The Role of Cannabis in the management of pain.

1. Cannabis:
Smoldering Considerations in
Chronic Pain Management
Title Art courtesy of: psychologytoday.com, Cartwright M “Food for Thought” Jan 8, 2014
Traci Hamer, PharmD
Pain Management Pharmacist
Kaiser Permanente Northwest

2. Burning questions…
Measure 91 vs
Medical
Marijuana?
Is it legal?
Is it
beneficial?
SAFE?
How does it
work?
Drug
interactions?
Monitor?
How to quit
using?
How do I talk to patients about
it?

3. http://www.dea.gov/resource-center/dir-ndta-unclass.pdf
First Specific Drug Associated with Initiation of Illicit Drug Use
Among Past Year Illicit Drug Initiates Aged 12 or Older 2012

4. Monitoring the Future:
Use, Perceived Harm, & Availability by
Youth
Monitoring the Future study, 2015 data, University of Michigan
~36% of 12th graders have used in the last year
(~25% 10th grade, ~15% 8th grade)
~32% of 12th graders view as “great risk”
(~43% 10th grade, ~58% 8th grade)
~80% of 12th graders say it is easy to acquire
(65% 10th grade, ~38% 8th grade)

5. Drug-Related ED Visits
National Drug Control Strategy: Data Supplement 2014
Available online: https://www.whitehouse.gov/sites/default/files/ondcp/policy-and-
research/ndcs_data_supplement_2014.pdf
See also references 24-30
Drug associated with ED visit 2011
Alcohol with drugs 606,653
Cocaine 505,224
Anti-anxiety/ insomnia meds 501,207
Cannabinoids
marijuana
synthetic
479,560
455,668
28,531
Opioids 420,040
Heroin 258,482
Methamphetamine 102,961

6. marijuana edibles
sinsemilla elixirs
hash oil cannabidiol oil
honey butane oil etc
Cannabis

7. Consideration #1:
Cannabis is “legal” in Oregon and Washington for
medical and recreational use, but federally is still a
Schedule I Controlled Substance.

8. Medical vs. Recreational
Medical Recreational
Registry ID card Yes (OR and WA) No; must be 21+ yo
Allowed to grow Yes (OR and WA) OR: up to 4 plants
WA: No
Limit to
possession
OR: 24 oz
useable MJ, 6
mature plants,
or up to 18
seedlings/ starts
WA: 24 oz
useable MJ, 15
plants, or
participate in
collective garden
OR: 8 oz of MJ, but no more
than 1 oz in public; 1 lb
edibles; 72 oz infused liquids;
1 oz extract. Cannot be used
in public or while driving.
WA: 1 oz useable MJ, 16 oz
MJ-infused product in solid
form, 72 oz of MJ-infused
product in liquid form, or 7
grams concentrate
Taxation No Yes

9. Consideration #2:
Cannabis has existed for >3000 years…
and yet we still lack high quality data for the
efficacy of any of its components for any medical
indication.
See also references 1-4

10. Medical Marijuana Indications
(Oregon and Washington*)
Supporting Evidence(1)
Malignant neoplasm
-chemotherapy-induced N/V Low quality data. Mixed results, effective.
-loss of appetite Low quality data. Megestrol superior.
Glaucoma Insufficient data. Other tx options superior.
HIV or AIDS
-loss of appetite
Low quality data; favors efficacy.
Agitation d/t Alzheimer Disease Insufficient data.
PTSD Insufficient data.
Medical condition that produces:
-cachexia Low quality data. Mixed results.
-severe pain Low to moderate quality. Mixed results.
-severe nausea Low quality data. Mixed results. PONV favors
efficacy; operative N/V ineffective.
-seizures (+/- epilepsy) Insufficient data. (CBD studies in progress.)
-persistent muscle spasms (+/- MS) Low to moderate quality data. Inconclusive.
*Crohn’s disease, hepatitis C, renal failure
requiring hemodialysis, traumatic brain injury
Insufficient data.

11. Summary of Randomized Controlled Trials for Pain
 cannabis: 0 RCT for chronic pain, 3 for neuropathic pain
 nabilone/dronabinol/nabiximols: 6 RCT for chronic pain, 2
for neuropathic pain
 n = 13-63
 duration: 2-15 weeks
 “low” to “moderate” quality data
Whiting PF et al. Cannabinoids for Medical Use: A Systematic
Review and Meta-analysis. JAMA. 2015; 313(24):2456-2473.
Hill KP. Medical Marijuana for Treatment of Chronic Pain and Other
Medical and Psychiatric Problems: A Clinical Review. JAMA.
2015;313(24):2474-2483.

12. Since then…
 Prospective cohort study, chronic non-cancer pain
 Primary endpoint: adverse effects
 Secondary endpoints: neurocognition, pulmonary function, efficacy, labs
 Limitations:
 Powered for n = 350. Starting n = 215. Finishing n = 138.
 Study and control groups not matched for age, gender, disability, tobacco,
alcohol, opioids, antidepressants, anticonvulsants, etc.
 High drop out rate (30%)
 Dose ranged 0.1-13.4 grams/day despite regulated product (11-14% THC)
 Inconsistent mechanism of consumption
 Didn’t administer all screening to all pts
Ware MA, et al. Cannabis for the Management of Pain: Assessment of Safety
Study (COMPASS). The Journal of Pain. 2015;15(12):1233-1242.

13. COMPASS: Pain Results
Changes in pain intensity over 1 yr for those w/ all 7 data points (n = 145 (study) and 157 (control)).
VAS = visual analog scale
Ware MA, et al. Cannabis for the Management of Pain: Assessment of Safety Study (COMPASS). The Journal of Pain. 2015;15(12):1233-1242.

14. Absence of Quality Evidence
 Few randomized controlled trials
 Poor study design
 Small n
 Short duration
 Difficult to blind
 Wide range of products, doses, routes of administration
 Poor tolerability, high drop out rates

15. “A gullible Googler could easily believe
we’re on the brink of a miracle cure.”
-Hampton Sides
National Geographic June 2015, Vol. 227, No. 6

16. Consideration #3:
The composition of cannabis varies depending upon
species, subspecies, growth manipulations,
exposure to heat, light, air, etc.
In general, cannabis contains hundreds of
pharmacologic entities.
See also references 5-8

17. Cannabis: A Chemical Stew
*even more when consider active metabolites and
variation with subspecies, growth manipulations, etc*
Cannabis
~480 pharmacologic entities
Cannabinoids
(~66-100)
Non-
cannabinoid
psychoactive
components
(~20-40+)
Other
(hundreds)
Combustion
~2000 chemicals

18. 3 Cannabinoids Hitting the News
√ = has some effect
√ ≠good at it
THC
(delta-9-
tetrahydro-
cannabinol)
CBD
(cannabidiol)
CBN
(cannabinol)
Psychoactive √ (√)
Anti-emetic √
Appetite
stimulant
√
Analgesic √ √
Anti-
inflammatory
√ √
Anti-seizure √ √
Anti-spasmodic √
Neuroprotective √

19. Consideration #4:
Cannabis has existed for >3000 years…
and yet we still don’t fully understand how it works
or everything it does.
How does it work?
See also references 5, 7, 9

20. Picture: Nature Reviews Cancer 3, 745-755 (October 2003)
CB1 and CB2: presynaptic receptors
Depending on site, inhibit neurotransmitter release
(GABA, glutamate, 5HT, DA, ACh)
?
Endocannabinoid System

21. Sites of Action
*affects nearly every major organ system*
As-of yet unidentified receptors?
Activity on non-cannabinoid receptors?
CB2:
Immune cells (T cells, B cells,
monocytes)
Spleen
Tonsils
Brain
Heart
Liver
Lungs
Other?
CB1:
Brain
Kidneys
Liver
Heart
GI Tract
Pancreas
Adipose
Muscle
Reproductive
organs
Other?

22. http://www.drugabuse.gov/publications/research-reports/marijuana/how-does-marijuana-produce-its-effects

23. Effects of Cannabis on the Brain
https://www.drugabuse.gov/publications/drugfacts/marijuana

24. Consideration #5:
The widespread distribution of CB receptors explains the
broad array of adverse effects with cannabis.
Patients may experience different adverse effects with
short-term use of cannabis compared to chronic use.
See also references 5, 7, 8, 10-21

25. Adverse Effects: Short-term
 anxiety, panic attacks
 distorted perception, hallucinations
 increased heart rate and blood pressure
 decreased memory & learning
 difficulty thinking & problem solving
 decreased coordination
 visuomotor skills deficit
*Effects transient, resolve without intervention.*
*Actual impairment persists past perceived
impairment*
*Effects primarily associated with THC*

26. Natural Antagonism
CBD
no (or less) euphoria
anti-anxiety
anti-psychotic
neuroprotective
bradycardia
Loss of antagonism may lead to
increased side effects and poor tolerability.
THC
euphoria
anxiety
psychosis
cognitive impairment
tachycardia

27. J Forensic Sci, September 2010, Vol. 55, No. 5
THC: CBD Ratio on the Rise…
Wrong Direction for Medicinal Use!
%
THC
time

28.  immunosuppression
 inhalation: increased risk cancer of head, neck,
lungs, respiratory tract
 increased risk testicular cancer
 occlusion brain arteries, increased stroke
 oculomotor control deficit
 hyperemesis syndrome
Adverse Effects: Long-term
“associated with”

29. Adverse Effects: Long-term, cont.
“associated with”
 Neurological changes
 sustained decreased IQ(17)
 adolescents: change in neuroanatomy?
 altered memory, esp verbal(19)
 decreased cerebral blood flow
 decreased neural efficiency
 increased DA neurotransmission, psychosis, anxiety disorder(s),
schizophrenia
genetics
mental illness
younger age + extent of
use

30. Consideration #6:
“The overwhelming consensus from mental
health professionals is that marijuana is not
helpful—and potentially dangerous—for
people with mental illness.”
-National Alliance on Mental Illness (NAMI)
Marijuana and Mental Illness Fact Sheet

31. Consideration #7:
Effects from cannabis vary widely depending upon:
 product
 duration/chronicity of use
 dosage form
 route of administration
 pharmacokinetics*
 pharmacogenetics
 drug interactions
*Pharmacokinetic properties also explain other safety concerns,
monitoring recommendations, etc.
See also references 5-8, 10-14, 22-23

32. Cannabis “raw materials”
Photo Source: www.dea.gov and cureepilepsy.org
hashish (~2-20%)
hash oil, marijuana concentrate (40-80%)
marijuana concentrate (40-80%)
“budder,” “butane honey oil”
marijuana (up to 20%+ THC)
cannabidiol oil

33.  Inhalation (smoking, vaporizing)
 onset: immediate
 bioavailability: 20-37%
Route of Administration
Source:http://www.fda.gov/NewsEvents/PublicHealthFocus/ucm172906.htm
Source:http://www.doh.wa.gov/YouandYourFamily/Tobacco/OtherTobaccoProduc
ts/ECigarettes
Source:http://www.drugabuse.gov/publications/drugfacts/marijuana Source: www.dea.gov

34.  Oral
 Onset: 30-60 minutes
 Bioavailability: 10-20%
 Oro-mucosal: similar to oral; highly variable
Route of Administration
Source: www.containerstore.com
Source: www.dea.gov

35.  Topical
 Onset: ? ~1-2h
 Bioavailability: ?
 Bypasses first pass
 Crossing aqueous layer is the rate limiting step, then perfuses well
Route of Administration
Source: www.containerstore.com Source:
http://www.jupitercompounding.com/

36. Eyeballing* the Math
 2-3mg  euphoria/cognitive effects
 impairment = ~~0.05-0.08 BAC*
 “joint” with 500mg of THC
 Inhalation: 100-185mg if consume ALL
 Oral: 50-100mg
 1 gram of 80%-THC marijuana oil = 800mg
 Inhalation = 160-296mg
 Oral: 80-160mg
*gross oversimplification, ignoring other modifying factors (other cannabinoids present, genetic
variables, drug interactions, chronicity of use, etc.)

37. Clinical Implications of Pharmacokinetics
Pharmacokinetic Property Clinical Implication
• Very lipophilic
• THC: Vd = ~10L/kg
• Distributes into tissues
• Long duration of effect
• Safety concerns in pregnancy and
lactation
• Hepatic metabolism (CYP3A4, 2C9,
2C19, 2D6)
• High first pass effect
• Genetic variability
• Many drug interactions
• Long half-life and many active
metabolites (THC: ~25-36h; tissue
5-7d)
• Elimination over days to weeks,
hundreds of metabolites, via urine
and feces
• Long duration of effect
• Natural taper when discontinued
• Prolonged exposure to toxins
• Affects timing of monitoring

38. Pregnancy & Lactation
*very lipophilic*
 Pregnancy: “Unsafe”
 Lower birth weight, shorter gestational
period, abnormal startle response,
tremulousness, smaller head size, premature
labor, prolonged or arrested deliveries
 Lactation: “Likely Unsafe”
 Poor attention, concentration, and judgment,
problem solving difficulties, ADHD

39. Drug-Cannabis Interactions: Concerning
Highlights
 Hundreds of drug-cannabis interactions
 Full therapeutic significance not yet known
 Extent likely varies with dose, content, route of
administration, chronicity of use, genetic
variation

40. Nature of Cannabis-Drug
Interaction
Interacting Agents
Enhanced CNS depression All CNS depressants
Enhanced cardiotoxicity Sympathomimetics: stimulants (caffeine,
amphetamine, methylphenidate, cocaine,
etc), beta adrenergic agonists,
decongestants, etc
Anticholinergics: (tricyclic antidepressants,
anticonvulsants, cyclobenzaprine,
antihistamines, overactive bladder
products, etc)
Decreased platelet
aggregation, prolonged
bleeding
All Anticoagulants
Note: also interferes with warfarin due to
decreased protein binding
Antiestrogenic effects Estrogen-based contraceptives or
replacement therapy
Drug-Cannabis Interactions:
General Categories

41. Metabolic Cannabis-Drug
Interactions
Interacting Agents
decreased CYP2E1
substrate effect
acetaminophen, anesthetics, theophylline, etc
cannabis may increase
CYP3A4 substrate effect
lovastatin, clarithromycin, cyclosporine,
diltiazem, estrogens, indinavir, triazolam, etc
CYP3A4 inducers decrease
cannabis effect
carbamazepine, phenobarbital, phenytoin,
rifampin, etc.
CYP3A4 inhibitors increase
cannabis effect
Strong: boceprevir, clarithromycin, darunavir,
indinavir, itraconazole, ketoconazole,
lopinavir, nefazodone, ritonavir, etc
Moderate: aprepitant, diltiazem,
erythromycin, fluconazole, grapefruit juice,
imatinib, verapamil
cannabis increases CYP2C9
inhibitor effect
capecitabine, fluorouracil, gemfibrozil,
sulfisoxazole, etc
cannabis (smoked)
decreases CYP1A2
substrate effect
duloxetine, estrogens, mirtazapine,
melatonin, olanzapine, ropinirole,
theophylline, etc
cannabis inhibits p- chemotherapeutic agents, antifungals,

42. Drug-Cannabis Interactions:
“Pain” Medications

43. Monitoring Recommendations
 Monitor if concurrent medication/condition where therapeutically
important
 Recheck cannabinoids in urine drug screen (UDS)
 1 month if sparing use
 2 months for chronic use
 Know your UDS: screen vs confirmation?
 If have THC quantification test
 Trend more important than actual #
 Change by 50% represents change in pattern of use

44. Polite Suggestion #1:
The medical community can be a pillar of education and
support surrounding cannabis use (and/or abuse).

45. Talk to Patients About Cannabis
*Suggested Scripting*
 I don’t recommend people use marijuana. There are too many
unknowns and too many safety concerns. For the conditions where
it may be helpful, we have other treatment options with more
information for safety and efficacy.
 Marijuana can interfere with your memory and coordination. You
can be impaired more and longer than you can tell. It may increase
your risk of accidents.

46. Talk to Patients About Cannabis
*Suggested Scripting*
 With chronic use, marijuana can increase your risk of cancer,
mental illness, and memory problems.
 Marijuana contains hundreds of chemicals, and we don’t yet know
what all of them do. Products and effects are highly variable.
There are many drug interactions.

47. Talk to Patients About Cannabis
*Suggested Scripting*
 CNS depressants: We don’t have enough information to say it is
safe to combine marijuana with (benzodiazepines, opioids, etc).
What information we do have suggests it is not safe. Your doctor
may ask you to choose one or the other.
 Stimulants: Marijuana depresses the nervous system and directly
works against stimulating medication. Marijuana may increase your
risk of heart-related side effects with stimulants. Your doctor may
ask you to choose one or the other.

48. How to Stop Cannabis Use
 Sudden discontinuation generally safe, no need to taper
*Long half-life helps with natural taper*
 Withdrawal syndrome:
If symptoms occur, may include:
-fatigue
-low energy
-depression
-anxiety
-insomnia
-decreased appetite
 No pharmacologic intervention needed (nor effective) for withdrawal

49. Addiction Treatment Options
 No medication-assisted treatment needed (nor effective) for cannabis
addiction
 Addiction Treatment:
 Cognitive Behavioral Therapy (CBT)
 recovery groups (Marijuana Anonymous)

50. In summary…
 Possible benefits of some components –
more research needed
 Known risks
 neurological deficits
 mental illness
 respiratory problems
 increased risk cancer
 increased risk stroke
 addiction
 drug interactions
 pregnancy and lactation
 lethargy, apathy
 Many unknowns remain

51. Gradient of Risk and Adverse Effects
MAY pose lower risk:
 Lower THC
 Lower dose
 Rare use
 Use initiated after
brain developed
 No drug interactions
 Otherwise healthy
Associated with higher
risk:
• Higher THC content
• Inhaled/injected
• Large dose
• Chronic use
• Use during brain
development
• Drug interactions that
increase concentration
or adverse effects
• Poor health status, liver
disease, etc.

52. legal ≠ safe
legal ≠ effective
wide therapeutic index ≠ benign

53. Any remaining burning questions?

54. A few reference slides…

55. Resources for the Layperson
 US National Library of Medicine, National Institutes of
Health
 Drug Enforcement Administration (DEA)
 Substance Abuse and Mental Health Services
Administration (SAMHSA)
 National Institute on Drug Abuse (NIDA)
 National Alliance on Mental Illness (NAMI)

56. References
1. Whiting PF et al. Cannabinoids for Medical Use: A Systematic Review and Meta-
analysis. JAMA. 2015; 313(24):2456-2473.
2. Hill KP. Medical Marijuana for Treatment of Chronic Pain and Other Medical and
Psychiatric Problems: A Clinical Review. JAMA. 2015;313(24):2474-2483.
3. Vandry R et al. Cannabinoid Dose Accuracy in Edible Cannabis Products. JAMA.
2015; 313(24):2491-2493.
4. Maldonado R et al. The endocannabinoid system and neuropathic pain. Pain.
2016;57(2). Supplement 1
5. Natural Medicines Database. Marijuana
6. Huestis MA. Human Cannabinoid Pharmacokinetics.Chem Biodivers. 2007 August ;
4(8): 1770–1804.
7. Health Canada Information for Health Care Professionals: Cannabis (marijuana,
marihuana) and the cannabinoids.
8. Ashton CH et al. Cannabinoids in bipolar affective disorder: a review and
discussion of their therapeutic potential. Journal of Psychopharmacology.
2005;19(3) 293–300.
9. Benarroch EE. Synaptic effects of cannabinoids. Neurology. 2014; 83: 1958-1967.
10. Hall W. What has research over the past two decades revealed about the adverse
health effects of recreational cannabis use? Addiction. 2014; 110: 19-35.

57. References, cont.
11. Hall W, Degenhardt L. Adverse health effects of non-medical cannabis use. Lancet
2009; 374: 1383–91.
12. Wang T et al. Adverse effects of medical cannabinoids: a systematic review.
CMAJ. 2008; 178(13):1669-1678.
13. Ramesh D et al. Marijuana’s Dose-Dependent Effects in Daily Marijuana Smokers.
Experimental and Clinical Psychopharmacology. 2013;21(4): 287–293.
14. US DOJ DEA publication: The Dangers and Consequences of Marijuana Abuse. May
2014.
15. Wolff V et al. Cannabis-related stroke: Myth or Reality. Stroke. 2013; 44:558-
563.
16. Malone DT et al. Adolescent cannabis use and psychosis: epidemiology and
neurodevelopmental models. British Journal of Pharmacology. 2010; 160:511-
522.
17. Meier MH et al. Persistent cannabis users show neuropsychological decline from
childhood to midlife. PNAS. 109(4). Published online August 27, 2012. E2657-
2664.
18. Shrivastava A et al. Cannabis use and cognitive Dysfunction. Indian J Psychiatry.
2011; 53(3):187-191.
19. Auer R et al. Association Between Lifetime Marijuana Use and Cognitive Function
in Middle Age: The Coronary Artery Risk Development in Young Adults (CARDIA)

58. References, cont.
21. Moore THM et al . Cannabis use and risk of psychotic or affective mental health
outcomes: a systematic review. Lancet 2007; 370: 319–28
22. National Institute on Drug Abuse publication: DrugFacts: Marijuana. September
2015.
23. Lexi-Comp
24. Gjerde H et al. Driving Under the Influence of Non-Alcohol Drugs—An Update.
Part 1: Epidemiological Studies. Forensic Sci Rev. 2015 Jul 27 (2):89-113.
25. Lenne M et al. The effects of cannabis and alcohol on simulated arterial driving:
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866.
26. Hartman RL, Huestis MA. Cannabis effects on driving skills. Clin Chem.
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28. Raemakers JG et al. Dose related risk of motor vehicle crashes after cannabis
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29. Anthony J et al. Comparative epidemiology of dependence on tobacco, alcohol,
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30. Kim HS et al. Marijuana Tourism and Emergency Department Visits in Colorado. N