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Orofacial Pain in Cancer: Part II—Clinical Perspectives and Management

¹ Department of Oral Medicine and Diagnostic Sciences, MC-838, College of Dentistry, 801 S. Paulina St., Chicago, IL 60612, USA;
² Department of Oral Medicine, the Hebrew University, Hadassah Faculty of Dental Medicine Jerusalem, Israel; and
³ Universities of Medicine and Dentistry at New Jersey, New Jersey Dental School, 110 Bergen Street, Newark, NJ 07103, USA

Correspondence: ^* corresponding author, jepstein{at}uic.edu

	ABSTRACT

TOP ABSTRACT (1) INTRODUCTION (2) OROFACIAL PAIN AS... (3) OROFACIAL PAIN DUE... (4) OROFACIAL PAIN DUE... (5) TREATMENT OF PAIN... (6) CONCLUSIONS REFERENCES

 
Cancer-associated pain is extremely common and is associated with significant physical and psychological suffering. Unfortunately, pain associated with cancer or its treatment is frequently under-treated, probably due to several factors, including phobia of opioids, under-reporting by patients, and under-diagnosis by healthcare workers. The most common etiology of cancer pain is local tumor invasion (primary or metastatic), involving inflammatory and neuropathic mechanisms; these have been reviewed in Part I. As malignant disease advances, pain usually becomes more frequent and more intense. Additional expressions of orofacial cancer pain include distant tumor effects, involving paraneoplastic mechanisms. Pain secondary to cancer therapy varies with the treatment modalities used: Chemo-radiotherapy protocols are typically associated with painful mucositis and neurotoxicity. Surgical therapies often result in nerve and tissue damage, leading, in the long term, to myofascial and neuropathic pain syndromes. In the present article, 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. As a presenting symptom of orofacial cancer, pain is often of low intensity and diagnostically unreliable. Diagnosis, treatment, and prevention of pain in cancer require knowledge of the presenting characteristics, factors, and mechanisms involved.

Key Words: orofacial pain in cancer • quality of life • management

	(1) INTRODUCTION

TOP ABSTRACT (1) INTRODUCTION (2) OROFACIAL PAIN AS... (3) OROFACIAL PAIN DUE... (4) OROFACIAL PAIN DUE... (5) TREATMENT OF PAIN... (6) CONCLUSIONS REFERENCES

 
Severe and uncontrolled pain is one of the most feared consequences of cancer. Indeed, in patients with terminal or advanced cancer, pain will occur in 75–90% of cases (Portenoy and Lesage, 1999). Unfortunately, it is estimated that 45–80% of all cancer patients suffer inadequate pain management (Cleeland et al., 1994; de Wit et al., 2001). Impediments to adequate pain management include patients’ reluctance to report pain (Thomason et al., 1998), deficient practices by physicians and nurses (Von Roenn et al., 1993), and patients’ preconceived negative ideas regarding and regulatory barriers to the use of opioids (Joranson and Gilson, 1998).

Cancer pain correlates with increased morbidity, reduced performance status, increased anxiety and depression, and diminished quality of life (QoL) (Portenoy, 1990; Caraceni and Portenoy, 1999). Head and neck (H&N) and oral pain management may be particularly challenging: Differential diagnosis is complex, the achievement of pain relief is compounded by neurotoxic and cytotoxic treatment protocols, and the patient’s general health is often compromised. The rich innervation of the H&N, particularly the orofacial region, makes this area susceptible to nerve damage and pain. The proximity and dense arrangement of structures such as blood vessels, nerves, and the central nervous system may translate into early invasion of pain-sensitive regions by the tumor. Pain referral is common. Speech, swallowing, and other motor functions of the H&N and oropharynx are constant pain triggers. The oral mucosa is exquisitely susceptible to the effects of systemic chemotherapy and regional radiotherapy, resulting in painful mucositis. Additionally, the oral microbial flora is a rich source of opportunistic secondary infection, with attendant pain and morbidity. The detrimental effects of orofacial pain on the patient’s ability to communicate and interact with family members compound the affective and cognitive impact of the pain experience.

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 vs. distant), or the primary initiating agent (tumor or tumor treatment). However, these classifications and mechanisms frequently overlap. It is convenient to examine cancer-related pain according to the timing of its appearance (e.g., presenting sign, therapy-related complication). Pain may be the first symptom in 20–50% of all cancer patients (Portenoy and Lesage, 1999), due to the primary malignancy, from metastatic disease in the H&N, or due to oral involvement in systemic cancers (e.g., leukemia). In H&N cancer, patients may complain of pain at various stages of disease (Sist and Wong, 2000), and pain may be the major reason (up to 85%) for seeking care (Epstein and Jones, 1993). However, the severity of pain at the diagnosis of oral squamous cell carcinoma (OSCC) is usually of low intensity (mean visual analog scale [VAS] = 3).

Orofacial pain associated with cancer management is a well-recognized adverse effect of treatment. Pain due to oral mucositis is the most frequently reported patient-related complaint affecting QoL during cancer therapy (Woo et al., 1993; Epstein et al., 1999; Bellm et al., 2000; Sonis et al., 2001; Stiff, 2001; Rose-Ped et al., 2002; Epstein and Schubert, 2003; Sonis, 2004b). Pain associated with oropharyngeal mucositis may prevent the oral intake of food and medications, affect speech and respiration, and result in severe pain requiring opioid analgesics. The economic impact of treatment-associated side-effects is demonstrated by chemotherapy- and radiotherapy-induced mucositis (Sonis et al., 2001; Oster et al., 2005). Severe and painful mucositis is associated with additional admissions to and prolonged periods in the hospital, leading to delayed, interrupted, or altered cancer therapy protocols that can affect prognosis and QoL. Graft-vs.-host disease (GVHD) remains a major complication of allogeneic hematopoietic cell transplant (HCT), occurring in 25–70% of patients. In both acute and chronic GVHD, the oral lesions are often painful (Woo et al., 1997).

Pain in cancer patients may also occur coincidentally due to other conditions unrelated to cancer, but may be interpreted by the patient as progression or recurrence of the cancer. This includes common conditions such as toothache, temporomandibular disorders (TMDs), sinusitis, headaches, and rarer entities such as herpes zoster.

In the present article, 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 (Table 1). The relevant molecular pathophysiology of inflammatory and neuropathic pain states, known paracrine mechanisms in the head and neck, and orofacial cancer pain have been reviewed in a previous article. Successful pain management requires knowledge of, and attention to, multiple pain mechanisms.

	(2) OROFACIAL PAIN AS A PRESENTING SYMPTOM OF CANCER

TOP ABSTRACT (1) INTRODUCTION (2) OROFACIAL PAIN AS... (3) OROFACIAL PAIN DUE... (4) OROFACIAL PAIN DUE... (5) TREATMENT OF PAIN... (6) CONCLUSIONS REFERENCES

Primary squamous cell carcinomas of the oral mucosa presented with pain in 39% of 138 cases, and correlated somewhat with tumor stage (Haya-Fernandez et al., 2004). In another study, 85% of patients presenting for diagnosis of oral cancer reported that oral discomfort was the first symptom leading to cancer diagnosis (Epstein and Stewart, 1993). The most common presenting symptom of osteosarcoma of the jaws was found to be a mass (85–95.5%) (Bennett et al., 2000; Mardinger et al., 2001), with pain in approximately half of cases, and trigeminal sensory disturbances in 21.2% of cases (Mardinger et al., 2001). This is surprising in view of the fact that cancer in long bones very often presents with pain (Rosier, 1992; Lipton, 1997; Fulfaro et al., 1998). Why some cases of bone malignancy induce pain and others do not is unclear, and appears to be related to more factors than just tumor type (Sabino et al., 2003).

Patients with nasopharyngeal cancer report pain that is often referred to the temporomandibular joint (TMJ) region, and may masquerade as TMD (Sharav and Feinsod, 1977; Turgman et al., 1978; Wang and Howng, 2001). In one study, 13.5% of 52 patients with nasopharyngeal cancer presented common TMD signs and symptoms, with 44.2% describing their pain as headache, earache, or jaw, midface, or neck pain. The most common qualitative descriptions of pain were ’aching’, ’dull’, or ’pressing’ (Epstein and Jones, 1993).

Intracranial malignancies may give rise to orofacial pain and headache (Anderson and Ogle, 1974; Bullitt et al., 1986; Schnetler and Hopper, 1989; Luyk et al., 1991; Monaghan and McKinlay, 1991; Puca et al., 1993). In a large series of patients presenting with facial pain, the incidence of intracranial tumors has been found to be 0.8–5.9% (Bullitt et al., 1986; Cheng et al., 1993). Based on an analysis of these patients, posterior fossa tumors are most likely to cause trigeminal neuralgia (TN)-like symptoms. However, unlike classic TN, pain is often accompanied by subtle neurological deficits (Bullitt et al., 1986; Cheng et al., 1993). Although most cases displayed an atypical clinical presentation, 2% had classic TN with no significant sensory aberration (Cheng et al., 1993). Classic TN symptomatology has also been observed in 33% of patients with middle and posterior cranial fossa tumors (Puca et al., 1995). Most of these patients are usually younger than expected for cases of TN, and develop cranial nerve deficits (Cheng et al., 1993). Moreover, even in diagnosed cancer patients, the prediction of intracranial metastases with new or changed headache is difficult. In one study, in cancer patients with headache, factors such as a diagnosis of non-tension-type headache, duration of fewer than 10 weeks, and vomiting were individually predictive of metastatic disease, while no information from the neurological examination contributed significantly to diagnosis (Christiaans et al., 2002). The clinical presentation is therefore often misleading, and neurological assessment may be of limited value. Clinical suspicion should remain high if persisting symptoms are to be pursued.

(2.2) Pain in Metastatic Malignancy
The skeleton is the most common organ to be affected by metastatic cancer. Tumors arising from the breast, prostate, thyroid, lung, and kidney possess a propensity to spread to bone (Coleman, 1997; D’Silva et al., 2006). Bone pain is the most common complication of metastatic bone disease (Coleman, 1997; Mercadante, 1997; Neville-Webbe and Coleman, 2003; D’Silva et al., 2006), resulting from structural damage, periosteal irritation, and nerve entrapment. Metastatic orofacial tumors are relatively rare, affecting jaw bones more than the oral soft tissues, and most commonly occur in the posterior mandible, angle of the jaw, and ramus (Hirshberg and Buchner, 1995). Common primary sources of metastatic tumors to the oral region include the breast, colon, lung, prostate, and kidney. Clinical presentation frequently includes the presence of a mass, pain, and neurologic changes. The breast is the most common primary site for tumors metastasizing to the jaw bones, whereas the lung is the most common source for metastases to the oral soft tissues (Sanchez Aniceto et al., 1990; Hirshberg et al., 1993, 1994; Hirshberg and Buchner, 1995). In nearly 30% of cases, the metastasis in the oral region is the first indication of a distant undiscovered malignancy (Hirshberg and Buchner, 1995). However, pain seems to be rare in soft-tissue metastases (Hirshberg et al., 1993), while in metastatic disease of the jaw bones, pain is reported in 39% and parasthesias in 23% of patients (Hirshberg et al., 1994).

(2.3) Pain in Systemic Cancer
Manifestations of systemic cancers, such as leukemia, that affect the H&N structures may cause pain and loss of function (McGuire et al., 1998). Hematologic cancers, and cancer therapies for solid tumors, increase the risk of secondary infections, which may cause pain. These infections (fungal, bacterial, or viral) may be due to exacerbation of latent or prior chronic infection, or to changes in flora that occur secondary to cancer treatment (Bubley et al., 1989; Bergmann and Andersen, 1990; Bergmann et al., 1990; Epstein et al., 1990). Lymphoma is the second most common neoplasm occurring in the oral region, and accounts for 3.5% of oral malignancies (Epstein et al., 2001a). Lymphoma may present in the H&N and oropharynx as a mass, associated with discomfort in approximately one-half of patients. Lymphomas and leukemias may also induce pain by infiltration of pain-sensitive structures, such as the periosteum and gingivae (Barrett, 1986). Multiple myeloma frequently presents with pain and, particularly when associated with the teeth, presents a diagnostic challenge (Epstein, 1997; Witt et al., 1997). Other orofacial malignancies, such as malignant melanoma and intra-oral sarcomas, are rare, presenting commonly as a mass that may be accompanied by discomfort (Gorsky and Epstein, 1998a,b). Primary or metastatic tumors in the infratemporal fossa may induce orofacial pain, often preceding tumor diagnosis by months (Johnson and Maran, 1982; Schreiber et al., 1991; Cohen and Rosenheck, 1998).

Pain is an unreliable indicator of orofacial malignancy, and reported intensity is highly variable. Indeed, pain in itself is not a major reason for patients with oral cancer to seek diagnosis: 65.5% of 1070 patients reported seeing a physician within 4 weeks of symptom onset, but of these, only 48.1% experienced any pain (Gellrich et al., 2002b). However, when the combination of numbness, pain, and swelling occurs together, it is highly predictive of malignancy (Lossos and Siegal, 1992). Patients who present with pain before treatment develop significantly higher impairment scores, due to pain during and after treatment (Gellrich et al., 2002b), suggesting that sensitization has occurred (see Part I).

(2.4) Pain Secondary to Non-metastatic Malignancy at a Distant Site
Orofacial pain has also been reported, albeit rarely, in patients suffering from a distant non-metastasized cancer, most commonly from the lungs (Des Prez and Freemon, 1983; Kanas et al., 1987; Bindoff and Heseltine, 1988; Nestor, 1991; Bongers et al., 1992; Schoenen et al., 1992; Nestor and Ngo, 1994; Capobianco, 1995; Shakespeare and Stevens, 1996; Goldberg, 1997; Abraham et al., 2003; Eross et al., 2003; Sarlani et al., 2003). Orofacial pain in lung cancer may be due to activation of nociceptive pathways in mediastinal or head and neck structures (Sarlani et al., 2003), or secondary to invasion or compression of the vagus nerve (Bindoff and Heseltine, 1988). The mechanism proposed is that although most vagal afferents terminate in the nucleus solitarius, some terminate in the spinal trigeminal nucleus, providing a potential mechanism for vagus-mediated referred facial pain (Contreras et al., 1982; Gwyn et al., 1985). Additionally, the phrenic nerve may refer pain from the pleura and sub-diaphragmatic areas to the neck and jaw (Goldberg, 1997). Pain induced by the production of cytokines and other tumor-related factors is discussed in Part I, but may also be a mechanism in orofacial pain secondary to distant, non-metastasized, lung cancer. A further mechanism may involve paraneoplastic processes in which peripheral neuropathies are common, particularly in lung cancer (Teravainen and Larsen, 1977). A common clinical feature in 32 recently reported cases was unilateral aching pain—often located around the ear, jaws, and temporal regions—that was ipsilateral to the lung tumor (Sarlani et al., 2003). Pain was continuous for the majority of the patients and, when episodic, was usually progressive. Weight loss, hemoptysis, persistent cough, and chest-wall pain were common associated features (Sarlani et al., 2003).

Reports of gastrointestinal or pancreatic cancer presenting with orofacial pain have been published (Delfino et al., 1982; Daggett and Nabarro, 1984; Gallager et al., 1988). Based on the sparse reports, however, it is not clear whether the pain is due to secondary cancer-related effects, such as anemia (Littlewood and Mandelli, 2002).

(2.5) Neuropathic Pain in Paraneoplastic Syndromes
Neuropathies are commonly (1.7–5.5%) reported in patients with malignancy due to direct effects of the tumor, para-neoplasia, and treatment-related toxicity (Amato and Collins, 1998). It has also been suggested that the association between malignancy and neuropathy may at times be a chance occurrence (Antoine et al., 1999). Of para-neoplastic syndromes, neuropathy is the most common and is reported in as many as 5% of all cancer patients (Anderson et al., 1987; Mallecourt and Delattre, 2000). Para-neoplastic neuropathy is most frequently associated with small-cell lung cancer, and less often with tumors of the stomach, colon, breast, or ovaries (Schafers and Sommer, 2001). In patients with lung cancer, peripheral neuropathy was found in 48% of cases prior to the initiation of chemotherapy (Teravainen and Larsen, 1977). Neuromuscular dysfunction has been found in 30% of patients with diverse tumors, commonly as a result of ovarian, testicular, or bronchogenic cancers (Paul et al., 1978). The effects of neurotoxicity are greater in patients with pre-existing nerve damage (Chaudhry et al., 2003), or with nutritional deficiencies (Barnouin et al., 2001). Cancer patients are therefore a vulnerable population, but fortunately only a subset of these will develop neuropathic pain. In affected cases, the most common clinical picture includes numbness, paresthesias, and burning pain (Amato and Collins, 1998), which may begin asymmetrically, with a predilection for the upper limbs (Chalk et al., 1992). These neuropathies are accompanied by detectable autoantibodies that may aid in diagnosis (Schafers and Sommer, 2001). The incidence of para-neoplastic neuropathies occurring in the orofacial region is unclear.

	(3) OROFACIAL PAIN DUE TO CANCER MANAGEMENT

TOP ABSTRACT (1) INTRODUCTION (2) OROFACIAL PAIN AS... (3) OROFACIAL PAIN DUE... (4) OROFACIAL PAIN DUE... (5) TREATMENT OF PAIN... (6) CONCLUSIONS REFERENCES

 
Orofacial pain may be a direct result of chemotherapy, radiotherapy, and surgical procedures. Additionally, pain may be secondary to therapy-associated factors, such as osteomyelitis and oral GVHD.

(3.1) Chemotherapy and Radiotherapy
The most common acute oral side-effect of cytoreductive pharmacologic treatment or radiotherapy is oral mucositis (Table 2). The clinical presentation of mucositis consists of erythema and ulceration of the oral mucosa. In chemotherapy-induced mucositis, the oral sites most commonly involved are the buccal and labial mucosae, ventral and lateral aspects of the tongue, soft palate, and floor of the mouth.

(3.1.2) Radiotherapy
In radiotherapy-induced mucositis, the temporal pattern of pain is different. Escalation of pain intensity and pain interference scores are seen at week 3, peaking at week 5 (Epstein et al., 2001b,c), and persisting for weeks, with a gradual remission of signs and symptoms. Multiple oral complaints occur following radiotherapy for oropharyngeal cancer and correlate with radiation treatment fields and dose (Epstein et al., 1999). Mucositis pain is common (58–75%), and interferes with daily activities in approximately one-third of patients (Gaston-Johansson et al., 1992; McGuire et al., 1993; Trotti et al., 2003; Bernier et al., 2004; Cooper et al., 2004; Sonis et al., 2004a), and with social activities and mood in 50– 60% of patients (Epstein et al., 1999). Additional oral complications include dry mouth (91.8%), dysgeusia (75.4%), dysphagia (63.1%), altered speech (50.8%), and chewing or eating difficulties (43%) (Epstein et al., 1999). These consequences greatly affect the patient’s total QoL (Epstein et al., 1999; List et al., 1999), and may lead to severe disability, including work absences or loss of active employment (Harrison et al., 1997).

(3.1.3) Combined Chemo-/Radiotherapy
Combined chemotherapy and radiotherapy have been documented to result in increased frequency, severity, and duration of mucositis (Bernier et al., 2004; Cooper et al., 2004; Modi et al., 2005). A combined chemoradiotherapy (twice-daily radiation, fluorouracil, hydroxyurea, and cisplatin) regimen, aimed at improving loco-regional control and survival, resulted in severe acute treatment toxicities (List et al., 1999). Marked improvement was seen by 12 months, with general functional and physical measures returning to baseline level. However, up to a third of the patients continued to report problems with swallowing, hoarseness, and mouth pain, which were present in similar magnitudes before cancer treatment (List et al., 1999; Bernier et al., 2004; Cooper et al., 2004).

(3.1.4) Other Complications of Chemo-/Radiotherapy
In addition to acute pain, mucosal pain may persist long after the mucositis resolves, and reports of sensitivity at one-year follow-up are common (Epstein and Stewart, 1993; Epstein et al., 1999), suggesting a long-term impact that may be related to epithelial atrophy, neurologic sensitization, and/or neuropathy. Patients with mucosal pain prior to cancer therapy experienced more severe mucositis-associated pain during treatment (Huang et al., 2003), suggesting the establishment of sensitization.

Mucositis and pain increase the costs of care, due to opioid analgesics, tube feeding, extended hospitalization, or unanticipated re-hospitalization, and can cause modification to or interruption of the cancer therapy itself (Kline et al., 1998; Sonis et al., 2001; Elting et al., 2003, 2005). These symptoms also have a dramatic impact on QoL (Epstein et al., 1999, 2001b, 2002a; Bellm et al., 2000; Sonis et al., 2001; Rose-Ped et al., 2002; Duncan et al., 2005). Mucositis pain can be severe, preventing oral function, ingestion of food and medications, and limiting interpersonal communication, with resulting psychosocial distress.

The breakdown of the epithelial barrier in mucositis is a potential portal for systemic infection, which could be life-threatening, and may lead to cancer treatment dose reduction, dose delay, or discontinuation of therapy, affecting cure rates (Sonis et al., 2001; Elting et al., 2003). Moreover, oral mucosal pain can be aggravated by dry mouth and secondary mucosal infection (e.g., candidiasis), resulting from the chemotherapy and/or radiotherapy (Epstein et al., 2002b).

In addition to this dominant side-effect, some cytotoxic agents may cause jaw pain and neuropathy (e.g., vincristine, vinblastine, platinum; see Part I).

Post-radiation osteonecrosis is another well-recognized complication that may be associated with pain (Marx, 1983; Marx and Johnson, 1987; Epstein et al., 1997). The current prevalence rate of osteoradionecrosis is < 4%, a dramatic decline from a prevalence of 15% some 20 years ago. Pain, bad breath or taste, trismus, bone exposure, and spontaneous fracture are among the major presenting symptoms (Marx, 1983; Epstein et al., 1987; Marx and Johnson, 1987). The onset of symptoms is variable and may appear decades post-radiotherapy, with accompanying severe pain (Komisar et al., 1985; Koka et al., 1990; McKenzie et al., 1993; Epstein et al., 1997; Reuther et al., 2003). Recently, osteonecrosis and osteomyelitis of the jaws have been recognized in bisphosphonate-treated patients (Marx, 2003; Ruggiero and Mehrotra, 2004). The clinical presentation may include pain, swelling, and bone exposure. The cumulative incidence with intravenous bisphosphonate is rising, and at present is reported to be 10% after 3 years of drug use (Durie et al., 2005).

Oral GVHD represents a local manifestation of a systemic disease following HCT (Woo et al., 1997). The classic oral presentation includes mucosal erythema, atrophy, pseudomembranous ulceration, hyperkeratotic striae, plaques, and papules that may be similar to oral lichen planus. Sclerodermatous changes can result in peri-oral fibrosis, with limited mouth-opening and reduced tongue mobility, both interfering with oral function. A review of GVHD-associated pain has been published (Woo et al., 1997).

Surgical procedures commonly result in acute orofacial pain, and establish conditions that may lead to painful post-traumatic neuropathy. In addition to tissue injury at tumor resection, morbidity is increased by concomitant procedures such as radical neck dissection, radiotherapy, or damage to major nerves (Terrell et al., 2000).

(3.2) Pain Due to Surgical Procedures
Orofacial pain following head and neck cancer therapy can develop due to musculoskeletal syndromes, including TMDs associated with muscular fibrosis, scar formation, and limited jaw-opening (Epstein and Schubert, 1993; Chapman et al., 1997; Dodd et al., 2001; Borbasi et al., 2002). Ablative surgery for orofacial cancer may lead to tissue defects that may cause significant loss of orofacial function, such as speech, chewing, and swallowing. Esthetic problems are common in spite of advanced reconstructive surgery. These, among other factors, lead to disability and a lack of restoration of functional social status of the patient (Terrell et al., 1999). The effects of surgical treatment may be particularly severe if discontinuity of the jaw, or fibrosis of muscles and soft tissue, occurs. Resection of the mandible for tumor excision will inevitably lead to sensory impairment (Chow and Teh, 2000), with 50% experiencing regional hyperalgesia or allodynia. At 2–5 years post-maxillectomy, 88–90% of patients reported persistent pain (Rogers et al., 2003). In an analysis of patients treated for laryngeal cancer, ablative surgery (with adjuvant chemo- and/or radiotherapy) was associated with more chronic pain and psychosocial morbidity than in patients treated by chemoradiation alone (Terrell et al., 1999), underscoring the impact of surgical intervention.

Examination of pain scores following surgery to treat H&N tumors has shown that the highest scores were for the oral cavity, followed by the larynx, oropharynx, and nasopharynx (Terrell et al., 1999). In a large survey of surgically treated oral cancer, functional problems were reported post-operatively in more than 50% of patients (Gellrich et al., 2002b). At review ( 6 months post-surgery), impairment due to moderate to severe pain was found in 34.3% of cases (Gellrich et al., 2002b). In two studies, the most frequent pain locations were the shoulder (31–38.5%), the neck (4.9–34.9%), the TMJ (4.9–20.1%), the oral cavity (4.2–18.7%), or the face and other head regions (4.2–15.6%) (Gellrich et al., 2002a,b), reflecting morbidity secondary to tumor and regional lymph node resection (Terrell et al., 2000; Taylor et al., 2004). Pain in the head was consistently rated as most severe (Gellrich et al., 2002b). Only 39.2% of patients reported being free of treatment- or cancer-related pain, yet in spite of this, 75% of all patients in the study were not taking any pain medications (Gellrich et al., 2002b). Moreover, analgesics and physiotherapy seem largely ineffective in treating chronic pain in these patients (Gellrich et al., 2002a). Fortunately, there is a tendency for symptoms to improve with time (Hammerlid et al., 2001). At 54–60 months post-surgery, a smaller proportion of reviewed patients (14.9%; n = 74) had persistent pain in any of the above sites (Gellrich et al., 2002a). In cancer patients, the post-operative pain experience is characterized by acute pain persisting 1–2 months, with a gradual improvement over time (Bjordal et al., 2001; Hammerlid et al., 2001; Hammerlid and Taft, 2001). Long-term H&N cancer survivors (> 3 yrs) still suffer from significantly more pain and functional problems than do matched control subjects, but with recovery of general function and mental health (Hammerlid et al., 2001; Hammerlid and Taft, 2001).

Surgically related pain involves inflammatory and neuropathic pain mechanisms, depending on the extent of surgery and its anatomic location. Functional consequences are often secondary to pain, but may involve wound contraction and scarring (Gellrich et al., 2002a).

	(4) OROFACIAL PAIN DUE TO OTHER ETIOLOGIES IN CANCER PATIENTS

TOP ABSTRACT (1) INTRODUCTION (2) OROFACIAL PAIN AS... (3) OROFACIAL PAIN DUE... (4) OROFACIAL PAIN DUE... (5) TREATMENT OF PAIN... (6) CONCLUSIONS REFERENCES

 
Orofacial pain of all types may be unrelated to cancer or its therapy, and may occur coincidentally. Pain may be due to any cause, including dental or periodontal disease and TMDs, and, when due to infection, may be of increased importance in an immunosuppressed patient (Schubert, 1991; Jones et al., 1993). Post-herpetic neuralgia may result in chronic pain, causing painful dysesthesias in the affected area that may persist for years (Johnson, 2001; Dubinsky et al., 2004). Approximately 10% of acute herpes zoster patients will suffer from post-herpetic neuralgia (Johnson, 2001; Dubinsky et al., 2004). Pain occurring in cancer patients is likely to be associated with heightened anxiety, which affects the presentation and associated behavior of pain (Syrjala and Chapko, 1995; Turk, 1999).

	(5) TREATMENT OF PAIN IN OROFACIAL CANCER

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Effective management requires accurate diagnosis of the multi-faceted etiology of orofacial pain in cancer patients. Treatment should be directed at the various factors involved in the pain experience.

An interdisciplinary team should provide comprehensive management of the cancer patient, including evaluation and treatment planning that incorporates the patient’s overall health, malignancy diagnosis, site and stage, psychosocial functioning, and cultural/socio-economic status. Assessment and education are crucial, and should be performed by team members as appropriate at all stages of cancer therapy. The treatment team should include physicians, nurses, and pharmacists, as well as dentists and dental hygienists knowledgeable in oral medicine. Additionally, services of other health-care workers—including physical therapists, social workers, and psychologists—enhance the patient’s treatment experience. The dental team treating cancer patients should have an expanded knowledge of oral medicine, the non-surgical interface between dental medicine and medicine.

New developments in the understanding of the molecular processes of tumor pain and pain due to cancer treatment are expected to lead to targeted interventions and new therapeutic approaches that will lead to improved pain management (see Part I).

(5.1) Assessment and Management
When the etiology of pain is identified, treatment directed at the cause of pain may have greater impact. Temporal onset of symptoms may provide guidance in determining the cause(s) of pain. For example, if increase in pain is related to re-activation of a viral agent, or is due to fungal or bacterial infection, specific treatment can be instituted to control the risk of progression of the infection, which will therefore control pain (Bubley et al., 1989; Epstein et al., 1990; Epstein and Polsky, 1998; Dignani et al., 2002). A diagnosis of oral GVHD may be followed by topical or systemic immunosuppressive treatment directed specifically at oral GVHD (Woo et al., 1997; Elad et al., 1999b, 2003).

Oral mucositis pain intensity is frequently determined by patient reports based on a VAS or a version of the "faces scale" for children (Epstein and Schubert, 1993; Fitzgibbon, 2001; Fitzgibbon and Richard, 2001). Patients’ reports of factors that aggravate or relieve the pain and the effectiveness of treatments used in previous episodes of mucositis and pain should be considered.

(5.2) Basic Oral Care
The goal of basic oral care is to maintain oral health, control dental plaque levels, reduce tissue irritation and damage, maintain tissue stability, and promote comfort. Reduction of oral microbial load and local infectious/inflammatory disease may minimize gingivitis and reduce the risk of gingival bleeding (Epstein et al., 1992, 1994; Borowski et al., 1994; Dodd et al., 2000; Dignani et al., 2002; Rubenstein et al., 2004). This may be attained by a high oral hygiene level consisting of regular toothbrushing, flossing, high fluid intake, and the use of bland oral rinses such as normal saline, sodium bicarbonate, or a mixture of these. While there are no controlled studies showing the effectiveness of basic oral care, such regimens are recommended in many care protocols (Dodd et al., 2000). There is evidence that the maintenance of improved oral hygiene will reduce the frequency and severity of oral mucositis and, therefore, of the associated pain (Borowski et al., 1994). With good oral hygiene, bacteremia is not increased, even in neutropenic patients.

(5.3) Prevention of Mucosal Damage
Treating malignancies with regimens that combine disease control and reduced toxicity is a continuing endeavor. Technical advances, such as intensity-modulated radiotherapy (IMRT), reduce the size of the high- dose field of irradiation and limit the exposure of adjacent vital structures, including the salivary glands; they may also limit the extent, but not the severity, of mucositis (Borgmann et al., 1994; Buchali et al., 2000; Eisbruch et al., 2001; Modi et al., 2005). Due to poor cure rates in H&N cancer, particularly at more advanced stages of disease, more intensive radiation protocols that include hyperfractionation, combined chemo-/radiotherapy, and re-irradiation for recurrence of second primary cancers increase the intensity, severity, and duration of mucositis (Trotti et al., 2003; Bernier et al., 2004; Cooper et al., 2004; Modi et al., 2005). Patients undergoing intensive regimens and dose-dense chemotherapy may benefit from the use of growth factors that reduce the severity and duration of neutropenia; mucositis, however, continues to be a limitation of therapy (Elting et al., 2003).

Mucositis in a prior course of chemotherapy increases the risk of mucositis with continuing therapy, and may lead oncologists to delay or modify the next course of therapy, thereby affecting the outcome of cancer therapy.

(5.4) Topical Approaches for Mucosal Pain Relief
The oral mucosa is easily accessible for topical medications, but saliva will dilute and reduce tissue contact time. Topical approaches in oral mucositis offer the potential for improved pain management with reduced systemic side-effects. The intensity of innervation of the oral mucosa and the relatively thin barrier of the epithelium make topical approaches possible for managing local symptoms such as pain. An understanding of the molecular events occurring in the mucosa will ultimately guide new topical interventions.

Topical anesthetics are used for mucositis pain, despite the lack of controlled clinical trials and a short duration of effect (15–30 minutes). They may sting with initial application on damaged mucosa, and may affect taste and the gag reflex. One study demonstrated limited systemic absorption across compromised mucosal surfaces (Elad et al., 1999a); however, this remains a potential concern. Some patients will apply local anesthetics directly to specific sites of ulceration, but no controlled studies exist. Topical anesthetics are often mixed with coating and antimicrobial agents, such as milk of magnesia, diphenhydramine, or nystatin. Numerous mixes of drugs (e.g., "magic mouthwash" or "oncology mouthwash") have been formulated, but there are insufficient data to support their routine use. These mixtures result in dilution of each of the medications provided and may limit the therapeutic effect. Moreover, various agents in the mix may interact, further reducing the effects of some of the components, the shelf-life of the product is unknown, and patients may find the taste and texture of such mixes difficult to tolerate. Acceptance and tolerability are therefore variable.

Topical benzydamine, an anti-inflammatory and analgesic/anesthetic agent, has been shown in randomized, controlled studies to reduce pain in oral mucositis and reduce the need for systemic analgesics (Epstein et al., 1989, 2001c; Pederson et al., 2000).

Topical doxepin, a tricyclic antidepressant, produces analgesia for 4 hours or longer, following a single application in cancer patients (Epstein et al., 2001d). In addition to an extended duration of pain relief, burning does not accompany application to damaged mucosa.

Topical morphine has been shown to be effective for relieving pain (Cerchietti et al., 2002), but there is concern about dispensing large volumes of the medication.

Topical ketamine, a general anesthetic agent, was shown in one case to reduce the allodynia and hyperalgesia of oral mucositis (Slatkin and Rhiner, 2003). Topical fentanyl, prepared as lozenges, was administered in a small randomized placebo-controlled study for the relief of oral mucositis pain (Shaiova et al., 2004). However, its analgesic potential was not demonstrated to be superior to that of a placebo at doses of 200 mcg in a small sample of 14 patients (Shaiova et al., 2004).

Topical capsaicin has been studied for the control of oral mucositis pain (Berger et al., 1995), but is poorly tolerated by patients. Pre-treatment initiation of capsaicin may represent an approach to "desensitize" patients prior to the onset of mucositis.

Topical coating agents have been promoted for use in managing pain of mucositis. Sucralfate may have a role to play in pain management, but has not been shown to reduce oral mucosal damage (Epstein and Wong, 1994). Other coating agents, such as antacids and milk of magnesia, often mixed as discussed above, have not been shown to reduce pain.

A non-pharmacologic approach for pain relief in cancer patients is the use of laser treatment. Lasers may be effective in reducing or preventing oral pain due to mucosal changes in cancer patients (Whelan et al., 2001; Genot and Klastersky, 2005), and ultraviolet light may relieve mucosal pain in GVHD patients (Elad et al., 1999b).

(5.5) Systemic Medications
The World Health Organization (WHO) Pain Management Ladder is a strategy that has been recommended for managing pain in cancer patients regardless of the cause(s) (Fig.) (Meuser et al., 2001). Increasing discussion about the effectiveness of the WHO Pain Management Ladder is taking place, leading to recommendations for modification of the ladder (Eisenberg et al., 2005). Effectiveness of the analgesic ladder has been assessed, and it was found that pain was reduced to one-third of pre-treatment intensity in approximately 70% of cases, and up to 90% in another study (Ventafridda et al., 1987; Zech et al., 1995). Therefore, 10–30% of cancer patients do not achieve adequate pain control according to the three-step ladder. The WHO analgesic ladder assumes gradual progression in pain intensity due to cancer. However, pain management must be directed at the severity of pain at the time of presentation, and a stepwise approach is not logical. A metanalysis has challenged the effectiveness of "weak" opioids (Step 2 medications). No difference was seen between the effectiveness of NSAIDs (Step 1) and weak opioids (Step 2), and side-effects were greater in those using weak opioids (Eisenberg et al., 1994; McNicol et al., 2004). These studies have shown that a move from Step 1 to Step 2 medications does not improve pain management, and that patients initiated on "strong" opioids (Step 3) have better pain control (Benedetti et al., 2000). Therefore, a change in the WHO ladder has been discussed, whereby Step 1 medications are used for mild pain, and, for more severe pain, the lowest effective dose of "strong" opioids should be titrated to provide sufficient pain control. Pain medications should be provided on a time-contingent basis. Adjuvant medications, such as tricyclic anti-depressants, and other centrally acting pain medications, such as neurontin, should be considered (Box) (Devulder et al., 2001; Ripamonti and Dickerson, 2001). The route of administration may be oral, transdermal, transmucosal, sublingual, transrectal, parenteral, or intrathecal. Daily assessment of pain levels and modification of pain medications following the WHO ladder have been shown to improve pain control in head and neck cancer patients receiving radiotherapy (Menzies et al., 2000). In addition to maintaining a steady state of analgesia, pain management plans should also provide analgesics for the management of breakthrough pain (Coluzzi et al., 2001; Payne et al., 2001; Lucas and Lipman, 2002).

View larger version (35K): [in this window] [in a new window]   Figure. The World Health Organization (WHO) Pain Ladder is used to assess the level of pain experienced by each patient. If pain occurs, there should be prompt oral administration of drugs in the following order: non-opioids; then, as necessary, mild opioids (codeine); then strong opioids, such as morphine, until the patient is free of pain. To calm fears and anxiety, additional drugs–"adjuvants"–should be used.

Opioids should be prescribed at appropriate doses, with frequency based upon the pharmacokinetic profile and effective pain relief (Chapman and Hill, 1989). Patient-controlled analgesia (PCA) has been shown to result in improved mucositis pain management for HCT patients, with lower total doses of opioid analgesics and fewer side-effects compared with those experienced by patients receiving intravenous bolus or oral dosing (Chapman and Hill, 1989; Hill et al., 1991; Dunbar et al., 1995; Coda et al., 1997; Pillitteri and Clark, 1998). Transdermal fentanyl has become widely used for extended-duration therapy in the management of pain in cancer patients. Safety and efficacy of fentanyl patches were shown in a study of 53 patients. Only 23 patients completed the full 84-day study, and the mean duration of fentanyl use was 58 ± 32 days. Final mean fentanyl dose was 169 ± 29 micrograms, with good to excellent pain relief reported by 82% of the subjects. Due to side-effects such as nausea (13%), vomiting (8%), skin rash (8%), and drowsiness (4%), some patients (17%) discontinued the study (Sloan et al., 1998). The use of an initial fentanyl delivery rate between 25 and 50 micrograms/hour (3g/hr) induced significant pain reduction by the third day and up to study completion with no adverse effects. Fentanyl delivery rate on day 42 was between 25 and 400 3g/hr (Mystakidou et al., 2002). High doses of fentanyl (up to 1000 3g/hr) have been used with good pain control and unaltered mental status (Menahem and Shvartzman, 2004).

Addiction in opioid therapy has become less of a concern in general and particularly for cancer patients, and the focus should be on escalating to stronger opioids as needed (based on assessment), and on the use of adjuvant approaches in an effort to provide adequate pain relief. Tolerance and physical side-effects—such as constipation, nausea, vomiting, and mental ’clouding’—are a concern with opioid use, and should be anticipated and managed prophylactically if possible. Laxative and other approaches to bowel management should be initiated concomitantly, and adequacy of the approach assessed on a regular basis.

The need for use and the dose required of systemic opioids to relieve the pain of mucositis can vary tremendously across oncology patient populations. It is important to realize that good basic oral care protocols and the use of topical pain relievers may result in shorter duration and lowered systemic pain medication needs. Topical agents should be continued even after systemic medications have been started. Patient response to symptomatic management should be evaluated and treatment adjusted accordingly.

Other approaches to enhancing pain control include opioid substitution and opioid rotation (Ashby et al., 1999; Coluzzi et al., 2001; Lucas and Lipman, 2002). Parenteral opioids have been shown to provide an improved balance between analgesia and opioid side-effects for cancer pain patients who have not responded to oral opioids, suggesting that a change in route of administration may be effective in some cases (Lema, 2002).

COX-2 is up-regulated in mucositis, and correlates with developing mucositis (Mohan and Epstein, 2003; Sonis et al., 2004b), and therefore COX-2 inhibitors represent potential agents that may affect pain and the evolution of mucositis. COX-2 inhibitors do not inihibit COX-1-dependent platelet aggregation and will not increase the risk of bleeding, as is the case with non-selective non-steroidal anti-inflammatory drugs (NSAIDs). Potential benefits include possible chemoprevention and an effect on angiogenesis (Lucas and Lipman, 2002; Mohan and Epstein, 2003; Ruoff and Lema, 2003). Additionally, in a study of patients with cancer pain and on steady doses of opioids, NSAIDs reduced the need for or dose of opioids (Enting et al., 2002). Although NSAIDS led to increased gastrointestinal discomfort, the reduction in opioids was associated with reduced constipation (Enting et al., 2002).

Adjuvant medications should be used in addition to analgesics for optimal pain management. Amitriptyline has been studied in a randomized placebo-controlled crossover trial, in addition to morphine, in neuropathic cancer pain (Mercadante et al., 2002); however, additional analgesic effect was slight, and side-effects included increased drowsiness, confusion, and dry mouth. The central actions of amitriptyline may improve sleep. Gabapentin is a voltage-sensitive sodium and calcium channel blocker that is used for the management of a variety of pain conditions. One report has demonstrated that gabapentin can improve pain control when used in addition to morphine in cancer patients, as assessed during changes in wound dressings (Devulder et al., 2001). Drugs that affect the n-methyl-d-aspartate receptor address the neuropathic component of pain (Ripamonti and Dickerson, 2001); gabapentin is one of these and is well-tolerated. Other agents that may be used in pain management may include cannabinoids, alpha 2 adrenergic receptor agonists, nicotine, lidocaine, and ketamine.

Co-administration of opioids may offer increased analgesic effects—for example, oxycodone, a µ opioid receptor, may provide additional analgesia when used in addition to morphine and methadone (Ripamonti and Dickerson, 2001).

Management of the symptoms related to pain is important. Pain can be intensified with non-restorative sleep, so adequate pain control should include the additional use of medications to promote sound sleep. Tricyclic antidepressants, some of the anxiolytic/hypnotics (e.g., zolpedim), and some of the benzodiazepines can be useful in these situations.

(5.6) Complementary Pain Management Strategies
Hypnosis has been reported to be useful in randomized trials as a "complementary method" of pain control in cancer patients (Magill, 2001). A variety of hypnotic techniques has been discussed, including vocal techniques, listening, and instrumental techniques, but controlled studies of the impact on cancer pain were not identified (Magill, 2001; Ripamonti and Dickerson, 2001). Additional psychological techniques, including counseling, distraction, relaxation techniques, and other cognitive and behavioral training programs, have been described (Box). Additional approaches to the management of orofacial pain include the use of ice chips for oral cooling, and cold compresses.

In a review of complementary and alternative medicine in the management of pain in terminal patients, 11 controlled and two non-controlled trials and eight case series were identified (Pan et al., 2000). In this report, acupuncture, transcutaneous nerve stimulation, group therapy, self-hypnosis, relaxation, imagery, cognitive behavioral training, and massage therapy were considered as potentially benefiting pain control in cancer patients (Pan et al., 2000). Relaxation and imagery were shown, in one controlled trial, to relieve pain in oral mucositis (Syrjala et al., 1995).

	(6) CONCLUSIONS

TOP ABSTRACT (1) INTRODUCTION (2) OROFACIAL PAIN AS... (3) OROFACIAL PAIN DUE... (4) OROFACIAL PAIN DUE... (5) TREATMENT OF PAIN... (6) CONCLUSIONS REFERENCES

 
Orofacial pain is a common manifestation in cancer patients and may be caused by the cancer and/or its treatment. Often, orofacial pain is associated with loco-regional cancer, but it can be a sign of systemic and distant cancer.

Pain management requires the diagnosis of the various causes and mechanisms of pain in cancer patients. Practitioners must obtain regular pain ratings during treatment of patients with cancer-related pain. Since pain is frequently multifactorial, addressing each of the dimensions of the patient’s pain can improve pain control. Attention should be paid to the patient’s overall medical as well as oral status.

Despite the availability of effective methods of controlling pain, pain management, even in cancer centers, is often inadequate. It is important to recognize and manage the side-effects of analgesic therapy, especially those induced by opioids and adjuvant medications. The use of effective topical pain therapy with the initial mucosal injury may allow for delay of systemic pain medications or reduced doses. Awareness of adjuvant approaches to management is essential, and both medications and complementary management with evidence of effect should be considered. The use of existing research as a foundation for pain management will help improve patients’ quality of life, but continuing research is needed to support advances in patient care. In particular, there is a paucity of data concerning pain severity and quality in oral cancer, and how these vary over the course of treatment.

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

	REFERENCES

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Journal of Dental Research, Vol. 86, No. 6, 506-518 (2007)
DOI: 10.1177/154405910708600605


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