Library
APS Bulletin • Volume 18, Number 3, 2008
Research Update
Judith Paice, PhD RN FAAN, Guest Department Editor
Trends in Cancer Pain Research: Quality-of-Life Concerns Take Center Stage
Jane Martinsons, Staff Writer
The media spotlight has strayed little from the issue of cancer over the years, but recently the focus has changed to reflect the new reality of cancer patients living much longer than ever before. The extension of both patients’ life spans and the length of their cancer treatments is giving rise to a host of quality-of-life concerns, including chronic cancer pain and chemotherapy-induced peripheral neuropathy.
“The number of people with neuropathy from treatment is exploding, which presents a double-edged sword in that the very treatments that allow people with cancer to live longer, with improved quality of life, also can lead to neuropathy, surgery-induced phantom limb pain, and radiation-induced chronic pain syndromes,” says Judith A. Paice, PhD RN FAAN, of Northwestern University Medical School in Chicago and immediate past president of the American Pain Society. “It appears that living longer comes at the cost of chronic pain.”
| “Mantyh predicts that in the next 10 years, we will tailor analgesic therapies for relieving different types of cancer pain just as we currently tailor the specific anticancer therapy for treating the underlying cancer itself.” |  |
Patrick W. Mantyh, PhD, agrees that the spotlight on cancer pain highlights concern with quality of life. A professor of pharmacology at the University of Arizona and a research scientist at the Minneapolis VA Medical Center, he says that current therapies that relieve pain have a variety of unwanted side effects; elderly patients, for instance, often experience sedation, constipation, and mental clouding.
Patients who have very aggressive cancer such as pancreatic cancer generally have less time to live and want to be “cognitively there” with the time they have available, he says. But patients with prostate or breast cancer, for example, can live for years, if not decades, with their cancer. For them, quality-of-life is of particular concern. “The side effects of morphine over that time can significantly interfere with patients’ quality of life and ability to function at the highest level,” he says.
Mantyh adds that a major goal of new therapies under development is to relieve pain more effectively and have fewer side effects than therapies currently available. This in turn may make it more likely that patients with difficult-to-treat cancers such as pancreatic or lung cancer will become more willing to enroll in novel cancer treatments and clinical trials.
Another issue gaining attention is the question over whether cancer is cured or considered a chronic-nondisabling disease. “Many cancer specialists are actually coming to the conclusion that the latter may be where we can park many of the cancers,” Mantyh says. “For example, many older prostate cancer patients will die of something other than their prostate cancer. If you can control the pain without significant side effects you can make the cancer a chronic-nondisabling disease.”
Gary J. Bennett, PhD, of the departments of dentistry and anesthesia at McGill University, is a leading researcher on chemotherapy-induced peripheral neuropathy, a problem that grows as the number of neurotoxic agents continues to rise. He says that several surveys show that pain control in patients with cancer pain is “less than optimal” and that achieving pain control is difficult.
Bennett says that many cancer patients experience ordinary inflammatory pain due to tumors directly damaging nerves. “When a surgeon debrides tumors, especially those growing in the brachial or lumbar plexus regions, there may be traumatic injury to the nerves. Radiation of tumors in surgical fields damages the blood supply to nerves and produces a radiation-evoked vascular neuropathy.”
Many drugs that kill tumor cells have the dose-limiting side effect of neurotoxicity and in many patients this evokes a neuropathic pain syndrome, Bennett says, adding that paclitaxel, cisplatin, oxaliplatin, and proteasome inhibitors produce painful peripheral neuropathies.
“The dose limiting side effect means that we are not giving drug doses of maximal tumor-killing ability,” Bennett says. “We are giving suboptimal doses for killing tumor cells that don’t produce terrible neuropathy in everybody. If we could prevent neuropathy and pain, we could give higher doses, kill more tumor cells, and probably save some lives. All of this is becoming a bigger problem because cancer patients are living longer than they used to.”
Innovative Cancer Pain Research
Mantyh’s research began in 1998 when there were no models of cancer pain with which to begin to dissect out different mechanisms. “If asked, they and other leading researchers would say that bone cancer pain is one of the most problematic ones to deal with because so many of the tumors such as breast, lung and prostate preferentially metastasize to bone,” Mantyh says.
“Until the first model of cancer pain was developed in 1999, we viewed cancer pain as if it was severe inflammatory pain. We didn’t have preclinical models of cancer pain to determine whether the cancer pain is driven by different mechanisms and factors versus what drives nonmalignant cutaneous pain. For example, we now know that there are a variety of mechanisms and factors that drive bone cancer pain that are quite different from what drive most cutaneous pains.”
What has also become clear is that different types of cancer pain are driven by different mechanisms and factors. For example, preclinical animal models have suggested that bone cancer pain and pancreatic cancer pain are two very different pains. Thus, while NSAIDs or COX-2 inhibitors may, at least initially, be effective in attenuating bone cancer pain they will have virtually no effect on pancreatic cancer pain, a visceral pain. “That’s where the neurobiology of pain is really headed—trying to understand why visceral pain is different from bone pain which is different from cutaneous pain. This is why it is important to have preclinical models of bone cancer pain versus pancreatic cancer pain. With these models in hand, you can address what specific mechanisms drive different types of cancer pain, and what therapies best relieve each type of cancer pain with the fewest side effects.
“I think that what we are finding is that there are some similarities and quite a few differences,” Mantyh says. “Understanding what drives different pains in different tissues and cancers will allow us to develop mechanism-based pain therapies without the side-effect profile of current therapies.”
Meanwhile, Bennett works with animal models to study painful peripheral neuropathies produced by the chemotherapeutic agents vincristine, paclitaxel, and oxaliplatin. “Nerve injury is a low-dose effect of these drugs,” Bennett says. “The rats used in the models don’t have cancer but receive anticancer drugs—and almost every single animal gets the pain syndrome. It lasts for months after chemotherapy is discontinued, similar to what happens with people. However, Jeff Mogil and his colleagues have shown that if you look at different strains of mice, you see differential susceptibility. That, of course, means that there is a genetic component at play.”
| “We’ve been looking at peripheral neuropathy in models of traumatic nerve injury for quite some time, but this recent work is different. It’s new and exciting area for pain research that’s clinically relevant and scientifically cutting-edge.” |
 |
Animal models are extremely important to finding pain-relieving drugs that work, Bennett says. Because aspirin-like drugs such as NSAIDs and opiates have little or no effect in treating neuropathic pain, other compounds are being studied. “We just published a paper in Pain Medicine (Xiao, Naso, & Bennett, 2008) that finds that quite a few drugs readily available on the market, such as tramadol, amitryptiline, ethosuximide and gabapentin, help these animals.” His laboratory also has evidence that a generic drug, acetyl-L-carnitine, can both prevent and reverse the chemotherapy-evoked pain syndrome. The hope is patients could try and eventually be helped by these drugs.
In trying to determine the cause of neuropathic pain syndrome, Bennett says that “the curious thing is that at the level of the peripheral nerve, we don’t find any abnormality—neither degenerating axons nor axons that appear abnormal. The only abnormality of nerves we see clearly is the distal tips of nerve fibers that innervate the skin.” It’s in the distal-most tips where anticancer drugs are having their effect, which is believed to be due to poisoning of the mitochondria in axons, he says. He hypothesizes that this leads to an energy-production deficit that has its greatest effect in places with the highest demand for energy, most likely the terminal receptors.
“Current measures of the function of mitochondria find that both paclitaxel and oxaliplatin impair the ability of mitochondria to make energy,” Bennett says. “That’s pretty exciting. This is the first time that mitochondria have been clearly implicated in a neuropathic pain syndrome. It suggests that we may be able to prevent it by finding ways to protect mitochondria.” Bennett stresses that if the poisoning of mitochondria is shown to be a primary pathology, it will open up a new field on ways to treat and prevent pain.
Future Trends
Mantyh predicts that in the next 10 years, we will begin to tailor therapies for relieving different types of cancer pain just as we tailor therapies for treating the underlying cancer itself. “That is going to be enormously useful because if we can control the cancer pain it not only has a significant impact on improving patients’ quality of life but it also allows them to proceed through the full chemotherapeutic or anticancer regimes.
“A major focus of this field is to develop clinically relevant animal models that can be useful in understanding what drives different types of cancer pain. Ultimately, the person who designs a clinical trial for a new therapy for prostate bone cancer pain needs to have some idea of the size of the effect, what end points should be incorporated into the study, and whether analgesics have an effect on the cancer itself. Thus, if you have animal models that closely mirror the human condition, you could look at a model of breast, lung, or prostate bone cancer to see whether one responds better than the others, and consider pooling all of your patients or having individual groups.
“Cancer pain, like our treatments and understanding of cancer, are really beginning to yield results. The key thing is that different cancer pains are actually driven by different mechanisms,” he says. “The more we learn about the mechanisms that drive different types of cancer pain, the more likely we can focus on therapies that have a better chance of seeing a positive signal—and actually develop specific pain therapies for specific cancer pains.”
Bennett is also optimistic about the future. The animal models appear to closely reflect what is happening in the patients, he says, and so drugs that successfully control the pain syndrome in the experimental animal have a good chance of working in patients. He notes that chemotherapy-evoked neuropathic pain is an especially attractive target because it offers the opportunity for preventive treatment. One can hope that it will be easier to prevent neuropathic pain than to cure it.
Mantyh is impressed by how much progress has been made in the field of cancer pain research as well understanding how much more remains to be accomplished. “For example, it is becoming increasingly clear that some analgesics have the potential to not only relieve cancer pain but also affect the underlying cancer itself,” he says. “This insight unites the fields of pain and cancer research and opens up the possibility of developing therapies that simultaneously decrease the cancer patient’s pain and reduce tumor growth and metastases.”
Mantyh further stresses that having such a dual effect would not only improve patients’ quality of life and functionality, but would increase their survival.
Reference
Xiao, W., Naso, L.,Bennett, G. J. (2008). Experimental studies of potential analgesics for the treatment of chemotherapy-evoked painful peripheral neuropathies. Pain Medicine, 9(5),505–517.
Suggested Reading:
Honore P., Luger N.M., Sabino, M.A., Schwei, M.J., Rogers, S.D., Mach, D.B., et
al. (2000). Osteoprotegerin blocks bone cancer-induced skeletal destruction,
skeletal pain and pain-related neurochemical reorganization of the spinal cord.
Nature Medicine, 6, 521-8.
Lindsay, T.H., Jonas, B.M., Sevcik, M.A., Kubota, K., Halvorson, K.G., Ghilardi, J.R., et al. (2005). Pancreatic cancer pain and its correlation with changes in tumor vasulature, macrophage infiltration, neuronal innervation, body weight and disease progression. Pain, 119, 233-46.
Mantyh, P.W. (2006). Cancer pain and its impact on diagnosis, survival and quality of life. Nature Reviews Neuroscience, 10, 797-809.
Sabino, M.A.C., Ghilardi, J.R., Jongen, J. L.M., Keyser, C.P., Luger, N.M., Mach, D.B., et al. (2002). Simultaneous reduction of cancer pain, bone destruction, and tumor growth by selective inhibition of cyclooxygenase 2. Cancer Research, 62, 7343-9.
Sevcik, M.A., Ghilardi, J.R., Peters, C.M., Lindsay, T.H., Halvorson, K.G., Jonas, B.M., et al. (2005). Anti-NGF therapy profoundly reduces bone cancer pain and the accompanying increase in markers of peripheral and central sensitization. Pain, 115, 128-41.
