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Orofacial Pain in Cancer: Part I—Mechanisms

¹ Department of Oral Medicine, The Hebrew University, Hadassah Faculty of Dental Medicine, PO Box 12272, Jerusalem 91120, Israel;
² Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, University of Illinois-Chicago, USA;
³ Universities of Medicine and Dentistry of New Jersey, New Jersey Dental School, 110 Bergen Street, Newark, NJ 07103, USA

Correspondence: ^* corresponding author, benoliel{at}cc.huji.ac.il

	ABSTRACT

TOP ABSTRACT (1) INTRODUCTION (2) FUNCTIONAL NEURO-ANATOMY (3) PAIN MECHANISMS IN... (4) MECHANISMS OF OROFACIAL... (5) CONCLUSIONS REFERENCES

 
The mechanisms involved, and possible treatment targets, in orofacial pain due to cancer are poorly understood. The aim of the first of this two-part series is to review the involved pathophysiological mechanisms and explore their possible roles in the orofacial region. However, there is a lack of relevant research in the trigeminal region, and we have therefore applied data accumulated from experiments on cancer pain mechanisms in rodent spinal models. In the second part, we review the clinical presentation of cancer-associated orofacial pain at various stages: initial diagnosis, during therapy (chemo-, radiotherapy, surgery), and in the post-therapy period. In the present article, we provide a brief outline of trigeminal functional neuro-anatomy and pain-modulatory pathways. Tissue destruction by invasive tumors (or metastases) induces inflammation and nerve damage, with attendant acute pain. In some cases, chronic pain, involving inflammatory and neuropathic mechanisms, may ensue. Distant, painful effects of tumors include paraneoplastic neuropathic syndromes and effects secondary to the release of factors by the tumor (growth factors, cytokines, and enzymes). Additionally, pain is frequent in cancer management protocols (surgery, chemotherapy, and radiotherapy). Understanding the mechanisms involved in cancer-related orofacial pain will enhance patient management.

Key Words: orofacial pain in cancer • mechanisms • biology

	(1) INTRODUCTION

TOP ABSTRACT (1) INTRODUCTION (2) FUNCTIONAL NEURO-ANATOMY (3) PAIN MECHANISMS IN... (4) MECHANISMS OF OROFACIAL... (5) CONCLUSIONS REFERENCES

 
Pain secondary to cancer (including head and neck tumors) is frequently associated with the tumor itself (87–92.5%), in 17–20.8%, pain is secondary to therapy, and some patients suffer both (Grond et al., 1996; Caraceni and Portenoy, 1999). A high percentage of patients ( 70%) may suffer pain from more than one site, involving inflammatory and neuropathic mechanisms (Grond et al., 1996). Unfortunately, a proportion of patients surviving orofacial cancer will subsequently develop chronic pain. A thorough understanding of the initiating mechanisms is therefore essential for managing clinicians.

In somatic and visceral pain directly related to the tumor, head and neck (H&N) syndromes have been reported as follows: base-of-skull syndrome (2.1%), headache (3.5%), damage to oral mucosa (2.9%), and infiltration of H&N muscles and fascia (5.2%) (Caraceni and Portenoy, 1999). In tumors specifically occurring in the H&N, 78% of patients reported pain in the head, face, or mouth, and 54% reported pain in the cervical region or shoulder (Grond et al., 1996). Moreover, some H&N patients reported pain in distant sites, such as the thorax (7%), lower back (7%), lower limbs (5%), and pelvic region (1%) (Grond et al., 1996). Other studies, on patients with H&N cancers, also reported pain in up to 80% of cases (Foley, 1985; Foley and Inturrisi, 1987). The vast majority ( 75%) of these patients will suffer from pain secondary to bone destruction and nerve injury (Koeller, 1990; Banning et al., 1991; Coleman, 1998; Foley, 1999), involving inflammatory and/or neuropathic mechanisms (Caraceni and Portenoy, 1999; Kanner, 2001).

Acute pain due to therapy for H&N cancer is extremely common secondary to ablative surgery, chemo- and/or radiotherapy protocols. Therapy-related pain usually involves an acute inflammatory response that may be associated with a variable degree of concomitant nerve injury. Chronic pain syndromes secondary to therapy are related to the extent of surgery and the type of adjuvant protocol used. In one series, post-radical neck dissection (0.6%) and post-cranial-radiotherapy or chemotherapy headaches (0.1% each) were the most common H&N syndromes (Caraceni and Portenoy, 1999).

Classification of orofacial pain in cancer patients may be based on the underlying pathophysiological mechanisms (e.g., nociceptive/inflammatory, neuropathic), the location of the tumor (local or distant), or the primary initiating agent (tumor or tumor treatment). The aim of the present article is to examine the mechanisms associated with each of these processes. In the clinical setting, however, these classifications and mechanisms frequently overlap, and it is convenient to examine the presentation of cancer-related pain according to the timing of its appearance. This is the approach that has been adopted in the second article ("Orofacial Pain in Cancer: Part II—Clinical Perspectives and Management").

Experimental models of cancer-induced pain have recently been published and have provided us with data on behavioral and neurochemical changes associated with tumor progression. This research has highlighted that, although similar to inflammatory and neuropathic pain, cancer-induced pain has several unique features. However, there is no specific experimental research on the mechanisms of pain in orofacial cancer, and we have thus extrapolated from experimental work performed on long bones and spinal nerves. The rich blood and nerve supply of the head and neck may modify the expression and progression of tumor growth, and an experimental model of orofacial cancer pain is needed.

The search strategy for the two articles involved the use of Pub Med searches with various combinations of key words: orofacial, oral, head and neck, cancer, tumor, pain, management, mechanisms, inflammation, neuropathy, neurotoxicity, radiotherapy, chemotherapy, and mucositis. The results of the search were reviewed by the authors and selected based on quality, originality (e.g., unusual but significant findings), and space considerations.

	(2) FUNCTIONAL NEURO-ANATOMY

TOP ABSTRACT (1) INTRODUCTION (2) FUNCTIONAL NEURO-ANATOMY (3) PAIN MECHANISMS IN... (4) MECHANISMS OF OROFACIAL... (5) CONCLUSIONS REFERENCES

 
Sensory information from craniofacial structures is transmitted to the brainstem and higher centers via trigeminal afferents whose cell bodies reside in the trigeminal ganglion (see Fig. 1). Based on electrophysiological and anatomical criteria, primary afferent fibers may be divided into nociceptors (A- and C-fibers) and non-nociceptive A-β fibers. Primary afferents express receptors to heat, cold, low pH, and mechanical stimulation. Nociceptors are able to detect threatening stimuli (e.g., thermal, mechanical, and chemical). Some nociceptors are found to be unresponsive until activated by injury, and are termed silent or ‘sleeping’ nociceptors.

View larger version (71K): [in this window] [in a new window]   Figure 1. Schematic (simplified) representation of pathways involved in trigeminal nociception. Peripheral nociceptors (1) in muscle, tooth, bone, or soft tissue may be activated by numerous potentially damaging stimuli. The cell bodies of these primary afferent nociceptors reside in the trigeminal ganglion (2). The central projections of these nociceptors synapse in trigeminal nucleus caudalis (3, medullary dorsal horn) on second-order neurons. (See also detail of this area in enlarged box.) The second-order neurons (4) may receive primary afferents from several peripheral sites (5, convergence), accounting for the referral patterns observed in orofacial pain. Primary afferents in the medullary dorsal horn are subject to modulation from higher centers that adjust the central release of neurotransmitters, termed ‘pre-synaptic modulation’ (6). Dorsal horn neurons also synapse with descending modulatory pathways (inhibitory and facilitatory) from higher central nervous system (CNS) centers (6) that adjust the cell’s reaction to peripheral stimuli (post-synaptic modulation). Both the central terminals of primary afferents and second-order neurons are also modulated by local interneurons and synaptic contacts from other primary afferents (mechanosensitive). The modulated message is then transmitted, ultimately reaching the sensory cortex (7). CNS structures involved in pain modulation include the cortex (8), the amygdala (9), the thalamus (10), the hypothalamus (11), and the peri-aqueductal gray (12). Regional tumors (13, primary or metastatic) induce numerous changes involving inflammatory reaction, and damage to major nerve branches (14) and to adjacent tissues such as muscle (15) (Fig. 2). Based on Benoliel et al.(2003).

Trigeminal nociceptors terminate centrally in the dorsal horn of the trigeminal nucleus caudalis, which is organized in a laminar structure similar to that of spinal regions (hence the alternative term, medullary dorsal horn). Trigeminal primary afferents often co-synapse with afferents from other regional structures on secondary-order neurones in the medullary dorsal horn; this is termed ‘convergence’ (Fig. 1) (Sessle et al., 1986). Extensive convergence of different types of afferents, particularly in cutaneous nociceptive neurones, suggests a role for these neurones in mediating deep pain, and the spread and referral of pain (Sessle et al., 1986). Moreover, with structures in the head and neck lying in such proximity, pain very often radiates and refers. For basic neurophysiology and anatomy involved in craniofacial nociception, the reader is referred to comprehensive reviews (Sessle, 2000, 2005).

(2.1) Pain Modulation: Overview
Neurotransmitter release from primary afferents at the spinal cord is modified by the integration of excitatory and inhibitory information from adjacent afferent neurones, from inter-neurones, and from descending central pathways (Sessle, 2000; Millan, 2002). This effect is termed ‘pre-synaptic modulation’; inhibition thus results in reduced neurotransmitter release. The second-order dorsal horn neurones are themselves subject to modification from higher centers and from local inter-neurones before transmitting to higher brain centers, an effect referred to as ‘post-synaptic modulation’. Post-synaptic inhibition reduces the effects of excitatory neurotransmitters on the dorsal horn neurones (Fig. 1, inset). Modulation is mediated by receptors on the central endings of primary afferents and on dorsal horn neurons. These include receptors for amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA), substance P (SP), serotonin (5-HT), noradrenaline (NA), opioids, cholecystokinin (CCK), and -aminobutyric acid (GABA). A variety of stimuli may activate inhibitory mechanisms, including stress, suggestion, learned behavior, and acute pain. Fibers descending from higher centers, local neurones, and interneurones act at these pre- and post-synaptic sites in a complex fashion to fine-tune the central sensitivity to painful stimuli (Sessle, 2000).

It has been well-established that descending controls from the peri-aqueductal grey (PAG), the rostral ventromedial medulla (RVM), and the parabrachial area (PBA) can modulate trigeminal nociceptive neurones (Chiang et al., 1994). Control between these sites and the spinal cord is bi-directional; anatomical studies have shown efferent descending connections from the PAG to the spinal cord (Basbaum and Fields, 1984), and physiological studies have demonstrated that these brainstem structures receive efferent input from lamina I in the spinal cord (McMahon and Wall, 1988).

2.2 Pain Modulation: Central Pathways; Inhibitory and Facilitatory Controls
In experimental animals, noxious but not innocuous stimuli have been shown to produce a diffuse inhibition of nociresponsive neurones in the spinal and trigeminal dorsal horns, termed ‘diffuse noxious inhibitory control’ (DNIC) (Le Bars et al., 1979). These experimental stimuli also dampen molecular markers of nociception (Morgan et al., 1994) and reduce pain-related animal behavior (Pitcher et al., 1995). Neurochemicals associated with neuronal inhibition in the dorsal horn and trigeminal nucleus caudalis include GABA, 5HT, and endogenous opioids (Grudt et al., 1995; Dallel et al., 1998). DNIC has also been confirmed between visceral and cutaneous noxious stimuli, where activation of one set of nociceptive neurones inhibited the other (Ness and Gebhart, 1991). Translating these findings to patient care—by, for example, counter-stimulation in patients with neuropathic pain—produced inconsistent effects on pain, underscoring the complexity of these controls (Bouhassira et al., 2003).

Facilitatory effects have also been shown and are mediated by a different set of pain-modulating neurones in the RVM, termed the ‘on-cells’, that are inhibited by local and systemic opioids (Bederson et al., 1990). The ‘off-cells’ are consistently related to the inhibition of nociceptive transmission and are stimulated by µ-opioid agonists (Dubner and Ren, 1999; Porreca et al., 2001). Experimental ablation of RVM neurones expressing the µ-opioid receptor both prevents and reverses experimental neuropathic pain, suggesting that unrestrained tonic-descending facilitation may underlie some chronic pain states (Porreca et al., 2001).

	(3) PAIN MECHANISMS IN LOCO-REGIONAL CANCER

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Tumor growth may compress pain-sensitive structures (including nerves, vessels, and bone) or invade surrounding structures, inducing extensive tissue damage (Fig. 2). In combination with other factors, this leads to inflammation, bone destruction, and nerve damage. Possible mechanisms of malignant bone pain include increased pressure within bone, microfractures, periosteal stretching, reactive muscle spasm, nerve root infiltration, and compression of nerves (Mercadante, 1997). Inflammatory and neuropathic pain mechanisms are prominent, and involvement of the masticatory apparatus (TMJ, muscles of mastication) results in dysfunction and pain. Unfortunately, there are currently no experimental models of cancer pain in the head and neck region. However, recently established rodent models of cancer pain have contributed greatly to our understanding of the mechanisms involved, and one may reasonably extrapolate these findings to the orofacial region. The models examine various aspects of cancer pain, including the initial inflammatory response (Eliav et al., 2004), the interactions with peripheral nerves (Cain et al., 2001; Wacnik et al., 2001; Simone and Cain, 2004), the effects on bone (Schwei et al., 1999; Honore et al., 2000a; Luger et al., 2001; Wacnik et al., 2003), and resulting central nervous system (CNS) changes.

View larger version (31K): [in this window] [in a new window]   Figure 2. Pain from regional tumors (1) may be induced via numerous mechanisms. Tumors secrete various agents, such as prostaglandins, cytokines, RANK ligand, and growth factors active in nociception and bone metabolism (see text). The initial response to tumors involves inflammation with recruitment of inflammatory cells (2) that also release prostaglandins and cytokines. Additionally, inflammation and tissue damage are associated with reduced pH, which acts synergistically with inflammatory mediators. Activation of osteoclasts (3) results in bone destruction (also associated with a low pH). Secretion of RANK-ligand by tumor sequesters osteoblast-derived osteoprotegerin, thus removing an important mechanism that modulates osteoclast activation (see text). The tumor may invade deeply and ultimately involve major nerve branches (4). In the case of the mandible, as shown, involvement of the inferior alveolar nerve (4) may induce neuropathic pain or, more commonly, numbness in the distal innervation (5), in this case the lip and chin (‘numb chin’ syndrome). Tumor invasion of adjacent structures, such as the temporomandibular joint or masticatory muscles (6), may cause further pain and dysfunction. Key: IL = interleukin, PG = prostaglandin, ET-1 = endothelin-1, RANK = receptor activator for nuclear factor-B, COX-2 = cyclo-oxygenase 2, TNF- = tumor necrosis factor-.

In locally invasive tumors, inflammation is probably the initial cause of pain or disturbed sensation. In both animal and human studies, early malignant processes are accompanied by sensory changes characteristic of inflammation (Eliav et al., 2002, 2004). An inflammatory response accompanies oral cancers and is initiated by the cascading release of mediators from circulating leukocytes, platelets, vascular endothelial cells, resident immune cells, and nerve fibers (sensory and sympathetic).

(3.1.1) Tumor, Inflammation, and Neural Interactions
Tumors secrete several agents, including growth factors and cytokines, that are active in the inflammatory or nociceptive pathways and in bone metabolism (Kurebayashi, 2000; Otsuki et al., 2000). The relation among carcinogenesis, tumor behavior, and inflammation is complex, with many molecules playing important and multiple roles in numerous etiological pathways. In this section, we present an overview of the prominent features of the inflammatory process, highlighting aspects relevant to cancer-related pain.

Inflammatory mediators act peripherally on primary afferents by direct and indirect effects, the latter mediated by leukocytes and the sympathetic nervous system (Levine and Reichling, 1999). Direct effects include activation of primary afferent nociceptors and sensitization of nociceptors, which results in increasing responses to various stimuli. Many of the mediators involved have both direct and indirect effects. The local inflammatory response leads not only to heightened sensitivity and activity of local nociceptors, but also to distant effects at the level of the CNS (Bhattacharya et al., 1988). These effects include increased excitability of dorsal horn neurones, altered descending pain control mechanisms, and adaptive changes in the thalamus, cortex, and higher centers (Millan, 1999).

(3.1.2) Inflammatory Mediators
(3.1.2.1) Inflammatory Soup
The in vivo combination of inflammatory mediators described below form the "inflammatory soup" that results in synergistic pro-inflammatory and -algesic effects (Kessler et al., 1992). The inflammatory soup alters the expression and sensitivity of important membrane ion channels, such as sodium channels, on nociceptors (Tanaka et al., 1998). Protons can also produce pain via a decrease in the activation threshold for several other receptors (see below), and are important in cancer-related bone pain (King et al., 1996; Caterina et al., 1997; Tominaga et al., 1998).

Bradykinin and serotonin (5HT) have long been recognized as important mediators of inflammatory pain (Whalley et al., 1989; Kumazawa et al., 1991; Babenko et al., 2000; Lischetzki et al., 2001; Farber et al., 2004). Glutamate, an excitatory amino acid, is one of the major neurotransmitters up-regulated in nociceptors at peripheral sites of inflammation, and is also released by macrophages (Westlund et al., 1992; Klegeris et al., 1997). The pro-nociceptive effects of glutamate are mediated by NMDA, AMPA, kainite, and the metabotropic receptors (Davidson et al., 1997). Nerve growth factor (NGF) is a major contributor to inflammatory pain (Woolf et al., 1994). NGF production is mediated by the inflammatory cytokine IL-1β, which, in turn, is up-regulated by TNF- (Woolf et al., 1997). NGF activates cutaneous mast cells to release inflammatory mediators and therefore induce pain (Lewin et al., 1994). Additionally, some of the effects of NGF are mediated via the sympathetic nervous system (Andreev et al., 1995). Indeed, NGF is thought to be a key element in the establishment of the anatomical sympathetic sensory interactions that follow nerve injury. The inflammatory process induces a novel noradrenaline (NA) sensitivity in primary afferents, independent of sympathetic post-ganglionic neurones (Sato et al., 1994). NA is able to induce hyperalgesia in the presence of tissue injury (Taiwo et al., 1990), possibly due to an increased expression of -adrenoreceptors on primary afferents.

(3.1.2.2) Mediators of Particular Importance in Cancer
   (3.1.2.2.1) Prostaglandins.
Prostaglandins (PG), prime examples of sensitizing agents, are synthesized by the actions of cyclo-oxygenase (COX) enzymes: COX-1 and COX-2. Several inflammatory mediators, including cytokines and growth factors, are able to induce COX-2 (Ballou et al., 2000). Tumors and their associated cells are able to secrete PGs (Bennett et al., 1980; Carter, 1985), and increased levels of PG have been associated with metastatic disease (Rolland et al., 1980; Mandell-Brown et al. , 1986). Experimentally, PGE₂ will induce sensitization of multiple classes of cutaneous afferents, including C-polymodal nociceptors and A- high-threshold mechano-nociceptors (Martin et al. , 1987). Furthermore, PGE₂ and PGI₂ have been found to mediate the hyperalgesia induced by BK and NA (Taiwo et al., 1990). COX-2 is up-regulated in the spinal cord, and COX-2 products contribute to the increased excitability of spinal cord neurones during persistent peripheral inflammation (Samad et al., 2001; Seybold et al., 2003). Elevation of COX-2 expression has been found in human head and neck and other cancers (Chan et al., 1999; Mestre et al., 1999; Fosslien, 2000; Kundu et al., 2001). COX inhibitors can control tumor growth (Lin et al., 2002; Yang et al., 2003), and selective inhibition of COX-2 in experimental cancer reduces tumor growth, bone destruction, and pain (Sabino et al., 2002). It is not surprising, therefore, that COX-1 and COX-2 inhibitors are effective analgesic and anti-inflammatory regimens and hold promise for the treatment of cancer pain and for cancer chemoprevention (Mohan and Epstein, 2003).

   (3.1.2.2.2) Nitric Oxide.
Nitric oxide (NO) is produced during inflammation-associated oxidative stress (Bruch-Gerharz et al., 1998). Peripheral administration of NO precursors will induce pain in animals and humans (Ashina et al., 2000; Tassorelli et al., 2003). Moreover, NO is involved in second-messenger mechanisms within neurones, and has been implicated in the etiology of neuropathic pain syndromes (Mabuchi et al., 2003). Other reactive oxygen species (ROS) play important pro-inflammatory roles, including endothelial cell damage and increased microvascular permeability (Droy-Lefaix et al., 1991), release of cytokines (Matata and Galinanes, 2002), and recruitment of neutrophils at sites of inflammation (Boughton-Smith et al., 1993). Furthermore, superoxide rapidly combines with nitric oxide (NO), removing an important homeostatic signaling molecule and at the same time forming peroxynitrite, a potent cytotoxic and pro-inflammatory agent (Beckman et al., 1990). The generation of oxidative stress in response to various external stimuli has been implicated in the activation of transcription factors, and to the triggering of apoptosis. Additionally, ROS stimulate bone resorption in vivo and in vitro by inducing the formation and activity of osteoclasts, and are therefore probably active in bone resorption and pain (Fujimiya et al., 1997).

   (3.1.2.2.3) Cytokines.
The roles of cytokines in malignancy and related symptoms are multiple. TNF-, IL-6, and IL-11 promote osteoclast formation and are likely to play an important role in malignant bone resorption (Blair and Athanasou, 2004). Tumor-induced bone remodeling has been established as a cause of pain in bone cancer (Honore et al., 2000a; Luger et al., 2001), which may be experimentally attenuated by blocking osteoclast maturation and activity. Thus, dysregulation of cytokines is probably involved in the initiation and development of malignancies, and in the accompanying symptoms and hyperalgesic states observed (Kurzrock, 2001). Cytokines have been implicated in the pathophysiology of cluster headache (Martelletti and Giacovazzo, 1996), and reports of cluster-like symptoms in cancer patients appear in the literature (Sarlani et al., 2003). The cytokine IL-1 is secreted by several cell types in painful conditions such as chronic inflammatory disease, cancer, and neuropathy (Kress and Sommer, 2004), and is thought to play a central role in the generation of mechanical hyperalgesia. IL-1 blockade by antibodies or antagonists reduces pain-associated behavior in experimental neuropathies (Cunha et al., 2000). The effects of IL-1 are probably mediated by a primary action at an IL-1 receptor and the secondary induction of NO, BK, and PGs. In chronic myelogenous leukemia, high leukocyte levels of IL-1β are seen in advanced disease and correlate with reduced survival (Kurzrock, 2001). In a similar fashion, IL-6 levels are elevated in patients with chronic lymphocytic leukemia (Fayad et al., 2001) and with malignant tumors (Smith et al., 2001). IL-6 is secreted from breast cancer tissue and may contribute to osteolysis, humoral hypercalcemia, and estrogen production (Kurebayashi, 2000). Serum levels of IL-6 are increased in patients with neuropathy and other painful conditions (Lindenlaub and Sommer, 2003), and IL-6 is thought to play an important role in the initiation of painful neuropathies. In neuropathic mice, nerve injury correlates with IL-6 levels and with pain-associated behavior (DeLeo et al., 1996). In a rat model of malignant neuritis (Eliav et al., 2004), IL-6 levels were significantly elevated in tumor-exposed nerves, but not in control nerves or in the tumor itself, illustrating that IL-6 may be derived from multiple sources at different stages of disease.

   (3.1.2.2.4) Endothelins.
In addition to various cytokines, the peptide endothelin-1 (ET-1) has been proposed to drive bone cancer pain (Davar, 2001). ET-1 is found in various tumors—including prostate (Kurbel et al., 1999), breast (Alanen et al., 2000), colon (Asham et al., 2001), and lung (Ahmed et al., 2000)—which have a propensity for metastases to bone, including the jaw. ET-1 has also been shown to play a role in tumor progression and resultant bone remodeling (Rosano et al., 2003; Yin et al., 2003), thereby expanding its potential mechanisms for the induction of pain. In a mouse model of bone sarcoma pain, ET-1 levels were highly elevated in tumor cells and in plasma (Peters et al., 2004). ET-1 has been shown to possess inherent nociceptive properties (Dahlof et al., 1990; Davar et al., 1998), mediated via activation of ET-A and ET-B receptor subtypes. Tumor-induced pain behavior was significantly reduced by treatment with ET receptor antagonists, in both the acute and chronic stages (Peters et al., 2004).

   (3.1.2.2.5) Tissue Acidosis.
Tumor-related tissue acidosis is a hallmark of solid tumors (Helmlinger et al., 2002) and may be secondary to the inflammatory response, compromised tumor cell metabolism, tumor cell apoptosis or necrosis, and release of intracellular contents. Acidosis is an important feature of inflammation, and an acidic pH will directly cause pain and hyperalgesia (Steen et al., 1995). Protons activate sensory neurones, mainly through acid-sensing ion channels (ASICs) (Julius and Basbaum, 2001). Acting together, inflammatory mediators increase the number of ASIC-expressing neurones and lead to a higher sensory neurone excitability (Mamet et al., 2002).

The role of acidosis may be particularly important in the generation of pain associated with bone cancer. Cancer involving bone induces rapid tissue turnover that is dependent on the proliferation of osteoclasts (Clohisy et al., 2001). Osteoclasts express specialized proteins that drive acid secretion, thus maintaining an acidic extracellular microenvironment (pH 4–5) for the dissolution of bone mineral (Blair and Athanasou, 2004). Osteoclast formation and activation need an acidic environment (pH < 6) and macrophage colony-stimulating factor. Additionally, they require an interaction between the receptor activator for nuclear factor B (RANK) on osteoclast precursors and RANK ligand found on osteoblasts (Lacey et al., 1998; Nakagawa et al., 1998). To prevent an unchecked positive feedback, osteoblasts also secrete osteoprotegerin (OPG), which binds and neutralizes RANK ligand, thus preventing unchecked osteoclast activation (Lacey et al., 1998). Cancer and associated immune cells may also secrete RANK ligand, thus sequestering OPG, leading to increased bone resorption (Standal et al., 2002). Decreased OPG levels have been associated with myeloma, a disease producing painful bone lesions (Seidel et al., 2001; Lipton et al., 2002). Animal models reveal that osteoclasts are essential players in both bone loss and bone cancer pain (Honore et al., 2000a; Luger et al., 2001). Osteoclast inhibition by OPG reduces experimental cancer pain behavior (Clohisy et al., 2000; Honore et al., 2000a; Honore and Mantyh, 2000; Luger et al., 2001), and has been shown to reduce bone resorption in humans (Sezer et al., 2003). Bisphosphonates, which induce osteoclast apoptosis, are used clinically due to significant pain relief in patients with bone metastases (Fulfaro et al., 1998; Mannix et al., 2000).

The effect of tumor on bone is dependent on the differential innervation of bone structures. The periosteum is the most densely innervated (Mach et al., 2002), but the bone marrow receives the greatest total number of sensory and sympathetic fibers, followed by mineralized bone. Therefore, periosteal involvement by tumor affects a large number of afferents that induce neuropeptide release, activation of nociceptive fibers, and pain (Urch, 2004). Neuropeptides themselves have also been implicated in bone metabolism (Hill et al., 1991; Serre et al., 1999). Much information has accumulated on the role of pro-inflammatory agents in the initiation, progression, and signs and symptoms associated with cancer. The discovery of additional molecules active in cancer-induced inflammation, tissue damage, and pain will ultimately lead to novel therapeutic approaches.

(3.1.2.3) Inflammatory to Neuropathic Pain
Inflammation accompanies most solid tumors, but, as tumor size increases, nerve damage and paraneoplastic neuropathic processes may predominate, with a consequent alteration in the clinical phenotype. The location of the tumor and ensuing inflammation within closed spaces may also accelerate the onset of nerve damage secondary to pressure-induced ischaemia; this will be particularly prominent in the head and neck (Benoliel et al., 2002b).

Inflammatory mechanisms themselves play an important role in initiating pain induced by nerve injury (DeLeo and Yezierski, 2001). Additionally, some cytokines, such as tumor necrosis factor (TNF), have prominent roles in the initiation of neuropathic pain. Members of the TNF superfamily mediate a wide variety of diseases, including cancer, arthritis, bone resorption, tumor metastases, and graft-vs.-host disease (Aggarwal et al., 2002). TNF-, normally expressed in mast cells, is a prototypic cytokine central in the activation of other cytokines and growth factors in inflammation (Aggarwal et al., 2002). Following injury, TNF- is detected in macrophages, fibroblasts, neutrophils, and Schwann cells (Wagner and Myers, 1996b). Tissue levels of TNF- have been positively linked to measures of pain and hyperalgesia (Lindenlaub and Sommer, 2003). Experimentally, TNF- will induce neuropathic pain (Wagner and Myers, 1996a; Wagner et al., 1998) and induces a markedly prolonged and severe discharge following injury (Schafers et al., 2003). Analysis of the data thus supports a substantial overlap between inflammatory and neuropathic mechanisms, with a prominent role for TNF-.

(3.2) Cancer and Neuropathic Pain Mechanisms
The following section deals with relevant aspects of the etiology of neuropathic pain (Woolf and Salter, 2000; Hunt and Mantyh, 2001; Scholz and Woolf, 2002) as it may relate to pain in cancer patients. It is reasonable to assume that cancer-induced nerve injury and neuropathic pain will involve mechanisms similar to those observed in models of traumatic neuropathies. These mechanisms are discussed below, along with a review on proven neuropathic mechanisms in experimental models of cancer pain.

Neuropathic pain may result from insult to the peripheral (PNS) or the central nervous system (CNS). Chronic pain resulting from nerve injury involves the interplay between the developing pathophysiological mechanisms in the PNS and the CNS (Doubell et al., 1999). Tumor invasion at both central and peripheral sites will lead to mechanical damage, proteolysis, and the release of inflammatory pain mediators that may result in damage to the surrounding tissues (Mercadante, 1997). Perineural invasion or the release of proteolytic enzymes by the tumor can cause injury to sensory and sympathetic fibers, possibly leading to neuropathic pain (Su and Lui, 1996). Axonal injury leads to inflammation and the activation of neural reparatory mechanisms that induces a state of hyperexcitability of primary afferents (peripheral sensitization), which, in the presence of continued excitation, will lead to central hyperexcitability (central sensitization). Co-morbid neurologic deficits, including impaired sensory and motor function, are frequent and may lead to muscle spasm and muscular atrophy (Luyk et al., 1991). Neuropathic pain in cancer patients may also result from surgical treatment or cytotoxic therapy of the tumor.

(3.2.1) Nerve Damage, Neuronal Hypersensitivity, and Ectopic Discharge
Different degrees of damage to a nerve axon (crush, pressure, cut, or inflammation) may lead to ectopic electrophysiological activity at the site of injury (Tal and Eliav, 1996; Eliav et al., 2001). Nerve transection may lead to cell death, but if the proximal stump survives, healing may involve disorganized sprouting of nerve fibers, which may form an ectopically active neuroma (Devor et al., 1989). Any form of nerve injury may therefore lead to increased nerve excitability and spontaneous activity.

The key elements in neuronal electrogenesis, voltage-gated sodium channels (VGSC), have been extensively studied as possible candidates for the electrophysiological phenomena described above. Indeed, there is an accumulation of VGSCs at sites of experimental nerve injury (Matzner and Devor, 1994) and in neuromas from humans with neuropathic pain (England et al., 1996). Many subtypes of VGSC have been identified in sensory neurones, and there are nearly a dozen sodium channel genes, each encoding a molecularly distinct channel (Waxman et al., 2000). Several VGSC subtypes, including NaV1.6–1.9, are normally predominantly expressed in the peripheral nervous system (Novakovic et al., 2001). Hyperexcitability of injured neurones involves the deployment of a different repertoire of sodium channels by the down-regulation of some sodium channel genes and the up-regulation of others, particularly the NaV1.8 and the NaV1.7 channels (Waxman et al., 1999). In humans with neuropathic pain, NaV1.8 is up-regulated (Coward et al., 2000).

Early increases in neuronal sensitivity are activity-dependent; however, with continuing stimuli, long-term changes are initiated in the dorsal root ganglion and dorsal horn neurones that involve modified gene expression and transcription, resulting in increased excitability. These transcription-dependent events result in modification of the neuronal phenotype and its properties, and the initiation of ectopic activity in the dorsal root ganglion (Devor et al., 1992). The ectopic activity of dorsal root ganglion cells and neuromas may be enhanced by non-synaptic interaction between neurones. At the level of the dorsal root ganglion, repetitive firing of a neurone has been shown to enable the depolarization of neighboring neurones, a phenomenon termed ‘crossed-after-discharge’ (Devor and Wall, 1990). Ephaptic cross-talk is observed in neuromas and in areas of axonal demyelination (Seltzer and Devor, 1979). In pathological states, these mechanisms are thought to amplify ectopic activity and set up reverberating circuits of activity. Moreover, these mechanisms may allow for the activation of one class of afferents by another class: Activation of C-fibers by the stimulation of A-β fibers would lead to pain secondary to an innocuous stimulus. These and the mechanisms described below underlie a conceptual change, in that pathological pain is also driven by non-nociceptive A-β fibers, a phenomenon currently termed ‘A-β pain’.

(3.2.2) Allodynia and A-β Pain: Underlying Anatomical and Phenotypic Changes
The biochemical and physiological status of primary afferents is maintained and modified by factors derived from the innervated tissues. These factors include NGF and glial-derived neurotrophic factors (GDNF) that are taken up and, by axonal transport, transferred to the cell bodies (in dorsal root/trigeminal ganglia), where they affect gene transcription and protein synthesis. Nerve injury or transection compromises the transport of these factors, ultimately resulting in phenotypic changes of the neurone, including pathological excitation (Woolf, 1996; Alvares and Fitzgerald, 1999). One of these changes involves the novel appearance of the excitatory neuropeptide SP in A-β fibers; innocuous stimuli will therefore lead to the release of SP and be interpreted as pain (Neumann et al., 1996). Nerve injury may also induce structural changes in the dorsal horn. Injured C-fiber terminals from the damaged nerve may atrophy and withdraw from lamina I/II, and, in their place, A-β fibers sprout into the superficial layers of the dorsal horn (Woolf et al., 1992). In this fashion, large myelinated A-β afferent fibers establish synaptic contact with interneurones and transmit innocuous information to the substantia gelatinosa. This functional re-organization of the sensory circuitry may contribute to mechanisms underlying sensory abnormalities following peripheral nerve injuries, and to the phenomenon of ‘A-β pain’.

(3.2.3) Central Sensitization
In response to injury and primary afferent activity, SP receptors are up-regulated in the superficial layers of the DH, leading to pain amplification (Abbadie et al., 1996). Repeated input from the primary nociceptive afferents will ultimately activate NMDA receptors, leading to further amplification of dorsal horn neurone responses secondary to primary afferent stimulation (Suzuki et al., 2000). For example, repeated stimulation of C-fibers leads to steadily increasing responses of dorsal horn neurones (wind-up) (Duale et al., 2001). The hypersensitivity of dorsal horn neurones eventually spreads to adjacent neurones, leading to an increased receptive field within the dorsal horn (Suzuki et al., 2000). This leads to pain perception in areas that are not normally innervated by the involved peripheral nerve. Increased receptive fields in thalamic neurones have also been demonstrated following injury to the infra-orbital nerve (Vos et al., 2000). These changes, which produce an amplification of pain, are termed ‘central sensitization’.

(3.2.4) Sensory Sympathetic Interactions
Interactions between the sympathetic nervous system and nociceptors are thought to account for some of the phenomena observed in neuropathic pain. Experimental injuries to spinal nerves in rats have resulted in sprouting of sympathetic fibers, with formation of basket-like plexi around sensory soma in the dorsal root ganglia (McLachlan et al., 1993). This forms an anatomical basis for the pathophysiological interactions between sensory afferents and sympathetic efferents often seen following nerve injury. However, the exact role of sympathetic invasion in chronic neuropathic pain following spinal nerve injury is unclear. Analysis of experimental data suggests that sympathetic innervation of the dorsal root ganglion may play an important role in the development and maintenance of sympathetically maintained neuropathic pain (SH Kim et al., 1993; HJ Kim et al., 1999). It is expected that similar sympathetic invasion would occur in the trigeminal ganglion following trigeminal nerve injury. However, in humans, sympathetically maintained craniofacial pain is rare (Melis et al., 2002), and experimental work has shown no sympathetic sprouting following trigeminal nerve injuries (Bongenhielm et al., 1999; Benoliel et al., 2001). In contrast to spinal nerves, sympathectomy did not reduce ectopic activity from neuromas of the inferior alveolar nerve of ferrets (Bongenhielm et al., 1998). These findings question the role of the sympathetic nervous system in orofacial neuropathies.

(3.2.5) Glial Cell Activation
Recent research implicates spinal cord glia in the initiation and maintenance of chronic pain (Watkins and Maier, 2002). Glia express receptors and transporter proteins for many neurotransmitters, so they are well-equipped to participate in pain modulation. Glia are activated by neurotransmitter release from primary afferent and dorsal horn neurones (Watkins et al., 2001). Activated glia release excitatory molecules, including pro-inflammatory cytokines, which enhance dorsal horn neurone and primary afferent hyperexcitability. While glial cell activation does not appear to change normal responses to acute pain, it may interfere with pathological pain. Bacteria and viruses also activate glial cells, which may explain the pain and allodynia often associated with some systemic infections. Because glial cells are involved in pathological pain, but not in acute nociceptive responses, they represent an attractive future therapeutic target (Watkins and Maier, 2002). In addition to glia, white cells and neurones may secrete pro-inflammatory cyto -kines that have been implicated in hyperalgesia and neuropathic pain (Watkins et al., 1995; Kress and Sommer, 2004).

(3.2.6) Alterations in Pain Modulation
Descending and local (spinal) modulatory controls may be altered following persistent tissue inflammation or injury, and are highly relevant for cancer patients. Experiments have indicated that inflammation enhances the activity of pain-inhibitory pathways, and DNIC-like effects are observed following neuropathic pain (see Section 2.1.1) (Danziger et al., 2001a). Trigeminal nerve injury has been shown to alter nocifensive behavior in rats subsequent to a second injury to the sciatic nerve (Benoliel et al., 2002a). Peripheral inflammatory injury has also been shown to modify the pharmacology of excitatory and inhibitory inputs to RVM neurones. Injection of µ- and -opioid receptor agonists into RVM following experimentally induced inflammatory hindpaw hyperalgesia demonstrated a time-dependent increase in anti-nociceptive effects (Hurley and Hammond, 2000). These results illustrate the bi-directional nature of controls between spinal and supraspinal sites. However, under certain conditions, extension of the experimental period revealed a waning in the level of inhibition of trigeminal neurones during the chronic stage, suggesting a re-organization of pain transmission and modulation in chronic inflammation (Danziger et al., 2001b).

The net interaction between supraspinal inhibitory and facilitatory mechanisms determines spinal dorsal horn excitability and fine-tunes the intensity of perceived pain, particularly following inflammation (Dubner and Ren, 1999). The most prevalent result following experimental injury and inflammation is, initially, a net increase in spinal inhibitory activity. However, analysis of the data discussed above suggests that there may be a waning in these effects in persistent pain states.

Nerve injury may induce excitotoxic cell death, secondary to glutamate effects, and selectively kill inhibitory interneurones, leading to increased pain. Moreover, there is evidence that chronic pain involves faulty pain inhibition from higher centers, and a tendency toward increased activity in facilitatory pathway activity (Dubner and Ren, 1999; Porreca et al., 2001; Ren and Dubner, 2002). It is interesting to speculate whether these mechanisms are active in cancer patients with pain, and how they change with illness progression.

Powerful endogenous controls also originate in the cortex. Attention and expectation have formidable influences upon the intensity of perceived pain. Distracting experimental subjects reduced perceived pain intensity, with evidence that this may involve the peri-aqueductal grey and the anterior cingulate cortex, and may be a useful technique for cancer patients (Bantick et al., 2002). Conversely, when subjects are conditioned to interpret specific cues as pain predictors, they will report pain on the application of non-noxious heat (Sawamoto et al., 2000; Ploghaus et al., 2003). The fear surrounding pain associated with cancer is expected to induce a heightened sense of expectation, to the detriment of the patient.

It remains unclear why some patients develop neuropathic pain following physical or chemical neural insults, while some remain resistant. In experimental models and human studies, genetic factors have been shown to be a major factor. The characteristics of the physical insult or the profile of the neurotoxic drug, in addition to the physical status of the patient, are further important prognostic factors.

(3.2.7) Evidence of Neuronal Plasticity in Experimental Cancer
As discussed above, tissue damage or inflammation alters nociceptor behavior such that electrical activity is initiated, either in response to previously subthreshold stimuli or spontaneously. These neuroplastic changes begin at the periphery, but, with continued nociceptive input, progress to the dorsal root ganglia and the central nervous system (see Table). Analysis of recent data suggests that these neuroplastic changes are an integral feature of cancer-related pain.

Analysis of the data, taken together, suggests that the experimental models accurately mimic the clinical presentation of cancer pain. Pain and sensory phenomena (e.g., allodynia, hyperalgesia) seen in cancer patients are secondary to peripheral tissue damage that initiates a cascade of neuronal events, leading to peripheral and central sensitization. Although the characteristics (behavioral and neurochemical) of experimental cancer pain are similar to those observed in experimental inflammatory and neuropathic pain, some features are unique, such as a lack of response to opioids and the electrophysiology of dorsal horn neurons. These features may even differ between cancer types (see Honore et al., 2000b; Sabino et al., 2003), and possibly between trigeminal and spinal locations.

	(4) MECHANISMS OF OROFACIAL PAIN DUE TO CANCER TREATMENT

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(4.1) Chemical Neurotoxicity
(4.1.1) Mechanisms
Peripheral neurotoxicity and neuropathic pain are clinically significant complications of cancer chemotherapy, associated with some chemotherapeutic agents (Havlin et al., 1999). Some of the most effective drugs induce neurotoxicity that is dose-limiting and may even preclude continuation of the drug. Indeed, cytostatic drugs frequently induce a dose-dependent sensory neuropathy (Wokke and van Dijk, 1997): In suramin protocols, up to 10% of patients suffer severe polyradiculopathy. In some of these patients, the neuropathy is complicated by pain that does not seem to correlate well with the degree of nerve damage (Forman, 2004). The vinca alkaloids—vincristine, vindesine, and vinblastine—cause axonal injury, with predominantly motor impairments (Hilkens and ven den Bent, 1997; Topp et al., 2000). Sensitization of neurones to suprathreshold stimuli (hyperalgesia) has been demonstrated in vincristine-related painful neuropathy (Tanner et al., 1998). In patients treated with vincristine, onset of pain occurs 3 days after vincristine administration, with a mean duration of 2 days (McCarthy and Skillings, 1992). Fifty percent of patients will be affected in the first week—22% with severe pain, and 12% with moderate pain—and symptoms become mild and infrequent in subsequent weeks. Multiple sites in the distribution of the trigeminal and glossopharyngeal nerves can be affected, primarily the TMJ, the mandible, mandibular teeth, and the ears. The tongue, lips, and edentulous ridges are more rarely affected. Cisplatin induces neuronal apoptosis (Gill and Windebank, 1998a) and leads to damage or loss of large myelinated sensory fibers, with minimal effects on smaller sensory and motor fibers (Gao et al., 1995). Suramin appears to affect peripheral nerves by interference with NGF and induction of lysosomal storage defects within the dorsal root ganglion (Gill and Windebank, 1998b). Other drugs used in tumor control have also been implicated in neuropathies (Hilkens et al., 1997b), and there is evidence to suggest additive effects resulting from drug combinations (Fazeny et al., 1996; Cavaletti et al., 1997). Additionally, non-cytostatic drugs often used in cancer treatment (e.g., interferons) or in supportive protocols (e.g., amphotericin-B) also induce paresthesias and other sensory neuropathies (Wokke and van Dijk, 1997).

More recently developed chemotherapeutic drugs with peripheral neurotoxicity include vinorelbine, thalidomide, oxalipatin, and the taxanes (Lagueny et al., 1986; Cella et al., 2003), but clinically significant neuropathies seem unusual (Forman, 2004). Oxaliplatin demonstrates intermediate neurotoxicity, which has been attributed to actions on specific forms of sodium channels, thus increasing nerve excitability (Gamelin et al., 2002). Recovery from neuropathies in these patients may be slow (Forman, 2004), due to the residual concentration of platinum in peripheral nerves and dorsal root ganglia (Gregg et al., 1992). The taxanes (paclitaxel, docetaxel) cause microtubular aggregation and are synergistic with platinum compounds in inducing neurotoxicity (Hilkens et al., 1997a).

(4.1.2) Treatment and Prevention
Treatment of these painful neuropathies is based on the use of tricyclic antidepressant and antiepileptic drugs, but, in spite of positive case reports (van Deventer and Bernard, 1999), these are not uniformly successful (Wilson et al., 2002). Neuroprotective and neurotrophic factors are therapeutic possibilities. Parenteral reduced glutathione, which may counter oxidative stress, has been proven beneficial in some trials (Cascinu et al., 2002). Amifostine and lipoic acid have been tested in the prevention of neurotoxicity caused by platinum agents (Bergstrom et al., 1999; Rybak et al., 1999). Growth factors (e.g., NGF) have shown promise in the laboratory (Hayakawa et al., 1999), but have been disappointing in the clinic (Apfel, 2001). Isaxinone enhances peripheral nerve regeneration and protects against vincristine-induced neuropathy, but is hepatotoxic at clinically relevant doses (Duhamel and Parlier, 1982). In one clinical trial, melatonin was shown to reduce chemotherapy-induced neurotoxicity (Lissoni et al., 1997), but its further use is hampered by problems related to its effective delivery. Glutamine may act as a neuroprotectant for patients receiving vincristine and other chemotherapeutic agents, but results in various trials have been conflicting (Jackson et al., 1988; Anderson et al., 1998), and, at best, it is only partially effective (Jacobson et al., 2003). It is clear that there are no universally accepted preventive or therapeutic protocols for chemotherapy-induced neurotoxicity.

(4.2) Radiotherapy and Pain
Radiation to the head and neck is accompanied by several short- and long-term changes to all the tissues in the therapeutic field (Rabin et al., 1996). Radiotherapy is well-known as a cause of severe mucositis (see below). However, mucosal pain may persist for up to one year, suggesting a long-term impact that may be related to epithelial atrophy and neuropathic mechanisms (see also Part II). The isolation of radiotherapy as a factor in the initiation of chronic cancer-related pain is problematic. Radiotherapy protocols are often delivered pre-, intra-, or post-operatively and often accompany ablative surgery, with or without chemotherapy.

Post-radiation neuropathy (sensory or motor) is well-documented following the treatment of head and neck cancers. The interval between treatment and onset has ranged from 1 to 10 years, and radiation dosages from 62.5–100 Gy units (Andrews et al., 1995; Ogunrinde et al., 1995; Kang et al., 2000; Mizobuchi and Kincaid, 2003; Voges et al., 2006). The incidence of neuropathy varies with protocols used and areas irradiated (Rocher et al., 1995; Chen et al., 2007). Radiation-induced peripheral nerve injury may occur by at least 4 mechanisms: Direct damage to neural tissues by high-dose irradiation is one mechanism observed in experimental set-ups (LeCouteur et al., 1989). Electronmicroscopy findings suggest axon damage and subsequent nerve fiber loss due to radiation-induced hypoxia as a mechanism of late radiation injury to the peripheral nerve (Vujaskovic, 1997). This particularly affects large nerve fibers at doses higher than 20 Gy. Radiation is also known to suppress proliferation of Schwann cells (Love et al., 1986), and, fourth, connective tissue fibrosis has been postulated to mediate neuropathy (Kang et al., 2000). In a series of patients who underwent neck dissection, with and without radiotherapy, for head and neck cancer, persistent neck pain and loss of sensation were commonly encountered (van Wilgen et al., 2004). Myofascial pain was most commonly detected (46%), and correlated to the extent of dissection. Neuropathic pain of the neck was present in 32% of patients and correlated with radiotherapy and dissection level. Patients with neuropathic pain experienced symptoms (hyperpathia, allodynia) during everyday activities such as shaving, exposure to wind, or low temperatures. Loss of sensation of the neck was present in 65% of patients and was also related to type of neck dissection and radiation therapy. Similarly, radiotherapy is a risk factor for post-mastectomy pain (Smith et al., 1999).

Multiple oral complaints occur following radiotherapy for oropharyngeal cancer and correlate with radiation treatment fields and doses (see ‘mucositis’, below) (Epstein et al., 1999). Pain is common (in 58.4% of patients) and interferes with daily activities in 30.8% of patients. Radiation therapy affects osteocytes, osteoblasts, and endothelial cells, resulting in hypocellular, hypovascular, and hypoxic tissue, leading to reduced capacity of bone to recover from injury and predisposing to osteonecrosis (Marx and Johnson, 1987). The current prevalence rate of osteonecrosis is less than 4%, which is a dramatic decline from a prevalence of 15% some 25 years ago (see Part II). Pain in necrosis involves inflammatory and neuropathic mechanisms (see above) and is increased in the presence of secondary infection.

(4.3) Oral Mucositis
Painful oral mucositis is a frequent complication of cytoreductive cancer chemotherapy and radiotherapy. In head-and-neck cancer patients, the temporal pattern of pain differs between chemo- and radiotherapy protocols. Generally, with cytotoxic chemotherapy, onset and peak pain occur more rapidly (10 and 14 days, respectively) than in radiotherapy protocols (21 and 35 days, respectively) (see Part II) (Kolbinson et al., 1988; Epstein et al., 2001a,b). Additionally, radiotherapy is associated with a more persistent mucositis (Epstein and Stewart, 1993; Epstein et al., 1999).

Based on Sonis’ model for oral mucositis, reactive oxygen species (ROS) are generated during the initial phase (Sonis, 2004). ROS may damage cells directly or trigger secondary mediators of injury, including nuclear factor-B (NF-B). Injury secondary to radio- or chemotherapy occurs in mucosal epithelium and connective tissue. As previously outlined, ROS activate molecular pathways of inflammation, which later stimulate primary afferents. For example, NO induces delayed burning upon intradermal injection (Holthusen and Arndt, 1994). Presently, there is little evidence for direct activation of sensory neurones by NO (Verge et al., 1992). However, the quantification of inducible NO-synthase (iNOS) gene expression in radiation-induced oral mucositis in an animal model was difficult, so its role in oral mucositis remains unclear (Sonis et al., 2002). Consequent to damage caused by ROS, cytokines such as TNF-, IL-1β, and IL-6 are generated, which can induce powerful hyperalgesia by indirect mechanisms (Cunha et al., 1992; Jonakait, 1993). TNF- has a positive feedback mechanism, leading to increased NF-B; this biological crosstalk leads to amplification of the inflammatory process. Likewise, the ceramide pathways that have been implicated in the amplification stage of oral mucositis have been shown to modulate systems important in the regulation of pain responses (Sonis et al., 2004; Malan and Porreca, 2005). Progression of this process and the accumulation of these products lead to the most symptomatic stage of mucositis, which is manifested clinically as ulceration and maximal pain. The ulcer serves as a focus for bacterial colonization, and secondary infection is common, thus exacerbating cytokine release. In addition to acute pain, there are clinical findings of sensitivity at one-year follow-up, long after the mucositis resolves, suggesting sensitization (Epstein and Stewart, 1993; Epstein et al., 1999). An important role for NF-B in the development of this sensitization has been suggested (Laughlin et al., 2000; Lee et al., 2004).

(4.4) Combined Chemo-Radiotherapy
In two Phase III trials, concurrent chemo-radiotherapy was shown to provide survival benefits, but at a cost of increased severity and duration of oral mucositis (Bernier et al., 2004). The clinical presentation is therefore more severe (see Part II). Survival benefit must be weighed against the increased side-effects of combined modes of therapy.

	(5) CONCLUSIONS

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Pain prevention and management will be improved with further understanding of the molecular and neurophysiologic mechanisms underlying the onset and maintenance of pain. Advances in our understanding of cancer and related pain provide further hope for improvement in pain management secondary to tumors and their treatment. Early intervention with pain-preventive drugs, as well as individually tailored drug prescriptions based on pain mechanisms involved, may eventually be possible. However, the trigeminal system and the anatomy of the head and neck differ substantially from their spinal counterparts, and we need models of head-and-neck cancer-induced pain to analyze these processes.

Received for publication June 14, 2006. Accepted for publication January 9, 2007.

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Journal of Dental Research, Vol. 86, No. 6, 491-505 (2007)
DOI: 10.1177/154405910708600604


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