The Search for the Magic Bullet: Can the Use of …...* Gaoni Y, Mehoulam R. Isolation, structure...

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The Search for the Magic Bullet: Can the Use of Medical Cannabis Decrease Opioid Use or Mortality? Ernest J. Dole, PharmD, PhC, FASHP, BCPS Clinical Pharmacist Pain Consultation & Treatment Center University of New Mexico Hospitals & Clinical Associate Professor University of New Mexico College of Pharmacy

Transcript of The Search for the Magic Bullet: Can the Use of …...* Gaoni Y, Mehoulam R. Isolation, structure...

Page 1: The Search for the Magic Bullet: Can the Use of …...* Gaoni Y, Mehoulam R. Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc 1964;86:1646-7.

TheSearchfortheMagicBullet:

CantheUseofMedicalCannabisDecreaseOpioidUse

orMortality?ErnestJ.Dole,PharmD,PhC,FASHP,BCPSClinicalPharmacist

PainConsultation&TreatmentCenterUniversityofNewMexicoHospitals

&ClinicalAssociateProfessorUniversityofNewMexico

CollegeofPharmacy

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TheDepartmentofHealth–MedicalCannabisProgram(DOH-MCP)cer>fiesthatalloftheinforma>oncontainedintheseslidesistrueandcorrect.Theslidedeckisavailableforusebyen>>esoutsideofDOH-MCPwithpermission.PLEASEBEAWAREthatifthismaterialispresentedbyanagencyotherthanDOH-MCP,DOH-MCPcannotaNesttothevalidityoftheinforma>onpresentedinconjunc>onwiththeseslides.

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�  Cannabisplantanditsusesdatetoasearlyas4000BC

q NamedforGreekwordforhemp,kannabis

�  Longrecordedhistoryinmedicalwriting;documenteduseforpain,dysentery,nausea/vomiting,spasms,andconvulsions

�  Renderedillegalin1937

�  DroppedfromtheUSPharmacopeiain1941

*  BoothM.Cannabis:Ahistory.NewYork:Picador(St.Martin’sPress),2003.*  GaoniY,MehoulamR.Isolation,structureandpartialsynthesisofanactive

constituentofhashish.JAmChemSoc1964;86:1646-7.*  MatsudaLA,LolaitSJ,etal.Structureofacannabinoidreceptorandfunction

expressionoftheclonedcDNA.Nature1990;346:561-4.*  GuindonJ,BeaulieuP,HohmannAG.Pharmacologyofthecannabinoid

system.In:BeaulieuP,LussierD,PorrecaF,DickensonAH,eds.PharmacologyofPain.Seattle,WA:IASPPress;2010.

BriefHistoryofCannabis

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*  Attheendofthispresentationtheparticipantwill:*  BeabletodiscussthepharmacologyofTHC&CBD*  Demonstrateanunderstandingofthe“entourage

effect”ofcannabis*  Appreciatehowtheuseofcannabiscandecrease

painforpatientwithchronicnoncancerpain(CNCP)*  Appreciatehowtheuseofcannabiscandecrease

theamountofopioidmedicationutilizedinpatientswithCNCP

Objectives

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n  1970-ControlledSubstancesActclassifiedmarijuanaasadrugwith“noacceptedmedicaluse”;ie:ScheduleI

n  1976-FederalCourtrulesRobertRandall’suseofmarijuanaa“medicalnecessity”

n  2018-29statesandtheDistrictofColumbiahaveapprovedmedicalcannabisprogramsand9statesandWashington,DChavelegalizedforcannabisadultforrecrea>onaluse.

BriefHistoryofCannabisintheUS

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Endocannabinoid System

https://www.youtube.com/watch?v=Vtc11kRinf4

Brain (CB1) GI Tract (CB2

and CB1)

Liver (CB1 and CB2)

Skeletal Muscle

Adipocyctes (CB1)

Peripheral Nerves (CB1)

Immune System (CB2)

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n  Theendocannabinoidsystemn  Innatebiologicsystemn  Responsibleforregula>onofmul>plebodysystemsn  CB1andCB2receptorsthroughoutthebodyn  Noreceptorsinbrainstem

n  Clinicaldataavailableontheuseofcannabistotreatsymptomsrelatedtoseriousmedicalcondi>ons

n  Cannabismayprovidereliefforpa>entswhosesymptomsareunrelievedbyothermeans

TheMedicalCannabisSystem

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n  Composed of up to 400 components, including non-intoxicating components n  120 terpenoids: aromatic compounds n  21 flavonoids: antioxidants n  11 plant sterols (seed) n  22 fatty acids

n  THC and CBD are the two main studied components of cannabis out of 60-100 active cannabinoids

n  CBD can mitigate adverse effects of THC*  CasciniF,AielloC,DiTannaG.Increasingdelta-9-tetrahydrocannabinol(Δ-9-THC)contentinherbalcannabisovertime:systematicreviewandmeta-analysis.CurrDrugAbuseRev.2012Mar;5(1):32-40.*  GuindonJ,BeaulieuP,HohmannAG.Pharmacologyofthecannabinoidsystem.In:BeaulieuP,LussierD,PorrecaF,DickensonAH,eds.PharmacologyofPain.Seattle,WA:IASPPress;2010.

CannabinoidComponents

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Endocannabinoids

v Naturalsubstancesproducedbythebody

v Bindtoreceptorsthroughoutthebody

v Noreceptorsinbrainstem

v Exogenouscannabisplanthas>60cannabinoids

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v euphoricv stimulant

v muscle-relaxingv analgesicv anti-emetic

v appetitestimulatingv lowersintra-ocularpressure

v AHighTHCis15-25%

THC(delta-9-tetrahydrocannabinol)

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ResearchedAttributesAnxiolyticAnti-psychoticAnticonvulsantAnti-oxidantAnti-inflammatory

Anti-ischemicAnti-emeticAnti-tumorNeuroprotection

CBD(Cannabidiol)

*CBDmitigatesthepsychoactivesideeffectofTHC-AhighCBDis5-15%

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EndocannabinoidSystem&Pain

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v NandP/QVSCCblockadev K-irpotentiationv VSSCblockadev mapKinaseactivationv mastcellinhibitionv modulationofGABAergic,glycinergic,andglutamatergicneurotransmission

EndocannabinoidSystem&Pain

ManzanaresJ,etal.Roleofthecannabinoidsysteminpaincontrolandtherapeuticimplicationsforthemanagementofacuteandchronicpainepisodes.CurrNeuropharmacol2006;4(3):239-257.GuindonJ,BeaulieuP,HohmannAG.Pharmacologyofthecannabinoidsystem.In:BeaulieuP,LussierD,PorrecaF,DickensonAH,eds.PharmacologyofPain.Seattle,WA:IASPPress;2010.WhitingPF,WolffRF,DeshpandeS,etal.CannabinoidsforMedicalUse:ASystematicReviewandMeta-analysis.JAMA.2015;313(24):2456-2473.doi:10.1001/jama.2015.6358

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Poten>alTherapeu>cEffects/BenefitsTHC(delta-9-tetrahydrocannabinol)*  Intoxica>ngeffects* Appe>tes>mulant* Decreasedintraocularpressure

* Analgesic/neuropathicpain

* An>spasmodic* An>eme>c

CBD(cannabidiol)*  Notintoxica>ng*  Analgesic/neuropathicpain

*  An>psycho>ceffects*  An>convulsant*  Neuro-protec>veeffects*  An>spasmodic*  An>eme>c

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v Preventionofpaclitaxel-inducedpainfulneuropathyv Medicationoveruseheadache,migraine,andclusterv Cancerpainv Neuropathicpainv Osteoarthritisv Centralsensitizationv Brachialplexusavulsionv Fibromyalgia*  BestardJA,etal.Anopen-labelcomparisonofnabiloneandgabapentinasadjuvanttherapyormonotherapyinthemanagement

ofneuropathicpaininpatientswithperipheralneuropathy.PainPractice2011;11(4):353-368.*  AkermanS,etal.EndocannabinoidsinthebrainstemmodulateduraltrigeminovascularnociceptivetrafficviaCB1andtriptan

receptors.JNeurosci2013;33(37):14869-14877.*  PortenoyRK,etal.Nabiximolsforopioid-treatedcancerpatientswithpoorly-controlledchronicpain.JPain2012;13(5):438-449.*  PiniLA,etal.Nabiloneforthetreatmentofmedicationoveruseheadache.JHeadachePain2012;13:677-684.*  GuindonJ,BeaulieuP,HohmannAG.Pharmacologyofthecannabinoidsystem.In:BeaulieuP,LussierD,PorrecaF,DickensonAH,

eds.PharmacologyofPain.Seattle,WA:IASPPress;2010.*  BurstonJJ,etal.CannabinoidCB2receptorsregulatecentralsensitizationandpainresponseassociatedwithosteoarthritisofthe

knee.PLOSOne2013;8(11):1-9.*  WhitingPF,WolffRF,DeshpandeS,etal.CannabinoidsforMedicalUse:ASystematicReviewandMeta-analysis.JAMA.

2015;313(24):2456-2473.doi:10.1001/jama.2015.6358

UtilityinPain

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v Low(6-20%)andvariablebioavailability v Peakplasmawithin1-6andmayremainelevatedforseveralhours

v Initiallyoxidizedinliverto11-OH-THC,apotentpsychoactivemetabolite

v Furtheroxidationof11-OH-THCleadstoeliminationproducts(urineandfeces)

v Terminalhalflife20-30hrs

OralTHCPharmacology

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v Rapidlyabsorbedintobloodstreamandredistributed

v Considerableamountofdoselostinsmoking

v Peakbloodlevelsachievedatendofsmoking,declinerapidlyover30minutes

v Smokingachieveshigherpeakconcentrationbutshorterdurationofeffect

v Smalleramountsof11OH-THCformed

SmokedTHCPharmacology

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n  Toxicityn  Nolethaloverdosesreportedfromcannabisalonen  Lesstoxicity/lethalityra>othanalcohol,opiates,

barbiturates,andsomecommonmedica>onsn  DependenceandWithdrawal

n  Es>matesofdependencearehighlycontroversialn  Mild,short-livedfeelingsofwithdrawaloccurforsome

n  OtherDrugUsen  Noconclusiveevidencecannabisleadstoothersubstances

ofabuseorthatmedicalprogramsincreaseuseamonggeneralpopula>on

n  Typical“gateways”aretobaccoandalcohol

CommonQues>ons

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n  CentralNervousSystemn  Canbetreatmentlimi>ng–generallyseeanxiety/

paranoian  StrainswithlowerTHCandhigherCBDcontentless

psychoac>ven  Neuropsychiatric

n  Teensandyoungerpopula>ons–ques>onsregardingcogni>vedevelopment,memory,andpsychiatricillness

n  Other–Generaln  Cardiovascular,appe>te,nausea,hyperemesis

syndrome,headache,decreasedcoordina>on/musclestrength,thirst/drymouth,red/dryeyes

Poten>alAdverseEffects

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Pharmaceu>calPrepara>onsn  Dronabinol(Marinol),issynthe>cΔ9-tetrahydrocannabinol

(THC),usedasanappe>tes>mulant,an>eme>c,andanalgesic.Approvedin1986forN&VfromChemotherapy;AIDSanorexiain1992

n  Nabilone(Cesamet),asynthe>ccannabinoidandananalogofMarinol.ItisScheduleIIunlikeMarinol,whichisScheduleIII

n  Nabiximols(Sa>vex),acannabinoidextractoralspraycontainingTHC,CBD,andothercannabinoidsusedforneuropathicpainandspas>cityin22countriesincludingEngland,CanadaandSpain(notavailableintheUS).Sa>vexisawhole-plantcannabinoidmedicine.

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n  Marinolissynthe>cTHCn  Onlyoneofmanycannabinoidsinthecannabisplant

(“EntourageEffect”)

n  Thepsychoac>vecomponentmaypresentadura>onofac>onthatisnotacceptabletothepa>ent

n  Manyothercannabinoidsintheplanthaveimportanteffectsn  An>-inflammatory,an>-nausea,neuroprotec>on

n  DifferentstrainsofcannabishavevaryingTHCcontentandvariouseffectsonsymptoms

n  Ifusedfornauseaandvomi>ng,pa>entmayhavedifficultytolera>ngoralmedica>ons

WhyIsn’tMarinolEnough?

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SafetyofPharmaceu>calCannabinoids

n  Lowabusepoten>alofprescrip>oncannabinoidsn  Dronabinol(Calhoun1998)n  Nabilone(Ware2010)n  Nabiximols(Robson2011)

n  Noevidenceoftolerance(Rog2007,Serpell,2013)

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v CNSsideeffectsprimarilyanxietyandparanoia

*  StrainswithlowerTHCcontentlesspsychoactive

v Generalphysicaleffects*  changesinappetite,thirst,nausea,headache,decreasedcoordination,reducedmusclestrength,drymouth,andsensitivitiesincludingrednessanddrynessoftheeyes.

v Toxicity*  Nolethaloverdosesreportedwithnonderivativeproducts

*  Lesstoxicity/lethalityratiothanalcohol,opiates,barbiturates,andsomecommonmeds

AdverseEffects

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v AcutemedicalriskofTHCareratherlowv Fataloverdosewithcannabisalonehasnotbeenreported

v Additiveeffectsofcannabis,anticholinergicsandCNSdepressants*  (e.g.,sedation,drymouth,dizziness,andconfusion)*  Smokingitself(cannabisortobacco)inducesCYP1A2v Mayincreaseclearanceofanti-psychoticsandanti-

depressantsv MetabolizedbyP450,littleevidencesupportingdrug-drug

interaction*  Chronicopiateusershaveseenapotentialreductionofdoseswheninconjunctionwithmedicalcannabis

AcuteDrugInteractions

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Cannabinoid-OpioidInteractioninChronicPain

v Objectivesv EvaluateeffectofvaporizedcannabisonBloodlevelsofprescribedopiates(SRmorphineandSROxycodone)

v Determinetheshort-termsideeffectsofco-administrationofcannabisandopioids

v AssesseffectofvaporizedcannabisonlevelofChronicpain

v N=21v FundedinpartbyNIDAandNIHCRCgrants

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*  Study*  21ptswithchronicpain,ontwice-dailydosesofsustainedreleasemorphineoroxycodonewereadmittedfora5-dayinpatientstay*  Askedtoinhalevaporizedcannabisintheeveningofday1,threetimesadayondays2–4,andinthemorningofday5*  Theextentofchronicpainwasassesseddaily*  Results*  NosignificantchangeintheAUCforeithermorphineoroxycodoneafterexposuretocannabis*  Painwassignificantlydecreased(average27%)aftertheadditionofvaporizedcannabis* AbramsDI,CoueyP,ShadeSB,KellyME,BenowitzNL.ClinPharmacolTher.2011Nov2.90(6):844-51.

Cannabinoid-OpioidInteractioninChronicPain

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v Co-administrationofvaporizedcannabiswithoralsustainedreleaseopiatesissafe

v Co-administrationofvaporizedcannabisinsubjectsonstabledosesofmorphineoroxycodoneappearstoenhanceanalgesia

v Co-administrationofvaporizedcannabistrendstowardsloweringconcentrationoftheopioidsoftheopioids*  ThePKeffectswouldbeexpectedtoreducetheanalgesiceffects

ofopioids.*  Theeffectsofvaporizedcannabistoenhanceopioidanalgesia

occursbyapharmacodynamic,notapharmacokineticeffectv AbramsDI,CoueyP,ShadeSB,KellyME,BenowitzNL.ClinPharmacolTher.2011Nov2.90(6):844-51.

Cannabinoid-OpioidInteractioninChronicPain

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v Cannabisusecommonamongopioid-dependentindividuals*  Rangefrom20%to95%*  Cannabisuseassociatedwithdrugdealingandneedlesharing

v Cannabiseffectsontreatmentforopioid-dependence*  Cannabisuseassociatedwithfasterrelapsetoalcohol,cocaine

andheroinuse*  Inchronicopioidtherapyforpain,cannabisusewasapositive

predictoroffutureopioidmisuse*  Cannabisusestronglyassociatedwithincreasedriskforother

substanceuseanddependence*  Thesewereself-selectedcannabisusers

v ScavoneJL,SterlingRC,VanBockstaeleEJ.Neuroscience.2013Sep17;248:637-54

Cannabis&OpioidUse/Abuse

.

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v Manystudieshavedemonstratedcannabisuseassociatedwithpositivetreatmentprognosisamongopioid-dependentcohorts*  Cannabisabuse&dependencewerepredictiveofdecreasedheroin&cocaineuseduringtreatment*  IntermittentuseofcannabiswasassociatedwithalowerpercentageofpositiveopioidUDSandimprovedmedicationcomplianceonnaltrexone*  Cannabisimprovedopioid-dependencetreatmentretention*  Cannabisusemaybenefitopioidusersinwithdrawal*  Thesewereself-selectedcannabisusers* ScavoneJL,SterlingRC,VanBockstaeleEJ.Neuroscience.2013Sep17;248:637-54

Cannabis&OpioidUse/Abuse

.

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*  Thesubstance-dependentpopulationmaydiffersignificantlyfromdrugnaïveorrecreationalsubstanceusers

*  Correlationwithmedicalcannabisusersisdifficultbutsuggeststhatasidefromdirect,pain-relatedbenefitsofcannabisindelayinginitiationandadjunctivepain-relief,cannabismayprovidepositiveeffectsinopioidabusersv ScavoneJL,SterlingRC,VanBockstaeleEJ.Neuroscience.2013Sep17;248:637-54

Cannabis&OpioidUse/Abuse

.

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v Receptorsystemsofbothcannabinoidsandopioidsareknowntomediatecommonsignalingpathways

v Drugsthattargetboththecannabinoidandmorphinereceptorsystemspossesssharedpharmacologicalprofiles* Agonistsofbothreceptortypeshavebeenshowntocausepainrelief,sedation,hypotension,motordepression,anddrugreward/reinforcementv ScavoneJL,SterlingRC,VanBockstaeleEJ.Neuroscience.2013Sep17;248:637-54

Cannabinoid-OpioidInteraction

.

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v Studiesdemonstratecross-tolerance,mutualpotentiation,andreceptorcross-talk* Impliesthatpainrelieffromcannabinoidsaremorethanjustpsychotropic-based

v Cannabinoidsmaymodulateopioidfunctionatanumberofdifferentlevelswithinthecell* Potentialforadditivepainreliefwithcombinationofopioids&cannabinoidsv ScavoneJL,SterlingRC,VanBockstaeleEJ.Neuroscience.2013Sep17;248:637-54

Cannabinoid-OpioidInteraction

.

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v Timeseriesanalysisofmedicalcannabislawsandstate-leveldeathcertificatedataintheUSfrom1999to2010;all50statesincluded

v Stateswithmedicalcannabislawshada24.8%lowermeanannualopioidoverdosemortalityrate(95%CI,-37%to-9%,P=0.003)

v ExaminationoftheassociationbetweenmedicalcannabislawsandopioidanalgesicoverdosemortalityineachyearofimplementationofthelawshowedalowerrateofODmortalityovertimethatgenerallystrengthenedovertime*  BachhuberMA,SalonerB,CunninghamCO,BarryCL.Medical

CannabisLawsandOpioidAnalgesicOverdoseMortalityintheUnitedStates,1999-2010.JAMAInternMed.2014;174(10):1668-1673.doi:10.1001/jamainternmed.2014.4005

MedicalCannabisLawsandOpioidAnalgesicOverdoseMortalityinTheUnitedStates1999-2010

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n  Theendocannabinoidsystemisaninnatebiologicsystemresponsibleforregula>onofbodymul>plesystems

n  Thereisclinicaldataontheuseofcannabistotreatsymptomsrelatedtoseriousmedicalcondi>ons

n  Cannabismayprovidereliefforpa>entssufferingfromillnessordiseaseunrelievedbyothermodali>es

n  Recommendingapa>entfortheprogramisprotectedunderstatelaw

Summary

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v TheuseofcannabishasaplaceinthetreatmentofCNCP

v TheuseofcannabismaydecreasetheuseofopioidmedicationinpatientswithCNCP

v Cannabishasafavorablesafetyprofile

Summary


1646 Main Street Brewster, MA 02631

1646 Main Street Brewster, MA 02631

HASHISH IN ISLAM 9TH TO 18TH CENTURY

HASHISH IN ISLAM 9TH TO 18TH CENTURY

Seizures of hashish (cannabis resin), 2014 · Seizures of hashish (cannabis resin), 2014 Weight in ton equivalents*. The present map includes data from countries and territories for

Seizures of hashish (cannabis resin), 2014 · Seizures of hashish (cannabis resin), 2014 Weight in ton equivalents*. The present map includes data from countries and territories for

1646–48 S. 12TH STREET

1646–48 S. 12TH STREET

Gottfried Leibniz (1646-1716)

Gottfried Leibniz (1646-1716)

Robert Bolling (1646-1709) · Mary Kennon Bolling Robert Bolling (1646-1709) Major John Bolling, Sr. (1676-1729) (C. 1678-1742)

Robert Bolling (1646-1709) · Mary Kennon Bolling Robert Bolling (1646-1709) Major John Bolling, Sr. (1676-1729) (C. 1678-1742)

Moroccan boys' play inspired by TV : 'the gendarmes and hashish smugglers'

Moroccan boys' play inspired by TV : 'the gendarmes and hashish smugglers'

HASHISH FROM QADIAN

HASHISH FROM QADIAN

Hashish about qadianis the views of Hazrat Allama Muhammad Iqbal

Hashish about qadianis the views of Hazrat Allama Muhammad Iqbal

Gottfried Wilhelm Leibniz (1646-1716) - Amazon S3

Gottfried Wilhelm Leibniz (1646-1716) - Amazon S3

HASHISH FROM QADIANdrshabbir.com/library/HASHISH--FINAL.pdf ·  · 2012-08-06creed in the name of Islam. ... Smoking or drinking Hashish causes intoxication. Why did Allama Iqbal

HASHISH FROM QADIANdrshabbir.com/library/HASHISH--FINAL.pdf ·  · 2012-08-06creed in the name of Islam. ... Smoking or drinking Hashish causes intoxication. Why did Allama Iqbal

Hashish - The Joy of Making and Curing

Hashish - The Joy of Making and Curing

Thomas Clarke of Painswick Inventory September 1646 ... · Thomas Clarke of Painswick Inventory September 1646 Gloucestershire Archives 1646/22 Image 1 An inventory taken the 19th

Thomas Clarke of Painswick Inventory September 1646 ... · Thomas Clarke of Painswick Inventory September 1646 Gloucestershire Archives 1646/22 Image 1 An inventory taken the 19th

Ariadne's Thread: Walter Benjamin's Hashish Passages · ARIADNE'S THREAD Walter Benjamin's Hashish Passages GARY SHAPIRO In a letter of 1932 to Gershom Scholem, Benjamin outlines

Ariadne's Thread: Walter Benjamin's Hashish Passages · ARIADNE'S THREAD Walter Benjamin's Hashish Passages GARY SHAPIRO In a letter of 1932 to Gershom Scholem, Benjamin outlines

thisted morsoe soender elsoe kirkebog 1646-1799

thisted morsoe soender elsoe kirkebog 1646-1799

University of California Center for Medicinal Cannabis Research · 2018-12-04 · partial synthesis of an active constituent of hashish. Y. Gaoni, Raphael Mechoulam. J. Am. Chem.

University of California Center for Medicinal Cannabis Research · 2018-12-04 · partial synthesis of an active constituent of hashish. Y. Gaoni, Raphael Mechoulam. J. Am. Chem.

US Supreme Court: 06-1646

US Supreme Court: 06-1646

NCh 1646.cR98

NCh 1646.cR98

1646 Mohawk Marketing Brochure

1646 Mohawk Marketing Brochure

1646 - Relay Coordination Table

1646 - Relay Coordination Table