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Pathophysiology of Bone Cancer Pain
Mary Ann C. Sabino, DDS, PhD, and Patrick W. Mantyh, PhD, JD
he negative impact that cancer pain has on quality of life cannot be overestimated. Advances in cancer detection and therapy are extending the life expectancy of cancer patients, leading to an increased focus on improving their quality of life. For many patients, pain is the ﬁrst sign of cancer, and 30%–50% of all cancer patients will experience moderate to severe pain [1, 2]. Cancer-associated pain can be present at any time during the course of the disease, but the frequency and intensity of cancer pain tend to increase with advancing stages of cancer. A total of 75%–95% of patients with metastatic or advanced-stage cancer will experience signiﬁcant amounts of cancer-induced pain [1, 2]. Although there is signiﬁcant patient-to-patient variability in the type, severity, and evolution of bone cancer pain, two major components generally are recognized. The ﬁrst component, known as ongoing pain, is most often the ﬁrst to present, described as a dull ache or throbbing in character,  and usually is associated with an increase in severity with disease progression . A second component of bone cancer pain frequently emerges over time and is more acute in nature. This second pain is known as breakthrough or incident pain, as it frequently occurs either spontaneously, with intermittent exacerbations of pain, or by movement of the cancerous bone [1, 4]. Commonly, breakthrough pain intensiﬁes near the end of a dosing interval of scheduled analgesics and represents one of the most serious and highly debilitating sequelae of cancer, as it is frequently difﬁcult to treat fully without being accompanied by signiﬁcant, unwanted side effects [1, 2].
Abstract The most common cancers, such as those affecting the breast, prostate, and lung have a strong predilection to metastasize to bone. Bone metastasis frequently results in pain, pathologic fractures, hypercalcemia, and spinal cord compression. Pain can have a devastating effect on the quality of life in advanced cancer patients and is a serious complication of cancer. Although signiﬁcant advances are being made in cancer treatment and diagnosis, the basic neurobiology of bone cancer pain is poorly understood. New insights into the mechanisms that induce cancer pain now are coming from animal models. Chemicals derived from tumor cells, inﬂammatory cells, and cells derived from bone appear to be involved simultaneously in driving this frequently difﬁcult-to-control pain state. Understanding the mechanisms involved in the pathophysiology of bone cancer pain will improve both our ability to provide mechanismbased therapies and the quality of life of cancer patients.
Scope of the Problem
The current treatments for cancer pain involve
Manuscript received May 20, 2004; accepted May 25, 2004. Correspondence to: Patrick W. Mantyh, PhD, JD, Neurosystems Laboratory, University of Minnesota, Minneapolis, MN 55455; telephone: (612) 626-0180; fax: (612) 626-2565; e-mail: email@example.com
J Support Oncol 2005;3:015–024 © 2005 Elsevier Inc. All rights reserved.
a variety of modalities. Therapies targeted at decreasing tumor size often are effective and include irradiation, chemotherapy, and/or surgery—but these options can be burdensome to administer and are accompanied by signiﬁcant unwanted side effects. Moreover, medications targeted at decreasing inﬂammation-associated pain, such as nonsteroidal anti-inﬂammatory drugs (NSAIDs) or opiates, are equally useful but also have many unwanted side effects. Largely because of treatment-associated side effects, it is has been reported that 45% of cancer patients have inadequate and undermanaged pain control [5, 6]. From the standpoint of treating bone cancer pain, a formidable obstacle has been that the neurobiologic basis for pharmacologic treatments is largely empirical and is centered on scientiﬁc studies of painful conditions other than cancer. The ﬁrst animal model of bone cancer pain involved the injection of mouse osteolytic sarcoma cells into the intramedullary space of the mouse femur (Figure 1). A critical component of this model is that the tumor cells are conﬁned within the marrow space of the injected femur and do not invade adjacent soft tissues . Following tumor injection, the ﬂuorescent cancer cells proliferate, and both ongoing and movement-evoked pain-related www.SupportiveOncology.net
Dr. Sabino is a Fellow in the Neurosystems Laboratory and a Resident in the Division of Oral and Maxillofacial Surgery, Departments of Diagnostic and Surgical Sciences and Preventive Sciences, University of Minnesota, Minneapolis. Dr. Mantyh is Professor in the Department of Preventive Sciences, Psychiatry and Neuroscience and Director of the Neurosystems Laboratory, University of Minnesota, Minneapolis.
VOLUME 3, NUMBER 1
In contrast. Sensory Neurons Primary afferent sensory neurons are the gateway by which sensory information from peripheral tissues is transmitted to the spinal cord and brain. joints. and periosteum are primary afferent sensory and sympathetic ﬁbers that mainly are associated with blood vessels [10–12]. researchers reported that mineralized bone received extrinsic innervation from both sensory and sympathetic neurons [10. tumor-induced bone destruction that ensues. There are two major types of sensory ﬁbers: myelinated A ﬁbers and smaller diameter unmyelinated C ﬁbers. from the periosteum [13–15]. More recent studies have shown that many of the nerve ﬁbers innervating mineralized bone. C). in bones. Recently. we have been able to measure hard. Since sensory and sympathetic neurons are present within all three structures. The cell bodies of sensory ﬁbers that innervate the head and body are housed in ganglia that maintain distinct dermatomes from head to toe. the prevailing opinion is that bone pain arises predominately. These pain behaviors correlate with the progressive. D). in a normal situation. most small-diameter sensory ﬁbers—unmyelinated C ﬁbers and ﬁnely myelinated A delta ﬁbers—are specialized sensory neurons known as nociceptors. is densely innervated by both sensory and sympathetic nerve ﬁbers within bone marrow. behaviors become more severe as the tumor develops.and soft-tissue volumes using highly sensitive techniques and have demonstrated that bone 16 www. or the presence of tumor cells and may play a unique but coordinated role in the generation of bone cancer pain. arrow denotes extensive bone destruction. the femur can be assessed at the whole-bone level for extraosseous invasion (none noted in B). Numerous studies have demonstrated that the periosteum is densely innervated by both sensory and sympathetic ﬁbers [17–19] and that. 11]. individual primary THE JOURNAL OF SUPPORTIVE ONCOLOGY Innervation of Bone Previously. ischemia. mineralized bone. Even in light of these data. which appears to mimic the condition seen in patients with primary or metastatic bone cancer [8. 9]. tumor burden (using excitation ﬁlters to visualize green ﬂuorescent protein expressed by tumor cells. and bone destruction (high-powered radiographic imaging. Their major function is to detect and convert environmental stimuli that are perceived as harmful into electrochemical signals that are transmitted to the central nervous system. do not conduct noxious stimuli . if not exclusively. This and other models have begun to provide insights into the mechanisms by which tumors cause pain and this sensory information is processed. Tumor cells are conﬁned within the intramedullary space by placement of an amalgam plug (arrow). and muscles. Such insights promise to fundamentally change the way cancer pain is controlled.SupportiveOncology. and periosteum (Figure 2) [20. Unlike primary sensory neurons involved in vision or olfaction. bone marrow. 21].Bone Pain Figure 1 Bone Cancer Pain Animal Model A radiograph of the lower half of an adult mouse (A) demonstrates the femur through which osteolytic ﬂuorescent sarcoma cells were injected. where there is no signiﬁcant periosteal involvement .net . This belief does not account for pain perceived by patients in whom the pathology is conﬁned principally to the bone marrow or mineralized bone. Two weeks later. Nearly all large-diametermyelinated A beta ﬁbers normally conduct nonpainful stimuli applied to the skin. respectively). it receives the greatest density of nerve ﬁbers per unit area. which are required to detect only one type of sensory stimulus (light or chemical odorants. and thus. all are potentially impacted by fractures.
NUMBER 1 ■ A peer viewpoint on this article by Dr. Therefore.SupportiveOncology. extracellular protons . whereby the nociceptor threshold level of activation is lowered. This change in phenotype of the sensory neuron in part underlies peripheral sensitization. and lipid metabolites [29. To accomplish this task. and chemical). the capsaicin receptor. and bone marrow (adapted with permission from Marieb and Mallat21). Damage to peripheral tissue has also been shown to activate previously “silent” or “sleeping” nociceptors. bradykinin . detects heat . and nerve growth factor .Sabino Mantyh CGRP fiber Haversion canal Mineralized bone Blood vessel Periosteum Figure 2 Innervation of Bone Histophotomicrographs of confocal (A) and histologic (B) serial images of normal bone are shown. They include protons [28. prostaglandins . nociceptors express a diverse repertoire of receptors and transduction molecules that can sense forms of noxious stimulation (thermal. In normal mice. endothelins . Reorganization of the Peripheral and Central Nervous Systems in Response to Cancer Pain In addition to expressing channels and receptors that detect tissue injury. which then become highly responsive to normally non-noxious or mildly noxious stimuli . NF200 = neuroﬁlament 200. In mice with bone cancer. 30]. Paice appears on page 26. 34]. remarkable progress has been made toward understanding molecules that nociceptors use to detect noxious stimuli. acid . including those of a physical and chemical nature [23. albeit with varying degrees of sensitivity (Figure 3) . NF200) and unmyelinated (green. All three tissues may be sensitized during the various stages of bone cancer pain. Judith A. transient receptor potential V-1 (TRPV-1). Note the extensive myelinated (red. 40]. B). Schematic diagram (C) demonstrating the innervation within the periosteum. and stimuli that would normally be perceived as non-noxious is perceived as noxious (allodynia). JANUARY/FEBRUARY 2005 17 . For example. stimuli that would normally be perceived as mildly noxious are perceived as highly noxious (hyperalgesia). analgesics. CGRP) nerve ﬁbers within bone marrow that appear to course along blood vessels (arrowheads. CGRP = calcitonin gene-related peptide sensory neurons of the pain pathway have the remarkable ability to detect a wide range of stimulus modalities. the neurotransmitter substance P is synthesized by nociceptors and released in the spinal cord when noxious—but not non-noxious—mechanical stress is applied to the femur. identiﬁcation of receptors expressed on the nociceptors’ surface has increased our understanding of how tumors generate pain as they invade and destroy bone.net Channels and Receptors Mediating Bone Pain In the past few years. mineralized bone. 33]. which is expressed by most nociceptors. There are several examples of nociceptor peripheral sensitization in experimental cancer models [7–9. what would www. Nociceptors also express both mechanically gated channels—which activate a signaling cascade upon excessive stretch —and several purinergic receptors. Nociceptors also express a complex array of receptors that are activated by inﬂammation-associated factors that are released from damaged tissue. which are activated by adenosine triphosphate (ATP) released from cells during excessive mechanical stimulation [32. Aside from providing promising targets for the development of more selective VOLUME 3. 24]. mechanical. sensory neurons are able to change their phenotype following sustained peripheral injury by altering their patterns of signaling peptide and growth factor expression .
These channels and receptors may serve as potential therapeutic targets for the treatment of cancer pain. 46]. Studies involving a murine model of bone cancer pain showed extensive neurochemical reorganization in the spinal cord segments that receive input from primary afferent neurons that innervate the tumor-bearing bone that were similar to phenotypic alterations and sensitization of peripheral nerves . 56]. epidermal growth factor . Nociceptors express a variety of channels and receptors that can detect and transduce pain signals by interacting with various mediators released by tumor cells or active macrophages. 44]. and platelet-derived growth factor [57–59]. Substance P in turn. therefore. 52. This and other spinal cord changes could be attenuated by blocking the tumor-induced tissue destruction and pain [9. tumor necrosis factor-alpha (TNFα) [47–50]. endothelins [35. and is at least partially maintained by. VR1 = vanilloid receptor. such as prostaglandins [45. 51]. This includes astrocyte hypertrophy. including immune cells such as macrophages. VRL-1 = vanilloid receptor-like 1. normally be a nonpainful level of mechanical stress can induce the release of substance P from primary afferent ﬁbers that terminate in the spinal cord. normally non-noxious input is ampliﬁed and perceived as a noxious stimulus (Figure 4). transforming growth factor-beta [55. This process results in increased extracellular levels of the excitatory neurotransmitter glutamate. in which neurochemical changes in the spinal cord and forebrain promote an increased transmission of nociceptive information. 42]. binds to and activates . nerve growth factor (NGF). and T lymphocytes. Tumor-Derived Products in the Generation of Bone Cancer Pain The tumor stroma is made up of many different cell types apart from cancer cells. Figure adapted with permission from Mantyh et al. These ﬁndings indicate that cancer pain induces. interleukin-1 and interleukin-6 [47. protons (H+). the neurokinin-1 receptor that is expressed by a subset of spinal cord neurons [41. TrKA = tyrosine kinase A. 40]. EP = prostaglandin E receptor. a state of central sensitization. neutrophils.25 P2X3 = ATP-sensitive purine receptor.Bone Pain Macrophage Tumor cell ET H+ ETAR DRASIC PGE2 VR1 Nociceptor EP VRL-1 TrKA P2X3 Na+ channel Membrane NGF H ATP Figure 3 Tumor and Inﬂammatory By-products Involved in the Sensitization of a Nociceptor Schematic diagram demonstrates presence of receptors and ion channels on peripheral nerve ﬁbers that transmit pain called nociceptors. They secrete a variety of factors that have been shown to sensitize or directly excite primary afferent neurons. such as prostaglandins (PGE2).net . which is accompanied by a decreased expression of glutamate reuptake transporters [43.SupportiveOncology. that lead to excitotoxicity within the central nervous system. ETAR = endothelin A receptor. 53]. and adenosine triphosphate (ATP). DRASIC = dorsal root ganglion acid sensing ion channel. THE JOURNAL OF SUPPORTIVE ONCOLOGY 18 www.
including mediation of pain and inﬂammation . Furthermore. so in addition to blocking cancer pain. Prostaglandins are lipid-derived eicosanoids that are synthesized from arachidonic acid by COX-1 and COX-2 isoenzymes. 79]. the enzyme responsible for the synthesis of prostaglandins [60–64]. Prostaglandins have been shown to be involved in the sensitization and/or direct excitation of nociceptors by binding to several prostanoid receptors expressed by nociceptors that sensitize or directly excite nociceptors . Both of these channels are sensitized and excited by a decrease in pH. drugs that target prostaglandins and the endothelins are the only ones currently used to control pain in cancer patients. stained with neuronal marker. they are generally not indicated for extended use in cancer patients because of signiﬁcant side effects. including prostate cancer . enhanced bleeding. (D) Nonmyelinating Schwann cells (green. NUMBER 1 ■ Figure 4 Neurochemical Changes in the Spinal Cord and Dorsal Root Ganglia in Bone Cancer Pain (A) This confocal image shows glial ﬁbrillary acidic protein (GFAP) expressed by astrocytes in the spinal cord of a tumor-bearing mouse. CD68) can also be seen. GFAP) and macrophage inﬁltration (yellow. COX-2 has also been associated with angiogenesis and tumor growth [69. Although NSAIDs are clinically effective in attenuating acute nonmalignant skeletal pain.net JANUARY/FEBRUARY 2005 19 . Like prostaglandins. and tumorigenesis . Tumor stroma  and arwww. NeuN). 78]. 79. 80] and the ASIC-3 [77. We have recently shown that chronic inhibition of COX-2 activity with selective COX-2 inhibitors resulted in signiﬁcant attenuation of bone cancer pain behaviors as well as many of the neurochemical changes suggestive of both peripheral and central sensitization in an animal model of bone cancer pain . (C) This confocal image shows a dorsal root ganglia (DRG) with injured neurons labeled with activating transcription factor 3 (magenta. 81]. such as gastrointestinal ulceration. bone homeostasis . Sabino Mantyh The Role of Acidosis in Bone Cancer Pain The ﬁnding that sensory neurons can be excited directly by protons or acid has generated intense interest in pain research [77.Receptors for many of these factors are expressed by primary afferent neurons. tate cancer . the advent of selective COX-2 inhibitors has improved the side-effect proﬁle of anti-inﬂammatory drugs signiﬁcantly while maintaining their analgesic efﬁcacy. Endothelins (endothelin-1. neutropenia. ATF-3). -2. (B) High-powered magniﬁcation of the spinal cord shows hypertrophy of astrocytes (green) without changes in neuronal numbers (red. Endothelin antagonists are a second type of pharmacologic agent that may show signiﬁcant promise in the management of cancer pain . Studies have shown that subsets of sensory neurons express different acid-sensing ion channels [24. 70]. Nonselective NSAIDs inhibit both COX-1 and COX-2. Cancer cells and tumor-associated macrophages both have been shown to express high levels of cyclooxygenase (COX)-2. Endothelins could contribute to cancer pain by directly sensitizing or exciting nociceptors. COX-2 inhibitors are capable of retarding tumor growth within bone . Although each of these factors may play an important role in the generation of pain in particular forms of cancer. The two major classes of acid-sensing ion channels (ASICs) expressed by nociceptors are TRPV-1 [30. In addition.SupportiveOncology. as a subset of small unmyelinated primary afferent neurons express endothelin-A receptors . direct application of endothelin to peripheral nerves induces the activation of primary afferent ﬁbers and induction of pain behaviors . endothelins that are produced by cancer cells are also thought be involved in regulating angiogenesis  and tumor growth . Note the increased expression (white box) only on the side ipsilateral to the tumorous limb. but also in reducing tumor growth and metastasis. and disruption in renal function . These ﬁndings indicate that endothelin antagonists may be useful not only in inhibiting cancer pain. Prostaglandins have also been implicated in a number of biologic and pathologic processes. and -3) are a family of vasoactive peptides that are expressed at high levels by several types of tumors. However. Clinical studies have shown a correlation between the severity of the pain and plasma levels of endothelins in patients with prosVOLUME 3.
Osteoprotegerin (OPG) is an agent that holds signiﬁcant promise for alleviating bone cancer pain (Table 1). Most sensory neurons that innervate bone express www. As inﬂammatory cells invade tumor stroma. Recent experiments in a murine model of bone cancer pain indicated that osteoclasts play an essential role in cancer-induced bone loss and contribute to the etiology of bone cancer pain [8. TRPV-1 or ASIC antagonists may be useful in reducing pain in patients with bony tumors by blocking excitation of the acid-sensitive channels on sensory neurons.0–5. Both osteolytic (bone-destroying) and osteoblastic (bone-forming) cancers are characterized by osteoclast proliferation and hypertrophy .Table 1 Mechanism-Based Therapies for the Treatment of Bone Cancer Pain DRUG CLASS TARGET ACTION INDICATION POTENTIAL COMPLICATION Tumor/Inﬂammatory Products Selective COX-2 Prostaglandin synthesis inhibitors Endothelin-receptor antagonists Anti-NGF antibody Acid-sensitive ion channels (TRPV-1. P2X = purinergic receptor. The large amount of apoptosis that occurs in the tumor environment may also contribute to the acidotic environment. typically exhibit lower pH than do surrounding normal tissues. they release protons that generate local acidosis. Osteoclasts are terminally differentiated. ASIC) Purinergic receptor antagonists Bone Remodeling Osteoprotegerin Bisphosphonates Nerve ﬁbers Smooth muscle cells NGF receptor blocker pH-sensitive nerve ﬁbers ATP-sensitive nerve ﬁbers Peripheral and central sensitization Tumor growth suppression Sensitization of nerve ﬁbers Analgesia Blockade of H+ through channels Blockade of P2X receptors Prostaglandindependent cancers Endothelin-sensitive cancers Cancers with inﬂammatory component Proton.net TRPV-1  and/or ASIC . ASIC = acid-sensing ion channel. so these sensory neurons may become activated and transmit pain signals to the spinal cord when exposed to the acidic extracellular microenvironment of the osteoclasts.0) at the osteoclast-mineralized bone interface . Tumor-induced release of protons and acidosis may be particularly important in the generation of bone cancer pain. 9. This decoy receptor prevents THE JOURNAL OF SUPPORTIVE ONCOLOGY 20 . NGF = nerve growth factor.SupportiveOncology. Bone Pain eas of ischemic necrosis. monocyte lineage cells that resorb bone by maintaining an extracellular microenvironment of acidic pH (4. 40]. OPG is a secreted soluble receptor that is a member of the tumor necrosis factor receptor (TNFR) family . TRPV-1 = transient receptor potential V-1. NE = norepinephrine. multinucleated. such as those observed in our bone cancer model. GDNF = glial cell line-derived neurotrophic factor.or acidproducing cancers Cancers that invade mechanically sensitive tissues Lytic bone pain Lytic and blastic bone pain Cardiotoxicity Nephrotoxicity Bone formation Hypotension Teratogenicity ? Delayed wound healing Altered taste Altered touch perception Osteoclast activation Osteoclast apoptosis Osteolysis inhibition Analgesia Tumor shrinkage Osteoclast activity suppression Aberrant neuronal discharge suppression Analgesia Anxiolysis Autoimmune response GI toxicity Fever Electrolyte abnormality Nerve Injury Anticonvulsants (gabapentin) Antidepressants Calcium channel subunit Neuropathic pain NE serotonin uptake Inhibition Neuropathic pain Musculoskeletal pain Opioid enhancement Neuropathic pain GDNF-like therapy (artemin) Growth factor receptor stimulation Analgesia Bone marrow suppression Ataxia Drowsiness Sedation Hypotension Cardiotoxicity Seizures Stimulated tumor growth COX-2 = cyclooxygenase-2. although antagonists to these channels are only in the developmental stage.
It has been noted in both clinical and preclinical studies that morphine is typically less efﬁcacious in blocking neuropathic pain than in blocking inﬂammatory pain [100–103]. and constipation [1. However. This may likely provide some explanation for the poor analgesic efﬁcacy of morphine but satisfactory treatment with gabapentin in patients with neuropathic pain. In an animal model of bone cancer pain. Inwww. Although OPG has been shown to decrease pain behaviors in an animal model of bone cancer [9. In fact. Thus. Tumor-induced Nerve Destruction in Bone: Neuropathic Component of Bone Cancer Pain Bone cancer pain in advanced cancer patients is typically recalcitrant to both NSAIDs and opioids. ie. causing them to rapidly target the mineralized matrix of bone . another class of antiresorptive compounds that induce osteoclast apoptosis. It is likely that the expression of ATF3 in sensory neurons of tumor-bearing animals is a result of peripheral nerve destruction within the tumor-bearing femur. when present. ATF-3 is a member of the ATF/cyclic adenosine monophosphate response element binding protein family of transcription factors. and then destroyed the distal processes of sensory ﬁbers that innervate the bone marrow and mineralized bone. the dose of opioids required to control cancer pain is usually signiﬁcantly higher than that required to treat nonmalignant pain. inducing their apoptosis by impairing either the synthesis of ATP or cholesterol—both of which are necessary for cell survival [89. as well as the upregulation of α2δ calcium channel subunits responsible for gabapentin (Neurontin) sensitivity . In these same animals. NUMBER 1 ■ sion of µ opioid receptors. These data correlate well with observations in humans. but they are strongly expressed in sensory neurons after injury to peripheral nerves in neuropathic pain models . in the deep stromal regions of the tumor.the activation and proliferation of osteoclasts by binding to and sequestering the OPG ligand (OPGL. Bisphosphonates are pyrophosphate analogs that display a high afﬁnity for calcium ions. a decrease in expresVOLUME 3. tumor cells were found to grow within the bone. and loss of the rufﬂed border that is indicative of apoptosis . although still in its infancy.SupportiveOncology. there was expression of activating transcription factor (ATF)-3 in the nucleus of sensory neurons that innervate the femur. nuclear fragmentation. Osteoclasts treated with bisphosphonates undergo morphologic changes. Some investigators suggest that this partially may be due to phenotypic alterations that occur at the level of the central nervous system. such as sedation. Bisphosphonates. they came into contact with. animal models of cancer pain that begin to mirror the clinical picture of human patients with cancer pain are now available. In an experimental model of nonmalignant neuropathic pain. chromatin condensation. Sensory ﬁbers that were immunoreactive for markers of myelinated and unmyelinated primary afferent sensory ﬁbers were observed at and within the leading edge of the tumor. a member of the glial cell linederived neurotrophic factor (GDNF) family . somnolence.net JANUARY/FEBRUARY 2005 21 . 2]. These drugs have been reported to act directly on osteoclasts. Studies in both clinical [92–94] and animal [97–99] models of bone cancer have reported antiresorptive effects of bisphosphonate therapy. OPG has been shown to increase bone mineral density and bone volume that is associated with a decrease in the number of active osteoclasts in women with osteoporosis . injured. it also has antiresorptive effects comparable to pamidronate when administered in a single dose to patients with bony malignancies . and its use often results in unwanted side effects. use of selective antagonists and antibodies against growth factors provide a novel approach toward the treatment of cancer-associated neuropathic pain. the cognate receptor for morphine. where sensory innervation of solid tumors is sparse and. these factors are not expressed at detectable levels in normal sensory neurons or in sensory neurons following peripheral inﬂammation. phenotypic changes in the sensory and spinal cord neurons as well as pain behaviors were inhibited with selective blockade of artemin. although the effect on long-term survival rates and tumor growth remains controversial. including cell shrinkage. is usually associated with the blood vessels near the leading edge of the growing tumor [104–107]. Sabino Mantyh Conclusion For the ﬁrst time. sensory nerve ﬁbers displayed a discontinuous and fragmented appearance and ultimately were undetectable by microscopy. 40]. have also been reported to reduce pain in patients with osteoclast-induced skeletal metastases [92–94]. it is still being developed for use in cancer patients. 96]. also known as the receptor for activator of nuclear factor-kappa B (NF-κB) ligand [RANKL]) [86–89].
Although this pattern of tumor-induced tissue destruction and nociceptor activation may be unique to bone cancer. the high levels of resulting apoptosis generate an acidic environment.3 2. Palpation-evoked pain (over 2-minute period) Guarding (sec) following nonpainful palpation Flinches (count) following nonpainful palpation 0. For example.3 ± 0.3 ± 0. Sarcoma P < 0.5 17.8 ± 0. Ongoing pain Guarding (sec) over 2-minute observation period Flinches (count) over 2-minute observation period II.2 2. Ambulatory pain Forced ambulation on rotarod (score) 5 (normal) to 0 (impaired) Limb use during normal ambulation (score) 4 (normal) to 0 (impaired) B. antagonists that block the mechanically gated channels and/ or ATP receptors in the richly innervated periosteum might reduce movement-associated pain. and complexity of cancer pain.9 5.2 2. in the mouse model of bone cancer. pain caused by osteoclastic activity could be blocked with antiresorptive drugs such as bisphosphonates or OPG.5 ± 0.1 * Ongoing and movement-evoked pain behaviors appear to worsen progressively over time. an evolving set of nociceptive events probably occurs in other cancers.9 ± 0. 22 www. sensory neurons innervating the marrow are compressed and destroyed.8 ± 0. Cancer pain frequently becomes more severe as the disease progresses (Table 2) and may require different types of analgesics at different times. and the spinal cord and forebrain areas involved in transmitting nociceptive signals change as the disease progresses.7 ± 1.SupportiveOncology.1 ± 0.6 ± 1.Bone Pain Table 2 Progression of Bone Cancer-Related Pain Behaviors* SARCOMA PAIN BEHAVIOR NAÏVE SHAM DAY 10 DAY 14 I.9 15.6 ± 0. severity.1 3. Advances in the understanding of the neurobiology of pain are now allowing scientists and clinicians to unravel the mysteries that underlie the heterogeneity. as bone destruction continues and the mechanical strength of the bone is compromised. the level of nociceptor activation. antagonists to TRPV-1 or ASICs could be used to attenuate the pain induced by acidosis. such as prostaglandins and endothelins released by the cancer cells that activate nociceptors in the bone marrow. COX-2 inhibitors and endothelin antagonists could be used to relieve this pain at this stage. As the tumor induces proliferation and hypertrophy of osteoclasts.9 ± 0.9 ± 2. Judith A. This pain may be caused by prohyperalgesic factors.9 6. Paice appears on page 26.4 19.2 3.4 ± 0.0 ± 0.5 2.7 ± 0. different therapies might be most efﬁcacious at particular stages of the disease. In this situation.2 2. A peer viewpoint on this article by Dr.0 4. painrelated behaviors are present before any signiﬁcant bone destruction is evident .2 ± 0.3 9.2 2. causing neuropathic pain that may respond to treatment with drugs such as gabapentin or artemin.2 2.3 ± 0.4 13. Since the type of tumor-induced tissue injury. pain is maximal 14 days after tumor injection into mice compared with sham-operated controls.05 vs sham.3 ± 0. Finally. formation generated from these models will shed light on the mechanisms that generate and maintain the different types of cancer pain.3 6. As the tumor continues to grow. As the cancer cells completely ﬁll the intramedullary space.6 11.7 5.net THE JOURNAL OF SUPPORTIVE ONCOLOGY .0 4. Movement-evoked pain A.0 ± 0.4 7.2 ± 0.0 ± 0.3 ± 0.3 0.4 ± 9.0 ± 0.
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