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Oral Dysesthesia

Giulio Fortuna, Joel Napenas, Nan Su, Miriam Gruskha, andGary D. Klasser

AbstractOral dysesthesia (OD) is an idiopathic andchronic medical condition, characterized bypain/discomfort in the oral cavity, for whichno local and/or systemic diseases can be iden-tified. The prevalence and the incidence areunknown, although a predisposition to peri-/postmenopausal females has been widelydocumented, and the etiopathogenesis is stilldebated. Currently OD is considered a multi-factorial condition, in which neurological andpsychosocial factors have been studied andlargely implicated. Clinically, in the majorityof OD patients, the discomfort includes primar-ily a burning sensation in the mouth and/ormany other different complaints that can beassociated with a cohort of different sensorysymptoms, such as pain, foreign body

sensation, increase or decrease of salivation,dysgeusia, or itching. Such symptoms involvemainly tongue and lips, followed by hardpalate, alveolar ridges, buccal mucosa, andfloor of the mouth. In addition, some ODpatients may report a wide variety of medicallyunexplained somatic comorbidities, such asirritable bowel disease or fibromyalgia. Thediagnosis is essentially clinical, relying ona thorough medical history, extra-oral andintra-oral examination, and laboratory testsand/or radiologic imaging, in order to ascertainthe absence of any local and/or systemic con-ditions. Management is very complex andbased on a multidisciplinary approach. It mayindeed include both pharmacologic interven-tions with the use of topical and systemic ther-apies, and/or psychological interventions suchas cognitive behavioral therapy.

KeywordsOral dysesthesia • Burning mouth syndrome •Altered sensation • Xerostomia • Glossodynia

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Definition and Classification . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Chorda Tympani Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Central Nervous System Changes . . . . . . . . . . . . . . . . . . . . . . 5Subclinical Trigeminal Neuralgia . . . . . . . . . . . . . . . . . . . . . . 5

G. Fortuna (*) • G.D. KlasserDepartment of Diagnostic Sciences, Louisiana StateUniversity School of Dentistry, New Orleans, LA, USAe-mail: [email protected]; [email protected]

J. NapenasDepartment of Oral Medicine, Carolinas Medical Center,Charlotte, NC, USAe-mail: [email protected]

N. SuNorman Bethune College of Medicine, Jilin, Chinae-mail: [email protected]

M. GruskhaDepartment of Dentistry, William Osler Hospital(Etobicoke), Toronto, ON, Canadae-mail: [email protected]

# Springer International Publishing AG 2018C.S. Farah et al. (eds.), Contemporary Oral Medicine,https://doi.org/10.1007/978-3-319-28100-1_36-2

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https://doi.org/10.1007/978-3-319-28100-1_36-2

Small Fiber Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7Psychological Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Signs and Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Associated Comorbidities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Diagnosis: Clinical Evaluation and AdjunctiveAssessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10Physical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Laboratory Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Adjunctive Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Empiric Treatment Targeting Secondary Causes . . . . . 14Treatment of Oral Dysesthesia . . . . . . . . . . . . . . . . . . . . . . . . 14Topical Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Systemic Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18Behavioral Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Conclusions and Future Directions . . . . . . . . . . . . . . . . . 19

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Introduction

Oral dysesthesia (OD) is an idiopathic andchronic medical condition, characterized bypain/discomfort in the oral cavity, for which nolocal and/or systemic diseases or alterations inblood tests and/or radiologic imaging can be iden-tified, and for which a complex multidisciplinarymanagement is often required (Zakrzewska 2010;Buchanan and Zakrzewska 2010).

Historically, OD was firstly known as burningmouth syndrome (BMS). However, over time,many other terms have been used in the literaturebased on the quality or location of pain in theoral cavity, such as “glossodynia” and“glossopyrosis,” referring specifically to a symp-tom localized on the tongue, “stomatopyrosis”and “stomatodynia,” referring to a patient’s sub-jective oral sensation (discomfort), without spec-ifying the etiology (idiopathic versus secondary),and other terminologies such as “sore tongue orburning tongue,” and “scalded mouth syndromeor burning mouth condition/disease” (Fortunaet al. 2013; Klasser et al. 2008).

Interestingly, there is still an ongoing debatewhether or not OD should be considered a syn-drome or a disorder. In fact, a syndrome refers tothe presence of several simultaneous signs andsymptoms of varying intensity, whereas a disorderrefers to a condition manifesting symptoms ofother diseases (Klasser et al. 2008). Therefore, ifOD is a symptom of other systemic (neurologicaland/or psychogenic) diseases, then it should bedefined as a disorder, otherwise the term syn-drome should be used to indicate a diagnosis ofexclusion by ruling out all other possibilities(Klasser et al. 2008).

Definition and Classification

OD has historically been known as BMS, as indi-cated above. Therefore, the majority of the defini-tions and classifications previously used the termBMS; however, in the present chapter this is cor-rectly referred to as OD henceforth.

The International Headache Society (IHS) inthe International Classification of Headache Dis-orders III (ICHD-3 Beta) have included OD in thecategory of painful cranial neuropathies and otherfacial pain (ICHD-III Beta: 13.10; ICD-10:K14.6) (Headache Classification Committee ofthe International Headache Society (IHS) 2013).The International Classification ICHD-3 Betadefined OD as an intraoral burning or dysestheticsensation, recurring daily for more than 2 h perday, over more than 3 months, without clinicallyevident causative lesions. It is characterized byfour diagnostic criteria: (i) Recurring daily for>2 h per day for >3 months, (ii) Pain has bothof the following characteristics: burning qualityand felt superficially in the oral mucosa, and (iii)Oral mucosa is of normal appearance and clinicalexamination including sensory testing is normal,and (iv) Not better accounted for by anotherICHD-3 diagnosis (Headache Classification Com-mittee of the International Headache Society(IHS) 2013).

Similarly, the International Association for theStudy of Pain (IASP) defines OD as a “distinctivenosological entity,” including all forms of burning

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sensation in the mouth, including complaintsdescribed as a stinging sensation or pain, involv-ing mainly the tongue and lips, followed bythe hard palate, alveolar ridges, buccal mucosa,and floor of the mouth, in association with anoral mucosa that appears clinically normal whichare not attributable to any known organic path-ologies and are inadequately supported by clin-ical findings (Merksey and Bogduk 1994;Zakrzewska 1995).

Lamey and Lewis in 1989 proposed the fol-lowing clinical classification for OD: (a) type 1:progressive pain throughout the day; (b) type 2:constant throughout the day; and (c) type 3:symptoms are intermittent and there are somesymptom-free days (Lamey and Lewis in 1989).The essential feature of type 2 OD is a chronicpersistence of the oral pain without any circadianfluctuation, probably due to psychogenic factors;in type 1, burning symptoms show a typical dailyfluctuation with evening worsening, probablydue to systemic diseases, such as nutritional defi-ciencies, while in type 3, burning symptoms areintermittent, probably due to contact with oralallergens (Lopez-Jornet et al. 2010).

OD has also been classified based on symp-toms: type 1 (35%): awaken without symptoms,progress throughout the day, present daily, andfood/drink relieve symptoms; type 2 (55%):awaken with symptoms, progress daily, andfood/drink relieve symptoms; type 3 (10%):occasional symptoms, worsen with food/drink,unusual oral sites affected, and increase incidenceof contact allergy (Muzyka and De Rossi 1999).

A more pragmatic and well-known classi-fication divides OD in two distinct clinicalforms (Scala et al. 2003): “primary OD,” or“essential/idiopathic OD,” for which organiclocal/systemic causes cannot be identified, and“secondary OD,” resulting from local/systemicpathological conditions and, therefore, potentiallysensitive to etiology-directed therapy. Similarly,others (Brailo et al. 2006; Sardella and Carrassi2001) have also used the term “true OD,” as asynonym for “primary/essential OD,” to indicatethe idiopathic form of OD.

Lastly, but not of less importance, it isworthwhile to mention that recently a new termi-nology has been proposed which challenges allthe previous ones: complex oral sensitivity disor-der (COSD), since it seems that the use of thepreviously mentioned multiple definitions andclassifications have led to some confusion andinconsistencies (Fortuna et al. 2013; Fortunaand Pollio 2012a, b). This new term summarizesthree important aspects of this complex disorder:“complex,” because the oral discomfort may pre-sent with single or multiple oral site involvementand symptoms, and because the same symptomscan be heterogeneous, since they may vary inintensity during the day, may not be present on adaily basis, may transform into a different type ofsymptom or multiply over time, while being sub-jective, in terms of severity. “Oral,” becausethe majority of OD patients (96.8%) presentwith additional unexplained extra-oral symptoms(Mignogna et al. 2011b). Therefore, whether ornot this last group of patients should be catego-rized within the COSD group requires furtherinvestigation. “Sensitivity,” because it may pre-sent with all types of sensory symptoms includingaberrant tactile, nociceptive, thermal (hot, warm,and cold), gustatory, and proprioceptive sensa-tions. It should be noted that the proposed diag-nostic criteria of COSD (Fortuna et al. 2013)have been slightly modified from those of theIASP and IHS (Headache Classifications 2013;Merksey and Bogduk 1994) and are summarizedas follows:

(a) Any type of oral and oropharyngeal symptomthat can be persistent or intermittent with pos-sible phases of remission/exacerbation duringthe day.

(b) Absence of any clinically and instrumentallydetectable oral and oropharyngeal lesion.

(c) Absence of any type of local and/or systemicfactors, such as oral diseases, drugs, trauma,hypersensitivity reactions, and physicochem-ical agents.

To establish the diagnosis, all three criteriamust be met, with an additional but not mandatory

Oral Dysesthesia 3

one: the chronicity, in which the state of beingsymptomatic is persistent (typically �3 months)(Fortuna et al. 2013).

Epidemiology

The exact incidence and prevalence of OD are stillunknown. One million individuals in the UnitedStates are estimated to be affected by OD (Liptonet al. 1993), with an estimated prevalence rangingfrom 0.7% to 4.6% in the general adult population(Scala et al. 2003; Lipton et al. 1993: Grushkaet al. 2006).

It is likely that such variation in prevalenceacross the studies might have been due to differentdefinitions of OD with subsequent different inclu-sion criteria (Klasser et al. 2008).

In fact, a study published in 1999 showed thatthe prevalence of OD was similar in males andfemales at the age of 20–40 years, but increased atdifferent rates in both genders reaching 3.6% inmales and 12.2% in females at the ages of 60–69(Bergdahl and Bergdahl 1999). Conversely, inanother study, the prevalence of OD amongelderly males was estimated much lower, aroundonly 1.7% (Riley et al. 1998).

Therefore, OD usually occurs in the fifth toseventh decade of life and is more common infemales than males, with an estimated ratio from3:1 to 16:1 (Klasser et al. 2008). It seems that inthe majority of female patients, OD onset mayvary from 3 years prior to 12 years post the begin-ning of menopause (Dahiya et al. 2013), thereforesuggesting a possible role for hormone replace-ment therapy (HRT) as a therapeutic option(Santoro et al. 2005).

These gender variations might be due to bio-logical, psychological, and sociocultural factorsthat have not yet been clarified (Scala et al.2003; Lipton et al. 1993: Grushka et al. 2006;Grushka and Sessle 1991).

As far as ethnicity is concerned, the estimateprevalence in the American white non- Hispanicpopulation was 19%, in Black, non-Hispanicwas 15%, in Hispanic was 22%, and in othernon-Hispanic was 44%, with the highest

prevalence in the age group of patients olderthan 75 years of age (Lipton et al. 1993).

Etiopathogenesis

The cause of OD remains unclear although itis unlikely that OD is the result of a singleprocess. Rather, it is more likely that it is multi-factorial, encompassing damage or dysfunction tothe peripheral and/or central nervous systemsinvolving factors related to taste, small fiber neu-ropathy, immune system, hormones, and/or psy-chosocial factors.

Chorda Tympani Damage

OD patients often complain of taste disturbancesincluding metallic taste and/or bitter taste andhave been found to have changes in taste, tactile,and pain thresholds suggesting changes to boththe taste system and trigeminal nerve (Grushka1987; Siviero et al. 2011: Just et al. 2010). Tasteis provided by the chorda tympani, a branch of thefacial nerve (CN VII), in the anterior two-thirds ofthe tongue and by the glossopharyngeal nerve(CN IX) in the posterior one-third of the tongue(Su et al. 2013). The trigeminal nerve (CN V)provides pain and thermal sensation to the anteriortongue through thinly myelinated Aδ and unmy-elinated C fibers (Su et al. 2013; Kaplan et al.2011; Schobel et al. 2012). Normally, the specialsensation of taste, mediated by the chorda tym-pani and glossopharyngeal nerves can inhibit thesensation of pain, mediated by the trigeminalnerve at the level of the central nervous system.

Studies have suggested that damage (mechan-ical, chemical and/or biologic) to the chorda tym-pani may lead to a loss of inhibition phenomenon.A centrally mediated loss of inhibition phenome-non has been reported in human studies whereunilateral local anesthetic administered to thechorda tympani has resulted in an increase ofpain after capsaicin application to the tongue,mediated by the trigeminal nerve, contralateral tothe anesthetized side but with pain reduced

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ipsilaterally (Schobel et al. 2012; Bartoshuk et al.2005). Damage to the chorda tympani from mid-dle ear infection has also been demonstrated toproduce increased pain sensation in the tongue(Bartoshuk et al. 2012). Electrogustatory testingof the anterior two thirds of the tongue hasalso shown increased taste thresholds in ODsuggesting a hypofunctioning chorda tympani(Eliav et al. 2007). In addition, application ofsugar and other taste stimulants to the tonguehave been found to inhibit the lingual painresponse to capsaicin (Schobel et al. 2012;Bartoshuk et al. 2005).

The presence of a loss of inhibition phenomenain OD is strengthened by the response in ODto the medication, clonazepam (Grushka et al.1998; Heckmann et al. 2012). Clonazepam is anagonist of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and may decrease theburning pain of OD by providing the inhibitionlost by damage to the chorda tympani.

In animal models, however, with bilateralchorda tympani dissection, capsaicin avoidancehas not been found, leading some to believe thatloss of inhibition may not be a cause of OD(Boucher et al. 2014). The lack of avoidance tocapsaicin has been suggested to possibly correlateto a loss of normal taste buds after damage to thechorda tympani or perhaps even as a result ofaccidental injury of the lingual nerve, a branchof the mandibular division of the trigeminalnerve, leading to loss of pain and heat sensitivityin the tongue (Li et al. 2015; Yilmaz et al. 2016).It has been suggested that when damage to thechorda tympani or the glossopharyngeal nerve ismild, there appears to be a loss of inhibition phe-nomenon and production of taste phantoms andpain, as well as increased intensity of tactile sen-sations carried by the trigeminal nerve. However,when damage is severe, the phantoms appear tobe absent, suggesting that oral phantoms includ-ing pain require the presence of at least someresidual taste and trigeminal function (Bartoshuket al. 2012).

It has also been suggested that damage to theglossopharyngeal nerve, such as from tonsillec-tomy, can also lead to phantoms such as bitter and

metallic taste (Heiser et al. 2010) contralateral tothe damage (Goins and Pitovski 2004) similar tothe taste phantoms found in OD.

Central Nervous System Changes

In a subpopulation of OD patients, autonomicdysfunctions including changes in heart rate var-iability and exhalation/inhalation ratio as well asprolonged latency in skin responses have beendescribed (Koszewicz et al. 2012; Mendak-Ziolkoet al. 2012).

These changes are similar to findings inParkinson disease, a cerebral degenerative diseaseassociated with decreased dopamine. In Parkinsondisease, 40% of patients report burning in the oralcavity, and this has led to speculation that a dys-function of the dopaminergic system may be pre-sent in OD (Koszewicz et al. 2012). Changes indopaminergic system have since been demon-strated in positron emission tomography (PET)studies, showing reduction in dopamine in thenigrostriatal neurons and the putamen in OD lend-ing support for this theory (Jaaskelainen 2012).It has been reported that OD patients treatedwith levodopa, a drug used in the treatment ofParkinson disease, showed a reduction in theoral burning pain (Prakash et al. 2012). However,in their study, they found an overlap in symptomsbetween OD and restless leg syndrome (RLS) andsuggested that levodopa responsive OD patientsare actually a variant of RLS (Prakash et al. 2012).

Subclinical Trigeminal Neuralgia

It has also been suggested that OD is a subclinicaltrigeminal neuralgia (TN). OD patients have beenreported to present with many similarities topatients with TN including abnormal blink reflex,mediated by the ophthalmic division of the tri-geminal nerve, presence of lingual or mandibularlesions in approximately 20% of OD patients, andlingual branch damage leading to clinical symp-toms similar to OD (Mendak-Ziolko et al. 2012;Kolkka-Palomaa et al. 2015).

Oral Dysesthesia 5

However, when quantitative sensory testinghas been performed, patients with OD andpatients with lingual nerve injury showed verydifferent responses, with OD patients reportingincreased sensitivity to stimuli while lingualnerve damage resulted in normal or decreasedsensitivity (Yilmaz et al. 2016). Although TNmay present with burning sensation within theoral cavity, the clinical presentation between ODand TN is strikingly different. The pain quality inTN is a sudden lancinating pain lasting only sec-onds to minutes within the distribution of thetrigeminal nerve and is unilateral, whereas thepain in OD is a persistent pain with intensityprogressing throughout the day and not restrictedto trigeminal nerve distribution, thus making thistheory less likely (Bangash 2011; Komiyama et al.2012; Grushka et al. 2002).

Small Fiber Neuropathy

Damage to peripheral small nerve fibers can alsoproduce a burning sensation and can result frommetabolic disorders, endocrine disorders, vita-min B12 deficiency, viral infection and autoim-mune disorders such as Sjogren’s syndrome(Tavee and Zhou 2009). Small fibers, includingthe myelinated A-δ and unmyelinated C fibers,are present in numerous numbers in thesub-epithelial regions of the tongue with fewernumbers in the epithelium of the tongue. In OD,tongue biopsies have shown a lower density ofsmall fibers in the symptomatic areas of thetongue suggesting a damage of peripheral smallfibers as a possible cause of burning(de Tommaso et al. 2011; Yilmaz et al. 2007).

Examination of the tongue in OD also revealedan increase in nociceptive receptors, which aresensitive to noxious and pain stimuli, includingthe transient receptor potential vanniloid channeltype 1 (TRPV-1) and voltage gated sodium chan-nel 1.8 (Nav 1.8) in the papillae and subepithelialregions of the tongue, respectively (Yilmaz et al.2007; Borsani et al. 2014). Both TRPV-1 and Nav1.8 are under the regulation of nerve growth factor

(NGF) which is elevated in OD in both the sub-epithelial and basal epithelial regions of thetongue. NGF supports the growth and mainte-nance of nociceptive neurons during developmentand can interact with immune cells such as mastcells to release inflammatory mediators (Borelliet al. 2010). The presence of increased NGF in thepresence of a decrease in substance P, an indicatorof nerve fiber presence, as well as an elevation innociceptive receptors present a possible scenariowhere peripheral small nerve damage togetherwith regeneration and maintenance of nociceptivefibers may result in a phantom burning pain(Borelli et al. 2010; Smith et al. 2004).

Immune System

The involvement of the immune system in ODis unknown; however, it may be that the acti-vation of the immune system may lead to anautoimmune type reaction against nerve tissueantigens resulting in peripheral small fiber neu-ropathy (Pavlakis et al. 2012), but more researchin this area is needed to determine if autoimmu-nity against nerve fibers plays a role in OD. Itmay be possible that changes in the immunesystem is unrelated to OD but rather related toaging and psychological stress causing a shiftfrom cell-mediated response to humoral responsesince OD has a predisposition in elderly females(Koike et al. 2014). However, various changes incytokines and immunoglobulin expression havebeen found in OD, including increased expressionof IL-6 and IL-9 in areas of small fiber neuropa-thy, decreased serum IL-2 and TNF-α, elevatedsalivary IL-6 and tryptase, and decreased salivarysIgA (Borelli et al. 2010; Pekiner et al. 2008; deSouza et al. 2015; Imura et al. 2016). Newerfindings suggest a delayed sensitivity inflamma-tion reaction may be involved in OD based on thefinding that 67% of OD patients tested with con-tact allergy patch testing showed evidence of apositive reaction (Lynde et al. 2014), although thereduction in burning pain following avoidance ofthese substances is unknown.

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Hormones

In view of the predisposition of OD in peri-/postmenopausal females, with the conditionmost commonly reported in the fifth to sixthdecade of life, dysfunction of the hypothalamus-pituitary-gonadal (HPG) axis has been suggestedto play a role. The oral mucosa and salivary glandscontain estrogen receptors and are histologicallysimilar to the vagina, responding similarly toestrogen (Kohorst et al. 2014; Suri 2014). In OD,low salivary dehydroepiandrosterone (DHEA), aprecursor for androgen and estrogen, as wellas low serum estradiol levels have been found,suggesting that the change in sex hormones,possibly as a result of menopause, may play arole in OD, although the exact mechanism isunclear (Suri 2014; Dias Fernandes et al. 2009).Additionally, reduced levels of DHEA have beenshown to be significantly correlated with ODin other studies (das Neves de Araujo Limaet al. 2016).

In animal models, ovariectomy, which cancause decreased estrogen and elevation of folliclestimulating hormones (FSH) thereby emulatingevents of menopause, has been shown to lead toavoidance of capsaicin, suggesting that perhaps ahigh FSH may play a role in burning pain and thatthe burning pain may be a symptom of menopause(Suri 2014; Boucher et al. 2014).

Estrogen receptors are greatly represented inthe hypothalamus-pituitary-adrenal (HPA) axisand can control the release of adrenal stress hor-mones at the level of hypothalamus. Elevated17β-estradiol, which has been found signifi-cantly elevated in saliva of OD patients as com-pared to healthy controls, has been described toattenuate functions within the HPA and androgendeprivation have resulted in increased emotionalliability and depressed mood (Kim et al. 2012;Jacobs et al. 2015; Donovan et al. 2015). Thismay help to explain the higher frequency ofmajor depressive disorder, generalized anxietydisorder, and other psychosocial disordersfound in OD patients (de Souza et al. 2012,2015).

Psychological Factors

Some investigations have hypothesized thatOD might be a manifestation of somatization(Grushka et al. 1987; Scardina et al. 2008; Eliet al. 1994; Trikkas et al. 1996). Several studieshave shown a high prevalence of psychiatricsymptoms and/or disorders in OD: social andpsychological comorbidities have been reportedto occur in 85% of OD patients (Kenchadze et al.2011; de Souza et al. 2012). Anxiety and/ordepression, somatization, hypochondria, cancerphobia, and insomnia are the most common diag-noses seen in this patient population (Galli et al.2016). It has been shown that 51% of patients withOD have a diagnosis of at least another psychiatricillness according to the Diagnostic and StatisticalManual of Mental Disorders (DSM-III-R) (Rojoet al. 1994) and also demonstrated that the major-ity of OD patients (85.7%) have at least oneaxis II personality disorder, mainly cluster A(odd, eccentric cluster), according to theDSM-IV (Maina et al. 2005).

In addition, it has been suggested that somaticcomplaints due to unfavorable life experiencesassociated with chronic pain may influence bothindividual personality and mood changes (Jerlang1997). Many OD patients, in fact, report one ormore adverse life events in their clinical/socialhistory, such as difficult infancy, inadequateparenting, poor adaptation to school and work,family or marital strife, and financial problems(van der Ploeg et al. 1987; Browning et al.1987). However, psychological problems aremore common in patients with chronic pain andmay be the result of experiencing chronic painrather than its cause (Rojo et al. 1993). Theyseem to be independent from symptom intensitybut appear to be mostly related to a prolongedperiod of pain and a long history of unsuccessfultreatment (Rojo et al. 1993). In addition, it hasbeen demonstrated that OD patients may experi-ence higher levels of pain, anxiety, and depression(Jerlang 1997; Grushka et al. 2002), where anxi-ety could determine a secondary demoralizationin OD patients (depression) and depressive

Oral Dysesthesia 7

symptoms could contribute to pain, accordingly.Therefore, pain could be a somatic feature ofdepression (Schiavone et al. 2012).

Contrarily, even though OD patients may dem-onstrate a greater incidence of anxiety and depres-sion, other studies have not found psychologicalfactors to be significantly associated with OD(Eli et al. 1994). One study using the Multi-dimensional Pain Inventory (MPI) and RevisedSymptom Checklist (SCL-90R) on 33 OD casescompared the data to that from population sam-ples which included both non-OD chronic painpatients and a normal non-clinical sample(Carlson et al. 2000). They concluded that therewas no evidence for significant clinical elevationson any of the SCL-90R subscales, includingdepression, anxiety, and somatization. Moreover,patients reported significantly fewer disruptions innormal activities as a result of their oral burningpain than did a large sample of chronic painpatients. It was noted that 21% of the OD caseshad substantially elevated psychologic distress.

Despite the common presence of psychologi-cal issues and the need for treatment of theseunderlying issues, it is acknowledged that ODmay also occur in the absence of a psycholog-ical diagnosis (Mendak-Ziolko et al. 2012). Itis possible for these psychological conditionsto be comorbidities, modifiers of the burningmouth condition, or a behavioral consequence ofhaving OD rather than an etiological factor.Regardless, these psychological issues, if present,must be addressed due to their impact on thequality of life as well on treatment outcomes(Souza et al. 2011).

Based on the current data present in the litera-ture, it is difficult to establish whether specificpsychiatric features (anxious traits, personalitydisorder, or somatization) may play a role inthe pathogenesis of OD or determine whethersome OD symptoms, or whether OD itself, likeother chronic pain disorders, may lead to second-ary psychiatric symptoms (Grushka et al. 2002).Thus, the question whether OD should be consid-ered a neuropathy or a somatoform pain disorderis trifling, as psychological disturbances andsomatic symptoms, which affect OD patients, are

likely to be considered expressions of the samepathological central nervous system (CNS) abnor-malities (Fedele et al. 2007).

Hence, appropriate management should there-fore include referral to health professionals whomay assist these patients with their mental healthstatus (de Souza et al. 2012). Another factor toconsider is that many of the medications used inthe treatment of these psychologic conditions mayresult in side effects such as dry mouth and tastealterations that may induce or exacerbate ODsymptoms.

Sleep disturbances have also been associatedwith OD as a recent case controlled study reportedthat OD patients have a greater incidence of sleepdisturbances than age and sex-matched controls(Chainani-Wu et al. 2011; Adamo et al. 2013).Pain and poor sleep can lead to decreased qualityof life including increased functional limitationand physical disability, and decreased vitalityand social function (Souza et al. 2011).

Clinical Presentation

Signs and Symptoms

The clinical presentation of OD is typically incon-sistent, with a high rate of variance between indi-viduals. However, the majority of OD patientsverbally describe their intra-oral symptoms withthe following words: painful, burning, tender, tin-gling, hot, scalding, and numbness yet sometimesthe sensation is merely described as discomfort,raw, and annoying (Lopez-Jornet et al. 2010).

The onset of pain is somewhat unpredictable,varying between gradual or sudden and customar-ily presents without recognized precipitating fac-tors. However, about 17% to 33% of the patientsattribute the onset of their symptoms to a previousillness such as an upper respiratory tract infection,previous dental procedure, or medication use(including antibiotic therapy) (Hammaren andHugoson 1989; Tammiala-Salonen et al. 1993)suggesting the possibility of neurologic alter-ations preceding the onset of burning in somepatients (Formaker et al. 1998). Traumatic life

8 G. Fortuna et al.

stressors, such as a loss of a beloved person, afamily issue, history of sexual assault, or a prob-lem in the work environment, have also beenimplicated with the onset of symptoms (Grushkaand Sessle 1991; van der Ploeg et al. 1987).

OD is characterized by both positive (burningpain, dysgeusia, and dysesthesia) and negative(taste loss and paresthesia) sensory symptoms(Suarez and Clark 2006). Typically, patients pre-sent with the complaint of pain or an unusual(often unpleasant) sensation that has been presentfor 4–6 months duration. The majority of patientsreport they experience mild to moderate levels ofpain that may be present at awakening or, as inmost cases, develops and intensifies as the dayprogresses (Grushka et al. 1987). Patients oftenreport their symptoms can be affected by oralintake (food and/or beverage) and talking. It isnoteworthy that in some cases, oral intake willtemporarily decrease or abort their symptoms,which is dissimilar to pain caused by organiclesions or neuralgia (Tatullo et al. 2012).However, many will avoid the intake of hot,spicy, or acidic food/liquids or alcoholic bever-ages as this may exacerbate the symptoms.Furthermore, personal stressors or fatigue, insome patients, will increase the symptoms ormake their symptoms more noticeable. It isunclear what the effects of tobacco, ethanol, ordietary factors are on the symptoms of OD.

The oral pain can be either continuous or inter-mittent, tends to present bilaterally and symmet-rically more so than unilaterally, and is typicallylocalized to the anterior two thirds of the tongue(71–78%) followed by the dorsum and lateralborders of the tongue (72%), the anterior aspectof the hard palate (25%), and the labial mucosa ofthe lips (24%), while often occurring in multiplesites (van der Ploeg et al. 1987; Grushka et al.1987; Gorsky et al. 1987, 1991). There have beensuggestions that burning of the lips be consideredas a single entity as this has been described fea-turing a thinned labial mucosa and inactive minorlabial salivary glands (Brown et al. 1996). Otherless commonly reported sites include the buccalmucosa, floor of the mouth, hard and soft palate,and the throat (36%) (Gorsky et al. 1991). Unlike

other painful conditions (trigeminal neuralgia),the burning pain does not follow peripheralnerve distributions. Interestingly, the site(s) ofpain do not appear to affect the course of thedisorder or the response to treatments.

It has been reported that other distant bodysites, such as the anogenital region (vulvodynia)may be affected concomitantly (Gaitonde et al.2002). Other potential associated pains that havebeen noted to occur concomitantly include backpain, diffuse myalgia, and in some cases, pain-ful temporomandibular disorders. Contrastingly,a recent systematic literature review aimed todetermine whether OD co-occurs with painsyndromes reported this is not the case [presentin only 0.8% (12 of 1512) of the retrieved studies]suggesting that OD depends on specific mecha-nisms, probably the trigeminal sensory pathwaysand associated central mechanisms (Moissetet al. 2016).

Associated Comorbidities

Two main common features associated with acomplaint of a burning sensation are dry mouth(xerostomia) and taste alterations. It has beenreported that more than two thirds of OD patientswill report dry mouth at presentation (Patton et al.2007). Most early studies did not show an objec-tive decrease in salivary flow rate in this popula-tion (Glick et al. 1976; Syrjanen et al. 1984).However, two recent studies did show a markedreduction in basal salivary flow in subjects withOD as compared to healthy subjects and thosewith oral lichen planus (Poon et al. 2014; Spadariet al. 2015). It is theorized that in some individualsthe dry mouth sensation is resultant from analtered oral sensation or from changes in the salivacomposition (Chimenos-Kustner and Marques-Soares 2002). While some studies have foundno differences in the composition of saliva ofOD patients when compared to that of healthyage and sex-matched controls (Tammiala-Salonenand Soderling 1993; Lundy et al. 1997), othersfound significant increases in the concentrationsof sodium, chloride, potassium, calcium, and

Oral Dysesthesia 9

phosphorous in OD subjects (Nagler andHershkovich 2004; de Moura et al. 2007).However, these concentration variances may beflow-rate dependent. Additionally, other studieshave demonstrated a significant increase in IgA,secretory IgA, IgG, and IgM concentrations insubjects with OD compared with controls (Naglerand Hershkovich 2004; Granot and Nagler 2005).Also, it is noted that altered salivary compositionis a relatively common finding around the time ofmenopause (Ben Aryeh et al. 1996).

Alterations of taste and phantom tastes andsmells have been reported by 11–69% of ODpatients (Grushka et al. 1987; Bergdahl andBergdahl 1999). The phantom tastes reported bythis group include a bitter or metallic taste or insome cases, a combination thereof (Grushka et al.1987; Grushka and Sessle 1988). Alterations intaste such as sour and bitter taste being perceivedas stronger, sweet tastes perceived as weaker andsalty tastes being weaker or stronger has also beenreported (Grushka et al. 1987). It has been dem-onstrated that saliva will impact the taste responseof the chorda tympani nerve based on concentra-tions of the salivary electrolytes (Na, K, Cl,HCO3) (Nagler and Hershkovich 2004). It hasbeen suggested that OD, taste disturbances,and xerostomia may well be different expressionsof a common neuropathic etiology potentiallyrepresenting a disorder of peripheral pain path-ways (Nagler and Hershkovich 2004). In contrastto these findings, another study found only aweak correlation between OD and perceivedtaste disturbance (Bergdahl and Bergdahl 2002).A recent case controlled study found male patientswith OD presented with concomitant taste com-plaints less frequently than postmenopausalfemale patients (Kim et al. 2012). This couldpotentially be explained by previously reportedgender differences in taste perception (Hyde andFeller 1981).

Recently, a new study has demonstrated thatOD patients may suffer from several additionalmedically unexplained extraoral comorbidities,indicating that OD requires a multidisciplinaryapproach and that OD is probably more

appropriately classified as a complex somatoformdisorder rather than a neuropathic pain entity(Mignogna et al. 2011b).

Diagnosis: Clinical Evaluationand Adjunctive Assessment

History

The diagnosis of OD is considered one of exclu-sion. In order to establish this definitive diagnosis,one must adhere to a strict clinical protocol andwhen necessary employ adjunctive tests (Fig. 1),in order to rule out local factors, such as dentureand/or dental trauma, parafunctional habits, lowsalivary flow or oral disease like fungal infections,and systemic factors, such as vitamin and min-eral deficiencies, endocrinopathies like diabetes,autoimmune disease like pemphigus vulgaris orSjogren’s syndrome, gastroesophgeal reflux, andmalignancies (Fig. 2). The clinical protocolshould involve a thorough medical and dentalhistory as well as a review of systems and listingof all current medications. The history shouldinclude the patient’s description of their presentconcern, including a history of their symptompresentation, any associated symptoms, and adescription of any previous and current treat-ments. The clinician should also elicit a measureof the intensity of the presenting pain usingappropriate scales (numeric rating or visual ana-logue), as well as the character and the distribu-tion of their pain presentation. Factors thataggravate or exacerbate and those that diminishor alleviate their pain should also be included inthe history. Questions regarding previous upperrespiratory tract infections, middle ear disease, orsurgery that may have damaged the chorda tym-pani nerve should be ascertained. The patientshould also be queried about their dietary habitsas well as the use of oral care products. Anappropriate psychosocial history must be part ofa comprehensive history to ascertain the pres-ence or status of any past or current psychosocialstressors or issues.

10 G. Fortuna et al.

Physical Examination

The main function of the clinical examination is toidentify or rule out factors that may contribute tothe patient’s concern. The extra-oral examinationshould include inspection of the head, face, andneck for any evidence of trauma, tumors, or pre-vious radiation therapy. The neck should be eval-uated for any evidence of thyroid enlargement,lymphadenopathy, or lymphadenitis. The tempo-romandibular joint complexes as well as themuscles of mastication should be appropriatelypalpated and jaw function assessed. A cursoryneurologic screening which includes a cranialnerve examination is recommended. The oral cav-ity should be inspected to assess the health of themucosa including all surfaces of the tongue,

periodontium, and dentition. The identificationand assessment of any parafunctional habitsshould be performed. Any dental prosthesisshould be thoroughly evaluated.

Laboratory Studies

Laboratory studies to rule out any local and sys-temic factors that may be responsible for the painpresentation should be ordered and evaluated.Suspicion of a specific secondary etiopathologymay lead to limited and very specific adjunctivetests. If symptoms are due to underlying localand/or systemic factors, then involvement of addi-tional health care providers is often necessary.When all clinical findings are within normal

Presentation with chief complaint of oral discomfort

1.Obtain a complete anamnesis (HPI, PMH, Psychological History, Medications, Allergies, Family history, Social habits)2.Perform a thorough extra-oral examination (TMJ, Head-neck muscles and lymph nodes, Cranial nerves)3.Perform a thorough intra-oral examination (Hard and soft tissues)4.Consult primary care physician for possible discontinuation of medications, potentially OD inducers5.Consult other specialists in case of presence of additional medically unexplained symptoms6.Order additional tests to complete the work-up:

Fasting 1C, Thyroid•Hematological tests (CBC with differential, glycaemia, Hemoglobin A Iron panel, panel, Autoimmune panel,Hormonal panel (for females), Total IgE, H. Pylori testing, Vitamin B complex, Folic acid)

•Salivary flow rate evaluation (stimulated and unstimulated) and possible minor salivary gland biopsy•Electrogustatory tests•Additional radiologic imaging, such as MRI and CT•Allergy tests, especially for dental materials

Before rendering a diagnosis of Oral Dysesthesia, rule out any possible local and/or systemic factors

Local Factors:• Denture and/or dental trauma• Mechanical and chemical irritants• Parafunctional habits• Allergic reaction to dental materials• Low salivary flow• Oral and oropharyngeal diseases• Orofacial pain

Systemic Factors:• Nutritional deficiencies• Endocrine disorders• Autoimmune diseases• Medications• Malignancies• Neurologic conditions• GERD

Fig. 1 Diagnostic algorithm for oral dysesthesia (OD). HPI history of present illness, PMH past medical history, TMJtemporomandibular joint, GERD gastroesophageal reflux disease, PS Psychological History

Oral Dysesthesia 11

limitations, a more comprehensive approach totesting is advisable. Studies usually recommendedwill include a complete blood count (CBC) withdifferential, fasting blood glucose; hemoglobinA1c; thyroid function (TSH,T3/T4); serum iron;ferritin; total IgE; vitamin B6, B12, D; serumantinuclear antibodies (ANA); antibodies to theribonucloproteins 60 kD Ro and La (SSA/Ro,SSB/La); erythrocyte sedimentation rate (ESR);and serum antibodies toH. pylori. Hormonal stud-ies in the female patient may also prove to behelpful, as several studies have shown that hor-monal imbalance such as cortisol, 17-beta estra-diol, may be implicated in oral burning (Kim et al.2012; Suri 2014; Boucher et al. 2014; Jacobs et al.2015; Donovan et al. 2015).

Adjunctive Testing

In some instances, it is prudent to gather addi-tional information in order to be definitive aboutthe diagnosis. As mentioned previously, OD is adiagnosis of exclusion. Imaging of the centralnervous system (CNS) via computed tomography(CT) or magnetic resonance (MRI) should beconsidered if the pain presentation appears morecomplex or atypical of the “normal” presentation.These atypical presentations may include findingsof sensory and/or motor disturbances, autonomicchanges, or any other evidence suggestive of CNSpathology or neurodegenerative processes.

Abnormalities or pathology of the salivarystructures may also be identified on appropriateimaging studies. If allergens are suspected, patch

Fig. 2 Oral disease that may cause oral burning.(a) Mixed red and white patch with central ulcerativelesion on the dorsal tongue consistent with ulcerative orallichen planus. (b) Oral lichenoid reaction of the right lateraltongue with erosive features. (c) Erythematous candidosis

of the dorsum of the tongue. (d) Erythematous and atrophicpatches on the dorsal tongue consistent with erythemamigrans/geographic tongue (Images courtesy of ProfessorCamile Farah, Perth Oral Medicine & Dental Sleep Centre,Perth WA, Australia)


testing may aid in the diagnostic process. Thistesting is typically reserved for patients with evi-dence of a lichenoid-like tissue reaction (Fig. 2)on oral examination, or in a few cases somepatients may develop an oral allergy syndrome,which mimics OD without lichenoid lesions.Sialometry may be used to determine if oraldryness is a key factor. This may involve unstim-ulated whole saliva (�0.1 mg/min), stimulatedwhole saliva (�0.7 mg/min), or perhaps stimu-lated parotid saliva production tests. The amountof saliva flow will vary from individual to indi-vidual and correlates poorly with the subjectivesensation of a dry mouth. However, in some stud-ies, salivary flow rates have shown decreasedunstimulated flow with normal stimulated flow(Poon et al. 2014). Taste testing may be a consid-eration as it is often associated with changes inwhole mouth thresholds (Bartoshuk et al. 2005).

Electrogustatory testing using the measure-ments of taste/tingling detection thresholds ratioand the taste detection thresholds (both elevated inOD patients) may assist practitioners in the diag-nosis of OD (Eliav et al. 2007). Other sophisti-cated testing (quantitative sensory testing) caninclude thresholds for cold, hot, and touch,although there is less data on an individual levelthan some of the other testing (Mo et al. 2015).

However, from a clinical perspective, someof these instrument-based diagnostic testingmethods may be best suited for a research envi-ronment rather than a chair side procedure due totheir cost and time-consuming nature. Eye blinkreflex testing to electrophysiologically examinealterations in the trigeminal–facial nerve systemhas been used to assess abnormalities in ODpatients (Jaaskelainen et al. 1997).

Biopsy of the minor salivary glands is appro-priate if Sjogren’s syndrome is suspected. Biopsyof other tissues should be reserved for instanceswhere pathology is suspected.

Due to the well-established association betweenpsychological and sleep disturbances, and OD,it may be advisable to evaluate the influenceof those factors with appropriate psychometricscales, such as the Symptom Checklist-90-Revised (SCL-90R) and the Minnesota Multi-phasic Personality Inventory (MMPI) to evaluate

the OD patients’ personality, and the HospitalAnxiety and Depression Scale (HADS) and theHamilton anxiety and depression (HAM-A andHAM-D) to evaluate their anxiety and depressivesymptoms. Additionally, we can evaluate thequality of sleep with the Pittsburgh Sleep QualityIndex (PSQI), the Medical Outcomes Study(MOS) Sleep scale, and/or the Epworth sleepi-ness scale (ESS), and the presence of obstructivesleep apnea with the Sleep Apnea Questionnaire(STOP-BANG) or the Berlin questionnaire.

Management

The diagnosis of OD is often challenging, as thedelay in obtaining a definitive diagnosis from thereported onset of symptoms averages 13 months,with a range of 1–34 months, after having seen anaverage of 3.1 medical or dental providers (range0 to 12) over this time span (Mignogna et al.2005). Most frequent misdiagnoses include oralcandidosis or non-specific stomatitis, with nodiagnosis given in 30% of cases (Mignognaet al. 2005). One must have an understanding ofpotential secondary local, systemic, and psycho-logical factors associated with oral burning com-plaints and address them (if potentially present)prior to establishing a diagnosis of primary OD(Klasser et al. 2011). Consequently, treatmentstrategies may initially address presenting symp-toms and associated clinical signs as they presentand make modifications based on response totherapy or results from further investigations.

Empiric treatment is often undertakenduring the process of establishing a diagnosis(Balasubramaniam et al. 2009; Klasser et al.2012). Initially, empiric treatment may be targetedtowards eliminating potential secondary local andsystemic causes of oral burning, which must bedistinguished from true OD not attributable tosecondary factors. This can serve both diagnosticand therapeutic purposes and/or provide analge-sia. In addition, if there are any secondary local,systemic, or psychological causes evident, thenan attempt should be made to address oreliminate them.

Oral Dysesthesia 13

Empiric Treatment TargetingSecondary Causes

Secondary factors may be responsible for oralburning (Fig. 1), which must be addressed beforerendering a diagnosis of OD.

For hyposalivation and xerostomia, patientsmay be encouraged to undergo local salivarystimulating factors (e.g., usage of sugar freegums or candies), use of oral saliva substitutesto ameliorate oral dryness symptoms, and/orbe prescribed systemic salivary stimulants (i.e.,-parasympathomimetics such as pilocarpine orcevimeline). Counseling to patients should begiven regarding modification of oral care prod-ucts, to include alcohol-free mouthwashes andoral care products without flavoring agents orcertain additives such as sodium lauryl sulfate.

If it is established that the patient has a hema-tinic deficiency (i.e., confirmed by abnormallylow serum values as determined by laboratorystudies), then supplementation with appropriatevitamin and mineral replacement is recommendedas an initial measure. Supplementation with vita-min B complex, B12, folic acid, and minerals likeiron and zinc have been demonstrated to lowermean serum homocysteine level and increaseblood hemoglobin levels with reported completeremission of oral symptoms (Sun et al. 2013).

In the case of hormonal abnormalities, suchas hypothyroidism, referral to the physician forappropriate management is warranted. Hormonereplacement therapy with conjugated estrogens(e.g., Premarin 0.625 mg/day for 21 days)and medroxyprogesterone acetate (e.g., Farlutal10 mg/day from day 12 through day 21, for threeconsecutive cycles) have been shown to relieveoral burning symptoms in peri- and postmeno-pausal women (Forabosco et al. 1992). Contrarily,in a large (3,173 females between 50–58 yearsof age) retrospective questionnaire study, it wasreported that the occurrence of burning or painfulmouth seemed to be associated with climactericsymptoms in general but the use of HRT didnot prevent these oral symptoms (Tarkkila et al.2001). Furthermore, other studies have suggestedthe use of HRT has increased the occurrence ofOD (Hakeberg et al. 1997; Maresky et al. 1993).

If there is concern that the patient carries outoral parafunctional activities (e.g., tongue thrust-ing towards roof of the mouth or towards thedentition, bruxism), then the patient may becounseled regarding awareness of these tenden-cies, or interceptive measures may be taken todiminish these habits such as with the use of oralappliances. Appliances such as a soft stent overteeth may also be employed for desensitizing pur-poses or providing protection of affected tissues(Fig. 3) (Axell 2008).

Treatment of Oral Dysesthesia

For OD not attributed to secondary causes, thor-ough patient education regarding the diagnosisand prognosis of the condition is important.Expectations must be set for the patient in thatthere are no consistently proven reliable curativeagents and that symptoms may not be entirelyeliminated. Setting such expectations may resultin improved outcomes in long-term (Bergdahlet al. 1995a).

Management of OD typically involves one ora combination of: topical medications, systemicmedications, and behavioral therapy (Table 1). AsOD is postulated to be a multifactorial chronicneuropathic condition, pharmacologic agents aretargeted to manage symptoms or address

Fig. 3 A soft stent over the mandibular teeth may be usedto protect the affected tissues from being traumatized bythe teeth. (Image courtesy of Dr Amanda Phoon, UWADental School, University of Western Australia, Perth WA,Australia)


Table 1 Therapeutic strategies for oral dysesthesia

Therapeutic strategies Dosage and prescriptiona Potential side effects

Topicalmedications

Benzodiazepine:

Clonazepam (oral rinse) 1 mg/10 mL for 3 min and spit/tid

Sedation

Clonazepam (oraldisintegrating tablets1 mg)

Suck 1 tab for 3 min and spit /tid

Calcineurin inhibitor:

Cyclosporine (oralrinse)

2 mL for 45 s and spit bid for2 weeks and then once daily for2 weeks

NR

Anesthetic:

Lidocaine (gel 2%) Apply 3–5 times per day for1 min

NR

Topical analgesic:

Capsaicin (cream0.025%)

Apply 2 times per day for 1 min Transient worsening of the burningsensation

Nonsteroidal anti-inflammatory:

Benzydamine 0.15%(Oral rinse)

Swish and spit 15 mL/tid for1 min

NR

Antimicrobial:

Lactoperoxidase (oralrinse) (Biotene®)

Swish and spit 15 mL 5 times perday

NR

Mucosal protectant:

Sucralfate (oral rinse20%)

Swish and spit 15 mL/qid NR

Chamomile (gel 2%) Apply 0.5 mL/bid NR

Aloe vera gel at 70% 0.5 mL/tid NR

Low level laser therapy Different types of lasers atdifferent powers with differentschedules per week have beenemployed

NR

Tongue protector Use daily for 15 min/tid NR

Systemicmedications

Benzodiazepine:

Clonazepam 0.5 mg/1–5 times per day Drowsiness, ataxia, palpitations, skinrash, dysuria, anorexia, xerostomia,muscle weakness, diplopia, slurredspeech, tremor, vertigo, hypotension

Chlordiazepoxide 5–10 mg/tid

Diazepam 6–15 mg/day

Anticonvulsants:

Gabapentin 300–2400 mg/day Weight gain, edema of lower limb,dizziness, drowsiness, sexualdysfunction, xerostomia, angioedema,gastrointestinal symptoms (nausea,vomiting, diarrhea), suicidal thoughts,mood disturbances, headache,metabolic acidosis (topiramate)

Pregabalin 50–300 mg/day

Topiramate 50–150 mg/bid

Tricyclic antidepressants:

Amitriptyline 10–50 mg/day Suicidal thoughts, serotonin syndrome,angle-closure glaucoma,QT-prolongation, xerostomia,dizziness and drowsiness, blurredvision, weight gain, trouble urinating,headache, dysguesia, constipation

Nortriptyline 10–50 mg/day

(continued)

Oral Dysesthesia 15

Table 1 (continued)


Atypical analgesic:

Capsaicin 0.25% Tab/tid Gastric pain

Selective serotonin reuptake inhibitors:

Paroxetine 10–40 mg/day Suicidal thoughts, serotonin syndrome,weight gain, gastrointestinal symptoms(nausea, vomiting, diarrhea),xerostomia, dizziness and drowsiness,sexual dysfunction, headache, liverenzymes elevation

Sertraline 50 mg/day

Trazodone 200 mg/day

Selective norepinepherine reuptake inhibitors:

Milnacipran 15–90 mg/day Suicidal thoughts, serotonin syndrome,gastrointestinal symptoms (nausea,vomiting, constipation), xerostomia,dizziness and drowsiness, sexualdysfunction, headache, liver enzymeselevation, hypertension (milnacipran),Stevens-Johnson syndrome(duloxetine)

Duloxetine 20–60 mg/day

Antioxidant:

α-Lipoic acid 600 mg/day Gastric complaints and headache

Atypical antipsychotic:

Amisulpride 50 mg/day Hyperprolactinemia, tardivedyskinesia, xerostomia, dizziness anddrowsiness, sexual dysfunction,headache, weight gain, hyperglycemia,hyperlipidemia, QT prolongation,seizure.

Levosulpride 50–100 mg/day

Aripiprazole 1 mg/day

Olanzapine 2.5–5 mg/day

Quetiapine 12.5–400 mg/day

Dopamine agonist:

Pramipexole 0.125–75 mg/day Somnolence, hypotension,compulsive/psychotic-like behaviors,dyskinesia, nausea, constipation,asthenia, general and peripheral edema

Histamine2 receptor antagonist:

Lafutidine 10 mg/bid Constipation, diarrhea, cutaneous rash,nausea, vomiting, dizziness

Herbal supplement:

Hypericum perforatum 300 mg/tid Anxiety, headache, muscle cramps,sweating, weakness, dry mouth,cutaneous irritation (H. Perforatum),somnolence, insomnia, weight gain,headache, diarrhea, vomiting(Catuama)

Herbal Catuama 310 mg/bid

Sialagogue agents:

Pilocarpaine 5 mg/tid-qid Sweating, runny nose, chills, flushing,frequent urge to urinate, dizziness,weakness, nausea, vomiting, diarrhea,constipation, abdominal cramps,blurred vision

Cevimiline 30 mg/tid

Bethanechol 5 mg/tid

Vitamin supplement:

Vitamin B complex 1 Tab/bid NR

Vitamin C 3000 mg/day

(continued)


comorbid or underlying local, systemic, or psy-chological factors (Klasser et al. 2012). Medica-tions used for OD include antidepressants,analgesics, antiepileptics, anxiolytics, and anti-psychotics. The following are the most commonpharmacological and non-pharmacological strate-gies currently utilized by clinicians.

Topical Medications

Topical clonazepam has been evaluated and iswidely used for treatment of OD. Administrationis in the form of tablets or dissolving wafers (0.25to 0.5 mg with total dose 0.25 to 2 mg daily) thatare sucked for a period of time and expectorated.Alternatively compounded formulations in gel orrinse form may be used to rinse for a period oftime and expectorated. Combination topical andsystemic therapies have been shown to have someefficacy in the treatment of OD (Amos et al. 2011;Barker et al. 2009). In a retrospective evaluationof 36 patients prescribed 0.5 mg of clonazepam

three times daily, the mean patient reported painscore (on a 0 to 10 scale) was reduced by 4.7� 0.4points, with 80% reporting more than a 50%reduction of pain in the 6-month treatment period(Amos et al. 2011).

Capsaicin was thought to inhibit substance P,but more recent studies have shown that it bindsTRPV-1 receptors causing a reduction of pain bya process best described as “defunctionalization”of nociceptor fibers (Anand and Bley 2011).It is available in the form of a 0.025% cream. Aprospective, double-blind cross over study of23 patients with OD involving capsaicin rinse(0.02%) compared to a placebo rinse, yielded sig-nificant differences in pain scores for burningdiscomfort after 1 week of treatment (Silvestreet al. 2012). However, discomfort from its useand increased toxicity limits its use in some patients(Grushka et al. 2002). As an alternative, some rec-ommend amouth rinsemade fromTabasco sauce orhot pepper (Moreno Gimenez 2015).

For analgesia, combination mouthwashescontaining lidocaine and diphenhydramine may

Table 1 (continued)


Artificial sweetener:

Sucralfate (1gmchewing tablets)

1 Tab/qid NR

Hormonal replacement therapy:

Conjugated estrogensandmedroxyprogesteroneacetate

0.625 mg/ day and 10 mg/day,respectively

NR

Behavioraltherapy

Cognitive behavioraltherapy

1 Session per week for12–15 weeks

NR

Group psychotherapy 1 Session per week for 12 weeksat least

Additionaltherapies

Electroconvulsivetherapy

12 Bilateral ECTs underpropofol and succinylcholineanesthesia

NR

Stellate ganglionirradiation

3 min session once a week for7 weeks

Stellate ganglionblockade

5 mL bupivacaine 0.5% Once aweek

Lingual nerve blockade Lidocaine injection

NR Not reported; bid (2 times per day); tid (3 times per day); qid (4 times per day)aDosage and Prescription are those reported in the literature specifically for oral dysesthesia

Oral Dysesthesia 17

be considered; however, contrarily, there is lim-ited data showing that topical anesthetics actu-ally increase burning sensation in OD patients(Formaker et al. 1998). Benzydamine is thoughtto have an analgesic, anesthetic, and anti-inflammatory effect. However, trials with 0.15%benzydamine hydrochloride rinse used three timesdaily have not shown consistent results, and itsavailability is not universal (Buchanan andZakrzewska 2004). Aloe vera gel (70%, applied3 times a day with a tongue protector appliance) hasshown some effectiveness (Lopez-Jornet et al.2013); however, lactoperoxidase and doxepinwere not found to be effective (Table 1).

Systemic Medications

Given the postulated neuropathic etiology ofOD, medications to treat neuropathic pain inother sites have been employed (Silvestre et al.2015). Tricyclic antidepressants (e.g., amitripty-line, desipramine, imipramine, clomipramine, andnortriptyline) have been shown to be effectivesystemic therapies. Typical administration iswith starting dosages of 5–10 mg/day and gradu-ally increasing to 50 mg/day. However, if thereis concern over concomitant dry mouth, thesemay be contraindicated as they may worsen thatcondition. In a comparison of different treatmentmodalities for OD, tricyclic antidepressantswere among the most effective only after habitawareness (Pinto et al. 2003). Selective serotoninreuptake inhibitor and selective serotonin nor-adrenaline reuptake inhibitors such as sertraline(50 mg/day), paroxetine (20 mg/day), andduloxetine (30–60 mg/day) have shown someefficacy (Mignogna et al. 2011a; Van Houdenhoveand Joostens 1995).

One study showed that duloxetine signifi-cantly reduced pain in patients with OD and atyp-ical odontalgia (persistent dentoalveolar pain),with onset of pain-relieving effects being after2 weeks of treatment (Nagashima et al. 2012).Antipsychotics such as amisulpride and levosul-piride have also been investigated and show some

efficacy (Silvestre et al. 2015). A preliminary openlabelled trial of patients taking amisulpride(50 mg/day) for 24 weeks illustrated significantimprovement in reported pain scores for burningmouth symptoms, in addition to improvements inthe Hamilton Rating Scale for Depression(HAM-D) and the Hamilton Rating Scale for Anx-iety (HASM-A), with no adverse effects(Rodriguez-Cerdeira and Sanchez-Blanco 2012).

Evidence on calcium channel blockers such asgabapentin and pregabalin are derived from case-reports, or small open labelled trials showing onlyminimal efficacy for OD (White et al. 2004;Heckmann et al. 2006; Ito et al. 2015).

Alpha-lipoic acid (ALA) has been employedfor other neuropathies. It is thought to work asan antioxidant, regenerate other antioxidantssuch as vitamin C and E, increase intracellularlevels of glutathione, thus acting as a neuro-protective agent that prevents nerve damage byfree radicals. There is limited data showing itseffectiveness for OD symptoms (Femiano 2002).A retrospective review of 31 patients showed 35%of patients reporting some benefit from its use,either reporting feeling “mostly better” (19%)or “somewhat better” (16%) from its use (Steeleet al. 2008). In an open study, a combination600 mg/day of ALA in combination with psycho-analysis was more beneficial than either therapyadministered alone over the same time span(Femiano et al. 2004). In a more recent double-blind, placebo-controlled trial of 60 patients,64% of patients on ALA reported some improve-ment of OD symptoms, with a level of 68.75%maintaining improvement 1 month after treat-ment, compared to 27.6% of patients in the pla-cebo group reporting some improvement (Palacios-Sanchez et al. 2015).

Systemic capsaicin (0.25% capsules, 3 timesa day, for 1 month) was studied in a small ran-domized double-blinded placebo controlled trialof 50 patients (Petruzzi et al. 2004). Patientsassigned to the trial of capsaicin had a slight, how-ever, statistically significant lower reported meanpain scores (5.84 +/�1.17) when compared to theplacebo (6.24 +/�0.96) after 30 days of use.


However, 32% of patients reported significant gas-tric pain; therefore its long-term use may belimited.

Systemic benzodiazepines have shown effi-cacy for patients with anxiety disorders. Medica-tions include clonazepam (0.5 mg/1–5 times perday) and diazepam (6–15 mg/day). A small ran-domized clinical trial of 20 patients randomlyassigned to 0.5 mg/day of clonazepam versus pla-cebo showed a significant improvement in painratings for those on clonazepam, with no significantdifferences in mood scales and depression scores(Heckmann et al. 2012). However, it remains to beseen whether both topical and systemic benzodiaz-epines work by addressing the underlying neuro-pathologic mechanism (Nagler and Hershkovich2004; Amos et al. 2011) (Table 1).

Behavioral Therapy

Psychological support may be indicated in refrac-tory cases with high anxiety or depression.Counseling may be provided for stress manage-ment (Abetz and Savage 2009). Some evidenceshows that cognitive behavioral therapy, compris-ing of weekly 1-h sessions for 4 months, reducedpain symptoms for up to 6 months in OD patients(Bergdahl et al. 1995a). Combination of psycho-therapy and appropriate medications has alsoshown some efficacy (Van Houdenhove andJoostens 1995) (Table 1).

Management of OD is challenging for clini-cians, as treatment is aimed at addressing thevarious contributing and exacerbating factorsand associated symptoms. Patients must be giventhe realistic expectation that definitive cure is notnecessarily attainable, with symptom relief some-times being only partial. Current clinical trials onOD are small and inconclusive, with short follow-up periods and high-variability in outcomes mea-sured. Of the limited trials, there is some datashowing efficacy for clonazepam, capsaicin,ALA, and psychotherapy over short periods oftime. However, further randomized controlled tri-als with larger populations and longer duration of

treatment (i.e., greater than 12 months) areindicated.

Conclusions and Future Directions

Oral dysesthesia still represents an enigmatic andchallenging condition, mostly because classifica-tions and definitions are still ambiguous, diagnos-tic criteria are too vague, etiology is unknown,and pathophysiology appears to be very complex,involving both neurological and psychosocialfactors. Therefore, the management is very com-plex, not universal, and based on a multi-disciplinary approach, the dental practitioner,including the oral medicine specialist, is leftwith no strong evidence-based material to betterassist OD patients, and the OD patients mustaccept the possibility that their oral discomfortmight not entirely resolve even after long-termmanagement.

There is no doubt that sophisticated research isfundamental in the field of etiology and diagnosis-treatment; if we are able to elucidate the underly-ing causes of this condition, we will be able tobetter determine the most appropriate diagnosticprotocol and deliver the most effective therapeuticregimen. To date, few investigations in this direc-tion have been performed making it imperativethat the profession engages in high quality studiesfor this condition. For instance, based on theetiological hypothesis of chorda tympani nervehypofunction, the use of quantitative sensorytesting has been studied, demonstrating the poten-tiality for clinicians to reach an objective diagno-sis of OD (Eliav et al. 2007; Nasri-Heir et al.2011). Other studies have investigated the influ-ence of salivary biomarkers, such as neuropep-tides (Borelli et al. 2010), interleukins (Simcicet al. 2006), and hormones (Kim et al. 2012) thatmight be applicable in clinical practice to helpclinicians with the OD diagnosis.

Similarly, some investigations have demon-strated involvement of the transient receptorpotential channel (TRPV1) and NGF in OD path-ogenesis, and therefore it has been hypothesized

Oral Dysesthesia 19

that both of these might constitute a potentialtarget for future therapies (Yilmaz et al. 2007).

Lastly, considering the increasing evidence ofthe role of psychosocial factors in the pathogene-sis of OD, other than anxiety and depression, abehavioral and psychiatric approach is warranted(Galli et al. 2016) with newer medications(Umezaki et al. 2016), complementary and alter-native remedies (Lopez-Jornet et al. 2011), and/orpsychological (Bergdahl et al. 1995a) or behav-ioral interventions (Arpone et al. 2016).

Despite all of these different therapeuticoptions, a recent Cochrane review on interven-tions for treating OD showed that the numberof clinical trials at low risk of bias is limited.Therefore, there is insufficient evidence to supportor refute the use of any interventions in managingOD (McMillan et al. 2016). Even more interest-ingly, a recent systematic review showed thatresolution of the symptomsmay occur in a portionof the control population as a result of treatmentwith a placebo (Kuten-Shorrer et al. 2014), whileanother study demonstrated that simple informa-tive intervention where clinicians reassure the ODpatient about his/her condition resulted in a sig-nificant reduction of symptoms and better qualityof life (Brailo et al. 2016).

These findings seem to support the conceptthat the oral health-care provider plays a pivotalrole in the overall management of OD patients.This may imply that a therapy for this category ofpatients cannot rely exclusively upon a pharma-cological/psychotherapeutic approach, withoutthe active intervention of an oral health-care pro-vider, who not only reassures the patient abouttheir conditions over many visits (Brailo et al.2016) but also inevitably establishes an emotionalentanglement (transference relationship) with theOD patient with the ultimate aim to alleviate theiroral symptoms and improve their quality of life(Fortuna 2016).

Cross-References

▶Biopsychosocial Aspects of Orofacial Pain▶Classification of Orofacial Pain▶Clinical Evaluation of Oral Diseases

▶Clinical Evaluation of Orofacial Pain▶Clinical Immunology in Diagnoses of Maxillo-facial Disease

▶ Interface between Oral and Systemic Disease▶LaboratoryMedicine and Diagnostic Pathology▶Neuropathic Orofacial Pain▶Neurophysiology of Orofacial Pain▶Neurosensory Disturbances including Smelland Taste

▶Oral and Maxillofacial Fungal Infections▶Oral Manifestations of Systemic Diseases andtheir Treatments

▶Orofacial Pain and Sleep▶Orofacial Pain in Patients with Cancer andMucosal Diseases

▶ Pharmacotherapeutic Approaches in OralMedicine

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