1. Medicinal Cannabis and Chronic Pain
Science-Based Education in Times of Legalization
Vivian Moise, MD
St. Luke’s Rehabilitation Institute
Spokane, WA

2. Based on education and slides provided by Dr. Greg Carter, MD

3. Disclosure statement
I do not have any financial relationships or affiliations that may have a direct bearing on the subject matter in this medical education activity

4. Overview Historical Background Endocannabinoid System
Pharmacologic effects of cannabinoids
Risks and benefits of medicinal use of cannabis
Clinical Applications in Chronic Pain

5. History in the USA
Hemp, a low THC variety of cannabis, is an important agricultural crop that has been cultivated for fiber, rope, clothing, seeds for oil and fuel.
Hemp was grown in China starting 6000 years ago, and in Europe for at least 700 years
<0.3% THC
>15% THC

6. History in the USA
Cannabis based medications were produced by Eli-Lilly, Parke Davis, and Sharp Dohme (now Merck Sharp Dohme).
Prescribed by physicians in the United States

7. Historical Perspective
Use of cannabis under increasing scrutiny by Federal Bureau of Narcotics (FBN).
The Marijuana Tax Act made possession or transfer of cannabis illegal throughout the United States under federal law.
The American Medical Association (AMA) opposed the act
All use of cannabis was criminalized in the United States; changed to schedule 1 drug, like heroin!

8. Turning Point: Discovery of Endocannabinoid System

9. Turning Point: Discovery of Endocannabinoid System
Intricately involved in normal human physiology.
Cannabinoid receptors are found in the brain and peripheral tissues – nerves, gut, immune cells.
Within brain, dense receptor concentration in the cerebellum, basal ganglia, and hippocampus.
Only few cannabinoid receptors in the respiratory areas in brainstem (so does not suppress respiration).

10. The Endocannabinoid Receptors
The CB1 and CB2 receptors consists of 7 transmembrane helices.
Courtesy of Patricia Reggio, PhD

11. The endocannabinoids Endogenous molecules in the human body
Anandamide
2-Arachidonoyl-glycerol
Endogenous molecules in the human body
Phospholipid-derived metabolites of the fatty acid arachidonic acid
Bind to and activate cannabinoid receptors.

12. Cannabinoid Receptors
Receptors are coupled to G-protein in cell membrane
CB1 receptors highly expressed in the brain
CB1 receptors also found in adipose tissue, liver, muscle, the GI tract, pancreas, and reproductive and cardiovascular tissue.
CB2 receptors are expressed primarily in immune cells
CB2 receptors may also be in neurons

13. Physiological Effects of Endocannabinoids
Endocannabinoids are often produced as an adaptive response to cellular stress, aimed at re-establishing cell homeostasis, with primarily neurologic and immune functions.

14. Examples of Physiological Effects of Endocannabinoids:
Inflammation
Tissue injury
Decrease cytokines
Decrease T-cell migration
Release of
endocannabinoids
Sympathetic nervous system activation (stress)
Release of stress glucocorticoids (cortisol)
Effect on brain to
improve mood, reduce anxiety
(help cope with stress)

15. The Endocannabinoid System
Neurologic effects of the endocannabinoids via CB1 receptors:
Effects pain perception
Effects appetite and gut motility
Effects mood
Effects sleep
Effects muscle coordination
Effects learning and memory
Non-neurologic effects of the endocannabinoids via CB1 receptors:
Modulates energy and metabolism
Modulates reproduction
Modulates bone formation
Modulates cardiovascular function
Immune effects via CB2 receptors:
Activation of GTPases in macrophages, neutrophils, and B/T cells.
Regulates migration of B cells
Maintains healthy IgM levels.
Suppresses inflammation

16. Endocannabinoids operate by Retrograde Neurotransmission
Classical neurotransmitter
Retrograde neurotransmitter
Presynaptic
Presynaptic
Postsynaptic
Endogenous cannabinoids are released from depolarized POST synaptic neurons and act retrograde on the presynaptic cannabinoid receptors to suppress neurotransmitter release
Postsynaptic

17. Cannabis plant: contains more than 60 cannabinoids that bind to cannabinoid receptors; most common are:
Tetrahydrocannabinol (THC) – mind altering properties, appetite stimulant
Cannabidiol (CBD): analgesia; anti-spasticity, moderates effects of THC.
Cannabinol (CBN): anticonvulsant.

18. Animal Research on pain
Cannabinoids have suppressed neuropathic nociception in 9 different animal models:
Chronic constriction injury: infraorbital nerve, saphenous nerve
Partial nerve ligation: sciatic, saphenous
Spinal nerve ligation: L5
Spared nerve injury
Spinal cord injury
Tibial nerve injury
Streptozotocin-induced diabetic neuropathy
Rahn EJ and Hohmann AG. Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside. Neurotherapeutics 2009; 7(4):

19. Animal Research on pain
Cannabinoid Suppression of Neuropathic Pain
Cannabis administered at non-psychoactive doses in cisplatin-treated rats alleviated mechanical allodynia.
This effect was proven to be mediated by both CB1 and CB2 cannabinoid receptors.
Vera G, Cabezos PA, Martín MI, Abalo R. Characterization of cannabinoid-induced relief of neuropathic pain in a rat model of cisplatin-induced neuropathy. Pharmacol Biochem Behav 2013; 105:

20. Human Research on pain
The discovery of the human endocannabinoid system has stirred research interest from medical field, but there are obstacles:
No pharmaceutical company funding
Laws making cannabis a schedule 1 dangerous drug (like heroin)

21. History of Human Research
COMPARED TO PHARMA - Studies are small, imperfectly controlled, use smoked cannabis, limited by regulations (National Institute on Drug Abuse--NIDA budgets of $500,000 versus millions in industry trials).
Feds require using Mississippi cannabis of poor composition and irregular bioavailability. Delivered as cigarettes.

22. EBM Class One Human Clinical Trials (randomized controlled trials)
Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, Kelly ME, Rowbotham MC, Petersen KL. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology 2007; 68(7):
Ellis RJ, Toperoff W, Vaida F, van den Brande G, Gonzales J, Gouaux B, Bentley H, Atkinson JH. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology 2009;34(3):
Rog DJ, Nurmikko TJ, Friede T, Young CA. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 2005; 65(6):812-9.

23. More EBM Class One Clinical Trials of Humans
Wallace et al Dose-dependent effects of smoked cannabis on Capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology 107:
Wilsey et al A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. Journal of Pain 9:
Ware et al Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ 182:
Johnson et al Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety and tolerability of THC: CBD extract in patients with intractable cancer-related pain. Journal of Symptom Management 39:

24. Well Done EBM Class 1 Study Example
Abrams DI, Rowbotham MC, Petersen KL, et al.
Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology 2007; 68(7):
Prospective, randomized control trial
Smoked cannabis cigarettes vs. identical placebo cigarettes with cannabinoids estracted, 3x/day for 5 days
Heat and capsaicin-induced sensitivity were assessed as a measure of skin hyperalgesic effects
50 patients completed the trial
Pain was reduced by average 34% in cannabis group vs. 17% in placebo group
Of responders, a marked reduction of pain was found in 52% of cannabis responders vs. 24% in placebo responders
No serious adverse effects were reported
Success % was similar to oral medications for neuropathic pain

25. Well Done EBM Class 1 Study Example
Abrams DI, Rowbotham MC, Petersen KL, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology 2007; 68(7):

26. Published Reviews of Human Data
Phillips TJ, Cherry CL, Cox S, Marshall SJ, Rice AS. Pharmacological treatment of painful HIV-associated sensory neuropathy: a systematic review and meta-analysis of randomised controlled trials. PLoS One 2010; 28;5(12):e14433.
Martín-Sánchez E, Furukawa TA, Taylor J, Martin JL. Systematic review and meta-analysis of cannabis treatment for chronic pain. Pain Med 2009; 10(8):
Campbell FA, Tramèr MR, Carroll D, Reynolds DJ, Moore RA, McQuay HJ. Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. BMJ 2001; 323(7303):13-6.
Machado Rocha FC, Stéfano SC, De Cássia Haiek R, Rosa Oliveira LM, Da Silveira DX. Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis. Eur J Cancer Care 2008;17(5):

27. One Excellent Review of Human Research
Lynch ME, Campbell F. Cannabinoids for Treatment of Chronic Non-Cancer Pain; a Systematic Review of Randomized Trials. Br J Clin Pharmacol (5): PMID:
Systematic review of randomized controlled trials for cannabis treating chronic non-cancer pain: neuropathic pain, fibromyalgia, rheumatoid arthritis, and mixed chronic pain.
Quality of trials = excellent.
15 of the 18 trials showed significant analgesic effect of cannabis.
No serious adverse effects; only a few withdrawals from the studies.
Overall evidence indicates that cannabinoids are safe and effective.

28. So How Does All This Work in Real Life Clinical Medicine?
Methods of use
Dosing paradigms
Side effects
Drug interactions
Patient instructions
What clinicians should know

29. Methods of Use DO NOT SMOKE Use vaporizer for fast effect.
Long term smoking of cannabis has been linked to risk of lung cancer (per National Institute of Health publication)
Use vaporizer for fast effect.
Oral or sublingual tincture ingestion for longer effect.
Topical for local effect.

30. Vaporization of Cannabis
Safe alternative to smoking
$30 to $90

31. How Do Vaporizers Work?
When cannabinoids are heated to between 285 °F (140 °C) and 392 °F (200 °C) they boil and vaporize – “e-cigarette.”
Studies show that vaporization is most effective at around 338 °F (170 °C).
A vaporization temperature over 392 °F (200 °C) will burn the cannabis, creating unwanted smoke.

32. Other Ways to Use Medicinal Cannabis?
Ingestion & sublingual drops? Takes about an hour to get effects so harder to dose but lasts longer.
Transdermal? Yes! Works well as a liniment.
Injectable: No.

33. Dosage & Type for pain treatment
Medical benefit for pain or spasticity comes primarily from CBD; the “high” comes from THC, so use cannabis that has high amount CBD and low amount THC
Dispensary staff can advise on CBD vs. THC content in each variety sold.
Patient should use high quality cannabis to improve efficacy
All cultivated varieties of marijuana have some THC in it

34. Dosing Paradigms Self titration - START LOW; GO SLOW.
2-3 inhalations (vaporizer), stop, wait ten minutes.
2-3 sublingual drops, stop, wait 1 hour.
Do not need to be high to get pain relief.

35. Side Effects Disinhibition, relaxation, drowsiness
Feeling of well being, exhilaration, euphoria
Sensory - perceptual changes
Impairment in memory, confusion
Paranoia, agitation
Balance/stability impaired
Decreased muscle strength, small tremor
Slowed reaction times, impaired complex motor tasks

36. Effects on Behavior
Don’t dose and Drive!

37. Side Effects
Recent studies show chronic recreational cannabis users have a higher risk of ischemic stroke
study did not prove causation
study did not screen for use of other drugs, like cocaine, meth or opioids that might have also been used and been the causative agent

38. Drug interactions
Cannabis may increase the sedating effects of drugs that cause drowsiness, including
Antidepressants
Alcohol
Antihistamines
Sleeping pills
Anti-anxiety pills (benzodiazepines)
Seizure medications
Muscle relaxers
Opioid pain medication

39. Clinical Pearl – Know This (and advise patients)
Safe, no overdose death risk
Well tolerated
No constipation
No respiratory suppression
Relieves pain, improves sleep
Decreases need for opioids
Works synergistically with opioids
Adverse effects are reversible & short lived (3-4 hours max)
Serious adverse effects NOT seen in chronic users.

40. Indications for Medicinal Cannabis
Severe, chronic pain (neuropathic or musculoskeletal)
Muscle spasms, spasticity
Cancer
Glaucoma
HIV/AIDS
Seizures (oral “Realm” oil, for children w/ severe intractable seizures, from plant strain w/ very low THC, high CBD, CBN content)
Severe nausea
Cachexia, anorexia, severe weight loss with muscle wasting/atrophy

41. Myths about medicinal cannabis
Pure CBD is available at marijuana dispensaries
False! All marijuana plants and formulations contain some THC
High CBD cannabis cannot cause side effects or make a person “high”
False! Even the small amount of THC in the high CBD varieties of cannabis may cause mild CNS effects, especially in new users.
If the person does not feel “high” at all, the pain medicine is not working
False! Like opiates, patients can get good pain relief or anti-spasm effects without feeling high at all

42. Myths about medicinal cannabis
Cannabis is not addictive.
Definitely less addictive than opioids, but…
There may be a risk for psychological addiction.
Tolerance is not common, but may develop in heavy, long term users who may need increase to higher doses.
Abrupt cessation may cause rebound hyperalgesia
No one has ever died from cannabis
An 11 month old baby died from myocarditis with high blood levels of THC and nothing else to explain the heart disease. THC was not proven to be the cause of death. (Keep cannabis away from young children!)

43. More – Working with Patients
Consider screening the patient for drug abuse risk--use any of the opioid screening tools (e.g. ORT, SOAPP, etc).
If the patient is legit, try the standard non-opioid drugs first: Anti-epileptic drugs, SSRIs, SNRIs, TCAs, NSAIDs.
If the standard first line meds do not work--then consider CANNABIS before OPIOIDS.
Starting patient on opioids poses much higher risk for dependency and dose escalation.
If patient already on opioids, then use cannabis to lower their dose of opioids (and other meds).

44. Working with Patients - Why Cannabis?
It works, Not many drug-drug interactions.
Side effects mild; low toxicity, NO LD50.
Cannabis has other potential benefits: reduces inflammation, neuroprotective, anti-tumor properties.
You still need to monitor the patient! Include duration on all cannabis Rx’s (max 1 year).
Patients may still ask you for opioids…but not all will, and you have leverage—keep opioid doses low if giving concurrent cannabis

45. Working with patients
If you choose to recommend medicinal cannabis. . .
FOLLOW STATE LAW
Since recreational cannabis is legal in WA state, why does a patient need a Rx?
They get a significant cost discount with a Rx for medicinal cannabis

46. Working with patients

47. Working with patients: Federal law
2009—Obama administration sent a memo to federal prosecutors encouraging them not to prosecute people who distribute marijuana for medical purposes in accordance with state law
2013—US Department of Justice updated it’s marijuana enforcement policy stating it expects states who have legalized marijuana to create state-based enforcement efforts and the federal DOJ would NOT challenge state’s legalization laws
2018—Attorney General Sessions issued a memorandum that rescinded the above 2013 memorandum and allows federal prosecutors to decide how to prioritize enforcement of federal marijuana laws and to “weigh all relevant considerations, including federal law enforcement priorities set by the Attorney General, the seriousness of the crime, the deterrent effect of criminal prosecution, and the cumulative impact of particular crimes on the community.”

48. Negatives with use of Cannabis
For the patient: Social stigma associated with purchasing or growing marijuana
For the patient: Private pay (no insurance coverage)—a month supply can cost $75-100
Chronic drug abusers may request Rx as a legal way to get high

49. What About Dronabinol (Marinol®)?
100% THC in pure form (anti-nausea, appetite stimulant and mind altering effects)
Indications include chemo-related N&V and AIDS-associated anorexia and weight loss
Is a schedule 3 drug (vs. natural cannabis that has 3-15% THC and is schedule 1, = dangerous with no medical use)
Do not recommend Dronabinol for pain or muscle spasms

50. Sativex? Step in Right Direction!
Prescription cannabis available in 15 countries (not yet in US) for the treatment of spasticity from MS
1:1 combination from two clonal cannabis cultivars yielding a high THC extract (Tetranabinex®) and a high CBD (Cannabidiol) extract (Nabidiolex®).
Each 100 μL pump-action oral spray provides 2.7mg of THC and 2.5mg of CBD
Intermediate onset: minutes
Allows dose titration

51. Epidiolex: First FDA approved pure CBD drug in the U.S
Liquid medication
Indicated only for severe childhood onset forms of epilepsy: Lennox-Gastaut syndrome and Dravet syndrome

52. www.leafly.com Finding a dispensary Can look up strains by diagnosis
Can find dispensaries in your area

53. Writing a prescription
Use the WA state form:
Print on tamper-resistant paper with WA state logo

54. Sample Prescription
Rx Medicinal Cannabis (high CBD, low THC content) 2 to 3 vaporized inhalations as needed for pain Quantity: QS (refill for 1 year)

55. Sample Prescription
Rx Medicinal Cannabis (high CBD, low THC content) Sublingual tincture 2 to 3 drops under tongue as needed for pain Quantity: QS (refill for 1 year)

56. The End