| ORIGINAL CONTRIBUTIONS [
PAIN UPDATE
Postradiation xerostomia and oral pain damage.1Salivary acinar cells are more sensitive to radia tion than are other cells. Radiation therapy is thought to induce a sterile inflammation that results in increased permeability of the endothelial cells of the periductal CLINICAL PROBLEM capillaries, which produces periductal edema.2,3 This edema leads to compression of the small salivary ducts 64-year-old man sought care at the Center of and destruction of the duct epithelium. The end result is Dental Medicine at the University of Zurich fibrosis, degeneration and atrophy of the salivary acinar for the first time. He had experienced dry cells. mouth since he had undergone radiation The development of intensity-modulated radiation therapy as primary treatment for squamous cell carcino therapy in recent years has decreased the incidence of ma (SCC) of the left lateral aspect of the tongue 14 years oral dryness in those receiving it, because organs unaf earlier. His chief complaint was pain when eating spicy food (for example, Mexican food) or when consum fected by the malignancy are spared from radiation.4 This shielding is achieved by virtual three-dimensional ing hot liquids or acidic fluids (for example, tea, salad planning (based on multidetector computed tomog dressing, fruit juice). He described his pain as a burning sensation throughout the oral cavity. This burning sensa raphy or magnetic resonance imaging), which enables the radiation oncologist to calculate radiation intensity tion was not triggered when he consumed mild foods or for variable beam angles. However, the literature is not cold drinks. entirely clear about the degree of protection for salivary His health history was positive for a high lifetime glands, since intensity-modulated radiation therapy only smoking habit (> 60 pack-years). In addition, he report partially reduces xerostomia. ed that he had had two to three glasses of whiskey every Furthermore, the subjective degree of xerostomia evening since adolescence. He was able to discontinue both habits after his SCC was diagnosed. Cancer follow does not necessarily correlate with objective salivary flow measurements.3,5 One possible explanation might up was suspended five years before the examination. be that salivary flow measurements primarily estimate Clinical and radiographic examinations revealed no parotid gland function, and the small salivary glands are tooth-related problems. The oral mucosa appeared pink, considered more relevant for the subjective experience slightly atrophic and dry, with no signs of candidiasis. of xerostomia.6 There is ample evidence that the effect of Therefore, we diagnosed postradiation xerostomia. xerostomia on the quality of life is strong, since it affects EXPLANATION OF POSTRADIATION XEROSTOMIA diverse phenomena such as speech, sleep and taste.7'12 In addition, there is a mucotoxic effect from antineoplastic This patient represented a typical patient throughout the world who had received treatment for SCC at a tumor agents (chemotherapy), which often are used as part of center. Both excessive smoking and alcohol consump the treatment concept in head and neck malignancies.13 tion still are the most important and prevalent risk HOW RADIATION THERAPY LEADS TO ORAL factors for SCC, although increasing attention is focused SENSITIVITY on the potential pathogenetic role of human papilloma The perception of temperature is linked to specialized viruses. Treatment decisions regarding the primary pores on nerve cells that are grouped under the term tumor require consideration of the patient’s needs and wants. Although he was aware that xerostomia was a “transient receptor potential (TRP) channels,” many of which are found in oral tissues.14 These thermosensory likely side effect, the patient opted for radiation therapy, which was, in his opinion, the “less invasive” therapeutic TRP (thermoTRP) channels are activated by changes in option compared with surgical removal of one-half of his environmental temperature, which result in neuronal tongue accompanied by neck dissection. signals that are conveyed to the human brain.15 A promi Dry mouth is a regular sequela of oropharyngeal nent member of the thermoTRP channel is TRP cation radiation therapy since both big and small salivary channel subfamily V member 1 (TRPVi), which was glands are within the field of radiation. Even a relatively named for its ability to be activated by substances with a vanilloid chemical structure (for example, the capsaicin low dose (25-45 grays) results in permanent glandular Heinz-Theo Lubbers, MD, DMD; Astrid L. Kruse, MD, DMD; Dominik A. Ettlin, MD, DMD
A
96 4
JADA 145(9)
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Septem ber 2014
| ORIGINAL CONTRIBUTIONS f
in hot chili peppers). Thus, these channels respond not only to temperature but also to chemicals and other stimuli.16 TRPVi is expressed prominently on small nociceptive neurons that innervate the oral mucosa, and damage to these fibers has resulted in oral burn ing .17’18 Since radiation therapy exerts toxicity on the oral mucosa and its innervation, it is likely that thermal and chemical hypersensitivity is attributable to thermoTRP dysfunction when the person consumes hot, spicy and acidic foods. THERAPEUTIC OPTIONS
No remedy exists for the xerostomia or for the burning sensations reported by the patient in our case. Paradoxi cally, repeated application of capsaicin to mucosal or dermal tissues results in reduced expression of TRPVi and, thus, decreased thermal and chemical tissue hyper sensitivity.19 This is why topical applications of capsaicin have become increasingly popular in pain management. Therefore, an attempt to desensitize oral tissues by rins ing frequently with increasing concentrations of cap saicin might be beneficial in selected patients .20 Large pharmaceutical companies have been investing in the development of new thermoTRP channel modulators for pain control.19 Xerostomia is addressed best by moisturizing the mouth frequently. In addition, any type of saliva substi tute in the form of lubricants, aerosols or liquids often is helpful to patients. Numerous products are listed in the ADA Dental Product Guide section of the American Dental Association website.21 ■ doiuo.i42i9/jada.20i3.4 Dr. Lubbers is an oral and maxillofacial surgeon in private practice in Winterthur, Switzerland, and an oral and maxillofacial surgeon, Clinic for Oral and Maxillofacial Surgery, Center of Dental Medicine, University of Zurich, Plattenstrasse 11,8032 Zurich, Switzerland, e-mail t.luebbers@ gmail.com. Address correspondence to Dr. Lubbers. Dr. Kruse is an oral and maxillofacial surgeon in private practice in Winterthur, Switzerland, and an oral and maxillofacial surgeon, Clinic for Oral and Maxillofacial Surgery, Center of Dental Medicine, University of Zurich. Dr. Ettlin is a dentist, Clinic for Masticatory Dysfunction, Removable Prosthodontics, Geriatric and Special Care Dentistry, Center of Dental Medicine, University of Zurich. Disclosure. None of the authors reported any disclosures. Pain Update is published in collaboration with the Neuroscience Group of the International Association for Dental Research. 1. Ortholan C, Chamorey E, Benezery K, et al. Modeling of salivary production recovery after radiotherapy using mixed models: determina tion of optimal dose constraint for IMRT planning and construction of
convenient tools to predict salivary function. Int J Radiat Oncol Biol Phys 2009 ;73(l):i78-i 86. 2. Stephens LC, Ang KK, Schultheiss TE, King GK, Brock WA, Peters W. Target cell and mode of radiation injury in rhesus salivary glands. Radiother Oncol I986;7(2):i65-i74. 3. Eisbruch A. Reducing xerostomia by IMRT: what may, and may not, be achieved. J Clin Oncol 2007;25(3t):4863-4864. 4. Little M, Schipper M, Feng FY, Vineberg K, Cornwall C, MurdochKinch CA. Reducing xerostomia after chemo-IMRT for head-and-neck cancer: beyond sparing the parotid glands. Int J Radiat Oncol Biol Phys 2012;83(3):1007-1014. 5. Wang SL, Zhao ZT, Li J, Zhu XZ, Dong H, Zhang YG. Investigation of the clinical value of total saliva flow rates. Arch Oral Biol i998;43(i):39-43. 6. Eisbruch A. Radiotherapy: IMRT reduces xerostomia and potentially improves QoL. Nat Rev Clin Oncol 2009;6(io):567-568. 7. Wang ZH, Yan C, Zhang ZY, et al. Impact of salivary gland dosimetry on post-IMRT recovery of saliva output and xerostomia grade for headand-neck cancer patients treated with or without contralateral subman dibular gland sparing: a longitudinal study. Int J Radiat Oncol Biol Phys 20 ti; 8i( 5):i479-i 487. 8. Jabbari S, Kim HM, Feng M, et al. Matched case-control study of quality of life and xerostomia after intensity-modulated radiotherapy or standard radiotherapy for head-and-neck cancer: initial report. Int J Radiat Oncol Biol Phys 2005;63(3):725-73i. 9. Parliament MB, Scrimger RA, Anderson SG, et al. Preservation of oral health-related quality of life and salivary flow rates after inverseplanned intensity-modulated radiotherapy (IMRT) for head-and-neck cancer. Int J Radiat Oncol Biol Phys 2004;58(3):663-673. to. Kasaba T, Onizuka S, Takasaki M. Procaine and mepivacaine have less toxicity in vitro than other clinically used local anesthetics. Anesth Analg 2003;97(i):85-90. 11. Franzen L, Funegard U, Ericson T, Henriksson R. Parotid gland function during and following radiotherapy of malignancies in the head and neck: a consecutive study of salivary flow and patient discomfort. Eur J Cancer i992;28(2-3):457-462. 12. Eisbruch A, Ten Haken RK, Kim HM, Marsh LH, Ship JA. Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer. Int J Radiat Oncol Biol Phys i999;45(3):577-587. 13. Kostler W[, Hejna M, Wenzel C, Zielinski CC. Oral mucositis com plicating chemotherapy and/or radiotherapy: options for prevention and treatment. CA Cancer J Clin 2oot;5i(5):290-3i5. 14. Wang B, Danjo A, Kajiya H, Okabe K, Kido MA. Oral epithelial cells are activated via TRP channels. J Dent Res 20ii;9o(2):i63-i67. 15. Ferrer-Montiel A, Fernandez-Carvajal A, Planells-Cases R, et al. Advances in modulating thermosensory TRP channels. Expert Opin Ther Pat 20i2;22(9):999-tot7. 16. Venkatachalam K, Montell'C. TRP channels. Annu Rev Biochem 2007;76:387-417. 17. Jaaskelainen SK. Pathophysiology of primary burning mouth syn drome. Clin Neurophysiol 20i2;i23(i):7i-77. 18. Lauria G, Majorana A, Borgna M, et al. Trigeminal small-fiber senso ry neuropathy causes burning mouth syndrome. Pain 2005;ii5(3):332-337. 19. O’Neill J, Brock C, Olesen AE, Andresen T, Nilsson M, Dickenson AH. Unravelling the mystery of capsaicin: a tool to understand and treat pain. Pharmacol Rev 20i2;64(4):939-97t. 20. Silvestre FJ, Silvestre-Rangil J, Tamarit-Santafe C, Bautista D. Appli cation of a capsaicin rinse in the treatment of burning mouth syndrome. Med Oral Patol Oral Cir Bucal 20i2;i7(i):ei-e4. 21. American Dental Association. ADA Dental Product Guide: product category—dry mouth products, dentist dispensed, www.ada.org/en/ publications/ada-dental-product-guide/product-category?catid=i39. Ac cessed July 23, 2014.
JADA 145(9)
http ://ja d a .a d a .o rg
Septem ber 2014
965
Copyright of Journal of the American Dental Association (JADA) is the property of American Dental Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
PAIN UPDATE
Postradiation xerostomia and oral pain damage.1Salivary acinar cells are more sensitive to radia tion than are other cells. Radiation therapy is thought to induce a sterile inflammation that results in increased permeability of the endothelial cells of the periductal CLINICAL PROBLEM capillaries, which produces periductal edema.2,3 This edema leads to compression of the small salivary ducts 64-year-old man sought care at the Center of and destruction of the duct epithelium. The end result is Dental Medicine at the University of Zurich fibrosis, degeneration and atrophy of the salivary acinar for the first time. He had experienced dry cells. mouth since he had undergone radiation The development of intensity-modulated radiation therapy as primary treatment for squamous cell carcino therapy in recent years has decreased the incidence of ma (SCC) of the left lateral aspect of the tongue 14 years oral dryness in those receiving it, because organs unaf earlier. His chief complaint was pain when eating spicy food (for example, Mexican food) or when consum fected by the malignancy are spared from radiation.4 This shielding is achieved by virtual three-dimensional ing hot liquids or acidic fluids (for example, tea, salad planning (based on multidetector computed tomog dressing, fruit juice). He described his pain as a burning sensation throughout the oral cavity. This burning sensa raphy or magnetic resonance imaging), which enables the radiation oncologist to calculate radiation intensity tion was not triggered when he consumed mild foods or for variable beam angles. However, the literature is not cold drinks. entirely clear about the degree of protection for salivary His health history was positive for a high lifetime glands, since intensity-modulated radiation therapy only smoking habit (> 60 pack-years). In addition, he report partially reduces xerostomia. ed that he had had two to three glasses of whiskey every Furthermore, the subjective degree of xerostomia evening since adolescence. He was able to discontinue both habits after his SCC was diagnosed. Cancer follow does not necessarily correlate with objective salivary flow measurements.3,5 One possible explanation might up was suspended five years before the examination. be that salivary flow measurements primarily estimate Clinical and radiographic examinations revealed no parotid gland function, and the small salivary glands are tooth-related problems. The oral mucosa appeared pink, considered more relevant for the subjective experience slightly atrophic and dry, with no signs of candidiasis. of xerostomia.6 There is ample evidence that the effect of Therefore, we diagnosed postradiation xerostomia. xerostomia on the quality of life is strong, since it affects EXPLANATION OF POSTRADIATION XEROSTOMIA diverse phenomena such as speech, sleep and taste.7'12 In addition, there is a mucotoxic effect from antineoplastic This patient represented a typical patient throughout the world who had received treatment for SCC at a tumor agents (chemotherapy), which often are used as part of center. Both excessive smoking and alcohol consump the treatment concept in head and neck malignancies.13 tion still are the most important and prevalent risk HOW RADIATION THERAPY LEADS TO ORAL factors for SCC, although increasing attention is focused SENSITIVITY on the potential pathogenetic role of human papilloma The perception of temperature is linked to specialized viruses. Treatment decisions regarding the primary pores on nerve cells that are grouped under the term tumor require consideration of the patient’s needs and wants. Although he was aware that xerostomia was a “transient receptor potential (TRP) channels,” many of which are found in oral tissues.14 These thermosensory likely side effect, the patient opted for radiation therapy, which was, in his opinion, the “less invasive” therapeutic TRP (thermoTRP) channels are activated by changes in option compared with surgical removal of one-half of his environmental temperature, which result in neuronal tongue accompanied by neck dissection. signals that are conveyed to the human brain.15 A promi Dry mouth is a regular sequela of oropharyngeal nent member of the thermoTRP channel is TRP cation radiation therapy since both big and small salivary channel subfamily V member 1 (TRPVi), which was glands are within the field of radiation. Even a relatively named for its ability to be activated by substances with a vanilloid chemical structure (for example, the capsaicin low dose (25-45 grays) results in permanent glandular Heinz-Theo Lubbers, MD, DMD; Astrid L. Kruse, MD, DMD; Dominik A. Ettlin, MD, DMD
A
96 4
JADA 145(9)
h ttp ://ja d a .a d a .o rg
Septem ber 2014
| ORIGINAL CONTRIBUTIONS f
in hot chili peppers). Thus, these channels respond not only to temperature but also to chemicals and other stimuli.16 TRPVi is expressed prominently on small nociceptive neurons that innervate the oral mucosa, and damage to these fibers has resulted in oral burn ing .17’18 Since radiation therapy exerts toxicity on the oral mucosa and its innervation, it is likely that thermal and chemical hypersensitivity is attributable to thermoTRP dysfunction when the person consumes hot, spicy and acidic foods. THERAPEUTIC OPTIONS
No remedy exists for the xerostomia or for the burning sensations reported by the patient in our case. Paradoxi cally, repeated application of capsaicin to mucosal or dermal tissues results in reduced expression of TRPVi and, thus, decreased thermal and chemical tissue hyper sensitivity.19 This is why topical applications of capsaicin have become increasingly popular in pain management. Therefore, an attempt to desensitize oral tissues by rins ing frequently with increasing concentrations of cap saicin might be beneficial in selected patients .20 Large pharmaceutical companies have been investing in the development of new thermoTRP channel modulators for pain control.19 Xerostomia is addressed best by moisturizing the mouth frequently. In addition, any type of saliva substi tute in the form of lubricants, aerosols or liquids often is helpful to patients. Numerous products are listed in the ADA Dental Product Guide section of the American Dental Association website.21 ■ doiuo.i42i9/jada.20i3.4 Dr. Lubbers is an oral and maxillofacial surgeon in private practice in Winterthur, Switzerland, and an oral and maxillofacial surgeon, Clinic for Oral and Maxillofacial Surgery, Center of Dental Medicine, University of Zurich, Plattenstrasse 11,8032 Zurich, Switzerland, e-mail t.luebbers@ gmail.com. Address correspondence to Dr. Lubbers. Dr. Kruse is an oral and maxillofacial surgeon in private practice in Winterthur, Switzerland, and an oral and maxillofacial surgeon, Clinic for Oral and Maxillofacial Surgery, Center of Dental Medicine, University of Zurich. Dr. Ettlin is a dentist, Clinic for Masticatory Dysfunction, Removable Prosthodontics, Geriatric and Special Care Dentistry, Center of Dental Medicine, University of Zurich. Disclosure. None of the authors reported any disclosures. Pain Update is published in collaboration with the Neuroscience Group of the International Association for Dental Research. 1. Ortholan C, Chamorey E, Benezery K, et al. Modeling of salivary production recovery after radiotherapy using mixed models: determina tion of optimal dose constraint for IMRT planning and construction of
convenient tools to predict salivary function. Int J Radiat Oncol Biol Phys 2009 ;73(l):i78-i 86. 2. Stephens LC, Ang KK, Schultheiss TE, King GK, Brock WA, Peters W. Target cell and mode of radiation injury in rhesus salivary glands. Radiother Oncol I986;7(2):i65-i74. 3. Eisbruch A. Reducing xerostomia by IMRT: what may, and may not, be achieved. J Clin Oncol 2007;25(3t):4863-4864. 4. Little M, Schipper M, Feng FY, Vineberg K, Cornwall C, MurdochKinch CA. Reducing xerostomia after chemo-IMRT for head-and-neck cancer: beyond sparing the parotid glands. Int J Radiat Oncol Biol Phys 2012;83(3):1007-1014. 5. Wang SL, Zhao ZT, Li J, Zhu XZ, Dong H, Zhang YG. Investigation of the clinical value of total saliva flow rates. Arch Oral Biol i998;43(i):39-43. 6. Eisbruch A. Radiotherapy: IMRT reduces xerostomia and potentially improves QoL. Nat Rev Clin Oncol 2009;6(io):567-568. 7. Wang ZH, Yan C, Zhang ZY, et al. Impact of salivary gland dosimetry on post-IMRT recovery of saliva output and xerostomia grade for headand-neck cancer patients treated with or without contralateral subman dibular gland sparing: a longitudinal study. Int J Radiat Oncol Biol Phys 20 ti; 8i( 5):i479-i 487. 8. Jabbari S, Kim HM, Feng M, et al. Matched case-control study of quality of life and xerostomia after intensity-modulated radiotherapy or standard radiotherapy for head-and-neck cancer: initial report. Int J Radiat Oncol Biol Phys 2005;63(3):725-73i. 9. Parliament MB, Scrimger RA, Anderson SG, et al. Preservation of oral health-related quality of life and salivary flow rates after inverseplanned intensity-modulated radiotherapy (IMRT) for head-and-neck cancer. Int J Radiat Oncol Biol Phys 2004;58(3):663-673. to. Kasaba T, Onizuka S, Takasaki M. Procaine and mepivacaine have less toxicity in vitro than other clinically used local anesthetics. Anesth Analg 2003;97(i):85-90. 11. Franzen L, Funegard U, Ericson T, Henriksson R. Parotid gland function during and following radiotherapy of malignancies in the head and neck: a consecutive study of salivary flow and patient discomfort. Eur J Cancer i992;28(2-3):457-462. 12. Eisbruch A, Ten Haken RK, Kim HM, Marsh LH, Ship JA. Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer. Int J Radiat Oncol Biol Phys i999;45(3):577-587. 13. Kostler W[, Hejna M, Wenzel C, Zielinski CC. Oral mucositis com plicating chemotherapy and/or radiotherapy: options for prevention and treatment. CA Cancer J Clin 2oot;5i(5):290-3i5. 14. Wang B, Danjo A, Kajiya H, Okabe K, Kido MA. Oral epithelial cells are activated via TRP channels. J Dent Res 20ii;9o(2):i63-i67. 15. Ferrer-Montiel A, Fernandez-Carvajal A, Planells-Cases R, et al. Advances in modulating thermosensory TRP channels. Expert Opin Ther Pat 20i2;22(9):999-tot7. 16. Venkatachalam K, Montell'C. TRP channels. Annu Rev Biochem 2007;76:387-417. 17. Jaaskelainen SK. Pathophysiology of primary burning mouth syn drome. Clin Neurophysiol 20i2;i23(i):7i-77. 18. Lauria G, Majorana A, Borgna M, et al. Trigeminal small-fiber senso ry neuropathy causes burning mouth syndrome. Pain 2005;ii5(3):332-337. 19. O’Neill J, Brock C, Olesen AE, Andresen T, Nilsson M, Dickenson AH. Unravelling the mystery of capsaicin: a tool to understand and treat pain. Pharmacol Rev 20i2;64(4):939-97t. 20. Silvestre FJ, Silvestre-Rangil J, Tamarit-Santafe C, Bautista D. Appli cation of a capsaicin rinse in the treatment of burning mouth syndrome. Med Oral Patol Oral Cir Bucal 20i2;i7(i):ei-e4. 21. American Dental Association. ADA Dental Product Guide: product category—dry mouth products, dentist dispensed, www.ada.org/en/ publications/ada-dental-product-guide/product-category?catid=i39. Ac cessed July 23, 2014.
JADA 145(9)
http ://ja d a .a d a .o rg
Septem ber 2014
965
Copyright of Journal of the American Dental Association (JADA) is the property of American Dental Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
