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