The Use of to Treat Pain Kevin F. Boehnke, PhD Research Investigator Anesthesiology Department, Chronic Pain and Fatigue Research Center The 1 Disclosures ■None

2 Medical in US

SCHEDULE 1

https://medicalmarijuana.procon.org/view.resource.php?resourceID3 =000881 4 Boehnke, Kevin F., et al. "Qualifying Conditions Of License Holders In The United 5 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

1: 2018 Medical Marihuana Act Statistical Report, Michigan 6 7 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)

https://medlineplus.gov/magazine/issues/spring11/ima ■Cross-sectional6-8 and ges/acetamenophen%20and%20codeine.jpg longitudinal support9-11

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 Research (2017). 9. Haroutounian et al,. Clinical Journal8 of Pain (2016). 10. Stith et al, PLOSone (2017) 11. Abuhasira et al, European Journal of Internal Medicine, (2018) Cannabis and Cannabinoids

■ Definitions and Background

■ Overview of Cannabinoid Risks

■ Role in Pain Management

■ Summary

9 Endocannabinoid system A 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

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 Cannabis-derived cannabinoids >100 known

■ (THC) ■ Analgesic, mood-altering, appetite stimulating ■ Partial agonist of CB1 and CB2

By Indirectantagonist - Own work, CC BY-SA 3.0, ■ (CBD) https://commons.wikimedia.org/w/index.php?curid=18534238 ■ Does not bind with significant affinity to CB receptors ■ Non-intoxicating, potentially protective against psychoactive effects of THC ■ Anti-inflammatory, anti-convulsant1

By Cannabis Training University - Own work, CC BY-SA 3.0, ■ Other cannabinoids: CBN, CBG, CBC, https://commons.wikimedia.org/w/index.php?curid=21152729 etc. –The “Entourage Effect”2

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

Agurell, Stig, et al. Pharmacological Reviews 38.1 (1986): 21-43. 12 U-Shaped Curve for cannabis effects Effects

Dose

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. 13 Cannabis and Cannabinoids

■ Definitions and Background

■ Overview of Cannabinoid Risks

■ Role in Pain management

■ Summary

14 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

http://arts.bio/en/products/budrot-mildew Acute: rust-control

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

■ Uncommon: Vomiting, hallucinations, paranoia, seizures

■ Uncertain quality of herbal preparation4

■ Vehicle accidents

http://www.clker.com/cliparts/6/4/b/1/13234884051988079243joint-hi.png 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, 15 engineering, and medicine. Health and cannabinoids (2017). Cannabis and Cannabinoids

■ Definitions and Background

■ Overview of Risks and Benefits of Cannabinoids

■ Role in Pain management

■ Summary

16 Role of Cannabinoids in Pain Management

■Mechanisms of pain

■Clinical trials in chronic pain

■Clinical trials in acute pain

17 Mechanistic Characterization of Pain Any combination may be present in a given individual Peripheral Peripheral Neuropathic Centralized Pain (nociceptive)

■ Inflammation or ■ Damage or dysfunction ■ Characterized by central mechanical damage of peripheral nerves disturbance in pain in tissues processing (diffuse ■ Responds to both hyperalgesia/allodynia) ■ NSAID, opioid peripheral (NSAIDs, responsive opioids, Na channel ■ Responsive to blockers) and central neuroactive compounds ■ Responds to (TCA’s, neuroactive altering levels of procedures compounds) neurotransmitters pharmacological involved in pain therapy transmission ■ Classic examples ■ Classic examples ■ Classic examples ■ Acute pain due to ■ Diabetic neuropathic ■ Fibromyalgia injury pain ■ Irritable bowel ■ Osteoarthritis Mixed■ Carpal Pain tunnel States syndrome ■ Rheumatoid arthritis ■ Sciatica ■ TMJD ■ Cancer pain ■ Tension headache 18 Role of Cannabinoids in Pain Management

■Mechanisms of pain

■ Clinical trials in chronic pain

■ Clinical trials in acute pain

19 Cannabis clinical trials for chronic pain

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

1. Dowell, Deborah, Tamara M. Haegerich, and Roger Chou. Jama 315.15 (2016): 1624-1645. 2. 22 MacCallum, Caroline A., and Ethan B. Russo. European journal of internal medicine (2018). Questions?

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