Sleep pills: What and How should we use...2/27/17 6 Benzodiazepines...

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Sleeppills:WhatandHowshouldweuse?

Dr.YotinChinvarunM.D.Ph.D.

CEPandSleepdisorderprogram,PMKhospital

Introduction

§Mostsleepingpillsareclassifiedas"sedativehypnotics."

§ That'saspecificclassofdrugsusedtoinduceand/ormaintain sleep.

§ Sedativehypnoticsincludebenzodiazepines,barbiturates,andvarioushypnotics

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Introduction

keyquestionsbeforechoosingyour sleep medicine

• Howlongdoesittakeforthesleepingpilltotakeeffect?

• Howlongdotheeffectslast?

• What'stheriskofbecomingdependentonthesleepingpill,physicallyorpsychologically?

GuidelinesfortheUseofSleepingpills

• Defineaclearindicationandtreatmentgoal

• Prescribethelowesteffectivedose

• Limitdurationofusetoafewweeks

• Individualizethedoseforeachpatient

• UselowerdosesinpatientsalsotakingaCNSdepressant,intheelderly,andinpatientswithhepaticorrenaldisorders.

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GuidelinesfortheUseofSleepingpills

• Avoidifpatientshavesleepapneaorrespiratorydisordersorahistoryofsedativeabuse,iftheyaredrinkingalcohol,oriftheyarepregnant

• Forpatientswhoneedlonger-termtreatment,considerintermittenttherapy

• Avoidabruptlystoppingthedrugifpossible(i.e,taperit)

• Re-evaluatedrugtreatmentregularly;assessefficacyandadverseevents

Ramelteon isanexception;itcanbegiventopatientswithmildtomoderateOSAorCOPDorahistoryofsedativeabuse.Low-dosedoxepinalsohasnoabuseliability.

Sleepingpills

Scope• Barbiturates• Benzodiazepine• Non-benzodiazepines• Others

• Melatonin• Antihistamines• Antidepressants• Antipsychotics• OrexinReceptorAntagonists

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Barbiturate

• Barbituratesactas CNS depressants,produceawidespectrumofeffects,frommild sedation tototal anesthesia

• Effectiveas anxiolytics,hypnotics,and anticonvulsants.Barbituratesalsohave analgesic effects;

• Havedependenceliability,both physical and psychological

• Barbituratesnowlargelybeenreplacedby benzodiazepines inroutinemedicalpractice,intreatmentofanxietyandinsomnia• becausebenzodiazepinessignificantlylessdangerousin overdose

Benzodiazepines

• HowItWorks• BindstogeneralGABAreceptorsinthe brain,inhibitNREMstage1and2sleep),whileasleep,drugsdisruptsleeparchitecture:decreasingsleeptime,delayingtimetoREMsleep,anddecreasingdeepslow-wavesleep

• DurationofEffects• Varies(from4hourstomorethan12)

• SideEffects• Sedation,lossofmusclecoordination,dizziness,habit-forming.

• DependenceRisk• Higher

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Benzodiazepines

• Ativan(lorazepam)• Halcion(triazolam)• Restoril(temazepam)• Valium(diazepam)• Xanax(alprazolam)

Benzodiazepines

• Benzodiazepinescanbeusefulforshort-termtreatmentofinsomnia

• Usebeyond2to4weeksnotrecommendedduetoriskofdependence

• Itispreferredbenzodiazepinesbetakenintermittentlyandatthelowesteffectivedose

• Improvesleep-relatedproblemsbyshorteningtimespentinbedbeforefallingasleep,prolongingsleeptime,and,reducingwakefulness

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Benzodiazepines

• Like alcohol, benzodiazepines arecommonlyusedtotreatinsomniaintheshort-term,butworsensleepinthelong-term

• Whilebenzodiazepinescanputpeopletosleep(i.e.,inhibitNREMstage1and2sleep),• whileasleep,BZPsdisrupt sleeparchitecture:decreasingsleeptime,delayingtimetoREMsleep,anddecreasingdeep slow-wavesleep

Benzodiazepines

• Otherdrawbacksofhypnotics,includingbenzodiazepines,are• Possibletolerancetotheireffects• Reboundinsomnia• Reducedslow-wavesleep• Withdrawalperiodtypifiedbyreboundinsomniaandaprolongedperiodofanxietyandagitation

• Olderadultsshouldnotusebenzodiazepinestotreatinsomniaunlessothertreatmentsfailedtobeeffective

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Ativan: LORAZEPAM

• This medication isusedtotreat anxiety

• Lorazepam belongstoaclassofdrugsknownas benzodiazepines whichactonthe brain andnerves(central nervoussystem)toproducecalmingeffect

• Thisdrugworksbyenhancingeffectsofacertainnaturalchemicalinthebody(GABA)

Valium:DIAZEPAM

• Diazepam isusedtotreat anxiety, alcoholwithdrawal,and seizures

• Itisalsousedtorelieve musclespasms andtoprovidesedationbeforemedicalprocedures

• This medication worksbycalmingthe brain andnerves

• Diazepambelongstoaclassofdrugsknownas benzodiazepines.

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Xanax: ALPRAZOLAM

• Alprazolam usedtotreat anxietyandpanicdisorders.Itbelongstoaclass benzodiazepines whichactonthe brain andnerves(central nervoussystem)toproduceacalmingeffectbyenhancingeffectsofGABA

• Dosageisbasedonyourmedicalcondition,age,andresponsetotreatment,dosemaybegraduallyincreaseduntilthedrugstartsworkingwell

• Thismedicationmaycausewithdrawalreactions,especiallyifusedregularlyforalongtimeorinhighdoses• withdrawalsymptoms(suchas seizures)mayoccurifyousuddenlystopusingthismedication.

• Mayrarelycauseabnormaldrug-seekingbehavior(addiction),increasedifhavingabusedalcoholordrugsinthepast

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Non-benzodiazepines

• Non-benzodiazepinesareaclassof psychoactivedrugs thatarevery"benzodiazepine-like"innature.

• Nonbenzodiazepines pharmacodynamics almostentirelysameas benzodiazepine drugs• Thereforeemploysimilarbenefits,side-effects,andrisks• Nonbenzodiazepines,however,havedissimilarorentirelydifferentchemicalstructures,andthereforeareunrelatedtobenzodiazepinesonamolecularlevel

• Examplesinclude• zopiclone (Imovane,Zimovane)• Eszopiclone (Lunesta)• Zaleplon (Sonata)• Zolpidem (Ambien,Stilnox,Stilnoct)

SelectiveGABAMedicines

• HowItWorks• BindstoaspecifictypeofGABAreceptorinthe brain

• DurationofEffects• 6-8hours

• SideEffects• Usuallyfew.Memorydisturbances, hallucinations,behaviorchangespossible.

• DependenceRisk• Medium(usuallylow)

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SelectiveGABAMedicines

• SelectiveGABAMedicines• Ambien(zolpidemtartrate)• AmbienCR(zolpidemtartrateextendedrelease)• Lunesta(eszopiclone)• Sonata(zaleplon)

SelectiveGABAMedicines:ZOLPIDEMTARTRATE

• Zolpidemisusedtotreat sleep problems(insomnia)inadults

• Zolpidembelongstoaclassofdrugscalledsedative-hypnotics.Itactsonyour brainto produceacalmingeffect.

• This medication isusuallylimitedtoshorttreatmentperiodsof1to2weeksorless

• Takethismedicationby onanemptystomach

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SelectiveGABAMedicines:ZOLPIDEMTARTRATE

• ADRse.g.pronounced amnesia andmorerarely hallucinations, especiallywhenusedinlargedoses

• Onrareoccasions,thesedrugscanproducefuguestate,whereinpatientsleepwalksandmayperformrelativelycomplexactions,includingcookingmealsordrivingcars,withnorecollectionoftheeventsuponawakening

• Memorydisturbances

• Daytimewithdrawal-relatedanxietycanalsooccurfromchronicnightlyused

• Long-termusersincreasedriskofdepression

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Others

• Melatonin

• Antihistamines

• Antidepressants

• Antipsychotics

Melatonin

• Melatonin,hormoneproducedinthepinealglandinthebrainandsecretedindimlightanddarkness,amongitsotherfunctions,promotessleepindiurnalmammals

• Duetoitshypnoticproperties,itisavailableonprescriptioninmanycountriesandisover-the-counterinothers

• Atimed-releaseversion,tradenameCircadin®,wasapprovedin2007inEurope(EU)foruseasatreatmentforprimaryinsomnia

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Melatonin

• Several melatoninreceptoragonists thatbindtoandactivatemelatoninreceptorsweredeveloped,include• Ramelteon,agomelatine,TIK-301andtasimelteon• Ramelteon (Rozerem®)wasapprovedfortreatmentofinsomniaintheUSin2005• In2009agomelatine (Valdoxan®,Melitor®,Thymanax®),primarilyusedfordepression,wasapprovedinEurope• BothTIK-301(in2004)andtasimelteon (Hetlioz®)tenyearslaterwereapprovedintheUSforcircadianrhythmsleepdisorder non-24-hoursleep–wakedisorder intotallyblindindividuals

Sleep-WakecycleModifiers

• HowItWorks• Stimulates melatonin receptorsinthe brain areathatcontrolsthesleep-wakecycle

• DurationofEffects• 4-6hours

• SideEffects• Headache,drowsiness, dizziness.Uncommonly,problemswith sexdrive.Lossofmensesorproblems gettingpregnant

• DependenceRisk• Low

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Sleep-WakecycleModifiers

• Rozerem(ramelteon)

Rozerem:RAMELTEON

• This medication isusedtotreatsleeplessness(insomnia).

• Ramelteon workslikeanaturalsubstancecalled melatonin thatisproducedbyyourbody• Ithelpsregulateyour sleep-wakecycle(circadianrhythm)

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Antihistamines

• Clinically,H1 antagonistsareusedtotreatcertain allergies

• Sedationisacommonside-effect,andsomeH1 antagonists,suchas diphenhydramine (Benadryl)and doxylamine,arealsousedtotreatinsomnia.

• Second-generationantihistamines crossthe blood–brainbarrier toamuchlowerdegreethanthefirstones,havingamuchlowersedativeeffect

Antihistamines:

• HowItWorks• Actsonhistaminereceptorsinthebraintocausedrowsiness

• DurationofEffects• 4-6hours(sleepinessmaylastlonger)

• SideEffects• Daytimesleepiness;confusionanddifficultyurinatinginolderpeople


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Antihistamines:Diphenhydramine

• Becauseofits sedative properties,diphenhydramineiswidelyusedinnonprescriptionsleepaidsforinsomnia

• Thedrugisaningredientinseveralproductssoldassleepaids,eitheraloneorincombinationwithotheringredientssuchas acetaminophen (paracetamol)

• Cancauseminorpsychologicaldependence

• Diphenhydraminecancause sedation andhasalsobeenusedasan anxiolytic

Tricyclic Antidepressants

• Some antidepressants havesedatingeffects

• Somemay increaseactualqualityofsleep(biologically)incontrasttoBenzodiazepinesthatdecreasequality

• Tricyclic Antidepressants• Serotoninantagonistsandreuptakeinhibitors:Trazodone• Tricyclicantidepressants:Amitriptyline,Doxepin,Trimipramine• Tetracyclicantidepressants:Mianserin,Mirtazapine

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• Takeninlowdosesatbedtime(e.g,doxepin25to50mg,paroxetine5to20mg,trazodone50mg,trimipramine 75to200mg)mayimprovesleep

• However,antidepressantsshouldbeusedintheselowdosesmainlywhenstandardhypnoticsarenottoleratedorinhigher(antidepressant)doseswhendepressionispresent

• Ultralowdosedoxepin(3or6mg)isindicatedforsleepmaintenanceinsomnia


• Aventyl(nortriptyline)• Elavil(amitriptyline)• Pamelor(nortriptyline)• Sinequan(doxepin)• Trazodone(desyrel)

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• HowItWorks• Bindstomultiplebrainreceptorsincludingacetylcholine;sedating.

• DurationofEffects• Notwellstudied

• SideEffects• Lowatusualdosesfor insomnia.Dizziness,blurry vision,difficultyurinating,cardiacarrhythmiaspossible.Trazodonecancauseprolonged,painfulerections.


Doxepin:Sinequan

• Treatmentmental/moodproblemssuchas depression and anxiety.Itmayhelpimprovemoodandfeelingsofwell-being,relieveanxietyandtension,helpyou sleep better,andincreaseyourenergylevel

• Usually1to3timesdaily,maytakeupto3weeksbeforegetafulleffect

• Toreduceyourriskofsideeffects(suchasdrowsiness, drymouth, dizziness),startthismedicationatalowdoseandgraduallyincreaseyourdose

• Donotstoptakingthismedicationabruptly.Someconditionsmaybecomeworsesuddenlystopped.Also,withdrawalADRssuchasmoodswings, headache,andtiredness.

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Nortriptyline:NORTRIPTYLINEHCL

• Thismedicationisusedtotreatmental/moodproblemssuchas depression.Itmayhelpimprovemoodandfeelingsofwell-being,relieve anxiety andtension,andincreaseyourenergylevel

• Thismedicationmayalsobeusedtohelp quitsmoking.

• Usually1to4timesdaily

• Toreduceyourriskofsideeffects(suchas drymouth, dizziness),startatalowdoseandgraduallyincreaseyourdose.

• WithdrawalADRsifdrugissuddenlystoppede.g. moodswings, headache,tiredness,and sleep change.

• Itmaytakeupto4weeksbeforegetthefulleffect.

AMITRIPTYLINE

• Thismedicationisusedtotreatmental/moodproblemssuchas depression.Itmayhelpimprovemoodandfeelingsofwell-being,relieve anxiety andtension,helpyou sleep better,andincreaseyourenergylevel.

• Thismedicationmayalsobeusedtotreat nervepain (suchas peripheralneuropathy, postherpeticneuralgia), eatingdisorder (bulimia),othermental/moodproblems(suchasanxiety,panicdisorder),ortoprevent migraineheadaches.

• Usually1to4timesdaily

• Toreduceyourriskofsideeffects(suchasdrowsiness, drymouth, dizziness),startatlowdoseandgraduallyincrease

• Donotstopabruptly,withdrawalADRse.g.moodswings, headache,tiredness,and sleep change.

• Toseesomebenefitwithinaweek,itmaytakeupto4weeksbeforegetfulleffect

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TRAZODONE

• Thismedicationisusedtotreat depression.Itmayhelptoimproveyourmood,appetite,andenergylevelaswellasdecrease anxiety and insomnia relatedtodepression

• Trazodone worksbyhelpingtorestorethebalanceofacertainnaturalchemical(serotonin)inthe brain.

• Usuallyonceortwicedailyafteramealorsnack• Ifdrowsinessisaproblemtaking1doseat bedtime

• Toreduceriskofsideeffects,startatalowdoseandgraduallyincreasedose

• Donotstoptakingabruptly.Anxiety,agitation,and troublesleeping canoccurifthedrugissuddenlystopped

• Maytake2to4weeksbeforegetafulleffectsofthemedication

Antipsychotics

• First-generation:• Chlorpromazine

• Second-generation:• Clozapine• Olanzapine• Quetiapine• Risperidone• Zotepine

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Miscellaneousothers

• Alpha-adrenergicagonist:• Clonidine• Guanfacine

• Cannabinoids• Cannabidiol• Tetrahydrocannabinol

• Orexinreceptorantagonist• Suvorexant

• Gabapentinoids• Pregabalin• Gabapentin

OrexinReceptorAntagonists

• Aseriousconcernisevidencesuggestingnonbenzodiazepine sleepingpillslinkedto dementia,earlymortality,increasedriskofcancer;?dangerouspsychiatricdrugs.

• Newerclassof(potentiallysafer)sleepingpillsunderdevelopmentdubbed the“orexinreceptorantagonists.”

• “Belsomra”(Suvorexant)approvedbytheFDAforthetreatmentofinsomnia

• However,remainsunknownwhetherthisnewclassofsleepingpillswillbesafeoverlong-term

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OrexinReceptorAntagonists:Belsomra (Suvorexant)

• Aseriousconcernisevidencesuggestingnonbenzodiazepine sleepingpillslinkedto dementia,earlymortality,increasedriskofcancer;?dangerouspsychiatricdrugs.

• Newerclassof(potentiallysafer)sleepingpillsunderdevelopmentdubbed the“orexinreceptorantagonists.”

• “Belsomra”(Suvorexant)approvedbytheFDAforthetreatmentofinsomnia

• However,remainsunknownwhetherthisnewclassofsleepingpillswillbesafeoverlong-term


• Clinicallyeffectiveinterventionforinsomniaforupto4weekscomparedtoaplacebo

• FDAapprovalinAugust2014and

• Newsleepingpill,relativelyexpensive

• ItremainsunknownwhetherthisdrugwillbepreferredovernonbenzodiazepineGABAergicoptionsinregardstolong-termsafety

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• Recommendeddoseis10mg,takenwithin30minofgoingtobed,withatleast7hr beforetheplannedtimeofawakening.

• Shouldnottoexceed20mgonce/day

• Mostcommonadverseeffectissomnolence

OrexinReceptorAntagonists:

• OtherNewdevelopmentOrexinreceptorantagonists

• Lemborexant (E-2006)

• MIN-202(JNJ-42847922)

• SB-649868

• ACT-462206

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TAKEHOMEMESSAGE:Tipsfortreatinginsomnia

• Cognitivebehaviortherapyforinsomnia(CBT-I)remainsthemosteffectivetreatment,

• Othernonpharmacologic methodsthatmaybepromisingincludeexercise,sleeprestriction,meditativemovement,andmindfulnessbasedstressreduction

• Amongpharmacologicaltreatments,suvorexant blocksorexinreceptors,anoveltargetforreducingwakefulnessandenhancingsleep

TAKEHOMEMESSAGE:Tipsfortreatinginsomnia

• Low-dosedoxepinisanantihistaminethathasafavorableefficacyandsafetyprofile

• Low-dosezolpidemhasbeenshowntobeeffectiveformiddleofthenightinsomniawithoutthenextdaysedationofregularzolpidem

• Thecontroversysurroundingthesafetyofchronicuseofsedativehypnotics• Drugsshouldbeprescribedwithcaution,preferablyfortheshorttermonly

Sleep pills: What and How should we use...2/27/17 6 Benzodiazepines...

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Transcript of Sleep pills: What and How should we use...2/27/17 6 Benzodiazepines...