sleep pills: what and how should we use...2/27/17 6 benzodiazepines...
TRANSCRIPT
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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
• DependenceRisk• Low
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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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Tricyclic Antidepressants
• Takeninlowdosesatbedtime(e.g,doxepin25to50mg,paroxetine5to20mg,trazodone50mg,trimipramine 75to200mg)mayimprovesleep
• However,antidepressantsshouldbeusedintheselowdosesmainlywhenstandardhypnoticsarenottoleratedorinhigher(antidepressant)doseswhendepressionispresent
• Ultralowdosedoxepin(3or6mg)isindicatedforsleepmaintenanceinsomnia
Tricyclic Antidepressants
• Aventyl(nortriptyline)• Elavil(amitriptyline)• Pamelor(nortriptyline)• Sinequan(doxepin)• Trazodone(desyrel)
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Tricyclic Antidepressants
• HowItWorks• Bindstomultiplebrainreceptorsincludingacetylcholine;sedating.
• DurationofEffects• Notwellstudied
• SideEffects• Lowatusualdosesfor insomnia.Dizziness,blurry vision,difficultyurinating,cardiacarrhythmiaspossible.Trazodonecancauseprolonged,painfulerections.
• DependenceRisk• Low
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
OrexinReceptorAntagonists:Belsomra (Suvorexant)
• Clinicallyeffectiveinterventionforinsomniaforupto4weekscomparedtoaplacebo
• FDAapprovalinAugust2014and
• Newsleepingpill,relativelyexpensive
• ItremainsunknownwhetherthisdrugwillbepreferredovernonbenzodiazepineGABAergicoptionsinregardstolong-termsafety
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OrexinReceptorAntagonists:Belsomra (Suvorexant)
• 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