Pharmacological Management of Orofacial Pain.

Orofacial pain is a category of complex disorders, including musculoskeletal, neuropathic and neurovascular disorders, that greatly affect the quality of life of the patient. These disorders are within the fields of dentistry and medicine and management can be challenging, requiring a referral to an orofacial pain specialist, essential for adequate evaluation, diagnosis, and care. Management is specific to the diagnosis and a treatment plan is developed with diverse pharmacological and non-pharmacological modalities. The pharmacological management of orofacial pain encompasses a vast array of medication classes and approaches. This includes anti-inflammatory drugs, muscle relaxants, anticonvulsants, antidepressants, and anesthetics. In addition, as adjunct therapy, different injections can be integrated into the management plan depending on the diagnosis and needs. These include trigger point injections, temporomandibular joint (TMJ) injections, and neurotoxin injections with botulinum toxin and nerve blocks. Multidisciplinary management is key for optimal care. New and safer therapeutic targets exclusively for the management of orofacial pain disorders are needed to offer better care for this patient population.

Interplay of Oral, Mandibular, and Facial Disorders and Migraine.

PURPOSE OF THE REVIEW: Migraine and other primary headache disorders can be localized in the face resembling facial or dental pain, indicating the influence of the trigeminovascular system in the structures innervated by the maxillary (V2) and mandibulary (V3) branches of the trigeminal nerve. Disorders of oral and craniofacial structures may influence primary headache disorders. In the current article, we review the potential links of this interplay. RECENT FINDINGS: This interplay may be related to anatomy, with the trigeminal pathway and the involvement of both peripheral and central mechanisms, and the presence of calcitonin gene-related peptide (CGRP), a key mediator in migraine pathophysiology. CGRP is also involved in the pathophysiology of temporomandibular disorders (TMD) and their comorbidity with migraine and is also implicated in dental and periodontal pathology. Inflammatory and pathological processes of these structures and their trigeminal nociceptive pathways may influence the trigeminovascular system and consequently may exacerbate or even potentially trigger migraine.

Burning mouth syndrome: a review of etiology, diagnosis, and management.

Burning mouth syndrome (BMS) is a chronic condition characterized by a burning sensation of the oral cavity and is often associated with taste disturbances and xerostomia. It primarily affects menopausal or postmenopausal women. Idiopathic or primary BMS can occur spontaneously and without any identifiable precipitating factors. When BMS is associated with systemic factors, it is defined as secondary BMS. While the exact etiology of BMS is still unknown, the condition appears to be multifactorial, and numerous local, systemic, and psychological factors have been associated with it. Primary BMS is a diagnosis of exclusion and can only be reached after all potential causes of secondary burning pain have been eliminated. Management strategies include reassurance of the patient as well as pharmacologic agents such as clonazepam, supplements such as α-lipoic acid, and psychological therapy.

Differentiation by NK cells is a prerequisite for effective targeting of cancer stem cells/poorly differentiated tumors by chemopreventive and chemotherapeutic drugs.

Natural Killer (NK) cells target oral, pancreatic, lung, breast, glioblastoma and melanoma stem-like/poorly differentiated tumors. Differentiation of the abovementioned tumors with supernatants from split-anergized NK cells decreases their susceptibility to NK cells, but increases their sensitivity to cisplatin (CDDP)-mediated cell death. Breast and melanoma tumor cells with CD44 knockdown display enhanced susceptibility to NK cell-mediated lysis, potentially due to decreased differentiation. We also demonstrate that sulindac, a non-steroidal anti-inflammatory drug and a chemopreventive agent, not only limits the growth of oral tumor cells, but also aids in cancer cell elimination by NK cells. Treatment of oral tumors with sulindac, but not adriamycin inversely modulates the expression and function of NFκB and JNK, resulting in a significant down-regulation of IL-6, and VEGF secretion by oral tumor cells. In addition, increased secretion of IL-6 and VEGF is blocked by sulindac during interaction of oral tumors with NK cells. Sulindac treatment prevents synergistic induction of VEGF secretion by the tumor cells after their co-culture with untreated NK cells since non-activated NK cells lack the ability to efficiently kill tumor cells. Moreover, sulindac is able to profoundly reduce VEGF secretion by tumor cells cultured with IL-2 activated NK cells, which are able to significantly lyse the tumor cells. Based on the data presented in this study, we propose the following combinatorial approach for the treatment of stem-like/ poorly differentiated tumors in cancer patients with metastatic disease. Stem-like/ poorly differentiated tumor cells may in part undergo lysis or differentiation after NK cell immunotherapy, followed by treatment of differentiated tumors with chemotherapy and chemopreventive agents to eliminate the bulk of the tumor. This dual approach should limit tumor growth and prevent metastasis.

Mucocutaneous Diseases: Oral Lichen Planus, Mucous Membrane Pemphigoid and Pemphigus Vulgaris.

Mucocutaneous diseases affect the oral cavity and can present a diagnostic challenge. They can have systemic involvement, necessitating multidisciplinary management. Frequently, patients will see their general dentists initially for evaluation. A better understanding of mucocutaneous diseases can prevent delay in appropriate diagnosis and treatment. Oral lichen planus, mucous membrane pemphigoid and pemphigus vulgaris are three mucocutaneous diseases that affect the oral mucosa. This review describes the clinical features, epidemiology, etiology, pathogenesis and management for each condition.

Cancer and Referred Facial Pain.

Orofacial pain may be a symptom of diverse types of cancers as a result of local or distant tumor effects. The pain can be presented with the same characteristics as any other orofacial pain disorder, and this should be recognized by the clinician. Orofacial pain also can arise as a consequence of cancer therapy. In the present article, we review the mechanisms of cancer-associated facial pain, its clinical presentation, and cancer therapy associated with orofacial pain.

Increased lysis of stem cells but not their differentiated cells by natural killer cells; de-differentiation or reprogramming activates NK cells.

The aims of this study are to demonstrate the increased lysis of stem cells but not their differentiated counterparts by the NK cells and to determine whether disturbance in cell differentiation is a cause for increased sensitivity to NK cell mediated cytotoxicity. Increased cytotoxicity and augmented secretion of IFN-gamma were both observed when PBMCs or NK cells were co-incubated with primary UCLA oral squamous carcinoma stem cells (UCLA-OSCSCs) when compared to differentiated UCLA oral squamous carcinoma cells (UCLA-OSCCs). In addition, human embryonic stem cells (hESCs) were also lysed greatly by the NK cells. Moreover, NK cells were found to lyse human Mesenchymal Stem Cells (hMSCs), human dental pulp stem cells (hDPSCs) and human induced pluripotent stem cells (hiPSCs) significantly more than their differentiated counterparts or parental lines from which they were derived. It was also found that inhibition of differentiation or reversion of cells to a less-differentiated phenotype by blocking NFkappaB or targeted knock down of COX2 in monocytes significantly augmented NK cell cytotoxicity and secretion of IFN-gamma. Taken together, these results suggest that stem cells are significant targets of the NK cell cytotoxicity. However, to support differentiation of a subset of tumor or healthy untransformed primary stem cells, NK cells may be required to lyse a number of stem cells and/or those which are either defective or incapable of full differentiation in order to lose their cytotoxic function and gain the ability to secrete cytokines (split anergy). Therefore, patients with cancer may benefit from repeated allogeneic NK cell transplantation for specific elimination of cancer stem cells.

Cluster headache and obstructive sleep apnea: are they related disorders?

Patients with cluster headache (CH) have a higher prevalence of sleep apnea, and a possible relationship between these two conditions has been proposed. Although patients suffering from CH attacks often wake up from sleep, sleep apnea has been suggested to be a trigger or an associated abnormality in CH. It has been proposed that regulation of the hypothalamus may be responsible for sleep apnea, and that similiarly CH is generated in the hypothalamus. However, there is evidence that CH and obstructive sleep apnea are not causal, but rather parallel processes both generated in the hypothalamus. The exact role that sleep apnea plays in the perpetuation or precipitation of CH is still to be determined. This paper discusses the proposed pathophysiological mechanisms of these two entities and the possible relationship between CH and sleep apnea.

Prevalence of hypertension in patients with trigeminal neuralgia.

It is unclear whether hypertension (HTN) is a predisposing factor for the development of trigeminal neuralgia (TN). The purpose of this study was to determine the prevalence of HTN in TN patients and controls at the USC Orofacial Pain and Oral Medicine Center. A retrospective chart review was conducted from a database of over 3,000 patient records from 2003 to 2007. We identified patients diagnosed with TN with or without HTN. A total of 84 patients (54 females; 30 males) between the ages of 33 and 93 years were diagnosed with TN; 37% had TN with HTN and 32% of controls had HTN. The increased prevalence of HTN in the TN patients was not statistically significant (P = 0.50). Since, both TN and HTN are seen in the elderly, it is likely that HTN is simply a co-existing condition in patients with TN and not a risk factor for its development.

Clinical characteristics and diagnosis of atypical odontalgia: implications for dentists.

BACKGROUND: Atypical odontalgia (AO) is a poorly understood and commonly misdiagnosed condition for which patients often undergo multiple unsuccessful dental or surgical procedures. The authors conducted a study to determine the prevalence and describe the characteristics of patients with AO seen at the University of Southern California Orofacial Pain and Oral Medicine Center (USC OFP-OM Center), Los Angeles. METHODS: The authors conducted a retrospective record review from a database of more than 3,000 patient records from June 2003 to August 2007 to identify patients diagnosed with AO. RESULTS: The authors identified 64 patients (44 women and 20 men) between the ages of 26 and 93 years as having a diagnosis of AO. Of those 64 patients, 71 percent initially consulted a dentist regarding their pain, and 79 percent had undergone dental treatment that failed to resolve the pain. The pain of 64 percent of the patients had no known cause. CONCLUSIONS: Dentists, who often are the first health care providers to see patients with AO, must be aware of this condition and must follow the appropriate steps to determine its diagnosis. CLINICAL IMPLICATIONS: Dentists and physicians should understand the implications and importance of early diagnosis of patients with AO and of referral to pain specialists for treatment.

Rapid and potent induction of cell death and loss of NK cell cytotoxicity against oral tumors by F(ab')2 fragment of anti-CD16 antibody.

Freshly isolated untreated NK cells undergo rapid apoptosis and lose their cytotoxic function upon the addition of F(ab')2 fragment of anti-CD16 antibodies. Loss of NK cell cytotoxic function after treatment with F(ab')2 fragment of anti-CD16 antibody can be seen against K562 and UCLA-2 oral tumor cells when either added immediately in the co-cultures of NK cells with the tumor cells or after pre-treatment of NK cells with the antibody before their addition to the tumor cells. Addition of Interleukin-2 (IL-2) in combination with anti-CD16 antibody to NK cells delayed the induction of DNA fragmentation in NK cells, and even though decreased cytotoxicity could still be observed against K562 and UCLA-2 oral tumors when compared to IL-2 alone treated NK cells, the cytotoxicity levels remained relatively higher and approached those obtained by untreated NK cells in the absence of antibody treatment. No increases in IFN-gamma, Granzymes A and B, Perforin and TRAIL genes could be seen in NK cells treated with anti-CD16 antibody. Neither secretion of IFN-gamma nor increased expression of CD69 activation antigen could be observed after the treatment of NK cells with anti-CD16 antibody. Furthermore, IL-2 mediated increase in CD69 surface antigens was down-modulated by anti-CD16 antibody. Finally, the addition of anti-CD16 antibody to co-cultures of NK cells with tumor target cells was not inhibitory for the secretion of VEGF by oral tumor cells, unlike those co-cultured with untreated or IL-2 treated NK cells. Thus, binding and triggering of CD16 receptor on NK cells may enhance oral tumor survival and growth by decreased ability of NK cells to suppress VEGF secretion or induce tumor cell death during the interaction of NK cells with oral tumor cells.

Potential contribution of naïve immune effectors to oral tumor resistance: role in synergistic induction of VEGF, IL-6, and IL-8 secretion.

The aim of this study is to identify the phenotype of resistant oral tumors, and to delineate the contribution of immune effectors to resistance of oral tumors. UCLA-1 oral tumors which were resistant to NK cell mediated cytotoxicity secreted increased amounts of IL-6, IL-1beta, GM-CSF, and IL-8 when cultured with or without immune effectors. In addition, the levels of vascular endothelial growth factor (VEGF) secretion in the co-cultures of naïve immune effectors with UCLA-1 rose significantly when compared to tumor cells alone. IL-2 activated NK cells decreased VEGF secretion in all tumor cells. However, NK cells which were induced to undergo cell death with anti-CD16 antibody were not only unable to decrease VEGF secretion, but they also contributed further to the increase in VEGF secretion by oral tumors. Overall, we show in this paper that naïve as well as non-viable immune effectors may contribute to the growth and resistance of oral tumors by triggering the secretion of key tumor cell growth factors.

Coengagement of CD16 and CD94 receptors mediates secretion of chemokines and induces apoptotic death of naive natural killer cells.

Down-modulation of CD16 (FcgammaRIII) receptors and loss of natural killer (NK) cell function have been observed in oral cancer patients. However, neither the mechanisms nor the significance of the decrease in CD16 receptors have been fully understood. The cytotoxic activity and survival of NK cells are negatively regulated by antibodies directed against CD16 surface receptor. The addition of anti-CD94 antibody in combination with either F(ab')(2) fragment or intact anti-CD16 antibody to NK cells resulted in significant inhibition of NK cell cytotoxic function and induction of apoptosis in resting human peripheral blood NK cells. Addition of interleukin-2 to anti-CD16 and/or anti-CD94 antibody-treated NK cells significantly inhibited apoptosis and increased the function of NK cells. There was a significant increase in tumor necrosis factor-alpha (TNF-alpha) but not IFN-gamma secretion in NK cells treated either with anti-CD16 antibody alone or in combination with anti-CD94 antibodies. Consequently, the addition of anti-TNF-alpha antibody partially inhibited apoptosis of NK cells mediated by the combination of anti-CD94 and anti-CD16 antibodies. Increase in apoptotic death of NK cells also correlated with an increase in type 2 inflammatory cytokines and in the induction of chemokines. Thus, we conclude that binding of antibodies to CD16 and CD94 NK cell receptors induces death of the NK cells and signals for the release of chemokines.

Inhibition of nuclear factor kappa B (NFkappaB) activity in oral tumor cells prevents depletion of NK cells and increases their functional activation.

The aim of this study is to identify candidate factors which may be responsible for the functional inactivation and depletion of NK cells by tumor cells. Inhibition of NFkappaB activity by an IkappaB super-repressor in HEp2 cells, a cell line commonly used as an oral tumor model, blocked tumor-induced NK cell death, and increased the function of NK cells significantly. Increased expression of CD69 early activation antigen on NK cells as well as augmented proliferation and secretion of IFN-gamma by NK cells were observed when these cells were co-incubated with IkappaB super-repressor transfected HEp2 cells (HEp2-IkappaB((S32AS36A))). More importantly, the secretion of IL-6 was significantly inhibited when NK cells were co-cultured with HEp2-IkappaB((S32AS36A)) cells. In addition, the survival and function of cytotoxic effector cells remained significantly elevated in the presence of IFN-gamma-treated HEp2-IkappaB((S32AS36A)) cells when compared to either untreated or IFN-gamma-treated vector-alone transfected HEp2 cells. Similar findings to those obtained using purified peripheral blood NK cells were also observed when non-fractionated peripheral blood mononuclear cells were used in the co-cultures of immune effectors with HEp2 cell transfectants. Addition of recombinant human IL-6 to the co-cultures of immune effectors with the NFkappaB knockdown HEp2 tumor cells substantially decreased the levels of secreted IFN-gamma. Thus, the results presented in this paper suggest that the inhibition of NFkappaB function in oral tumors may serve to activate and expand the function and numbers of NK cells. Moreover, NFkappaB-mediated increase in IL-6 secretion by oral tumors may in part be responsible for the observed inactivation and death of the immune effectors.

Cytokine dependent inverse regulation of CD54 (ICAM1) and major histocompatibility complex class I antigens by nuclear factor kappaB in HEp2 tumor cell line: effect on the function of natural killer cells.

The aim of this study is to investigate the mechanisms by which elevated nuclear factor kappaB (NFkappaB) activity in HEp2 cells can modulate the function and survival of immune effector cells. Inhibition of NFkappaB functional activity by stable expression of IkappaB super-repressor rendered HEp2 cells (HEp2-IkappaB((S32AS36A))) susceptible to natural killer (NK) cell mediated cytotoxicity. Increase in surface ICAM1 expression was greater on HEp2-IkappaB((S32AS36A)) cells than on the surface of vector alone transfected HEp2 cells when these cells were treated with IFN-gamma. In contrast, tumor necrosis factor alpha (TNF-alpha) treatment augmented ICAM-1 expression on the surface of vector-alone transfected HEp2 cells and not on the HEp2-IkappaB((S32AS36A)) cells. Moreover, synergistic augmentation of ICAM-1 by a combination of TNF-alpha and interferon-gamma (IFN-gamma) treatment was completely abrogated on the surface of HEp2-IkappaB((S32AS36A)) cells. The addition of blocking antibody to ICAM-1 surface antigen partially inhibited the increased cytotxicity mediated by interleukin-2 treated NK cells against HEp2-IkappaB((S32AS36A)) cells. In contrast to ICAM-1, the expression of major histocompatibility complex (MHC) class I antigens were downregulated when the function of nuclear NFkappaB was inhibited in HEp2 cells. The addition of IFN-gamma to HEp2-kappaB((S32AS36A)) cells increased the expression of MHC class I antigen and rendered these cells less susceptible to NK cell mediated cytotoxicity. Secretion of IFN-gamma and granulocyte macrophage-colony-stimulating factor (GM-CSF) by NK cells was also significantly increased in the presence of HEp2-IkappaB((S32AS36A)) cells, and the treatment of these tumor cells with IFN-gamma prior to their addition to the cultures of NK cells decreased the released IFN-gamma and GM-CSF by NK cells. However, the levels of NK cell mediated cytotoxicity and IFN-gamma secretion remained significantly higher in the presence of both untreated and IFN-gamma treated HEp2-IkappaB((S32AS36A)) cells when compared with vector-alone transfected HEp2 cells. Thus, NFkappaB regulates inversely the expression of ICAM-1 and MHC class I antigens on HEp2 tumor cells and this may contribute to the resistance of these cells to NK cell mediated cytotoxicity.