Joshua Blum MD ACP Member

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Alexandrina Barker
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1 Joshua Blum MD ACP Member

2 Disclosures Stock Options/Holdings Genii Corporation

3 Cannabis: brief history Associated with witchcraft in 15 th century Extracts, tinctures, plasters, cigarettes made by 19 th century drug manufacturers Rapidly supplanted by ASA Illegal by 1937 Δ9-THC identified in 1964 Endocannabinoid system initially characterized in 1990 s

4 Cannabis: brief history Historical conditions treated: Gout Glaucoma Migraines Seizures Depression Dandruff Malaria Rheumatism Constipation Female reproductive disorders Current uses: Pain Spasticity Chemotherapy-induced nausea and vomiting Weight loss Anxiety

6 Cyclic Vomiting Syndrome First described by Gee 1882 in children Adult case series first reported 1988 Recurrent episodes of incapacitating nausea and vomiting Relatively symptom-free intervals of days-months May be associated with colicky, epigastric abdominal pain Hejazi RA, McCallum RW. Aliment Pharmacol Ther 2011;34:

7 Cyclic vomiting syndrome 1. Well phase 2. Pre-emetic: intense nausea, pallor, sweating 3. Vomiting: episodes/day for 1 day-1 week 4. Recovery phase Hejazi RA, McCallum RW. Aliment Pharmacol Ther 2011;34:

8 Rome III criteria Episodes of nausea/vomiting with stereotypical onset and duration 3 discrete episodes in the previous year Absence/infrequency of nausea between episodes Symptom onset 6 months before diagnosis

9 CVS treatment TCA generally effective for 80% Second-line agents include levetiracetam, zonisamide, L-carnitine

10 Cannabinoid Hyperemesis First described in 19 patients by Allen and colleagues in 2004 in Adelaide, Australia May be a subset of CVS Cannabinoid-induced CVS not associated with migraine history or psychosocial stressors

11 Cyclic Vomiting Syndrome vs. other functional bowel syndromes Case-control study of 82 adult patients with CVS, Functional Vomiting (FV) or IBS Cannabis users 2.4x more likely to have CVS compared with other syndromes Compared with IBS patients, those with CVS had: Lower rate of psychiatric disease Lower rate of migraine headache Choung RS, Locke, III, GR, et al. Neurogastroenterol and Motil 2012; 24:

12 Clinical characteristics for diagnosis of Cannabinoid Hyperemesis Essential for diagnosis: History of regular cannabis use for years Major clinical features: Severe nausea and vomiting Recurrent vomiting in cyclic pattern over months Resolution of symptoms after cannabis cessation Supportive features: Compulsive hot baths with symptom relief Colicky abdominal pain No evidence of gallbladder, pancreatic inflammation Sontineni S, et al. World J Gastroenterol 2009;15(10):

14 Cannabis preparations Feature Marijuana Dronabinol Nabilone Δ9- THC/cannabi diol combo Source Component of cannabis plant Turcotte D, et al. Expert Opin Pharmaother 2010;11(1):17-31 Synthetic Synthetic Synthetic Brand names Marinol Cesamet Sativex Route of administration Official indications Onset of action Duration of action Inhalation of smoked dried flowering tops of female plant None Capsule Capsule Oromucosal spray AIDS-related anorexia, chemo-induced severe refractory n/v Chemo-induced severe refractory n/v Adjunctive neuropathic pain relief for adults with MS Minutes min min min 1-2 hours 4-6 hours 8-12 hours variable

15 Good but old evidence: Chemotherapy-induced nausea/vomiting 30 RCTs Most small (<50 pts) 18 included in meta-analysis Dronabinol, nabilone, levonantradol vs. Placebo Prochlorperazine Domperidone Haloperidol Metoclopramide Other neuroleptics Machado Rocha, FC et al. European Journal of Cancer Care 17:

16 Chemotherapy-induced nausea and vomiting Machado Rocha, FC et al. European Journal of Cancer Care 17:

17 Cannabis for chemotherapy-induced nausea and vomiting: side effects Paranoid delusions Hallucinations Dysphoria/depression More patients preferred the cannabinoid product to conventional therapy Machado Rocha, FC et al. European Journal of Cancer Care 17:

18 Chemotherapy-induced nausea and vomiting: standard of care Acute emetic phase: 5-HT3 antagonist + dexamethasone + aprepitant Delayed emetic phase: dexamethasone + aprepitant No studies comparing cannabinoids with current standard of care

19 Chemotherapy-induced nausea/vomiting: role of cannabinoids Dronabinol superior to prochlorperazine, other neuroleptics Dropout rate high Cannabinoids considered 3 rd - or 4 th -line Unique mechanism of action may have a role in combination with other anti-emetics patients with inadequate response to current standard of care

20 Appetite stimulation: marginal evidence Dronabinol: FDA indication in HIV/AIDSrelated anorexia Doubling of visual analog scale for hunger Trend towards weight stabilization Nabilone: may improve appetite but not formally studied Beal J, et al. J Pain Symptom Manage 1997;14:7-14

21 Cannabinoids and pain transmission Cannabinoid receptors located in PNS and CNS Mast cells: decrease degranulation, histamine release, bradykinin production Sensory primary afferent neurons: decreased neuronal excitability DRG cells: decreased intracellular Ca Thalamus, cortex, PAG, RVM

22 Cannabinoids and pain transmission Multiple complex effects and interactions Depending on tissue, CB receptor stimulation can: Decrease NE Decrease 5-HT Decrease NMDA Increase Dopamine

23 Best evidence/best studied: neuropathic pain Dronabinol, Nabilone, smoked cannabis all studied and found to be modestlymoderately effective All studies short (average: 25 days), small (typically n<100) Cannabis and THC derivatives all associated with side effects, mostly CNS Frank B, et al. BMJ 2008;336: Wilsey B, et al. J Pain 2008;9: Wade DT, et al. Clin Rehabil 2003;17:21-9 Ellis RJ, et al. Neuropsychopharmacol 2009;34: Nurmikko TJ, et al. Pain 2007;133: Berman JS, et al. Pain 2004;112:

24 Cannabis for neuropathic pain 23-patient crossover trial 3 cannabis potencies plus placebo 25 mg inhalation 3x/day X 5 days, then 9-day washout 9.4% THC cannabis showed statistically better pain relief than placebo Average VAS decrease of -0.7 (Average pain score: 5.4 vs. 6.1; CI: to -1.4) Ware MA, et al. CMAJ 2010;182:E

25 Also reasonably well studied: MS spasticity and central pain Marijuana extract, dronabinol, nabilone, Δ9-THC/cannabidiol combo all studied in RCTs Studies consistently favor treatment over placebo Rog DJ, et al. Neurology 2005;65: Nurmikko TJ, et al. Pain 2007;133: Berman JS, et al. Pain 2004;112: Hagenbach U, et al. Spinal Cord 2007;45: Wade DT, et al. Mult Scler 2004;10: Wissel J, et al. J Neurol 2006;253:

26 MS spasticity and central pain Largest study of cannabis extract (n=630) showed improvements in pain VAS and other secondary measures Patient-rated spasticity severity Sleep quality No statistically significant improvements on Ashworth Score of Spasticity May have been confounded by continued baseline anti-spasmodic use Zajicek, J, et al. Lancet 2003;362:

27 Probably effective: fibromyalgia One cross-sectional analysis of 56 MMJ users Cannabis users reported improvements in pain, stiffness, sense of well-being, and sleep 2 hours after use 2 nabilone studies: 4-week RCT of 40 patients, nabilone added to usual therapy effective Randomized cross-over trial vs. amitriptyline showed small improvements in sleep, restfulness Fiz J, et al. PLoS ONE 2011;6(4):e18440

28 Acute pain: no evidence Smoked marijuana, THC capsules, and nabilone studied No benefits seen for: Post-operative pain Sunburn pain Intradermal capsaicin pain Conclusion: no role for cannabinoids in acute pain treatment Wallace M, et al. Anesthesiology 2007;107: Kraft B, et al.. Anesthesiology 2008;109: Beaulieu P. Can J Anaesth 2006;53:769-75

30 Acute cannabis side effects CNS: Euphoria Fatigue/sleepiness Increased appetite Fogginess Physical: Tachycardia Hypotension Diaphoresis

31 Acute cannabis side effects CNS: Euphoria Fatigue/sleepiness Increased appetite Fogginess Physical: Tachycardia Hypotension Diaphoresis Getting high is the side effect!

32 Psychomotor function 10 heavy, chronic users studied on a closed research unit Assessments before and up to 6h after smoking one 6.8% THC cigarette Included critical tracking and dividedattention task measures No significant differences seen in critical tracking or divided-attention task performance Schwope DM, et al. Journal of Analytical Toxicology 2012;36(6):

33 Acute cannabis use and MVA risk Meta-analysis of nine high- and moderate-quality case-control studies Recent cannabis use associated with a near doubling of crash risk (OR=1.92) Higher-quality studies showed greater effect size Asbridge M, Hayden J, Cartwright J. BMJ 2012;344:e536

34 Acute coronary syndrome Large retrospective study Higher risk for ACS, MI within 1 hour after exposure to marijuana smoke Mittleman MA, et al. Circulation 2001;103:

35 Stable angina Smoking marijuana: Increases heart rate Decreases stroke volume Increases cardiac output Decreases exercise tolerance Decreases time to angina symptoms by 48% Compared to 28% decrease after cigarette smoking Marijuana smokers have a 3-fold increased mortality risk following MI Singla S, Sachdeva R, Mehta J. Cin Cardiol 2012;35(6):

36 ECS and cardioprotection CB1 and CB2 receptors have opposing roles in cardiac metabolic risk and atherogenesis CB2 stimulation, CB1 inhibition may minimize reperfusion injury Rimonabant: CB1 agonist/antagonist

37 CVA risk: multifocal angiopathy 2-year prospective study of 48 patients <45 yo admitted with ischemic stroke 13 reported cannabis use All had binged prior to stroke 10/13 showed pattern of multifocal cranial stenosis on angiography Cannabis consumption OR=113 for multifocal angiopathy Wolf V, et al. Stroke 2011;42:

38 Psychosis risk Causes short-term psychotic symptoms in 15% of users Schizophrenia 4x more likely by age 26 in users <15 yo No clear evidence showing that cannabis use causes schizophrenia In schizophrenic patients, heavy use can lead to relapse Kendell R. Addictions 2003;98: Shapiro GK, Buckley-Hunter L. J Psychosomatic Research 2010;69:

39 Impact of chronic use on physical and mental health Observational study comparing current with former users Patient surveys, including SF-36 Cannabis use found to have a direct negative effect on the mental health of men and women and the physical health of men. van Ours JC, Williams J. J Health Econ 2012;31(4):

40 Chronic cannabis and intellect

41 Pulmonary function CARDIA study: >5000 young men and women studied for 20 years with repeated PFT measurements No clear association between low, cumulative exposure and loss of function Heavy users not adequately studied Pletcher MJ, et al. JAMA 2012;207(2):

42 Pulmonary function Blue line: marijuana smokers Black line: tobacco smokers Pletcher MJ, et al. JAMA 2012;207(2):

43 Cancer risk THC: Non-mutagenic Marijuana smoke: Mutagenic Multiple carcinogenic compounds as in tobacco smoke Up to 50% higher concentrations 3x tar Despite this, studies linking marijuana to either head/neck,lung, and other cancers have been inconsistent

44 Cancer risk Despite presence of carcinogens, multiple studies inconsistent 65,855 HMO members classified as experimenters, former users, or current users No association with HNSCC, lung, colorectal, melanoma, breast cancer Sidney S, et al. Am J Public Health 1997;87:

45 Marijuana drug-drug interactions CNS depressants: additive or synergistic effects Barbiturates: competes with metabolism and raises levels Theophylline: increased metabolism similar to tobacco Warfarin: may increase INR marginally Sympathomimetics may enhance tachycardic effect Ritonavir may inhibit metabolism

46 Conclusions Habitual, heavy marijuana use can cause cannabis hyperemesis syndrome Symptoms resolve with cessation Therapeutic uses for which at least fair evidence exist include: Chronic, intractable neuropathic pain MS spasticity Fibromyalgia Chemotherapy-induced nausea/vomiting AIDS-associated anorexia and weight loss

47 Conclusions, continued Acute side effects and chronic complications include: Getting high Driving impairment Impaired mental health, psychosis Lower intellect ACS and MI CVA secondary to multifocal angiopathy However, cannabis not clearly carcinogenic

48 Conclusions, continued Cannabis and related products have few significant drug interactions Avoid with other CNS depressants, especially alcohol, barbiturates

49 Questions?

Dr. G. Michael (Michael) Allan EDMONTON AB Dr. Christina (Tina) S. Korownyk EDMONTON AB MEDICAL CANNABANOIDS IN PRIMARY CARE

Society of Rural Physicians of Canada 26TH ANNUAL RURAL AND REMOTE MEDICINE COURSE ST. JOHN'S NEWFOUNDLAND AND LABRADOR APRIL 12-14, 2018 262 Dr. G. Michael (Michael) Allan EDMONTON AB Dr. Christina (Tina)