CANNABISANDPAIN

DebraKimless,M.D.MedicalDirector,ForwardGro

MAOPAnnualMeetingSeptember14,2018

FDA APPROVAL: PREGABALIN, DULOXETINE, MILNACIPRAN FOR FIBROMYALGIA PREGABALIN, DULOXETINE FOR NEUROPATHIC PAIN ALL OTHER RECOMMENDED MEDICINES ARE OFF-LABEL USE

HOW SUCCESSFUL ARE THESE MEDICATIONS? 50% People treated with PREGABALIN experienced a 30% reduction in pain versus placebos that experienced 19% reduction in pain. People treated with DULOXETINE experienced 49% reduction in pain as compared with placebo that received 32% reduction in pain A larger number of patients using MILNACIPRAN (25%) than placebo (19%) had at least a 30% reduction in pain

SIDE EFFECTS:

DULOXETINE : asthenia,constipation,diarrhea,dizziness,drowsiness,fatigue,hypersomnia,insomnia,nausea,sedation,headache,andxerostomia.Othersideeffectsinclude:agitation,erectiledysfunction,nervousness,psychomotoragitation,tension,vomiting,abdominalpain,anorexia,decreasedappetite,decreasedlibido,hyperhidrosis,abnormalorgasm,suicide

PREGABALIN : infection, ataxia, blurred vision, constipation, diplopia, dizziness, drowsiness, fatigue, headache, peripheral edema, tremor, weight gain, visual field loss, accidental injury, and xerostomia. Other side effects include: abnormal gait, abnormality in thinking, amnesia, arthralgia, asthenia, cognitive dysfunction, confusion, edema, neuropathy, sinusitis, speech disturbance, vertigo, visual disturbance, myasthenia, amblyopia, increased appetite, and twitching, disorientation, confusion, anxiety, serotonin syndrome in combo with SSRI’s

MILNACIPRAN : hypertensive crisis, constipation, dizziness, headache, hot flash, nausea, and insomnia. Other side effects include: hypertension, increased heart rate, migraine, palpitations, skin rash, vomiting, anxiety, increased pulse, increased serum alanine aminotransferase, increased serum aspartate aminotransferase, hyperhidrosis, and xerostomia

UnitedStates,inparticular,acetaminophenaccountsformorethan50%ofoverdose-relatedacuteliverfailure

National Overdose Deaths Number of Deaths Involving All Drugs

63,632

72,306

0

10,000

20,000

30,000

40,000

50,000

60,000

70,000

80,000 TotalFemaleMale

Source:NationalCenterforHealthStatistics,CDCWonder

AVERAGEERVISITCOSTS$1917

2MILLIONDOLLARSPERDAY!!!!!!

Biochemical Mechanisms of Pain Control by Cannabinoids (endogenous or exogenous) • Serotonergic• Dopaminergic• Anti-inflammatory• Cannabinoid-OpioidInteractions• PeriaqueductalGrayMatter• NMDA/GlutamateReceptors• SubstanceP• Synergy/EntourageEffect

MULTI-MODALMECHANISMSFORMODULATINGPAIN

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•  The ECS is active in tonic fashion in control of pain

•  ECS functions in nociceptive areas of CNS

•  Integrative control of pain in PAG

•  VPL where CBs 10-fold more potent than morphine in WDR neurons mediating pain

MULTI-MODAL MECHANISMS FOR MODULATING PAIN

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•  ECS active in spinal cord pain mechanisms including NMDA, wind-up, and allodynia

•  ECS also active in periphery on pain, inflammation, hyperalgesia

•  Homeostasis of Activators and Sensitizers

through both CB1 and CB2

Analgesic and Anti-inflammatory Compounds in Cannabis

• Tetrahydrocannabinol(THC)• Cannabidiol(CBD)• Tetrahydrocannabinolicacid(THCA)• Cannabidiolicacid(CBDA)• BetaCaryophyllene• Plusmanyothers

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CANNABINOID-OPIOIDSYNERGY

• Both produce analgesia through a G-protein-coupled mechanism that blocks the release of pain-propagating neurotransmitters in the brain and spinal cord

• Cannabinoids may interact with delta and kappa receptors

• Adding a cannabinoid to opioid therapy may lead to greater pain relief at lower opioid doses and less adverse effects

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Cannabinoids – Mechanisms of action are distinct from opioids •  THCandCBDhaveanalgesicefficacyinanimalmodels•  MechanismsareduetoactivityatCB1andCB2receptors(THC),andatTRPV1receptors(CBD).•  CBDhasanti-inflammatorypropertiesinvitro•  Opioidefficacyrelatedtoactivityatmuopioidreceptors•  CBreceptorsarescarceincardiorespiratorycentresincontrasttoopioidreceptorsSONOOVERDOSEDEATHSFROMCARDIORESPIRATORYARREST!!!!!

BUT•  Cannabinoidsenhancereleaseofendogenousopioids•  CBreceptorsmayco-localisewithmuopioidreceptorsANDNoevidenceofclinicallyrelevantadversedrug-druginteractionbetweencannabinoidsandopioids

IBUPROFEN: 636mg/kg CAFFEINE :192mg/kg NICOTINE: 50 mg/kg HEROIN: 22 mg/kg Itwouldtakea70kgmantosmoke1,500lbsina15minutestimeperiodtodie FrancisL.Young,AdministrativeLawJudgefortheUSDrugEnforcementAdministration(DEA)wroteinhisSep.6,1988decisioninacaseattemptingtoreschedulemarijuanasothatitcanbeprescribedbyphysicians:

LD 50

Potential Warnings with Cannabis use:

TACHYCARDIA HTN SOMNOLENCE HYPEREMESIS EUPHORIA ALTERED TIME PERCEPTION/PARANOIA, HALLUCINATIONS TOLERANCE

Empirical Medicine of the 19th Century •  Combinedmorphine,cannabis,andcapsicum•  Providedaphyto-opioid,phytocannabinoid,andphytovanilloidinonepreparation

•  Affectedthe3knownendogenousbiochemicalsystemsmediatingpain:endorphin/enkephalin,endocannabinoid,vanilloid

•  Arguablymayhaveprovidedbetteroutpatientpainreliefthaniscurrentlyavailableinthe21stcentury

•  19thcenturyphysiciansnotedabilityofcannabistoproduceopiatesparing,reducemorbidity,andtreatopiatewithdrawal

EBR

NationalAcademiesofSciences,Engineering,andMedicine:HealthandMedicineDivision2017Report,440pagesFulltextavailablefree:https://www.nap.edu/download/24625

Thereisconclusiveorsubstantialevidencethatcannabisorcannabinoidsareeffective:

•  Forthetreatmentofchronicpaininadults(cannabis)(4-1)

•  Asanti-emeticsinthetreatmentofchemotherapy-inducednauseaandvomiting(oralcannabinoids)(4-3)

•  Forimprovingpatient-reportedmultiplesclerosisspasticitysymptoms(oralcannabinoids)(4-7a)

Thereismoderateevidencethatcannabisorcannabinoidsareeffectivefor:

•  Improvingshort-termsleepoutcomesinindividualswithsleepdisturbanceassociatedwithobstructivesleepapneasyndrome,fibromyalgia,chronicpain,andmultiplesclerosis(cannabinoids,primarilynabiximols)(4-19)

Cannabis for the Management of Pain: Assessment of Safety Study (COMPASS) , Mark Ware et al, Journal of Pain December 2015. Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) inthe treatment of pain caused by rheumatoid arthritis D. R. Blake et al, Rheumatology, 2006. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis, David J. Rog et al, Neurology, 2005. Cannabis in painful HIV-associated sensory neuropathy: A randomized placebo-controlled trial, D. Abrams et al., Neurology, 2007. Given the choice, patients will reach for cannabis over prescribed opioids, University of British Columbia, 2017

CANNABIS FOR PAIN

Noyes, R., Jr., Brunk, S. F., Avery, D. A. H., & Canter, A. C. (1975). The analgesic properties of

delta-9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther, 18(1), 84-89.

WHATABOUTCBD????

CBD1.   ISTHESECONDMOSTABUNDANTCANNABINOID2.   CONSIDEREDNON-INTOXICATING3.   HASAMULTI-MODALMECHANISMOFACTION4.   CURRENTLY,SCIENCEIDENTIFIEDMORETHAN65MOLECULAR

TARGETS5.   STILLBEINGINVESTIGATED

CBD

• DOESN’TBINDTOCB1ORCB2RECEPTORS• MODULATESNON-CANNABINOIDRECEPTORSANDIONCHANNELS• ACTSTHROUGHRECEPTOR-INDEPENDENTPATHWAYS

CBDANDNON-CANNABINOIDRECEPTORS

1.   ACTIVATES5-HT1ASERATONINRECEPTORS:FORANTI-ANXIETY

ADDICTIONMITIGATION,APPETITEMODULATION,SLEEP,PAIN,NAUSEAANDVOMITING2.TRPV1VANILLOID(CAPSAICIN)RECEPTORS:MEDIATESPAINPERCEPTION,INFLAMMATION,TEMPERATUREREGULATION3.GPR55RECEPTOR:CBDISANANTAGONIST.MODULATESBP,ANDBONEDENSITY(INHIBITSOSTEOCLASTFUNCTION),INHIBITSCANCERCELLPROLIFERATION

CBDANDNON-CANNABINOIDRECEPTORS(continued)

4.PPAR(peroxisomeproliferatoractivatedreceptors)CBDISANAGONISTWHICHHASACANCERCELLANTI-PROLIFERATIVEEFFECT,INDUCESTUMORREGRESSIONINSOMECANCERS,MAYDEGRADEAMYLOID-BETAPLAQUE,MODULATESMETABOLISMANDMAYPLAYAROLEINDIABETES(MAYREDUCEINSULINRESISTENCE)

REUPTAKEINHIBITOR

1.   RECENTLYREPORTED:FABPsESCORTENDOCANNABINOIDSINTOACELL

2.   ONCEINSIDETHECELLECGETBROKENDOWN

3.   CBDCOMPETESFORFABPsallowingformorecirculatingEC

ThisisthoughttobethemechanismofactionforCBDandBrainProtection,anti-seizure.

REUPTAKEINHIBITOR(continued)

1.   ADENOSINEREUPTAKEINHIBITORBYCBDWHICHINCREASESBRAINADENOSINELEVELS.

2.CONFERSANTI-INFLAMMATORY/ANTI-ANXIETYEFFECTS,ALONGWITHCARDIOVASCULARFUNCTION.

ALLOSTERICMODULATOR

1.   POSITIVE:ONTHEGABARECEPTOR,WHICHAMPLIFIESANXIOLYTICEFFECTSOFGABA2.NEGATIVE:ONTHECB1RECEPTOR,MODULATESTHEINTOXICATINGEFFECTSOFTHC

WHAT WOULD NIDA DO?

November09,2017

WEIGHINGRISKSV.BENEFITSWHICHDOYOUCHOOSE?