R E V I E W

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 rst 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 signicant amounts of cancer-induced pain [1, 2]. Although there is signicant patient-to-patient variability in the type, severity, and evolution of bone cancer pain, two major components generally are recognized. The rst component, known as ongoing pain, is most often the rst to present, described as a dull ache or throbbing in character, [3] and usually is associated with an increase in severity with disease progression [4]. 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 intensies 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 difcult to treat fully without being accompanied by signicant, 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 signicant 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, inammatory cells, and cells derived from bone appear to be involved simultaneously in driving this frequently difcult-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: manty001@umn.edu
J Support Oncol 2005;3:015024 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 surgerybut these options can be burdensome to administer and are accompanied by signicant unwanted side effects. Moreover, medications targeted at decreasing inammation-associated pain, such as nonsteroidal anti-inammatory 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 scientic studies of painful conditions other than cancer. The rst 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 conned within the marrow space of the injected femur and do not invade adjacent soft tissues [7]. Following tumor injection, the uorescent 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.

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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 uorescent sarcoma cells were injected. Tumor cells are conned within the intramedullary space by placement of an amalgam plug (arrow). Two weeks later, the femur can be assessed at the whole-bone level for extraosseous invasion (none noted in B), tumor burden (using excitation lters to visualize green uorescent protein expressed by tumor cells, C), and bone destruction (high-powered radiographic imaging, arrow denotes extensive bone destruction, D).

behaviors become more severe as the tumor develops. These pain behaviors correlate with the progressive, tumor-induced bone destruction that ensues, which appears to mimic the condition seen in patients with primary or metastatic bone cancer [8, 9]. This and other models have begun to provide insights into the mechanisms by which tumors cause pain and this sensory information is processed. Such insights promise to fundamentally change the way cancer pain is controlled.

is densely innervated by both sensory and sympathetic nerve bers within bone marrow, mineralized bone, and periosteum (Figure 2) [20, 21]. Since sensory and sympathetic neurons are present within all three structures, all are potentially impacted by fractures, ischemia, or the presence of tumor cells and may play a unique but coordinated role in the generation of bone cancer pain.

Sensory Neurons
Primary afferent sensory neurons are the gateway by which sensory information from peripheral tissues is transmitted to the spinal cord and brain. The cell bodies of sensory bers that innervate the head and body are housed in ganglia that maintain distinct dermatomes from head to toe. There are two major types of sensory bers: myelinated A bers and smaller diameter unmyelinated C bers. Nearly all large-diametermyelinated A beta bers normally conduct nonpainful stimuli applied to the skin, joints, and muscles, and thus, in a normal situation, do not conduct noxious stimuli [22]. In contrast, most small-diameter sensory bersunmyelinated C bers and nely myelinated A delta bersare specialized sensory neurons known as nociceptors. 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. Unlike primary sensory neurons involved in vision or olfaction, which are required to detect only one type of sensory stimulus (light or chemical odorants, respectively), individual primary THE JOURNAL OF SUPPORTIVE ONCOLOGY

Innervation of Bone
Previously, researchers reported that mineralized bone received extrinsic innervation from both sensory and sympathetic neurons [10, 11]. More recent studies have shown that many of the nerve bers innervating mineralized bone, bone marrow, and periosteum are primary afferent sensory and sympathetic bers that mainly are associated with blood vessels [1012]. Even in light of these data, the prevailing opinion is that bone pain arises predominately, if not exclusively, from the periosteum [1315]. This belief does not account for pain perceived by patients in whom the pathology is conned principally to the bone marrow or mineralized bone, where there is no signicant periosteal involvement [16]. Numerous studies have demonstrated that the periosteum is densely innervated by both sensory and sympathetic bers [1719] and that, in bones, it receives the greatest density of nerve bers per unit area. Recently, we have been able to measure hard- and soft-tissue volumes using highly sensitive techniques and have demonstrated that bone

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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. Note the extensive myelinated (red, NF200) and unmyelinated (green, CGRP) nerve bers within bone marrow that appear to course along blood vessels (arrowheads, B). Schematic diagram (C) demonstrating the innervation within the periosteum, mineralized bone, and bone marrow (adapted with permission from Marieb and Mallat21). All three tissues may be sensitized during the various stages of bone cancer pain. NF200 = neurolament 200; CGRP = calcitonin gene-related peptide

sensory neurons of the pain pathway have the remarkable ability to detect a wide range of stimulus modalities, including those of a physical and chemical nature [23, 24]. To accomplish this task, nociceptors express a diverse repertoire of receptors and transduction molecules that can sense forms of noxious stimulation (thermal, mechanical, and chemical), albeit with varying degrees of sensitivity (Figure 3) [25].

analgesics, identication of receptors expressed on the nociceptors surface has increased our understanding of how tumors generate pain as they invade and destroy bone.

Reorganization of the Peripheral and Central Nervous Systems in Response to Cancer Pain
In addition to expressing channels and receptors that detect tissue injury, sensory neurons are able to change their phenotype following sustained peripheral injury by altering their patterns of signaling peptide and growth factor expression [38]. This change in phenotype of the sensory neuron in part underlies peripheral sensitization, whereby the nociceptor threshold level of activation is lowered. Therefore, stimuli that would normally be perceived as mildly noxious are perceived as highly noxious (hyperalgesia), and stimuli that would normally be perceived as non-noxious is perceived as noxious (allodynia). Damage to peripheral tissue has also been shown to activate previously silent or sleeping nociceptors, which then become highly responsive to normally non-noxious or mildly noxious stimuli [39]. There are several examples of nociceptor peripheral sensitization in experimental cancer models [79, 40]. In normal mice, the neurotransmitter substance P is synthesized by nociceptors and released in the spinal cord when noxiousbut not non-noxiousmechanical stress is applied to the femur. In mice with bone cancer, what would www.SupportiveOncology.net

Channels and Receptors Mediating Bone Pain

In the past few years, remarkable progress has been made toward understanding molecules that nociceptors use to detect noxious stimuli. For example, the capsaicin receptor, transient receptor potential V-1 (TRPV-1), which is expressed by most nociceptors, detects heat [26], acid [27], extracellular protons [28], and lipid metabolites [29, 30]. Nociceptors also express both mechanically gated channelswhich activate a signaling cascade upon excessive stretch [31]and several purinergic receptors, which are activated by adenosine triphosphate (ATP) released from cells during excessive mechanical stimulation [32, 33]. Nociceptors also express a complex array of receptors that are activated by inammation-associated factors that are released from damaged tissue. They include protons [28, 34], endothelins [35], prostaglandins [36], bradykinin [36], and nerve growth factor [37]. Aside from providing promising targets for the development of more selective VOLUME 3, NUMBER 1

A peer viewpoint on this article by Dr. Judith A. Paice appears on page 26.

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Bone Pain

Macrophage

Tumor cell
ET H+

ETAR DRASIC
PGE2

VR1 Nociceptor

EP VRL-1 TrKA P2X3 Na+ channel

Membrane

NGF

ATP

Figure 3

Tumor and Inammatory By-products Involved in the Sensitization of a Nociceptor

Schematic diagram demonstrates presence of receptors and ion channels on peripheral nerve bers that transmit pain called nociceptors. 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, such as prostaglandins (PGE2), protons (H+), nerve growth factor (NGF), and adenosine triphosphate (ATP). These channels and receptors may serve as potential therapeutic targets for the treatment of cancer pain. Figure adapted with permission from Mantyh et al.25 P2X3 = ATP-sensitive purine receptor; VRL-1 = vanilloid receptor-like 1; TrKA = tyrosine kinase A; EP = prostaglandin E receptor; DRASIC = dorsal root ganglion acid sensing ion channel; ETAR = endothelin A receptor; VR1 = vanilloid receptor.

normally be a nonpainful level of mechanical stress can induce the release of substance P from primary afferent bers that terminate in the spinal cord. Substance P in turn, binds to and activates , the neurokinin-1 receptor that is expressed by a subset of spinal cord neurons [41, 42]. 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 [7]. This includes astrocyte hypertrophy, which is accompanied by a decreased expression of glutamate reuptake transporters [43, 44]. This process results in increased extracellular levels of the excitatory neurotransmitter glutamate, that lead to excitotoxicity within the central nervous system. This and other spinal cord changes could be attenuated by blocking the tumor-induced tissue destruction and pain [9, 40]. These ndings

indicate that cancer pain induces, and is at least partially maintained by, a state of central sensitization, in which neurochemical changes in the spinal cord and forebrain promote an increased transmission of nociceptive information; therefore, normally non-noxious input is amplied and perceived as a noxious stimulus (Figure 4).

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, including immune cells such as macrophages, neutrophils, and T lymphocytes. They secrete a variety of factors that have been shown to sensitize or directly excite primary afferent neurons, such as prostaglandins [45, 46], tumor necrosis factor-alpha (TNF) [4750], endothelins [35, 51], interleukin-1 and interleukin-6 [47, 52, 53], epidermal growth factor [54], transforming growth factor-beta [55, 56], and platelet-derived growth factor [5759]. THE JOURNAL OF SUPPORTIVE ONCOLOGY

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Receptors for many of these factors are expressed by primary afferent neurons. Although each of these factors may play an important role in the generation of pain in particular forms of cancer, drugs that target prostaglandins and the endothelins are the only ones currently used to control pain in cancer patients. Cancer cells and tumor-associated macrophages both have been shown to express high levels of cyclooxygenase (COX)-2, the enzyme responsible for the synthesis of prostaglandins [6064]. Prostaglandins are lipid-derived eicosanoids that are synthesized from arachidonic acid by COX-1 and COX-2 isoenzymes. 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 [65]. Prostaglandins have also been implicated in a number of biologic and pathologic processes, including mediation of pain and inammation [24], bone homeostasis [66], and tumorigenesis [67]. Nonselective NSAIDs inhibit both COX-1 and COX-2. Although NSAIDs are clinically effective in attenuating acute nonmalignant skeletal pain, they are generally not indicated for extended use in cancer patients because of signicant side effects, such as gastrointestinal ulceration, neutropenia, enhanced bleeding, and disruption in renal function [68]. However, the advent of selective COX-2 inhibitors has improved the side-effect prole of anti-inammatory drugs signicantly while maintaining their analgesic efcacy. We have recently shown that chronic inhibition of COX-2 activity with selective COX-2 inhibitors resulted in signicant 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 [8]. In addition, COX-2 has also been associated with angiogenesis and tumor growth [69, 70], so in addition to blocking cancer pain, COX-2 inhibitors are capable of retarding tumor growth within bone [8]. Endothelin antagonists are a second type of pharmacologic agent that may show signicant promise in the management of cancer pain [71]. Endothelins (endothelin-1, -2, and -3) are a family of vasoactive peptides that are expressed at high levels by several types of tumors, including prostate cancer [35]. Clinical studies have shown a correlation between the severity of the pain and plasma levels of endothelins in patients with prosVOLUME 3, NUMBER 1

Figure 4

Neurochemical Changes in the Spinal Cord and Dorsal Root Ganglia in Bone Cancer Pain

(A) This confocal image shows glial brillary acidic protein (GFAP) expressed by astrocytes in the spinal cord of a tumor-bearing mouse. Note the increased expression (white box) only on the side ipsilateral to the tumorous limb. (B) High-powered magnication of the spinal cord shows hypertrophy of astrocytes (green) without changes in neuronal numbers (red, stained with neuronal marker, NeuN). (C) This confocal image shows a dorsal root ganglia (DRG) with injured neurons labeled with activating transcription factor 3 (magenta, ATF-3). (D) Nonmyelinating Schwann cells (green, GFAP) and macrophage inltration (yellow, CD68) can also be seen.

tate cancer [72]. Endothelins could contribute to cancer pain by directly sensitizing or exciting nociceptors, as a subset of small unmyelinated primary afferent neurons express endothelin-A receptors [73]. Furthermore, direct application of endothelin to peripheral nerves induces the activation of primary afferent bers and induction of pain behaviors [74]. Like prostaglandins, endothelins that are produced by cancer cells are also thought be involved in regulating angiogenesis [75] and tumor growth [76]. These ndings indicate that endothelin antagonists may be useful not only in inhibiting cancer pain, but also in reducing tumor growth and metastasis.

Sabino Mantyh

The Role of Acidosis in Bone Cancer Pain

The nding that sensory neurons can be excited directly by protons or acid has generated intense interest in pain research [77, 78]. Studies have shown that subsets of sensory neurons express different acid-sensing ion channels [24, 79]. The two major classes of acid-sensing ion channels (ASICs) expressed by nociceptors are TRPV-1 [30, 80] and the ASIC-3 [77, 79, 81]. Both of these channels are sensitized and excited by a decrease in pH. Tumor stroma [82] and arwww.SupportiveOncology.net

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Table 1

Mechanism-Based Therapies for the Treatment of Bone Cancer Pain

DRUG CLASS TARGET ACTION INDICATION POTENTIAL COMPLICATION

Tumor/Inammatory Products Selective COX-2 Prostaglandin synthesis inhibitors Endothelin-receptor antagonists Anti-NGF antibody Acid-sensitive ion channels (TRPV-1; ASIC) Purinergic receptor antagonists Bone Remodeling Osteoprotegerin Bisphosphonates Nerve bers Smooth muscle cells NGF receptor blocker pH-sensitive nerve bers ATP-sensitive nerve bers

Peripheral and central sensitization Tumor growth suppression Sensitization of nerve bers Analgesia Blockade of H+ through channels Blockade of P2X receptors

Prostaglandindependent cancers Endothelin-sensitive cancers Cancers with inammatory component Proton- 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; NGF = nerve growth factor; TRPV-1 = transient receptor potential V-1; ASIC = acid-sensing ion channel; P2X = purinergic receptor; NE = norepinephrine; GDNF = glial cell line-derived neurotrophic factor.

Bone Pain

eas of ischemic necrosis, such as those observed in our bone cancer model, typically exhibit lower pH than do surrounding normal tissues. As inammatory cells invade tumor stroma, they release protons that generate local acidosis. The large amount of apoptosis that occurs in the tumor environment may also contribute to the acidotic environment. Tumor-induced release of protons and acidosis may be particularly important in the generation of bone cancer pain. Both osteolytic (bone-destroying) and osteoblastic (bone-forming) cancers are characterized by osteoclast proliferation and hypertrophy [83]. Osteoclasts are terminally differentiated, multinucleated, monocyte lineage cells that resorb bone by maintaining an extracellular microenvironment of acidic pH (4.05.0) at the osteoclast-mineralized bone interface [84]. Most sensory neurons that innervate bone express www.SupportiveOncology.net

TRPV-1 [85] and/or ASIC [79], 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. 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, although antagonists to these channels are only in the developmental stage. 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, 9, 40]. Osteoprotegerin (OPG) is an agent that holds signicant promise for alleviating bone cancer pain (Table 1). OPG is a secreted soluble receptor that is a member of the tumor necrosis factor receptor (TNFR) family [86]. This decoy receptor prevents THE JOURNAL OF SUPPORTIVE ONCOLOGY

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the activation and proliferation of osteoclasts by binding to and sequestering the OPG ligand (OPGL; also known as the receptor for activator of nuclear factor-kappa B (NF-B) ligand [RANKL]) [8689]. Although OPG has been shown to decrease pain behaviors in an animal model of bone cancer [9, 40], it is still being developed for use in cancer patients. 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 [90]; it also has antiresorptive effects comparable to pamidronate when administered in a single dose to patients with bony malignancies [91]. Bisphosphonates, another class of antiresorptive compounds that induce osteoclast apoptosis, have also been reported to reduce pain in patients with osteoclast-induced skeletal metastases [9294]. Bisphosphonates are pyrophosphate analogs that display a high afnity for calcium ions, causing them to rapidly target the mineralized matrix of bone [95]. These drugs have been reported to act directly on osteoclasts, inducing their apoptosis by impairing either the synthesis of ATP or cholesterolboth of which are necessary for cell survival [89, 96]. Osteoclasts treated with bisphosphonates undergo morphologic changes, including cell shrinkage, chromatin condensation, nuclear fragmentation, and loss of the rufed border that is indicative of apoptosis [95]. Studies in both clinical [9294] and animal [9799] models of bone cancer have reported antiresorptive effects of bisphosphonate therapy, although the effect on long-term survival rates and tumor growth remains controversial.

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. In fact, the dose of opioids required to control cancer pain is usually signicantly higher than that required to treat nonmalignant pain, and its use often results in unwanted side effects, such as sedation, somnolence, and constipation [1, 2]. It has been noted in both clinical and preclinical studies that morphine is typically less efcacious in blocking neuropathic pain than in blocking inammatory pain [100103]. Some investigators suggest that this partially may be due to phenotypic alterations that occur at the level of the central nervous system, ie, a decrease in expresVOLUME 3, NUMBER 1

sion of opioid receptors, the cognate receptor for morphine, as well as the upregulation of 2 calcium channel subunits responsible for gabapentin (Neurontin) sensitivity [78]. This may likely provide some explanation for the poor analgesic efcacy of morphine but satisfactory treatment with gabapentin in patients with neuropathic pain. In an animal model of bone cancer pain, tumor cells were found to grow within the bone; they came into contact with, injured, and then destroyed the distal processes of sensory bers that innervate the bone marrow and mineralized bone. Sensory bers that were immunoreactive for markers of myelinated and unmyelinated primary afferent sensory bers were observed at and within the leading edge of the tumor. However, in the deep stromal regions of the tumor, sensory nerve bers displayed a discontinuous and fragmented appearance and ultimately were undetectable by microscopy. These data correlate well with observations in humans, where sensory innervation of solid tumors is sparse and, when present, is usually associated with the blood vessels near the leading edge of the growing tumor [104107]. In these same animals, there was expression of activating transcription factor (ATF)-3 in the nucleus of sensory neurons that innervate the femur. ATF-3 is a member of the ATF/cyclic adenosine monophosphate response element binding protein family of transcription factors; these factors are not expressed at detectable levels in normal sensory neurons or in sensory neurons following peripheral inammation, but they are strongly expressed in sensory neurons after injury to peripheral nerves in neuropathic pain models [108]. 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. In an experimental model of nonmalignant neuropathic pain, phenotypic changes in the sensory and spinal cord neurons as well as pain behaviors were inhibited with selective blockade of artemin, a member of the glial cell linederived neurotrophic factor (GDNF) family [109]. Thus, although still in its infancy, use of selective antagonists and antibodies against growth factors provide a novel approach toward the treatment of cancer-associated neuropathic pain.

Sabino Mantyh

Conclusion
For the rst time, animal models of cancer pain that begin to mirror the clinical picture of human patients with cancer pain are now available. Inwww.SupportiveOncology.net

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Bone Pain

Table 2

Progression of Bone Cancer-Related Pain Behaviors*

SARCOMA PAIN BEHAVIOR NAVE SHAM DAY 10 DAY 14

I. Ongoing pain Guarding (sec) over 2-minute observation period Flinches (count) over 2-minute observation period II. Movement-evoked pain A. Ambulatory pain Forced ambulation on rotarod (score) 5 (normal) to 0 (impaired) Limb use during normal ambulation (score) 4 (normal) to 0 (impaired) B. Palpation-evoked pain (over 2-minute period) Guarding (sec) following nonpainful palpation Flinches (count) following nonpainful palpation

0.9 0.2 2.0 0.5

2.4 9.7 5.3 0.9

6.3 0.4 13.5 0.3

9.2 0.9 15.4 0.9

5.0 0.0 4.0 0.0

4.3 0.2 3.8 0.1

3.6 0.2 2.7 0.2

2.2 0.2 2.3 0.3

0.8 0.2 2.3 0.3

2.1 0.3 6.6 1.4

7.9 0.5 17.0 0.6

11.7 1.4 19.9 2.1

* Ongoing and movement-evoked pain behaviors appear to worsen progressively over time; pain is maximal 14 days after tumor injection into mice compared with sham-operated controls. Sarcoma P < 0.05 vs sham.

formation generated from these models will shed light on the mechanisms that generate and maintain the different types of cancer pain. Advances in the understanding of the neurobiology of pain are now allowing scientists and clinicians to unravel the mysteries that underlie the heterogeneity, severity, and complexity of cancer pain. Cancer pain frequently becomes more severe as the disease progresses (Table 2) and may require different types of analgesics at different times. For example, in the mouse model of bone cancer, painrelated behaviors are present before any signicant bone destruction is evident [9]. This pain may be caused by prohyperalgesic factors, 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 continues to grow, sensory neurons innervating the marrow are compressed and destroyed, causing neuropathic pain that may respond to treatment with drugs such as gabapentin or artemin. As the tumor induces proliferation

and hypertrophy of osteoclasts, pain caused by osteoclastic activity could be blocked with antiresorptive drugs such as bisphosphonates or OPG. As the cancer cells completely ll the intramedullary space, the high levels of resulting apoptosis generate an acidic environment. In this situation, antagonists to TRPV-1 or ASICs could be used to attenuate the pain induced by acidosis. Finally, as bone destruction continues and the mechanical strength of the bone is compromised, antagonists that block the mechanically gated channels and/ or ATP receptors in the richly innervated periosteum might reduce movement-associated pain. Although this pattern of tumor-induced tissue destruction and nociceptor activation may be unique to bone cancer, an evolving set of nociceptive events probably occurs in other cancers. Since the type of tumor-induced tissue injury, the level of nociceptor activation, and the spinal cord and forebrain areas involved in transmitting nociceptive signals change as the disease progresses, different therapies might be most efcacious at particular stages of the disease.

A peer viewpoint on this article by Dr. Judith A. Paice appears on page 26.

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