Virtual Lectures Planning Committee Disclosure Summary · Virtual Lectures Planning Committee Disclosure Summary As a provider accredited by ACCME, College of Medicine, Mayo Clinic

© MFMER© MFMER

VIRTUAL LECTURES

THE ROLL OF MEDICAL CANNABIS: IS IT TIME TO BURN ONE DOWN?

© MFMER

Virtual Lectures Planning Committee Disclosure Summary As a provider accredited by ACCME, College of Medicine, Mayo Clinic (Mayo School of CPD) must ensure balance, independence, objectivity and scientific rigor in its educational activities. Course Director(s), Planning Committee Members, Faculty, and all others who are in a position to control the content of this educational activity are required to disclose all relevant financial relationships with any commercial interest related to the subject matter of the educational activity. Safeguards against commercial bias have been put in place. Faculty also will disclose any off label and/or investigational use of pharmaceuticals or instruments discussed in their presentation. Disclosure of these relevant financial relationships will be published in activity materials so those participants in the activity may formulate their own judgments regarding the presentation.

Relevant financial relationship(s) with industry: None

References to off-label and/or investigational usage(s) of pharmaceuticals or instruments in their presentation: None

Listed below are individuals with control of the content of this program who have disclosed:

Program SpeakerThomas Pittelkow, D.O., M.P.H.

Program Planning CommitteeCurtis Hanson, M.D.Bobbi Pritt, M.D., MSc, DTMHSharon PreussMelissa Peterson

© MFMER

Thomas Pittelkow, D.O., M.P.H.

Department of Anesthesiology-Pain MedicineMayo ClinicRochester, Minnesota

Senior Associate Consultant, Pain Clinic

©2016 MFMER | slide-4

The roll of medical cannabis:Is it time to burn one down?

Thomas P. Pittelkow, D.O., M.P.H.Division of Pain MedicineDepartment of Anesthesiology and Perioperative Medicine

October 4, 2017


Disclosures

Relevant Financial Relationship(s)

None

Off Label Usage

Medical cannabis is not FDA-approved

Products produced by:

Minnesota Medical Solutions

Leafline Labs




Learning Objectives

• Identify the key cannabinoids, receptors, and basic physiology of medical cannabis

• Specify conditions where use of medical cannabis is potentially indicated

• Articulate role of medical cannabis in pain treatment algorithm


Medical Potential

• Over 20,000 published articles on cannabinoids• Evidence for symptom relief

• Nausea and vomiting – chemotherapy• Pain – neuropathic/central• Muscle spams - MS• Spasticity - MS• Cachexia – HIV/AIDS• Mental health – anxiety, PTSD, etc.

• Significant potential role in chronic pain and multiple chronic health conditions


Framework

• History

• Physiology

• Rx Cannabinoids

• Minnesota Registry

• Indications• Pain• Spasticity

• Considerations

• Summary


Case

• 35 year-old Female, MN resident

• Hormone receptor positive, HER-2 negative, metastatic breast carcinoma

• Metastases to the liver, lung and bone

• Multiple symptoms• Cancer-associated pain, mixed-type• Nausea• Anorexia• Insomnia• Fatigue


Reflection

• Would you certify this patient?



Patient perspectives

• Social media

• Traditional medication side effects

• Stigma of “strong medicine”• Fears – dependence, addiction

• Mistrust

• Natural medicine

• Alleviate suffering

• Hope


Physician considerations

• Adequate current medication regimen?

• Expert for complex symptom management?

• Pharmacotherapy interactions?

• Psychosocial and financial domains?

• Prior substance abuse/dependence?

• Routine follow-up?



History of Cannabis and Opioids

Early use in China

3000 B.C.

O’Shaughnessy -Testing in disease;Therapeutic potential

1800’s 1900’s

1937 Marihuana Tax Act

1940Synthetic form devised

THC identified psychoactive component

1964

Controlled Substances Act

1970CA 1st state to legalize medical cannabis

1996

500 B.C.

Reference to opium elixir

1500’s

Opium elixir for analgesia

1804Opium extracted from poppy

1817Morphine marketed in Germany

1900’sSynthetic morphine equivalents devised

1970Opioid receptors discovered

1975Endogenous opioids -endorphins

CO and WA 1st state to legalize recreational cannabis

2012

1914Harrison Act -Prohibited Rx of opiates to addicts

1990sIncrease in opioid prescriptions

1999Rise of opioid-related deaths


Anatomy of a Cannabis Plant


What makes those buds so special?• Nearly 500 natural compounds in the Cannabis sativa plant

• Over 70 cannabinoids• Delta-9-tetrahydrocannabinol (THC)

• Psychoactive component• Euphoria, hallucinations, tachycardia, anxiety

• Cannabidiol (CBD)• Analgesia• Neuroprotective• Anti-inflammatory

• Anandamide• Endogenous cannabinoid• Glutamatergic and GABA-ergic• Pain, muscle tone, emotion


The Endocannabinoid System

CB1 receptor

(THC)

CB2 receptor

(CBN)

eCB = endocannabinoid; produced by the body

CBD - Cannabidiol • Inhibits the breakdown of

anandamide (FAAH)• Microglial cell activation


The Endocannabinoid System

CB1 receptor

(THC)

CB2 receptor

(CBN)

• Primarily in brain, spinal cord, peripheral nerves, GI and reproductive tract

• Highly expressed in immune tissues

• Regulate cytokine release

• ? Role in pain


Microenvironment Direct inhibitor: ACh, DA, Glut

Indirect effect: GABA, NMDA, μ, 5-HT


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Cannabis derived products

• Dronabinol (Marinol ®)

• Nabilone (Cesamet ®)

• Nabiximols (Sativex ®)

• Cannador

• Epidiolex


Dronabinol (Marinol ® )

• Synthetic THC (no CBD)

• Oral capsule

• Schedule III Controlled Substance

• FDA approved indications: • Treatment of anorexia associated with weight loss in

patients with AIDS• Treatment of nausea and vomiting associated with

cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments


Nabilone (Cesamet ® )

• Synthetic analogue of THC

• Oral capsule

• Schedule II Controlled Substance

• FDA approved indication:• Treatment of nausea and vomiting

associated with cancer chemotherapy in patients who have failed to respond adequately to conventional therapy


Nabiximols (Sativex ® )

• Oromucosal spray

• Not available in the USA

• Whole plant extract (phytocannabinoid)

• 1:1 ratio of THC:CBD

• 100 microliter spray (2.7mg THC, 2.5mg CBD)

• Approved for pain treatment in >24 countries

• Phase 3 clinical trials in US


Cannador

• THC:CBD combination (~2:1 ratio)

• Oral capsule

• Phytocannabinoid

• Prominent psychoactive side effects

• Not available in the USA


Epidiolex ®

• Liquid formulation of pure plant-derived cannabidiol (CBD), no THC

• Treatment of pediatric epilepsy syndromes • Dravet, Lennox-Gastaut, Infantile Spasms• Phase 3 clinical trials


The Reviews

• Cannabinoids for Medical Use: A Systematic Review and Meta-analysis

• JAMA. 2015;313(24):2456-2473.

• Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems: A Clinical Review

• JAMA. 2015;313(24):2474-2483.

• The Effects of Cannabis Among Adults With Chronic Pain and an Overview of General Harms: A Systematic Review

• Ann Intern Med. 2017;167:319-331.

• The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research

• The National Academies Press, 2017


The Evidence of Cannabinoid Efficacy

• Conclusive quality evidence • Chronic pain (neuropathic) • Spasticity (MS)• Nausea, chemotherapy-induced

• Moderate quality evidence• Improved short-term sleep outcomes

• Limited quality evidence• Weight gain in serious illness (HIV, Cancer)• Improved symptoms of anxiety or PTSD

JAMA. 2015;313(24):2456-2473.JAMA. 2015;313(24):2474-2483.Ann Intern Med. 2017;167:319-331.The Health Effects of Cannabis and Cannabinoids. National Academies Press. 2017



Current Cannabis State Laws


Minnesota Medical Cannabis Program


Minnesota – 11 Qualifying Conditions• Cancer associated with severe/chronic pain, nausea or severe vomiting, or cachexia

or severe wasting

• Glaucoma

• HIV/AIDS

• Tourette’s Syndrome

• Amyotrophic Lateral Sclerosis (ALS)

• Seizures, including those characteristic of epilepsy

• Severe and persistent muscle spasms, including those characteristic of Multiple Sclerosis

• Crohn’s Disease

• Terminal illness, with a life expectancy of less than one year, if the illness or treatment produces severe/chronic pain, nausea or severe vomiting, cachexia or severe wasting

• Intractable pain

• Post-Traumatic Stress Disorder

Use of medical cannabis products is experimental


Minnesota – Certification

• Physicians, physician’s assistants, and advanced practice registered nurses

• MDH will not maintain or publish a list of practitioners who certify

• Practitioners do not have to participate in certifying patients

• Practitioners will not determining strength of medical cannabis

• Practitioners must have registry account


Minnesota - No Prescription Needed

• Federal policy dictates that physician who prescribes marijuana or other Schedule I drugs to a patient may be stripped of his or her federal license to prescribe drugs and prosecuted

• “Recommend” or “certify”


Minnesota - Medical Cannabis Industry


Minnesota – Dispensary

• Pharmacist works with patient to determine an appropriate cannabis dose

• Disease• Symptoms• Tolerable side-effects

• MN 2nd state to use pharmacists to dispense

• No guidelines for pharmacists to dose different medical conditions

• Based on genetic strain• THC:CBD


Minnesota – Methods of Delivery

• Edibles – capsules, solutions, tinctures

• Topicals – balm, bars, patches

• Vaporization – prefilled cartridge, oil

• “Start low, go slow”


Mayo Clinic Policy

• Establish a medical relationship

• Full assessment of the patient's medical history and current medical condition

• Disclose experimental nature of therapeutic use of medical cannabis; risk, benefits, and side effects; Tennessen warning

• Patient will have regular follow-up for qualifying health condition with certifier




Organizational support

• IOM, AMA, ACP, ASAM• Support more research• Develop of safe and reliable delivery

systems• Reclassification of Class I status• Apply “established research standards”


Pills, joints, and the Volcano…

• Many ways for ingestion

• Different mediums = different [THC]• Flowers/buds – 2-10%• Hash – 30%• Shatter – 80%

• Bioavailability – large first pass effect• PO – 10-20%• Inhalation – 30-50%

• THC – metabolized by CYP2C9 and CYP3A4


Research - Pain


Pain Treatment – Early Years

• Research in animal models beneficial effect• Chemical, mechanical, thermal pain stimuli• Chronic pain of neuropathic and

inflammatory origin

• Endocannabinoids exert synergistic anti-nociceptive effects when combined with NSAIDs

• Functional interplay between endocannabinoid and opioid receptor systems in modulating analgesic responses

British Jour of Pharmacology. 2016. 173(16): 2521-31. Trends in Pharm Sci. 2015. 36(5): 277-296.Eur J Pharmacol. 2007. 556:75-83Pain. 2004. 109:124-131.


Pain Treatment – Rx Cannabinoids

• Nabiximols reduced neuropathic pain in patients• Traumatic peripheral nerve injury (allodynia)• Multiple sclerosis

• Dronabinol provided modest analgesic effects in multiple sclerosis

• Orally administered cannabis extract (THC) effective in pain relief

• Analgesic efficacy of smoked cannabis in treating neuropathic pain

Clin Rehab. 2003. 17(1):21-9.Anaesthesia. 2004. 59(5):440-52.BMJ. 2004. 31;329(7460):253. Lancet. 2003. 8;362(9395):1517-26.Neurology. 2005. 27;65(6):812-9.


Synergistic Effect with Opioids

• Lesser of two evils• Chronic pain – stable systemic opioid therapy• Inhaled vaporized cannabis• Significant decrease in pain with cannabis

• Either-or model• States with medical cannabis laws - 25%

lower mean annual opioid-overdose mortality

• Better together• Opioid with cannabinoid receptor agonist

reduced nerve injury-induced allodynia

Clin Pharmacol Ther. 2011. 90(6):844-51JAMA Intern Med. 2014. 174(10):1668-73.Br J Pharmacol. 2016. 173(16):2521-31.


Research - Spasticity


Cannabis as Treatment for Spasticity

• Most trials have been in patients with multiple sclerosis

• Multiple studies showing benefit in reduction of MAS and functional gains

• Decrease in sleep disruption

• Precise ratio of THC:CBD is not clear

• ? Safety and potential long-term effects on cognitive function

Eur J Neurol. 2011. 18(9):1122-31. Mult Scler. 2012. 18(2):219-28. Neurol Res. 2010. 32(5):451-9.


High times for research

• Challenges with separation of social and medical policies

• Funding for cannabis research

• Growing body of evidence supporting benefit

• Studies with little-to-no benefit demonstrate that cannabis is relatively safe

• Low-moderate doses are typically well tolerated, especially when spread over time



Risks?

• ‘Marijuana doesn’t have any risks—it’s a flower. It’s not like morphine.’ – Dispensary Owner


Expectations, Risks, and Drug Interactions

• Common side effects• Dizziness• Tiredness• Confused• Lose touch with reality• Memory impairment• Trouble concentrating

• Driving impairment

• Addiction

• Stroke, MI, mental health disorders

• Drug Interactions• Evidence for synergy

with opioids• Benzodiazepines and

other sedatives• Antidepressants• Warfarin and

anticoagulants• NSAIDs (COX2-

selective)

• Not recommended for pregnant or nursing women


So, that’s what the future looks like…

• Expansion of state-based approval with variety of laws and regulations

• Ongoing research and clinical trials• Anti-proliferative effect

• Responsibility to stay current with legislation, regulations, and medical advancement in respective area of practice

• Encourage regular collaboration with patients and pharmacists

• Dosages• Side-effects • Symptom control


What happened…

• 35 yo Female with metastatic breast cancer• Continues to get treatment• Holistic and natural care focus• Rick Simpson cannabis (C. indica)• IDD for pain (turned off)


In Summary

• Medical cannabis• Delta-9-tetrahydrocannabinol (THC)• Cannabidiol (CBD)

• Best evidence – depends on perspective• Intractable central/neuropathic pain• MS associated spasticity and pain related to

muscle spasms

• There is no formally accepted role for the use of medical cannabis in typical treatment algorithm

• If all else fails…



Interesting Reads• University of California – San Diego, Medical Cannabis Research Center http://www.cmcr.ucsd.edu/

• Health Canada document for physicians: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/marihuana/med/infoprof-eng.pdf

• Minnesota Department of Health – A Review of Medical Cannabis Studies http://www.health.state.mn.us/topics/cannabis/practitioners/dosage.pdf

• The University of Washington Alcohol and Drug Abuse Institute. http://learnaboutmarijuanawa.org/factsheets/cannabinoids.htm

• The American Cancer Society, “Marijuana and Cancer.” http://www.cancer.org/treatment/treatmentsandsideeffects/complementaryandalternativemedicine/herbsvitaminsandminerals/marijuana

• The National Cancer Institute at the National Institutes of Health. Cannabis and Cannabinoids. http://www.cancer.gov/cancertopics/pdq/cam/cannabis/healthprofessional/

• International Association for Cannabinoid Medicines, http://www.cannabis-med.org/index.php?lng=en

• The National Academies of Sciences, Engineering, and Medicine . The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research (2017). https://www.nap.edu/catalog/24625/the-health-effects-of-cannabis-and-cannabinoids-the-current-state


References• Izzo AA, et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends

Pharmacol Sci. 2009 Oct;30(10):515-27.

• Whiting PF, et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA. 2015 Jun 23-30;313(24):2456-73.

• Hill KP. Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems: A Clinical Review. JAMA. 2015 Jun 23-30;313(24):2474-83.

• Pacher P, et al. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006 Sep;58(3):389-462.

• Wade DT, et al. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil. 2003 Feb;17(1):21-9.

• Notcutt W, et al. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 'N of 1' studies. Anaesthesia. 2004 May;59(5):440-52.

• Aggarwal SK and CD Blinderman. Cannabis for symptom control #279. J Pall Med. 2014 May;17(5):612-4.

• Carter GT, et al. Cannabis in palliative medicine: improving care and reducing opioid-related morbidity. Am J Hosp PalliatCare. 2011 Aug;28(5):297-303.

• Abrams D and M Guzman. Cannabis in cancer care. Clin Pharmacol Ther. 2015 Jun;97(6):575-86.

• Wilsey B, et al. The Medicinal Cannabis Treatment Agreement: Providing Information to Chronic Pain Patients Through a Written Document. Clin J Pain. 2015 Dec;31(12):1087-96.

• Pacher P, et al. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006 Sep;58(3):389-462.


References• Svendsen KB, et al. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind

placebo controlled crossover trial. BMJ. 2004 Jul 31;329(7460):253.

• Zajicek J, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet. 2003 Nov 8;362(9395):1517-26.

• Rog DJ, et al. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology. 2005 Sep 27;65(6):812-9.

• Wilsey B, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain. 2008 Jun;9(6):506-21.

• Serpell M, et al. A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment. Eur J Pain. 2014 Aug;18(7):999-1012.

• Abrams DI, et al. Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther. 2011 Dec;90(6):844-51.

• Bachhuber MA, et al. Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999-2010. JAMA Intern Med. 2014 Oct;174(10):1668-73.

• Wilsey B, et al. Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain. 2013;14(2):136-48.

• Noyes R Jr, et al. Analgesic effect of delta-9-tetrahydrocannabinol. J Clin Pharmacol. 1975. 15(2-3):139-43.

• Noyes R Jr, et al. The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther. 1975. 18(1):84-9.

• Johnson JR, et al. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manage. 2010. 39(2):167-79.


References• Johnson JR, et al. An open-label extension study to investigate the long-term safety and tolerability of THC/CBD

oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage. 2013 Aug;46(2):207-18.

• 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):438-49

• Novotna A, et al. A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex(®) ), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur J Neurol. 2011. 18(9):1122-31.

• Notcutt W, et al. A placebo-controlled, parallel-group, randomized withdrawal study of subjects with symptoms of spasticity due to multiple sclerosis who are receiving long-term Sativex® (nabiximols). Mult Scler. 2012. 18(2):219-28.

• Collin C, et al. A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurol Res. 2010. 2(5):451-9.

• Wilsey B, et al. The Medicinal Cannabis Treatment Agreement: Providing Information to Chronic Pain Patients via a Written Document. Clin J Pain. 2015. 31(12):1087-96

• Koppel BS et al., Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014 Apr 29;82(17):1556-63.

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Virtual Lectures Planning Committee Disclosure Summary · Virtual Lectures Planning Committee Disclosure Summary As a provider accredited by ACCME, College of Medicine, Mayo Clinic