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date: 22 January 2019

Cancer and Pain

Abstract and Keywords

Pain is a common and feared complication for many cancer patients. Cancer pain covers numerous pain syndromes; since the treatment is complex, it is essential to assess each individual patient with cancer pain thoroughly. Cancer pain includes not only elements of inflammatory and neuropathic pain, but also, importantly, cancer-specific elements. Starting with the clinical aspects of cancer pain and the current knowledge from in vivo models, this chapter provides an overview of the neurobiology known to drive cancer-induced bone pain as it evolves through the complex interplay between primary afferents, tumor cells, and bone cells. There continue to be many uncertainties and unknown mechanisms involved in cancer pain, and an effort to discover novel therapeutic targets should be emphasized as cancer pain poses an increasing clinical and socioeconomic burden.

Keywords: cancer pain, cancer-induced bone pain, in vivo models, clinical aspects, neurobiology

Introduction

Pain is a common complication for many cancer patients and has a negative impact on their quality of life (Kurita et al., 2013). Indeed, patients with cancer cite pain as their most burdensome and restrictive symptom (Stromgren et al., 2006); pain management is therefore a crucial aspect of a patients’ treatment.

While cancer incidence is increasing, mortality is decreasing. In 2012, the estimated number of newly diagnosed adult cancer cases worldwide was 14.1 million. Concurrently, 8.2 million people died from cancer, while 32.6 million people were estimated to live with cancer (Ferlay et al., 2015). Consequently, the number of patients living with cancer and the number of cancer survivors have increased, with both groups experiencing problematic pain (Brown & Farquhar-Smith, 2017; Paice et al., 2016). Patients with cancer are usually affected by not only cancer pain, but also pain arising from cancer treatment and surgical interventions (Brown & Farquhar-Smith, 2017). This results in poor quality of life for patients and poses increasing clinical and socioeconomic problems (Hauben & Hogendoorn, 2010; Kurita et al., 2013; Laird et al., 2011).

Pain is a complex sensory and emotional experience. This means that, in addition to the physiological basis, pain is affected by psychological processes, including emotion, cognition, motivation, and social factors (Edwards, Dworkin, Sullivan, Turk, & Wasan, 2016). Significant comorbidities (e.g., anxiety and depression) are often involved (Laird, Boyd, Colvin, & Fallon, 2009; McMillan, Tofthagen, & Morgan, 2008; Syrjala et al., 2014). Patients with cancer also experience a wide range of physical symptoms caused by the cancer and the treatment, including fatigue, nausea, dyspnea, and constipation (Cleeland et al., 2000; Stromgren et al., 2006). Thus, the treatment of the patient with cancer is complex, and it is essential to make a full assessment of the patient and address all aspects of the cancer disease to achieve a meaningful improvement of the patient’s quality of life.

This chapter provides an overview of the different aspects of cancer pain. A general description of the patient with cancer pain and the complications associated with metastatic spread to the bones are first discussed, followed by an introduction to the animal models and methods commonly used to model cancer pain. Last, the current mechanistic knowledge of the neurobiology involved is reviewed.

The Heterogeneity of the Patient with Cancer Pain

Patients with cancer pain are a heterogeneous entity. The patients typically present with one or more pain modalities caused by various underlying mechanisms (Banning, Sjogren, & Henriksen, 1991; Grond, Zech, Diefenbach, Radbruch, & Lehmann, 1996; Kurita et al., 2013). Of these patients, 30–40% are estimated to have pain at the time of diagnosis and up to 75% at the advanced disease stage, with around 50% of patients with advanced, metastatic, and terminal disease reporting moderate-to-severe pain (Daut & Cleeland, 1982; Kurita et al., 2013; van den Beuken-van Everdingen, Hochstenbach, Joosten, Tjan-Heijnen, & Janssen, 2016). Patients with metastatic cancer are more likely to report pain than patients with nonmetastatic disease, and their pain severity is usually higher (Banning et al., 1991; Caraceni et al., 2004; Daut & Cleeland, 1982). Although an awareness of cancer pain has increased (van den Beuken-van Everdingen et al., 2016), 10–23% of patients still receive inadequate pain relief; moreover, a subset of patients experiencing moderate-to-severe pain are left untreated (Breivik et al., 2009; Kurita et al., 2013). This means that potentially 3.3 million people are left with a significant burden of pain (Banning et al., 1991; Breivik et al., 2009; Daut & Cleeland, 1982; Ferlay et al., 2015; Kurita et al., 2013).

To complicate things further, the term cancer pain covers numerous pain syndromes (Koh & Portenoy, 2009). Cancer pain can be caused by the cancerous growth itself, which may press on or damage pain-sensitive structures or release inflammatory mediators that cause or worsen the pain. The pain can be initiated by several underlying mechanisms and may, as indicated, include not only both inflammatory and neuropathic elements, but also cancer-specific elements (Falk & Dickenson, 2014; Grond et al., 1996; Koh & Portenoy, 2009; Kurita et al., 2013). Moreover, the pain can be associated with trauma after surgery, radiation, and chemotherapy (Koh & Portenoy, 2009; Kurita et al., 2013; Mulvey et al., 2017). Patients with cancer experience on average two distinct pain types (Banning et al., 1991; Grond et al., 1996). These may include somatic, visceral, and neuropathic pains or a mixture. It is estimated that up to 40% of patients with cancer pain have a neuropathic pain component (Bennett et al., 2012; Kurita et al., 2013; Roberto et al., 2016). Particularly, chemotherapy-induced peripheral neuropathy is a common pain type observed in 30% of patients 6 months or later after treatment with neurotoxic chemotherapeutic agents (Brozou, Vadalouca, & Zis, 2018). Figure 1 reflects a cancer patient with common pain syndromes, including a list of psychological and social factors, as well as other distressing symptoms, all factors that affect the pain experience. For an elaborate overview of pain syndromes, please see the work of Koh and Portenoy (2009).

Cancer and PainClick to view larger

Figure 1. The cancer patient. Schematic representation of common pain syndromes observed in cancer pain, including psychological, social, and spiritual factors that affect the pain, and other factors that cause distress and lower the patient’s quality of life.

Regardless of the cancer diagnosis, the pain is dynamic, and its intensity, quality, and localization typically change over time due to disease progression (Mercadante, 1997). Thus, continuous evaluation of the pain is necessary to ensure adequate pain management, and pain treatment should include not only disease-modifying agents and analgesia but also adjuvant therapy, physiotherapy, and occupational therapy. It is vital also that the psychological and social aspects of pain are dealt with (Banning et al., 1991; Syrjala et al., 2014). Patient involvement and expected outcomes regarding pain control should be at the forefront of the treatment plan; patients may prioritize freedom from sedation and maintenance of physical activity and psychological performance over complete pain control (Banning et al., 1991; Kurita et al., 2013).

Cancer-Induced Bone Pain

Bone metastases are a major cause of pain (Breivik et al., 2009; Mercadante, 1997), and it is reported that 35–85% of patients with metastatic bone disease experience pain (Breivik et al., 2009; Grond et al., 1996). Patients with cancer-induced bone pain typically present with a steady level of background pain that develops gradually as the cancer progresses and becomes more severe over time (P. Mantyh, 2013; Mercadante, 1997). This pain is often described with terms such as dull, annoying, gnawing, and aching (Laird et al., 2011; Mercadante, 1997). In addition, the patients are prone to breakthrough pain episodes, which are transient severe pain exacerbations (Banning et al., 1991; Caraceni et al., 2004; Laird et al., 2011).

Cancer-induced bone pain is predominantly seen after spread of the cancer from the primary site (Mercadante, 1997). Metastatic spread is common in many types of cancer and is found postmortem in 30–70% of patients with breast, prostate, kidney, lung, or thyroid cancers (Coleman, 2006; Tubiana-Hulin, 1991). The most common sites of bone metastases are the vertebrae and pelvis, followed by the ribs, femur, and skull (Tubiana-Hulin, 1991). The site of metastasis is associated with distinct pain syndromes; metastases at the base of the skull are associated with headache, neuralgia, and nerve palsies; vertebral metastases are associated with neck and back pain and complications caused by epidural extension or spinal cord compression; and pelvis and femoral metastases are associated with pain in the back and lower limbs (Coleman, 2006). Pathological microfractures can occur as a result of mechanical instability, and in the progressed state, fractures of weight-bearing skeletal structures are observed (Coleman, 2006). The patient may further develop hypercalcemia due to increased bone destruction, with common symptoms being fatigue, anorexia, and constipation. If untreated, the rise in serum calcium levels may cause deterioration of renal and mental functions (Coleman, 2006).

Breakthrough pain is seen in up to 75% of patients with cancer-induced bone pain (Caraceni et al., 2004; Davies et al., 2013; Laird et al., 2011). This can occur spontaneously or in relation to predictable or unpredictable triggers, with pain induced by movement being a major and disabling cause of breakthrough pain (Banning et al., 1991; Davies et al., 2013). Breakthrough pain has a strong impact on the patients’ quality of life as it affects their ability to move; also, the unpredictable nature of the pain limits the patients’ social engagement, thus increasing the risk of social isolation (Banning et al., 1991; Caraceni et al., 2004; Davies et al., 2013). Therapeutically, breakthrough pain poses a challenge due to the often rapid onset and severe pain intensity (Caraceni et al., 2004; Laird et al., 2011).

Despite major progress, cancer-induced bone pain is still undertreated (Kirou-Mauro et al., 2009; Laird et al., 2011), and there is an apparent need for optimized use of currently available analgesics and novel therapeutic approaches to handle both background and breakthrough pain.

In Vivo Modeling of Cancer Pain

To gain mechanistic insight regarding the molecular and cellular pathology involved, several animal models of cancer pain have been developed over the last few decades. The models are inherently artificial, and the translational value and limitations of the models must be considered (Klinck et al., 2017; Mogil & Crager, 2004). Nevertheless, the models are currently the best available tool to dissect the mechanisms driving and modulating cancer pain; they are proposed to accurately mimic the pain condition observed in patients (Blackburn-Munro, 2004). The models of metastatic pain were originally based on blood-borne spread after intracardiac injection of cancer cells (Arguello, Baggs, & Frantz, 1988). However, this approach resulted in high interanimal variation and poor health of the animals due to metastatic spread to multiple sites; the model was therefore replaced by several more target-specific preclinical models. The first model of bone-associated cancer pain was based on injection of cancer cells around the calcaneus bone (Cain et al., 2001). This site, however, is not particularly translational to the clinical setting, so the model was further refined to involve direct injection and confinement of cancer cells in the tibia, femur, or humerus (Schwei et al., 1999). Other models of cancer pain also been established, including models of orofacial cancer pain (Lam, Dang, Zhang, Dolan, & Schmidt, 2012); skin cancer (H. H. Wu, Lester, Sun, & Wilcox, 1994); and pancreatic cancer (Lindsay et al., 2005).

Because models of cancer-induced bone pain are among the most widely used (Currie, Sena, Fallon, Macleod, & Colvin, 2014) and have provided fundamental insights into the neurobiology of cancer pain, these models are used to exemplify the mechanisms currently known to drive cancer pain. In models of cancer-induced bone pain, the injected cancer cells initially proliferate and form a tumor that is confined within the intermedullary space of long bones. Only in the late and progressed stage will the cancer cells start to invade the adjacent soft tissue. This results in reproducible and well-controlled models with low interanimal variations and minor or no impact on the general health of the animal compared to the intracardial-based models. These refined models allow simultaneous studies of several components of the pathology, including pain-related behaviors, tumor growth, bone degradation, and peripheral and central neurochemical changes. Today, several models of cancer-induced bone pain have been developed based on this approach, with variations in the cancer cell lines, species, strains, and site of implantation. The best described models are shown in Table 1. For further details on additional animal models, please see recent reviews (Currie et al., 2013; Slosky, Largent-Milnes, & Vanderah, 2015).

Table 1. Animal Models of Cancer-Induced Bone Pain

Species and Strain

Cancer Type

Cell Line

Injection Site

Syngenic

Reference

Mouse

Balb/c

Mammary pad—adenocarcinoma

4T1

Femur

x

Goblirsch et al. (2006)

C57BL/6

Lung—carcinoma

Lewis Lung

Femur

x

Huang, Huang, Yan, Wu, and Wang (2008)

C3H

Mesenchyme—osteosarcoma

NCTC 2472

Femur

x

Schwei et al. (1999)

Tibia

Menéndez et al. (2003)

Calcaneus

Cain et al. (2001)

Nude nu/nu

Breast—adenocarcinoma

MDA-MB-231

Intracardiac

Morony et al. (2001)

Mammary pad

Hiraga, Williams, Mundy, and Yoneda (2001)

Femur

Ungard, Seidlitz, and Singh, (2014)

Rat

Sprague-Dawley

Mammary pad—gland carcinoma cells

MRMT1

Tibia

x

Medhurst et al. (2002)

Mammary gland—carcinoma

Walker 256

Tibia

Yao et al. (2008)

Copenhagen

Prostate—adenocarcinoma

AT-3

Tibia

x

Zhang et al. (2005)

Wistar

Mammary pad—gland carcinoma cells

MRMT1

Tibia

(x)

Tomotsuka et al. (2014)

x, syngenic; (x), origin undefined albino rat.

The pain phenotype is affected by the choice of cancer cell line, species, strain, and site of implantation, and several behavioral assays have been adapted to assess the pain modalities presented in the different models. The field of cancer-induced bone pain has merged cancer research and chronic pain research, and a part of the field has therefore intuitively adapted the behavioral assays traditionally used to assess neuropathic and inflammatory pain, such as quantification of skin hypersensitivity under the paw of the affected limb in the form of mechanical allodynia (von Frey test) or thermal hyperalgesia (Hargreaves test). However, these behavioral outcomes do not always translate well to the clinical setting, as they are not necessarily relevant to the pain experienced by the cancer patients because only stimuli-evoked threshold responses are tested. In the literature, there are only a few studies describing altered sensations in the skin overlying the area of the metastatic site, with about half or fewer of the patients experiencing either increased or reduced sensation (Kerba, Wu, Duan, Hagen, & Bennett, 2010; Scott, McConnell, Laird, Colvin, & Fallon, 2012).

Instead, spontaneous pain and pain evoked by weight bearing or movement are major complaints and have a much stronger impact on the patients’ quality of life (Banning et al., 1991; Caraceni et al., 2004; Davies et al., 2013; Laird et al., 2011). Nevertheless, the von Frey test has historically been the most commonly used behavioral outcome for assessment of cancer-induced bone pain in animal models (Currie et al., 2013). But, the relevance of skin hypersensitivity as a surrogate measure for cancer-induced bone pain is now increasingly questioned in the animal models. Guedon et al. recently demonstrated that in the NCTC2472 model in C3H mice, the mechanical hypersensitivity detected in the hind paw was effectively blocked without affecting skeletal pain behaviors, in this case defined as spontaneous nocifensive behavior (guarding and flinching) and weight bearing on the affected leg (Guedon et al., 2016). Also, in the Lewis lung model, C57BL/6 mice did not develop mechanical allodynia (Minett et al., 2014), and in the MRMT-1 model in Sprague-Dawley rats, mechanical allodynia, in some animals, turned into a numbness of the paw in the late and progressed state (Falk, Schwab, et al., 2015).

Increased focus has therefore been put on the development of new behavioral assays that are more bone pain specific and better reflect the pain reported by patients. These include spontaneous flinching; guarding behavior (Honore, Luger, et al., 2000); limb use scoring in the open field or on a rotarod (Honore, Luger, et al., 2000); dynamic or static weight bearing (Dore-Savard et al., 2010); pressure pain (Randall Sellito test) (Falk, Ipsen, et al., 2015); running wheel (Tang et al., 2016); night/daytime activity (Majuta, Guedon, Mitchell, Kuskowski, & Mantyh, 2017); grip force (Wacnik et al., 2003); and climbing behavior (Falk, Gallego-Pedersen, & Petersen, 2017). Currently, conditioned place preference is being tested in an attempt to assess the motivational drive for relief of ongoing pain (Nakamura et al., 2017; Remeniuk et al., 2015), but further studies are needed to validate and standardize the test for assessment of cancer-induced bone pain.

Spontaneous nocifensive behaviors (flinching and guarding) are commonly used behavioral readouts, though inconsistencies have been reported; these behaviors are not observed in all models and are not always observed within the same model (De Felice, Lambert, Holen, Escott, & Andrew, 2016; Remeniuk et al., 2015). This inconsistency might relate to differences in animal vendor or cell line supplier. Currently, limb use scoring and weight-bearing assessment seem to provide the most consistent measures across animal models and research groups, and both are highly relevant to the pain reported by patients. However, as all behavioral assays have limitations, a battery of tests assessing multiple pain modalities is preferential to cover the different aspects of the complex pain state.

Molecular and Cellular Mechanisms of Cancer-Induced Bone Pain

Primary afferent sensory neurons are the gateway by which sensory information is transmitted to the central nervous system. The primary afferent neurons, located with their cell bodies in the dorsal root ganglia (DRG), synapse with second-order neurons in the dorsal horn of the spinal cord, which subsequently relay the signal to higher brain centers (Basbaum, Bautista, Scherrer, & Julius, 2009). Cancer-induced bone pain arises in the periphery and evolves as a consequence of a complex interplay between peripheral afferents, tumor cells, and bone cells (Figure 2). Once the cancer has metastasized to the bone, a vicious cycle of tumor growth, bone destruction, nerve damage, and sprouting begins; various factors are released; and these pathological events eventually lead to pain, skeletal fractures, and hypercalcemia (Coleman, 2006). The sensitization and persistent drive of primary afferent sensory nerves induce plastic changes in the spinal cord, ultimately leading to a state of central sensitization. Because peripheral, spinal, and supraspinal mechanisms contribute to nociceptive processing and the overall pain experienced by patients with cancer, all levels of the nervous system can potentially serve as therapeutic targets for pain relief.

Cancer and PainClick to view larger

Figure 2. Molecular mechanisms of cancer-induced bone pain. Schematic illustration of key elements and molecular and cellular mediators driving cancer-induced bone pain. AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ASIC, acid-sensing ion channel; ATP, adenosine triphosphate; BDNF, brain-derived neurotrophic factor; EP, prostaglandin receptor; ETαR, endothelin receptor; ET, endothelin; IL-1β, interleukin 1 beta; IL-6, interleukin 6; MCP-1, monocyte chemoattractant protein 1; MIP-1α, macrophage inflammatory protein 1 alpha; NGF, nerve growth factor; NMDAR, N-methyl-d-aspartate receptor; OPG, osteoprotegerin; P2XR, P2X receptors; PAR2, protease-activated receptor 2; PGE2, prostaglandin E2; PTHrP, parathyroid hormone–related protein; RANK, receptor activator of nuclear factor kappa-β; RANKL, receptor activator of nuclear factor kappa-β ligand; TGF-β, transforming growth factor β; TNF-α, tumor necrosis factor alpha; TrkA/B, tyrosine kinase A or B; TRPV1, transient receptor potential cation channel subfamily V member 1.

Tumor Microenvironment

Tumors consist of stromal and cancer cells, with the stromal cells typically far outnumbering the cancer cells. The stroma consist of various cell types, such as endothelial cells, fibroblasts, and immune cells like macrophages, mast cells, neutrophils, and T lymphocytes (Joyce & Pollard, 2009). Together, these cells secrete a plethora of factors known to sensitize or directly excite the primary afferent neurons, including bradykinin, cannabinoids, endothelins, interleukin (IL) 6, granulocyte–macrophage colony-stimulating factors (GM-CSFs), nerve growth factor (NGF), proteases, and tumor necrosis factor alpha (TNF-α) (Joyce & Pollard, 2009; Julius & Basbaum, 2001). A key player in the pathology of cancer-induced bone pain is NGF via its interaction with the tropomyosin receptor kinase A (TrkA) expressed on the nerve endings of the peripheral sensory neurons. NGF induces changes both in the periphery and in the dorsal horn of the spinal cord, and its effect on the sensory neurons is discussed in more detail in the next section. Interestingly, it has been suggested that NGF is also involved in survival and proliferation of some cancers (Descamps et al., 2001). Other essential factors secreted by the tumor cells are parathyroid hormone–related peptide (PTHrP) and receptor activator of nuclear factor kappa-β ligand (RANKL), which act on bone cells and are involved in bone destruction.

The immune cells secrete an abundance of cytokines, chemokines, and inflammatory mediators, such as IL-6, IL-1β, TNF-α, tumor growth factor beta (TGF-β), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1α (MIP-1α), fractalkine, and adenosine triphosphate (ATP), which recruit additional immune cells and contribute to the local inflammation in the bone. TNF-α is released by several immune cells and is significantly elevated in cancer-bearing bone and spinal cord (Baamonde et al., 2007; Lozano-Ondoua et al., 2013; Wacnik, Eikmeier, Simone, Wilcox, & Beitz, 2005). At high concentrations, it can induce excessive inflammation and tissue damage (Tracey, Klareskog, Sasso, Salfeld, & Tak, 2008). TNF-α promotes pain through direct activation of TNF-α receptor type 2 and transient receptor potential channel vanilloid 1 (TRPV1) expressed on peripheral sensory neurons and indirectly through an increase in the levels of prostanoids and sympathetic amines (Constantin et al., 2008; Verri et al., 2006). Interleukins, such as IL-1β and IL-1, also contribute to the inflammatory process and are upregulated in murine models of cancer-induced bone pain (Baamonde et al., 2007; Wacnik et al., 2005). IL-1β and IL-1 are secreted by macrophages, monocytes, and cancer cells and are critical to pain as they fuel the production and release of additional inflammatory mediators, including prostaglandins and NGF (Slosky et al., 2015).

Therapeutic Approach

Several strategies for analgesic treatment target the tumor microenvironment. Chemotherapy is an obvious and indirect approach with a high success rate, as decreased tumor burden is often correlated with decreased pain. The inflammatory component has been targeted to secure antinociceptive effects. Multiple animal studies have tested the therapeutic potential of cyclooxygenase (COX) inhibitors, which reduce local production of prostaglandins. Although some studies demonstrated a clear antinociceptive effect of COX-2 inhibition, others found no effect (Medhurst et al., 2002; Sabino et al., 2002; Walker et al., 2002). Clinically, treatment with paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs) is recommended for mild cancer pain (Kane, Hoskin, & Bennett, 2015; Ripamonti et al., 2012; Schug & Chandrasena, 2015), although two recent systematic Cochrane reviews concluded that the use of paracetamol and NSAIDs for mild cancer pain cannot be supported or refuted due to low-quality evidence (Derry et al., 2017; Wiffen et al., 2017). However, a randomized, double-blind study has suggested that dexketoprofen is effective in the early treatment of cancer-induced bone pain (Rodriguez et al., 2003).

Peripheral Sensory Fibers

As the tumor cells invade and proliferate in the bone tissue, they come into close contact with the distal processes of the sensory fibers innervating the bone, which they injure and eventually destroy. Nerve-ending damage was associated with increased ongoing and movement-evoked pain behaviors in several animal models, possibly reflecting a neuropathic element of cancer-induced bone pain (Falk & Dickenson, 2014). Another mechanism contributing to the pain is pathological sprouting and formation of neuroma-like structures of the nerve fibers innervating the bone. Notably, mouse studies have suggested that bone tissue has a different sensory innervation than skin, with bone largely being innervated by thinly myelinated (Aδ-) and unmyelinated (C-) peptidergic fibers that express TrkA (Castaneda-Corral et al., 2011; W. G. Mantyh et al., 2010).

In mouse models of cancer-induced bone pain, substantial sprouting of both sensory and sympathetic fibers is observed in the periosteum, mineralized bone, and bone marrow (P. W. Mantyh, 2014; Peters et al., 2005), causing a general increase in the overall nerve fiber density. The neuroma-like structures appear similar to the structures observed in conditions associated with spontaneous ectopic pain episodes, such as complex regional pain syndrome, and it is speculated that these cancer-induced, neuroma-like structures contribute to the breakthrough pain observed in patients with bone metastases (Janig & Baron, 2003; W. G. Mantyh et al., 2010). In healthy bone, sensory and sympathetic fibers display distinguished morphologies, with the sensory fibers having long and linear morphology and the sympathetic fibers a spiral-like appearance as they wrap around associated blood vessels (Mach et al., 2002).

The cancer-induced sprouting generates a reorganization: The sensory and sympathetic fibers are intermixed, thereby increasing the risk of sympathetic fibers triggering the sensory fibers (W. G. Mantyh et al., 2010). The sprouting has been linked to an increased release of NGF. NGF directly activates the TrkA-expressing sensory neurons, and the retrogradely transported NGF/TrkA complex increases the synthesis of peptide neurotransmitters (substance P and calcitonin gene–related peptide), sodium channels (TRPV1 and NaV1.8), transcription factors (ATF3), and structural molecules (neurofilaments and sodium channel–anchoring molecule p11). In addition, NGF modulates the trafficking and insertion of Nav1.8 and TRPV1 in the sensory neurons (Gould et al., 2000; Ji, Samad, Jin, Schmoll, & Woolf, 2002). NGF also impacts nonneuronal cells that are known to influence pain, such as Schwann cells and macrophages (Heumann, Korsching, Bandtlow, & Thoenen, 1987; Heumann, Lindholm, et al., 1987; Obata et al., 2002).

The expression of multiple acid-sensing ion channels, including TRPV1 and acid-sensitive ion channels (ASICs), is increased in models of cancer-induced bone pain. TRPV1 receptors are expressed at the peripheral terminals and in the cell bodies of a significant proportion of C- and Aδ-sensory fibers that innervate the bone (Ghilardi et al., 2005). TRPV1 is activated by pH lower than 6, capsaicin, noxious heat, voltage, and endovanilloids. The acid-induced activation is critical in cancer-induced bone pain; the bone–tumor microenvironment is acidic due to protons secreted from osteoclasts during bone resorption and protons produced by tumor and immune cells during lactate secretion (Yoneda et al., 2011). ASICs are voltage-insensitive, proton-gated Na2+ channels that are expressed in the entire nervous system and found in high numbers in the DRG. Although conflicting data exist, both ASIC3 and ASIC1a/b are upregulated in the DRGs in models of cancer-induced bone pain (Nagae, Hiraga, & Yoneda, 2007; Qiu, Wei, Zhang, Yuan, & Mi, 2014), and these may participate in the acidosis-induced nociception.

The P2X receptors also play a role in cancer-induced bone pain. The P2X receptor family consists of nonselective cation channels that are activated by extracellular ATP; the P2X3 receptor definitely plays a role in cancer-induced bone pain (Hansen et al., 2012; Kaan et al., 2010; Liu et al., 2013; J. X. Wu et al., 2012), whereas there are conflicting results regarding the role of the P2X7 receptor (Falk, Schwab, et al., 2015; Hansen et al., 2011; Huang et al., 2014). The P2X3 receptor is highly expressed in C- and Aδ-fibers and is presumably found in the cell bodies and at peripheral and central terminals (Falk, Uldall, & Heegaard, 2012). Several studies have demonstrated an upregulation of P2X3 receptors in the DRGs in response to bone cancer, and it is established that inhibition of the receptor attenuates cancer-induced bone pain (Hansen et al., 2012; Kaan et al., 2010; Liu et al., 2013; J. X. Wu et al., 2012).

Therapeutic Approach

Therapies that block the NGF/TrkA pathway effectively attenuate both early and late-stage cancer-induced bone pain in both prostate carcinoma and sarcoma-induced mouse models of cancer-induced bone pain; such therapies were found to be more effective than acute administration of morphine (Halvorson et al., 2005; Sevcik et al., 2005). Anti-NGF treatment or TrkA inhibition largely blocks pathological sprouting of the nerve fibers (Jimenez-Andrade, Ghilardi, Castaneda-Corral, Kuskowski, & Mantyh, 2011; W. G. Mantyh et al., 2010) and reduces the neurochemical changes in the DRG and spinal cord, suggestive of a reduction in both peripheral and central sensitization (Sevcik et al., 2005). Results from a placebo-controlled, proof-of-concept study and a noncontrolled, open-label study with tanezumab, a humanized monoclonal antibody that blocks the binding of NGF to TrkA, suggest that the NGF-driven pathology may hold true in patients, although only a numeric and not statistically significant decrease was found in pain scores (Sopata et al., 2015).

Bone Microenvironment

In healthy bone, remodeling is balanced by coordinated bone resorption and bone formation. Old bone is resorbed by osteoclasts, while new bone is formed by osteoblasts (Suva, Washam, Nicholas, & Griffin, 2011). The tumor disrupts normal bone homeostasis, and both osteoblastic (net deposition) and osteolytic (net resorption) cancers will eventually compromise the microarchitecture and overall strength of the bone (Suva et al., 2011). Most bone metastasizing cancers are osteolytic; hence, they cause osteolytic lesions in bone. The lesions are characterized by proliferation and hypertrophy of osteoclasts and subsequent release of acidic and lytic enzymes, inducing bone degradation and production of an acidic local environment (Clohisy, Perkins, & Ramnaraine, 2000; Honore & Mantyh, 2000).

Cancer cells and their associated stromal cells secrete RANKL, which binds to the RANK (receptor activator of nuclear factor kappa-β) receptors expressed on osteoclast to initiate proliferation and hypertrophy (Clohisy et al., 2000; Honore, Rogers, et al., 2000). Furthermore, the tumor cells secrete PTHrP, which in turn stimulates osteoblasts to produce additional RANKL. RANKL, under normal conditions, is expressed by the osteoblasts and, along with colony-stimulating factor 1 (CSF-1), is essential for osteoclast maturation. The RANKL/RANK pathway is normally controlled by osteoprotegrin (OPG), which is released by the osteoblasts and interrupts the binding of RANKL to RANK to inhibit osteoclast activation. The tumor-induced increased pool of RANKL disrupts this balance and accelerates bone resorption. Studies have shown that OPG treatment in mice significantly decreases bone degradation, nocifensive behaviors, and spinal cord neurochemical changes in cancer-bearing animals, without affecting the overall tumor load (Honore, Luger, et al., 2000; Luger et al., 2001). TGF-β is, along with other bone-derived growth factors, released during bone resorption and secreted from tumor cells. TGF-β drives a feedforward loop by stimulation of further tumor proliferation and osteolysis mediated through release of various osteolytic factors, including PTHrP, IL-11, and vascular endothelial growth factor (Slosky et al., 2015).

Therapeutic Approach

Because the bone-degrading component of bone cancer is a major cause of pain pathology, bisphosphonates are a widely used therapy that acts through inhibition of the osteoclastic bone resorption (Kane et al., 2015; Ripamonti et al., 2012; Schug & Chandrasena, 2015). The osteoclasts are also targeted therapeutically by drugs that interfere with RANKL binding to RANK, such as denosumab. This class of drugs has been demonstrated to effectively reduce tumor-induced osteoclastic bone resorption in both animal and humans (Lipton & Jun, 2008). Interference with the RANKL/RANK pathway causes significant depletion of activated osteoclasts, marked reduction in plasma markers of bone resorption, and significant attenuation of pain-related behavior in a mouse model of cancer-induced bone pain (Honore, Luger, et al., 2000). Several studies have demonstrated that this effect translates to patients, significantly improving their quality of life and functional status (Lipton & Goessl, 2011; P. W. Mantyh, 2014; Schwarz & Ritchlin, 2007). Because loss of mechanical strength and stability of the mineralized bone is an issue of both osteoblastic and osteolytic tumors, bisphosphonates and anti-RANKL therapy are useful in the management of both types of metastatic bone disease.

Central Mechanisms

The sensitization of primary afferent sensory neurons and the increased sensory input induces pathological changes in the central nervous system that contribute to the generation and maintenance of cancer-induced bone pain (Falk & Dickenson, 2014). Several studies have demonstrated molecular modifications in the spinal cord segments receiving inputs from the tumor-bearing bone leading to hyperexcitability of the spinal dorsal horn neurons. The modifications involve changes in the expression of dynorphin, galanin, ATF3, c-Fos, and substance P (Schwei et al., 1999), and astrocyte and microglia activation is seen in some, but not all, models (Ducourneau et al., 2014; Medhurst et al., 2002). Most changes correlate with disease progression in the preclinical models, although clinically the size of the tumor does not always correlate with the degree of pain (Mercadante, 1997).

The alterations in the dorsal horn include general hyperexcitability of spinal neurons and thus cause an enhanced response to evoked stimuli (Donovan-Rodriguez, Dickenson, & Urch, 2004; Urch, Donovan-Rodriguez, & Dickenson, 2003). A phenotypical change in the proportion of wide dynamic range (WDR) neurons to nociceptive-specific (NS) neurons have been demonstrated, and there is an increased proportion of WDR neurons in cancer-bearing animals compared to normal animals (Urch et al., 2003). In addition, the receptive field of neurons in the superficial dorsal horn is increased. Overall, this contributes to central sensitization and increases the probability of a pain-like response to low-threshold peripheral inputs.

The dorsal horn serves as a relay station for the ascending pathways in order to transmit signals from the periphery to higher brain centers. In addition, the dorsal horn is modulated by descending pathways and, as such, is supraspinally modulated by top-down control of excitatory and inhibitory signals. The descending serotonergic pathway, facilitatory via dorsal horn 5-HT3 (5-hydroxytryptamine type 3) receptors, is enhanced in two rat models of cancer-induced bone pain (Donovan-Rodriguez, Urch, & Dickenson, 2006; Huang et al., 2014). Inhibition of the system, either at the level of the rostral ventromedial medulla (RVM) or the spinal cord, results in an antinociceptive effect, quantified as decreased neuronal and behavioral responses to peripheral stimulation. Thus, there is a clear and important role for descending facilitation in cancer-induced bone pain (Donovan-Rodriguez et al., 2006; Huang et al., 2014).

Descending inhibitory pathways are thought to be altered in bone cancer models, a claim that is mainly based on the observed effect of opioids. Although opioids can act peripherally, their main effects are mediated through the central nervous system (Dickenson & Kieffer, 2013). Opioid receptors are expressed in many regions of both the peripheral and the central nervous system, and opioids consequently act at multiple levels. The main analgesic effect is mediated via inhibition of neurotransmitter release from the primary afferent terminals in the spinal cord, inhibition of neuronal firing of opioid receptor–expressing spinal neurons, and activation of the descending inhibitory pathway in the midbrain (Dickenson & Kieffer, 2013). The descending inhibitory pathway outlined consists of monoamine and opioid projection neurons that utilize noradrenaline, serotonin, and endogenous opioids as neurotransmitters to inhibit or facilitate pain sensations. As discussed in the next section, the efficiency of opioids in treating cancer-induced bone pain is complex, and animal studies suggest that this type of pain can be resistant to morphine analgesia (Hou et al., 2017; Luger et al., 2002; Yamamoto, Kawamata, Niiyama, Omote, & Namiki, 2008), possibly explained by a decreased expression of the μ-opioid receptors in both supraspinal and spinal regions (Hou et al., 2017; Nakamura et al., 2013; Yamamoto et al., 2008; Zhu et al., 2017). Nevertheless, opioids are currently the gold standard treatment for cancer pain in the clinic.

Therapeutic Approach

The mainstay treatment of cancer pain follows the World Health Organization’s (WHO) three-step analgesic ladder (WHO, 1996). However, a major drawback of the WHO ladder is that drug choices are mainly based on pain severity and not the underlying mechanisms, and current guidelines therefore elaborate use of adjuvant therapy and nonpharmacological interventions promoting a multifaceted approach to pain management (Caraceni et al., 2012; Fielding, Sanford, & Davis, 2013; Ripamonti et al., 2012). Although there are some controversies regarding the efficiency of the WHO ladder due to methodological concerns, it is estimated that 80–90% of patients receive adequate pain relief when the guidelines are followed (Ferreira, Kimura, & Teixeira, 2006; Schug & Chandrasena, 2015). The first step is treatment with a nonopioid analgesic, followed by the use of first weak and then strong opioids. Immediate-release, short-lasting opioids are recommended to manage spontaneous and incident breakthrough pain and can be used preemptively, but appropriate titration of around-the-clock opioid therapy is equally important (Caraceni et al., 2012; Ripamonti et al., 2012; Zeppetella & Davies, 2013). Adjuvant treatment can be added at all steps to achieve further analgesia or to treat adverse effects caused by the therapy (WHO, 1996). Antidepressant drugs and anticonvulsants are used for the treatment of cancer pain that presents with a neuropathic pain component (Schug & Chandrasena, 2015; WHO, 1996), but the evidence for an effect on cancer-induced bone pain is limited (Kane et al., 2015). There is an ongoing debate regarding the analgesic efficacy of weak opioids in cancer-induced bone pain, and it is recommended that low-dose strong opioids should be used if nonopioid analgesics fail to provide analgesia (Caraceni et al., 2012; Ripamonti et al., 2012).

Despite providing sufficient pain relief for many patients, long-term use of opioids has several drawbacks. In clinical practice, adverse effects, such as constipation, nausea, and sedation (Breivik et al., 2009), and misconceptions about opioid addiction often lead to reduced doses of opioids, leading to inadequate pain relief (Paice & Von Roenn, 2014). Also, the development of tolerance and opioid-induced hyperalgesia is a concern (Bannister, 2015; Colvin & Fallon, 2010; Paice & Von Roenn, 2014), yet the impact on cancer pain is far from clear. Several animal studies have demonstrated clear antinociceptive effect of opioids (Luger et al., 2002; Mouedden & Meert, 2007), whereas one study reported morphine-induced acceleration of both pain-related behavior and bone loss (King et al., 2007). These findings are in line with several clinical studies and case reports demonstrating development of opioid-induced allodynia in a subset of patients with cancer pain (Chu, Angst, & Clark, 2008; Mercadante, Ferrera, Arcuri, & Casuccio, 2012). In addition, chronic cancer pain and high-dose opioid use are linked to the development of opioid tolerance (Viet et al., 2017).

The issues related to opioid tolerance have prompted the development of dual-acting opioid-based compounds. Tapentadol acts as both a µ-opioid receptor agonist and a noradrenaline reuptake inhibitor and shows promise as an analgesic in the treatment of cancer-induced bone pain in both animals and patients (Coluzzi et al., 2015; Falk, Patel, Heegaard, Mercadante, & Dickenson, 2015). Tapentadol significantly decreased pain intensity and improved the quality of life in a study of 25 opioid-naïve patients with myeloma-induced pain; importantly, it also reduced the number of patients presenting with a neuropathic pain component, suggesting therapeutic efficacy in patients with a mixed pain state (Coluzzi et al., 2015). Overall, tapentadol is considered well tolerated, producing analgesia at levels comparable to morphine but with fewer gastrointestinal effects (Mercadante, 2017).

Conclusion and Future Directions

A significant number of patients with cancer remain in pain despite analgesic treatment, and still a subset of patients is left untreated. Increasing awareness of cancer pain and the major impact pain has on patients’ lives is key to improve cancer pain management. It is vital that the use of current available analgesics and nonpharmacological interventions is optimized, and a thorough assessment of each individual patient with cancer pain is essential. As cancer pain is a multidimensional experience, a biopsychosocial approach should be used, including patient involvement and therapeutic expectation for the effective management of pain control.

The neurobiology of cancer pain is still not fully elucidated. The first model specific for cancer-induced bone pain was developed in 1999 (Schwei et al., 1999), and it is hence less than two decades since cancer pain was suggested to be an entity separate from neuropathic and inflammatory pain and studied accordingly. Still, there are many uncertainties and unknown mechanisms involved in cancer pain, and an effort to discover novel targets should be emphasized as cancer pain poses an increasing clinical and socioeconomic burden.

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