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Jacob S. Minor, MDa,*,Joel B. Epstein, DMD, MSD, FRCD(C), FDS RCS(Ed)b,c KEYWORDS Burning mouth syndrome  Glossodynia  Stomatopyrosis  Neuropathy  Taste change  Xerostomia Burning mouth syndrome (BMS) is an idiopathic condition causing a deep burning painof the oral mucosa, despite an absence of identifiable dental or medical pathology,lasting at least 4 to 6 months.1–7 BMS should be distinguished from secondary oralburning reported by patients with a variety of documented oral mucosal and medicalconditions. BMS was first described by Fox8 in 1935 and has gone by many aliases,including glossodynia, glossopyrosis, oral dysesthesia, sore tongue, stomatodynia,and stomatopyrosis.9 The International Classification of Diseases (ICD-9) uses theterm glossodynia with the descriptors glossopyrosis or painful tongue for code529.6.10 In this article BMS is used to refer to idiopathic oral burning not associatedwith oral mucosal or systemic conditions.
BMS is found in a 7:1 female to male ratio and approximately 90% of sufferers are perimenopausal women.5 In one study of 130 patients, a burning sensation was notedin the tongue in 72%, in the hard palate in 25%, in the lips in 24%, and other sites suchas buccal and labial mucosa, soft palate, and floor of mouth in 36%. Whereas somepatients had burning confined to the tongue only, others had other or multiple sitesof involvement.11 Another study showed similar prevalence of tongue involvement,though with palate and lip involvement in only 5.7% of respondents.12 In many casessymptomatic complaints are bilaterally distributed. Many patients also report The authors have nothing to disclose.
a Department of Otolaryngology, University of Colorado at Denver, 12631 East 17th Avenue,B-205, Denver, CO 80045, USAb Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, University ofIllinois at Chicago, MC 838, 801 South Paulina Street, Chicago, IL 60612, USAc Department of Otolaryngology and Head and Neck Surgery, University of Illinois at Chicago,MC 838, 801 South Paulina Street, Chicago, IL 60612, USA* Corresponding author.
E-mail address: [email protected] Otolaryngol Clin N Am 44 (2011) 205–219doi:10.1016/j.otc.2010.09.008 0030-6665/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved.
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associated symptoms of oral dryness and alteration in taste, such as a metallic bittersensation, as well as worsening with stress, excessive speaking, or hot foods, andimprovement with cold food, work, and relaxation.5,7,13–15 Taste change and oraldryness may be associated with etiology in some cases. In general, BMS does notinterfere with sleep, but may be present on waking or increase later in the day.16 Inthe patients who report xerostomia, measurement of saliva may or may not confirmhyposalivation, suggesting that in some cases the sensation reported of drynessmay be related to altered sensation and not a change in saliva.14 Because of thelack of findings on physical examination, BMS may be a source of frustration for thecaregiver, the patient, and significant others related to the patient.1 This article surveysthe current state of knowledge regarding BMS with the aim of assisting the practitionerin forming a strategy for diagnosis and management of this condition.
Several studies have attempted to assess the prevalence of BMS in various popula-tions. The largest United States study surveyed more than 42,000 households forvarious types of orofacial pain, and estimated a BMS prevalence of 0.7%.17 Thismethod, of course, precluded examination to rule out other pathology and oralburning. A Swedish study in 1999 surveying 669 men and 758 women found a preva-lence of 1.6% among men and 5.5% among women, with increasing prevalence withage up to more than 12% among the oldest women.12 Patients in this study werebrought in for examination if they reported burning mouth symptoms. In that studyno BMS was found in men younger than 40 or in women younger than 30 years. Otherstudies have also confirmed that BMS is predominant in women,6,18,19 especially inthose who are perimenopausal.20 Although there is no confirmed cause of BMS, the general consensus, including that ofthe International Headache Society, is that the condition represents a neuropathyresulting in chronic pain.7,21–23 Evidence in favor of this is seen both on histopathologyand in neurologic testing. Current areas of debate regarding the etiology of BMSinclude its status as primarily a central or peripheral neuropathic phenomenon, andthe role of dysguesia as a primary or secondary event. Also, the nature of associationsbetween BMS, menopause, and psychiatric disease remains unclear. Finally, it isimportant to understand the wide variety of other conditions causing oral burningsymptoms, ensuring that patients diagnosed with BMS are not in fact experiencingburning secondary to a potentially treatable mucosal or systemic condition.
Evidence for BMS as a Peripheral Neuropathy BMS is associated with unique histopathologic findings and alterations of levels ofsalivary neuropeptides. Lauria and colleagues24 evaluated the innervation of theepithelium of the anterolateral tongue in 12 patients with BMS present for at least 6months using 3-mm punch biopsies of the region. In addition, samples were obtainedfrom 9 normal patients as a control. Immunohistochemical and confocal microscopycolocalization studies were performed with cytoplasmatic, cytoskeletal, Schwanncell, and myelin markers for pathologic changes. Of note, BMS patients showeda significantly lower density of epithelial nerve fibers than controls, with a trend towardcorrelation with the duration of symptoms. There was no correlation between densityof fibers and severity of symptoms. Epithelial and subpapillary nerve fibers alsoshowed diffuse morphologic changes reflecting axonal degeneration, demonstrating Author's personal copy
Burning Mouth Syndrome and Secondary Oral Burning that BMS is associated with a small-fiber sensory neuropathy or axonopathy of thetongue and that biopsy can be used to assess the diagnosis. The investigators notethat these findings correlate with histologic findings in burning disorders of the lowerlimbs, and that the nociceptive stimulation of these fibers may be contributory to theaccompanying dysguesia.24 A recent study by Borelli and colleagues25 examined thelevels of salivary neuropeptides in 20 BMS patients and matched controls, and foundsignificantly increased nerve growth factor peptide and tryptase activity in saliva ofBMS subjects. Conversely, levels of substance P were shown to be significantly lowerwhile neutrophil markers were unchanged. The investigators felt these substancesmight be useful biomarkers for diagnosis and monitoring of BMS.
There are alterations in trigeminal nerve function in BMS patients. Two studies by Jaaskelainen and colleagues examined alteration in function of the trigeminal nerveamong BMS patients. Their 1997 article23 reported on 11 patients with BMS for at least1 year and 10 healthy controls. Following a thorough neurologic and laboratory eval-uation to rule out any other contributory factors, the patients underwent electrophys-iologic evaluation of the blink reflex and jaw reflex, and needle electromyographicevaluations of facial and masticatory muscles were performed on those with abnormalblink reflexes. Although all other testing was normal, there was a significant abnor-mality noted in the blink reflexes of patients with BMS, suggestive of trigeminaldysfunction. A follow-up study in 200221 confirmed the findings of abnormal blinkreflexes in 52 BMS patients, and correlated them with quantitative thermal thresholdsin 46 of the patients. Seventy-six percent of patients tested had thermal sensoryabnormalities, the majority of those some variety of hypoesthesia. Less than 10% ofall patients had entirely normal electrophysiological testing of the trigeminal nerve.
Some potential mechanisms include neuropathy due to causes such as injury duringprocedures in the mouth and throat, and viral-induced neuropathy.
Evidence for BMS as a Central Neuropathy Central neuropathic mechanisms are also felt to be involved in BMS. Albuquerque andcolleagues26 demonstrated differences in perception of trigeminal pain between BMSand normal patients on functional magnetic resonance imaging (fMRI) in a 2006 study.
In follow-up to their aforementioned work in trigeminal abnormalities in BMS, Jaaske-lainen and colleagues27 evaluated the nigrostriatal dopaminergic pathway in 10 BMSpatients and 14 controls using modified positron emission tomography (PET). Findingsof decreased uptake in the right putamen indicated decreased dopaminergic inhibitionin BMS patients. Another study by the same group in 2003 found alterations consistentwith a decline in endogenous dopamine levels in the putamen in BMS patients.28 Evidence for BMS as a Phantom Pain The role of dysguesia as a primary or secondary phenomenon in BMS remains a pointof investigation. Whereas some have felt dysguesia is a secondary event arising fromtrigeminal dysfunction,24 others question if loss of taste might be an inciting event,playing a primary role in the etiology of some cases of BMS.29–31 It is hypothesizedthat BMS represents a central oral phantom pain secondary to damage to the gusta-tory system and disinhibition of central nociceptive regions.29,31–34 Other taste phan-toms may also be associated with a similar etiology.35 Other supporting evidence isthat anesthesia of the chorda tympani has been demonstrated to increase the contra-lateral pain response to capsaicin,36 and that overlap exists between brain regionsinvolved in taste and pain perception.37 Supertasters, those with a genetic alterationcausing increased number of fungiform papillae and an ability to taste the bittercompound phenylthiocarbamide,38,39 may be at increased risk.32,33 BMS patients Author's personal copy
may also have a higher likelihood of taking medications interfering with taste.31Evidence that BMS is a form of oral phantom pain is both tantalizing and revealing,given the challenges experienced in treating the most common phantom sensationin otolaryngology, namely, tinnitus. Like tinnitus, BMS has an association with psycho-pathology and central and peripheral factors, as well as limited success with currentmedical therapies and a need for careful counseling of those affected.
Evidence for BMS as Variable Disorder with Subcategories One recent effort to investigate a central versus peripheral origin for BMS wasa double-blind, randomized crossover trial comprising 20 patients with BMS. Thepatients underwent lidocaine and saline injection of the lingual nerve, and althoughthe group overall showed no significant difference in response, central (n 5 7) andperipheral (n 5 13) subgroups were identified. In the peripheral group, there wasa significant decrease in burning with lidocaine injection compared with saline,whereas the central group had a nonsignificant trend toward worse burning with lido-caine. In addition, the peripheral group had a trend toward improved response to clo-nazepam, and had significantly less evidence of concomitant psychiatric issues ona validated survey. The 2 groups identified in this small study should be consideredin the design of future treatment trials.40 Contributions of Psychiatric and Hormonal Disturbances Several studies have investigated relationships between BMS and psychiatricdisease.6,41–49 Indeed, for several years BMS was felt by some to be primarily psycho-logical in origin,24 although studies were unable to demonstrate a link between itsonset and a stressful life event.46 Similar to other chronic pain patients, one groupfound an Axis I diagnosis in more than 50% of BMS patients, with depression predom-inating. Anxiety, when present, had an additional marked impact.43 Another studyassessed Axis II diagnoses in 70 BMS patients compared with a normal populationand a group of patients with somatoform disorders. Whereas only 24% of the normalgroup had a personality disorder, 86% of the BMS patients and 88% of the somato-form patients had an Axis II disorder, although interestingly Cluster A predominatedamong BMS patients whereas somatoform patients had a higher incidence of ClusterB disorders.42 Other potential psychogenic factors may include obsessive-compul-sive disorder, depression, anxiety, and cancerophobia.13 Psychopathology mayalso increase the likelihood of the patient's presentation and worsen the severity ofthe complaint, as is the case in chronic pain in general. So while considerable psychi-atric comorbidity is present among BMS patients, this is felt to be usually a concurrentor secondary factor rather than its primary cause.
Menopause also has a definite but unclear relationship with BMS.6,18,20,22 As mentioned earlier, up to 90% of patients with BMS are perimenopausal women.5 Sug-gested explanations for this finding have included age-related changes, estrogen-related decreased perception of bitter tastes,33 coexistence of depression andanxiety, and subtle mucosal changes. Pisanty and colleagues50 relate the lack ofevidence regarding the effects of estrogens on oral mucosa. Woda and colleagues51recently proposed that at menopause, the drastic decrease in gonadal steroids leadsto altered production of neuroactive steroids, resulting in neurodegenerative changesof small nerve fibers of the oral mucosa and/or some brain areas involved in oralsomatic sensations. These investigators posit that these neuropathic changesbecome irreversible and precipitate the burning pain, dysguesia, and xerostomiaassociated with BMS, which all involve small nerve fibers.
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Burning Mouth Syndrome and Secondary Oral Burning Distinguishing BMS from Secondary Oral Burning One difficulty in assessing the literature regarding BMS is that it is often unclearwhether local and systemic underlying conditions have been adequately assessedand excluded. Danhauer and colleagues52 examined patients with BMS andcompared them with patients who had oral burning derived from other clinical abnor-malities. These investigators concluded that although the 2 categories of patients mayinitially present with similar clinical and psychosocial features, they are distinguishablewith careful diagnosis that often enables successful management of symptoms foreach group. Failure to rule out secondary oral burning will result in inappropriatemanagement strategies. Because of this, it is important to understand the potentialcauses of secondary oral burning and symptom presentation. In BMS, complaintsof oral burning may decrease when eating or chewing; symptoms are typically bilateralin presentation and may be present at multiple oral sites. Secondary oral burningrelated to mucosal changes may be localized to areas of mucosal lesions, and is typi-cally increased with eating, particularly spicy or acidic foods. Secondary oral burningassociated with systemic conditions may be bilateral.
One classification divides etiology of secondary oral burning into factors related to the mouth (such as decreased salivary production), systemic factors, and psycholog-ical conditions.12,49 Another article by Cerchiari and colleagues13 goes into furtherdetail and includes etiologic categories of local, systemic, psychogenic, and idio-pathic. In cases identifying local or systemic factors, the definition of idiopathicBMS is not met. Local factors might include parafunctional behaviors such as tonguemovements or habits causing mucosal irritation,53 dental disease or galvanism,allergic reactions to dental materials, dentures, or other local factors,54 stomatitis,and infectious conditions such as candidiasis. Possible systemic causes of secondaryoral burning include salivary dysfunction, endocrine disturbances, nutritional disorderssuch as vitamin B complex, folate, iron, or zinc deficiencies, gastrointestinal diseaseincluding gastritis, reflux, or Helicobacter pylori infection, medication-related causes,other distinct cranial neuropathies, and possibly primary psychiatric disease.13,31,55 Limited studies have been done thus far to assess prognosis.56 A retrospective reviewin 2006 including 48 women and 5 men with a mean age of 67.7 years (range 33–82years) demonstrated a complete spontaneous remission in 3% of the patients within5 years after the onset of BMS and moderate improvement in fewer than 30% of thesubjects.57 Other investigators have noted the tendency of BMS to persist for manyyears.6 EVALUATION AND DIAGNOSIS As mentioned earlier, the diagnosis of BMS is primarily one of exclusion. To that end, itis important to conduct a history and physical examination of a patient with thecomplaint of oral burning, with the goal of identifying any primary etiology. Laboratorystudies should also be guided by this principle in a cost-effective manner. Box 1outlines components of a thorough evaluation for BMS.
The idea that BMS represents a form of chronic neuropathy is reflected in the mostcommon approaches to clinical management. Recent reviews have examinedevidence for various therapeutic interventions, including a 2004 Cochrane review58 Author's personal copy
Box 1Recommended evaluation for oral burning symptoms Characteristics of the burning, including location, quality, severity, onset, duration, courseover the day, aggravating/relieving factors: work, stress, foods, talking Associated symptoms: taste disturbances, oral dryness Medical history including ear disease, dental or oral disease, dentures, zoster, menopause,diabetes, thyroid disease, peripheral neuropathy, depression/anxiety Surgical history including oral, ear, and intracranial surgery Medications: angiotensin-converting enzyme inhibitors, antiretrovirals, tricyclicantidepressants, others (review side effect profiles) Physical Examination Highlights General: age, gender, affect/mood Head: evidence of radiation or previous trauma or tumor Ears: examine for middle ear disease or evidence of surgery that might have damaged thechorda tympani Oral cavity: evaluate mucosa, dental health, salivary production, taste testing, tenderness topalpation, local anesthetic testing Neck: evaluate for goiter, lipodystrophy secondary to antiretrovirals, evidence of radiation Neurologic: peripheral neuropathy, complete neurologic examination Laboratory Evaluation Random blood glucose, Fasting blood glucose, hemoglobin A1c Alanine and aspartate transaminase Thyroid function (T3/T4) Serum iron, ferritin, total IgE, vitamin B6, B12, D Serum antinuclear antibodies, erythrocyte sedimentation rate Serum antibodies to H pylori Oral swab for Candida and a more recent review by Buchanan and Zakrzewska.56 Strategies that have thusfar been investigated for treatment of BMS include clonazepam, a-lipoic acid, lafuti-dine, hormone replacement therapy, antidepressants, a variety of topical applications,anticonvulsants, medications for neuropathic pain, and psychiatric therapies. Thereare limited data on treatment approaches; although most represent small cohortstudies, they do provide some guidance in treatment. Box 2 summarizes currentrecommendations regarding management of BMS.
Three studies of a-lipoic acid (ALA) in BMS,69–71 all by Femiano and colleagues, wereincluded in the Cochrane review mentioned previously.58 ALA is mitochondrial coen-zyme with antioxidant effect that has been shown to be neuroprotective in previousstudies of diabetic neuropathy.64 The first study included 42 patients with BMS in Author's personal copy
Burning Mouth Syndrome and Secondary Oral Burning Box 2Current approach to management of BMS  Diagnosis: rule out local and systemic conditions that may cause oral burning; if present treat accordingly and assess outcome Treatment of hyposalivation or tongue/jaw habit if present53  Medication trials First-line therapies Lafutidine if available (not currently approved by Food and Drug Administration[FDA])55 Second-line therapies (poor evidence supporting) Not recommended: a-lipoic acid,64–66 hormone replacement therapy50  Counseling and possible referral for formal psychiatric intervention Cognitive behavioral therapy67 Group psychotherapy68 an open placebo-controlled trial. Forty-two percent of patients in the ALA arm initiallyhad "decided improvement" versus 0% of placebo, and overall 76% reported "anyimprovement" versus 14% of placebo. After the placebo arm was crossed over,52% of those patients had "decided improvement" and 63% reported "any improve-ment."70 The second study of ALA was done in a double-blind, randomized controlledfashion in 2002 and featured 60 patients split into 2 arms. After 2 months, there was"any improvement" in 97% of the ALA arm versus 40% of placebo, and "decidedimprovement or resolution" in 87% of the ALA arm versus 0% of placebo(P<.0001).71 The third study compared ALA with bethanecol, Biotene, and placebo,using 4 groups of 20 patients with BMS. The study found ALA of remarkable benefitwith minimal adverse effects as compared with the other arms. Further multi-institu-tional double-blind, randomized controlled trials were recommended.69 It is unclearwhether any of the patient data are duplicated in these 3 studies by the same authorspublished within a similar timeframe.56 Recently, 3 randomized, double-blinded, placebo-controlled studies of ALA for BMS have been published, all by investigators and institutions unrelated to the afore-mentioned studies and each other. The first recent study features 66 patients enrolledin a 3-arm trial (ALA, ALA with multivitamin, and placebo) with treatment of ALA, 400mg twice daily for 2 months in both ALA groups.65 Fifty-two patients completed thetrial and responders were those who had at least a 50% decrease in pain scoresmeasured by the Visual Analog Scale (VAS) at 2 and 4 months. The study showeda significant response to intervention in all 3 groups (including placebo), with about30% of each group responding. A second recent study by Lopez-Jornet andcolleagues66 included 60 patients split into 2 groups (ALA 800 mg daily and placebo)with responses also measured on the VAS. Again, no significant difference was found Author's personal copy
with ALA versus placebo. A third trial completed by 31 patients also failed to demon-strate the effectiveness of ALA over placebo.72 These 3 well-designed trials castserious doubt on the efficacy of ALA in the treatment of BMS.
Several studies have examined the use of antidepressant medications in BMS,although in a limited fashion. A single double-blind, randomized controlled trial of tra-zodone versus placebo has been reported.73 This study, which was done in Finland in1999, included 37 women and failed to show any effect over the 8-week trial period;the trazodone group showed significantly worse symptoms of drowsiness and dizzi-ness versus placebo. An open-label, single-arm, dose-escalation pilot study of theeffect of paroxetine (Paxil) in treatment of BMS reported 80% of patients with painreduction after 12 weeks of paroxetine treatment, with only minor transient sideeffects. These results suggest that paroxetine may be useful in the treatment ofpatients with BMS.61 A third trial in 2002 compared 2 selective serotonin reuptake inhibitors, paroxetine and sertraline (Zoloft), and amisulpride, an atypical antipsychotic.62 The study wassingle-blinded without a placebo arm. Overall, 76 patients without concurrent majordepression were enrolled in the 8-week trial and assigned to sertraline 50 mg daily,paroxetine 20 mg daily, or amisulpride 50 mg daily. Results were assessed usinga VAS as well as the Hamilton Rating Scale for Depression and the Hamilton RatingScale for Anxiety. Overall, 69.6% to 72.2% of patients responded, with mean VASpain scores decreasing in all 3 arms from an initial range of 7.2 to 7.0 to a final rangeof 3.3 to 2.8 at week 8 (P<.001). Although no adverse events were noted in any arm ofthe trial,62 paroxetine may cause congenital malformations when given in the firsttrimester,74 and patients who do have concurrent major depressive disorder shouldbe managed in coordination with a physician with appropriate experience in psychi-atry.56 Again, the study was limited by lack of a placebo arm.
Clonazepam and Chlordiazepoxide Inspired by earlier promising successful open-label studies of topical59 and systemic30clonazepam (Klonopin) for BMS, a multicenter, double-blinded, randomizedcontrolled trial of topical clonazepam versus placebo was conducted with 84 patients(40 women and 44 men) in France and published in 2004.60 The prior studies assessedlow-dose systemic clonazepam without topical contact and reported improvement inoral burning in the majority of patients. Patients in the study were instructed to sucka tablet (either 1 mg clonazepam or placebo) for 3 minutes and swishing the dissolvedmedicine around the painful oral sites without swallowing before expectorating themedicine. The therapy was given 3 times daily for a total of 2 weeks. Pain was ratedon a standard zero to 10 numerical scale before and after the intervention. Pain scoresdecreased 2.4  0.6 in the clonazepam group versus 0.6  0.4 in the placebo group(P 5 .014). There was no significant difference in adverse events between placebo andcontrol. Despite the finding in the same study that the swish and spit techniqueresulted in significantly lower blood levels of clonazepam versus swallowing a 1-mgtablet, Buchanan and Zakrzewska56 remind physicians of the addictive potential ofbenzodiazepines.
One other study of lower quality that remains interesting is a large nonrandomized nonplacebo controlled trial of multiple medications in 130 BMS patients in 1991 thatincluded 78 patients who were placed on chlordiazepoxide (Librium), a benzodiaze-pine relative.11 Of these, 14% had complete resolution, 35% had marked benefit,15% had slight benefit, and 36% showed no change. The study design, however, Author's personal copy
Burning Mouth Syndrome and Secondary Oral Burning was poor. By contrast, the cohort studies of clonazepam show more positiveoutcomes.30,60 Of note, although both drugs bind to benzodiazepine receptors andenhance the action of g-aminobutyric acid, clonazepam is used in the treatment ofneuralgias and neuropathies, whereas chlordiazepoxide is not.75,76 Given the likelyneuropathic nature of BMS, the greater efficacy of clonazepam is perhapsunsurprising.
Gabapentin (Neurontin) has been of interest in BMS on account of the putative neuro-pathic nature of the illness (or some subset thereof), but evidence in the literature insupport of its use is discouraging. A trial of gabapentin34 cited by Grushka andcolleagues77 in one review article was unavailable through PubMed and the journal'sWeb site. Another article in support is a single case report.78 More importantly, theonly multipatient trial currently available is an open dose-escalation study, in which15 patients took gabapentin at doses from 300 up to 2400 mg per day over a courseof 3 weeks. No significant improvement in pain, mood scales, or Beck DepressionInventory scores was seen after the 3-week period. These data indicate that gabapen-tin should not be used for trials except after the failure of other medications. A largerrandomized trial of this medication may confirm its lack of efficacy for BMS.63 Hormone Replacement Therapy The most recent Cochrane review of BMS58 reports one trial of hormone replacementtherapy. Pisanty and colleagues50 conducted a blinded trial of estrone cream versusestrone and progesterone cream versus placebo in 1975. The 3 arms of the trial had 6,9, and 7 patients, respectively. The results of the trial showed minimal effect, with nomore than 25% of patients in any arm reporting improvement in the burning sensation.
Many aspects of the trial were unclear, including criteria for diagnosis, baseline char-acteristics of the 3 groups, and whether randomization was performed. Buchanan andZakrzewska56 identified 3 other similarly poor-quality studies with unclearimplications.
Lafutidine is a unique histamine H2-receptor antagonist (H2RA) that has a sensitizingeffect on capsaicin-sensitive afferent neurons. Because of this it was felt to havepotential for treatment of BMS, and in a randomized controlled trial 34 BMS patientsswitched blindly to lafutidine from their previous H2-blocker and 30 BMS controlsremained on their original H2-blocker. Both groups also did azulene sulfonate rinses.
Symptoms were scored using a VAS at 4, 8, and 12 weeks. The improvement rate wasconsistently higher in the lafutidine group than in the control group; the differencesbetween the groups were significant (P<.05).55 Lafutidine is not currently approvedby the FDA and is not available in the United States at present.79 Other Medical Treatments Other treatments studied in the literature with minimal findings have included topicalanesthetics, topical anti-inflammatory medications, capsaicin, sucralfate (Carafate),and St John's wort, among others. Oral habit appliances have been mentioned foruse in patients with evidence of active tongue habits and lingual fasciculations;however, no clinical data are available. The topical anesthetic dyclonine hydrochloridewas studied by Formaker and colleagues33 in an open noncontrolled study of 33patients. Of those, 12 had increased burning, 14 had no change, and 7 had improve-ment. A single trial in 1999 of benzydamine hydrochloride, a topical anti-inflammatory, Author's personal copy
failed to show an effect.80 Therefore, limited study to date does not support the use oflocally applied anesthetic or analgesic agents for idiopathic BMS.
Two articles discuss the use of capsaicin in BMS,81,82 but the results are unclear, as one article in Italian does not give any information about patient response to capsaicinin the English abstract,82 while the other includes only 2 patients classified as BMSamong many with neuropathic oral pain. Of those two patients who used the topicalcapsaicin 0.025% cream, one had symptom resolution and the other discontinuedthe study with minimal improvement.81 A single small nonplacebo controlled studyin 1997 of sucralfate found very mixed results in 14 patients with BMS, with improve-ment in 6 patients and worsening of symptoms in 4.83 Another recent study investi-gated possible therapy for BMS with Hypericum perforatum (St John's wort) ina placebo-controlled, double-blind, randomized controlled trial comprising 39patients.84 Unfortunately, the study failed to show any significant reduction in painwith this treatment.
Although amitriptyline (Elavil) and nortripyline (Pamelor) have been cited as thera- peutic options for BMS in the same review,77 there does not appear to be any reasonto support this beyond anecdotal evidence. Despite this, it seems to be a not unrea-sonable third-line medication to try with otherwise unresponsive patients, given theapparent neuropathic nature of the disease. The nonrandomized noncontrolled trialby Gorsky and colleagues11 of BMS therapies mentioned earlier also included patientswho were trialed on antifungal agents, amitriptyline, prednisone, pilocarpine, vitamin Bcomplex, and diazepam. Aside from diazepam, on which 4 of 6 patients noted consid-erable improvement, the results of the other groups were uniformly poor.
Cognitive Behavioral Therapy and Group Psychotherapy Although there are various case reports in the literature,85,86 only one randomizedcontrolled trial has investigated cognitive behavioral therapy (CBT) for BMS. This trialfrom Umea University in Sweden included 30 patients split into 2 equal groups. Thefirst group received CBT in the form of 12 to 15 sessions for 1 hour per week andthe second attention and placebo group (APG) received a similar number of sessions,but without the CBT techniques. Pain was measured with a VAS (scale of 1–7).
Pretreatment scores were similar between the 2 groups (CBT 5 5.0, APG 5 4.3). Aftertreatment the CBT group showed an average score decrease of 3.6 versus an increaseof 0.4 for the APG (P<.001). Weaknesses of the study included minimal informationprovided about other characteristics of the 2 groups and the lack of a validatedpain scale.67 A recent study by Miziara and colleagues68 investigated group psychotherapy as an additional modality for treatment of BMS. Of 44 diagnosed patients, 24 underwentgroup psychotherapy while 20 had placebo therapy. Improvement occurred among71% of patients in the treatment group versus 40% in the placebo group (P 5 .04).
Several recent case reports and studies have emerged concerning possible noveltherapies for BMS. A 2007 article describes a single patient with BMS who hadadverse reactions to initial therapy with carbamazepine (Tegretol) and gabapentin,but resolved completely with topiramate (Topamax).87 A noncontrolled trial wasrecently reported using levosulpiride, 100 mg daily for 8 weeks, in 44 patients.88 Ofthe 39 patients who completed the study, 28 showed some improvement, althoughnone had complete resolution. Those with improvement tended to be patients witha shorter history of symptoms. The study is limited by its lack of a control arm. A thirdreport in 2008 describes a patient with severe BMS who failed multiple initial attempts Author's personal copy
Burning Mouth Syndrome and Secondary Oral Burning at therapy but who responded to pramipexol (Mirapex).89 This case seems unusual,however, because the patient had relief of symptoms with tongue motion. Similarityto documented modulation of tinnitus with head and neck motions is curious,90–92and may represent a subcategory of BMS patients able to modulate the burningsensation. These reports, though intriguing, will require further investigation beforethey could be recommended as possible alternative therapies.
Patients who present for evaluation of oral burning symptoms require a thorough eval-uation to distinguish between secondary oral burning and primary BMS. Ensuring thatother confounding conditions have been addressed prior to diagnosis of BMS is key topreventing improper attempts at treatment. While the exact etiology of BMS remainsunclear, it seems most likely a neuropathy, with variable central and peripheral contri-butions among individuals. It is hoped that future efforts for BMS will include largerrandomized therapeutic trials of both medical and psychiatric therapies as well ascontinued research into its exact origin.
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