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OfficialreprintfromUpToDate www.uptodate.com2015UpToDate

AuthorsMichaelHBonnet,PhDDonnaLArand,PhD

SectionEditorRuthBenca,MD,PhD

DeputyEditorAprilFEichler,MD,MPH

ThecontentontheUpToDatewebsiteisnotintendednorrecommendedasasubstituteformedicaladvice,diagnosis,ortreatment.Alwaysseektheadviceofyourownphysicianorotherqualifiedhealthcareprofessionalregardinganymedicalquestionsorconditions.TheuseofthiswebsiteisgovernedbytheUpToDateTermsofUse2015UpToDate,Inc.

Treatmentofinsomnia

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.Literaturereviewcurrentthrough:May2015.|Thistopiclastupdated:Apr17,2015.

INTRODUCTIONInsomniawaspreviouslyviewedasasleepdisturbancethatwassecondarytoamedicalcondition,psychiatricillness,sleepdisorder,ormedication,andwouldimprovewithtreatmentoftheunderlyingdisorder[1].However,evidenceoverthepast20yearsindicatesthatthisviewisincorrect.

Itisnowrecognizedthatinsomniaisoftenanindependentdisorder[2,3].Insomniamayoccurintheabsenceofcoexistingconditionsand,whencoexistingconditionsexist,maypersistdespitesuccessfultreatmentofthecoexistingcondition.Treatmentdirectedattheinsomniaandthecomorbiditymaybenecessary.Sinceinsomniacanprecipitate,exacerbate,orprolongcomorbidconditions,treatmentofinsomniamayimprovecomorbidities[47].

Treatmentofinsomniaisdescribedinthistopicreview.Thedefinition,types,epidemiology,clinicalfeatures,consequences,anddiagnosticevaluationofinsomniaarereviewedelsewhere.(See"Overviewofinsomnia"and"Clinicalfeaturesanddiagnosisofinsomnia".)

GENERALAPPROACHAllpatientswithinsomniashouldreceivetherapyforanymedicalcondition,psychiatricillness,substanceabuse,orsleepdisorderthatmaybeprecipitatingorexacerbatingtheinsomnia(table1).Theyshouldalsoreceivebasicbehavioralcounselingaboutsleephygiene(table2)andstimuluscontrol(table3).

Forpatientswhocontinuetohaveinsomniathatissufficientlyburdensometowarrantotherinterventions,reasonableapproachesincludebehavioraltherapy,medication,orboth:

Theapproachshouldbeindividualizedaccordingtothepatient'svaluesandpreferences,theavailabilityofadvancedbehavioraltherapies,theseverityandimpactoftheinsomnia,andthepotentialbenefitsversustherisks,costs,andinconveniences.Giventhepotentialsideeffectsassociatedwithpharmacologictherapyandtoalesserextentwithbehavioraltherapy,thedecisiontotreatchronicinsomniamustalsofactorinthepotentialhealthrisksofnotprovidingtreatment,whichincludedecreasedqualityoflife,increasedriskforpsychiatriccomorbiditiesandsubstanceabuse,decreasedperformance,andtheassociationbetweenchronicinsomniaandriskofcardiovascularmorbidityandallcausemortality.(See"Overviewofinsomnia",sectionon'Consequences'.)

Behavioraltherapiesbeyondsleephygieneandstimuluscontrolincluderelaxation,sleeprestrictiontherapy,cognitivetherapy,andcognitivebehavioraltherapy.Thesetherapiesarenotavailableinallmedicalcenters.(See'Behavioraltherapy'below.)

Approvedmedicationsusedtotreatinsomniaincludebenzodiazepines,nonbenzodiazepinesedatives,melatoninagonists,andantidepressants.(See'Medications'below.)

Combinationtherapyinvolvesinitiallyprescribingbothcognitivebehavioraltherapyandamedication(usuallyforsixtoeightweeks),thentaperingthemedicationoffortoanasneededschedulewhilecontinuingcognitivebehavioraltherapy.(See'Combinationtherapy'below.)Theuseofmedicationpriortotheinitiationofbehavioraltherapyappearstobelesseffective[8].

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Inclinicalpractice,initialtreatmenttypicallyinvolvessleephygieneinstructionandstimuluscontrolprocedures.Iffollowupindicatesthatfurthertreatmentisneeded,thenmoreformalcognitivebehavioraltherapyaloneorincombinationwithamedicationmaybeusedforsixweeks.Forpatientswhorespondtotherapy(ie,reportbothimprovedsleepatnightandimprovementofdaytimedeficits),themedicationcanbetaperedorusedasneededwhilecontinuingthecognitivebehavioraltherapy.Patientswhosesymptomsrecurafterdiscontinuationoftherapymayrequirereevaluationforreferralforpolysomnographyoradditionalcognitivebehavioraltherapy,withorwithoutpharmacologictherapy.Anexceptiontothisapproachispatientswhohaveshortterminsomniaduetoaselflimitedstressorsuchpatientsmaybenefitfromshorttermmedicationalone.

BEHAVIORALTHERAPYBehavioraltherapiesforinsomniaincludesleephygieneeducation,stimuluscontrol,relaxation,sleeprestrictiontherapy,cognitivetherapy,andcognitivebehavioraltherapy.Patientswhoseinsomniahasbeensuccessfullytreatedbybehavioraltherapyarelikelytoreportdecreaseddaytimesymptomsandimprovementofdaytimefunction,qualityoflife,andcomorbidities.Behavioraltherapyiswelltoleratedandhasalowriskofadverseeffects,butitisnotreadilyavailableinmanyplaces.

Behavioraltherapybeyondanintroductiontosleephygieneandstimuluscontrolistypicallyimplementedoveraseriesofapproximately6to10sessions.Theevidencesuggeststhatthesuccessofthetherapyisrelatedtotheexperienceoftheindividualimplementingit[9].

SleephygieneSleephygienereferstoactionsthattendtoimproveandmaintaingoodsleep(table2)[10]:

Sleephygienecounselingalonehasnotbeendirectlycomparedwithnointerventionorashamintervention.However,numerousclinicaltrialshaveusedsleephygienecounselingaloneasthecontrolinterventionandshowedsomeimprovementinsleepbutlessthanthatseenwithpharmacotherapyorcognitivebehavioraltherapy[1214].

StimuluscontrolPatientswithinsomniamayassociatetheirbedandbedroomwiththefearofnotsleepingorotherarousingevents,ratherthanthemorepleasurableanticipationofsleep.Thelongeronestaysinbedtryingtosleep,thestrongertheassociationbecomes.Thisperpetuatesthedifficultyfallingasleep.

Stimuluscontroltherapyisastrategywhosepurposeistodisruptthisassociationbyenhancingthelikelihoodofsleep(table3)[15].Patientsshouldnotgotobeduntiltheyaresleepyandshouldusethebedprimarilyforsleep(andnotforreading,watchingtelevision,eating,orworrying).Theyshouldnotspendmorethan20minutesinbedawake.Iftheyareawakeafter20minutes,theyshouldleavethebedroomandengageinarelaxingactivity,suchasreadingorlisteningtosoothingmusic.Patientsshouldnotengageinactivitiesthatstimulatethemorrewardthemforbeingawakeinthemiddleofthenight,suchaseatingorwatchingtelevision.Inaddition,theyshouldnotreturntobeduntiltheyaretiredandfeelreadytosleep.Iftheyreturntobedandstillcannotsleepwithin20minutes,theprocessshouldberepeated.Analarmshouldbesettowakethepatientatthesametimeeverymorning,includingweekends.Daytimenapsarenotallowed.

Patientsmaynotimproveimmediately.However,accumulatingsleepinesswillfacilitatesleepduringsuccessivenights.

Sleepaslongasnecessarytofeelrested(usuallyseventoeighthoursforadults)andthengetoutofbedMaintainaregularsleepschedule,particularlyaregularwakeuptimeinthemorningTrynottoforcesleepAvoidcaffeinatedbeveragesafterlunchAvoidalcoholnearbedtime(eg,lateafternoonandevening)Avoidsmokingorothernicotineintake,particularlyduringtheeveningAdjustthebedroomenvironmentasneededtodecreasestimuli(eg,reduceambientlight,turnoffthetelevisionorradio)

Avoidprolongeduseoflightemittingscreens(laptops,tablets,smartphones,ebooks)beforebedtime[11]ResolveconcernsorworriesbeforebedtimeExerciseregularlyforatleast20minutes,preferablymorethanfourtofivehourspriortobedtimeAvoiddaytimenaps,especiallyiftheyarelongerthan20to30minutesoroccurlateintheday

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Stimuluscontroltherapyhasimprovedsleepinrandomizedtrialsanditseffectsmaybelonglasting[1618].Onestudysuggestedthatstimuluscontroltherapyismoreeffectiveamongpatientswhoarenotalreadytakingmedicationsforinsomnia[19].

RelaxationRelaxationtherapymaybeimplementedbeforeeachsleepperiod.Therearetwocommontechniquesforrelaxationtherapy:progressivemusclerelaxationandtherelaxationresponse.

Onetrialrandomlyassigned57patientswithinsomniatoreceiveprogressiverelaxationtherapyornotherapy[20].Progressiverelaxationtherapyimprovedmeasuresofsleep,butnotdaytimefunction.Anotherrandomizedtrialsimilarlyfoundimprovementinsleepmeasuresamongpatientswhoreceivedrelaxationtherapycomparedwithashamtherapy,buttheimprovementwasmodestandsmallerthanthatachievedwithcognitivebehavioraltherapy[21].Relaxationtherapyissometimescombinedwithbiofeedbacktoreducesomaticarousal.

SleeprestrictiontherapySomepatientswithinsomniastayinbedlongertotrytomakeupforlostsleep.Thiscausesacircadianshiftandareductioninthehomeostaticdrivethatmakessleeponsetthefollowingnightmoredifficultandresultsintheneedtostayinbedevenlonger.Sleeprestrictiontherapycounteractsthistendencybylimitingthetotaltimeallowedinbed,includingnapsandothersleepperiodsoutsideofbed,inordertoincreasethedrivetosleep[22].Thisconsolidatessleepandimprovessleepefficiency(thepercentageoftimeinbedthatthepatientisasleep).

Sleeprestrictiontherapybeginsbydecreasingthetimespentinbedtothesameamountoftimethatthepatientreportssleeping(usuallydeterminedfromsleepdiariesorlogscompletedbythepatient),butnotlessthanfivehourspernight(table4).Onadailybasis,thepatientreportstheamountofsleepobtainedthepreviousnightandtheamountoftimespentinbed.Theclinicianthencomputesthesleepefficiency,whichisthereportedtimeasleepdividedbythereportedtimeinbed.Thetimeinbedisincreasedby15to30minutesoncethesleepefficiencyexceeds85percent.Thisprocessisrepeateduntilthepatientreportsimprovedsleepwithoutresidualdaytimesleepiness.However,totaltimeinbedforsomepatientscanremainatsixhoursorlessforlongperiodsoftime.Napsarenotpermitted.

Toimprovecompliance,therationaleforthetherapyneedstobecarefullyexplainedtopatientsandsomecareneedstobeusedtodetermineandschedulethetimeinbedinamannerthatmaximizestheabilitytosleepandisacceptabletothepatient.Olderpatientstendtohavemoredifficultymaintainingsleepevenwhenrestrictedtherefore,theyaregivenmorelenientcriteria.

A2014systematicreviewidentifiedfourrandomizedtrialsofsleeprestrictiontherapyasastandalonetherapyversusanotherinterventionorcontrolforchronicinsomnia[23].Theweightedeffectsizesforimprovementinsubjectivesleepvariablesweremediumtolargeandcomparabletothoseachievedwithcognitivebehavioralinterventionsinothermetaanalyses[24,25].Inthelargestindividualstudy,179olderadultswithprimaryinsomniawererandomlyassignedtosixweeksofsleeprestrictiontherapy,stimuluscontroltherapy,amulticomponentbehavioralintervention,orwaitlistcontrol[26].Alltreatmentsresultedinsignificantimprovementsindiaryreportedsleepoutcomescomparedwithcontrol,andtherewasnoadvantagetoamulticomponentinterventionoverasinglecomponentintervention.Effectsizesweregenerallymoderatetolargeandmaintainedat3and12monthsposttreatment.

Potentialadverseeffectsofsleeprestrictiontherapyincludeincreaseddaytimesleepinessanddecreased

Progressiverelaxationisbaseduponthetheorythatanindividualcanlearntorelaxonemuscleatatimeuntiltheentirebodyisrelaxed.Beginningwiththemusclesintheface,themusclesarecontractedgentlyforonetotwosecondsandthenrelaxed.Thisisrepeatedseveraltimes.Thesametechniqueisusedforothermusclegroups,usuallyinthefollowingsequence:jawandneck,upperarms,lowerarms,fingers,chest,abdomen,buttocks,thighs,calves,andfeet.Thiscycleisrepeatedforapproximately45minutes,ifnecessary.

Therelaxationresponsebeginsbylyingorsittingcomfortably.Theeyesareclosedandrelaxationisallowedtospreadthroughoutthebody.Arelaxed,abdominalbreathingpatternisestablished.Thoughtsareredirectedawayfromeverydaythoughtsandtowardaneutralmentalfocusingdevice,suchasapeacefulwordorimage.

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reactiontimes,aswellaspossibleexacerbationofbipolardisorder.(See'Adverseeffects'below.)

CognitivetherapyPatientswhoareawakeatnightcommonlybecomeconcernedthattheywillperformpoorlythenextdayiftheydonotobtainadequatesleep.Thisworrycanexacerbatetheirdifficultyfallingasleep,creatingaviciouscycleofwakefulnessandconcern.Apersonmaybegintoblameallnegativeeventsintheirlifeonpoorsleep.Duringcognitivetherapy,apersonworkswithatherapisttodealwithanxietyandcatastrophicthinking,whileestablishingrealisticexpectationsrelatedtoinsomniaandtheneedforsleep.

CognitivebehavioraltherapyCognitivebehavioraltherapy(CBT)isastrategythatcombinesseveralofthepreviouslydescribedapproachesoverseveralweeks[27].AsampleeightsessionCBTprogrammayincludeanintroductorysleepeducationsession,followedbytwosessionsthatfocusonstimuluscontrolandsleeprestriction.Thesemaybefollowedbytwosessionsthatfocusoncognitivetherapyandthenasessiononsleephygiene.Finally,theremaybeasessionthatreviewsandintegratestheprevioussessionandasessionthataddressesfutureproblems,suchasstressandrelapse[28].Patientsareencouragedtocompletesleeplogsastheylearnandapplythevariousstrategies.Thisallowsimprovementtobemeasured.

TheadvantageoftheeducationalnatureofCBTisthatitprovidespatientswithtoolstoapplyinthefuture.DisadvantagesofCBTincludethedurationoftherapyandtherelativelyfewclinicianswhoareskilledatallofitscomponents.ThebenefitofCBTmaybereducedwhenitisadministeredbylessexperiencedclinicians[9].

CBThasprovenefficaciousinmoderatetohighqualityrandomizedtrials[1].AmetaanalysisofbehavioraltherapiesforinsomniathatfoundthatCBTimprovedsubjectivesleepqualityanddecreasedsubjectivewaketimeduringthenight[29].ThebenefitsofCBTappeartopersistwellbeyondtheterminationofactivetreatment[1].SmallrandomizedstudieshavealsosuggestedthatalternativedeliverymethodssuchastelephonebasedCBT[30,31]andinternetbasedCBT[3235]maybeeffectivetreatmentoptionsthatcouldovercomesomeoftheaccessandeconomicbarriersthatexistfortraditionalCBT.However,largerstudiesdirectlycomparingthesemethodswithtraditionalCBTareneeded[36].

CBTisparticularlyrecommendedforuseinsituationswheremedicationsarecontraindicatedormaybemorelikelytoproducesideeffects,suchasolderadults,pregnantwomen,andpatientswithrenal,hepatic,orpulmonarydisease.

OtherapproachesOtherbehavioraltherapiesthatmayemergeasusefulinthetreatmentofinsomniaincludemindfulnessmeditation[3740]andexercisetraining[41].However,asmallrandomizedtrialcomparingtaichiwithCBTinolderadultsfoundthatCBTwasassociatedwithgreaterandmoresustainedimprovementinsleepquality,fatigue,anddepressivesymptomsthantaichi[42].

AdverseeffectsAdverseeffectsofbehavioraltherapyhavenotbeenwelldescribed,butoneareaofcautionrelatestosleeprestriction.Sleeprestrictiondecreasessleeplatencyandincreasessleepefficiencybycausingsleepdeprivation(ie,totalsleeptimeisdecreased,notincreased).Inonestudy,subjectsreportedincreasedsleepinessandhadslowerreactiontimesduringafourweektreatmentperiodthatthenreturnedtobaselinethreemonthslater,whentimeinbedhadincreasedtoaboutsevenhours[43].Theseeffectsaresimilartothoseseenduringchronicpartialsleepdeprivationandsuggestthatpatientsusingthistherapyshouldbecarefullymonitoredandinstructedtoavoidhazardousactivityanddrivingwhentimeinbedhasbeensignificantlyreduced.Sleeprestrictionshouldbeusedwithcautioninpatientswithunderlyingbipolardisorder,sincesleepdeprivationcantriggermanicepisodes[44].

MEDICATIONSMedicationsthatarecommonlyusedtotreatinsomniaincludebenzodiazepines,nonbenzodiazepinesedatives,andmelatoninagonists.Patientswhoseinsomniahasbeensuccessfullytreatedwithpharmacologictherapyarelikelytoreportimprovementofdaytimefunction,betterqualityoflife,andfewercomorbidities(eg,depressedmood).Risksofpharmacologictherapyincludesideeffects,aswellasphysicalandpsychologicaladdictionwithlongtermuse.Theserisksmaybeincreasedincertainclinicalsettings:

PregnancySedativehypnoticsmayincreasetheriskoffetalmalformationsifusedduringthefirsttrimester.

AlcoholconsumptionSedativehypnoticsshouldnotbecombinedwithalcoholbecausethereisariskofexcessivesedationandrespiratorysuppressionwhenevercentralnervoussystemsuppressantsare

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ChoiceofanagentRandomizedtrialsdirectlycomparingtheeffectofdifferentmedicationsoninsomniaarerare.Indirectcomparisonsofbenzodiazepinesandnonbenzodiazepinessuggestthattheseclassesofmedicationhaveasimilarimpactonsleeponsetlatency(ie,theydecreaseobjectivesleeponsetlatencybyapproximately10minutesandsubjectivesleeponsetlatencyby15to20minutes)[45].However,thebenzodiazepinesaremorelikelytoprolongtotalsleeptime,perhapsbecausetheytendtohavelongerhalflives[45,46].

Inoneofthefewtrialsthatdirectlycompareddifferentmedications,382patientswithprimaryinsomniareceivedeachofsixinterventionsinrandomorderfortwonightseach,withathreetosevendaywashoutperiodinbetween[47].Theagentsincludedplacebo,eszopiclone(1,2,2.5,and3mg),andzolpidem(10mg).Comparedwithplacebo,eszopicloneatdosesof2.5and3mgdecreasedthemedianwaketimeaftersleeponset,butzolpidemandeszopicloneatdosesof1and2mgdidnot.Thewaketimeaftersleeponsetreferstotheamountoftimethatthepatientisawakebetweensleeponsetandthefinalmorningarisingtime.Therewerenodifferencesinanyoftheobjectivesleepoutcomeswheneszopiclone(2and3mg)andzolpidemwerecompareddirectly.

Mostcliniciansselectasedativehypnoticonthebasisofthetypeofinsomnia(ie,sleeponsetorsleepmaintenance)andthedurationofeffect:

Otherissuestobeconsideredwhenprescribingamedicationforinsomniaincludecostandadverseeffects.Thebenzodiazepinesandoffpatentnonbenzodiazepines(specifically,zaleplonandzolpidem)tendtobelessexpensivethantheothernonbenzodiazepinesandramelteon.Theadverseeffectsarediscussedbelow.(See'Risksandsideeffects'below.)

BenzodiazepinesBenzodiazepinesareaclassofsleeppromotingmedicationsthatbindtoseveralgammaaminobutyricacid(GABA)typeAreceptorsubtypes[48].Theyreducethetimetotheonsetofsleep,prolongstage2sleep,prolongtotalsleeptime,andmayslightlyreducetherelativeamountofrapideyemovement(REM)sleep[49].Inaddition,theydecreaseanxiety,impairmemory,andhaveanticonvulsiveproperties.

combined.

RenalorhepaticdiseaseMostsedativehypnoticmedicationsundergohepaticandrenalclearance.Metabolicclearancemaybedelayedinpatientswhohaverenalorhepaticdisease,leadingtoaccumulationandexcessivesedation.

PulmonarydiseaseorsleepapneaManysedativehypnoticsarerespiratorysuppressantsthatcanworsenobstructivesleepapneaorhypoventilation.

NighttimedecisionmakersSedativehypnoticsshouldnotbetakenbyindividualswhomaybecalledupontomakeimportantdecisionsduringthenight(eg,cliniciansoncallorsingleparentsresponsibleforthecareofyoungchildren)becausetheycancauseexcesssedationandimpairdecisionmaking.

OlderadultsTheriskofadverseeffectsisincreasedinolderadults,especiallythosewhoareolderthan75years.Thisisaconsequenceofmultiplecomorbiditiesandcentralnervoussystemchangesassociatedwithaging.(See'Olderadults'below.)

Forpatientswithsleeponsetinsomnia,ashortactingmedicationisareasonablechoiceforaninitialtrialofpharmacologictherapy.Thismayimprovetheinsomniawithlessresidualsomnolencethefollowingmorning.Examplesofshortactingmedications(durationofeffect8hours)includezaleplon,zolpidem,triazolam,lorazepam,andramelteon.

Forpatientswithsleepmaintenanceinsomnia,alongeractingmedicationispreferableforaninitialtrialofpharmacologictherapy.Examplesoflongeractingmedicationsincludezolpidemextendedrelease,eszopiclone,temazepam,estazolam,andlowdosedoxepin.However,thesemedicationsmayincreasetheriskforhangoversedationandpatientsmustbewarnedaboutthispossibility.

Forpatientswithawakeninginthemiddleofthenight,bothzaleplonandaspecificsublingualtabletformofzolpidemhavebeendevelopedforuseduringthenight,withtheconstraintthattherewillbeatleastfourhoursoftimeinbedremainingafteradministration.

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Benzodiazepinescommonlyusedforthetreatmentofinsomniaincludetriazolam,estazolam,lorazepam,temazepam,flurazepam,andquazepam.Aprimarydifferenceamongthesemedicationsistheirdurationofaction.Triazolamisshortactingestazolam,lorazepam,andtemazepamareintermediateactingflurazepamandquazepamarelongacting(table5)[49].Diazepamisalsolongacting,butisgenerallynotusedtotreatinsomniabecauseithasalongdurationofeffectandcanleadtotheaccumulationofactivemetabolites.Thelongactingbenzodiazepinesshouldbeavoidedinolderadultsbecausethereisincreasedriskforadverseeffectsinthispatientpopulation[50].

Metaanalysesofrandomized,placebocontrolledtrialsindicatethatbenzodiazepinesdecreasesleeplatencyandthenumberofawakenings,whileimprovingsleepdurationandsleepquality[45,46,51,52].Typicalchangesassociatedwiththesemedicationsincludedecreasesinthedurationtosleeponsetbyapproximately10minutesandincreasesinthetotalsleeptimeof30to60minutes[45,46].

Thesideeffectsofbenzodiazepinesaredescribedbelow.(See'Risksandsideeffects'below.)

NonbenzodiazepinesNonbenzodiazepinereceptoragonistshaveastructurethatisdifferentfromthebenzodiazepinesandincludesmoretargetedactionatoneGABAtypeAreceptor.Aconsequenceoftheirgreaterspecificityislessanxiolyticandanticonvulsantactivity.

Nonbenzodiazepinesappeartoimprovebothsubjectiveandobjectivesleepoutcomes.Specifically,metaanalysesofrandomized,placebocontrolledtrialsindicatethatnonbenzodiazepinesdecreasesleeplatencyandthenumberofawakenings,whileimprovingsleepdurationandsleepquality[45,46,5153].Nonbenzodiazepineshaveincreasedadverseeventscomparedwithplacebo.

Nonbenzodiazepinescommonlyusedtotreatinsomniaincludezaleplon,zolpidem,eszopiclone,andzolpidemextendedrelease(table6):

Zaleplonhasaveryshorthalflifeofaboutonehour.Asaresult,itiseffectiveforpatientswhohavedifficultyfallingasleep(ie,sleeponsetinsomnia),butmaynotbeeffectiveforpatientswhohavedifficultymaintainingsleep(ie,sleepmaintenanceinsomnia)[54].Duetotheveryshorthalflife,thepotentialforhangoversleepinessisminimalafternormalsleepperiods.Occasionalsideeffectsincludeheadache,dizziness,nausea,abdominalpain,andsomnolence[48].Zaleplonisnotindicatedforlongtermuse.

Zolpidemhasahalflifeofapproximately1.5to2.4hours.Itisindicatedfortheshorttermtreatmentofinsomniacharacterizedbydifficultywithsleepinitiation[55].Themostcommonsideeffectsareheadache,dizziness,andsomnolence,whichcaninturnleadtofalls.Zolpidemisnotapprovedforlongtermuse.

Zolpidemisalsoavailableinadissolvabletabletandasanoralsprayforpatientswhohavedifficultyswallowingapill.Adissolvabletablet(1.75to3.5mg)canbetakeninthemiddleofthenightforsleepmaintenanceinsomnia,withtherequirementthatatleastfourhoursbeavailabletosleepafteradministrationandatleastfivehoursbeavailablepriortodriving.InJanuaryof2013,theUSFoodandDrugAdministration(FDA)issuedasafetyannouncementrecommendinguseofalowerdoseinwomenthanhadbeenpreviouslyrecommended[56].Thisshouldalsobeconsideredinmen.(See'Dosingprecautions'below.)

Zolpidemextendedreleasealsohasahalflifeofabout1.5to2.4hours,butisreleasedoveralongerduration.Itwasdevelopedtoimprovebothsleeponsetinsomniaandsleepmaintenanceinsomniawhileavoidinghangovereffects,althoughithasneverbeendirectlycomparedwithregularzolpidem[57].Sideeffectsofzolpidemextendedreleasearerelativelyfew,withthemostcommonbeingheadache,somnolence,anddizziness,whichcaninturnleadtofalls[48].InJanuaryof2013,theFDArecommendeduseofalowerdoseinwomenthanhadbeenpreviouslyrecommended[56].Thislowerdoseshouldalsobeconsideredformen.Inafollowupsafetyannouncement,theFDAaddedawarningthatpatientsshouldnotdriveorengageinotheractivitiesthatrequirecompletementalalertnessthedayaftertakingzolpidemextendedreleasebecausezolpidemlevelscanremainhighenoughthenextdaytoimpairtheseactivities[58].

Sleepmaybeworseduringthefirstnightfollowingdiscontinuationofthismedicine.Zolpidemextended

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Mostclinicaltrialsevaluatedshorttermtherapy(eg,sevendays),althoughafewlongerclinicaltrialshavebeenperformed.Inonerandomizedtrial,patientstreatedwitheszopicloneforsixmonthshadimprovedqualityoflife,decreasedworklimitation,andimprovedsleepcomparedwithplacebo[61].Thispersistedthroughoutthetrialandthesubsequentsixmonthopenlabelextension.Inanotherrandomizedtrialof1018patientswithinsomnia,zolpidemextendedreleasetakenforuptosixmonthsimprovedsleeponset,sleepmaintenance,morningsleepiness,nextdayconcentration,andworkperformancecomparedwithplacebo[62,63].

Adverseeffectsassociatedwiththenonbenzodiazepinesaresimilartothoseassociatedwithbenzodiazepines.Thisisdiscussedbelow.(See'Risksandsideeffects'below.)

MelatoninagonistsRamelteonisamelatoninagonist.Inrandomizedtrials,shorttermuseoframelteonisassociatedwithimprovementinsomesleepparametersinpatientswithinsomnia,buttheeffectsizeisrelativelysmall.

A2014metaanalysisthatincluded11trialsandover5700patientsfoundthatramelteonwasassociatedwithsignificantimprovementinsubjectivesleeplatency(4.6minutes)andtotalsleeptime(7.3minutes)comparedwithplacebobutnosignificantdifferenceinotherparameters,includingsubjectivetotalsleeptime,numberofawakenings,andwakefulnessaftersleeponset[64].Althoughmoststudiesexaminedshorttermtreatmentandoutcomeinmiddleagedadults[64],asmallnumberofindividualtrialshavedemonstratedpersistenceofsubjectivebenefitforatleastsixmonths,andimprovementinolderadults[6569].Subjectiveefficacyextendedtooneyearinanopenlabeltrial[70].

AlthoughramelteonisapprovedintheUnitedStatesandJapan,theEuropeanMedicinesAgency(EMA)concludedin2008thattherewasinadequateevidencethatthedrugwaseffectiveforinsomnia[71].Itdidnotapproveramelteonforuse.TasimelteonisasecondmelatoninagonistthathasbeenapprovedintheUnitedStatesfortreatmentofnon24hoursleepwakedisorder,acircadiansleepwakerhythmdisorderthatoccursprimarilyinblindindividuals[72].

Ramelteonbindstomelatoninreceptorsexpressedinthesuprachiasmaticnucleuswithmuchhigheraffinitythanmelatoninitselfandhasahalflifeof1.5to5hours[73,74].Ramelteonismetabolizedbytheliverandshouldbeusedwithcautioninpatientswithhepaticinsufficiency.Itiscontraindicatedinpatientstakingfluvoxamine,sincefluvoxaminemaydecreasethemetabolismoframelteon[75].Ramelteonismoreeffectiveintreatingsleeponsetinsomniacomparedwithsleepmaintenanceinsomnia.

Adverseeffectsassociatedwithmelatoninagonistsaregenerallymilderthanthoseassociatedwithbenzodiazepinesandnonbenzodiazepines.Themostcommonadverseeffectissomnolence.(See'Adverseeffectsofmelatoninagonists'below.)

OrexinreceptorantagonistsOrexinreceptorantagonistsareanovelclassofdrugsindevelopmentforthetreatmentofinsomnia.OrexinAandorexinBarehypothalamicneuropeptidesthatplayakeyroleinpromotingwakefulnessandregulatingthesleepwakecycle[76].Suvorexant,anoraldualorexinreceptorantagonistwitha12hourhalflife,wasapprovedbytheFDAinAugust2014[77].

Theefficacyofsuvorexantwasdemonstratedinamulticenterinternationaltrialof781patientswithprimary

releaseisnotlimitedtoshorttermuseandthereislittleevidenceforabuseordependenceinmostpatients.Intheory,however,suchmedicationscouldbehabitformingwithlongtermuse.(See'Adverseeffectsofnonbenzodiazepines'below.)

Eszopiclonehasthelongesthalflifeoftheapprovednonbenzodiazepines,approximatelyfivetosevenhours.Thismayextendtoninehoursinolderadultpatients.Eszopicloneiseffectiveforbothsleeponsetinsomniaandsleepmaintenanceinsomnia[59].Patientstakingeszopiclonemayreportanunpleasantmetallictaste.Otherreportedsideeffectsaresharedwithnonbenzodiazepinesasaclass(headache,dizziness,parasomnias,nextdayimpairmentinsomepatients)[48,60].(See'Adverseeffectsofnonbenzodiazepines'below.)

Sleepmaybeworseonthefirstnightafterdiscontinuationofthismedication.Eszopicloneisnotlimitedtoshorttermuseandthereislittleevidenceforabuseordependenceinmostpatients.Intheory,however,suchmedicationscouldbehabitformingwithlongtermuse.

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insomniawhowererandomlyassignedtoreceivenightlysuvorexantorplaceboina2:1ratioforoneyear,followedbyatwomonthrandomizeddiscontinuationphase[78].Thedoseofsuvorexantusedwas40mgforpatients

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constipation,andincreasedintraocularpressure[1].Routineuseofdiphenhydraminetotreatinsomniaisnotrecommended.

AntipsychoticsAntipsychoticshavebeenusedtotreatinsomnia.However,therearefewtrialsthatdemonstrateeffectivenessofthesemedicationsandallhavepotentiallysignificantadverseeffects.Theroutineuseofantipsychoticstotreatinsomniainpatientswithoutpsychosisisnotrecommended[1].

BarbituratesBarbiturateshavesimilarlybeenusedtotreatinsomnia.However,thereislittleevidencethatthesemedicationsimproveinsomniaandallhavepotentiallysignificantadverseeffects.Routineuseofbarbituratestotreatinsomniaisnotrecommended[1].

OverthecounterHerbalproducts,hormones,andalcoholicbeverageshavebeenusedassleepaidsbypatientswithinsomniabuttherearesparsedatauponwhichtoevaluatetheirefficacy.TheseagentsarenotregulatedbytheFDA.

Risksandsideeffects

CommontoallhypnoticsThemostcommonadverseeffectsassociatedwiththebenzodiazepinesandnonbenzodiazepinesareresidualdaytimesedation,drowsiness,dizziness,lightheadedness,cognitiveimpairment,motorincoordination,anddependence[1,45,46,51].Inaddition,mosthypnoticsarerespiratorysuppressantsthatcanworsenobstructivesleepapneaorhypoventilation.

Longtermusemaybehabitformingandreboundinsomniamayoccurwhensomeshortactingmedicationsarediscontinued.Lesscommonadverseeffectsincludecomplexsleeprelatedbehaviors(eg,sleepwalking,driving,makingtelephonecalls,eating,orhavingsexwhilenotfullyawake),anterogradeamnesia(particularlywithtriazolamorwhenusedwithalcohol),aggressivebehavior,andsevereallergicreaction[49,92].Lethaloverdoseisrare[93],unlessthereisconcurrentuseofalcoholoranothercentralnervoussystemdepressant.

AdverseeffectsofnonbenzodiazepinesGenerallyspeaking,theadverseeffectsassociatedwiththenonbenzodiazepinesaresimilartothoseassociatedwiththebenzodiazepines,buttheirfrequencyandseveritymaybeless[45,46].Thisisprobablyrelatedtotheirshorterhalflives,althoughasdiscussedbelow,nextmorningimpairmenthasbeenincreasinglyrecognizedwithhigherdosesandincertainpatientpopulations.(See'Dosingprecautions'below.)

Mostofthecomplexsleeprelatedbehaviorsthathavebeenreportedinpatientstakingnonbenzodiazepineswererelatedtozolpidem,butitisunknownwhetherthisreflectsthewidespreaduseofzolpidemoranassociationbetweentheagentandthesideeffect[49].Inonestudy,zolpidemaccountedfor12percentofall

HerbalproductsAvarietyofherbalproductsarepurportedtobeusefulforinsomnia.Thereislittleevidencefromrandomizedcontrolledtrialsabouttheefficacyofmanyherbals,however,andforthosethathavebeenwellstudied(eg,valerian),thereislittleevidenceofbenefit.Ametaanalysisthatincluded14randomizedtrialsinover1600patientsfoundnosignificantdifferencebetweenanyherbalmedicineandplaceboonanyof13clinicalefficacymeasuresofinsomnia[84].Themajorityofthetrials(11outof14)studiedvalerianchamomile,kava,andwulingwerestudiedinonetrialeach.Unliketheotherherbalsstudied,valerianwasassociatedwithagreaternumberofadverseeventsperpersoncomparedwithplacebo.Valerianmayalsoproducehepatotoxiceffects[1].Contaminationwithundesirablesubstancesposesaproblemformanysuchnaturalremedies.

MelatoninMelatoninisahormonethatisnormallysecretedbythepinealgland.Itdoesnotappeartobebeneficialasatreatmentforinsomniainmostpatientswithtwoexceptions:itmaybeusefulinpatientswhohavedelayedsleepphasesyndromeandinasubgroupofpatientswithlowmelatoninlevels[1,8590].Itappearstobesafewhenusedshortterm(threemonthsorless)[87].(See"Classificationofsleepdisorders",sectionon'Circadianrhythmsleepwakedisorders'.)

AlcoholAlcoholiscommonlyselfprescribedasasleepaidbecauseitdecreasesthetimerequiredtofallasleep,atleastintheshortterm.However,alcoholcanpromotesleepdisturbanceslaterinthenightandpromotesupperairwayinstabilityandsleepapnea.Thesenegativeeffects,coupledwiththesignificantriskofdependenceandinteractionwithothermedications,precludetheuseofalcoholtotreatinsomnia[91].

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emergencydepartmentvisitsforadversedrugeventsrelatedtopsychiatricmedicationintheUnitedStatesovertheperiodof2009to2011,and21percentofallsuchvisitsinvolvingadults65yearsofage[94].Othersideeffectsthathavebeenreportedinpatientstakingnonbenzodiazepinesincludeanunpleasanttaste(eszopiclone)andhallucinations(zolpidem).

Theincidenceofinfection(eg,upperrespiratory,otitismedia,urinarytract,conjunctivitis,others)mayalsobeincreasedamongpatientstakinganonbenzodiazepine,accordingtoonemetaanalysis[95].Twosubsequentstudies,oneinhumansandoneinmice,havealsoreportedanincreasedriskofpneumoniaassociatedwithbenzodiazepinesandthenonbenzodiazepinezopiclone,possiblyrelatedtomodificationofGABAtypeAactivityduringinfection[96,97].Astudyinmicesuggestedthatthisriskcouldextendtoallhypnoticsthatactatthissite[97].

DosingprecautionsDosingrecommendationsforhypnoticmedicationshavetraditionallybeenbasedongroupstatisticaleffectsratherthanindividualresponses.However,therehasbeenincreasingrecognitionthatvariabilityinnonbenzodiazepinemetabolismmayaffectnextmorningdruglevelsandsideeffects.Thesafetyannouncementsreviewedbelowsuggestthatcliniciansshouldhaveincreasedsensitivitytonextdayresidualeffectswhenprescribinganyofthedrugsinthisclassandshouldeducatepatientsaccordingly.

AdverseeffectsofmelatoninagonistsRamelteonhasfewersideeffectsthanthenonbenzodiazepinesorbenzodiazepines[99].Itisnotassociatedwithhypnoticsideeffects(eg,nextdayresidualperformancedeficits),withdrawal,orreboundinsomnia,anditdoesnotappeartobehabitforming[69,99].RamelteonhaslittleabusepotentialandisnotascheduledsubstancewiththeUnitedStatesDrugEnforcementAdministration(DEA),unlikemostotherdrugsusedtotreatinsomnia.Themostcommonsideeffectsaresomnolence,dizziness,nausea,fatigue,andheadache[1,49].Elevatedprolactinlevelsanddecreasedtestosteronelevelsmayoccur,butroutinemonitoringofeitherisnotindicatedintheabsenceofotherclinicalindications.

OlderadultsOlderadultshaveaparticularlyhighriskofadverseeffects,includingexcessivesedation,cognitiveimpairment,delirium,nightwandering,agitation,postoperativeconfusion,balanceproblems,fallandfractures,andimpairedperformanceofdailyactivities[100102].Inametaanalysisof24randomizedtrials(2417patients)thatevaluatedtheimpactofpharmacotherapyinadultsolderthan60yearswithinsomnia,therewasanimprovementofsleepquality,totalsleeptime,andfrequencyofnighttimeawakening[103].However,themagnitudeofthesebenefitswasrelativelysmallcomparedwiththetwotofivefoldincreaseinadversecognitiveorpsychomotorevents.Thissuggeststhatadditionalcautionisnecessarywhendecidingwhetherpharmacotherapyisindicatedforanolderpatientwithinsomnia.

MortalitySeveralobservationalstudieshavefoundanassociationbetweenuseorprescriptionofhypnoticdrugsandallcausemortality,withadjustedhazardratiosrangingfrom1.1to4.5[104109].Theassociationhasbeenobservedinthegeneraladultpopulation[104106,108,109],postmenopausalwomen

In2013,theFDApublishedasafetycommunicationthattherecommendeddoseforzolpidembesetatthelowestdose(5mgforallexceptzolpidemextendedrelease,whichisnow6.25mg)forwomenandalsobeconsideredformen[56].Inaddition,anewwarningwasissuedforzolpidemextendedrelease,advisingthatindividualsrefrainfromdrivingorotheractivitiesthatrequirementalalertnessthedayaftertakingthedrug[58].Theserecommendationswerebasedonstudiesshowingthatbloodlevelsofzolpidemaboveabout50ng/mLappearedcapableofimpairingdrivingsufficientlytoincreasetheriskofanaccident.Thisbloodlevelwasfoundinabout15percentofwomenand3percentofmeneighthoursafteradministrationof10mgofzolpidem.Eighthoursafteruseoftheextendedreleaseformulationofzolpidem,33percentofwomenand25percentofmenstillhadthiselevatedbloodlevel.

Additionalrecommendationswerenotmadeforolderadults,whohavepreviouslybeenadvisedtousethelowestdosesofthesemedications,butadditionalcareiswarrantedforthesepatients.(See'Olderadults'below.)

In2014,asimilarsafetycommunicationwasissuedforeszopiclone,basedondatathatthe2and3mgdosesmaybeassociatedwithimpairmentofdrivingskills,memory,andcoordinationlastingmorethan11hourswithoutsubjectiveawarenessinsomepatients[98].Astartingdoseof1mgisnowrecommendedinallpatients.

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[107],andinpatientswithschizophrenia[110].Otherstudiesinolderadultshavefailedtofindasignificantassociationbetweenhypnoticuseandmortalityafteradjustingforpotentialconfounders[111,112].

Oneofthelargerstudiessuggestedthathypnoticdrugs(includingfrequentlyprescribedagentssuchaszolpidemandtemazepam)wereassociatedwithanincreasedriskofbothcanceranddeath,evenatprescriptionlevelsoflessthan18dosesperyearovera2.5yearduration[104].Anotherlargeretrospectivecasecontrolstudyincludedover34,000patientsage16yearsandolderfirstprescribedananxiolyticorhypnoticdrugorbothbetween1998and2001,matchedbyage,gender,andprimarycarepracticewithnearly70,000controls[109].Overanaveragefollowupperiodof7.6years,prescriptionofanxiolyticandhypnoticdrugswasassociatedwithatwofoldincreasedhazardofdeathafteradjustingforawiderangeofpotentialconfounders,includingmedicalandpsychiatriccomorbidities,sleepdisorders,andotherdrugs.Afterexcludingdeathsduringthefirstyearoffollowup,thiseffecttranslatedtofourexcessdeathsper100peoplefollowedoverasevenyearperiod.

Itisimportanttoemphasize,however,thatthisevidenceisobservationaland,therefore,doesnotindicatecausality.Chronicinsomniahasbeenassociatedwithavarietyofmedicalandpsychiatriccomorbidities,manyofwhichareassociatedwithprematuremortality,anditisdifficulttoexcluderesidualconfoundingbyindicationorotherunmeasuredfactors.Aprospectiveinvestigationoflongtermhypnoticusecomparedwithplaceboandbehavioraltreatmentisneeded.

DruginteractionsConcurrentuseofanysleepingmedicationandalcohol(oranothercentralnervoussystemdepressant)increasestheriskofcentralnervoussystemdepressionand,therefore,iscontraindicated.

Mostbenzodiazepines(exceptlorazepam,oxazepam,andtemazepam)andnonbenzodiazepinesaremetabolizedbytheCYP3A4system[49].InhibitorsoftheCYP3A4system(eg,clarithromycin)increasetheriskoftoxicityrelatedtobenzodiazepinesandnonbenzodiazepines,whileinducersoftheCYP3A4system(eg,rifampin)maydecreasetheeffectivenessofbenzodiazepinesandnonbenzodiazepines.

RamelteonismetabolizedbytheCYP1A2systemand,toalesserextent,theCYP2C9andCYP3A4systems[49].FluvoxamineisapotentinhibitoroftheCYP1A2systemandshouldnotbeusedwithramelteonbecauseitmarkedlyincreasesserumconcentrationsoframelteon.OtherinhibitorsoftheCYP1A2(eg,ciprofloxacin),CYP2C9,orCYP3A4systemsmayalsoincreasetheriskoframelteontoxicity,whileinducersoftheCYPsystems(eg,rifampin)maydecreasetheeffectivenessoframelteon.

COMBINATIONTHERAPYCombinationtherapyinvolvesprescribingbothcognitivebehavioraltherapy(CBT)andamedication,usuallyforsixtoeightweeks.Themedicationisthentaperedoffortoanasneededschedule,whilecontinuingtheCBT.

Twotrialsfromthesameinvestigatorsillustratetheeffectsofcombinationtherapy:

Thefirsttrialrandomlyassigned78patientswithpersistentinsomniatoreceiveCBTalone,temazepamalone,CBTplustemazepam,orplaceboforeightweeks[113].Attheendofthetreatmentphase,allofthetherapieshadsignificantlydecreasedthewaketimeaftersleeponsetcomparedwithplacebo,althoughtherewerenosignificantdifferenceswhenthetreatmentgroupswerecomparedwitheachother.Twoyearsfollowingthecompletionoftreatment,onlytheCBTalonegrouphadmaintaineditsreductioninthewaketimeafterinitialsleeponset.

Thesecondtrialrandomlyassigned160patientswithpersistentinsomniatoreceiveCBTpluszolpidemorCBTaloneforsixweeks[114].Bothgroupshaddecreasedsleeponsetlatency,decreasedwaketimeaftersleeponset,andincreasedsleepefficiencywhencomparedwithbaselineaftersixweeks.However,therewasnosignificantdifferenceintheremissionratewhenthegroupswerecomparedwitheachother(44versus39percent).Thepatientsthenunderwentsecondaryrandomization.PatientsintheCBTalonegroupwererandomlyassignedtonotreatmentormaintenanceCBT,whilepatientsintheCBTpluszolpidemgroupwererandomlyassignedtoeithermaintenanceCBTormaintenanceCBTplusasneededzolpidem.Theimprovementofsleeplatency,waketimeaftersleeponset,andsleepefficiencywasmaintainedinallgroupsatsixmonths,whencomparedwithbaseline.TheremissionratewashigheratsixmonthsamongthegroupsthathadreceivedCBTpluszolpidemduringtheinitialsixweeksofthetrial,thanamongthegroupsthathadinitiallyreceivedCBTalone(56versus43percent).

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Takentogether,theevidenceindicatesthatCBTalone,drugtherapyalone,andcombinationtherapyallimprovemeasuresofinsomnia(eg,waketimeaftersleeponset)withinweeksofinitiatingthetherapy.ContinuingCBTaloneafterthecompletionofinitialtherapyappearstobethebestoptionformaintainingimprovementlongterm.CBTalsoincreasesthelikelihoodthatthemedicationcaneventuallybetapered[115].

Ifsleeprestrictiontherapyiscombinedwithhypnoticmedication,cliniciansshouldbeawarethatthecombinationofchronicpartialsleepdeprivationandmedicationhangovercouldsignificantlyincreasedaytimesleepinessandbehavioralrisk.(See'Adverseeffects'above.)

Theevidenceisinsufficienttojustifycombinationtherapyasroutineinitialmanagementforinsomniapatients.ManypatientswillimprovewithCBTalone,withoutpharmacologictherapy.

FOLLOWUPIfthetreatmentissuccessful,patientswillreportbothimprovedsleepatnightandimprovementofdaytimedeficits.Discontinuationofthemedicationshouldbeconsideredinanypatientwhoisreceivingpharmacologictherapyaloneorcombinationtherapy.

Patientswhohavelittleimprovementduringtheinitialtrialofcognitivebehavioraltherapy,pharmacologictherapy,orcombinationtherapymayhaveothercausesofpoorsleep.Adherencewiththeprescribedtherapyshouldbeconfirmedandthenadditionaldiagnosticevaluationperformed.Suchpatientsoftenrequirereferraltoasleepdisorderscentertobeevaluatedforsleepapneaorotherunderlyingcauses.Suchanevaluationisindicatedearlier(ie,priortothefailureofroutinetherapy)ifthereisclinicalsuspicionthatsleepapneaoranotheretiologyexists.(See"Clinicalfeaturesanddiagnosisofinsomnia",sectionon'Othersleepdisorders'.)

Otherpatientsmayrespondinitiallytopharmacologictherapybutlaterrelapsewhilestilltakingthesamedrug.Insuchcases,clinicalreevaluationiswarrantedtodeterminewhethertherearelifestylechangesorothernewfactorsthatmaybeexacerbatingtheinsomnia.Therearelimiteddataontoleranceandcrosstoleranceamongvariousmedicationsusedtotreatinsomnia,butsomeamountoftolerancelikelyexistsforthebenzodiazepinesandnonbenzodiazepinereceptoragonists[116118].Treatmentdecisionsinpatientswithpossibletolerancemustbeindividualized,takingintoaccountfactorssuchassideeffects,durationoftherapy,priortherapies,andavailabilityofalternativeoptions,suchasbehavioraltherapy.Iflifestylechangesandotherexacerbatingfactorshavebeenruledout,weconsiderthefollowingapproaches:

INSOMNIARELATEDTOCIRCADIANRHYTHMDISORDERSPatientswhohaveinsomniaassociatedwithacircadianrhythmdisordermaybenefitfromphototherapyorchronotherapy.

PhototherapyExposuretobrightlightwhenawakeningisaneffectivetherapyforpatientswhosesleeponsetinsomniaisduetodelayedsleepphasesyndrome,aconditioninwhichtheonsetofsleepisdelayedbecausetheindividual'ssleepwakerhythmislongerthan24hours[83].(See"Classificationofsleepdisorders",sectionon'Circadianrhythmsleepwakedisorders'.)

Patientsundergoingphototherapysitinfrontof5000to10,000luxlightbox(oroutdoorsorinfrontofawindowwithsunlight)for30to40minutesuponawakening(averageindoorlightingis300to500lux,averagesunnysummerdayis100,000lux).Inaddition,theymarkedlyreducetheirexposuretobrightlightintheevening(eg,theymaykeeptheirshadesdownandindoorlightsdim).Aresponsetotherapyisgenerallyevidentaftertwotothreeweeks[119].Indefinitetreatmentisfrequentlynecessarytomaintainthebenefits.Inlessseverecases,consistentawakeningatagiventimeinthemorning,followedbyphysicalactivitywithexposuretooutdoorlight(eg,awalkoutside,sittingnexttoawindowwiththeshadesandcurtainsopen),maybesufficientevenonacloudyday.

Inapatientwhocomplainsoflossofefficacyfromashortactingnonbenzodiazepine,suchaszolpidem,wesuggestatrialofalongeractingdrug,suchaseszopiclone,orswitchtomedicationfromadifferentclass,suchaslowdosedoxepin.

Somepatientsmaybenefitfromadrugholiday,afterwhichtimetheymayagainrespondtotheinitialdrugtherapy.

Institutionofbehavioraltherapycanhelptransitionsomepatientsawayfromlongtermuseofabenzodiazepineornonbenzodiazepinereceptoragonist.(See'Behavioraltherapy'above.)

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Phototherapymayalsobebeneficialtopatientswhoseinsomniaisduetoadvancedsleepphasesyndrome,aconditioninwhichtheindividualdesiressleepearlyandawakensearlybecausetheirsleepwakerhythmhasshiftedearlier.Inthissituation,exposuretobrightlightintheeveningcanhelpdelaysleeponset.

ChronotherapyChronotherapyisabehavioralstrategythatcanbeusedinpatientswithdelayedsleepphasesyndrome.Itreferstotheintentionaldelayofsleeponsetbytwotothreehoursonsuccessivedaysuntilthedesiredbedtimeisreached.Afterthis,thepatientstrictlyenforcesthissleepwakeschedule.Onestudyreportedahighsuccessrateamongpatientswithdelayedsleepphasesyndrome,evenwhenthedisorderhadbeenpresentformanyyears[120].

Chronotherapyrequiresclosemonitoringofschedules.Patientsmustcontinuetodelaytheirsleeptimesuntilthedesiredbedtimehasbeenreached,whichmeansadheringtoseveralafternoonandeveningbedtimes.Thisisanarduousscheduleandpatientsgenerallydonotadheretotheirscheduleafteradjustmentandlapseintotheiroriginalsleephabits.Insomeindividuals,chronotherapycanresultinafreerunningcircadianrhythmandshouldthereforebeusedwithcaution.

JETLAGJetlagisacommoncauseofinsomniathatisdiscussedseparately.(See"Jetlag".)

INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"and"BeyondtheBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5 to6gradereadinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.Thesearticlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.BeyondtheBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe10 to12 gradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortablewithsomemedicaljargon.

Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthesetopicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon"patientinfo"andthekeyword(s)ofinterest.)

SUMMARYANDRECOMMENDATIONS

th th

th th

Basicstopic(see"Patientinformation:Insomnia(TheBasics)")

BeyondtheBasicstopics(see"Patientinformation:Insomnia(BeyondtheBasics)"and"Patientinformation:Insomniatreatments(BeyondtheBasics)")

Allpatientswithinsomniashouldreceivetherapyforanymedicalcondition,psychiatricillness,substanceabuse,orsleepdisorderthatmaybeprecipitatingorexacerbatingtheinsomnia.Theyshouldalsoreceivegeneralbehavioralsuggestions,particularlyadviceregardingsleephygiene(table2)andstimuluscontrol(table3).(See'Generalapproach'above.)

Forpatientswhocontinuetohaveinsomniathatissevereenoughtorequireanintervention,wesuggestcognitivebehavioraltherapy(CBT)astheinitialtherapy(Grade2B).AnalternativetypeofbehavioraltherapyisreasonableifCBTisnotavailable.(See'Generalapproach'aboveand'Behavioraltherapy'above.)

ForpatientswhoseinsomniacontinuestobesevereenoughtorequireaninterventiondespiteCBT,wesuggesttheadditionofamedicationtoCBTratherthanchangingtoastrategyofmedicationalone(Grade2B).(See'Generalapproach'aboveand'Medications'above.)

Forpatientswhorequiremedicationforsleeponsetinsomnia,wesuggestashortactingmedicationratherthanalongeractingagent(Grade2C).(See'Choiceofanagent'above.)

Forpatientswhorequiremedicationforsleepmaintenanceinsomnia,wesuggestalongeractingmedicationratherthanashortactingagent(Grade2C).Alternatively,anewformulationofzolpidemhasbeenapprovedforuseinthemiddleofthenight.Patientsshouldbewarnedabouttheriskfordaytimedrowsiness,impaireddriving,dizziness,andlightheadedness.(See'Choiceofanagent'above.)

Patientsgivenbehavioralpluspharmacologictherapyshouldcontinuebehavioraltherapyforsixtoeight

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UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

REFERENCES

1. NationalInstitutesofHealth.NationalInstitutesofHealthStateoftheScienceConferencestatementonManifestationsandManagementofChronicInsomniainAdults,June1315,2005.Sleep200528:1049.

2. KatzDA,McHorneyCA.Clinicalcorrelatesofinsomniainpatientswithchronicillness.ArchInternMed1998158:1099.

3. KrystalAD.Psychiatriccomorbidity:thecasefortreatinginsomnia.SleepMedClin20061:359.4. FavaM,McCallWV,KrystalA,etal.Eszopiclonecoadministeredwithfluoxetineinpatientswith

insomniacoexistingwithmajordepressivedisorder.BiolPsychiatry200659:1052.5. RoehrsT,HydeM,BlaisdellB,etal.SleeplossandREMsleeplossarehyperalgesic.Sleep2006

29:145.6. TashjianRZ,BanerjeeR,BradleyMP,etal.Zolpidemreducespostoperativepain,fatigue,andnarcotic

consumptionfollowingkneearthroscopy:aprospectiverandomizedplacebocontrolleddoubleblindedstudy.JKneeSurg200619:105.

7. SackRL,AuckleyD,AugerRR,etal.Circadianrhythmsleepdisorders:partII,advancedsleepphasedisorder,delayedsleepphasedisorder,freerunningdisorder,andirregularsleepwakerhythm.AnAmericanAcademyofSleepMedicinereview.Sleep200730:1484.

8. ValliresA,MorinCM,GuayB.Sequentialcombinationsofdrugandcognitivebehavioraltherapyforchronicinsomnia:anexploratorystudy.BehavResTher200543:1611.

9. EspieCA,MacMahonKM,KellyHL,etal.Randomizedclinicaleffectivenesstrialofnurseadministeredsmallgroupcognitivebehaviortherapyforpersistentinsomniaingeneralpractice.Sleep200730:574.

10. StepanskiEJ,WyattJK.Useofsleephygieneinthetreatmentofinsomnia.SleepMedRev20037:215.

11. ChangAM,AeschbachD,DuffyJF,CzeislerCA.EveninguseoflightemittingeReadersnegativelyaffectssleep,circadiantiming,andnextmorningalertness.ProcNatlAcadSciUSA2015112:1232.

12. GuilleminaultC,ClerkA,BlackJ,etal.Nondrugtreatmenttrialsinpsychophysiologicinsomnia.ArchInternMed1995155:838.

13. EdingerJD,SampsonWS.Aprimarycare"friendly"cognitivebehavioralinsomniatherapy.Sleep200326:177.

14. ChenHY,ChiangCK,WangHH,etal.Cognitivebehavioraltherapyforsleepdisturbanceinpatientsundergoingperitonealdialysis:apilotrandomizedcontrolledtrial.AmJKidneyDis200852:314.

15. BootzinRR,PerlisML.Nonpharmacologictreatmentsofinsomnia.JClinPsychiatry199253Suppl:37.16. PallesenS,NordhusIH,KvaleG,etal.Behavioraltreatmentofinsomniainolderadults:anopenclinical

trialcomparingtwointerventions.BehavResTher200341:31.17. EspieCA,LindsayWR,BrooksDN,etal.Acontrolledcomparativeinvestigationofpsychological

treatmentsforchronicsleeponsetinsomnia.BehavResTher198927:79.18. EngleFriedmanM,BootzinRR,HazlewoodL,TsaoC.Anevaluationofbehavioraltreatmentsfor

insomniaintheolderadult.JClinPsychol199248:77.19. RiedelB,LichsteinK,PetersonBA,etal.Acomparisonoftheefficacyofstimuluscontrolformedicated

andnonmedicatedinsomniacs.BehavModif199822:3.20. MeansMK,LichsteinKL,EppersonMT,JohnsonCT.Relaxationtherapyforinsomnia:nighttimeandday

timeeffects.BehavResTher200038:665.21. EdingerJD,WohlgemuthWK,RadtkeRA,etal.Cognitivebehavioraltherapyfortreatmentofchronic

primaryinsomnia:arandomizedcontrolledtrial.JAMA2001285:1856.22. SpielmanAJ,YangC,GlovinskyPB.Insomnia:Sleeprestrictiontherapy.In:InsomniaDiagnosisand

weeks.Inpatientswhorespondtotherapy,themedicationcanbetaperedwhilecontinuingthebehavioraltherapy.Patientswhosesymptomsrecurmayrequireevaluationinasleepdisorderscenter,priortotheinstitutionoflongtermtherapy.(See'Generalapproach'aboveand'Followup'above.)

Longtermtreatmentwithmedicationaloneisnottheoptimaltreatmentstrategyforpatientswithinsomnia.(See'Risksandsideeffects'above.)

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Treatment,SateiaMJ,BuysseDJ(Eds),InformaUKLtd,London2010.p.277.23. MillerCB,EspieCA,EpsteinDR,etal.Theevidencebaseofsleeprestrictiontherapyfortreating

insomniadisorder.SleepMedRev201418:415.24. MontgomeryP,DennisJ.Cognitivebehaviouralinterventionsforsleepproblemsinadultsaged60+.

CochraneDatabaseSystRev2003:CD003161.25. IrwinMR,ColeJC,NicassioPM.Comparativemetaanalysisofbehavioralinterventionsforinsomnia

andtheirefficacyinmiddleagedadultsandinolderadults55+yearsofage.HealthPsychol200625:3.26. EpsteinDR,SidaniS,BootzinRR,BelyeaMJ.Dismantlingmulticomponentbehavioraltreatmentfor

insomniainolderadults:arandomizedcontrolledtrial.Sleep201235:797.27. SmithMT,NeubauerDN.Cognitivebehaviortherapyforchronicinsomnia.ClinCornerstone20035:28.28. MorinCM.InsomniaPsychologicalAssessmentandManagement,TheGuilfordPress,NewYork1993.29. McCurrySM,LogsdonRG,TeriL,VitielloMV.Evidencebasedpsychologicaltreatmentsforinsomniain

olderadults.PsycholAging200722:18.30. ArnedtJT,CuddihyL,SwansonLM,etal.Randomizedcontrolledtrialoftelephonedeliveredcognitive

behavioraltherapyforchronicinsomnia.Sleep201336:353.31. BastienCH,MorinCM,OuelletMC,etal.Cognitivebehavioraltherapyforinsomnia:comparisonof

individualtherapy,grouptherapy,andtelephoneconsultations.JConsultClinPsychol200472:653.32. VincentN,LewyckyS.Loggingonforbettersleep:RCToftheeffectivenessofonlinetreatmentfor

insomnia.Sleep200932:807.33. RitterbandLM,ThorndikeFP,GonderFrederickLA,etal.EfficacyofanInternetbasedbehavioral

interventionforadultswithinsomnia.ArchGenPsychiatry200966:692.34. vanStratenA,EmmelkampJ,deWitJ,etal.GuidedInternetdeliveredcognitivebehaviouraltreatment

forinsomnia:arandomizedtrial.PsycholMed201444:1521.35. HolmqvistM,VincentN,WalshK.Webvs.telehealthbaseddeliveryofcognitivebehavioraltherapyfor

insomnia:arandomizedcontrolledtrial.SleepMed201415:187.36. EspieCA."Steppedcare":ahealthtechnologysolutionfordeliveringcognitivebehavioraltherapyasa

firstlineinsomniatreatment.Sleep200932:1549.37. OngJ,SholtesD.Amindfulnessbasedapproachtothetreatmentofinsomnia.JClinPsychol2010

66:1175.38. GrossCR,KreitzerMJ,ReillySpongM,etal.Mindfulnessbasedstressreductionversus

pharmacotherapyforchronicprimaryinsomnia:arandomizedcontrolledclinicaltrial.Explore(NY)20117:76.

39. BrittonWB,HaynesPL,FridelKW,BootzinRR.Mindfulnessbasedcognitivetherapyimprovespolysomnographicandsubjectivesleepprofilesinantidepressantuserswithsleepcomplaints.PsychotherPsychosom201281:296.

40. OngJC,ManberR,SegalZ,etal.Arandomizedcontrolledtrialofmindfulnessmeditationforchronicinsomnia.Sleep201437:1553.

41. YangPY,HoKH,ChenHC,ChienMY.Exercisetrainingimprovessleepqualityinmiddleagedandolderadultswithsleepproblems:asystematicreview.JPhysiother201258:157.

42. IrwinMR,OlmsteadR,CarrilloC,etal.Cognitivebehavioraltherapyvs.TaiChiforlatelifeinsomniaandinflammatoryrisk:arandomizedcontrolledcomparativeefficacytrial.Sleep201437:1543.

43. KyleSD,MillerCB,RogersZ,etal.Sleeprestrictiontherapyforinsomniaisassociatedwithreducedobjectivetotalsleeptime,increaseddaytimesomnolence,andobjectivelyimpairedvigilance:implicationsfortheclinicalmanagementofinsomniadisorder.Sleep201437:229.

44. KaplanKA,HarveyAG.Behavioraltreatmentofinsomniainbipolardisorder.AmJPsychiatry2013170:716.

45. BuscemiN,VandermeerB,FriesenC,etal.Theefficacyandsafetyofdrugtreatmentsforchronicinsomniainadults:ametaanalysisofRCTs.JGenInternMed200722:1335.

46. HolbrookAM,CrowtherR,LotterA,etal.Metaanalysisofbenzodiazepineuseinthetreatmentofinsomnia.CMAJ2000162:225.

47. ErmanMK,ZammitG,RubensR,etal.Apolysomnographicplacebocontrolledevaluationoftheefficacyandsafetyofeszopiclonerelativetoplaceboandzolpideminthetreatmentofprimaryinsomnia.JClinSleepMed20084:229.

48. LiebermanJA.Updateonthesafetyconsiderationsinthemanagementofinsomniawithhypnotics:

2/6/2015 Treatmentofinsomnia

http://www.uptodate.com/contents/treatmentofinsomnia?topicKey=SLEEP%2F7691&elapsedTimeMs=0&view=print&displayedView=full 16/19

incorporatingmodifiedreleaseformulationsintoprimarycare.PrimCareCompanionJClinPsychiatry20079:25.

49. Drugsforinsomnia.TreatGuidelMedLett20097:23.50. BloomHG,AhmedI,AlessiCA,etal.Evidencebasedrecommendationsfortheassessmentand

managementofsleepdisordersinolderpersons.JAmGeriatrSoc200957:761.51. NowellPD,MazumdarS,BuysseDJ,etal.Benzodiazepinesandzolpidemforchronicinsomnia:a

metaanalysisoftreatmentefficacy.JAMA1997278:2170.52. KrystalAD.Acompendiumofplacebocontrolledtrialsoftherisks/benefitsofpharmacological

treatmentsforinsomnia:theempiricalbasisforU.S.clinicalpractice.SleepMedRev200913:265.53. HuedoMedinaTB,KirschI,MiddlemassJ,etal.Effectivenessofnonbenzodiazepinehypnoticsin

treatmentofadultinsomnia:metaanalysisofdatasubmittedtotheFoodandDrugAdministration.BMJ2012345:e8343.

54. ElieR,RtherE,FarrI,etal.Sleeplatencyisshortenedduring4weeksoftreatmentwithzaleplon,anovelnonbenzodiazepinehypnotic.ZaleplonClinicalStudyGroup.JClinPsychiatry199960:536.

55. Ambien(zolpidemtartrate)prescribinginformation.Availableat:http://products.sanofiaventis.us/ambien/ambien.html(AccessedonJune27,2009).

56. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm334738.htm.

57. HindmarchI,LegangneuxE,StanleyN,etal.Adoubleblind,placebocontrolledinvestigationoftheresidualpsychomotorandcognitiveeffectsofzolpidemMRinhealthyelderlyvolunteers.BrJClinPharmacol200662:538.

58. http://www.fda.gov/Drugs/DrugSafety/ucm352085.htm.59. RothT,WalshJK,KrystalA,etal.Anevaluationoftheefficacyandsafetyofeszopicloneover12

monthsinpatientswithchronicprimaryinsomnia.SleepMed20056:487.60. AncoliIsraelS,KrystalAD,McCallWV,etal.A12week,randomized,doubleblind,placebocontrolled

studyevaluatingtheeffectofeszopiclone2mgonsleep/wakefunctioninolderadultswithprimaryandcomorbidinsomnia.Sleep201033:225.

61. WalshJK,KrystalAD,AmatoDA,etal.Nightlytreatmentofprimaryinsomniawitheszopicloneforsixmonths:effectonsleep,qualityoflife,andworklimitations.Sleep200730:959.

62. KrystalAD,ErmanM,ZammitGK,etal.Longtermefficacyandsafetyofzolpidemextendedrelease12.5mg,administered3to7nightsperweekfor24weeks,inpatientswithchronicprimaryinsomnia:a6month,randomized,doubleblind,placebocontrolled,parallelgroup,multicenterstudy.Sleep200831:79.

63. ErmanM,GuiraudA,JoishVN,LernerD.Zolpidemextendedrelease12.5mgassociatedwithimprovementsinworkperformanceina6monthrandomized,placebocontrolledtrial.Sleep200831:1371.

64. KuriyamaA,HondaM,HayashinoY.Ramelteonforthetreatmentofinsomniainadults:asystematicreviewandmetaanalysis.SleepMed201415:385.

65. MiniLJ,WangWeigandS,ZhangJ.Selfreportedefficacyandtolerabilityoframelteon8mginolderadultsexperiencingseveresleeponsetdifficulty.AmJGeriatrPharmacother20075:177.

66. ZammitG,ErmanM,WangWeigandS,etal.Evaluationoftheefficacyandsafetyoframelteoninsubjectswithchronicinsomnia.JClinSleepMed20073:495.

67. RothT,SeidenD,WangWeigandS,ZhangJ.A2night,3period,crossoverstudyoframelteon'sefficacyandsafetyinolderadultswithchronicinsomnia.CurrMedResOpin200723:1005.

68. RothT,SeidenD,SainatiS,etal.Effectsoframelteononpatientreportedsleeplatencyinolderadultswithchronicinsomnia.SleepMed20067:312.

69. MayerG,WangWeigandS,RothSchechterB,etal.Efficacyandsafetyof6monthnightlyramelteonadministrationinadultswithchronicprimaryinsomnia.Sleep200932:351.

70. RichardsonGS,ZammitG,WangWeigandS,ZhangJ.Safetyandsubjectivesleepeffectsoframelteonadministrationinadultsandolderadultswithchronicprimaryinsomnia:a1year,openlabelstudy.JClinPsychiatry200970:467.

71. http://www.emea.europa.eu/htms/human/opinion/opinion.htm(AccessedonJanuary28,2009).72. HardelandR.Tasimelteon,amelatoninagonistforthetreatmentofinsomniaandcircadianrhythmsleep

disorders.CurrOpinInvestigDrugs200910:691.73. TurekFW,GilletteMU.Melatonin,sleep,andcircadianrhythms:rationalefordevelopmentofspecific

2/6/2015 Treatmentofinsomnia

http://www.uptodate.com/contents/treatmentofinsomnia?topicKey=SLEEP%2F7691&elapsedTimeMs=0&view=print&displayedView=full 17/19

melatoninagonists.SleepMed20045:523.74. KatoK,HiraiK,NishiyamaK,etal.Neurochemicalpropertiesoframelteon(TAK375),aselective

MT1/MT2receptoragonist.Neuropharmacology200548:301.75. CajochenC.TAK375Takeda.CurrOpinInvestigDrugs20056:114.76. MiedaM,SakuraiT.Overviewoforexin/hypocretinsystem.ProgBrainRes2012198:5.77. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm409950.htm.78. MichelsonD,SnyderE,ParadisE,etal.Safetyandefficacyofsuvorexantduring1yeartreatmentof

insomniawithsubsequentabrupttreatmentdiscontinuation:aphase3randomised,doubleblind,placebocontrolledtrial.LancetNeurol201413:461.

79. HerringWJ,SnyderE,BuddK,etal.Orexinreceptorantagonismfortreatmentofinsomnia:arandomizedclinicaltrialofsuvorexant.Neurology201279:2265.

80. RiemannD,SpiegelhalderK.Orexinreceptorantagonists:anewtreatmentforinsomnia?LancetNeurol201413:441.

81. KrystalAD,DurrenceHH,ScharfM,etal.EfficacyandSafetyofDoxepin1mgand3mgina12weekSleepLaboratoryandOutpatientTrialofElderlySubjectswithChronicPrimaryInsomnia.Sleep201033:1553.

82. WalshJK,ErmanM,ErwinCW,etal.SubjectivehypnoticefficacyoftrazadoneandzolpideminDSMIIIRprimaryinsomnia.HumPsychopharmacol199813:191.

83. MendelsonWB.Areviewoftheevidencefortheefficacyandsafetyoftrazodoneininsomnia.JClinPsychiatry200566:469.

84. LeachMJ,PageAT.Herbalmedicineforinsomnia:Asystematicreviewandmetaanalysis.SleepMedRev201424C:1.

85. AlmeidaMontesLG,OntiverosUribeMP,CortsSotresJ,HeinzeMartinG.Treatmentofprimaryinsomniawithmelatonin:adoubleblind,placebocontrolled,crossoverstudy.JPsychiatryNeurosci200328:191.

86. BaskettJJ,WoodPC,BroadJB,etal.Melatonininolderpeoplewithagerelatedsleepmaintenanceproblems:acomparisonwithagematchednormalsleepers.Sleep200124:418.

87. BuscemiN,VandermeerB,HootonN,etal.Theefficacyandsafetyofexogenousmelatoninforprimarysleepdisorders.Ametaanalysis.JGenInternMed200520:1151.

88. LegerD,LaudonM,ZisapelN.Nocturnal6sulfatoxymelatoninexcretionininsomniaanditsrelationtotheresponsetomelatoninreplacementtherapy.AmJMed2004116:91.

89. ZhdanovaIV,WurtmanRJ,ReganMM,etal.Melatonintreatmentforagerelatedinsomnia.JClinEndocrinolMetab200186:4727.

90. vanGeijlswijkIM,KorziliusHP,SmitsMG.Theuseofexogenousmelatoninindelayedsleepphasedisorder:ametaanalysis.Sleep201033:1605.

91. MendelsonWB.Hypnoticmedications:mechanismsofactionandpharmacologiceffects.In:Principlesandpracticeofsleepmedicine,KrygerM,RothT,DementWC(Eds),Saunders,Philadelphia2005.p.444.

92. FDArequestslabelchangeforallsleepdisorderdrugproducts.FDANews.ReleasedonMarch14,2007http://www.fda.gov/bbs/topics/NEWS/2007/NEW01587.html(AccessedonFebruary26,2008).

93. BuckleyNA,DawsonAH,WhyteIM,O'ConnellDL.Relativetoxicityofbenzodiazepinesinoverdose.BMJ1995310:219.

94. HamptonLM,DaubresseM,ChangHY,etal.Emergencydepartmentvisitsbyadultsforpsychiatricmedicationadverseevents.JAMAPsychiatry201471:1006.

95. JoyaFL,KripkeDF,LovingRT,etal.Metaanalysesofhypnoticsandinfections:eszopiclone,ramelteon,zaleplon,andzolpidem.JClinSleepMed20095:377.

96. ObioraE,HubbardR,SandersRD,MylesPR.Theimpactofbenzodiazepinesonoccurrenceofpneumoniaandmortalityfrompneumonia:anestedcasecontrolandsurvivalanalysisinapopulationbasedcohort.Thorax201368:163.

97. SandersRD,GodleeA,FujimoriT,etal.Benzodiazepineaugmentedaminobutyricacidsignalingincreasesmortalityfrompneumoniainmice.CritCareMed201341:1627.

98. www.fda.gov/Drugs/DrugSafety/ucm397260.htm(AccessedonMay27,2014).99. GriffithsRR,JohnsonMW.Relativeabuseliabilityofhypnoticdrugs:aconceptualframeworkand

algorithmfordifferentiatingamongcompounds.JClinPsychiatry200566Suppl9:31.

2/6/2015 Treatmentofinsomnia

http://www.uptodate.com/contents/treatmentofinsomnia?topicKey=SLEEP%2F7691&elapsedTimeMs=0&view=print&displayedView=full 18/19

Disclosures:MichaelHBonnet,PhDNothingtodisclose.DonnaLArand,PhDConsultant/AdvisoryBoards(spouse):Merck[insomnia(suvorexant)].RuthBenca,MD,PhDGrant/Research/ClinicalTrialSupport:Merck(Insomniaresearch[suvorexant]).Consultant/AdvisoryBoards:Merck(Insomnia[suvorexant])JazzPharmaceuticals[Hypersomnia(sodiumoxybate)].AprilFEichler,MD,MPHEquityOwnership/StockOptions:Johnson&Johnson[Dementia

100. GraySL,LaCroixAZ,HanlonJT,etal.Benzodiazepineuseandphysicaldisabilityincommunitydwellingolderadults.JAmGeriatrSoc200654:224.

101. CummingRG,LeCouteurDG.Benzodiazepinesandriskofhipfracturesinolderpeople:areviewoftheevidence.CNSDrugs200317:825.

102. KudohA,TakaseH,TakahiraY,TakazawaT.Postoperativeconfusionincreasesinelderlylongtermbenzodiazepineusers.AnesthAnalg200499:1674.

103. GlassJ,LancttKL,HerrmannN,etal.Sedativehypnoticsinolderpeoplewithinsomnia:metaanalysisofrisksandbenefits.BMJ2005331:1169.

104. KripkeDF,LangerRD,KlineLE.Hypnotics'associationwithmortalityorcancer:amatchedcohortstudy.BMJOpen20122:e000850.

105. HauskenAM,SkurtveitS,TverdalA.Useofanxiolyticorhypnoticdrugsandtotalmortalityinageneralmiddleagedpopulation.PharmacoepidemiolDrugSaf200716:913.

106. BellevilleG.MortalityhazardassociatedwithanxiolyticandhypnoticdruguseintheNationalPopulationHealthSurvey.CanJPsychiatry201055:558.

107. HartzA,RossJJ.Cohortstudyoftheassociationofhypnoticusewithmortalityinpostmenopausalwomen.BMJOpen20122.

108. KripkeDF,KlauberMR,WingardDL,etal.Mortalityhazardassociatedwithprescriptionhypnotics.BiolPsychiatry199843:687.

109. WeichS,PearceHL,CroftP,etal.Effectofanxiolyticandhypnoticdrugprescriptionsonmortalityhazards:retrospectivecohortstudy.BMJ2014348:g1996.

110. TiihonenJ,SuokasJT,SuvisaariJM,etal.Polypharmacywithantipsychotics,antidepressants,orbenzodiazepinesandmortalityinschizophrenia.ArchGenPsychiatry201269:476.

111. GisevN,HartikainenS,ChenTF,etal.MortalityassociatedwithbenzodiazepinesandbenzodiazepinerelateddrugsamongcommunitydwellingolderpeopleinFinland:apopulationbasedretrospectivecohortstudy.CanJPsychiatry201156:377.

112. VinkersDJ,GusseklooJ,vanderMastRC,etal.Benzodiazepineuseandriskofmortalityinindividualsaged85yearsorolder.JAMA2003290:2942.

113. MorinCM,ColecchiC,StoneJ,etal.Behavioralandpharmacologicaltherapiesforlatelifeinsomnia:arandomizedcontrolledtrial.JAMA1999281:991.

114. MorinCM,ValliresA,GuayB,etal.Cognitivebehavioraltherapy,singlyandcombinedwithmedication,forpersistentinsomnia:arandomizedcontrolledtrial.JAMA2009301:2005.

115. BaillargeonL,LandrevilleP,VerreaultR,etal.Discontinuationofbenzodiazepinesamongolderinsomniacadultstreatedwithcognitivebehaviouraltherapycombinedwithgradualtapering:arandomizedtrial.CMAJ2003169:1015.

116. ArankoK,MattilaMJ,NuutilaA,PellinenJ.Benzodiazepines,butnotantidepressantsorneuroleptics,inducedosedependentdevelopmentoftolerancetolorazepaminpsychiatricpatients.ActaPsychiatrScand198572:436.

117. SangerDJ,ZivkovicB.Investigationofthedevelopmentoftolerancetotheactionsofzolpidemandmidazolam.Neuropharmacology198726:1513.

118. ArankoK.Taskdependentdevelopmentofcrosstolerancetopsychomotoreffectsoflorazepaminman.ActaPharmacolToxicol(Copenh)198556:373.

119. ChessonALJr,LittnerM,DavilaD,etal.Practiceparametersfortheuseoflighttherapyinthetreatmentofsleepdisorders.StandardsofPracticeCommittee,AmericanAcademyofSleepMedicine.Sleep199922:641.

120. CzeislerCA,RichardsonGS,ColemanRM,etal.Chronotherapy:resettingthecircadianclocksofpatientswithdelayedsleepphaseinsomnia.Sleep19814:1.

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(galantamine),Epilepsy(topiramate)].Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.Conflictofinterestpolicy