Kevin F. Boehnke, PhD

Research Investigator

Anesthesiology Department,

Chronic Pain and Fatigue Research Center

The University of Michigan

The Use of Cannabinoids to Treat Pain

1

Disclosures

■None

2

Medical cannabis in US

3https://medicalmarijuana.procon.org/view.resource.php?resourceID=000881

SCHEDULE 1

4

5Boehnke, Kevin F., et al. "Qualifying Conditions Of Medical Cannabis License Holders In The United

States." Health Affairs 38.2 (2019): 295-302.

Medical cannabis in Michigan

■ Michigan Medical Marihuana Act of 2008:■ Many conditions/symptoms covered

■ In 2018: 91.1% of the 297,515 patients in Michigan have their license for severe and chronic pain1

61: 2018 Medical Marihuana Act Statistical Report, Michigan

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Cannabis as an opioid substitute for chronic pain?

■Cannabis as a synergist with opioids1,2

■State-wide analyses3-5

■ Importance of Dispensaries in these studies (Powell et al, 2018)

■Cross-sectional6-8 and longitudinal support9-11

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1. Abrams et al, Clinical Pharmacology and Therapeutics, (2011) 2. Cooper, Ziva D., et al. Neuropsychopharmacology (2018) 3.

Bachhuber MA et. al. JAMA Int Med (2014). 4. Bradford and Bradford Health Affairs, (2016) 5. Bradford and Bradford, Health Affairs

(2017). 6. Boehnke, Kevin F., Evangelos Litinas, and Daniel J. Clauw. The Journal of Pain (2016). 7. Lucas et al, Journal of

International Drug Policy (2017) 8. Reiman et al, Cannabis and Cannabinoid Research (2017). 9. Haroutounian et al,. Clinical Journal

of Pain (2016). 10. Stith et al, PLOSone (2017) 11. Abuhasira et al, European Journal of Internal Medicine, (2018)

https://medlineplus.gov/magazine/issues/spring11/ima

ges/acetamenophen%20and%20codeine.jpg

Cannabis and Cannabinoids

■ Definitions and Background

■ Overview of Cannabinoid Risks

■ Role in Pain Management

■ Summary

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Aizpurua-Olaizola, Oier, et al. "Targeting the endocannabinoid system: future therapeutic strategies." Drug discovery

today22.1 (2017): 105-110. Fonseca et al, Prostaglandins & other lipid mediators 102 (2013): 13-30. 10

Endocannabinoid systemA set of receptors and their naturally occurring ligands

(endocannabinoids) and enzymes regulating control

Functions: “Relax,

eat, sleep, forget,

protect”

• Memory

• Neurogenesis

• Analgesia

• Immune function

• Stress

• Appetite

Cannabis-derived cannabinoids>100 known

■ Tetrahydrocannabinol (THC)

■ Analgesic, mood-altering, appetite stimulating

■ Partial agonist of CB1 and CB2

■ Cannabidiol (CBD)

■ Does not bind with significant affinity to CB receptors

■ Non-intoxicating, potentially protective against psychoactive effects of THC

■ Anti-inflammatory, anti-convulsant1

■ Other cannabinoids: CBN, CBG, CBC, etc. –The “Entourage Effect”2

By Indirectantagonist - Own work, CC BY-SA 3.0,

https://commons.wikimedia.org/w/index.php?curid=18534238

By Cannabis Training University - Own work, CC BY-SA 3.0,

https://commons.wikimedia.org/w/index.php?curid=21152729

1. Devinsky, Orrin, et al. New England Journal of Medicine 376.21 (2017): 2011-2020. 2.

Russo, Ethan B. British journal of pharmacology 163.7 (2011): 1344-1364. 11

Pharmacokinetics

12Agurell, Stig, et al. Pharmacological Reviews 38.1 (1986): 21-43.

U-Shaped Curve for cannabis effects

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Dose

Effects

1. Hill KP. Jama. 2015;313(24):2474. 2. Wallace M, Schulteis G, Atkinson JH, Wolfson T, Lazzaretto D, Bentley H, et al.

Anesthesiology. 2007;107(5):785–96. 3. Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, et al.

J Pain. Elsevier Ltd; 2012;13(5):438–49.

Cannabis and Cannabinoids

■ Definitions and Background

■ Overview of Cannabinoid Risks

■ Role in Pain management

■ Summary

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Risks of cannabinoids (recreational)Long term:

■ Respiratory effects

■ Dependence and addiction

■ Psychotic illnesses:1.5-2.4x rate developed under age of 25

■ Long term effects on memory and brain structure

Acute:

■ Common: Dizziness, somnolence, euphoria, light-headedness, anxiety, and others

■ Uncommon: Vomiting, hallucinations, paranoia, seizures

■ Uncertain quality of herbal preparation4

■ Vehicle accidents

1. Hall W. Drug Test Analysis 2014:6:39-45 2. Radhakrishnan R. Frontiers in Psychiatry

2014:5(54):1-6. 3. James et. al. Psychiatry Research: Neuroimaging 2013; 214:181-9. 4.

Russo, Ethan B. Frontiers in Pharmacology 7 (2016). 5. National Academies of Sciences,

engineering, and medicine. Health effects of cannabis and cannabinoids (2017).

http://arts.bio/en/products/budrot-mildew

rust-control

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http://www.clker.com/cliparts/6/4/b/1/13234884051988079243joint-hi.png

Cannabis and Cannabinoids

■ Definitions and Background

■ Overview of Risks and Benefits of Cannabinoids

■ Role in Pain management

■ Summary

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Role of Cannabinoids in Pain Management

■Mechanisms of pain

■Clinical trials in chronic pain

■Clinical trials in acute pain

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Mechanistic Characterization of Pain Any combination may be present

in a given individualPeripheral

(nociceptive)

■ Inflammation or mechanical damage in tissues

■ NSAID, opioid responsive

■ Responds to procedures

■ Classic examples■ Acute pain due to

injury■ Osteoarthritis■ Rheumatoid arthritis■ Cancer pain

Peripheral Neuropathic

■ Damage or dysfunction of peripheral nerves

■ Responds to both peripheral (NSAIDs, opioids, Na channel blockers) and central (TCA’s, neuroactive compounds) pharmacological therapy

■ Classic examples■ Diabetic neuropathic

pain■ Carpal tunnel■ Sciatica

Centralized Pain

■ Characterized by central disturbance in pain processing (diffuse hyperalgesia/allodynia)

■ Responsive to neuroactive compounds altering levels of neurotransmitters involved in pain transmission

■ Classic examples■ Fibromyalgia■ Irritable bowel

syndrome■ TMJD■ Tension headache

Mixed Pain States

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Role of Cannabinoids in Pain Management

■Mechanisms of pain

■ Clinical trials in chronic pain

■ Clinical trials in acute pain

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▪ Limited: short length, small sample size, unrepresentative

dosing▪ Most support in neuropathic pain (THC+CBD).

▪ Recent clinical trial suggest that CBD may be useful in nociceptive

pain3 but not centralized pain4

▪ Mismatch with observational studies

1. Stockings, Emily, et al. Pain 159.10 (2018): 1932-1954.. 2. Nugent, Shannon M., et

al. Annals of internal medicine 167.5 (2017): 319-331. 3. Hunter, D., et al. Osteoarthritis

and Cartilage 26 (2018): S26. 4. van de Donk, Tine, et al. Pain (2018).20

Cannabis clinical trials for chronic pain

Cannabis and Cannabinoids

■ Definitions and Background

■ Overview of Risks and Benefits of Cannabinoids

■ Role in Pain Management

■Summary

21

Summary

■ Cannabinoids and chronic pain: plausibility for therapeutic value at right dose and in right person

■ Be mindful of dose, cannabinoid content, and administration routes

■ Since little or no efficacy of opioids in chronic pain,1

consider using cannabinoids before opioids.

■ If planning to use cannabis/cannabinoids:2

■ “Start low, go slow”

■ Use verifiable source with credible third party testing

■ Minimize harm by avoiding smoking

221. Dowell, Deborah, Tamara M. Haegerich, and Roger Chou. Jama 315.15 (2016): 1624-1645. 2.

MacCallum, Caroline A., and Ethan B. Russo. European journal of internal medicine (2018).

Questions?

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