antiquity
06-02-2002, 11:49 PM
Reported June 3, 2002
Managing Bone Pain -- Full-Length Doctor's Interview
In this full-length doctor's interview, Patrick Mantyh, Ph.D., explains a new approach to treating pain from bone cancer.
Ivanhoe Broadcast News Interview with
Patrick Mantyh, Ph.D., Pain researcher
University of Minnesota, Minneapolis, Minnesota
Topic: Managing Bone Pain
How serious is the problem of chronic pain?
Dr. Mantyh: I think it's a very significant problem. It frequently overwhelms the underlying disease as far as contributing to the deterioration of the patient's quality of life. If you think about people with arthritis and people with cancer and ask those individuals what thing most affects their ability to get out and enjoy life or enjoy a normal day, it's the pain. And when you ask a person with cancer what do they fear most about the disease once they understand they have cancer, I think it's really dying in pain and having significant pain over the course of the disease.
What is the biggest challenge in discovering pain treatments?
Dr. Mantyh: I think there are currently very good drugs to treat cancer pain. They are all more or less based around century-old drugs such as aspirin which was originally isolated from the willow bark and morphine which was isolated from the poppy and cocaine which isolated from coke leaves. But, the problem with all of those drugs is that they have significant side effects. Especially with cancer pain, which frequently becomes more severe over time, the side affect profile begins to overwhelm the individual and really contributes to a precipitous drop in the quality of life. The major attack we have in our research is to try to understand the mechanism by which the pain is generated and develop more specific therapies that go after the pain and don't have the side affect profile of currently used drugs.
Tell me a little bit more about those side effects you speak of.
Dr. Mantyh: Opiates are an excellent example -- they are the mainstay of the treatment of severe pain. But with time, one develops side effects such as depression, sedation, and constipation, and, especially at the doses required to treat severe pain, these side effects really contribute to a major reduction in the quality of life in the individual. Individuals, with advanced bone cancer pain for example, given enough of the opiate to adequately relieve all of the pain find that it's difficult for to really appreciate their surroundings as they did before.
How is the drug you have discovered and experimented with in the mice different
as far as side effects?
Dr. Mantyh: What we've really discovered is one of the principle agents causing the pain in individuals with bone cancer pain. It is this thing called an osteoclast. Everyone has them in their bones normally because our bones are constantly being remodeled over the course of our lives. But, in the case of people with bone cancer, the tumor comes in to the bone and it basically hijacks the cell. This causes a dramatic increase in the number of these osteoclast cells. Then these osteoclasts destroy bone. When they're destroying bone, they release a variety of factors that directly stimulate sensory nerves, which innervate bone and cause the pain. What we've done is target those specific cells that are out in the bone and basically do not allow the hypertrophy and the proliferation to occur. This therefore keeps the therapy out in the peripheral tissue and [the patients] don't have the C&S side effects, which are the major problem with morphine.
How do you stop the pain?
Dr. Mantyh: In our normal bone, in our normal every day life both you and I have osteoclast and osteoblast. Most people remember it by the C, the clast is the one that cuts, and the blast is the one that builds. Our bone is constantly being turned over and the reason we need these is if we fracture bone and as bone gets old, it's basically replaced with the new bone over the course of our life. When the tumor comes in, it hijacks the normal cells of the bone and it causes excessive bone destruction. Instead of having for example one osteoclast in your bone, there are now thousands of osteoclast, constantly eating away at the bone. This stimulates sensory nerves, which then result in this severe pain.
How does OPG turn off this process?
Dr. Mantyh: It basically comes in and it does not allow that proliferation, that increase in osteoclast. It doesn't allow the osteoclast to gnaw away at the bone day and night, and it returns the bone to its more normal state where there are very few osteoclast. The key is that by having this model we can begin to identify what are the critical factors causing pain and really dissect out what the molecules involved in this, then come up with more specific therapies to target the process, rather than simply giving a drug that acts through out the body.
Is OPG preliminary?
Dr. Mantyh: No. It is currently in clinical trials. I think the major thing we've done is identify the cell that we want to target to reduce the pain. Before the study, we really did not know what was causing the pain. We simply knew that when tumors invade bone, eventually one comes up with a very severe pain. But other than that, we really didn't know the process by which it occurs. I think that is really what's going to revolutionize medicine over the next decade or two decades, to begin to understand mechanism based therapies. What that allows you to do is to come in with a molecular scalpel and to go after one cell or one molecule and stop that, while leaving the rest of the cells and the rest of the molecules in the body in their normal state. That is where the side effects come from usually. When you give a drug such as morphine, it acts out in the peripheral tissue, it acts in the spinal cord, and it acts in the brain. Yes, it relieves the pain, but it also has these side effects because it can act in all these other areas. The only place that OPG is going to act is in the bone itself. It just stops the bone destruction and it doesn't have the same side effect profile because it doesn't have the actions in the brain, it doesn't have actions in the spinal cord.
How does OPG help relieve pain without causing drowsiness?
Dr. Mantyh: One of the problems with the opiates is that there are receptors for opiates in your cortex, in your central nervous system, and in your parts of the brain that you use for thinking, remembering, and emotions. When you give a person an opiate, the drug will act in the C&S, the brain, as well as the periphery. That's where the side effects come from. In contrast, the only cell OPG really targets is the one that's in the bone, which is normally involved in remodeling the bone. It's much more specific as far as its sight of action than in something like an opiate which has multiple sites of action, including in the brain, in the spine cord, and in the gut. That is one of morphine's major problems as a therapeutic agent. There are opiate receptors through out the gut and it really slows motility down. The gut goes much slower and you eventually develop severe constipation.
Is OPG a temporary or permanent fix?
Dr. Mantyh: I think that one continues to have to take the drug, but it does not appear as though the actions of OPG lessen with time. You get rid of these osteoclast and you can probably take that therapy for years. Once it basically gets rid of those cells that are causing the pain, it will continue to do so.
Do you consider this a cure for cancer?
Dr. Mantyh: Absolutely not. There appears to be some relationship though between tumors and bone destruction. When the tumor causes bone destruction, there appears to be a feedback loop so that the bone appears to release something, which causes further tumor growth. It may be that we can slow down the growth of cancer, but we're not eliminating it within the bone at the same time we're relieving pain.
In addition to OPG, do you find that patients still use other medication?
Dr. Mantyh: I don't think that we have completely eliminated all other drugs and even morphine. I don't think we have basically eliminated the need for morphine in these patients. What the hope is that we can drop the amount of morphine and the amount of analgesics down significantly, so it's a level where they do get relief of pain without the significant side effects. Where the side effects come from is that the doses they need are so high. If you begin to chip away at the different parts of the pain using these other drugs, such as OPG, you could basically keep reducing the amount of opiates you need. You can get those to a level where you get the analgesia without significant side effects.
What's the next step?
Dr. Mantyh: I think the next step is to use the model to begin to understand what are the molecules that drive this bone cancer pain. I think that the results will come up with other therapies, which can help treat prostate cancer, for example, when it actually occurs or breast cancer when it occurs. I think this ability to identify individual molecules with specific types of cancer will again allow these mechanism-based therapies to identify what specifically is occurring, targeting that cell and only that cell, and not have the side affect profile that we currently have with the drugs that are available.
Is OPG only for terminally ill people?
Dr. Mantyh: The original market that OPG was going after was osteoporosis. I think that the findings that we're making will probably have a major impact on all skeletal pain, whether its fractures, whether it's osteoporosis, whether it's something called Paget's disease. People with sickle cell anemia frequently have bone pain. I think these findings on bone cancer pain, which is probably the most severe skeletal pain that you encounter, will also have a significant impact on our understanding and ability to treat other skeletal pains.
Is the pain associated with chronic pain ever simply "all in the patients head?"
Dr. Mantyh: It's not all in their head. I think that there are dramatic neurochemical reorganizations that occur in patients with chronic pain, in dogs with chronic pain, and other experimental animals with chronic pain. By understanding what those changes are and how they amplify pain signals coming in to the body, we are going to be able to come up with therapies to put those neurochemical changes back to where they are when they're normal. In that way, reduce the amplification of chronic pain that occurs in those patients. The dog is interesting because it really is going to allow us to use these therapies, not only for humans but also in relieving pain that spontaneously occurs in dogs, which are obviously important in many people's lives.
Managing Bone Pain -- Full-Length Doctor's Interview
In this full-length doctor's interview, Patrick Mantyh, Ph.D., explains a new approach to treating pain from bone cancer.
Ivanhoe Broadcast News Interview with
Patrick Mantyh, Ph.D., Pain researcher
University of Minnesota, Minneapolis, Minnesota
Topic: Managing Bone Pain
How serious is the problem of chronic pain?
Dr. Mantyh: I think it's a very significant problem. It frequently overwhelms the underlying disease as far as contributing to the deterioration of the patient's quality of life. If you think about people with arthritis and people with cancer and ask those individuals what thing most affects their ability to get out and enjoy life or enjoy a normal day, it's the pain. And when you ask a person with cancer what do they fear most about the disease once they understand they have cancer, I think it's really dying in pain and having significant pain over the course of the disease.
What is the biggest challenge in discovering pain treatments?
Dr. Mantyh: I think there are currently very good drugs to treat cancer pain. They are all more or less based around century-old drugs such as aspirin which was originally isolated from the willow bark and morphine which was isolated from the poppy and cocaine which isolated from coke leaves. But, the problem with all of those drugs is that they have significant side effects. Especially with cancer pain, which frequently becomes more severe over time, the side affect profile begins to overwhelm the individual and really contributes to a precipitous drop in the quality of life. The major attack we have in our research is to try to understand the mechanism by which the pain is generated and develop more specific therapies that go after the pain and don't have the side affect profile of currently used drugs.
Tell me a little bit more about those side effects you speak of.
Dr. Mantyh: Opiates are an excellent example -- they are the mainstay of the treatment of severe pain. But with time, one develops side effects such as depression, sedation, and constipation, and, especially at the doses required to treat severe pain, these side effects really contribute to a major reduction in the quality of life in the individual. Individuals, with advanced bone cancer pain for example, given enough of the opiate to adequately relieve all of the pain find that it's difficult for to really appreciate their surroundings as they did before.
How is the drug you have discovered and experimented with in the mice different
as far as side effects?
Dr. Mantyh: What we've really discovered is one of the principle agents causing the pain in individuals with bone cancer pain. It is this thing called an osteoclast. Everyone has them in their bones normally because our bones are constantly being remodeled over the course of our lives. But, in the case of people with bone cancer, the tumor comes in to the bone and it basically hijacks the cell. This causes a dramatic increase in the number of these osteoclast cells. Then these osteoclasts destroy bone. When they're destroying bone, they release a variety of factors that directly stimulate sensory nerves, which innervate bone and cause the pain. What we've done is target those specific cells that are out in the bone and basically do not allow the hypertrophy and the proliferation to occur. This therefore keeps the therapy out in the peripheral tissue and [the patients] don't have the C&S side effects, which are the major problem with morphine.
How do you stop the pain?
Dr. Mantyh: In our normal bone, in our normal every day life both you and I have osteoclast and osteoblast. Most people remember it by the C, the clast is the one that cuts, and the blast is the one that builds. Our bone is constantly being turned over and the reason we need these is if we fracture bone and as bone gets old, it's basically replaced with the new bone over the course of our life. When the tumor comes in, it hijacks the normal cells of the bone and it causes excessive bone destruction. Instead of having for example one osteoclast in your bone, there are now thousands of osteoclast, constantly eating away at the bone. This stimulates sensory nerves, which then result in this severe pain.
How does OPG turn off this process?
Dr. Mantyh: It basically comes in and it does not allow that proliferation, that increase in osteoclast. It doesn't allow the osteoclast to gnaw away at the bone day and night, and it returns the bone to its more normal state where there are very few osteoclast. The key is that by having this model we can begin to identify what are the critical factors causing pain and really dissect out what the molecules involved in this, then come up with more specific therapies to target the process, rather than simply giving a drug that acts through out the body.
Is OPG preliminary?
Dr. Mantyh: No. It is currently in clinical trials. I think the major thing we've done is identify the cell that we want to target to reduce the pain. Before the study, we really did not know what was causing the pain. We simply knew that when tumors invade bone, eventually one comes up with a very severe pain. But other than that, we really didn't know the process by which it occurs. I think that is really what's going to revolutionize medicine over the next decade or two decades, to begin to understand mechanism based therapies. What that allows you to do is to come in with a molecular scalpel and to go after one cell or one molecule and stop that, while leaving the rest of the cells and the rest of the molecules in the body in their normal state. That is where the side effects come from usually. When you give a drug such as morphine, it acts out in the peripheral tissue, it acts in the spinal cord, and it acts in the brain. Yes, it relieves the pain, but it also has these side effects because it can act in all these other areas. The only place that OPG is going to act is in the bone itself. It just stops the bone destruction and it doesn't have the same side effect profile because it doesn't have the actions in the brain, it doesn't have actions in the spinal cord.
How does OPG help relieve pain without causing drowsiness?
Dr. Mantyh: One of the problems with the opiates is that there are receptors for opiates in your cortex, in your central nervous system, and in your parts of the brain that you use for thinking, remembering, and emotions. When you give a person an opiate, the drug will act in the C&S, the brain, as well as the periphery. That's where the side effects come from. In contrast, the only cell OPG really targets is the one that's in the bone, which is normally involved in remodeling the bone. It's much more specific as far as its sight of action than in something like an opiate which has multiple sites of action, including in the brain, in the spine cord, and in the gut. That is one of morphine's major problems as a therapeutic agent. There are opiate receptors through out the gut and it really slows motility down. The gut goes much slower and you eventually develop severe constipation.
Is OPG a temporary or permanent fix?
Dr. Mantyh: I think that one continues to have to take the drug, but it does not appear as though the actions of OPG lessen with time. You get rid of these osteoclast and you can probably take that therapy for years. Once it basically gets rid of those cells that are causing the pain, it will continue to do so.
Do you consider this a cure for cancer?
Dr. Mantyh: Absolutely not. There appears to be some relationship though between tumors and bone destruction. When the tumor causes bone destruction, there appears to be a feedback loop so that the bone appears to release something, which causes further tumor growth. It may be that we can slow down the growth of cancer, but we're not eliminating it within the bone at the same time we're relieving pain.
In addition to OPG, do you find that patients still use other medication?
Dr. Mantyh: I don't think that we have completely eliminated all other drugs and even morphine. I don't think we have basically eliminated the need for morphine in these patients. What the hope is that we can drop the amount of morphine and the amount of analgesics down significantly, so it's a level where they do get relief of pain without the significant side effects. Where the side effects come from is that the doses they need are so high. If you begin to chip away at the different parts of the pain using these other drugs, such as OPG, you could basically keep reducing the amount of opiates you need. You can get those to a level where you get the analgesia without significant side effects.
What's the next step?
Dr. Mantyh: I think the next step is to use the model to begin to understand what are the molecules that drive this bone cancer pain. I think that the results will come up with other therapies, which can help treat prostate cancer, for example, when it actually occurs or breast cancer when it occurs. I think this ability to identify individual molecules with specific types of cancer will again allow these mechanism-based therapies to identify what specifically is occurring, targeting that cell and only that cell, and not have the side affect profile that we currently have with the drugs that are available.
Is OPG only for terminally ill people?
Dr. Mantyh: The original market that OPG was going after was osteoporosis. I think that the findings that we're making will probably have a major impact on all skeletal pain, whether its fractures, whether it's osteoporosis, whether it's something called Paget's disease. People with sickle cell anemia frequently have bone pain. I think these findings on bone cancer pain, which is probably the most severe skeletal pain that you encounter, will also have a significant impact on our understanding and ability to treat other skeletal pains.
Is the pain associated with chronic pain ever simply "all in the patients head?"
Dr. Mantyh: It's not all in their head. I think that there are dramatic neurochemical reorganizations that occur in patients with chronic pain, in dogs with chronic pain, and other experimental animals with chronic pain. By understanding what those changes are and how they amplify pain signals coming in to the body, we are going to be able to come up with therapies to put those neurochemical changes back to where they are when they're normal. In that way, reduce the amplification of chronic pain that occurs in those patients. The dog is interesting because it really is going to allow us to use these therapies, not only for humans but also in relieving pain that spontaneously occurs in dogs, which are obviously important in many people's lives.