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Burning Mouth Syndrome: An evolving neuropathy in women

Burning Mouth Syndrome: An evolving neuropathy in women. Joel Epstein DMD, MSD, FRCD(C), FDS RCS( Edin ), Diplomate American Board Oral Medicine Director, Oral Medicine Service Division of Otolaryngology, Head and Neck Surgery City of Hope National Medical Center Duarte, CA

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Burning Mouth Syndrome: An evolving neuropathy in women

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  1. Burning Mouth Syndrome: An evolving neuropathy in women Joel Epstein DMD, MSD, FRCD(C), FDS RCS(Edin), Diplomate American Board Oral Medicine Director, Oral Medicine Service Division of Otolaryngology, Head and Neck Surgery City of Hope National Medical Center Duarte, CA Division of Dentistry Cedars Sinai Health System Los Angeles, CA

  2. Burning Mouth Syndrome: Definition • burning pain in the tongue or other oral mucous membrane in the absence of mucosal lesions & laboratory abnormalities • prevalence 0.7%-4.6% general population (1.3 million US adults) • Female:Male 7:1 • most common 38-78 yrs • Lipton et al JADA 1993

  3. Characteristics of BMS • Burning, scalded, tingling, numb • Often bilateral • Intensity similar to toothache • Pain often ↑ after waking, may ↑ during the day, does not wake at night • Pain frequently relieved with oral stimulation (chewing, eating)

  4. Burning Mouth Syndrome:Associated Complaints • Xerostomia ~1/2-2/3 of patients • dysguesia ~ 2/3 of patients: altered taste (bitter, metallic or both) or changes in intensity of taste • Local anesthetic application ↑ local burning, ↓dysguesia • Symptoms associated with menopause • Mood, sleep disturbances

  5. Burning Mouth Symptoms: Local Factors • Mucosal lesions • Inflammatory/infectious, erosive or ulcerative lesions: lichen planus, aphthae, mucositis, candidiasis, glossitis • Hyposalivation • Medication induced • Immune disease • Radiotherapy, cancer chemotherapy • Parafunctional habits • Tongue

  6. Burning Mouth SyndromeSystemic Factors • Xerostomia • Anxiety/Depression • Drug related • CT/immune disease • Most studies have not demonstrated ↓ salivary flow rates • Altered salivary content • Alterations in mucin, IgA, phosphates, pH & electrical resistance • May be due to altered sympathetic output from stress or altered interactions between CN serving taste and pain sensations

  7. Burning Mouth Symptoms:Systemic Factors • Hematologic: Anemia • Deficiency: Fe, B12, Folate, Vitamin D • Endocrine Disorders • Diabetes mellitus (type II non-insulin dependent) • neuropathy & angiopathy • Hypothyroidism • Dysgeusia & elevated taste thresholds to bitter • Menopause or hormonal • ~ 90% of females are peri-postmenopausal • Onset from 3 years before -12 years after menopause • Little evidence supporting HRT • GI: Acid reflux (GERD)

  8. Burning Mouth SyndromeSystemic Factors • Medications • Hyposalivation; damage to taste • ACE inhibitors (captopril, enalapril, lisinopril) • BMS has remitted following discontinuation • Loss of taste sensation has been reported with ACE inhibitors • Crit Rev Oral Biol Med 2004 15 (4) 221-239 (Table 5 p.225) • Neuropathy: cancer chemotherapy & targeted therapies; cancer survivorship

  9. BMS: Psychological factors* • Psychogenic • Depression and anxiety • Obsessive compulsive disorder • Somatoform disorder • Cancerphobia • Psychosocial stressors • *May be cause or effect

  10. Burning Mouth SyndromeHypothetical Model • BMS follows damage to taste • Taste phantoms (taste sensations in the absence of stimulation) are associated with damage to taste • Damage to taste can cause BMS: • nutritional factors, organic changes, oral infections, decreased estrogen, allergic reactions, traumatic or viral injury or common local injuries

  11. Burning Mouth Syndrome Hypothetical Model - Mechanism • Taste loss in chorda tympani (CN VII) or glossopharyngeal nerve (CN IX) ↓central inhibition of trigeminal nerve (CN V) result in sensory burning and taste phantoms • Taste is a primitive sensation, with redundancy resulting in limited awareness of loss or altered taste

  12. Burning Mouth SyndromeHypothetical Model: Menopauase • Females are more likely to be supertasters • Bitter taste is under hormonal control • Reduced following menopause • Reduction in bitter taste acts like taste damage • ↓ taste input to the CNS • ↓ inhibition of CN V • ↑ intensity of oral burning in supertasters

  13. Chorda tympani dysfunction in BMS • 48 pts; 22 BMS (61 yrs, 16 ♀, 6♂); 14 2YBMS, 12 controls • quantitative sensory testing: electrogustatory & detection/tingling thresholds in the anterior tongue • 82% BMS patients chorda tympani dysfunction (13 bilateral & 5 bilateral) ↑ mean detection thresholds (p<.001); unilateral stimulation caused bilateral burning in 13/22 BMS pts • Supporting one model of BMS: central sensitization or taste disinhibition of V • Eliav E. JADA 2007;138:628-33.

  14. Burning Mouth Syndrome Laboratory Studies • CBC/differential • Fe, TIBC, serum ferritin, folate, B12 • FBG/HgB A1C • Thyroid: TSH, T3, T4ESR, Estradiol, FHS, LH • Immune: ANA, RF, anti-SSA + anti- SSB • Salivary flow rates (by weight) • Unstimulated: 0.3-0.4 mg/min • Stimulated: 0.75-2.0 mg/min • Fungal culture • Gastric reflux studies

  15. Management of Neuropathic Pain: Evidence-Based recommendations • Step 1: Assess & Diagnose • assess pain, diagnose NP & etiology (refer); DX & TX comorbities; explain to pt & realistic expectations • Step 2: Medications • secondary amine TCA (nortriptyline, desipramine) or SNRI (duloxetine, venlafaxine) • Ca channel α2-δligand (gabapentin, pregabalin) • Combined with analgesics (Tramadol, opioid); topical tx • Step 3: Assess: • Pain < 3/10, tolerable SE, continue • Pain > 4/10, after adequate trial, +other first line meds • No/inadequate relief after adequate trial, switch med • Step 4: Refer pain specialist/pain center Dworkin RH et al. Pain 2007;132:237-51 • Dworkin RH et al. Pain 2007;132:237-51

  16. Clonazepam in BMS -30 pts,(29F); pretx pain 7.0+1.9 VAS x 1month-12 yrs (median 2.5 yrs): -0.25 mg up to 3.0 mg/d, mean dose 1.1 mg+0.65mg -pain ↓ 70%; partial-complete relief 43%; effective but SE 27%; no benefit 30% Grushka M, Epstein J, Mott A. Oral Surg Oral Med 1998;86:557-61 -Retrospective review 194 patients: clonazepam: 37 or diazepam: 157 -Full or partial response: clonazepam 71%, no effect 29% -Full or partial response: diazepam 55%, no effect 45% Barker KE, Batstone MD, Savage NW. Aust Dent J 2009;54:300-4

  17. Clonazepam and BMS • 66 pts, topical placebo v clonazepam, VAS F/U 6 mos 70% (22/33) on clon >50%; ↓ 6% (2/33) in placebo no difference in complete resolution • Rodriguez de Rivera CE, Lopez LJ, Chimenos KE. Bull Group IntRechStomatolOdontol 2010;49:19-29 • 20 pts randomized clonazepam/placebo No difference between groups in mood/depression, taste & saliva flow Pain ↓ with clonazepam (p=.001) • Heckmann SM, Kirchner E, Grushka M et al. Laryngoscope 2012;122:813-8

  18. Topical and systemic Clonazepam for BMS • 36 pts (27 F); VAS pain • Clonazepam 0.5 mg tid, disolved in H2O rinse & swallow • 1/3 complete resolution; 1 pt no effect • 80% >50% pain ↓; mean pain ↓ 4.7+0.4 VAS • Amos K, Yeoh SC, Farah CS. J Orofac Pain 2011;25:125-30

  19. Gabapentin and BMS • Case report: 67 yo F; adverse effects with nortriptyline, sertraline, & anesthetics, gabapentin↓ pain White TL, Kent PF, Kutz DB, Emko P. Arch Otolaryngol Head Neck Surg 2004;130:766-8 • 4 pts, 900-2,400 mg gabapentin↓ pain 1.2+0.2 (0-3 scale) in 7-21 days Meiss F, Fiedler KM, Tau be W. DermatolPsychosom 2004;5:17-21 • Little effect report in open-label study Heckmann SM, Heckmann JG, Ungethum A et al. Eur J Neurol 2006;13:e6-7

  20. Duloxetine and BMS • Case report: 65 yo F, 3 yr HX BMS • Duloxetine 60 mg pood • Complete remission • Mignogna MD, Adamo D, Schiavone V, et al. Pain Med 2011;12:466-9

  21. SNRI for Neuropathy due to oxaliplatin • Open label 39 pts stage III/IV CRC; 12 wk f/u Duloxitene 30 ↑to 60 mg/day after 1 wk VAS + CTCAE v3.0 23% d/c duloxitene due to AE 30: • 63.3% VAS ↓; 47.4% CTCAE grade ↓ remainder stable grade • Yang Y-H, Lin J-K, Chen W-S. Support Care Cancer 2012;20:1491-7 • Venlafaxine 48 pts, CRC 73%; venlafaxine 37.5mg bid v placebo • Complete pain relief 31.3% v 5.3% placebo (p=0.03) • Durand JP, Duplanque G. Ann Oncol 2012;23:200-5

  22. Duloxetine in CIPN • Phase III CALGB170601: 231 pts, VAS pain >4/10 • Duloxetine 30 mg/d x 1wk, ↑to 60 mg/d x 4 wk; washout x 2 week then crossover to placebo & vice versa • Initial period: • duloxetine 59% any pain ↓ v 38% • pain ↓>30%: 33% v 17% • pain ↓ >50% 21% v 9% • Well tolerated • Smith EL. ASCO AbstCRA9013 June 2012

  23. Topiramate for BMS • 65 yo F, 4 month hx of BMS, carbemezipine no effect, gabapentin D/C SE, topiramate complete remission • Effect: block sodium & calcium channels, ↑ GABA concentration, ↓glutamate function • Siniscalchi A, Gallelli L, Marigliano NM et al. Pain Med 2007;8:531-4

  24. Combination Therapy for BMS • Alpha lipoic acid (ALA) & gabapentin double blind controlled trial: • 4 groups: A n=20: ALA 600 /d; Group B (n=20) 300 Gaba/d; group C (n=20) ALA & Gaba; Group D (n=60) placebo • All 120 completed tx; 70% in GABA ALA group ↓ with 13.2 x probability than placebo • Lopez-D’alessandro E, Escovich. Med Oral Patol Oral Cir cucal 2011;16:e635-40.

  25. Alpha-lipoic Acid and BMS(1 of2) • Open trial ALA (antioxidant) 4 groups of 20 pts ALA v bethanechol, biotene & placebo; ALA beneficial • Femiano F. Minerva Stomatol 2002;51:405-9 • Dble-blind ALA v placebo, 2 month F/U, 60 pts ↓ oral burning in 70% at 1 year F/U • Femiano F, Scully C J Oral Pathol Med 2002;31:267-9 • Open study 192 pts, ALA 600 mg/d+phsychotx (2 x 1 hr sessions), F/U 2 months, 35% reported ↓ with ALA best ALA+psychotx > psychotx alone (p<0.005) • Femiano F, Gombos F, Scully C. Med oral 2004;9:8-13 • 47 pts, ALA 600 mg/d; 66% completed trial: 19% improved, 16% some ↓; 45% no effect, 13% uncertain Placebo effect comparable to effect of ALA • Steele JC, Bruce AJ, Drage LA, Rogers RS. Oral Dis 2008;14:529-32

  26. Alpha-lipoic Acid and BMS (2 of 2) 66 pts (54 F) 8 wk trial ALA (400mg/d) v. placebo >50% ↓30% in drug/placebo groups; no difference Carbonne M, Pentenero M, Carrozzo M, et al. Eur J Pain 2009;13:492-6 60 pts (54F); 30 ALA 800 mg/d x 8 wks, 30 placebo; 39 (23 ALA, 16 placebo) completed TX F/U 1,2 mos, no statistically significant difference Lopez-Jornet P, Camacho-alonso F, Leon-Espinosa S. J Oral Rehabil 2009;36:52-7 38 pts (34F), ALA/placebo; 31 completed study, crossover with washout 20 days No difference in drug/placebo Cavalcanti DR, daSilveira FR. J Oral Pathol Med 2009;38:254-61

  27. Other Management Approaches for BMS Low level laser therapy: • 11 pts, 6J/Cm2 to site of burning, F/U 6 wks 80.4% ↓ in BMS (p<0.01) Kato IT, Pellegrini VD, Prates RA et al. Photomed Laser Surg 2010;28:835-9 • 10 pts, LLT 1x/wk x 10 wks; 660nm, 20 J/cm2 VAS ↓ 58% by 10thtx (p=0.002) Dos Santos LdeF, Carvalho AA, Leao JC et al. Photo9med laser Surg 2011;29:793-6 • 17 pts Tx: 1.5W/cm2 to site of BMS; mean ↓ 47.6% (9.3-91.8%), unchanged for up to 12 mos • Yang HW, Huang YF. Photomed Laser Surg 2011;29:123-5 • 40 pts, 4 wks LLLT; ↓salivary levels TNFa, IL-6 (p<0.001) • Pezelj-Riaric S, Kqiku L, Brumini G et al. Lasers Med Sci 2012; epub Acupuncture: • 30 pts, 30 controls, 3 wks TX • change in micocirculation on videocapillaroscopy of the tongue observed baseline, 1 and 5 minutes • mean PreTX pain 8/10; end of 3 wk TX: 2/10; benefits at 6 month F/U 3/10 • Scardina GA, Ruggieri A, Provennzano F, Messina P. Br Dent J 2010;209;epub

  28. Tricyclics • Analgesic effect separate from antidepressant effect • Effective analgesic dose lower & earlier in onset than antidepressant effect • Action: norepinephrine/serotonin reuptake; on various signaling systems: ion channels, NMDA receptor, G protein coupled receptors; possible action at delta opioid receptor • Strumper D, Druieux ME. RegAnesth Pain Med 2004;29:277-85 • Benbouzid M, Gaveriaux-Ruff C et al. Biol Psychiatry 2007

  29. Burning Mouth Syndrome • Diagnosis local oral conditions • Mucosal lesions, dry mouth • Diagnose/rule out systemic conditions, acid reflux, diabetes, vitamin/mineral deficiencies • Diagnosis BMS: bilateral, no lesions, no systemic conditions • Improve local conditions: dry mouth • Gum, ice, rinses • Medications: neuropathic pain • Cognitive behavioral therapy • Other: LLLT, acupuncture?

  30. Burning Mouth Syndrome Management • Grushka M, Epstein J, Gorsky M. Burning Mouth Syndrome. Am Fam Phys 2002;65:615-22

  31. Oral burning in Oncology • Mucosal hypersensitivity common following cancer therapy • 2/3 of patients following cancer therapy have persisting oral sensitivity • Risk for neuropathy following cancer therapy: • Direct effects: • Surgery • Radiation therapy • Chemotherapy: taste, neuropathy • Indirect effects: • Hyposalivation, candidiasis, post-viral neuropathy, anemia, nutritional compromise • Pschological factors: anxiety, depression

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