Townhall: Benefits, Risks and Applications of Medical Cannabis

Transcription

1 Townhall: Benefits, Risks and Applications of Medical Cannabis Laura M. Borgelt, PharmD, FCCP, BCPS Professor and Associate Dean University of Colorado Skaggs School of Pharmacy Annual Meeting & Exposition Seattle, Washington March Photo:

2 Disclosures Dr. Borgelt has no relevant financial disclosures. Dr. Borgelt will be discussing unapproved drugs and uses. Dr. Borgelt receives grant funding from Colorado Department of Public Health and Environment (CDPHE) for a study evaluating cannabidiol for epilepsy and honoraria from PharmCon, Inc. for providing continuing education to pharmacists. Dr. Borgelt has served as a member of eight working groups: Amendment 64 (Marijuana Legalization) Task Force Working Group: Consumer Safety and Social Issues State Licensing Authority Labeling, Packaging, Product Safety and Marketing State Licensing Authority Medical and Retail Marijuana Mandatory Testing and Random Sampling State Licensing Authority Serving Size and Product Potency CDPHE Retail Marijuana Public Health Advisory Committee CDPHE Pregnancy and Breastfeeding Guidelines Committee Legislation Implementation for HB : Authorize Marijuana Clinical Research CDPHE Provider s Marijuana Advisory Task Force 2

3 CPE Information Target Audience: Pharmacists and Pharmacy Technicians ACPE#: L03 P/T Activity Type: Application based 3

4 The Story 4

5 Learning Objectives At the completion of this application based activity, participants will be able to: Describe the current regulatory status of cannabis. Using the current legal landscape, discuss health system policies and procedures regarding cannabis use. Explain the clinical pharmacology of cannabis and its active components. Interpret clinical studies with various conditions, including opioid use disorder, to determine the effectiveness and adverse effects of medical cannabis. Recommend actions that should be performed by pharmacists to improve patient safety issues, manage potential drug interactions, and provide effective counseling for patients using cannabis. 5

6 Assessment Question 1. A patient is using cannabis to relieve severe pain refractory to Food and Drug Administration (FDA) approved medications. Which of the following pairs identifies the endocannabinoid and receptor that is activated? A. 2 arachidonoyl glycerol and CB2 receptor B. N arachidonoyl dopamine and GPR55 receptor C. Anandamide and CB1 receptor D. Virodhamine and PPAR receptor 6

7 Assessment Question 2. Which of the following forms of cannabis is currently approved by the U.S. Food and Drug Administration (FDA) and available as an oral formulation? A. Cannabidiol B. Nabiximols C. Cannabis sativa D. Cannabigerol E. There is no form of cannabis that has been approved by the FDA 7

8 Assessment Question 3. Which of the following conditions has conclusive or substantial evidence that cannabis or cannabinoids are effective? A. Increasing appetite and decreasing weight loss with HIV/AIDS B. Improving intraocular pressure associated with glaucoma C. Patient reported multiple sclerosis spasticity symptoms D. Improving symptoms of posttraumatic stress disorder E. I have no idea 8

9 Assessment Question 4. A patient is taking valproic acid for management of seizures. The patient would like to try cannabidiol for additional seizure reduction. Which of the following recommendations is best for this patient? A. Avoid concurrent use of valproic acid and cannabidiol B. Decrease the dose of valproic acid when cannabidiol is initiated C. Start cannabidiol at a dose that is 50% lower than typical starting dose D. Start at a decreased dose of both cannabidiol and valproic acid 9

10 Learning Objectives Describe the current regulatory status of cannabis. Using the current legal landscape, discuss health system policies and procedures regarding cannabis use. Explain the clinical pharmacology of cannabis and its active components. Interpret clinical studies with various conditions, including opioid use disorder, to determine the effectiveness and adverse effects of medical cannabis. Recommend actions that should be performed by pharmacists to improve patient safety issues, potential drug interactions, and provide effective counseling for patients using cannabis. 10

11 Cannabis Single molecule pharmaceuticals Dronabinol (Schedule III) Nabilone (Schedule II) Liquid extract: nabiximols (Sativex ) Approved in 29 countries; U.S. Phase 2 and 3 trials Liquid extract: cannabidiol (Epidiolex ) FDA approved June 2018 (Schedule V) Phytocannabinoid dense botanicals Cannabis sativa medicinal plant 11

12 Chemical Constituents of Cannabis sativa Cannabinoids (100+) 9 tetrahydrocannabinol THC Cannabidiol CBD Cannabinol CBN Terpenes/Terpenoids Flavonoids Sterols Thiols Phenols Lipids/waxes Fibrous material Photo: 12

13 Legality of Cannabis in the United States Legal Legal for medical use Legal for medical use with limited THC content Prohibited for any use By Lokal_Profil, CC BY SA 2.5, 13

14 Federal Status of Cannabidiol and Cannabis Cannabidiol Cannabis Schedule V Schedule I Photo: Photo: 14

15 Key Opinion Considerations for medical use of marijuana are different than considerations for recreational use of marijuana. Medical use: benefit risk Recreational use: risk risk 15

16 Learning Objectives Describe the current regulatory status of cannabis. Using the current legal landscape, discuss health system policies and procedures regarding cannabis use. Explain the clinical pharmacology of cannabis and its active components. Interpret clinical studies with various conditions, including opioid use disorder, to determine the effectiveness and adverse effects of medical cannabis. Recommend actions that should be performed by pharmacists to improve patient safety issues, potential drug interactions, and provide effective counseling for patients using cannabis. 16

17 Pharmacy and Cannabis The profession lacks a uniform impression on medical cannabis Pharmacists dispense medical marijuana in 4 states (CT, MN, NY, LA) through medical dispensaries NOT THE PHARMACY Remember: pharmacies, not pharmacists are registered with DEA Pharmacists maintain constitutional rights to advise and counsel patients on marijuana and are licensed under State Law DEA, State Legislature, and Boards regulate pharmacy practice Photo: (17) /fulltext

18 ABCDs of Malpractice A legal duty Breach of that duty Causation Legal and proximate Damages Actual injury Professional standard of care Expert testimony Special considerations Assumption of risk Role of malpractice insurance 18

19 Pharmacist Standard of Practice ACCP Clinical Practice Standards Process of Care Patient Assessment Evaluation of Medication Therapy Development and implementation of a plan of care Follow up Evaluation and Medication Monitoring Documentation Legal Standard of Practice Clerical Accuracy vs. Skill and Knowledge Education and Counseling Alternative therapies and risks Drug Drug Interactions Drug Disease Interactions Product Selection Duty to Warn 19

20 Cannabis in the Health System Patient admitted to hospital and asks to have vaporizer for sleep. Approval? Institutional support? Board of Directors, Medical Staff, P&T Committee, Risk Management Joint Commission Medication Management: MM Policies and Procedures? Consistently applied? Issues of adulteration (purity)? Misbranding (labeling)? Dosing? Security? Other risks involved? 20

21 Learning Objectives Describe the current regulatory status of cannabis. Using the current legal landscape, discuss health system policies and procedures regarding cannabis use. Explain the clinical pharmacology of cannabis and its active components. Interpret clinical studies with various conditions, including opioid use disorder, to determine the effectiveness and adverse effects of medical cannabis. Recommend actions that should be performed by pharmacists to improve patient safety issues, potential drug interactions, and provide effective counseling for patients using cannabis. 21

22 Endogenous Cannabinoid System Endocannabinoids and their receptors found throughout body Cannabinoid system performs different tasks goal is always homeostasis Endocannabinoids are eicosanoids made naturally by the body and stimulate cannabinoid receptors Anandamide 2 arachidonoylglycerol (2 AG) When cannabinoid receptors are stimulated, variety of physiologic processes CB1 receptors: nervous system, connective tissues, gonads, glands, organs CB2 receptors: immune system and associated structures Hillard C. Chapter One The Endocannabinoid Signaling System in the CNS: A Primer. Int Rev of Neurobiol. 2015;125:1 47. Sulak D. Introduction to the endocannabinoid system. Available at: to the endocannabinoid system. Accessed September 2, Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9 tetrahydrocannabinol, cannabidiol and Δ9 tetrahydrocannabivarin. Br J Pharmacology. 2008;153: Maccarrone M, Finazzi Agró A. The endocannabinoid system, anandamide and the regulation of mammalian cell apoptosis. Cell Death and Differentiation 2003;10:

23 Functional Effects of Anandamide at CB1 and CB2 Receptors Structure Anandamide regulation Resultant effect Spinal cord Parasympathetic system Sympathetic system Inhibits GLU and info transfer between body and brain Decreased pain sensitivity Inhibits Ach release, HR regulation, urination regulation Inhibits NE release, HR regulation, blood vessel constriction HR stimulation, sometimes inhibits urination Delayed reduction in HR and blood pressure Neuronal cells Inhibits GLU induced excitotoxicity Neuroprotective effect, prevent cell injury Adipose tissue Stimulates lipogenesis Increased adiposity, insulin resistance Reproductive Reduces testosterone, luteinizing hormone Reduced fertility, altered menstrual cycle tissue Skin Reduces histamine Antipruritic effect General Role in relaxing, eating, sleeping, forgetting, Provide relief from stress, reduction of injury protecting General Inhibits immune B lymphocytes, natural killer cells Anti inflammatory activity Hillard C. Chapter One The Endocannabinoid Signaling System in the CNS: A Primer. Int Rev of Neurobiol. 2015;125:1 47. Sulak D. Introduction to the endocannabinoid system. Available at: to the endocannabinoid system. Accessed September 2, Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9 tetrahydrocannabinol, cannabidiol and Δ9 tetrahydrocannabivarin. Br J Pharmacology. 2008;153: Maccarrone M, Finazzi Agró A. The endocannabinoid system, anandamide and the regulation of mammalian cell apoptosis. Cell Death and Differentiation 2003;10:

24 Cannabis Pharmacology Photo: National Institute on Drug Abuse. 24

25 Endocannabinoid System Photo: events/nidanotes/2017/03/endocannabinoid regulates cocaine reward (Accessed September 2, 2018) What happens when there is potential endocannabinoid deficiency, dysregulation, destabilization, or decreased binding? 25

26 Photo: National Institute on Drug Abuse. How does marijuana produce its effects? does marijuana produce its effects. Accessed September 2,

27 Cannabidiol Little binding affinity to CB1/CB2 Suppresses enzyme fatty acid amide hydroxylase ( FAAH ) enzyme that breaks down anandamide Opposes THC at CB1 receptor Stimulates release of 2 AG TRPV 1 receptor agonist 5 HT1A receptor activation GPR55 antagonist Devinsky O, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 2014;55(6): Project CBD. How CBD works. Available at: cbd works/ Accessed September 2,

28 Cannabidiol (Epidiolex ) Formulation: Oral solution Indication: treatment of seizures associated with Lennox Gastaut syndrome or Dravet syndrome in patients 2 years of age and older Dosage: 2.5 mg/kg taken twice daily (5 mg/kg/day). After one week, the dosage can be increased to a maintenance dosage of 5 mg/kg twice daily (10 mg/kg/day). Based on individual clinical response and tolerability, can be increased up to a maximum recommended maintenance dosage of 10 mg/kg twice daily (20 mg/kg/day). Monitoring: Obtain serum transaminases (ALT and AST) and total bilirubin levels in all patients prior to starting treatment. Increased risk with concurrent valproate and high doses Dosage adjustment recommended with moderate or severe hepatic impairment Most common adverse effects (>10%): somnolence; decreased appetite; diarrhea; transaminase elevations; fatigue, malaise, and asthenia; rash; insomnia, sleep disorder, and poor quality sleep; and infections Package insert. Epidiolex. Greenwich Biosciences, Inc., December

29 Adverse Effects Effects of Short term Use Impaired short term memory Impaired motor coordination Altered judgment Motor vehicle accidents (2x) Paranoia and psychosis (high doses) Effects of Long term/heavy Use Addiction (9% overall) Altered brain development* Cognitive impairment (with lower IQ)* Diminished life satisfaction and achievement* Poor educational outcome Symptoms of chronic bronchitis Increased risk of chronic psychosis disorders *Effect is strongly associated with initial marijuana use early in adolescence Volkow ND, Baler RD, Compton WM, Weiss SRB. Adverse effects of marijuana use. N Engl J Med 2014;370: Hall W, Degenhardt L. Adverse effects of non medical cannabis use. Lancet 2009;374(9698): doi: /S (09)

30 Myth: Marijuana is Not Addictive Photo: brains behavior science addiction/drugs brain Accessed December 13,

31 Lifetime Dependency Risk % Marijuana addiction risk in teens % 23% 17% 15% 9% Hall W, Degenhardt L. Adverse effects of non medical cannabis use. Lancet 2009;374(9698): doi: /S (09) Center for Behavioral Health Statistics and Quality. The CBHSQ report. Rockville (MD): Substance Abuse and Mental Health Services Administration (US); Available at: Accessed April 11,

32 Brain Development in Adolescence Limbic region Immediate rewards Impulsive behavior Prefrontal cortex Long term gain Thoughtful behavior Photo: adolescentsubstance use disorder treatment research based guide/introduction (accessed 2018 April 11) 32

33 Summary: Endocannabinoid System and THC THC Photo: resources/brain basics/brain basics.shtml 33

34 Learning Objectives Describe the current regulatory status of cannabis. Using the current legal landscape, discuss health system policies and procedures regarding cannabis use. Explain the clinical pharmacology of cannabis and its active components. Interpret clinical studies with various conditions, including opioid use disorder, to determine the effectiveness and adverse effects of medical cannabis. Recommend actions that should be performed by pharmacists to improve patient safety issues, potential drug interactions, and provide effective counseling for patients using cannabis. 34

35 National Academies: Health Effects of Cannabis Conclusive or substantial evidence that cannabis or cannabinoids are effective: for treatment of chronic pain in adults (cannabis) for improving patient reported multiple sclerosis (MS) spasticity symptoms, but limited evidence for clinician measured spasticity (oral cannabinoids) As anti emetics in the treatment of chemotherapyinduced nausea and vomiting (oral cannabinoids) National Academies of Sciences, Engineering, and Medicine The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. Washington, DC: The National Academies Press. doi: /

36 National Academies: Health Effects of Cannabis Moderate evidence that cannabinoids, primarily nabiximols, are an effective: to improve short term sleep outcomes in patients with sleep disturbance associated with obstructive sleep apnea, fibromyalgia, chronic pain, and MS. National Academies of Sciences, Engineering, and Medicine The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. Washington, DC: The National Academies Press. doi: /

37 National Academies: Health Effects of Cannabis Limited evidence that cannabis or oral cannabinoids are effective for increasing appetite and decreasing weight loss associated with HIV/AIDS (cannabis and oral cannabinoids) improving symptoms of Tourette syndrome (THC capsules) Improving anxiety symptoms in individuals with social anxiety (cannabidiol) improving symptoms of posttraumatic stress disorder (nabilone) better outcomes (i.e., mortality, disability) after a traumatic brain injury or intracranial hemorrhage statistical association Limited evidence that cannabis or oral cannabinoids are ineffective for improving symptoms of dementia (cannabinoids) improving intraocular pressure associated with glaucoma (cannabinoids) reducing depressive symptoms in individuals with chronic pain or MS (nabiximols, dronabinol, and nabilone) 37 National Academies of Sciences, Engineering, and Medicine The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. Washington, DC: The National Academies Press. doi: /24625

38 National Academies: Health Effects of Cannabis No or insufficient evidence to support or refute that cannabinoids are effective for cancer associated anorexia cachexia syndrome and anorexia nervosa cancers, including glioma irritable bowel syndrome epilepsy spasticity in patients with paralysis due to spinal cord injury chorea and certain neuropsychiatric symptoms associated with Huntington s disease symptoms associated with amyotrophic lateral sclerosis (ALS) Parkinson s disease or levodopa induced dyskinesia dystonia treatment for mental health outcomes in individuals with schizophrenia or schizophreniform psychosis achieving abstinence in the use of addictive substances National Academies of Sciences, Engineering, and Medicine The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. Washington, DC: The National Academies Press. doi: /

39 Inhaled Cannabis for Neuropathic Pain: Meta Analysis of Individual Data Synthesizes the individual participants' original data obtained from the studies' principal investigators Five randomized controlled trials evaluating inhaled cannabis Compared proportion of patients experiencing >30% clinical improvement in chronic neuropathic pain assessed with a continuous patient reported instrument (e.g., visual analog scale) at baseline and after inhaled cannabis RESULTS 178 patients with 405 observed responses Estimated OR (CI) for >30% in pain score: 3.22 ( ) Number needed to treat (CI): 5.55 ( ) Note: gabapentin NNT 5.9 ( ) for diabetic neuropathy Andreae MH, et al. Inhaled cannabis for chronic neuropathic pain: a meta analysis of individual patient data. J Pain 2015;16: Cochrane Database Syst Rev Apr 27;(4):CD

40 Adverse Effects from Meta Analysis Serious adverse effects Placebo: 1 (psychosis) Cannabis: 2 (hypertension, increased pain) Mild adverse effects Anxiety, disorientation, difficulty concentrating, headache, dry eyes, burning sensation, dizziness, and numbness Psychoactive effects (such as feeling high ) were statistically significantly associated with treatment allocation in 2 studies and increased in frequency with increasing dose Andreae MH, et al. Inhaled cannabis for chronic neuropathic pain: a meta analysis of individual patient data. J Pain 2015;16:

41 Limitations and Conclusions Ineffective participant blinding Placebo effects likely Different causes of neuropathy Small number of studies and participants Difficult to estimate bioavailable cannabis Short term data only (up to two weeks) Inhaled cannabis results in short term reductions in chronic neuropathic pain for 1 in every 5 to 6 patients treated. Andreae MH, et al. Inhaled cannabis for chronic neuropathic pain: a meta analysis of individual patient data. J Pain 2015;16:

42 Medical Cannabis and Opioid Use Limited evidence that states with legal medical marijuana have a lower rate of opioid analgesic overdose hospitalizations and deaths compared to states without legal medical marijuana. Colorado Department of Public Health and Environment. Marijuana use trends and health effects. health report. Accessed January 27, Photo: nida/noras blog/2015/04/taking science informed approach to medical marijuana Iaccessed 2018 April 11) Photo: (accessed 2018 April 11) 42

43 Medical Cannabis Laws and Opioid Analgesic Mortality in the United States, States with medical cannabis laws had a 24.8% lower mean annual opioid overdose mortality rate (95% CI, 37.5% to 9.5%; P =.003) compared with states without medical cannabis laws. This association strengthened over time Year 1 ( 19.9%; 95% CI, 30.6% to 7.7%; P =.002) Year 2 ( 25.2%; 95% CI, 40.6% to 5.9%; P =.01) Year 3 ( 23.6%; 95% CI, 41.1% to 1.0%; P =.04) Year 4 ( 20.2%; 95% CI, 33.6% to 4.0%; P =.02) Year 5 ( 33.7%; 95% CI, 50.9% to 10.4%; P =.008) Year 6 ( 33.3%; 95% CI, 44.7% to 19.6%; P <.001) Bachhuber MA, Saloner B, Cunningham CO, et al. Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in the United States, JAMA Intern Med. 2014;174(10): doi: /jamainternmed

44 Medical Cannabis and Opioid Use 244 medical cannabis patients with chronic pain in Michigan Survey of 46 questions Medical condition(s) for which cannabis was used Method/frequency of cannabis use Changes in noncannabis medication use and medication side effects Quality of life changes since starting cannabis use Demographic information 2011 Fibromyalgia Survey Criteria (0 31 score) J Pain Jun;17(6): doi: /j.jpain Epub 2016 Mar

45 Results: Medical Cannabis and Opioid Use OUTCOME OF INTEREST Fibromyalgia score (0-31) 9.23 (5.52) Opioid use change 63% (46%) Degree to which side effects of medication affect daily function 6.44 (2.91) (before using medical cannabis); scale from 1 to 10 Degree to which side effects of medication affect daily function (after 2.77 (2.35) using medical cannabis); scale from 1 to 10 Number of medication classes used (before cannabis use) 2.35 (1.43) Number of medication classes used (after cannabis use) 1.82 (.94) Quality of life change 45% (28%) PATIENT RESPONSES (n=244) Mean (SD) J Pain Jun;17(6): doi: /j.jpain Epub 2016 Mar

46 Cannabis as a Substitute for Prescription Drugs 1,248/2,774 (45%) patients that used cannabis in past 90 days reported using cannabis as a substitute for Rx drugs 2,473 substitutions reported (~2/patient) Odds 4.59 (95% CI, ) greater among medical vs. non medical cannabis users 24% of non medical users reported substituting cannabis for Rx drugs Number of substitutions Number of substitutions State laws did not influence decision to substitute cannabis Corroon JM, Mischley LK, Sexton M. Cannabis as a substitute for prescription drugs a cross sectional study. J Pain Res. 2017;10: doi: /JPR.S

47 Cannabis Use and Risk of Prescription Opioid Use Disorder Determine associations between cannabis use at wave 1 ( ) and nonmedical prescription opioid use and prescription opioid use disorder at wave 2 ( ) Increased use and disorder Nonmedical Cannabis opioid use use: appears adjusted OR=2.62, to increase 95% CI= risk of developing nonmedical Opioid use disorder: prescription adjusted OR=2.18, opioid 95% use CI= and opioid use disorder. In patients with pain Nonmedical opioid use: adjusted OR=2.99, 95% CI= Opioid use disorder: adjusted OR=2.14, 95% CI= Olfson M, Wall MM, Liu SM, Blanco C. Cannabis use and risk of prescription opioid use disorder in the United States. Am J Psychiatry Jan 1;175(1): doi: /appi.ajp

48 Cannabidiol: Dravet Syndrome Randomized, double blind, placebo controlled trial of 120 children and young adults Cannabidiol oral solution 20 mg/kg/day or placebo and standard antiepileptic treatment Primary end point: convulsive seizure frequency over 14 weeks versus 4 week baseline Median no. seizures/month Difference: 22.8% ( 41.1 to 5.4; P=0.01) % Seizure Frequency Cannabidiol Placebo Cannabidiol Placebo Convulsive Seizures Total Seizures Baseline Difference: 19.2% ( 39.3 to 1.2; P=0.03) 13.3% 28.6% Treatment Period % Devinsky O, et al. Trial of cannabidiol for drug resistant seizures in the Dravet Syndrome. N Engl J Med 2017;376: Adverse effects Reported in 93% of cannabidiol and 75% of placebo Cannabidiol: 84% mild or moderate Vomiting, fatigue, pyrexia, upper respiratory infec on, appetite, convulsion, lethargy, somnolence, and diarrhea 8 withdrew from trial Placebo: 95% mild or moderate 1 withdrew from trial 48

49 Cannabidiol: Lennox Gastaut Randomized, double blind, placebo controlled trial of 171 children and young adults Cannabidiol oral solution 20 mg/kg/day or placebo in addition to standard antiepileptic treatment Primary end point: drop seizure frequency over 14 weeks compared with 4 week baseline Median no. seizues/month Seizure Frequency Difference: ( to 4.09; P=0.0135) 43.9% Cannabidiol Placebo Cannabidiol Placebo Drop Seizures Total Seizures Baseline 21.8% Treatment period Difference: 21.1 ( 33.3 to 9.4; P=0.005) 41.2% 13.7% Adverse effects Reported in 86% of cannabidiol and 69% of placebo Cannabidiol: 78% mild or moderate Diarrhea, somnolence, pyrexia, appe te, vomi ng 14 withdrew from trial Placebo: 97% mild or moderate 1 withdrew from trial 49 Thiele EA, et al. Cannabidiol in patients with seizures associated with Lennox Gastaut syndrome (GWPCARE4): a randomised, double blind, placebo controlled phase 3 trial. Lancet 2018; 391:

50 Cannabidiol: Lennox Gastaut Dosing Study Randomized, double blind, placebo controlled trial of 225 children and young adults Cannabidiol oral solution 10 mg/kg/day or 20 mg/kg/day or placebo in addition to standard antiepileptic treatment Primary end point: drop seizure frequency over 14 weeks compared with 4 week baseline MEDIAN % REDUCTION: SEIZURES/MO p=0.005 p=0.002 Seizure Frequency Placebo 10 mg/kg/day 20 mg/kg/day p=0.009 p= p values not calculated Drop Seizures Total Seizures Non Drop Seizures Adverse effects Reported in 94% of 20 mg/kg/day Reported in 84% of 10 mg/kg/day Reported in 72% of placebo Most (89%) consider mild or moderate severity Somnolence, pyrexia, appe te, vomiting, diarrhea 8 withdrew from trial (most due to elevation of liver enzymes) 6 in 20 mg/kg/day 1 in 10 mg/kg/day 0 in 10 mg/kg/day 50 Devinsky O, et al. Effect of cannabidiol on drop seizures in the Lennox Gastaut syndrome. N Engl J Med 2018;378:

51 Summary: Clinical Trials Cannabidiol and cannabis are used for many different medical conditions. While benefit may be obtained, adverse effects can occur and should be monitored. 51

52 Learning Objectives Describe the current regulatory status of cannabis. Using the current legal landscape, discuss health system policies and procedures regarding cannabis use. Explain the clinical pharmacology of cannabis and its active components. Interpret clinical studies with various conditions, including opioid use disorder, to determine the effectiveness and adverse effects of medical cannabis. Recommend actions that should be performed by pharmacists to improve patient safety issues, potential drug interactions, and provide effective counseling for patients using cannabis. 52

53 Patient Safety Issues Unintentional exposure Consistency (or lack thereof) Quality and purity Packaging Labeling Testing content and contaminants Accuracy of education provided Drug interactions Photos: marijuana/pages/packagingla belingpreapproval.aspx (accessed 2018 April 1) 53

54 Cannabis Drug Interactions: THC Chlorpromazine Clobazam Clozapine CNS depressants Disulfiram Hexobarbital Hydrocortisone Ketoconazole Protease inhibitors (indinavir, nelfinavir) MAO inhibitors Phenytoin Theophylline Tricyclic antidepressants Warfarin *Note: significant synergistic interaction found between CBD and levetiracetam. Significant antagonistic interactions noted with CBD + clobazam and CBD + carbamazepine. Colorado Department of Public Health and Environment. Marijuana use trends and health effects. health report. Accessed December 13,

55 Cannabis Drug Interactions: THC Y=yes; N=no; P=possible Concomitant Drug/Drug Class Description of Interaction Contraindicated? THC Effect? CNS Depressant Effect? Concomitant Drug Effect? Concomitant Drug Effect? Chlorpromazine Marijuana smoking increased clearance of chlorpromazine N P Clobazam Increased clobazam levels (60 80% higher) with CBD use N Y P Clozapine Possible increased clozapine metabolism by marijuana induction of CYP1A2 N P (with marijuana cessation) P (with marijuana continuation) Colorado Department of Public Health and Environment. Marijuana use trends and health effects. health report. Accessed December 13,

56 Cannabis Drug Interactions: THC Concomitant Drug/Drug Class CNS Depressants (e.g., alcohol, benzodiazepines) Description of Interaction Additive drowsiness and CNS depression Disulfiram Possible hypomanic / psychotic reaction Hexobarbital Hydrocortisone Enhanced CNS depressant effect. CBD decreased metabolism but did not have effect. THC increased serum cortisol, but effect blunted in frequent users Contraindicated? N N THC Effect? P CNS Depressant Effect? Y N Y P N Concomitant Drug Effect? P Y=yes; N=no; P=possible Concomitant Drug Effect? Colorado Department of Public Health and Environment. Marijuana use trends and health effects. health report. Accessed December 13,

57 Cannabis Drug Interactions: THC Concomitant Drug/Drug Class Ketoconazole MAO inhibitors Phenytoin Protease inhibitors Description of Interaction Peak THC concentration increased by 27% Possible enhancement of orthostatic hypotension May enhance CNS depressant effect. Possible increased phenytoin metabolism by marijuana induction. Significant decrease in peak concentration of indinavir and nelfinavir. Contraindicated? THC Effect? N P P N CNS Depressant Effect? Concomitant Drug Effect? N Y P (with marijuana cessation) N Y=yes; N=no; P=possible Concomitant Drug Effect? P (with marijuana continuation) P Colorado Department of Public Health and Environment. Marijuana use trends and health effects. health report. Accessed December 13,

58 Cannabis Drug Interactions: THC Concomitant Drug/Drug Class Theophylline Tricyclic antidepressants Warfarin Description of Interaction Smoked marijuana lowers theophylline concentrations May cause transient cognitive changes, delirium, or tachycardia Possible enhanced anticoagulant effect Contraindicated? N THC Effect? CNS Depressant Effect? N P P N Concomitant Drug Effect? P Y=yes; N=no; P=possible Concomitant Drug Effect? P Colorado Department of Public Health and Environment. Marijuana use trends and health effects. health report. Accessed December 13,

59 Drug Interactions: Cannabidiol Moderate or strong inhibitors of CYP3A4 or CYP2C19: Consider dose reduction Examples: clarithromycin, ketoconazole, protease inhibitors, valproic acid, omeprazole Strong inducer of CYP3A4 or CYP2C19: Consider dose increase Examples: carbamazepine, phenytoin, primidone, rifampin Substrates of UGT1A9, UGT2B7, CYP2C8, CYP2C9, and CYP2C19: Consider dose reduction Examples: citalopram, aripiprazole, sertraline Co administration of cannabidiol and clobazam has shown 3 fold increase in clobazam metabolite concentrations consider dose reduction of clobazam if adverse reactions occur Substrates of CYP1A2 and CYP2B6 may also require dose adjustment Examples: theophylline, clozapine, zolmitriptan Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46(1):

60 Drug Interactions Cannabinoid CYP 450 2C9 CYP 450 2C19 CYP 450 3A4 Δ 9 THC * * Δ 8 THC * * CBD * * CBN * * Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46(1):

61 Summary Pharmacists should conduct drug drug interaction screening for patients using cannabidiol or cannabis. Pharmacists may be the only health provider with information about all medications taken by the patient. 61

62 Communication Strategies Photo: 62

63 Patient Case 2 year old male patient with lethargy is brought to the emergency department of Children s Hospital Colorado. Several tests are performed including: Urinalysis Comprehensive metabolic panel Complete blood count APAP/ASA levels ECG Urine toxicology CT head Chest X ray Centers for Disease Control and Prevention. What are potential causes of his lethargy? Should he be admitted? 63

64 Patient Case, con t Admitted to hospital Unintentional exposure to marijuana Source of marijuana: babysitter What counseling should occur for this patient and/or family? 64

65 Patient Case 17 yo male displays unusual behavior in the classroom and is brought to the counselor s office Counselor verifies that the student is high and obtained cannabis (gummy bears) from a friend Student admits to using cannabis several times per week; claims it reduces his anxiety and anger Student does not think it impacts his school grades or ability to play sports (football and basketball) U.S. Drug Enforcement Administration. What counseling should occur for this student? 65

66 Patient Case 27 year old female patient comes to clinic for second trimester prenatal visit (24 weeks pregnant) Medications: prenatal vitamin once daily Social history: no alcohol, no tobacco, smokes cannabis one to two times daily Initially started cannabis to relieve nausea in first trimester; continued cannabis because it improved sleep She has heard about cannabis having potential harm on the fetus, but doesn t think studies were done well enough to make conclusions about harm; feels benefits outweigh any risks National Institutes of Health. content/woman Pregnant.jpg What counseling should occur for this patient? 66

67 Patient Case 62 year old female patient with long standing diabetes and severe neuropathic pain; other conditions include hypertension, dyslipidemia, and arthritis For neuropathic pain and arthritis, she has tried seven different FDA approved or OTC medications; currently taking APAP, oxycodone, and pregabalin Started cannabis about 3 months ago Vaporizes THC:CBD (1:1) twice daily Reduced oxycodone dose by 30% since cannabis; has continued APAP, pregabalin, and cannabis What counseling should occur for this patient? 67

68 Counseling Strategies: Medical Cannabis REASON FOR USE Patients use cannabis for many different conditions. For what condition(s) are you using cannabis? CANNABIS USE (formulation, dose, frequency) By what method(s) do you use cannabis? What strain and/or cannabinoid concentrations are you using? How often are you using cannabis? CONCURRENT DRUG USE What other medications are you taking at this time? Screen for drug interactions Parmar JR, et al. Medical marijuana patient counseling points for health care professionals based on trends in the medical uses, efficacy, and adverse effects of cannabis based pharmaceutical drugs.res Social Adm Pharm 2016;12(4): doi: /j.sapharm

69 Counseling Strategies: Medical Cannabis WHAT TO EXPECT What benefits did your provider tell you to expect by using cannabis? What side effects did your provider tell you to expect? WHEN TO SEEK FURTHER MEDICAL ATTENTION Bothersome psychoactive effects Cannabinoid hyperemesis syndrome (cyclic vomiting) Withdrawal symptoms (if discontinuing) FOLLOW UP WHEN NEEDED Contact pharmacist or prescriber if any adverse effect becomes too bothersome or if any questions about marijuana use Parmar JR, et al. Medical marijuana patient counseling points for health care professionals based on trends in the medical uses, efficacy, and adverse effects of cannabis based pharmaceutical drugs.res Social Adm Pharm 2016;12(4): doi: /j.sapharm

70 Role Play: Counseling in Pregnancy 70

71 Summary Counseling strategies vary based on individual patient situations. Efforts should be made to determine medical history, medication history, social history, and other patient specific factors to determine what, why, and how cannabis is being used. 71

72 Pharmacist Roles As with any substance for medical use, pharmacists are expected to Complete medication review to assess: Appropriateness of Therapy Appropriate Drug, Dose, Route and Duration Allergies & Drug Interactions Contraindications Abuse & Misuse Provide patient education and counseling Dispense cannabis (in some states) 72

73 Closing remarks/conclusion Medical marijuana laws have been enacted in most states; however, marijuana remains a Schedule I drug. Health system policies should be carefully evaluated regarding cannabis use. Homeostatic effects of the endogenous endocannabinoid system can be provided by exogenous cannabis with applications to some medical conditions. While cannabis appears to be effective for select conditions, there are conflicting observational studies regarding cannabis as an alternative option for opioid or prescription drug abuse. Pharmacists have an important role in monitoring patient safety, screening for potential drug interactions, and providing effective counseling for patients using cannabis. 73

74 Assessment Question 1. A patient is using cannabis to relieve severe pain refractory to FDAapproved medications. Which of the following pairs identifies the endocannabinoid and receptor that is activated? A. 2 arachidonoyl glycerol and CB2 receptor B. N arachidonoyl dopamine and GPR55 receptor C. Anandamide and CB1 receptor D. Virodhamine and PPAR receptor 74

75 Assessment Question 2. Which of the following forms of cannabis is currently approved by the U.S. Food and Drug Administration (FDA) and available as an oral formulation? A. Cannabidiol B. Nabiximols C. Cannabis sativa D. Cannabigerol E. There is no form of cannabis that has been approved by the FDA 75

76 Assessment Question 3. Which of the following conditions has conclusive or substantial evidence that cannabis or cannabinoids are effective? A. Increasing appetite and decreasing weight loss with HIV/AIDS B. Improving intraocular pressure associated with glaucoma C. Patient reported multiple sclerosis spasticity symptoms D. Improving symptoms of posttraumatic stress disorder E. I have no idea 76

77 Assessment Question 4. A patient is taking valproic acid for management of seizures. The patient would like to try cannabidiol for additional seizure reduction. Which of the following recommendations is best for this patient? A. Avoid concurrent use of valproic acid and cannabidiol B. Decrease the dose of valproic acid when cannabidiol is initiated C. Start cannabidiol at a dose that is 50% lower than typical starting dose D. Start at a decreased dose of both cannabidiol and valproic acid 77

78 Townhall: Benefits, Risks and Applications of Medical Cannabis Laura M. Borgelt, PharmD, FCCP, BCPS Professor and Associate Dean University of Colorado Skaggs School of Pharmacy Annual Meeting & Exposition Seattle, Washington March Photo: