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

The Department of Health – Medical Cannabis Program (DOH-MCP) cerfies that all of the informaon contained in these slides is true and correct. The slide deck is available for use by enes outside of DOH-MCP with permission.

PLEASE BE AWARE that if this material is presented by an agency other than DOH-MCP, DOH-MCP can not aest to the validity of the informaon presented in conjuncon with these slides. Brief History of Cannabis — Cannabis plant and its uses date to as early as 4000 BC q Named for Greek word for hemp, kannabis — Long recorded history in medical writing; documented use for pain, dysentery, nausea / vomiting, spasms, and convulsions — Rendered illegal in 1937 — Dropped from the US Pharmacopeia in 1941

* Booth M. Cannabis: A history. New York: Picador (St. Martin’s Press), 2003. * Gaoni Y, Mehoulam R. Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc 1964;86:1646-7. * Matsuda LA, Lolait SJ, et al. Structure of a cannabinoid receptor and function expression of the cloned cDNA. Nature 1990;346:561-4. * Guindon J, Beaulieu P, Hohmann AG. Pharmacology of the cannabinoid system. In: Beaulieu P, Lussier D, Porreca F, Dickenson AH, eds. Pharmacology of Pain. Seattle, WA: IASP Press;2010. Objectives

* At the end of this presentation the participant will : * Be able to discuss the pharmacology of THC & CBD * Demonstrate an understanding of the “entourage effect” of cannabis * Appreciate how the use of cannabis can decrease pain for patient with chronic noncancer pain (CNCP) * Appreciate how the use of cannabis can decrease the amount of opioid medication utilized in patients with CNCP Brief History of Cannabis in the US n 1970 - Controlled Substances Act classified marijuana as a drug with “no accepted medical use”; ie: Schedule I n 1976 - Federal Court rules Robert Randall’s use of marijuana a “medical necessity” n 2018 - 29 states and the District of Columbia have approved medical cannabis programs and 9 states and Washington, DC have legalized for cannabis adult for recreaonal use. GI Tract (CB2 Brain (CB1) and CB1) Adipocyctes (CB1) Endocannabinoid System https://www.youtube.com/watch?v=Vtc11kRinf4 Liver Peripheral (CB1 and CB2) Nerves (CB1)

Skeletal Muscle Immune System (CB2) The Medical Cannabis System n The endocannabinoid system

n Innate biologic system n Responsible for regulaon of mulple body systems n CB1 and CB2 receptors throughout the body n No receptors in brainstem n Clinical data available on the use of cannabis to treat symptoms related to serious medical condions n Cannabis may provide relief for paents whose symptoms are unrelieved by other means Cannabinoid Components 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 * Cascini F, Aiello C, Di Tanna G. Increasing delta-9-tetrahydrocannabinol (Δ-9- THC) content in herbal cannabis over time: systematic review and meta- analysis. Curr Drug Abuse Rev. 2012 Mar;5(1): 32-40. * Guindon J, Beaulieu P, Hohmann AG. Pharmacology of the cannabinoid system. In: Beaulieu P, Lussier D, Porreca F, Dickenson AH, eds. Pharmacology of Pain. Seattle, WA: IASP Press;2010. Endocannabinoids

v Natural substances produced by the body v Bind to receptors throughout the body v No receptors in brainstem v Exogenous cannabis plant has > 60 cannabinoids THC (delta-9-tetra hydrocannabinol)

v euphoric v stimulant v muscle-relaxing v analgesic v anti-emetic v appetite stimulating v lowers intra-ocular pressure v A High THC is 15-25%

CBD (Cannabidiol)

Researched Attributes

Anxiolytic Anti-ischemic Anti-psychotic Anti-emetic Anticonvulsant Anti-tumor Anti-oxidant Neuroprotection Anti-inflammatory

*CBD mitigates the psychoactive side effect of THC - A high CBD is 5-15% Endocannabinoid System & Pain Endocannabinoid System & Pain

v N and P/Q VSCC blockade v K-ir potentiation v VSSC blockade v mapKinase activation v mast cell inhibition v modulation of GABAergic, glycinergic, and glutamatergic neurotransmission

Manzanares J, et al. Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes. Curr Neuropharmacol 2006;4(3):239-257. Guindon J, Beaulieu P, Hohmann AG. Pharmacology of the cannabinoid system. In: Beaulieu P, Lussier D, Porreca F, Dickenson AH, eds. Pharmacology of Pain. Seattle, WA: IASP Press;2010. Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA.2015;313(24):2456-2473. doi: 10.1001/jama.2015.6358

Potenal Therapeuc Effects/Benefits THC CBD (delta-9- (cannabidiol) tetrahydrocannabinol) * Not intoxicang * Intoxicang effects * Analgesic/neuropathic * Appete smulant pain * Anpsychoc effects * Decreased intraocular * Anconvulsant pressure * Neuro-protecve effects * Analgesic/neuropathic * Anspasmodic pain * Anemec * Anspasmodic * Anemec

Utility in Pain v Prevention of paclitaxel-induced painful neuropathy v Medication overuse headache, migraine, and cluster v Cancer pain v Neuropathic pain v Osteoarthritis v Central sensitization v Brachial plexus avulsion v Fibromyalgia * Bestard JA, et al. An open-label comparison of nabilone and gabapentin as adjuvant therapy or monotherapy in the management of neuropathic pain in patients with peripheral neuropathy. Pain Practice 2011;11(4):353-368. * Akerman S, et al. Endocannabinoids in the brainstem modulate dural trigeminovascular nociceptive traffic via CB1 and triptan receptors. J Neurosci 2013;33(37):14869-14877. * Portenoy RK, et al. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain. J Pain 2012;13(5):438-449. * Pini LA, et al. Nabilone for the treatment of medication overuse headache. J Headache Pain 2012;13:677-684. * Guindon J, Beaulieu P, Hohmann AG. Pharmacology of the cannabinoid system. In: Beaulieu P, Lussier D, Porreca F, Dickenson AH, eds. Pharmacology of Pain. Seattle, WA: IASP Press;2010. * Burston JJ, et al. Cannabinoid CB2 receptors regulate central sensitization and pain response associated with osteoarthritis of the knee. PLOS One 2013;8(11):1-9. * Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA. 2015;313(24):2456-2473. doi:10.1001/jama.2015.6358 Oral THC Pharmacology v Low (6-20%) and variable bioavailability v Peak plasma within 1-6 and may remain elevated for several hours v Initially oxidized in liver to 11-OH-THC, a potent psychoactive metabolite v Further oxidation of 11-OH-THC leads to elimination products (urine and feces) v Terminal half life 20-30 hrs Smoked THC Pharmacology vRapidly absorbed into bloodstream and redistributed vConsiderable amount of dose lost in smoking vPeak blood levels achieved at end of smoking, decline rapidly over 30 minutes vSmoking achieves higher peak concentration but shorter duration of effect vSmaller amounts of 11 OH-THC formed Common Quesons n Toxicity n No lethal overdoses reported from cannabis alone n Less toxicity/lethality rao than alcohol, opiates, barbiturates, and some common medicaons n Dependence and Withdrawal n Esmates of dependence are highly controversial n Mild, short-lived feelings of withdrawal occur for some n Other Drug Use n No conclusive evidence cannabis leads to other substances of abuse or that medical programs increase use among general populaon n Typical “gateways” are tobacco and alcohol Potenal Adverse Effects n Central Nervous System

n Can be treatment liming – generally see anxiety/ paranoia n Strains with lower THC and higher CBD content less psychoacve n Neuropsychiatric

n Teens and younger populaons – quesons regarding cognive development, memory, and psychiatric illness n Other – General

n Cardiovascular, appete, nausea, hyperemesis syndrome, headache, decreased coordinaon/muscle strength, thirst/dry mouth, red/dry eyes Pharmaceucal Preparaons n Dronabinol (Marinol), is synthec Δ9-tetrahydrocannabinol (THC), used as an appete smulant, anemec, and analgesic. Approved in 1986 for N&V from Chemotherapy; AIDS anorexia in 1992 n Nabilone (Cesamet), a synthec cannabinoid and an analog of Marinol. It is Schedule II unlike Marinol, which is Schedule III n Nabiximols (Savex), a cannabinoid extract oral spray containing THC, CBD, and other cannabinoids used for neuropathic pain and spascity in 22 countries including England, Canada and Spain (not available in the US). Savex is a whole-plant cannabinoid medicine. Why Isn’t Marinol Enough? n Marinol is synthec THC

n Only one of many cannabinoids in the cannabis plant (“Entourage Effect”)

n The psychoacve component may present a duraon of acon that is not acceptable to the paent n Many other cannabinoids in the plant have important effects

n An-inflammatory, an-nausea, neuroprotecon n Different strains of cannabis have varying THC content and various effects on symptoms n If used for nausea and voming, paent may have difficulty tolerang oral medicaons Safety of Pharmaceucal Cannabinoids n Low abuse potenal of prescripon cannabinoids n Dronabinol (Calhoun 1998) n Nabilone (Ware 2010) n Nabiximols (Robson 2011) n No evidence of tolerance (Rog 2007, Serpell, 2013)

Adverse Effects vCNS side effects primarily anxiety and paranoia * Strains with lower THC content less psychoactive vGeneral physical effects * changes in appetite, thirst, nausea, headache, decreased coordination, reduced muscle strength, dry mouth, and sensitivities including redness and dryness of the eyes. vToxicity * No lethal overdoses reported with non derivative products * Less toxicity/ lethality ratio than alcohol, opiates, barbiturates, and some common meds

Acute Drug Interactions vAcute medical risk of THC are rather low vFatal overdose with cannabis alone has not been reported vAdditive effects of cannabis, anticholinergics and CNS depressants * (e.g., sedation, dry mouth, dizziness, and confusion) * Smoking itself (cannabis or tobacco) induces CYP 1A2 v May increase clearance of anti-psychotics and anti- depressants v Metabolized by P450, little evidence supporting drug-drug interaction * Chronic opiate users have seen a potential reduction of doses when in conjunction with medical cannabis

Cannabinoid-Opioid Interaction in Chronic Pain vObjectives vEvaluate effect of vaporized cannabis on Blood levels of prescribed opiates (SR morphine and SR Oxycodone) vDetermine the short-term side effects of co- administration of cannabis and opioids vAssess effect of vaporized cannabis on level of Chronic pain vN = 21 vFunded in part by NIDA and NIH CRC grants Cannabinoid-Opioid Interaction in Chronic Pain * Study * 21 pts with chronic pain, on twice-daily doses of sustained release morphine or oxycodone were admitted for a 5-day inpatient stay * Asked to inhale vaporized cannabis in the evening of day 1, three times a day on days 2–4, and in the morning of day 5 * The extent of chronic pain was assessed daily * Results * No significant change in the AUC for either morphine or oxycodone after exposure to cannabis * Pain was significantly decreased (average 27%) after the addition of vaporized cannabis * Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL. Clin Pharmacol Ther. 2011 Nov 2. 90(6):844-51. Cannabinoid-Opioid Interaction in Chronic Pain v Co-administration of vaporized cannabis with oral sustained release opiates is safe v Co-administration of vaporized cannabis in subjects on stable doses of morphine or oxycodone appears to enhance analgesia v Co-administration of vaporized cannabis trends towards lowering concentration of the opioids of the opioids * The PK effects would be expected to reduce the analgesic effects of opioids. * The effects of vaporized cannabis to enhance opioid analgesia occurs by a pharmacodynamic , not a pharmacokinetic effect vAbrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL. Clin Pharmacol Ther. 2011 Nov 2. 90(6):844-51.

Cannabis & Opioid Use/Abuse v Cannabis use common among opioid-dependent individuals * Range from 20% to 95% * Cannabis use associated with drug dealing and needle sharing v Cannabis effects on treatment for opioid-dependence * Cannabis use associated with faster relapse to alcohol, cocaine and heroin use * In chronic opioid therapy for pain, cannabis use was a positive predictor of future opioid misuse * Cannabis use strongly associated with increased risk for other substance use and dependence * These were self-selected cannabis users vScavone JL, Sterling RC, Van Bockstaele EJ. Neuroscience. 2013 Sep 17;248:637-54 . Cannabis & Opioid Use/Abuse vMany studies have demonstrated cannabis use associated with positive treatment prognosis among opioid-dependent cohorts * Cannabis abuse & dependence were predictive of decreased heroin & cocaine use during treatment * Intermittent use of cannabis was associated with a lower percentage of positive opioid UDS and improved medication compliance on naltrexone * Cannabis improved opioid-dependence treatment retention * Cannabis use may benefit opioid users in withdrawal * These were self-selected cannabis users * Scavone JL, Sterling RC, Van Bockstaele EJ. Neuroscience. 2013 Sep 17;248:637-54 . Cannabis & Opioid Use/Abuse

* The substance-dependent population may differ significantly from drug naïve or recreational substance users * Correlation with medical cannabis users is difficult but suggests that aside from direct, pain- related benefits of cannabis in delaying initiation and adjunctive pain-relief, cannabis may provide positive effects in opioid abusers vScavone JL, Sterling RC, Van Bockstaele EJ. Neuroscience. 2013 Sep 17;248:637-54

. Cannabinoid-Opioid Interaction vReceptor systems of both cannabinoids and opioids are known to mediate common signaling pathways vDrugs that target both the cannabinoid and morphine receptor systems possess shared pharmacological profiles * Agonists of both receptor types have been shown to cause pain relief, sedation, hypotension, motor depression, and drug reward/reinforcement . vScavone JL, Sterling RC, Van Bockstaele EJ. Neuroscience. 2013 Sep 17;248:637-54

Cannabinoid-Opioid Interaction vStudies demonstrate cross-tolerance, mutual potentiation, and receptor cross-talk * Implies that pain relief from cannabinoids are more than just psychotropic-based vCannabinoids may modulate opioid function at a number of different levels within the cell * Potential for additive pain relief with . combination of opioids & cannabinoids vScavone JL, Sterling RC, Van Bockstaele EJ. Neuroscience. 2013 Sep 17;248:637-54 Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in The United States 1999-2010 v Time series analysis of medical cannabis laws and state-level death certificate data in the US from 1999 to 2010; all 50 states included v States with medical cannabis laws had a 24.8% lower mean annual opioid overdose mortality rate (95%CI, -37%to -9%, P = 0.003) v Examination of the association between medical cannabis laws and opioid analgesic overdose mortality in each year of implementation of the law showed a lower rate of OD mortality over time that generally strengthened over time * Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in the United States, 1999-2010. JAMA Intern Med.2014;174(10): 1668-1673. doi:10.1001/jamainternmed.2014.4005 Summary n The endocannabinoid system is an innate biologic system responsible for regulaon of body mulple systems n There is clinical data on the use of cannabis to treat symptoms related to serious medical condions n Cannabis may provide relief for paents suffering from illness or disease unrelieved by other modalies n Recommending a paent for the program is protected under state law Summary vThe use of cannabis has a place in the treatment of CNCP vThe use of cannabis may decrease the use of opioid medication in patients with CNCP vCannabis has a favorable safety profile