Slide 1 THIS SESSION IS BEING RECORDED UVM Project ECHO: Chronic Pain Facilitators: Mark Pasanen, MD Charles Maclean, MD Liz Cote Agenda • Introductions and announcements • Session objectives • Didactic presentation (20-25 min) • Q & A • Case presentations • Clarifying questions • Discussion • First, participants – then program faculty • Summary of recommendations • Session parking lot items for follow up • Closing reminders • Complete session evaluation (session recording info included in this email) • Session slides posted at www.vtahec.org • Submit a new case, template posted at www.vtahec.org Slide 3 CME Disclosures University of Vermont (UVM) Office of Continuing Medical and Interprofessional Education (CMIE) is approved as a provider of Continuing Medical Education (CME) by the ACCME. UVM designates this educational activity for a maximum of 1.5 AMA PRA Category 1 Credits. Participants should claim only the credit commensurate with the extent of their participation in the activity. Interest Disclosures: • As an organization accredited by the ACCME to sponsor continuing medical education activities, UVMCMIE is required to disclose any real or apparent conflicts of interest (COI) that any speakers may have related to the content of their presentations. Slide 4 UVM Project ECHO Chronic Pain: Cannabinoids for Chronic Pain Speaker: Mac Abernathy, MD April 3, 2020 Medical Cannabis for Chronic Pain Mac W. Abernathy, M.D. Assistant Professor of Psychiatry Larner College of Medicine University of Vermont Attending/Consulting Neuro-Psychiatrist Comprehensive Pain Program University of Vermont Medical Center Objectives ● Educate medical professionals on the basics of cannabis and the pharmacology of the cannabinoid system. ● Understand the evidence for medical cannabis in the treatment of chronic pain. ● Teach medical professionals the nuances of the medical cannabis law and application process in Vermont. ● Discuss the different formulations of medical cannabis and and how to best utilize them for symptom management. ● Understand harm reduction strategies with medical cannabis and how to detect and treat cannabis use disorder. I have no conflicts of interest or financial relationships to disclose. Cannabis is a family of flowering plants with three species: • Cannabis sativa • Cannabis indica • Cannabis ruderalis The Ancient History of Cannabis ● Hemp (a cultivar of cannabis) has been used for fiber and rope since the Neolithic Age (12,000 years ago). Fibers have been found embedded in pottery dating to ~5000 BC. ● Incense burners from ~2500 BC were discovered in funerary tombs from the Pamir mountains in Central Asia. These burners contained residue high in CBN, the oxidative product of THC. ● From The Histories by Herodotus in 440 BC: “The Scythians…take some of this hemp-seed flower, and, creeping under the felt coverings, they throw it upon the red-hot stones; immediately it smokes, and gives out such a vapour as no Grecian vapour-bath can exceed; the Scyths, delighted, shout for joy..." Ancient Medical Cannabis ● Cannabis was used as medication by many ancient civilizations including China, India, Egypt, Greece, and Arabia ● Indications included diarrhea, nausea, cramps, spasms, convulsions, pain, inflammation, fever and The Eber’s Papyrus, dated to 1500 BC, contains a hemorrhoids. cannabis prescription for inflammation. “Medical” Cannabis: mid-1800’s to 1920’s Cannabinoid Receptor System Basics ● There are two major cannabinoid receptors: CB1 and CB2. ● CB1 receptors are mostly expressed within the central and peripheral nervous system. ● CB1 is the major receptor that produces the subjective and objective effects of cannabis. ● CB2 receptors are mostly expressed in the immune system. Cannabinoid Receptor System: CB1 ● CB1 receptors are G-protein coupled receptors expressed predominantly in the central and peripheral nervous system. ● Activation of CB1 receptors leads to DECREASED cAMP production which leads to a total relative decrease in peripheral and central neurotransmission (CNS depression). ● CB1 receptors are expressed highly on GABAergic neurons of the hippocampus. CB1 activation suppresses glutamate release in the hippocampus and likely plays a significant role in memory selectivity. Cannabinoid Receptor System: CB1 ● CB1 receptors are found on interneurons of the dorsal horn of the spinal cord as well as the periaqueductal grey - both of these areas are heavily involved in pain processing. ● CB1 receptors are also present in the basal ganglia, cerebellum, and neocortex. This receptor distribution indicates a role for cannabinoids in the motor system. Cannabinoid Pharmacology: Endocannabinoids ● Anandamide is a fatty acid neurotransmitter derived from the metabolic breakdown of arachidonic acid. Along with other fatty acids, anandamide binds to cannabinoids receptors. ● Anandamide is believed to be involved in memory, motivation, feeding, embryonic implantation into the uterine wall, and the rewarding effects of exercise. ● Anandamide is the primary endogenous ligand for CB1 receptors. Cannabinoid Receptor System: CB2 ● CB2 receptors are G-protein coupled receptors expressed predominantly in the immune system. This receptor plays a very sophisticated role in immune response. The receptors are found on hematopoietic stem cells, monocytes, T-cells, B-cells, and macrophages. ● CB2 receptors mediate and/or modulate several immune functions including cytokine release, immunosuppression, cell migration, gene transcription (through a reduction in cAMP) and immune cell apoptosis. Cannabinoid Receptor System: CB2 ● CB2 receptors are present on microglia of the central nervous system. It is generally believed that CB2 receptors are not found at high expression levels in the brain otherwise; this is an area of scientific debate. ● CB2 receptors are expressed in peripheral nerve terminals and there is substantial speculation they are involved in nociception. Cannabinoid Pharmacology: Phytocannabinoids ● Phytocannabinoids can be defined as any plant-derived natural product capable of either directly interacting with cannabinoid receptors and/or sharing chemical similarity with cannabinoids. ● The major cannabinoids present in the cannabis plant are: ❏ THC (tetrahydrocannabinol) ❏ CBV (Cannabivarin) ❏ CBD (Cannabidiol) ❏ THCV (Tetrahydrocannabivarin) ❏ CBN (Cannabinol) ❏ CBDV (Cannabidivarin) ❏ CBG (Cannabigerol) ❏ CBCV (Cannabichromevarin) ❏ CBC (Cannabichromene) ❏ CBGV (Cannabigerovarin) ❏ CBL (Cannabicyclol) ❏ CBGM (Cannabigerol Monomethyl) Cannabinoid Pharmacology: Phytocannabinoids ● However, there are ~113 different phytocannabinoids present in the cannabis plant... Cannabis Pharmacology: Phytocannabinoids ● Female cannabis plants in active flowering (marijuana) contain the highest concentration of cannabinoids. ● Trichomes are sticky surface glands on the female cannabis plant that are designed to catch pollen. These glands contain cannabis resin/oil which is the major source of cannabinoids in the female cannabis plant. Leaves and stems have low cannabinoid content. *Phytocannabinoids are also produced in other plant species, the most studied of which is Echinacea. Phytocannabinoid Pharmacology: THC ● Tetrahydrocannabinol (THC) is the primary psychoactive constituent of cannabis and functions as a CB1 and CB2 receptor partial agonist. ● Pharmacokinetics of THC -vary as a function of its route of administration. ○ Inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15-30 minutes, and taper off within 2-5 hours. ○ Orally ingested THC has a delayed onset of psychotropic effects, typically 30- 90 minutes. Maximum effects occur after 2-3 hours and last for about 4-12 hours, depending on dose. ○ THC has poor oral bioavailability (6-20%) but is absorbed at a higher rate when inhaled (10-35%). Oral THC has a half-life of 25-36 hours and is metabolized by the liver primarily by CYP2C9, CYP2C19, and CYP3A4. Phytocannabinoid Pharmacology: THC THC Effects THC Adverse effects ● Intoxication, a varied syndrome ● Tachycardia/palpitations ● Sedation ● Anxiety/paranoia ● Stimulation with some strains ● Hypotension ● Bodily relaxation ● Motor discoordination ● Increased appetite ● Xerostomia ● Nausea suppression ● Nausea (at very high doses) ● Analgesia ● Suppression of seizure activity Phytocannabinoid Pharmacology: THC ● Serious Adverse Reactions ○ Cannabis Use Disorder ○ Exacerbation of prior existing mental illness ○ Psychosis/Hallucinations ○ Cannabis induced hyperemesis (years of daily use implicated) ● Long term and/or heavy cannabis use can cause amotivational syndrome. ● Cannabis use during pregnancy is associated with lower birth weight in the infant. Phytocannabinoid Pharmacology: CBD ●Cannabidiol (CBD) has complex allosteric effects at CB1 and CB2 receptors. CBD has low binding affinity for CB1/CB2 and behaves as an antagonist of CB1/CB2 agonists despite this low affinity. ●CBD has been shown to act as a serotonin 5-HT1A receptor partial agonist. ●CBD allosterically modulates the μ- opioid and δ-opioid receptors. ●Cannabidiol has poor oral bioavailability (<7%) but is absorbed at a higher rate when inhaled (median 31%). CBD has a half-life of 18-30 hours and is metabolized by the liver and gut, primarily by CYP2C19 and CYP3A4 and secondarily by glucuronidation. Phytocannabinoid Pharmacology: CBD ● CBD (Epidolex) was approved in June 2018 by the FDA to decrease seizure frequency in two severe forms of childhood epileptic encephalopathy,