Ari C. Greis, D.O.Clinical Assistant ProfessorDepartment of Rehabilitation Medicine, Sydney Kimmel Medical College at TJUSenior Fellow, Institute of Emerging Health Professions Director, Medical Cannabis Department at Rothman Orthopedic Institute

Recommending Cannabis for

the Treatment of Pain

Disclosures

• I have no relevant financial relationships

Objectives

• Describe the chemical constituents of Cannabis and how they interact with the endocannabinoid system• Discern medically appropriate Cannabis products• Learn how to recommend Cannabis to a variety of patients• Evaluate the scientific evidence on Cannabis for pain as an

alternative to opioids

33 legal medical marijuana states plus D.C.11 legal recreational marijuana states plus D.C.

Legalization of Medical Cannabis

2014 2016

The CDC updated its recommendations in the spring of 2016, stating that most cases of chronic pain should be treated with non-opioids

Marijuana Hemp

Cannabinoids

Cannabis Sativa

Sativa vs Indica vs Hybrid “Effects”

Phytocannabinoids

• Tetrahydrocannabinol (THC)• Can be intoxicating • Altered perception of time• Decreased short term memory• Increases appetite• Potentially neuroprotective• Pain relieving

• Cannabidiol (CBD)• Non-intoxicating• Involved in neuromodulation• Anti-inflammatory, anti-

convulsant, antioxidant, and anxiolytic properties

Also many pharmacologically active terpenoids and flavonoids

Cannabinol (CBN), Cannabichromene (CBC), Cannabigerol (CBG), Cannabivarin (CBV)

Cannabis is a Constellations of Compounds With Different Therapeutic Actions

Endogenous Cannabinoid vs Opioid System

Cannabinoid• Cannabinoid receptors• CB1 – mostly CNS• CB2 – mostly immune cells, glia

• Endocannabinoids • Anandamide• 2-Arachidonoylglycerol (2-AG)

Opioid• Opioid receptors• Delta, Kappa, Mu

• Endogenous peptides• Endorphins• Dynorphins• Endomorphins• Enkephalins

The Endocannabinoid System

• Known physiological functions:• Analgesia• Stress modulation• Appetite regulation• Energy balance and metabolism• Memory• Immune suppression• Bone remodeling

Analgesic mechanismsTHC

• CB1 partial agonism• Local anti-inflammation• Descending pain modulation

• systemic administration• requires decarboxylation

THCa 🔥 Δ9-THC

CBD, THCa, minor cannabinoids & terpenes

• Potential for synergy• Anti-inflammation

• COX• Prostaglandin

• Many sites of action (CB2+)• Potentiation (additive, synergy)

Russo, 2011, Wilson-Poe, 2013

Cannabis Routes of Delivery

Vape Illness• Cannabis + Additives, diluents,

flavors, carrier oils• Carcinogens• Mutagens• Cytotoxic degradation products

• Lipoid pneumonia• Harm reduction

• No additives: pure cannabis oil• “Rosin” cartridges• Ceramic coils• Low (variable) voltage batteries

Gotts, J., 2019 Am J Physiol Lung Cell Mol Physiol

Controlled Substance Act of 1970

1985

100% Synthetic THC

Schedule IISchedule III1999

2010

Oromucosal Spray with 1:1 ratio CBD:THC

2018Schedule V

CBD for Rare Forms of Pediatric Epilepsy

Legality and Scheduling of CBD

• Hemp derived

• Marijuana derived• Schedule I• Medical

• Epidiolex• Schedule V

• Now federally legal, state regulated

• Federally illegal in all 50 states• Legal in 46 states

• Federally legal in 50 states

Medically Appropriate Cannabis Products

• Full spectrum extraction• Hemp vs medical cannabis CBD• Lower %/mg of THC combined with CBD• Route of Delivery• Sublingual and/or topical to start• Vaporization prn and/or oral products (edible, pill) once non-

intoxicating dose determined

• TITRATION > dosing. Start low, go slow

• Oral/sublingual

• THC (< 2.5 mg: if already tolerant, 5 mg)

• 1:1 products (equal THC:CBD)

• Add hemp-derived CBD (20-30 mg BID)

• Inhalation – 1-2 small puffs

• low THC (<15%), equal or higher CBD (flower)

• < 50% THC rosin/oil (additive-free)

• Topical THC +/- CBD applied locally

• Daytime: Non-impairing dose 1-3 x day

• Nighttime: Titrate up THC ~1 hour before bed

• Higher dose THC for increased pain & sleep

• Periodic breaks (2 or more days)

• When symptoms improve, attempt to lower dose, increase

breaks

Pain Protocol

Wilson-Poe & Greis, unpublished, MacCallum & Russo 2018

Cannabis and Cannabinoid Research

January 2017

Medical Cannabis Research

• Substantial/conclusive evidence that cannabis improves: • Chronic pain in adults• Nausea and vomiting due to chemotherapy • Patient related symptoms due to muscle spasticity from MS

•Moderate evidence that cannabis improves sleep• Access to cannabis is correlated with reduced opioid

consumption and overdose fatalities

Efficacy of Cannabis for Chronic Pain

•Dried flower = greatest relief• THC potency

•Nabiximols (CAN, UK)• THC+CBD+others

•Dronabinol• Tolerability issues

Stith 2019, MacCallum & Russo 2018, National Academy of Sciences, 2017

Barriers to Accessing Medical Cannabis

• Employment• Urine drug screens• Operating heavy machinery, driving• Federal

• Firearms• Travel• Cost

Safety of CannabisRisks

• Pregnant & breastfeeding• Adolescents• Smoking• May lead to the development of

schizophrenia or other psychoses• Impaired cognition, balance• Cannabis hyperemesis syndrome• Cannabis use disorder (CUD)

Benefits• Limited risk of dependence,

withdrawal, abuse• No GI, Renal, Hepatic, CVS risk• Not associated with cancer• Very few drug interactions with low

dose cannabinoids (CYP inhibition)• Alcohol substitution• Non-lethal

My Experience Recommending Cannabis>2 years, >900 patients

•Why?• Chronic pain practice• Evidence for cannabis in

treating pain• Opioid crisis• Safety profile

• How?• Register with PA DoH

• 4 hour CME course• Internal and external referrals

• Review medical records and PDMP• Get opioid prescribers on board

• Certify patients for access to MMJ• Collect outcome measures

My Experience Recommending Cannabis

• Mostly elderly, LBP, DJD, Neuropathy, Fibromyalgia• Many cannabis naïve• Many seeking to wean off of

opioids• Others with prior benefit

• Many with decreased pain and improved sleep• Very few side effects with low

dose THC combined with CBD• Preferred dosage and route of

delivery varies greatly

The Process

• Patients register w/ DoH• Get certified• Purchase MMJ ID card• Shop at an approved

dispensary• Follow up with doctor

•MMJ visit• Informed consent• Outcome measures• Online certification• Discuss active ingredients, delivery

methods, ways to minimize chance of intoxication/side effects

• Review a local dispensary menu• Make product recommendations

MMJ Patient Outcome Measures

• Low back pain• Neck pain• Knee pain• Shoulder pain• Hip pain• Neuropathy

• ODI, PROMIS, VAS, IMCU• NDI, PROMIS, VAS, IMCU• KOOS Jr, PROMIS, IMCU• ASES/SANE/SST, PROMIS, IMCU• HOOS Jr, POMIS, IMCU• PROMIS, IMCU

Demographics

• Low Back pain = 255 patients • Age range 20-94, average 62, median 64• 97 females, 86 males, 7 not recorded

• Neck pain = 63 patients • Age range 26-79, average 55, median 56

• Other pain = 150 patients (knee, hip, shoulder, neuropathy, fibromyalgia)• Age range 18-97, average 62, median 64

MMJ Follow Up

• 3 months• Outcome measures• Inventory of medical

cannabis use (IMCU)• Review products• Make additional

recommendations

• Anecdotes:• I’m sleeping better than ever• I feel more relaxed, happy• I am drinking less alcohol• I can deal with my pain better• I am taking less pharmaceuticals

Medical Cannabis Products in PA

• 195 THC products, 36 with CBD on a local menu• Vaporization: 68 flower, 65 cannabis oil• Concentrates: 36• Sublingual tinctures: 12 (7 with CBD)• Capsules: 12 (9 with CBD)• Topicals: 2

• Prices range from $8-120 (most $40-50)

What about getting high? Impaired?

• You can get high from medical cannabis!• You can get too high = intoxicated = impaired• You can also get “a little” high• Euphoria, happy…• Relaxed, sedated• Less anxious• Change in perspective, sensations

What about getting high? Impaired?

146 157

FEEL IN G OF HIGH OR INTOXICATIO N

NO FEEL IN G OF HIGH OR INTOXICATIO N

NUM

BER

OF P

ATIE

NTS

INTOXICATION AFTER USE OF MEDICAL CANNABIS

125

32

85

38

23

FEEL IN G OF HIGH OR INTOXICATIO N

NO FEEL IN G OF HIGH OR INTOXICATIO N

NUM

BER

OF P

ATIE

NTS

INTOXICATION AFTER USE OF MEDICAL CANNABIS

Did not like it

Enjoyed it

Did not interfere with daily activities

No symptom relief

Symptom relief

Low Back Pain Outcomes

6.85

5.324.84 4.89

0

1

2

3

4

5

6

7

8

1

Low Back Pain (VAS)

Series1 Series2 Series3 Series4

7.06

5.585.32 5.44

0

1

2

3

4

5

6

7

8

1

Back Pain Intensity

Series1 Series2 Series3 Series4

7.58

6.235.90 5.69

0

1

2

3

4

5

6

7

8

1

Back Pain Frequency

Series1 Series2 Series3 Series4

Baseline255

3 mos213

6 mos119

1 year85

Neck Pain Outcomes

Baseline63

3 mos53

6 mos36

1 year25

47.27

36.34 35.61 34.40

0

10

20

30

40

50

1

NDI

Series1 Series2 Series3 Series4

6.34

4.40 4.75 4.50

012345678

1

Neck Pain (VAS)

Series1 Series2 Series3 Series4

6.56

4.655.15 4.83

012345678

1

Neck Pain Intensity

Series1 Series2 Series3 Series4

7.24

5.61 5.76 6.00

012345678

1

Neck Pain Frequency

Series1 Series2 Series3 Series4

Controlled Substance Use OutcomesOpioids (N=231)

Patients on Opioids at time of certification

Still on Opioids at 6 months after certification

Discontinued Opioids at 6 months after certification

Patients on <20 MME at time of certification

Still on Opioids 6 months after certification

Discontinued Opioids 6 months after certification

38%62% 46% 54%

Controlled Substance Use OutcomesBenzodiazapines (N= 129)

Patiens on Benzos at time of certification

Still on benzos 6 months after certification Discontinued benzos 6 months after certification

35%

65%

Cannabis vs Opioidsfor Pain

• Better for chronic than acute• Less side effects• Less risk of dependence• Mild withdrawal symptoms• Nonlethal

• Better for acute than chronic• Frequent side effects• High risk of dependence• Significant withdrawal symptoms• Potential for overdose

and death

The Present

• Potential • Exciting basic science evidence• Growing clinical evidence• Enticing anecdotal evidence• Wide range of target and

treatment options• Appears to be safe• Non-intoxicating options

• Questions• What are the best:

• Indications• Cannabinoids, terpenes• Dosages• Delivery methods

• Challenges• Need large well designed controlled

human clinical trials• Current regulatory landscape

Conclusions

• Cannabis contains a number of chemicals that affect human physiology by interacting with the endocannabinoid system • Medically appropriate Cannabis products are not smoked, contain low

dose THC, and are usually combined with CBD• Proper Cannabis recommendations involve finding the best routes of

delivery and THC dosage for a given patient• Cannabis is safer and may be more effective than opioids for certain

types of chronic pain• Cannabis is an alternative to other controlled substances

References• The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. National Academies of Sciences, Engineering, and Medicine.

2017. Washington, D.C.: The National Academies Press.

• Luvone T et al. Cannabidiol: A promising Drug for Neurodegenerative Disorders? 2009. CNS Neuroscience & Therapeutics, 15:65-75.

• Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999-2010. JAMA Intern Med. 2014;174(10):1668-73.

• Lu HC and Mackie K. An introduction to the endogenous cannabinoid system. Biol Psychiatry. 2016 April 1; 79(7): 516–525.

• Malfait et al. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. PNAS, August 15, 2000, vol. 97, no. 17, pp 9561-9566.

• Reiman et al. Cannabis as a substitute for prescription drugs- a cross-sectional study. Journal of Pain Research. 2017:10 989-998.

• Boehnke et al. Medical Cannabis Use is Associated With Decreased Opiate Medication Use in a Retrospective Cross-Sectional Survey of Patients With Chronic Pain. The Journal of Pain. Vol 17, No 6 (June)2016: pp 739-744.

• Ennis ZN et al. Acetaminophen for Chronic Pain: A Systematic Review on Efficacy. Basic & Clinical Pharmacology & Toxicology, 2016, 118, 184-189.

• Ong C et al. An Evidence-Based Update on Nonsteroidal Anti-Inflammatory Drugs. Clin Med Res. 2007 Mar; 5(1): 19-34.

• MaIzels, M, McCarberg B. Antidepressants and Antiepileptic Drugs for Chronic Non-Cancer Pain. American Family Physicians. Vol 71, No 3, Feb 2005.

• Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United States, 2010. JAMA 2013;309:657-659

• Whiting et al. Cannabinoids for Medical Use A Systematic Review and Meta-analysis. JAMA. 2015;313(24):2456-2473. doi:10.1001/jama.2015.6358

• Gotts, J., High-power vaping injures the human lung. Am J Physiol Lung Cell Mol Physiol, May 1, 2019;316(5):L703-L704