The Detection of Small-Fiber Neuropathies in Burning Mouth Syndrome and Iatrogenic Lingual Nerve Injuries: Use of Quantitative Sensory Testing

Aims: To assess thermal pain perception in patients with burning mouth syndrome (BMS) and lingual nerve injury (LNI) by using a quantitative sensory testing (QST) protocol. Methods: QST was used to assess cool, warm, cold pain, and heat pain thresholds in healthy control subjects (n = 17) and in patients with BMS (n = 22) and LNI (n = 47). Capsaicin (10 μg/mL) and ethyl chloride–evoked hypersensitivities at the anterior two-thirds of the tongue were measured using a visual analog scale. Data were analyzed using Microsoft Excel with descriptive statistics, scatter graphs, and two-tailed Student t tests with 95% confidence interval and 5% level of significance. Results: Patients with BMS significantly reported the most pain at rest (P < .001) and capsaicin hypersensitivity (P < .01). Despite this increased sensitivity to capsaicin and significantly lower warm threshold than the control subjects (P < .05), these patients did not show heat pain hyperalgesia. There was increased sensitivity to ethyl chloride and cold pain hyperalgesia in patients with BMS (P < .05) compared with reduced or no sensation of cold or heat pain in patients with LNI. Conclusions: This study has demonstrated that the assessment of capsaicin and ethyl chloride–evoked sensitivities as well as the use of QST to assess thermosensitivity are useful approaches for detecting hyperalgesia or hypoalgesia to heat and cold in patients with BMS and LNI.

burning mouth syndrome; hyperalgesia; hypoalgesia; lingual nerve injury; quantitative sensory testing

1. Renton T. An update on pain. Br Dent J 2008;204:335–338.

2. Baron R, Binder A, Wasner G. Neuropathic pain: Diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol 2010;9:807–819.

3. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: Risk factors and prevention. Lancet 2006;367:1618–1625.

4. Zakrzewska JM. Multi-dimensionality of chronic pain of the oral cavity and face. J Headache Pain 2013;14:37.

5. Coculescu EC, Tovaru S, Coculescu BI. Epidemiological and etiological aspects of burning mouth syndrome. J Med Life 2014;7: 305–309.

6. Jääskeläinen SK. Pathophysiology of primary burning mouth syndrome. Clin Neurophysiol 2012;123:71–77.

7. Robinson PP, Boissonade FM, Loescher AR, et al. Peripheral mechanisms for the initiation of pain following trigeminal nerve injury. J Orofac Pain 2004;18:287–292.

8. Gordon DB, Love G. Pharmacologic management of neuropathic pain. Pain Manag Nurs 2004;5:19–33.

9. Granot M, Nagler RM. Association between regional idiopathic neuropathy and salivary involvement as the possible mechanism for oral sensory complaints. J Pain 2005;6:581–587.

10. Miles TS, Nauntofte B, Svensson P. Clinical Oral Physiology. Copenhagen: Quintessence, 2004.

11. Baad-Hansen L, Jensen TS, Svensson P. A human model of intraoral pain and heat hyperalgesia. J Orofac Pain 2003;17: 333–340.

12. Scala A, Checchi L, Montevecchi M, Marini I, Giamberardino MA. Update on burning mouth syndrome: Overview and patient management. Crit Rev Oral Biol Med 2003;14:275–291.

13. Lund J, Lavigne GJ, Dubner R, Sessle B. Orofacial Pain: From Basic Science to Clinical Management: The Transfer of Knowledge in Pain Research to Education. Chicago: Quintessence, 2001.

14. Maltsman-Tseikhin A, Moricca P, Niv D. Burning mouth syndrome: Will better understanding yield better management?Pain Pract 2007;7:151–162.

15. Sun A, Wu KM, Wang YP, Lin HP, Chen HM, Chiang CP. Burning mouth syndrome: A review and update. J Oral Pathol Med 2013;42:649–655.

16. Riley JL 3rd, Gilbert GH, Heft MW. Orofacial pain symptom prevalence: Selective sex differences in the elderly? Pain 1998; 76:97–104.

17. Bergdahl M, Bergdahl J. Burning mouth syndrome: Prevalence and associated factors. J Oral Pathol Med 1999;28:350–354.

18. Tammiala-Salonen T, Hiidenkari T, Parvinen T. Burning mouth in a Finnish adult population. Community Dent Oral Epidemiol 1993; 21:67–71.

19. Grushka M, Sessle BJ, Howley TP. Psychophysical assessment of tactile, pain and thermal sensory functions in burning mouth syndrome. Pain 1987;28:169–184.

20. Grushka M. Clinical features of burning mouth syndrome. Oral Surg Oral Med Oral Pathol 1987;63:30–36.

21. Lauria G, Majorana A, Borgna M, et al. Trigeminal small-fiber sensory neuropathy causes burning mouth syndrome. Pain 2005; 115:332–337.

22. Grushka M, Sessle BJ. Burning mouth syndrome. Dent Clin North Am 1991;35:171–184.

23. Dworkin SF, Burgess JA. Orofacial pain of psychogenic origin: Current concepts and classification. J Am Dent Assoc 1987; 115:565–571.

24. Zegarelli DJ. Burning mouth: An analysis of 57 patients. Oral Surg Oral Med Oral Pathol 1984;58:34–38.

25. Hagelberg N, Forssell H, Rinne JO, et al. Striatal dopamine D1 and D2 receptors in burning mouth syndrome. Pain 2003; 101:149–154.

26. Heckmann SM, Heckmann JG, HiIz MJ, et al. Oral mucosal blood flow in patients with burning mouth syndrome. Pain 2001;90:281–286.

27. Forssell H, Jääskeläinen S, Tenovuo O, Hinkka S. Sensory dysfunction in burning mouth syndrome. Pain 2002;99:41–47.

28. Yilmaz Z, Renton T, Yiangou Y, et al. Burning mouth syndrome as a trigeminal small fibre neuropathy: Increased heat and capsaicin receptor TRPV1 in nerve fibres correlates with pain score. J Clin Neurosci 2007;14:864–871.

29. Renton T, Yilmaz Z. Profiling of patients presenting with posttraumatic neuropathy of the trigeminal nerve. J Orofac Pain 2011;25:333–344.

30. Yeler H, Ozeç I, Kiliç E. Infection-related inferior alveolar and mental nerve paresthesia: Case reports. Quintessence Int 2004;35:313–316.

31. Pogrel MA, Lee JS, Muff DF. Coronectomy: A technique to protect the inferior alveolar nerve. J Oral Maxillofac Surg 2004; 62:1447–1452.

32. Scolozzi P, Lombardi T, Jaques B. Successful inferior alveolar nerve decompression for dysesthesia following endodontic treatment: Report of 4 cases treated by mandibular sagittal osteotomy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004;97:625–631.

33. Renton T, Thexton A, Hankins M, McGurk M. Quantitative thermosensory testing of the lingual and inferior alveolar nerves in health and after iatrogenic injury. Br J Oral Maxillofac Surg 2003;41:36–42.

34. Graff-Radford SB, Evans RW. Lingual nerve injury. Headache 2003;43:975–983.

35. Loescher AR, Smith KG, Robinson PP. Nerve damage and third molar removal. Dent Update 2003;30:375–380, 382.

36. Robinson PP, Smith KG. Lingual nerve damage during lower third molar removal: A comparison of two surgical methods. Br Dent J 1996;180:456–461.

37. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, ed 3 (beta version). Cephalalgia 2013;33: 629–808.

38. Zakrzewska JM, Forssell H, Glenny AM. Interventions for the treatment of burning mouth syndrome. Cochrane Database Syst Rev 2005:CD002779.

39. Charleston L 4th. Burning mouth syndrome: A review of recent literature. Curr Pain Headache Rep 2013;17:336.

40. Zakrzewska JM. Differential diagnosis of facial pain and guidelines for management. Br J Anaesth 2013;111:95–104.

41. Krumova EK, Geber C, Westermann A, Maier C. Neuropathic pain: Is quantitative sensory testing helpful? Curr Diab Rep 2012; 12:393–402.

42. Rolke R, Baron R, Maier C, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Standardized protocol and reference values. Pain 2006;123: 231–243.

43. Maier C, Baron R, Tolle TR, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. Pain 2010;150:439–450.

44. Jääskeläinen SK, Teerijoki-Oksa T, Forssell H. Neurophysiologic and quantitative sensory testing in the diagnosis of trigeminal neuropathy and neuropathic pain. Pain 2005;117:349–357.

45. Matos R, Wang K, Jensen JD, et al. Quantitative sensory testing in the trigeminal region: Site and gender differences. J Orofac Pain 2011;25:161–169.

46. de Siqueira SR, Teixeira MJ, de Siqueira JT. Orofacial pain and sensory characteristics of chronic patients compared with controls. Oral Surg Oral Med Oral Pathol Oral Radiol 2013; 115:e37–e45.

47. Di Stefano G, La Cesa S, Biasiotta A, et al. Laboratory tools for assessing neuropathic pain. Neurol Sci 2012;33(suppl 1): S5–S7.

48. Haanpaa M, Attal N, Backonja M, et al. NeuPSIG guidelines on neuropathic pain assessment. Pain 2011;152:14–27.

49. Backonja MM, Attal N, Baron R, et al. Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus. Pain 2013;154:1807–1819.

50. Cruccu G, Sommer C, Anand P, et al. EFNS guidelines on neuropathic pain assessment: Revised 2009. Eur J Neurol 2010; 17:1010–1018.

51. Chéliout-Héraut F, Zrek N, Khemliche H, et al. Exploration of small fibers for testing diabetic neuropathies. Joint Bone Spine 2005;72:412–415.

52. Siao P, Cros DP. Quantitative sensory testing. Phys Med Rehabil Clin N Am 2003;14:261–286.

53. McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 2002;416:52–58.

54. Rashid MH, Inoue M, Kondo S, Kawashima T, Bakoshi S, Ueda

H. Novel expression of vanilloid receptor 1 on capsaicin-insensitive fibers accounts for the analgesic effect of capsaicin cream in neuropathic pain. J Pharmacol Exp Ther 2003; 304:940–948.

55. Boivie J. Central pain and the role of quantitative sensory testing (QST) in research and diagnosis. Eur J Pain 2003;7:339–343.

56. Hilz MJ, Stemper B, Axelrod FB, Kolodny EH, Neundörfer

B. Quantitative thermal perception testing in adults. J Clin Neurophysiol 1999;16:462–471.

57. Gracely RH, Lynch SA, Bennett GJ. Painful neuropathy: Altered central processing maintained dynamically by peripheral input. Pain 1992;51:175–194.

58. Vinik AI, Suwanwalaikorn S, Stansberry KB, Holland MT, McNitt PM, Colen LE. Quantitative measurement of cutaneous perception in diabetic neuropathy. Muscle Nerve 1995;18: 574–584.

59. Bansal V, Kalita J, Misra UK. Diabetic neuropathy. Postgrad Med J 2006;82:95–100.

60. Sorensen L, Molyneaux L, Yue DK. The level of small nerve fiber dysfunction does not predict pain in diabetic neuropathy: A study using quantitative sensory testing. Clin J Pain 2006; 22:261–265.

61. Krishnan AV, Kiernan MC. Altered nerve excitability properties in established diabetic neuropathy. Brain 2005;128:1178–1187.

62. Morin C, Bushnell MC, Luskin MB, Craig AD. Disruption of thermal perception in a multiple sclerosis patient with central pain. Clin J Pain 2002;18:191–195.

63. Martin C, Solders G, Sönnerborg A, Hansson P. Painful and non-painful neuropathy in HIV-infected patients: An analysis of somatosensory nerve function. Eur J Pain 2003;7:23–31.

64. Svensson P, Bjerring P, Arendt-Nielsen L, Kaaber S. Sensory and pain thresholds to orofacial argon laser stimulation in patients with chronic burning mouth syndrome. Clin J Pain 1993; 9:207–215.

65. Rolke R, Magerl W, Campbell KA, et al. Quantitative sensory testing: A comprehensive protocol for clinical trials. Eur J Pain 2006;10:77–88.

66. Hansson P, Backonja M, Bouhassira D. Usefulness and limitations of quantitative sensory testing: Clinical and research application in neuropathic pain states. Pain 2007;129:256–259.

67. Mo X, Zhang J, Fan Y, Svensson P, Wang K. Thermal and mechanical quantitative sensory testing in Chinese patients with burning mouth syndrome—A probable neuropathic pain condition? J Headache Pain 2015;16:84.

68. Grushka M, Sessle BJ, Miller R. Pain and personality profiles in burning mouth syndrome. Pain 1987;28:155–167.

69. Albuquerque RJ, de Leeuw R, Carlson CR, Okeson JP, Miller CS, Andersen AH. Cerebral activation during thermal stimulation of patients who have burning mouth disorder: An fMRI study. Pain 2006;122:223–234.

70. Holland GR. Experimental trigeminal nerve injury. Crit Rev Oral Biol Med 1996;7:237–258.

71. Cao Y, Wang H, Chiang CY, Dostrovsky JO, Sessle BJ. Pregabalin suppresses nociceptive behavior and central sensitization in a rat trigeminal neuropathic pain model. J Pain 2013; 14:193–204.

72. Iwata K, Imamura Y, Honda K, Shinoda M. Physiological mechanisms of neuropathic pain: The orofacial region. Int Rev Neurobiol 2011;97:227–250.

73. Jordt SE, McKemy DD, Julius D. Lessons from peppers and peppermint: The molecular logic of thermosensation. Curr OpinNeurobiol 2003;13:487–492.

74. Caterina MJ, Julius D. The vanilloid receptor: A molecular gateway to the pain pathway. Annu Rev Neurosci 2001;24:487–517.

75. McCleskey EW, Gold MS. Ion channels of nociception. Annu Rev Physiol 1999;61:835–856.

76. Park JJ, Lee J, Kim MA, Back SK, Hong SK, Na HS. Induction of total insensitivity to capsaicin and hypersensitivity to garlic extract in human by decreased expression of TRPV1. Neurosci Lett 2007;411:87–91.

77. Holland GR, Robinson PP, Smith KG, Pehowich E. A quantitative morphological study of the recovery of cat lingual nerves after transection or crushing. J Anat 1996;188:289–297.

78. Grushka M, Bartoshuk L. Burning mouth syndrome and oral dysaesthesias. Canad J Diag 2000;Jun:99–109.

79. Whitehead MC, Frank ME, Hettinger TP, Hou LT, Nah HD. Persistence of taste buds in denervated fungiform papillae. Brain Res 1987;405:192–195.

80. Levine JD, Alessandri-Haber N. TRP channels: Targets for the relief of pain. Biochim Biophys Acta 2007;1772:989–1003.

81. Martos-Fernández M, de-Pablo-Garcia-Cuenca A, Bescós-Atín MS. Lingual nerve injury after third molar removal: Unilateral atrophy of fungiform papillae. J Clin Exp Dent 2014;6: e193–e196.

82. Phan CL, Kashmere JL, Kalra S. Unilateral atrophy of fungiform papillae associated with lingual nerve injury. Can J Neurol Sci 2006;33:428–429.

83. Abe J, Hosokawa H, Okazawa M, et al. TRPM8 protein localization in trigeminal ganglion and taste papillae. Brain Res Mol Brain Res 2005;136:91–98.

84. Nassini R, Materazzi S, Benemei S, Geppetti P. The TRPA1 channel in inflammatory and neuropathic pain and migraine. RevPhysiol Pharmacol 2014;167:1–43.

85. Avivi-Arber L, Martin R, Lee JC, Sessle BJ. Face sensorimotor cortex and its neuroplasticity related to orofacial sensorimotor functions. Arch Oral Biol 2011;56:1440–1465.

86. Ren K, Dubner R. The role of trigeminal interpolaris-caudalis transition zone in persistent orofacial pain. Int Rev Neurobiol 2011;97:207–225.

87. Van Sickels JE, Zysset M, Nishioka GJ, Thrash WJ. A comparative study of normal sensibility of the inferior alveolar nerve and the infraorbital nerve. Oral Surg Oral Med Oral Pathol 1989; 67:255–257.

88. Green BG, Gelhard B. Perception of temperature on oral and facial skin. Somatosens Res 1987;4:191–200.

89. Green BG. Thermal perception on lingual and labial skin. Percept Psychophys 1984;36:209–220.

90. Harding LM, Loescher AR. Adaptation to warming but not cooling at slow rates of stimulus change in thermal threshold measurements. Somatosens Mot Res 2005;22:45–48.

91. Kelly KG, Cook T, Backonja MM. Pain ratings at the thresholds are necessary for interpretation of quantitative sensory testing. Muscle Nerve 2005;32:179–184.

92. Chen AC, Niddam DM, Arendt-Nielsen L. Contact heat evoked potentials as a valid means to study nociceptive pathways in human subjects. Neurosci Lett 2001;316:79–82.

93. Szallasi A, Cortright DN, Blum CA, Eid SR. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nat Rev Drug Discov 2007;6:357–372.

94. Tominaga M, Caterina MJ. Thermosensation and pain. J Neurobiol 2004;61:3–12.

95. Baumgärtner U, Greffrath W, Treede RD. Contact heat and cold, mechanical, electrical and chemical stimuli to elicit small fiber-evoked potentials: Merits and limitations for basic science and clinical use. Neurophysiol Clin 2012;42:267–280.