Melatonin Treatment in Patients with Burning Mouth Syndrome: A Triple-Blind, Placebo-Controlled, Crossover Randomized Clinical Trial

Aims: To evaluate the efficacy of melatonin compared to placebo in reducing pain associated with burning mouth syndrome (BMS), as well as side effects of treatment and effects on sleep quality, anxiety, and serum and salivary melatonin levels. Methods: In this triple-blind, randomized clinical trial, 20 BMS patients (mean age ± standard deviation: 64.4 ± 11.5 years; range: 35 to 82 years) were enrolled to receive melatonin (12 mg/day) or placebo for 8 weeks in a crossover design. After treatment, changes in pain from baseline were ascertained by patient self-assessment with a verbal category scale and a visual analog scale. Secondary outcomes included evaluation of changes in sleep quality and anxiety. Data were subjected to analysis of variance (ANOVA), Fisher exact test, paired t test, Wilcoxon signed rank test, or chi-square test, as appropriate. Results: Melatonin was not superior to placebo in reducing pain. Melatonin significantly improved anxiety scores, though without strong clinical relevance. Independent of treatment, sleep quality did not significantly change during the trial, although melatonin slightly increased the number of hours slept. After active treatment, the mean ± standard error serum melatonin level peaked at 1,520 ± 646 pg/mL. A generally safe pharmacologic profile of melatonin was observed, and the placebo and melatonin treatments resulted in similar adverse effects. Conclusion: Within the limitations of this study, melatonin did not exhibit higher efficacy than placebo in relieving pain in BMS patients.

anxiety;indoleamine;orofacial pain;sleep;stomatodynia

1.International Headache Society. Burning mouth syndrome [code to specify aetiology] 13.8.5 G44.847. http://www. ihs-klassifikation.de/en/02_klassifikation/04_teil3/13.18.05_ facialpain.html. Accessed 31 January 2018.

2.Lopez-Jornet P, Molino Pagan D, Andujar Mateos P, Rodriguez Agudo C, Pons-Fuster A. Circadian rhythms vari-ation of pain in burning mouth syndrome. Geriatr Gerontol Int 2015;15:490–495.

3.López-Jornet P, Camacho-Alonso F, Lucero-Berdugo M. Quality of life in patients with burning mouth syndrome. J Oral Pathol Med 2008;37:389–394.

4.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.

5.Galli F, Lodi G, Sardella A, Vegni E. Role of psychologi-cal factors in burning mouth syndrome: A systematic review and meta-analysis. Cephalalgia 2017;37:265–277.

6.Marino R, Picci RL, Ferro G, Carezana C, Gandolfo S, Pentenero M. Peculiar alexithymic traits in burning mouth syndrome: Case-control study. Clin Oral Investig 2015;19:1799–1805.

7.Eliav E. Altered structure and function in hippocampus and medial frontal cortex in patients with burning mouth syndrome. Pain 2014;155:1424–1425.

8.Imura H, Shimada M, Yamazaki Y, Sugimoto K. Characteristic changes of saliva and taste in burning mouth syndrome pa-tients. J Oral Pathol Med 2016;45:231–236.

9.Amenábar JM, Pawlowski J, Hilgert JB, et al. Anxiety and sal-ivary cortisol levels in patients with burning mouth syndrome: Case-control study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:460–465.

10.Simcic´ D, Pezelj-Ribaric´ S, Grzic´ R, Horvat J, Brumini G, Muhvic´-Urek M. Detection of salivary interleukin 2 and inter-leukin 6 in patients with burning mouth syndrome. Mediators Inflamm 2006;2006:54632.

11.Lopez-Jornet P, Lucero-Berdugo M, Castillo-Felipe C, Zamora Lavella C, Ferrandez-Pujante A, Pons-Fuster A. Assessment of self-reported sleep disturbance and psychological status in patients with burning mouth syndrome. J Eur Acad Dermatol Venereol 2015;29:1285–1290.

12.Adamo D, Schiavone V, Aria M, et al. Sleep disturbance in pa-tients with burning mouth syndrome: A case-control study. J Orofac Pain 2013;27:304–313.

13.Chainani-Wu N, Madden E, Silverman S Jr. A case-control study of burning mouth syndrome and sleep dysfunction. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;112:203–208.

14.Lee CF, Lin KY, Lin MC, Lin CL, Chang SN, Kao CH. Sleep disorders increase the risk of burning mouth syndrome: A ret-rospective population-based cohort study. Sleep Med 2014; 15:1405–1410.

15.Almoznino G, Benoliel R, Sharav Y, Haviv Y. Sleep disorders and chronic craniofacial pain: Characteristics and manage-ment possibilities. Sleep Med Rev 2017;33:39–50.

16.Kisely S, Forbes M, Sawyer E, Black E, Lalloo R. A systematic review of randomized trials for the treatment of burning mouth syndrome. J Psychosom Res 2016;86:39–46.

17.McMillan R, Forssell H, Buchanan JA, Glenny AM, Weldon JC, Zakrzewska JM. Interventions for treating burning mouth syn-drome. Cochrane Database Syst Rev 2016;11:CD002779.

18.Sardella A, Lodi G, Tarozzi M, Varoni E, Franchini R, Carrassi A. Acupuncture and burning mouth syndrome: A pilot study. Pain Pract 2013;13:627–632.

19.Sardella A, Demarosi F, Barbieri C, Lodi G. An up-to-date view on persistent idiopathic facial pain. Minerva Stomatol 2009;58:289–299.

20.Cui Y, Xu H, Chen FM, et al. Efficacy evaluation of clonaze-pam for symptom remission in burning mouth syndrome: A meta-analysis. Oral Dis 2016;22:503–511.

21.Gremeau-Richard C, Woda A, Navez ML, et al. Topical clonaz-epam in stomatodynia: A randomised placebo-controlled study. Pain 2004;108:51–57.

22.Danilov A, Kurganova J. Melatonin in chronic pain syndromes. Pain Ther 2016;5:1–17.

23.Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev 2002;(2): CD001520.

24.Lewy AJ, Ahmed S, Jackson JM, Sack RL. Melatonin shifts hu-man circadian rhythms according to a phase-response curve. Chronobiol Int 1992;9:380–392.

25.Cassone VM. Effects of melatonin on vertebrate circadian sys-tems. Trends Neurosci 1990;13:457–464.

26.Boeve BF, Silber MH, Ferman TJ. Melatonin for treatment of REM sleep behavior disorder in neurologic disorders: Results in 14 patients. Sleep Med 2003;4:281–284.

27.Carpentieri A, Díaz de Barboza G, Areco V, Peralta López M, Tolosa de Talamoni N. New perspectives in melatonin uses. Pharmacol Res 2012;65:437–444.

28.Reiter RJ, Rosales-Corral SA, Liu XY, Acuna-Castroviejo D, Escames G, Tan DX. Melatonin in the oral cavity: Physiological and pathological implications. J Periodontal Res 2015;50:9–17.

29.Trotti LM, Karroum EG. Melatonin for sleep disorders in pa-tients with neurodegenerative diseases. Curr Neurol Neurosci Rep 2016;16:63.

30.Adamczyk-Sowa M, Pierzchala K, Sowa P, et al. Melatonin acts as antioxidant and improves sleep in MS patients. Neurochem Res 2014;39:1585–1593.

31.Jehan S, Masters-Isarilov A, Salifu I, et al. Sleep disorders in post-menopausal women. J Sleep Disord Ther 2015;4. pii:1000212.

32.de Zanette SA, Vercelino R, Laste G, et al. Melatonin anal-gesia is associated with improvement of the descending en-dogenous pain-modulating system in fibromyalgia: A phase II, randomized, double-dummy, controlled trial. BMC Pharmacol Toxicol 2014;15:40.

33.Vidor LP, Torres IL, Custódio de Souza IC, Fregni F, Caumo W. Analgesic and sedative effects of melatonin in temporoman-dibular disorders: A double-blind, randomized, parallel-group, placebo-controlled study. J Pain Symptom Manage 2013; 46:422–432.

34.Zurowski D, Nowak L, Machowska A, Wordliczek J, Thor PJ. Exogenous melatonin abolishes mechanical allodynia but not thermal hyperalgesia in neuropathic pain. The role of the opioid system and benzodiazepine-gabaergic mechanism. J Physiol Pharmacol 2012;63:641–647.

35.International Headache Society. IHS Classification ICHD-3 Beta. 13.11 Burning Mouth Syndrome (BMS). https://www. ichd-3.org/13-painful-cranial-neuropathies-and-other-facial-pains/13-11-persistent-idiopathic-facial-pain-pifp/. Accessed 2 January 2018.

36.Varoni EM, Federighi V, Decani S, Carrassi A, Lodi G, Sardella A. The effect of clinical setting on the unstimulated salivary flow rate. Arch Oral Biol 2016;69:7–12.

37.Rozen TD. How effective is melatonin as a preventive treat-ment for hemicrania continua? A clinic-based study. Headache 2015;55:430–436.

38.Brigo F, Igwe SC. Melatonin as add-on treatment for epilepsy. Cochrane Database Syst Rev 2016;3:CD006967.

39.Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM. Clinical importance of changes in chronic pain intensity measured on an 11- point numerical pain rating scale. Pain 2001;94:149–158.

40.Collins SL, Moore RA, McQuay HJ. The visual analogue pain intensity scale: What is moderate pain in millimetres? Pain 1997;72:95–97.

41.Sardella A, Lodi G, Demarosi F, Tarozzi M, Canegallo L, Carrassi A. Hypericum perforatum extract in burning mouth syndrome: A randomized placebo-controlled study. J Oral Pathol Med 2008;37:395–401.

42.Matza LS, Morlock R, Sexton C, Malley K, Feltner D. Identifying HAM-A cutoffs for mild, moderate, and severe generalized anx-iety disorder. Int J Methods Psychiatr Res 2010;19:223–232.

43.The Epworth Sleepiness Scale. About the ESS. http://epworthsleepinessscale.com/about-the-ess/. Accessed 2 January 2018.

44.Varoni EM, Vitalini S, Contino D, et al. Effects of red wine in-take on human salivary antiradical capacity and total polyphe-nol content. Food Chem Toxicol 2013;58:289–294.

45.Grémeau-Richard C, Dubray C, Aublet-Cuvelier B, Ughetto S, Woda A. Effect of lingual nerve block on burning mouth syndrome (stomatodynia): A randomized crossover trial. Pain 2010;149:27–32.

46.Cavalcanti DR, da Silveira FR. Alpha lipoic acid in burning mouth syndrome—A randomized double-blind placebo-controlled tri-al. J Oral Pathol Med 2009;38:254–261.

47.Silvestre FJ, Silvestre-Rangil J, Tamarit-Santafé C, Bautista D. Application of a capsaicin rinse in the treatment of burning mouth syndrome. Med Oral Patol Oral Cir Bucal 2012;17:e1–e4.

48.Gupta SK. Intention-to-treat concept: A review. Perspect Clin Res 2011;2:109–112.

49.White IR, Carpenter J, Horton NJ. Including all individuals is not enough: Lessons for intention-to-treat analysis. Clin Trials 2012;9:396–407.

50.Joshi N, Biswas J, Nath C, Singh S. Promising role of mela-tonin as neuroprotectant in neurodegenerative pathology. Mol Neurobiol 2015;52:330–340.

51.Mauriz JL, Collado PS, Veneroso C, Reiter RJ, González-Gallego J. A review of the molecular aspects of melatonin’s anti-inflammatory actions: Recent insights and new perspec-tives. J Pineal Res 2013;54:1–14.

52.Iriti M, Varoni EM. Melatonin in Mediterranean diet, a new per-spective. J Sci Food Agric 2015;95:2355–2359.

53.Kuten-Shorrer M, Kelley JM, Sonis ST, Treister NS. Placebo effect in burning mouth syndrome: A systematic review. Oral Dis 2014;20:e1–e6.

54.Scholtens RM, van Munster BC, van Kempen MF, de Rooij SE. Physiological melatonin levels in healthy older people: A sys-tematic review. J Psychosom Res 2016;86:20–27.

55.Hays RD, Martin SA, Sesti AM, Spritzer KL. Psychometric properties of the Medical Outcomes Study Sleep measure. Sleep Med 2005;6:41–44.

56.Hansen MV, Halladin NL, Rosenberg J, Gögenur I, Møller AM. Melatonin for pre- and postoperative anxiety in adults. Cochrane Database Syst Rev 2015;(4):CD009861.

57.Clark GT. Nocebo-responsive patients and topical pain con-trol agents used for orofacial and mucosal pain. In: Clark GT, Dionne R (eds). Orofacial Pain: A Guide to Medications and Management. Chichester: Wiley-Blackwell, 2012:84–94.

58.Varoni EM, Lodi G, Sardella A. The nocebo effect might affect treatment expectations in patients with burning mouth syn-drome. Pain 2015;156:356.

59.Mills EJ, Chan AW, Wu P, Vail A, Guyatt GH, Altman DG. Design, analysis, and presentation of crossover trials. Trials 2009;10:27.