissue damage,” Schmidt says. For example, in some people, “tumors can get really large and not cause pain; we don’t understand that.” Around twenty percent of oral cancer patients don’t have pain, while others suffer excruciating pain. “Part of that equation is patient susceptibility to pain,” Schmidt says, an unpredictable factor that researchers are working to understand in the general population. Unlike other aspects of cancer that can be measured with imaging tools and blood tests, pain is invisible, as there is no objective medical test for pain.
Is cancer pain different from non-cancer pain?
While cancer- and cancer treatment-related pain may differ very little from non-cancer pain in terms of the molecular mechanisms in peripheral nerves and the spinal cord that cause pain, the experience of pain is much more than a physical sensation. The emotional component of pain—the suffering—depends on widespread activity throughout the brain, and the circumstances associated with pain have a tremendous impact on the experience.
“We know that most pain is exacerbated by catastrophizing, by thinking about it,” and fearing the worst, Mantyh says. Cancer may be unique among chronic pain conditions in that the threat is very real. “It’s difficult to have cancer and not wonder whether every new pain isn’t some tumor cell infiltrating your joints or bone or lung,” Mantyh says. Understanding that fear is a very important part of maintaining a good quality of life for individuals with cancer, he added.
“A very important part of cancer pain is the suffering,” says Eija Kalso, a pain researcher at the University of Helsinki, Finland. “What the pain means to a patient has a significant impact on the emotional experience. If it is a terminal case of cancer, the patient may be in crisis.” Fear of death, worrying about what will happen to one’s children, concerns about finances—all these sources of anxiety lead to enhanced pain. “The most common reason for uncontrollable pain is anxiety, depression and fear related to loved ones left behind,” Kalso says. The field has made very important progress of late in providing psychosocial support. “It’s very important and should be available for all patients,” she says, and particularly for younger patients in the prime of life. That support should include access to a psychologist or psychiatrist as well as social services and other resources, she says.
How do researchers study cancer pain?
Researchers are investigating cancer pain in animal models to better understand the cellular and molecular mechanisms at play. But as with all animal models of disease, researchers struggle to create conditions that mimic the human situation.
In one of the most commonly used models of cancer pain, mice receive an injection of tumor cells directly into their bones—something that does not occur in humans. In most studies, mice are injected with sarcoma cells, which form primary bone tumors, a type of cancer that accounts for only three percent of human cancer cases, says Durga P. Mohapatra, a cancer pain researcher at Washington University in Saint Louis, US. Moreover, the tumors contain rodent cancer cells, not human cancer cells. “There are big differences in the expression signatures of genes in rodent and human cancers,” he says, meaning that the cells turn on and off different genes and produce different proteins. Mohapatra is working to create animal models of cancer pain that might better translate to people. “Not a single animal model that we have now—or possibly will ever have—is a complete recapitulation of the human situation, but the goal is to get as close as possible,” he says.
To achieve that aim, Mohapatra and his team have developed a model in which mice develop tumors made of human cancer cells, which then metastasize—a process in which cells break away from the initial tumor site and circulate throughout the body, landing in new locales—just as they do in people. In the animal model, the cells preferentially metastasize to bones.
“Metastasis is a biological process common in human cancer, so we wanted to develop and utilize such models,” he says. Following metastasis, new tumors frequently develop inside bones, particularly with cancers that originate in the lung, breast, prostate, and skin (melanoma). “Every year, these four cancers account for over half a million new cases in the US alone, and on average forty to seventy percent of these metastasize to bones,” Mohapatra says. Why metastatic cancer cells end up preferentially in bone is not clear to researchers, but one idea is that they are able to infiltrate the space inside bones containing marrow, where they may be able to “hide” from chemotherapeutic agents and radiation treatments.
Once the researchers introduced human cancer cells to mice with compromised immune systems—leaving them unable to fight off the invasion—the mice developed metastatic bone tumors. By genetically labeling the cancer cells with a glowing protein derived from fireflies, the researchers were able to visualize the site of tumor growth by imaging the animals’ entire bodies in a machine that detects bioluminescence.
“We are trying to understand the cancer and the associated pain sensitization as it exists within the microenvironment of the bone,” Mohapatra says. To accomplish that, the investigators flush saline fluid through the metastatic tumor-ridden mouse bones and collect the cells and chemicals that emerge. Mohapatra hopes to identify chemical factors in the cancerous bone environment that are highly enriched or are not normally found there, nor in animals with tumors growing elsewhere. Once they do so, the researchers plan to investigate the effects of these factors on the sensory neurons specialized to detect pain. “Then we can go back to the live animals, and test whether these same molecules are critical for ongoing pain behavior by targeting them with drugs.”
How do cancer treatments causes harm?
Paradoxically, the very treatments that may save a cancer patient’s life can also cause chronic pain. Nerve damage from surgery or radiation therapy can lead to neuropathic pain, and chemotherapy can cause a condition called chemotherapy-induced peripheral neuropathy (CIPN). As many as three-quarters of patients receiving chemotherapy may develop CIPN, and about a third of patients still experience CIPN six months after stopping treatment. Much like other pain conditions, physicians cannot yet predict who will develop CIPN, but risk factors include smoking and previous neuropathic pain.
“In some patients, CIPN never develops, in some it develops and goes away, and in others it never goes away,” says Daniela Salvemini, a researcher studying CIPN at Saint Louis University, Missouri, US. “It has a huge impact on patients’ quality of life—there’s no doubt about that.”
Just in the past few years, researchers have determined that chemotherapeutic drugs damage nerves by causing dysfunction in mitochondria, the energy-generating machines within cells. “We hypothesize that, as a consequence of that dysfunction, nerves develop abnormal, spontaneous [electrical] discharge,” Salvemini says. That discharge in peripheral nerves likely starts a domino reaction that leads to peripheral nerve damage and CIPN, she says, but cells in the spinal cord and brain may also be directly affected. But, research is providing new hope that one day soon, medications may be able to halt or even prevent the nerve damage caused by chemotherapy.
Salvemini and others have shown that a molecule called sphingosine-1 phosphate (S1P) acts at a specific receptor, a molecule called S1P1R, in the spinal cord, leading to ongoing pain from CIPN. “That is the receptor that novel therapeutic approaches should be focused on,” Salvemini says. S1P is a type of sphingolipid, an enigmatic class of molecules identified in 1870 and so-named for the sphinx, a mythical creature with a human head and a lion’s body. Originally thought to provide structural support to the cell membrane (which separates the inside of cells from the environment that surrounds them), sphingolipids are now recognized to play important roles in cell signaling as well as in disease.
In addition to potentially halting chemotherapy-induced nerve damage and the resultant pain, future drugs aimed at the S1P1R receptor might have a major fringe benefit: “S1P actually inhibits a cell death process called apoptosis and promotes cell proliferation—meaning it increases cancerous cell growth. So by blocking the actions of S1P at the S1P1R receptor, there may be an opportunity to block both pain and cancer itself,” Salvemini says. If that bears out, such a drug “might kill two birds with one stone,” she added.
Treatments aimed at the S1P1R receptor might come sooner rather than later for cancer patients, because such a drug—called fingolimod—is already being used to treat multiple sclerosis (MS). “We know it’s safe in humans, and we can capitalize on that drug for pain purposes,” Salvemini says. Another benefit is that “the doses needed for this application will be very much lower than those required for treating MS,” she added.
What tools are available to treat cancer pain?
As researchers continue to investigate new treatments for cancer-related pain, what medications are currently available? Unfor-tunately, just as is the case for chronic pain in the general population, when it comes to tools for treating cancer pain, Schmidt says, “there are not many, and they are not good—they are blunt tools.” And just as patients differ in their experience of pain, so do they in their responses to pain medications. However, a better understanding of the specific type of pain patients suffer from can help physicians choose the best tools available to treat it.
Some patients receive “nerve blocks,” in which local anesthetics are delivered to nerves in an affected area. “If we can anesthetize the nerves innervating [i.e., supplying] the cancer, the patient can get relief,” Schmidt says. Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen can help combat inflammatory pain, and a class of drugs called bisphosphonates can help neutralize the acidic environment that contributes to the bone pain often seen in cancer patients. And neuropathic pain from cancer or chemotherapy can sometimes be eased with anti-depressant or anti-seizure medications prescribed for other neuropathic pain conditions. Those drugs are thought to enhance pain-dampening signals from the brain to the spinal cord.
Opioid drugs such as morphine, which mimic the brain’s own natural pain-killing molecules, are the most powerful drugs available for severe pain, including cancer-related pain, but “not everyone responds to them,” Schmidt says, “and they are associated with significant side effects.” Constipation may sound like a minor issue, but it can be a major problem, especially for people managing cancer and cancer treatment. Also, as patients take opioid drugs for pain, they may become tolerant, requiring ever-higher doses to achieve pain relief. And opioids carry the risk of death due to respiratory depression. Chronic opioid use can also cause a lesser-known side effect called opioid-induced hyperalgesia, in which the drugs actually worsen pain. And perhaps most concerning of all, there is evidence that opioid drugs may promote cancer progression, though evidence in human patients is murky.
The considerations for how to use opioid drugs to manage pain should include the type, stage, and treatment conditions of the patient’s cancer. “If a patient has a terminal cancer with no cure, then we can accept more risks to control pain,” says Kalso. Higher-risk treatments include high doses of opioids as well as invasive techniques such as injecting anesthetics into the spinal cord or implanting a pump to deliver nerve-blocking anesthetics. “When life expectancy is short, and a patient is suffering, we should use all the available tools. But if a patient has a chronic condition with a good life expectancy, then the risk-benefit ratio must be considered,” Kalso says.
Kalso said that the acceptance of higher risks from opioids in terminal cancer patients contributed to rampant overuse of opioids in chronic pain management. In 1986, the World Health Organization (WHO) published what came to be known as the “analgesic stepladder,” a document that advised stepping up the dose of opioid drugs to very high doses to control pain. The guidelines, intended for patients with terminal cancer, were meant to reduce the stigma associated with prescribing and taking opioid drugs and to prevent people from dying in severe untreated pain. But the recommendations have been widely applied to patients with non-terminal cancers and other chronic pain conditions. “There needs to be a division between terminal and non-terminal cancer pain treatment, because the goals are so different,” Kalso emphasizes. “Pain treatment in a cancer survivor shouldn’t be any different from other chronic pain patients,” who should not receive chronic opioids in ever-increasing doses, she added.
Focusing on the whole person
How important is pain management for patients with cancer? “It’s enormous,” says Mantyh. Today, people may live for decades with cancer-related pain. “In order to allow them to live the life they want to live, we have got to control the pain,” he stresses. To do that, Mantyh suggests patients advocate for pain relief as part of their course of treatment. “Treating the cancer is the foremost concern, but pain management should be built into any treatment strategy.” That may require inclusion of a pain specialist on the treatment team. Cancer research and pain research are both very rapidly changing fields, so asking an oncologist to expertly manage pain is like asking that person to have two specialties at once, he says. “It’s very challenging to be up-to-date on both. It’s not that [oncologists] don’t care, but they’re focused on the latest cancer treatments,” Mantyh says.
In the past, cancer treatment was aimed primarily—if not entirely—on eradicating tumors, with little consideration of the patient in a holistic sense. That is changing, and many cancer centers excel at considering every aspect of a patient’s experience—not just survival. Such a holistic approach can also help reduce pain, Kalso says, particularly when it comes to reducing sources of anxiety. For example, a patient may feel best cared for at home, but should plan ahead with their physicians for how to manage pain should it arise. Pain experts agree: this approach is better than playing catch-up once pain has already started. Finally, patients often receive many different and even conflicting bits of information about their illness and treatment, which can contribute to anxiety and pain. “It helps to be in an environment that provides patients with a sense of trust,” Kalso says.