Opioids,DyspneaandRisks

OpioidsandRespira1on

•  Opioidsdelayinspira.onthroughhyperpolariza.onofpre-Botzingercomplexneuronstherebyslowingrespiratoryratebydelayinginspira.on

•  Tidalvolumecompensatoriallyincreaseswhendosesarelowtherebymaintainingminuteven.la.onwhichislostwithhigheropioiddoses

•  Aninspiratorycycleismissed(calledquantalbreathingorintegermul.plesofthecontrolperiodofbreathingintheabsenceoftheopioid

OpioidsandRespira1on

•  OpioidsarenotassociatedwithCheyne-Stokesrespira.on

•  Hypoxicdriveisdepressedtoagreaterextentthanhypercapnicdriveandsuppressionislongerlas.ng

•  OpioidsbluntresponsestohypoxiabybindingtomureceptorswithintheNucleusTractusSolitarius,blockingneurotransmissionfromGlomuscellstothemedulla

OpioidsandRespira1on

•  Breathtobreath.dalvolumevariabilityanddelayedhyperven.la.onresponsetorisingpCO2levelssuggestsbothacentralandperipheralopioideffect

•  Bluntedrespiratoryresponsetocontextcues(breathholding)isincreased

NotAllOpioidsAreTheSame

U1lityFunc1on

UFallowsobjec.veandreliablecharacteriza.onofindividualopioidbenefitsandrisksover.meanddoseinordertodeterminewhichopioidissafertouseandwhichdosingstrategyplacesthepa.entattheleastriskduringopioidtherapyKharaschE2013

Buprenorphine,FentanylPK/PD

•  D-prospec.veanimalstudy•  P-Mousemodel•  I-BuprenorphineandFentanyl•  O-PK/PDPlethysmographytoquan.tateven.la.onTailflickan.nocicep.onRespiratorydepression-“yes/no”at50%declineinven.la.onAn.nocicep.on-”yes/no”attailflicklatency>10sConcentra.on/effectoddsra.oYassenA2007

Buprenorphine,Fentanyl,PK/PDEffec1veness,Safety•  Buprenorphinean.nocicep.onOR28.5

(6.9-50.1)favoringanalgesia•  BuprenorphinerespiratorydepressionOR

2.10(0.71-3.49)•  Fentanylan.nocicep.onOR3.03

(1.87-4.21)•  FentanylrespiratorydepressionOR2.54

(1.26-3.82)•  OR(PA/PR)13to1infavorof

buprenorphine(PA>PR)YassenA2007

PK/PDRespiratoryEffectsFentanylandBuprenorphine

•  D-Prospec.vestudy•  P-Healthyvolunteers(n=74)•  I-Buprenorphinedoses0.05to0.6mg,fentanyldoses0.075to0.5mg

•  O-RespiratoryresponsetoPetCO2at50%

PK/PDmodelingYassenA2007

PK/PDBuprenorphine,FentanylRespiratoryDepression

•  Biophaseequilibrium-16vs.75minutes(buprenorphine)

•  Buprenorphinewasapar.alagonistwithintrinsicac.vityof0.51andceilingeffect

•  Fentanylwasafullagonistwithanintrinsicac.vityof0.91

YassenA2007

VulnerablePopula1ons

ChronicPain,SDBw/woOpioids•  Acomparisonofpa.entsonopioid

therapyforchronicpainandasimilarcohortofpa.entswithchronicpainnotonopioidsfoundaAHIof41inthoseonopioidsand22inthosenotonopioids(p=0.018).

•  Inasubsetwhounderwentopioidtaper,theAHIdecreasedto16-17(p<0.01).

•  Centralsleepapnearesolvedoffopioids.HypoxiaduringREMsleepwhichhadoccurredin27%ofindividualsbeforeopioidtaperalsoimprovedsignificantly(p<0.01)

COPDandSDB•  ThosewithSBDandcomorbid

COPD(overlapsyndrome)orthosewithcardiovasculardiseaseareatgreaterriskofforarrhythmiasatnight.

•  Theoverlapsyndromecompoundstheriskofnocturnalarrhythmiasrela.vetoCOPDorSDBalone.

•  Thosewiththeoverlapsyndromehavea2.5-foldgreaterriskoftachyarrhythmiasrela.vetothosewithOSAalone

CardiovascularDiseaseandSDB•  Pa.entwithapre-exis.ng

cardiovasculardiseaseandSDBhavehigherhealthcarecostsandagreaterriskforadversecardiovasculareventswithanoddsra.o(OR)of4.1(95%CI1.8–9.3)comparedwithmatchedcontrolswithoutSDB

•  Thenumberofobstruc.veeventsandthedegreeofhypoxemiaduringsleepstronglypredictsforoccurrenceofanarrhythmia

Author(Reference) Numbers Benefits/Risks NNT Comments

ElkstromM N=271 Dyspnearelief 7-9 AllbutIstudy<30daysindura.on

BarnesH Systema.creviewof26studieswithN=526

Dyspnearelief 9-10 AllbutIstudy<30daysindura.on

VozorisNT N=130,979 Risks HR/NNH Opioid

Matched-cohortstudy

Hospitaliza.ons HR1.5/NNH66 Short-ac.ngopioids

COPD/pneumoniarelatedmortality

HR4.79/NNH77 Short-ac.ngopioids

All-causemortality

HR3.38/NNH28 Mortalityrelatedtocardiacevents

VozorisNT N=22,912 Hospitaliza.ons HR1.73/NNH71 Morphinedose<30mg/day

Matched-cohortstudy

COPD/pneumoniarelatedmortality

HR7.55/NNH71 Morphinedose<30mg/day

All-causemortality

HR5.19/NNH17 Morphinedose<30mg/day

Summary•  Opioidsadverselyinfluencerespiratoryfunc.onandworsensleepdisorderedbreathingrenderingcertainpopula.onsatriskforsuddendeathsandcardiovasculardeaths.

•  Physiciansrarelyscreenindividualsforrisks

•  Notallopioidsarethesamebutfurtherclinicalstudiesneedtoexplorethis