1. Samson, Kurt

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The current opioid epidemic, coupled with increased long-term survival rates, is driving research into a myriad of potential alternatives for treating cancer-associated pain. However, it may be some time before these are available for suffering patients, researchers say.

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On Jan. 23, 2019, the NCI released an overview of where things currently stand with cancer-related pain research, emphasizing the need for better treatment options because patients are living longer with advanced cancer, and the number of long-term cancer survivors continues to grow.


"The increased prevalence of cancer pain and the impact of the opioid epidemic on cancer pain management-and on managing chronic pain in general-have sparked renewed interest in developing new, nonaddictive pain medications as well as nondrug approaches for managing chronic pain," according to the NCI report.


Even so, less than 2 percent of the NIH budget goes toward pain research, Cindy Steinberg, the U.S. Pain Foundation's National Director of Policy and Advocacy, told a Senate hearing Feb. 12, 2019.


"The opioid crisis has revealed decades of underinvestment in research aimed at understanding the underlying mechanisms and treatment of pain, such that we have no completely effective therapies that will eliminate chronic pain and only a handful of good ones that substantially help carefully selected patients," she said.


Marcin Chwistek, MD, Associate Professor of Hematology/Oncology and Director of the Pain and Palliative Care Program at Fox Chase Cancer Center in Philadelphia, agreed. "At this moment in cancer pain management, there has not been much progress. We're still using the same medications that we have used for years," he told Oncology Times. "Opioids are still the best we have."


Finding alternatives is "the Holy Grail" of pain research, with research on neuromodulation and neurostimulation rapidly progressing but still in the early stages, he said.


Although the pace of cancer pain research may be slow, advances are being made. For example, Indiana University of Medicine investigators announced Feb. 19, 2019, that they had developed the first ever blood test using pain severity biomarkers they said can objectively measure pain severity.


In addition to providing an objective measure of pain, the blood test might help match the biomarkers with potential treatment options, according to Alexander Niculescu, MD, PhD, and his colleagues (Mol Psychiatry 2019; doi:10.1038/s41380-018-0345-5).


"It's been a goal of many researchers and a dream to find biomarkers for pain," according to Niculescu, who conducted the study among patients at the Roudebush VA Medical Center in Indianapolis. "We have come out of left field with an approach that had worked well in psychiatry for suicide and depression in previous studies. We applied it to pain, and we were successful."


Cautious Optimism

According to the NCI review, new animal models of some types of cancer pain have helped researchers begin to better understand its underlying biology, especially in identifying molecules that generate pain signals and gaining insights into how the nervous system transmits these signals to the brain. These have led to many ongoing clinical trials including some large studies needed for FDA approval.


"Understanding cancer pain is challenging and the number of researchers working in this area is small. Nevertheless, scientists who study cancer pain are cautiously optimistic that better treatments are on the horizon," said Ann O'Mara, PhD, recently retired as Head of Palliative Research in NCI's Division of Cancer Prevention, in the NCI report.


William Maixner, DDS, PhD, President of the American Pain Society and Director of the Center for Translational Pain Medicine, at Duke University Medical Center, also noted several advances in understanding underlying pain mechanisms, notably findings that there is a common mechanism in tumor growth, differentiation, and neurobiology in pain processing.


He told Oncology Times that there are signs that epidermal growth factor receptor tyrosine kinase inhibitors block inflammatory and neuropathic pain, and convergence of similar mechanisms being studied, he noted, as well as recognition that some of the substances we use may be pro-growth related.


"There are also signs that taxol and other chemotherapy can have profound effects on the somatosensory system. This could be one reason why many patients have more disabling pain after chemo."


Patrick Mantyh, PhD, of the University of Arizona in Tucson, shared progress in cancer-related bone pain. His lab developed a mouse model of bone tumors and found such tumors stimulate growth of nearby pain-transmitting nerve fibers.


Tanezumab, which blocks the activity of nerve growth factor (NGF), a pain-signaling molecule, is currently being tested in phase III trials in bone pain, while another approach seeks to block NGF receptor TrkA (tropomyosin receptor kinase A) activity on sensory nerve fibers.


Head & Neck Cancer

In the NCI report, Brian Schmidt, DDS, MD, PhD, of New York University's College of Dentistry, discussed progress in treating head and neck pain due to oral cancer, which is especially intense. He noted that 70-75 percent of such patients suffer pain, and to study this he collects tumor-produced, pain-causing substances during surgery using microdialysis.


"The cancer tissue degenerates rapidly after surgery. By sampling the cancer microenvironment with the tumor in place, we glean a more accurate understanding of how the tumor causes pain," he explained.


In other cases, Schmidt removes small pieces of tumor as well as normal tissue from an adjacent area in the mouth and, from these samples, his lab is working to identify pain-promoting substances found in the cancerous, but not the normal, tissue.


Prime suspects they have identified include proteases that break down proteins and help cancer spread by destroying surrounding tissues. The enzymes can also attach to and activate the protease-activated receptor-2 (PAR2) on neurons, an area of considerable research interest by pain investigators.


"When proteases activate PAR2 on neurons, PAR2 can cause other pain receptors on neurons to become more sensitive," Schmidt said. As a result, "a stimulus that is not normally painful, such as a potato chip hitting the tongue, can become exquisitely painful."


He and Nigel Bunnett, PhD, of Columbia University, are currently collaborating in research on a new class of inhibitors to block PAR2, as well as investigating NGF and endothelin receptors in metastatic cancer.


Peripheral Neuropathies

Other research teams are making progress against chemotherapy-induced peripheral neuropathy (CIPN) that can be so disabling that some patients have therapeutic doses reduced or even have treatment terminated. The mechanisms behind CIPN are unknown, but animal and human studies suggest that chemotherapy drugs that can cause neuropathies may stress neurons and lead to nerve inflammation and damage.


"The nonpainful components such as numbness in the hands and feet also greatly impact patient function and well-being," noted Patrick Dougherty, PhD, in the NCI research summary. Dougherty is an investigator in the Department of Pain Medicine at the University of Texas MD Anderson Cancer Center.


Recent progress in CIPN includes results from an animal study that found several synthetic cannabinoids that reduced CIPN symptoms in rats by bypassing the central nervous system, eliminating any psychoactive concerns in patients.


Researchers are also investigating agents that could target the source of the problem and reverse or, ideally, prevent CIPN. Some of these agents also have known antitumor effects, making them especially attractive, according to Dougherty.


"Some new types of agents are coming to clinical trials, and right now the data [from animal studies] is very promising."


Several agents that block histone deacetylase activity in order to enhance response to chemotherapy are in clinical trials are also being studied in CIPN. "However, when it comes to new drugs to treat or prevent CIPN, we are still very much in a discovery mode," he noted.


The NCI report also reviews research into non-drug approaches for relieving cancer-related pain, including cognitive behavioral therapy, acupuncture, yoga, tai chi, and mindfulness meditation, all of which are currently being investigated in clinical trials, in addition to therapeutic cannabis and its extracts that can reduce pain or help patients better cope with symptoms.


Cannabinoid Research Barriers

Witnesses at the Feb. 14 Senate hearing on the opioid crisis told lawmakers that promising research on cannabinoids is being stymied by the continued federal prohibition of marijuana as a Schedule 1 substance under the DEA. Even though many states have legalized medical marijuana and its extracts, institutional research efforts continue to be limited by legal concerns and multi-agency regulatory issues, they said.


"The whole field of cannabis research is very exciting," Chwistek told Oncology Times. "We have found that that endocannabinoid system plays a role in regulating pain by stimulating or inhibiting pain signals in the nervous system."


However, he and other witnesses told lawmakers that federal law continues to inhibit cannabis research even though 33 states have cleared the use of medical marijuana.


"There is a tremendous amount of interest in this among patients and providers, but we are pretty much still in the dark, research-wise. I think that we have to forge ahead with clinical trials," Chwistek concluded.


Kurt Samson is a contributing writer.