Medical Use of Cannabinoids in Palliative Care

Multiple Sclerosis (Canada) http://www.youtube.com/watch?v=b8_5ebsjk8i Medical Use of Cannabinoids in Palliative Care Craig D. Blinderman, MD, MA Director, Adult Palliative Medicine Service Associate Professor of Medicine Columbia University Medical Center Seizures (Colorado) http://www.tokeofthetown.com/2013/02/powerful_video_shows_ins tant_relief_for_epileptic_cannabis_patient.php CP Stutter (Missouri) http://sploid.gizmodo.com/watch the instant change when girl withcerebral palsy 1478892426 Parkinson's (Israel) http://www.youtube.com/watch?v=rhmbnjcnrqm Severe Tourette s (Germany) http://www.youtube.com/watch?v=pinkduxoqac Disclosure No relevant financial conflicts related to this subject. Objectives 1. Describe the pharmacology of cannabinoids 2. Name 3 indications for the use of cannabinoids in palliative care 3. Recognize the side effects and potential harms of medical marijuana use

Outline Background of cannabinoids History Pharmacology Medical Use in Palliative Care Cannabis Synthetic cannabinoids Side Effects and Safety Concerns Legal and Ethical Issues Background A SHORT HISTORY OF CANNABINOIDS Cannabinoids and Opioids: An Historical Perspective Notable history of cannabis Cannabinoids 1988: CB 1 receptor identified. 9 THC identified 1990: CB 1 receptor cloned as main 1992: Anandamide discovered, CB2 First Medicinal psychoactive receptor identified evidence of cannabis W.B. O Shaughnessey s agent in 1993: CB2 receptor cloned medicinal use work popularizes Cannabis sativa 1998: Endogenous cannabinoid use in China declines cannabis use plant ligands shown to be analgesic 1900 s 3000 BC 1800 s 1964 1988 1998 500 BC 1522 1804 1817 1874 1900 s 1970 1975 Earliest known Paracelsus 1804: Morphine Morphine analogs 1970s: Discovery of opioid receptors reference for reference to extracted from opium synthesized: µ(mu), к (kappa), δ (delta) opium based laudanum, poppy plant 1874: Diacetylmorphine elixir opium based (heroin) 1975: Discovery of endogenous opioid elixir, as a 1817: Morphine first 1900s: codeine, peptides endorphins potent painkiller marketed in Germany dihydromorphine, as analgesic oxycodone, pethidine, oxymorphone Opioids Shen Nung, an emperor of China (also the discoverer of tea and ephedrine), is held to be among the first to report on therapeutic uses of cannabis in a medicinal compendium that dates to 2737 BCE. In 1839, William O Shaughnessy, a British doctor working in India, published a paper on cannabis as an analgesic and appetite stimulant that also tempered nausea, relaxed muscles, and might ameliorate epileptic seizures. Led to widespread medical use of cannabis in the United Kingdom (E.g. it was prescribed to Queen Victoria for relief of menstrual discomfort) Slide courtesy of M. Ware 1. Mack A & Joy J., 2001. 2. Notcutt W., 2004. Groopman, J. NYRB, 2014.

Legal prohibition of cannabis for medical use in the U.S. Today: States that have legalized cannabis for medical purposes 1937: Harry J. Anslinger, a prominent prohibitionist, successfully lobbied Congress to pass the Marihuana Tax Act, making access to the plant costly. Anslinger was the head of the Federal Bureau of Narcotics and presented cannabis use to the public as an unalloyed danger, resulting in reefer madness. The AMA opposed the Marihuana Tax Act, fearing that it would limit medicinal study and potential prescription of the plant. 1942: Marijuana was removed from the United States Pharmacopeia, a compendium that set standards for medicines and foods. 1970: Congress enacted the Controlled Substances Act, classifying marijuana along with heroin as a Schedule I drug. Groopman, J. NYRB, 2014. Overview of Cannabinoid Pharmacology Cannabis strains may vary by morphology, odor, and chemotype, producing plant resin with varying ratios of pharmacologically active cannabinoids, principally tetrahydrocannabinol (THC) and cannabidiol (CBD), terpenoids, flavonoids, and other molecules. Background PHARMACOLOGY Although other receptors play a role, the majority of the effects of THC from cannabis are mediated through partial agonism of central and peripheral cannabinoid receptors, CB1 and CB2, respectively. Activation of CB1 and CB2 directly inhibits the release of multiple neurotransmitters including acetylcholine, dopamine, and glutamate while indirectly affecting γ aminobutyric acid, N methyl D aspartate, opioid, and serotonin receptors. Russo EB. Br J Pharmacol. 2011; 163:1344 64. Wilson RI, Nicoll RA. Nature. 2001; 410:588 592. Aggarwal SK. Clin J Pain. 2013; 29(2):162 171. Davison SN, et al. J Pain Symptom Manage. 2011; 41(4):768 78

Overview of Cannabinoid Pharmacology Cannabinoid receptors (CB1, CB2) are part of the endocannabinoid system (ECS), a pro homeostatic modulatory system composed of several endogenous ligands (e.g. anandamide and 2 arachidonylglycerol) Cannabinoid Receptors Physiologically, the ECS been shown to impact pain perception, movement, appetite, aversive memory extinction, hypothalamic pituitary adrenal (stress) axis modulation, immune function, mood, inflammation, and others. Russo EB. Br J Pharmacol. 2011; 163:1344 64. Wilson RI, Nicoll RA. Nature. 2001; 410:588 592. Aggarwal SK. Clin J Pain. 2013; 29(2):162 171. Davison SN, et al. J Pain Symptom Manage. 2011; 41(4):768 78 CB1 Receptor Activation Cannabinoid binding (activation) negatively coupled to adenylate cyclase, suppresses neuronal Ca 2+ conductance, inhibits inward rectifying K + conductance suppression of neuronal excitability Cannabinoid receptors are found in the pain neural matrix CB1 Periaqueductal gray Rostral ventromedial medulla (nucleus raphe magnus antinociceptive actions of cannabinoids within RVM are primarily due to presynaptic inhibition of GABAergic neurotransmission) Thalamus Dorsal root ganglion Amygdala Cortex CB2 Immune cells, including microglia cytokine, chemokine modulation Dorsal root ganglion Brainstem Thalamus Periaqueductal gray Cerebellum

Regulation of nausea and vomiting by the endocannabinoid system CB1 receptors are found in the dorsal vagal complex (medullary nucleus solitarius, area postrema, dorsal motor nucleus of the vagus). CB1 receptor agonists reduce in intestinal 5 HT release, suggesting enterochromaffin cells express functional CB1 receptors. Cannabinoid inhibition of 5 HT3 receptor activity in this region increased GABAergic activity Receptor independent pathways too 1. Cannabinoids induce cancer cell death 2. Cannabinoids inhibit angiogenesis, invasion and metastasis Anti cancer properties? Sharkey KA, et al. European Journal of Pharmacology. 2014;722:134-146. Martin BR and Wiley JL. Mechanism of Action of Cannabinoids: How It May Lead to Treatment of Cachexia, Emesis, and Pain. Journal of Supportive Oncology. 2004;2(4):305-316. Pacher P, Batkai S, Kunos G. The Endocannabinoid System as an Emerging Target of Pharmacotherapy. Pharmacological Reviews. 2006;58(3):389-462. Velasco G, et al. The use of cannabinoids as anticancer agents. Prog Neuro Psychopharmacol Biol Psychiatry (2015) http://dx.doi.org/10.1016/j.pnpbp.2015.05.010 Pharmacokinetics 95 99% THC is plasma protein bound (lipoproteins) Metabolism via hydroxylation, oxidation, and conjugation (CYP2C9 and CYP3A) First pass metabolism with oral admin. (11 OH THC) Rapidly cleared from plasma (70% tissues / 30% metabolized) Elimination over several days (adipose) THC is excreted via both hepatic and renal mechanisms. No specific studies have been done with cannabis based medicines in patients with significant hepatic or renal impairment, but it can be expected that effects would be more exaggerated or prolonged in these settings. Breastmilk distribution Pregnancy Category C Excretion: days to weeks 20 35% found in urine 65 80% found in feces 5% as unchanged drug (when given PO) MEDICAL CANNABIS SYMPTOM MANAGEMENT IN PALLIATIVE CARE

The evidence Over the last several decades cannabis and cannabinoid therapeutics have been studied in over 100 controlled clinical trials of varying size and quality, investigating a wide range of conditions. As with the evidence for most pharmacologic symptom interventions, there are a lack of comparative data between cannabis and other commonly used treatments. Hazekamp A, Grotenhermen F: Review on clinical studies with cannabis and cannabinoids 2005 2009. Cannabinoids 2010;5:1 21 Hill KP et al. JAMA 2015;313(24):2474 2483) Slide courtesy of Sunil Aggarwal, MD Total: 24,023 2.3 publications/day for last 20 years 2013 projected: 280 in first 38 days 2689. Cancer Pain For cancer pain, a multicenter RCT, involving 360 patients, investigated oral cannabis to treat breakthrough cancer pain in subjects who were started on a long acting opioid. It showed analgesic efficacy in the low and medium dose ranges, which were also welltolerated. Portenoy RK, et al. Nabiximols for opioid treated cancer patients with poorly controlled chronic pain: a randomized, placebo controlled, graded dose trial. J Pain. 2012; 13(5):438 449. Painful Neuropathy Two RCTs of inhaled cannabis for painful HIV sensory neuropathy involving 89 subjects in total showed significant analgesic efficacy,with a combined NNT of 3.38, superior to all other medications similarly tested for this indication. Abrams DI, et al.: Cannabis in painful HIV associated sensory neuropathy. Neurology 2007; 68:515 521. Ellis RJ, et al.: Smoked medicinal cannabis for neuropathic pain in HIV: A randomized, crossover clinical trial. Neuropsychopharmacology 2009;34:672 680. Phillip TJ, et al.: Pharmacological treatment of painful HIV associated sensory neuropathy: A systematic review and meta analysis of randomised controlled trials. PLoS One 2010;5:e14433.

Chronic, intractable neuropathic pain Three RCTs of inhaled cannabis for chronic, intractable neuropathic pain due to multiple etiologies, involving 100 subjects in total, all showed efficacy for smoked and vaporized cannabis. Nausea and Vomiting Three RCTs, involving 43 subjects in total, investigating inhaled cannabis for nausea and vomiting secondary to active cancer chemotherapy, demonstrated inhaled cannabis to be an efficacious antiemetic. Wilsey B, et al.: A randomized, placebo controlled cross over trial of cannabis cigarettes in neuropathic pain. J Pain 2008;9:506 521. Ware MA, et al.: Smoked cannabis for chronic neuropathic pain: Arandomized controlled trial. CMAJ 2010;182: E694 E701. Wilsey B, et al.: Low dose vaporized cannabis significantly improves neuropathic pain. J Pain 2013;14:136 148. Chang AE, et al. Ann Intern Med 1979;91:819 824. Chang AE, et al. Cancer 1981;47: 1746 1751. Levitt M, et al. Proc Am Soc Clin Oncol 1984;3:91(abstr C 354). Appetite Stimulation for Anorexia Three RCTs of inhaled cannabis involving 107 subjects in total congruently showed efficacy for appetite stimulation and weight gain in patients with AIDS wasting syndromes. No studies have reported a benefit in cancer patients. Spasticity in Multiple Sclerosis Spasticity (both objective and subjectively assessed), spasm frequency, insomnia, pain, and impaired mobility were shown to be significantly improved in a 630 subject multicenter RCT over a 12 month period. Abrams DI, et al.: Short term effects of cannabinoids in patients with HIV 1 infection. Ann Intern Med 2003;139:258 266. Haney M, et al.: Dronabinol and marijuana in HIV+ marijuana smokers: Acute effects on caloric intake and mood. Psychopharmacology 2005;181:170 178. Haney M, et al.: Dronabinol and marijuana in HIV positive marijuana smokers. J Acquir Immune Defic Syndr 2007;45: 545 554. Zajicek J, et al.: Cannabinoids in multiple sclerosis (CAMS) study: Safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatry 2005;76:1664 1669.

FDA Regulated Cannabinoid Based Medicines: Prescribing medical marijuana resin containing herbal flowers, which can be heated and delivered to the lungs via inhalation of smoke or vapor, cannabis based extracts, which include oral, oromucosal, rectal, and topically delivered preparations in the form of concentrates, suppositories, edibles, and salves. Photo from pharmer.org Exact dosages depend on individual patient need and tolerance of side effects. No evidence based guidelines on dosing have been developed. Cannabis preparations include: Chemicals, Extracts, Botanicals Photo from epocrates.com Photo from nida.org Dronabinol (Marinol ) Nabilone (Cesamet ) Cannabis Sativa L. Extracts (Sativex ) From: Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems: A Clinical Review Cannabis Sativa L. Cigarettes Photo from Russo et al. 2002 Photo from wikipedia.org Aggarwal S, Blinderman CD. Fast Facts #279 JPM, 2014 Photo from Russo et al. 2002 1985 1985 2006 Approximately 460 chemical constituents, >100 phytocannabinoids 1976 Prescribing medical marijuana JAMA. 2015;313(24):2474-2483. doi:10.1001/jama.2015.6199 Cannabinoids are lipophilic and have nearly immediate onset of action when smoked or vaporized. Vaporization has the advantage of rapid onset of effect and easy dose titration. Patients can be advised to pause briefly between inhalations to ascertain effectiveness of the medicine and to stop when maximum effect is achieved. Oral ingestion of cannabis products has a delayed onset of action compared to inhalation and titration is more difficult. Maximum cannabinoid blood levels are reached up to six hours post oral ingestion, with a half life of 20 to 30 hours. Date of download: 6/29/2015 Copyright 2015 American Medical Association. All rights reserved. Aggarwal S, Blinderman CD. Fast Facts #279 JPM, 2014

Nausea and Vomiting Dronabinol and nabilone are FDA approved for the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond to conventional antiemetics. SYNTHETIC CANNABINOIDS (DRONABINOL AND NABILONE) SYMPTOM MANAGEMENT IN PALLIATIVE CARE There are no published studies comparing dronabinol and nabilone to newer antiemetic agents. Arnold RM, Wilner LS. Fast Facts #93 Cannabinoids In The Treatment Of Symptoms In Cancer And Aids Orexigenic (appetite stimulation) Only dronabinol is FDA approved for the treatment of anorexia associated with weight loss in patients with HIV/AIDS. Early studies of dronabinol in this population showed promising increases in caloric intake and stabilization or gains in weight. However, later analysis showed that the effect sometimes represented accumulation of water or fat instead of the preferred lean body mass. Neither dronabinol or nabilone are indicated for cancer associated anorexia. Dosing synthetic cannabinoids Dronabinol (Marinol) Chemotherapy induced N/V: 5mg/m 2 PO 1 3 hours before and Q2 4 hr after chemo; may be increased in 2.5mg/m 2 increments to 15mg/m 2 ; not to exceed 4 6 doses/day Appetite stimulation: 2.5mg PO Q12hr, may be increased to 20mg/day Nabilone (Cesamet) Chemotherapy induced N/V: 1 2mg PO Q8 12h Arnold RM, Wilner LS. Fast Facts #93 Cannabinoids In The Treatment of Symptoms In Cancer and AIDs.

Safety and Public Health Concerns Safety: Occasional and low cumulative marijuana use was not associated with adverse effects on pulmonary function (Pletcher MJ, et al. JAMA 2012) Medical cannabis laws (from 1999 2010) are associated with significantly lower opioid overdose mortality rates. (Bachhuber MA, et al. 2014) Unlike opioid overdose, marijuana toxicity is not fatal. MEDICAL CANNABIS AND CANNABINOIDS SAFETY AND PUBLIC HEALTH CONCERNS Concerns: Marijuana adverse effects acute and chronic (Volkow ND, et al. NEJM, 2014) Increased risk of MVA s with acute marijuana impairment (Hartman RL, Huestis MA. Clin Chem, 2013) Preliminary research points to an association between marijuana use and MI, stroke, and PVD (Thomas G,et al.. Am J Cardiol. 2014) Adverse Effects of Short Term Use and Long Term or Heavy Use of Marijuana. Level of Confidence in the Evidence for Adverse Effects of Marijuana on Health and Well Being. Effects of short term use Impaired short term memory Impaired motor coordination, interfering with driving skills and risk of injuries Altered judgment, increasing risk of sexual behaviors, transmission of STDs High doses: paranoia and psychosis Effects of long term or heavy use Addiction ~9% of users overall, 17% of those who begin use in adolescence, and 25 50% of daily users Altered brain development Poor educational outcome, increased likelihood of dropping out of school Cognitive impairment Diminished life satisfaction and achievement Symptoms of chronic bronchitis Increased risk of chronic psychosis disorders in persons with predisposition Volkow ND et al. N Engl J Med 2014;370:2219 2227. Volkow ND et al. N Engl J Med 2014;370:2219 2227.

Increases over Time in the Potency of Tetrahydrocannabinol (THC) in Marijuana and the Number of Emergency Department Visits Involving Marijuana, Cocaine, or Heroin. Synthetic Cannabinoids: Legal Alternative to Marijuana Volkow ND et al. N Engl J Med 2014;370:2219 2227. Clusters of Cases of Adverse Health Effects or Severe Toxic Effects and Deaths Associated with Synthetic Cannabinoid (SC) Product Use. Trecki J et al. N Engl J Med 2015;373:103 107.

Legal and Ethical Issues Integrating medical marijuana in clinical practice LEGAL AND ETHICAL ISSUES Federal law vs state law Annas, G. NEJM, 2014 Protection to discuss marijuana as part of doctorpatient confidentiality Protected under federal law even in states where it is illegal to prescribe Conflict of interest Should physicians who serve as scientific advisors to marijuana growers/suppliers be allowed to prescribe? Take Home Points Questions? Cannabinoids act on unique G protein receptors (CB1 and CB2) found in the CNS, immune system, and elsewhere in the body. High quality studies have demonstrated that cannabinoids can be of benefit in patients with cancer pain, neuropathic pain, anorexia, nausea/vomiting, and spasticity. There are no evidence based dosing guidelines for inhaled or ingested cannabis. Side effects (short and long term) may be significant and should be reviewed with patients in whom cannabinoids are being considered.