- Email: [email protected]
A mechanism based understanding of cancer pain
Pain 96 (2002) 1–2 www.elsevier.com/locate/pain
Editorial
A mechanism based understanding of cancer pain In 2000 in the United States alone, 1.2 million new cases of cancer were diagnosed and 500,000 individuals died from cancer (American Cancer Society, 2001). Many of these patients have severe pain as pain is one of cancer’s most common symptoms and two-thirds of cancer patients have pain severe enough to require treatment at some point during the course of their disease (Foley, 1999; Portenoy and Lesage, 1999). The good news for patients with cancer is that with improvements in detection and treatment, cancer patients are surviving for significantly longer periods than in the past. Unfortunately, the quality of life of these patients is frequently diminished and pain can be a major contributor to this decrease in the quality of life (Foley, 2001; Portenoy et al., 1999). The greatest obstacles for developing new treatments for cancer pain are our limited knowledge of the basic neurobiological mechanisms that generate cancer pain (Payne, 2000; Payne et al., 2001). Thus, while there have been significant improvements in empirically based strategies for treating cancer pain, full relief of cancer-induced pain is often achieved with difficulty and accompanied by lifeimpairing sides effects (Foley, 1999; Portenoy and Lesage, 1999). The relative ineffectiveness of current treatments reflects the realities that therapies have not changed for decades and that existing therapies can be burdensome to administer and are often accompanied by significant side effects and complications (Portenoy et al., 1999). Probably most importantly from the standpoint of developing new therapies is that the neurobiological basis for pharmacological treatments is largely empirical and is based on scientific advances in pain conditions other than those induced by cancer (Honore and Mantyh, 2000). In attempting to define the mechanisms that generate and maintain cancer pain, a major problem was the lack of a well-developed animal model of cancer pain. In the past 2 years, this has dramatically changed with the introduction of a mouse model of bone cancer pain, which appears to mirror many of the changes observed in patients with bone cancer pain. In this model, mouse sarcoma cells are injected into the marrow space of the mouse femur and the injection hole sealed, confining the tumor cells to the bone (Schwei et al., 1999). Two to three weeks after injection of the tumor cells, animals showed tumor-induced bone destruction of the
injected femur, both ongoing and movement evoked painrelated behaviors and a stereotypic set of neurochemical changes in the spinal cord dorsal horn that receives sensory inputs from the affected femur. A key question that was addressed using this model was whether bone cancer pain was simply a type of inflammatory or neuropathic pain or whether it had a distinct neurochemical signature. Experiments which examined the behavioral and neurochemical changes induced by the bone cancer, inflammatory or neuropathic pain, all of which were generated in the same strain of mouse, demonstrated that each of these pain conditions generated a unique set of behavioral changes and a unique set of neurochemical changes in the spinal cord and sensory neurons (Honore et al., 2000b). This data suggested that cancer pain will not simply be a type of inflammatory or neuropathic pain but different types of cancer pain may be unique persistent pain states that change with the evolution of the disease. In the present issue of Pain, Medhurst et al. (2002) significantly add to our knowledge and the models available for studying cancer pain by introducing the first rat model of cancer pain using the injection of rat mammary carcinoma cells into the rat tibia (Medhurst et al., 2001). This paper is important as it not only provides another highly needed model of cancer pain in a different species than mouse, but the authors demonstrate that many of the same neurochemical and behavioral changes observed in mice with bone cancer are also observed in a rat model of bone cancer. Additionally, this paper describes several novel behavioral changes such as weight bearing on the affected limb and general changes in the activity levels of the animals with bone cancer that are similar to those observed in humans with bone cancer pain (Mercandante and Arcuri, 1998). A critical question in assessing the usefulness of any model of a disease is not only whether it permits insights into the pathophysiology and mechanisms that drive the disease process but also whether the model can be used to test new therapies to treat the disease. In both the mouse and rat models of bone cancer pain, this appears to be the case. Thus, in the mouse model, it was shown that osteoprotegerin, a naturally secreted decoy receptor that inhibits tumor-induced-osteoclast survival, maturation and hypertrophy could significantly inhibit bone destruction, bone cancer pain related pain behaviors and bone cancer induced
0304-3959/02/$20.00 q 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. PII: S 0304-395 9(01)00482-1
2
P.W. Mantyh / Pain 96 (2002) 1–2
neurochemical alterations in the spinal cord (Luger et al., 2001; Honore et al., 2000a). In the rat model of bone cancer pain, it is shown that morphine is effective in reducing bone cancer related pain behaviors whereas at least at advanced stages of bone destruction, inhibitors of cycolooxygenase-2 were not effective (Medhurst et al., 2001). Together these data suggest that these and other models of cancer pain that have been developed (Cain et al., 2001) can provide insight into the mechanisms that generate and maintain cancer pain as well as serving as an important pre-clinical tool for the development of novel therapies to treat cancer pain. While we have made significant progress in the last 2 years and are now getting our first glimpse of the mechanisms that drive cancer pain, we are still at the beginning. For the first time, animal models of cancer pain are now available that mirror the clinical picture of human patients with cancer pain. Information generated from these models should provide information and a platform for dissecting out the various mechanisms that generate and maintain the different types of cancer pain. Since the cancer models have been developed in rodents, human tumors can be implanted in immuno-compromised rodents, should allow definition of whether a different set of factors generate pain in different types of human tumors. These animal models may also offer insight into one of the major conundrums of cancer pain, which is why the severity of cancer pain is so variable from tumor to tumor and even between patients with the same tumor. Newer molecular techniques using microarrays, proteomics and cluster analysis will provide additional data about the features of different tumors and how they can differentially induce cancer pain in various peripheral tissues. Once the mechanisms by which the different types of cancer induce pain is elucidated, this should lead to the identification of molecular targets and the development of mechanism based therapies (Hunt and Mantyh, 2001; Julius and Basbaum, 2001). Ultimately, the key to success in this field will be to integrate tumor biology with our increasing understanding of the molecular and cell biology of how pain is generated and maintained. The goal of this research is clear, to use the knowledge gained from the newly developed models of cancer pain to improve the quality of life of all those who suffer from cancer pain.
Cain DM, Wacnik PW, Eikmeier L, Beitz A, Wilcox GL, Simone DA. Functional interactions between tumor and peripheral nerve in a model of cancer pain in the mouse. Pain Med 2001;2:15–23. Foley KM. Advances in cancer pain. Arch Neurol 1999;56:413–417. Foley KM. Easing the suffering of cancer patients. The Scientist 2001;15:6. Honore P, Mantyh PW. Bone cancer pain: from mechanism to model to therapy. Pain Med 2000;1:303–309. Honore P, Luger NM, Sabino MA, Schwei MJ, Rogers SD, Mach DB, O’Keefe PF, Ramnaraine ML, Clohisy DR, Mantyh PW. Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord. Nat Med 2000a;6:521–528. Honore P, Rogers SD, Schwei MJ, Salak-Johnson JL, Luger NM, Sabino MAC, Clohisy DR, Mantyh PW. Murine models of inflammatory neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons. Neuroscience 2000b;98:585–598. Hunt SP, Mantyh PW. The molecular dynamics of pain control. Nat Rev Neurosci 2001;2(2):83–91. Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature 2001;413:203–210. Luger NM, Honore P, Sabino MAC, Schwei MJ, Rogers SD, Mach DB, Clohisy DR, Mantyh PW. Osteoprotegerin diminishes advanced bone cancer pain. Cancer Res 2001;61:4038–4047. Medhurst SJ, Walker K, Bowes M, Kidd BL, Glatt M, Muller M, Hattenberger M, Vaxelaire J, O’Reilly T, Wotherspoon G, Winter J, Green J, Urban L. A rat model of bone cancer pain. Pain 2002;96:129– 140. Mercadante S, Arcuri E. Breakthrough pain in cancer patients: pathophysiology and treatment. Cancer Treat Rev 1998;24:425–432. Payne R. Chronic pain: challenges in the assessment and management of cancer pain. J Pain Symptom Manage 2000;19:S12–S15. Payne R, Santiago-Palma J, Cheville A. Cancer rehabilitation in the new millennium – introduction. Cancer 2001;92:969. Portenoy RK, Lesage P. Management of cancer pain. Lancet 1999;353: 1695–1700. Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: characteristics and impact in patients with cancer pain. Pain 1999;81:129–134. Schwei MJ, Honore P, Rogers SD, Salak-Johnson JL, Finke MP, Ramnaraine ML, Clohisy DR, Mantyh PW. Neurochemical and cellular reorganization of the spinal cord in a murine model of bone cancer pain. J Neurosci 1999;19:10886–10897.
Patrick W. Mantyh a,b,* Departments of Preventive Sciences, Neuroscience, Psychiatry, and Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA b VA Medical Center, Minneapolis, MN 55417, USA a
References American Cancer Society: Annual Cancer Statistics for the US in 2000, 2001.
* Tel.: 11-612-626-0180; fax: 11-612-626-2565. E-mail address: [email protected] (P. W. Mantyh).
Editorial
A mechanism based understanding of cancer pain In 2000 in the United States alone, 1.2 million new cases of cancer were diagnosed and 500,000 individuals died from cancer (American Cancer Society, 2001). Many of these patients have severe pain as pain is one of cancer’s most common symptoms and two-thirds of cancer patients have pain severe enough to require treatment at some point during the course of their disease (Foley, 1999; Portenoy and Lesage, 1999). The good news for patients with cancer is that with improvements in detection and treatment, cancer patients are surviving for significantly longer periods than in the past. Unfortunately, the quality of life of these patients is frequently diminished and pain can be a major contributor to this decrease in the quality of life (Foley, 2001; Portenoy et al., 1999). The greatest obstacles for developing new treatments for cancer pain are our limited knowledge of the basic neurobiological mechanisms that generate cancer pain (Payne, 2000; Payne et al., 2001). Thus, while there have been significant improvements in empirically based strategies for treating cancer pain, full relief of cancer-induced pain is often achieved with difficulty and accompanied by lifeimpairing sides effects (Foley, 1999; Portenoy and Lesage, 1999). The relative ineffectiveness of current treatments reflects the realities that therapies have not changed for decades and that existing therapies can be burdensome to administer and are often accompanied by significant side effects and complications (Portenoy et al., 1999). Probably most importantly from the standpoint of developing new therapies is that the neurobiological basis for pharmacological treatments is largely empirical and is based on scientific advances in pain conditions other than those induced by cancer (Honore and Mantyh, 2000). In attempting to define the mechanisms that generate and maintain cancer pain, a major problem was the lack of a well-developed animal model of cancer pain. In the past 2 years, this has dramatically changed with the introduction of a mouse model of bone cancer pain, which appears to mirror many of the changes observed in patients with bone cancer pain. In this model, mouse sarcoma cells are injected into the marrow space of the mouse femur and the injection hole sealed, confining the tumor cells to the bone (Schwei et al., 1999). Two to three weeks after injection of the tumor cells, animals showed tumor-induced bone destruction of the
injected femur, both ongoing and movement evoked painrelated behaviors and a stereotypic set of neurochemical changes in the spinal cord dorsal horn that receives sensory inputs from the affected femur. A key question that was addressed using this model was whether bone cancer pain was simply a type of inflammatory or neuropathic pain or whether it had a distinct neurochemical signature. Experiments which examined the behavioral and neurochemical changes induced by the bone cancer, inflammatory or neuropathic pain, all of which were generated in the same strain of mouse, demonstrated that each of these pain conditions generated a unique set of behavioral changes and a unique set of neurochemical changes in the spinal cord and sensory neurons (Honore et al., 2000b). This data suggested that cancer pain will not simply be a type of inflammatory or neuropathic pain but different types of cancer pain may be unique persistent pain states that change with the evolution of the disease. In the present issue of Pain, Medhurst et al. (2002) significantly add to our knowledge and the models available for studying cancer pain by introducing the first rat model of cancer pain using the injection of rat mammary carcinoma cells into the rat tibia (Medhurst et al., 2001). This paper is important as it not only provides another highly needed model of cancer pain in a different species than mouse, but the authors demonstrate that many of the same neurochemical and behavioral changes observed in mice with bone cancer are also observed in a rat model of bone cancer. Additionally, this paper describes several novel behavioral changes such as weight bearing on the affected limb and general changes in the activity levels of the animals with bone cancer that are similar to those observed in humans with bone cancer pain (Mercandante and Arcuri, 1998). A critical question in assessing the usefulness of any model of a disease is not only whether it permits insights into the pathophysiology and mechanisms that drive the disease process but also whether the model can be used to test new therapies to treat the disease. In both the mouse and rat models of bone cancer pain, this appears to be the case. Thus, in the mouse model, it was shown that osteoprotegerin, a naturally secreted decoy receptor that inhibits tumor-induced-osteoclast survival, maturation and hypertrophy could significantly inhibit bone destruction, bone cancer pain related pain behaviors and bone cancer induced
0304-3959/02/$20.00 q 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. PII: S 0304-395 9(01)00482-1
2
P.W. Mantyh / Pain 96 (2002) 1–2
neurochemical alterations in the spinal cord (Luger et al., 2001; Honore et al., 2000a). In the rat model of bone cancer pain, it is shown that morphine is effective in reducing bone cancer related pain behaviors whereas at least at advanced stages of bone destruction, inhibitors of cycolooxygenase-2 were not effective (Medhurst et al., 2001). Together these data suggest that these and other models of cancer pain that have been developed (Cain et al., 2001) can provide insight into the mechanisms that generate and maintain cancer pain as well as serving as an important pre-clinical tool for the development of novel therapies to treat cancer pain. While we have made significant progress in the last 2 years and are now getting our first glimpse of the mechanisms that drive cancer pain, we are still at the beginning. For the first time, animal models of cancer pain are now available that mirror the clinical picture of human patients with cancer pain. Information generated from these models should provide information and a platform for dissecting out the various mechanisms that generate and maintain the different types of cancer pain. Since the cancer models have been developed in rodents, human tumors can be implanted in immuno-compromised rodents, should allow definition of whether a different set of factors generate pain in different types of human tumors. These animal models may also offer insight into one of the major conundrums of cancer pain, which is why the severity of cancer pain is so variable from tumor to tumor and even between patients with the same tumor. Newer molecular techniques using microarrays, proteomics and cluster analysis will provide additional data about the features of different tumors and how they can differentially induce cancer pain in various peripheral tissues. Once the mechanisms by which the different types of cancer induce pain is elucidated, this should lead to the identification of molecular targets and the development of mechanism based therapies (Hunt and Mantyh, 2001; Julius and Basbaum, 2001). Ultimately, the key to success in this field will be to integrate tumor biology with our increasing understanding of the molecular and cell biology of how pain is generated and maintained. The goal of this research is clear, to use the knowledge gained from the newly developed models of cancer pain to improve the quality of life of all those who suffer from cancer pain.
Cain DM, Wacnik PW, Eikmeier L, Beitz A, Wilcox GL, Simone DA. Functional interactions between tumor and peripheral nerve in a model of cancer pain in the mouse. Pain Med 2001;2:15–23. Foley KM. Advances in cancer pain. Arch Neurol 1999;56:413–417. Foley KM. Easing the suffering of cancer patients. The Scientist 2001;15:6. Honore P, Mantyh PW. Bone cancer pain: from mechanism to model to therapy. Pain Med 2000;1:303–309. Honore P, Luger NM, Sabino MA, Schwei MJ, Rogers SD, Mach DB, O’Keefe PF, Ramnaraine ML, Clohisy DR, Mantyh PW. Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord. Nat Med 2000a;6:521–528. Honore P, Rogers SD, Schwei MJ, Salak-Johnson JL, Luger NM, Sabino MAC, Clohisy DR, Mantyh PW. Murine models of inflammatory neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons. Neuroscience 2000b;98:585–598. Hunt SP, Mantyh PW. The molecular dynamics of pain control. Nat Rev Neurosci 2001;2(2):83–91. Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature 2001;413:203–210. Luger NM, Honore P, Sabino MAC, Schwei MJ, Rogers SD, Mach DB, Clohisy DR, Mantyh PW. Osteoprotegerin diminishes advanced bone cancer pain. Cancer Res 2001;61:4038–4047. Medhurst SJ, Walker K, Bowes M, Kidd BL, Glatt M, Muller M, Hattenberger M, Vaxelaire J, O’Reilly T, Wotherspoon G, Winter J, Green J, Urban L. A rat model of bone cancer pain. Pain 2002;96:129– 140. Mercadante S, Arcuri E. Breakthrough pain in cancer patients: pathophysiology and treatment. Cancer Treat Rev 1998;24:425–432. Payne R. Chronic pain: challenges in the assessment and management of cancer pain. J Pain Symptom Manage 2000;19:S12–S15. Payne R, Santiago-Palma J, Cheville A. Cancer rehabilitation in the new millennium – introduction. Cancer 2001;92:969. Portenoy RK, Lesage P. Management of cancer pain. Lancet 1999;353: 1695–1700. Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: characteristics and impact in patients with cancer pain. Pain 1999;81:129–134. Schwei MJ, Honore P, Rogers SD, Salak-Johnson JL, Finke MP, Ramnaraine ML, Clohisy DR, Mantyh PW. Neurochemical and cellular reorganization of the spinal cord in a murine model of bone cancer pain. J Neurosci 1999;19:10886–10897.
Patrick W. Mantyh a,b,* Departments of Preventive Sciences, Neuroscience, Psychiatry, and Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA b VA Medical Center, Minneapolis, MN 55417, USA a
References American Cancer Society: Annual Cancer Statistics for the US in 2000, 2001.
* Tel.: 11-612-626-0180; fax: 11-612-626-2565. E-mail address: [email protected] (P. W. Mantyh).