Oral Diseases. 2018;1–12.  | 1wileyonlinelibrary.com/journal/odi

Received:7August2017  |  Revised:7November2017  |  Accepted:8November2017DOI: 10.1111/odi.12807

O R I G I N A L A R T I C L E

The association between burning mouth syndrome and sleep disturbance: A case–control multicentre study

D Adamo1  | A Sardella2 | E Varoni2 | C Lajolo3 | M Biasotto4 | G Ottaviani4 |  P Vescovi5 | T Simonazzi5 | M Pentenero6  | M Ardore6 | F Spadari7 |  G Bombeccari7 | L Montebugnoli8 | DB Gissi8 | G Campisi9 | V Panzarella9 |  M Carbone10 | L Valpreda10 | M Giuliani11 | M Aria12 | L Lo Muzio11† | MD Mignogna1†

1OralMedicineComplexUnit,Head&NeckClinicalSection,DepartmentofNeurosciences,ReproductiveandOdontostomatologicalSciences,“FedericoII”UniversityofNaples,Naples,Italy2UnitofOralPathology,OralMedicineandGerodontology,DepartmentofBiomedical,SurgicalandDentalSciences,AOSanPaoloHospitalofMilan,UniversityofMilan,Milan,Italy3OralPathologyandMedicine,SchoolofDentistry,CatholicUniversityofRome,Rome,Italy4OralMedicineandPathologyUnit,DepartmentofMedical,SurgicalandHealthSciences,UniversityofTrieste,Trieste,Italy5UnitofOralPathology,MedicineandLaserSurgery,DepartmentofBiomedical,BiotechnologicalandTranslationalSciences,UniversityofParma,Parma,Italy6OralMedicineandOralOncologyUnit,DepartmentofOncology,UniversityofTurin,Turin,Italy7UnitofOralPathologyandMedicine,DepartmentofBiomedical,SurgicalandDentalSciences,UniversityofMilan,OspedaleMaggiorePoliclinicoIRCCSCa’GrandaFoundation,Milan,Italy8UnitofOralPathologyandMedicine,DepartmentofBiomedicalandNeuromotorSciences,UniversityofBologna,Bologna,Italy9DepartmentofSurgical,Oncological,andOralSciences,SectorofOralMedicine“ValerioMargiotta”,UniversityofPalermo,Palermo,Italy10OralMedicineSection,DepartmentofSurgicalSciences,CIRDentalSchool,UniversityofTurin,Turin,Italy11DepartmentofClinicalandExperimentalMedicine,UniversityofFoggia,Foggia,Italy12LaboratoryandResearchGroupSTADStatistics,Technology,DataAnalysisDepartmentofEconomicsandStatistics,“FedericoIIUniversityofNaples”,Naples,Italy

©2017JohnWiley&SonsA/S.PublishedbyJohnWiley&SonsLtd.Allrightsreserved

CorrespondenceDanielaAdamo,OralMedicineComplexUnit,Head&NeckClinicalSection,DepartmentofNeurosciences,ReproductiveandOdontostomatologicalSciences,“FedericoII”UniversityofNaples,Naples,Italy.Email:danielaadamo.it@gmail.com

Funding informationTheworkwassupportedbytheDepartmentofNeurosciences,ReproductiveandOdontostomatologicalSciences,OralMedicineUnit,ofthe“FedericoIIUniversityofNaples,”Italy.

Objectives:ToinvestigatethequalityofsleepandthepsychologicalprofilesofalargecohortofItalianpatientswithburningmouthsyndrome(BMS)andtoclarifytherela-tionshipsbetweenthesevariablesandpain.Methods: Inthiscase–controlstudy,200patientswithBMSvsanequalnumberofage-andsex-matchedhealthycontrols,recruitedin10universities,wereenrolled.ThePittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), HamiltonRatingScale forDepression (HAM-D),HamiltonRatingScale forAnxiety (HAM-A),NumericPainIntensityScale(NRS)andTotalPainRatingIndex(T-PRI)wereadminis-tered. Descriptive statistics, including the Mann–Whitney U test and hierarchicalmultiplelinearregressionanalysis,wereused.Results:Poorsleepquality(PSQI≥5)waspresentin78.8%(160)patientswithBMS.BMSpatientshadstatisticallyhigherscoresinallitemsofthePSQIandESSthanthehealthycontrols(p<.001).Adepressedmoodandanxietycorrelatedpositivelywithsleep disturbance. The Pearson correlations were 0.570 for the PSQI vs HAM-D(p<.001)and0.549for thePSQIvsHAM-A (p<.001).Pain intensity (NRS)poorly

†Thelasttwoauthorscontributedequallytothepaper.

2  |     ADAMO et Al.

1  | INTRODUCTION

Burningmouthsyndrome(BMS)isanidiopathic,chronicorofacialpaindisorderinwhichthepatientpresentswiththesensationofburningandpain in theoralmucosa (Grushka,Epstein,&Gorsky,2002), al-thoughthisisnotassociatedwithclinicalmucosalalterationsandlab-oratorytests(Scala,Checchi,Montevecchi,Marini,&Giamberardino,2003;Sunetal.,2013).

Theprevalenceis0.7%–4.6%,withmiddle-agedwomenafterthemenopausemorecommonlyafflicted(Charleston,2013;Spanemberg,RodríguezdeRiveraCampillo,Salas,&LópezLópez,2014).

Theoraldiscomfortsmaybevariableinintensityandcausewith,in severecases, a serious impairment in thepatient’squalityof life.ThesymptomsofBMSusuallycontinueforaminimumof4–6months,remainingconsistentandbilateral,onlyalleviatedatmealtimes;paintendstoincreaseinthelateafternoonorintheevening(Scalaetal.,2003).

Anoral andperi-oralburning sensation is themost frequentlyreportedsymptom,withpatientsoftendescribingthepainasscald-ing,tingling,ornumbing(Grushka,Epstein,&Gorsky,2003).Othersubjective oral symptoms, such as dysgeusia, xerostomia, sialor-rhea,and intra-oral roughnessorgranularitysensation,havebeenreported (Adamo etal., 2015). Commonly, there are no obviousprovoking factors, although in some casesBMSpatients have re-portedantecedentdentalprocedures,theinitiationofnewmedicaltreatment,orstressfullifeevents(Frutos,Rodríguez,Miralles-Jorda,&Machuca,2002).

There is no consensus concerning the etiopathogenesis ofBMSwith conflicting opinions reported in the literature. Some researchstudiesfocusingontheperipheralalterationsindicatethatBMScouldresultfromaneuropathictrigeminalcondition(Jääskeläinen&Woda,2017). In other studies, a central brain dysfunction, such as an im-pairedendogenousdopaminesystem,hasbeenidentified(Hagelbergetal.,2004).Inaddition,severalstudieshaveshownahighprevalenceofpsychiatricdisordersorofpsychologicalproblems(Abetz&Savage,2009;Maina,Albert,Gandolfo,Vitalucci,&Bogetto,2005;Schiavoneetal.,2012)andsleepdisturbance(SD)inBMSpatients(Adamoetal.,2013;Lopez-Jornetetal.,2015).

Sleep is increasingly being recognized as essential to maintainmentalandphysicalhealthwithpoorsleepacknowledgedtocontrib-utetoareducedqualityoflife.

Sleep disturbance includes those disease conditions in whichsleepingpatternsaredisturbedwithasignificantandnegativeimpactonpatienthealth.SDisfrequentlyreportedinthegeneralpopulation,withagreater incidenceamongwomenandpeoplewithpsychiatricdiseases(Morinetal.,2011;Roy&Smith,2010).InsomniaisthemostcommonSD.According toDSM-5,adiagnosisof insomnia isdeter-minedaccordingtothefollowingcriteria:(i)dissatisfactionwithsleepquantityorquality,includingdifficultyinitiatingandmaintainingsleepandwakingup intheearlymorning; (ii)anSDthatcausesaseriousreductioninnormaldaytimeactivity(e.g.,cognitiveimpairment,mooddisturbance, impairedwork function); (iii) an SD that arises at leastthreenightsperweekandhasbeenoccurringforatleast3months;and(iv)asleep impairmentthatariseseven ifthere issufficientop-portunity for sleep [American Psychiatric Association (APA), 2013].Estimatesoftheprevalenceofinsomniadifferaccordingtothecrite-rionunderconsideration.Ingeneral,35%–50%ofthegeneralpopula-tionreportthattheyareaffectedbyoneormoreofthesymptomsofinsomnia(Walsh,Salkeld,Knowles,Tasker,&Hunneyball,2010).

Sleepdisturbance is a complexphenomenonand the subjectofmuchdebate.SomeresearchersconsiderSDtobeaclinicalconditioninitselfbutforothersitisonlyasymptomofanothermentaldisorder(Billiard&Bentley,2004;Leeetal.,2013;Ohayon,2007).Indeed,pa-tientswithSD, frequently,presentwithotherchronic illnessessuchashypertension,diabetes,obesity,depression,andanxiety.Moreover,SDhasafrequentassociationwithsomaticandpainsymptoms(Chung&Tso,2010).

Sleepdisturbance,somaticchronicpain,andmooddisordersareclosely connected (Finan&Smith, 2013;Ohayon, 2009). Sleep andpainhaveareciprocalrelationshipandlongitudinalpopulationstudieshavehighlightedthatSDcanprovokeanincreasedsensitivitytopainleadingtoanexacerbationofothersymptoms.Furthermore,patientsaffectedby chronic pain suffer froman inadequate quality of sleepincluding sleep latency, sleep inefficiency, andawakeningsafter theonsetofsleep(deTommasoetal.,2014).

Various researchstudieshavesuggested thatbetween67%and88% of patients suffering from chronic pain disorders report sleepcomplaints (Morin etal., 2011; Smith & Haythornthwaite, 2004)andthatapproximately50%ofpeopleaffectedbyinsomniapresentchronicpain(Tayloretal.,2007).

The association of SD with a negative mood, particularly withanxiety and depression, has, frequently, been described in relation

correlated tosleepquality; thePearsoncorrelationwas0.162for thePSQIvsNRS(p =.021).Conclusions:TheBMSpatientsshowedapoorsleepquality,anxietyanddepression,as comparedwith the controls, highlighting the relationshipsbetweenoralburning,sleepandmood.

K E Y W O R D S

anxiety,burning,insomniasymptoms,mooddisorders,pain,sleep

     |  3ADAMO et Al.

to common underlying pathophysiological mechanisms (Benca &Peterson, 2008; Cox & Olatunji, 2016; Rumble, White, & Benca,2015).Indeed,depressionandanxietyareregardedbymanycliniciansas risk factors forSD (Smagula,Stone,Fabio,&Cauley,2016)whilepoorsleep,inturn,maybeaprecursorofmooddisordersthatsubse-quentlyarise(Leeetal.,2013;Neckelmann,Mykletun,&Dahl,2007).Moreover, persistent insomnia is frequently reported by depressedpatients,contributingtonon-remission(Ohayon,2007).

Sleep disturbance in BMS is poorly documented, but recentlytherehasbeenincreasingattentiondevotedtothetopic;afewsin-glecenterstudieshaveevaluatedthecomorbiditybetweenmoodandsleepimpairmentsinBMS(Adamoetal.,2013;Chainani-Wu,Madden,&Silverman,2011;Lopez-Jornetetal.,2015).

The aims of the presentmulticenter study have been to ana-lyze the prevalence of insomnia, daytime sleepiness, anxiety, anddepressioninanextensivecohortofItalianpatientswithBMS,com-pared toacontrolgroupofhealthy individuals, and to investigatetherelationshipsbetweenthesevariablesandpaintohaveagreaterawarenessoftheimportanceofSDinthemanagementandtherapyofBMSpatients.

2  | MATERIALS AND METHODS

2.1 | Study design

This observational and descriptive case–control study was carriedoutbetweenMarch2014and January2015.Ten ItalianUniversityOralMedicineUnitsacrossthecountryparticipatedinthestudy.ItiscompliantwiththeethicalprinciplesoftheWorldMedicalAssociationDeclarationofHelsinki.All patients andcontrols gave theirwritteninformedconsent.TheEthicsCommitteeoftheFedericoIIUniversityofNaplesapprovedthestudy(No.222/14).

The reporting of data followed the guidelines of the STROBEstatement.

2.2 | Participants

TwentyBMSpatientsand20healthycontrolsubjectswererecruitedand randomly selected with IBM SPSS software (version 19; IBMcorporationArmonkNY,USA)in10OralMedicineUnitsofdifferentItalianUniversities(sevennorthern,onecentralandtwosouthernuni-versities)makingatotalof200BMSpatientsand200healthycontrolsubjects.

Theidentificationofthesetwogroupswascarriedouttakingintoaccounttheinclusion/exclusioncriteriareportedbelow(Figure1).

The BMS group inclusion criteria were, in accordance withthe International Classification of Headaches (the InternationalClassificationofHeadacheDisorders:3rdedition,2013):

1. Male or female, aged at least 18.2. Continuoussymptomsoforalburningorpainpersistingforatleast2hr/day,lastingforlongerthan3months,withnoparoxysmandnotfollowinganyunilateralnervetrajectory.

3. Noclinicalmucosalalterations.4. Normalbloodtestfindings (includingbloodcount,bloodglucose,serumiron,ferritinandtransferrin,folicacid,andvitB-12levels).

5. Abodymassindex(BMI)lessthan30.

TheBMSgroupexclusioncriteriawereasfollows:

1. Patients with diseases that could be recognized as a causativefactor of BMS.

2. Patientsintreatmentwithanxiolytics,antidepressants,anticonvul-santsand/orpsychotropicdrugs.

F IGURE  1 Flowchartofthestudy

Subjects assessed for eligibility (n = 406)

Patients with BMS(n = 204)

BMS patients included(n = 200)

BMS patients excluded (n = 4):• 2 patients treated with

psychotropic drug• 2 patients with oral symptoms

lasting for less than 3 months

Healthy patients(n = 202)

Healthy patients included(n = 200)

Healhty patients excluded (n = 2):• 1 patient treated with psychotropic

drug• 1 patient with metastatic breast

cancer

4  |     ADAMO et Al.

3. ABMIgreaterthan30.4. Historyordiagnosisofobstructivesleepapnea(OSA).5. Heavysmokers(≥20cigarettes/day)andheavydrinkers(14units/week).

Thecontrolgroupincludedarandomizedclusterofpatientspresent-ingattheUniversityexclusivelyfordentalcare,duringthestudyperiod.

Thehealthysubjectgroupinclusioncriteriawereasfollows:

1. Male or female, aged at least 18.2. Nooralmucosallesions.3. Norecordofpsychiatricillness.4. ABMIlessthan30.

Theexclusioncriteriaencompassed:

1. Patients with debilitating medical conditions.2. Patientsintreatmentwithanxiolytics,antidepressants,anticonvul-sants,and/orpsychotropicdrugs.

3. ABMIgreaterthan30.4. Historyordiagnosisofobstructivesleepapnea(OSA).5. Heavysmokers(≥20cigarettes/day)andheavydrinkers(14units/week).

Body mass index in kg/m2 was calculated from self-reportedweight andheight. Short sleepduration and impaired sleepqual-ityarepositivelyassociatedwithaBMIgreaterthan30.Therefore,wedecidedtoexcludethesesubjectsfromthestudy(Patel&Hu,2008).

Datarelatingtosociodemographicfactorswereanalyzedforeachgroup.

Duringhospitalization,eachsubjectunderwentacarefulmedicalanamnesis,ageneralmedicalexamination,anintra-oralandextra-oralexamination,laboratorytests,andENT(ear,noseandthroat)andpsy-chiatricevaluation.

Thedatacollectionwasperformedbystandardizedclinicalinter-view,conductedbyanindividualinterviewerateachUniversity.

The patients responded to the following evaluation battery scale:

1. The Pittsburgh Sleep Quality Index (PSQI) and the EpworthSleepiness Scale (ESS) for the evaluation of quality of sleep anddaytime sleepiness.

2. The Hamilton Rating Scale for Depression (HAM-D) and theHamiltonRatingScaleforAnxiety (HAM-A)fortheevaluationofdepressionandanxiety.

3. TheNumericPainIntensityScale(NRS)andtheTotalPainRatingIndex(T-PRI)theNRSandT-PRIfromtheshortformoftheMcGillPainQuestionnaire (SF-MPQ) for the assessment of discomfort,painintensity,andquality.

Allthesescaleswereexaminedforcompletenessandwereadminis-teredintheirItalianversion.

2.3 | Assessment of sleep

ThePSQIisastandardizedself-reportquestionnaireevaluatingsleepqualityanddisturbance.Itconsistsof19items,relatingtosevendo-mains:subjectivesleepquality,sleeplatency,sleepduration,habitualsleepefficiency,sleepdisturbance,theuseofsleepmedication,anddaytime dysfunction. For each domain, a direct score is assigned,ranging from0 to3according to thedegreeofseverity (ascoreofzero indicatesnoproblemwhile three indicates a seriousproblem).Thescoresareaddedtogethertoproduceaglobalscorerangingfrom0to21.Globalscoresabovefiveindicatepoorsleepers,suchafindingbeingreportedtohaveahighsensitivity (90%–99%)andspecificity(84%–87%)(Carpenter&Andrykowski,1998).

TheESSisasimple,self-administeredquestionnaireusedtoeval-uatedaytimesleepinessbymeansofeightitems.Thesubjectisaskedtoassesstheprobabilityoffallingasleepineightcommonsituationsthatmostpeopleexperienceindailylife.TheESSscoresforeachitemrangefrom1to3,3indicatingthegreatestprobability.ThetotalESSscoreisthesumoftheseitems,themaximumscorethereforebeing24withacutoffvalueof10.Scoresintherangeof0–9areconsiderednormal,andthose intherangeof10–24indicatea levelofdaytimesleepinessthatwarrantsmedicaladvice(Johns,1991,1992).

2.4 | Assessment of the level of depression and anxiety

TheHAM-Disaratingscaleusedtoevaluatetheseverityofdepres-sivesymptoms.Itincludesaconsiderationof21itemswiththescorerangingfrom0to54.Ascoregreaterthan10indicatesimpairment.Scoresbetween10and17indicatemilddepression,scoresbetween18and24indicatemoderatedepression,andscoresover24indicateseveredepression(Hamilton,1960).

TheHAM-Aisaratingscaledevelopedtomeasuretheseverityofanxietysymptoms.Itevaluates14items,eachdefinedbyaseriesofsymptoms.Scorescanrangefrom0to56.Ascorebelow17indicatesmildanxiety,scoresinthe18-24rangeindicatemildtomoderateanxi-ety,andscoresfrom25to30indicatemoderatetosevereanxiety.Thetestprovidesanassessmentofthedegreeofoverallanxiety,psychicanxiety,andsomaticanxiety.It isalsousedtoassesstheefficacyofanxiolyticandotherpsychotropicdrugsinimprovinglevelsofanxiety(Hamilton,1958).

2.5 | Assessment of pain

Thenumericalratingscale(NRS-11)isusedforanassessmentoftheintensityofpain(painandburning).Thetestisadministeredbymeansofaninterviewperformedbyaclinicianwhoasksthepatienttogivearatingtoreflectthedegreeofpain.Thescalerangesfrom0to10,with0indicatingtheabsenceofanyoralsymptomsand10indicatingtheworstimaginablesymptomintensity.TheNRSisawell-validatedinstrument,whichiseasytoadminister.Itisthereforefrequentlyrec-ommendedforpainassessment,particularlyforanevaluationofthedegreeofanalgesiainresponsetotreatment.

     |  5ADAMO et Al.

TheT-PRIoftheShortformoftheMcGillPainQuestionnaire(SF-MPQ) ofMelzack is a validatedmultidimensional test of perceivedpain.Itgivesusefulinformationonthesensoryandaffectivedimen-sionsoftheexperienceofpain.Itisaself-reportquestionnaireconsist-ingof15descriptors[11sensory(descriptors1–11)andfouraffective(descriptors12–15)].Eachdescriptor is rankedonan intensityscalerangingfrom0to3,0 indicatingtheabsenceofanydiscomfortand3indicatingseverepain.ThetotalT-PRIscoreiscalculatedbyaddingtogethertheitemscores(thetotalscorethereforerangingfrom0to45).Thereisnoestablishedcriticalcutpointforscoreinterpretationbutobviously,asfortheMPQ,thehigheristhescoretheworseisthepain(Hawker,Mian,Kendzerska,&French,2011).

2.6 | Statistical analysis

Demographicandclinicalparametersandscaleshavebeensummarizedusingclassicdescriptivestatistics.DifferencesbetweenBMSpatientsandcontrolshavebeentestedbythetwo-samplesttest,fornormaldis-tributions,andbytheMann–Whitneyprocedurefornon-normaldata.

Thesignificanceoftherelationshipbetweenanyqualitativevari-ableshasbeenmeasuredbythePearsonchi-squaretest.Differencesassociatedwithpvalues less than .05or .01havebeen consideredmoderatelyorstronglysignificant,respectively.

Theoddsofsleepdisturbance,sociodemographiccharacteristics,andconfoundingfactorsamongBMSpatientsandcontrolshavebeencalculatedusingunconditionallogisticregression.Theinternalconsis-tencyofthePSQIhasbeenmeasuredbytheCronbach’salphatesttoestimatethereliabilityofthescores.

The importance of disease-related and psychological factors asdeterminantsofsleepqualityhasbeenmeasuredwithmultipleregres-sionanalysesconsidering,atthesametime,theeffectofdemographiccharacteristics.

3  | RESULTS

Thedemographicandclinicalfindingsrelatingtothepatientsandcon-trolsaresummarizedinTable1.

TABLE  1 SociodemographicandclinicalcharacteristicsofBMSpatientsandcontrolsubjects

Demographic variablesBMS patients, n = 200 Control patients, n = 200

p- ValueMean ± SD Mean ± SD

Age 61.92 ± 12.16 53.91 ± 9.81 <.001**

Yearsofeducation 9.23 ± 4.00 10.20 ± 4.24 .019*

Gender

Male 37(18.5%) 64(32.0%) .002**

Female 163(81.5%) 136(68.0%)

Familystatus

Married 153(76.5%) 147(73.5%) .565

Single 17(8.5%) 21(10.5%)

Divorced 11(5.5%) 23(11.5%)

Widowed 19(9.5%) 9(4.5%)

Employmentstatus

Employed 57(28.5%) 123(61.5%) <.001**

Retired 89(44.5%) 28(14.0%)

Unemployed 54(27.0%) 49(24.5%)

Clinical parameters Median—IQR Median—IQR p- Value

PSQI 9[6–12] 4[2–5] <.001**

HAM-D 13[8–20] 4[2–6] <.001**

HAM-A 16[9–22] 5[2–6] <.001**

ESS 5[2–9] 3[2–4] <.001**

NRS 7[4–8] 0[0–0] <.001**

T-PRI 9[5–14] 0[0–0] <.001**

IQR,interquartilerange;BMS,burningmouthsyndrome;PSQI,PittsburghSleepQualityIndex;HAM-D,HamiltonRatingScaleforDepression;HAM-A,HamiltonRatingScaleforAnxiety;ESS,EpworthSleepinessScale;NRS,NumericPainIntensityScale;T-PRI,TotalPainRatingIndex.ThesignificanceoftherelationshipbetweenthequalitativevariableswasmeasuredbythePearsonchi-squaretest.Thesignificanceofthedifferencebetweenthemeanswasmeasuredbythetwo-samplesttest.ThesignificanceofthedifferencebetweenthemedianswasmeasuredbytheMann–WhitneyU test.*Moderatelysignificant.01<p≤.05.**Stronglysignificantp≤.01.

6  |     ADAMO et Al.

TheBMSpatientsandcontrolsshowedsignificantdifferencesinage,education,gender,andemploymentstatus.ThemeanageoftheBMSpatientsandcontrolswas61.92±12.16and53.91±9.81years,respectively.Themeanofyearsofeducationwas9.23±4.00forthepatientsand10.20±4.24forthecontrols.Thecontrolsarecharacter-izedbyasignificantlyhigherpercentageofemploymentandahigherproportionofmalesthantheBMSpatients.

Inourstudy,thepatientsandcontrolsarenotmatchedduetothelarge sample size. Case–controlmatching isvery difficult to obtain,especiallywhen the matching is related to several factors (Song &Chung,2010).

Therefore,weevaluatedtheeffectofconfoundingfactorsthroughanunconditionallogisticregression.TheresultsareshowninTable2.

Table2showsthattheoddsratiosofthesociodemographicfac-torsbetweentheBMSpatientsandcontrols,exceptforage,donothavesignificantvalues.

TheratiooftheoddsofthePSQIamongthecasesandcontrols,adjustedforconfoundinganddemographicfactors,wassignificantlyhigherthan1(OR1.196).

3.1 | PSQI reliability

InTable3,wereportthereliabilityanalysisofthePSQIcomponentsintheBMSpatients.ACronbach’sαgreaterthan.7andanitem-scalecorrelationgreater than0.3 indicate a satisfactoryoverall reliabilityandagooditemcontributiontothescale,respectively.

3.2 | Sleep quality

TheglobalandcomponentscoresforthePSQIweresignificantlydif-ferentbetweenthepatientsandcontrols(Tables1and4).

Patientswith BMS had highermean PSQI scores, indicating apoorer sleep quality for these patients compared to the healthy

controls; 158 patients (79%) were poor sleepers with a PSQIglobal scoregreater than5.Among theBMSpatients, the clinicalparameters of good (PSQI<5) and poor (PSQI>5) sleeperswerecompared. Depression (HAM-D), anxiety (HAM-A) and daytimesleepiness (ESS)were found to be significantly different betweenthetwogroups(p<.001),while intensityandqualityofpainwerenot (p=.069) (Table5).However, thevalue of theESSwas lowerthan the cutoff of 10 in the poor (median 3) and good sleepers (median6).

3.3 | Dependence of sleep quality

Table6showsthepositivecorrelationbetweendepression(HAM-D)anxiety(HAM-A)andqualityofpain(T-PRI)withsleepquality,andthepoorcorrelationbetweenpainintensity(NRS)anddaytimesleepiness(ESS)withsleepquality.

In addition, in the analysis of the demographic characteristics,yearsofeducationcorrelatednegativelywithsleepqualityandmaritalstatusandjobstatuswerepoorlycorrelatedwithsleepquality.

3.4 | Association with sleep quality

The results of the simultaneousmultiple linear regression analysespredictingsleepqualityareshowninTable7.

Themodeltestingthecontributionofthedemographicvariablesandconfoundingfactorstosleepqualitywasfoundtobestatisticallysignificant(R2=44.5%p≤.001).

Considering demographic variables, only age and marital statusweresignificant.Inaddition,anxietyanddepressionwereconfirmedtohaveastrongeffectonsleepquality.

4  | DISCUSSION

Burningmouthsyndromeisacomplexdisorder,frequentlyassociatedwith extra-oral somatic comorbidity and psychiatric illnesses such

TABLE  2 OddsofPSQIandconfoundingfactorsamongBMSpatientsandcontrols

Variables OR p Value 95% CI for OR

PSQI 1.196 .002** 1.069–1.338

Age 1.042 .017** 1.007–1.077

Education 1.044 .323 0.958–1.137

Female 1.401 .358 0.683–2.872

Married 0.939 .858 0.474–1.861

Employed 0.549 .110 0.263–1.145

HAM-D 1.194 <.001** 1.086–1.313

HAM-A 1.116 .006** 1.032–1.207

ESS 0.982 .721 0.888–1.085

BMS, burning mouth syndrome; PSQI, Pittsburgh Sleep Quality Index;HAM-D,HamiltonRatingScaleforDepression;HAM-A,HamiltonRatingScaleforAnxiety;ESS,EpworthSleepinessScale;OR,oddsratio.ORshavebeencalculatedusingunconditionallogisticregression.*Moderatelysignificant.01<p≤.05.**Stronglysignificantp≤.01.

TABLE  3 ReliabilityanalysisofthePittsburghSleepQualityIndex(PSQI)scaleinburningmouthsyndrome(BMS)patientsandcontrolsubjects

PSQI components

BMS cases Control cases

Item- scale correlation ρ

Subjectivesleepquality 0.55 0.41

Sleeplatency 0.56 0.37

Sleepduration 0.66 0.48

Habitualsleepefficiency 0.65 0.33

Sleepdisturbances 0.36 0.24*

Useofsleepmedications 0.22* 0.47

Daytimedysfunction 0.34 0.13*

Cronbach’salpha 0.76 0.65

*Poorcorrelationbetweenasingleitemandtheglobalscale(ρ<0.3).

     |  7ADAMO et Al.

asdepression, anxiety, andSD (Galli, Lodi, Sardella,&Vegni,2016;Mainaetal.,2005;Mignognaetal.,2011).

Previousresearcharticleshaveanalyzedtheroleofsleepdysfunc-tioninBMS;inourpreviousstudy,wefoundaprevalenceofSD,in-cludinginsomniaanddaytimesleepiness,in80%ofpatientswithBMS(Schiavone etal., 2012). In accordancewith our data, Lopez-Jornetetal.(2015)foundSDin67.1%ofpatientswithBMScomparedwith

acontrolgroupofhealthysubjects.Adamoetal. (2013)andArbabi-Kalati,Bakhshani,Tahmtan, andMovahedinejad (2015) foundSD in78%ofpatientswithBMSvs38.7%ofhealthysubjects.

Inaddition,arecentretrospectiveworkon47,941Taiwanesepa-tientswithSDhasdemonstratedthatpoorsleepincreasestheriskofBMS,highlightingtheimportanceofsleepimpairmentinthisdisease(Leeetal.,2014).

PSQI components

BMS cases Control cases

p- ValueMedian IQR Range Median IQR Range

Subjectivesleepquality

1 1–2 0–3 1 0–1 0–2 <.001**

Sleeplatency 1 0–2 0–3 0 0–1 0–3 <.001**

Sleepduration 1 0–2 0–3 1 0–1 0–3 <.001**

Habitualsleepefficiency

1 0–2 0–5 0 0–1 0–3 <.001**

Sleepdisturbances

1 1–2 0–3 1 1–1 0–3 <.001**

Useofsleepmedications

1 0–3 0–3 0 0–0 0–3 <.001**

Daytime dysfunction

1 0–3 0–3 0 0–0 0–2 <.001**

IQR,interquartilerange.BMS,burningmouthsyndrome;PSQI,PittsburghSleepQualityIndex.ThesignificanceofthedifferencebetweenthemedianswasmeasuredbytheMann–WhitneyU test.*Moderatelysignificant.01<p≤.05.**Stronglysignificantp≤.01.

TABLE  4 ComparisonofcomponentsofthePSQIinBMSpatientsandcontrolsubjects

TABLE  5 ComparisonbetweenBMSpatientgoodandpoorsleepers

PSQI components

PSQI ≤ 5 (n = 42, 21.0%) PSQI > 5 (n = 158, 79.0%)

p-ValueMedian IQR Range Median IQR Range

Depression(HAM-D) 6 2–11 0–22 16 10–21 6–36 <.001**

Anxiety(HAM-A) 8 3–16 0–25 18 13–22 12–56 <.001**

Daytimesleepiness(ESS) 3 0–6 0–12 6 3–9 0–17 <.001**

NRS 5 4–8 0–10 7 4–8 0–10 .069

T-PRI 7 4–11 0–36 9 6–15 0–40 .069

Frequencies (%) Frequencies (%) p-Value

Depression(HAM-D)

0–9 29(69.0%) 39(24.7%) <0.001**

10–17 11(26.2%) 53(33.5%)

18–24 2(4.8%) 45(28.5%)

>24 0(0%) 21(13.3%)

Anxiety(HAM-A)

0–17 34(81.0%) 76(48.1%) <0.001**

18–24 7(16.7%) 47(29.7%)

>24 1(2.4%) 35(21.5%)

IQR,interquartilerange;BMS,burningmouthsyndrome;PSQI,PittsburghSleepQualityIndex;HAM-D,HamiltonRatingScaleforDepression;HAM-A,HamiltonRatingScaleforAnxiety;ESS,EpworthSleepinessScale;NRS,NumericPainIntensityScale;T-PRI,TotalPainRatingIndex.ThesignificancedifferencebetweenthemedianswasmeasuredbytheMann–WhitneyU test.*Moderatelysignificant.01<p-value≤.05.**Stronglysignificantp-value≤.01.

8  |     ADAMO et Al.

In this present Italian multicenter study, in agreementwith thefindingsofotherstudiesreportedinliterature,wehavefoundaprev-alenceofSDin79%(158)ofBMSpatients.

Incontrastwithourpreviousstudy,wedidnotfindanydaytimesleepiness in the poor sleeper patientswith BMS. However, in theliterature,patientswith insomniareported,overtime,daytimefunc-tional impairment, with sleepiness, and concentration and memoryloss (Ancoli-Israel&Roth,1999).Therefore, thesedataarepossiblyrelatedtoamorerecentonsetofSDinoursampleofpatients.

RegardingtheassociationofmooddisorderswithchronicpainandwithBMS,itiswellknown,asseveralstudieshavedemonstrated,thatanxietyanddepressionmaybe importantcausativeandaggravatingfactors inBMS (Buljan, Savić,&Karlović, 2008). In a recent reviewarticle,Gallietal.(2016)confirmedthatpsychiatricfactorsplayaroleinBMSandthatanxietyanddepressionseemtobethemostcommoncomorbiddiseasesamongpatientswithBMS.

Inoursample,wefoundmilddepressionandmildanxietyinthepatientswithBMScomparedwiththehealthysubjects.InthepoorsleeperBMSpatients,we found a higher prevalence ofmoderateandseveredepression(41.8%),andahigherprevalenceofmoder-ate and severe anxiety (51.2%) suggesting also an important rela-tionshipbetweensleepandmood.ThesedataareconfirmedinthedependenceanalysisinTable7(pvalue<.001**)andremainsignif-icant in themultiple simultaneous regression analyses confirming

thatdepressionandanxietymaybeimportantriskfactorsofSDinBMSpatients.However,while in our previous study the standardmultipleregressionanalysisof thefinal fullmodel inwhichall thevariables were entered simultaneously could explain 62% of thevariance insleepquality, inthecurrentstudythemodelcouldex-plainonly44.5%ofthevariance.Thesedatahighlightthatanxietyand depression have an important role in sleep quality, but that,sometimes,poorsleepinBMSpatientsmaybeanindependentfac-torthatshouldbeanalyzedandtreatedseparately.Furthermore,asitisanindependentfactor,itcouldhaveanonsetbeforethatoftheBMSsymptoms.

Although it iswidely assumed that SD is a common comorbid-itywithpsychiatricdisorders,mostnotably inmajordepression,andshouldbeconsideredasanassociatesymptom(secondaryinsomnia),morerecentlyaccumulativeevidencehassuggestedthatinsomniaisnot necessarily an epiphenomenon, and should be considered as aseparatedisease/disorder(primaryinsomnia).

Theauthorsofsuchstudieshavehypothesizedthatinsomniahasbeenconsideredasaprimarydisorderonlyintheabsenceofanyclin-icallyrelevantpsychiatricdisease(Baglionietal.,2011;Harvey,2001).

Primary insomnia is also a predictor of depression; individ-ualswith SD, especiallywomen, have a higher risk of developingdepression (Baglioni etal., 2011; Riemann & Voderholzer, 2003).Timesequenceanalysisfromseveralstudiesshowsthattheonset

TABLE  6 DependenceofsleepqualitywithclinicalparametersanddemographiccharacteristicsforBMSpatients

Clinical parameters Pearson ρ coefficient p-Value

Depression(HAM-D) 0.570 <.001**

Anxiety(HAM-A) 0.549 <.001**

Daytimesleepiness(ESS) 0.159 .024*

NRS 0.162 .021*

T-PRI 0.191 .006**

Demographic characteristics Pearson ρ coefficient p-Value

Age 0.197 .005**

Yearsofeducation −0.099 .159

Median—IQR Median—IQR p-Value

Gender Male 9.0;[5.5–12.3]

Female 9.0;[6.0–12.0]

.613

Marital status Yes9.0;[6.0–13.0]

No 8.0;[4.3–9.8]

.030*

Employment Yes 8.0;[4.0–11.0]

No 9.0;[7.0–13.0]

.015*

IQR, interquartile range; BMS, burning mouth syndrome; HAM-D,HamiltonRatingScaleforDepression;HAM-A,HamiltonRatingScaleforAnxiety; ESS, Epworth Sleepiness Scale; NRS, Numeric Pain IntensityScale;T-PRI,TotalPainRatingIndex.For thenumerical variables, thep-valueswereobtainedby thePearsoncorrelationtest.Forthequalitativecharacteristics,thep- values were ob-tainedbytheMann–Whitneytest.*Moderatelysignificant.01 < p-value ≤.05.**Stronglysignificantp- value ≤.01.

TABLE  7 MultiplelinearregressionmodelpredictingsleepqualityinBMSpatients

Predictors Beta SE T statistics p- Value

Intercept −2.091 2.223 −0.941 .348

Age 0.080 0.025 3.223 .001**

Yearsofeducation

0.029 0.074 0.399 .691

Gender:female 0.268 0.630 0.426 .671

Marital status: married

1.495 0.566 2.643 .009**

Occupation:yes −0.004 0.679 −0.006 .995

Depression(HAM-D)

0.207 0.045 4.587 <.001**

Anxiety(HAM-A) 0.131 0.039 3.391 .001**

Daytime sleepiness(ESS)

0.082 0.067 1.234 .219

NRS −0.115 0.115 −1.002 .318

T-PRI −0.022 0.041 −0.552 .582

Modelgoodnessoffitstatistics

R2=41.4%;F statistics = 14.76; p-value < .001**

BMS, burning mouth syndrome; HAM-D, Hamilton Rating Scale forDepression; HAM-A, Hamilton Rating Scale for Anxiety; ESS, EpworthSleepiness Scale; NRS, Numeric Pain Intensity Scale; T-PRI, Total PainRatingIndex.SEarethestandarderrorsofthebetaestimates.Thep-values were ob-tainedbythehypothesistestonregressioncoefficients.*Moderatelysignificant.01 < p-value≤ .05.**Stronglysignificantp- value ≤ .01.

     |  9ADAMO et Al.

of insomnia canprecede, evenby severalyears, the firstonsetofdepressioninmanycases(Johnson,Roth,&Breslau,2006;Ohayon& Roth, 2003). Riemann and Voderholzer (2003) reported thatsymptomsof insomnia for aperiodof at least2weekspredict anincreasedriskofdevelopingdepressionwithinthefollowing3years.Itwould seem that insomnia has a higher predictivevalue for fu-turedepressionthananxiety(Jansson-Fröjmark&Lindblom,2008;Morphy,Dunn,Lewis,Boardman,&Croft,2007).

Inaddition,SDalsoplaysanimportantroleindepressionrelapseandthetransitioningofdepressionintoachronicstatebecauseitcanrepresentaresidualphaseofamajormooddisorder(Falussy,Balla,&Frecska,2014;Perlisetal.,2006).

In thiscontext, theearlydetectionandtreatmentofSD inBMSpatientswithoutanyhistoryofdepressionandanyevidenceofanxietyanddepression(HAM-DandHAM-A<7)canresultinbothasignifi-cantimprovementinthepatient’squalityoflifeandalsointhepreven-tionofsecondarymooddisorders.Inaddition,inpatientswithBMS,withanxietyanddepressionwithanSDcomorbidity,thetreatmentofresidualinsomniaisnecessarynotonlytoaidtheremissionofdepres-sionbutalsotopreventanyrelapse.

Moreover,changesinsleeppatternsareapartofthenormalagingprocessandincreasingageisassociatedwithinsomnia(Schubertetal.,2002);thesedatawereconfirmedinourstudybythemultiplesimul-taneousregressionanalyses inwhichage isan importantriskfactorofSD.

Inaddition,wefoundacorrelationbetweenmaritalstatusandSDinwhichmarriedpatientsarepronetodevelopinsomnia;thisispossi-bleconsideringthatanegativemaritalrelationshipincreasedtheriskofinsomniasymptomsthroughanincreaseinmooddisorders;thesedatawereconfirmedbyapreviousstudy(Chen,Waite,&Lauderdale,2015).

Regarding the relationshipsbetweenpainandSD inour samplepatientswithBMS,nostatisticallysignificantdifferencesinthequalityandintensityofpainbetweenthepoorandgoodsleeperswithBMSwerefound,becausetheNRSandT-PRIvalueswerehigher inbothgroups(themedianvaluesoftheNRSandT-PRIinthegoodsleeperswere5and7andinthebadsleepers7and9,respectively).Thisresultwasinaccordancewithourpreviousstudy(Schiavoneetal.,2012)butin contrastwith the studyof Lopez-Jornet etal. (2015)wherepoorsleeperBMSpatientswerepronetoincreasedpain.

The relationshipbetweenSDandpain iscomplexandnotcom-pletely understood; significant research studies report that thisrelationship is bidirectional (Fishbain, Hall, Meyers, Gonzales, &Mallinckrodt,2008).

Sleepdisturbance is frequently reportedbypatientsafflictedbychronicpain,butitisoftenseenasasecondarysymptomratherthananindependentsymptom.Becausepainmediatessleepproblems,ad-equatepainmanagementisthoughttoleadtoimprovedsleepinpa-tientswithchronicpain(Park,Yoon,Yoon,Moon,&Kim,2016;Power,Perruccio,&Badley,2005).

However,thispointofviewhasshiftedovertimewithnewev-idence suggesting insomnia as the primary disorder from whichchronicpainoftendevelops(Asih,Neblett,Mayer,Brede,&Gatchel,

2014); recently, Finan, Goodin, and Smith (2013) have found thatsleep impairments are a reliable predictor of the recurrence andworsening of chronic pain, to a greater extent than pain predictssleepimpairments.Inagreement,Walsh,Muehlbach,Lauter,Hilliker,and Schweitzer (1996) showed that benzodiazepine, by enhancingsleepquality, relievedthesubjectivesymptomsof jointpain inpa-tientswith rheumatoidarthritisevenwhen therewasnoobjectiveimprovement.

Thesedatahavebeenconfirmedbyresearchsuggestingthatmanypatients with chronic pain continue to experience sleep problemsevenwhen good pain control is achievedwhile an improvement ofinsomniaresultsinbetterpaintreatmentoutcomesinthesepatients(Gustavsson&vonKoch,2006;Tang,2008).

Fromabiophysiologicalperspective,insomniaislinkedtoahigherproduction of inflammatorymediators,which can potentially aggra-vatepain,causingahyperalgesicstatewithalowpainthreshold,andleadingtoaninabilitytosufficientlyactivatethepaininhibitorypath-ways(Haacketal.,2012).Thiseffectremainsevenaftertheotherpsy-chologicalsymptomsarecontrolled(Quartana,Finan,Page,&Smith,2015;Spiegel,Leproult,&VanCauter,1999).

Moreover,inpatientssufferingfromamajordepressivedisorder,insomniaisasignificantpredictorofpain,evenaftercheckingfortheseverityofanxietyanddepression(Ohayon,2007).

Inourstudy,aclearrelationshipbetweeninsomniaandpaincouldnotbeestablishedbecause the intensityofpainwashigher inbothgoodandpoorsleepers.Apossiblebiasofourstudycouldbethelackofanyanalysisofthedurationeitheroftheillnessortheinsomnia;itmaynotbeunlikelythatprolongedpain,overtime,maycauseSDaswellasthatpersistentinsomniamayworsentheperceptionofsymp-toms in patients with BMS, contributing to an exacerbation of thedisease.

This studyhashighlighted the complexityofBMS inwhich it isnecessarytoconsiderthepsychologicalprofileofBMSpatients,andthepresenceofpainandinsomnia,tohaveamorecompleteassess-ment. Anxiety, depression, and sleep are, in some cases, intercon-nected,eachaffectingeachother.SDandmooddisorders leadtoacontinuouslyperpetuatingcycleandcanaggravateBMSandpreventhealing.However,manypatientsmayhave a primary insomnia thatrequiresaspecificassessmentandtreatment.

Finally, the findings from this study lead to the conclusion thatsleep quality should also be considered in the treatment approachforBMSbecausethemanagementofSDmaynotonlyamelioratethesymptomsofBMSbutalsoaiddepressionremissionand/orpreventlate-lifedepression.

4.1 | Study limitations

Our study has several limitations that suggest directions for futureresearch.

First,ourfindingsarecross-sectionalinnature,limitingourabilityto identifyacausalrelationshipbetweenpsychologicalfactors,pain,and sleep disturbance. Prospective and longitudinal studies with acleartemporalprecedenceandcausalityareneededtoevaluatethe

10  |     ADAMO et Al.

influenceofpsychologicalsymptomsand insomniaonpain intensityinBMS.

Secondly, the sleep assessmentwas based on self-report ques-tionnaireswithout any confirmation by full-night polysomnographicstudies of poor sleeper patients. However, questionnaires could beconsideredasaninitialevaluationofSDandsubsequentlyintegratedwithotherdiagnosticinvestigationsinpatientswithimpairedsleep.

5  | CONCLUSIONS

Thisisthelargestmulticentrestudythathasconfirmedthecomorbid-ity of sleepdisturbances andmooddisorders in patientswithBMSsuggestingthatSDandmooddisordersareacommonproblemandanaggravatingfactorinBMS.Incontrast,painintensityandqualitydidnotcorrelatewithsleepquality.

Thesefindingsconfirmthenecessityofamultidisciplinaryteamap-proach inwhicha close collaborationbetweendentists, psychiatrists,psychologists,andneurologistsisrequiredfortheevaluationofcomor-biditiesandforasuitablyindividualizedsequentialtreatmentofpatients.

Clinicianscouldevaluatetherapiesnotonlytoreducepainbuttoimprovesleepandtoreducelevelsofanxietyanddepression,consid-eringantidepressant andanticonvulsants in themanagementofpa-tientswithBMS.Treatmentshouldbeindividualizedforeachpatientinrelationtothepatient’sage,gender,comorbidity,systemicdiseases,anddrugintake.

Future studies should try tobetterunderstand the relationshipsbetweenpain,SD,andmooddisorderstodeterminewhichoftheseconditionsoccursfirstand,accordingly,whichstrategyisthemostef-fectiveintermsofimprovingthetreatmentofBMS.

CONFLICT OF INTEREST

Alloftheauthorsdeclarethattheydonothaveanyconflictofinterest.

AUTHOR CONTRIBUTIONS

Allauthorshavecontributedintheresearchdesign,acquisition,analy-sisandinterpretationofdata.Allauthorshaveapprovedthefinalver-sionofthepaper.

ETHICAL APPROVAL

Thisstudyhasbeencarriedoutinaccordancewiththeethicalstand-ardsoftheinstitutionaland/ornationalresearchcommitteeandwiththe1964Helsinkideclarationanditslateramendmentsorcomparableethical standards. Informedconsentwasobtained fromall the indi-vidualparticipantsincludedinthestudy.

ORCID

D Adamo http://orcid.org/0000-0002-3784-4229

M Pentenero http://orcid.org/0000-0003-3972-1203

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How to cite this article:AdamoD,SardellaA,VaroniE,etal.Theassociationbetweenburningmouthsyndromeandsleepdisturbance: A case–control multicentre study. Oral Dis. 2018;00:1–12. https://doi.org/10.1111/odi.12807