1 Revisiting the evidence as the rules change Lori Montgomery, MD CCFP Prepared with Joyce Côté,...

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Revisiting the evidence as the rules change

Lori Montgomery, MD CCFPPrepared with Joyce Côté, BSc Pharm ACPR

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DisclosuresFaculty: Lori Montgomery and Joyce Cote

Relationships with commercial interests:Grants/Research Support: noneSpeakers Bureau/Honoraria: noneConsulting Fees: none

3Lynch M. Pain Management & Research, Volume 10 Suppl A, Autumn 2005

brain

brainstem

spinal cord

primaryafferentreceptor

dorsal rootganglion

PAG RVM

Locationof CB

receptors1

Cannabinoids

http://www.cbc.ca/news2/interactives/marijuana/

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New Regulations

“aim to treat marijuana as much as possible like any other narcotic used for medical purposes”

“access to quality-controlled marijuana for medical purposes, produced under secure and sanitary conditions... while strengthening the safety of Canadian communities”

“more choices of marijuana strains and commercial suppliers”

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New RegulationsNo specialist opinion required to initiate authorization process

No Health Canada documentation of license to possess

No central monitoring (federally) of patient access

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The “bottom line”Physicians are expected to know and

comply with the regulations and policies of their College.

Physicians are not obliged to complete a medical document for medical marijuana if they are unfamiliar with its treatment use or feel it is medically inappropriate.

http://www.cmpa-acpm.ca/cmpapd04/docs/resource_files/web_sheets/2013/com_w13_005-e.cfm

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The “bottom line”If a physician chooses to complete a

medical document, it is important that a meaningful consent discussion be held, and that the consent discussion be captured in the medical record.

Members should not hesitate to contact the CMPA for advice on this issue.

http://www.cmpa-acpm.ca/cmpapd04/docs/resource_files/web_sheets/2013/com_w13_005-e.cfm

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http://www.cpsa.ab.ca/Resources/StandardsPractice/DeliveryofMedicalServices/marihuana-for-medical-purposes

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Clearly proven risks and benefits for pain patients

Bostwick JM, Blurred boundaries: the therapeutics and politics of medical marijuana, Mayo Clinic Proceedings 87.2 (Feb. 2012): p172.

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Neuropathic painFibromyalgiaBack painHIV neuropathyMS painMuscle spasmMyofascial painPelvic painMigraineTension headache

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“In its April 2003 issue, the British medical journal The Lancet reported that marijuana relieves pain in virtually every test that scientists use to measure pain relief.”(2)

Baker D, Pryce G, Giovannoni G, and Thompson AJ, The therapeutic potential of cannabis, Lancet Neurology 2003; 2: 291–98

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“In its April 2003 issue, the British medical journal The Lancet reported that marijuana relieves pain in virtually every test that scientists use to measure pain relief.”(2)

“Cannabinoids inhibit pain in virtually every experimental pain paradigm either via CB1 or by a CB2-like activity in supra- spinal, spinal, or peripheral regions, dependent on the type of nociceptive pathway being studied.32,33”

(references are basic science pharmacology papers speculating about the mechanism of analgesia)


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Conclusion “As we learn more about the pharmacological

activities of compounds in cannabis and their biological targets outside the cannabinoid system, varieties of cannabis might be tailored to different diseases or used in combination with known drugs. Whatever the future holds, there are many challenges to be overcome before we view cannabinoids as routine medicine in neurological disorders.”


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Smoking(Tashkin 1988 vs 2006)

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Neurocognitive effects

Kids

Psychotic disorders

Memory impairment

www.scienceblog.cognifit.com

Natania A. Crane & Randi Melissa Schuster & Paolo Fusar-Poli & Raul Gonzalez, Effects of Cannabis on Neuroacognitive Functioning: Recent Advances, Neurodevelopmental Influences, and Sex Differences, Neuropsychol Rev (2013) 23:117–137

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Cardiac effects

Raises heart rate

Decreases HR variability

Inconsistent effects on BP

m.medindia.net

Natania A. Crane & Randi Melissa Schuster & Paolo Fusar-Poli & Raul Gonzalez, Effects of Cannabis on Neuroacognitive Functioning: Recent Advances, Neurodevelopmental Influences, and Sex Differences, Neuropsychol Rev (2013) 23:117–137

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Mood

Happy, relaxed, sleepy

Anxious, agitated,depressed, hallucinations

www.blackcat060.blogspot.com

Ste-Marie PA, Fitzcharles MA, Gamsa A, Ware MA, Shir Y, Association of Herbal Cannabis Use With Negative Psychosocial Parameters in Patients With Fibromyalgia, Arthritis Care & Research, Vol. 64, No. 8, August 2012, pp 1202–1208

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Takes time and frequent use

9-12% prevalence

Unclear with medical use

Tongtong Wang MSc, Jean-Paul Collet PhD MD, Stan Shapiro PhD, Mark A. Ware MBBS MSc, Adverse effects of medical cannabinoids: a systematic review, CMAJ • June 17, 2008 • 178(13)

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Diversion

- 2011 study: most users in a US rehab program accessed MJ from a medical user - Need similar controls to opioids- Difficult with current regulations

deathandtaxes.mag.com

Thurstone C, Lieberman SA, Schmiege SJ, Medical marijuana diversion and associated problems in adolescent substance treatment, Drug Alcohol Depend. 2011 November 1; 118(2-3): 489–492.

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What we don’t know:

Better sleep (possibly for some)

Improved Pain (maybe)Quality of life (not at all clear)

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HIV neuropathy: Abrams et al

Abrams, D. I., Jay, C. A., Shade, S. B., Vizoso, H. and others. (2007). Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology. 68: 515-521.

• 2007 RCT HIV medication-related neuropathy• N=50• Smoking 0.9g cigarettes, 3.56% THC or

placebo• 5-day inpatient intervention phase• Previous cannabis use required (“so that they

would know how to inhale and what neuropsychologic effects to expect”)

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HIV neuropathy: Abrams et al


• 52% of cannabis patients had >30% reduction in VAS, compared to 24% of placebo group

• Median reduction in pain levels was 34%• No discontinuations due to side effects• No changes in mood reported

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Mixed neuropathic pain: Wilsey et al

Wilsey, B., Marcotte, T., Tsodikov, A., Millman, J. and others. (2008). A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J.Pain. 9: 506-521.

• 2008 crossover RCT mixed neuropathic pain conditions

• N=38• Smoking high dose (7%), low dose (3.5%) or

placebo, total 9 puffs per session• Previous cannabis use required (“to minimize

psychoactive adverse effects”)• Tested VAS and experimental pain

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Mixed neuropathic pain: Wilsey et al


• 0.0035 points per minute decrease in VAS• VAS ~5.5 -> 3 vs 5.5 -> 4• No difference in experimental pain• No difference in analgesia between low and

high dose, described as a “ceiling effect”• Impairments greater with high dose• Analgesia began to diminish within 1-2 hours

after dose

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Neuropathic pain: Ware et al

Ware MA, Wang T, Shapiro S, Robinson A, Ducruet T, Huynh T, Gamsa A, Bennett GJ, Collet JP, Smoked cannabis for chronic neuropathic pain: a randomized controlled trial, CMAJ October 5, 2010, 182(14): E694-701

• 2010, Crossover design, unblinded by the end• N= 21, former marijuana smokers• THC Concentrations of 0%, 2.5%, 6%, 9.4%• 25mg tid for five days each dose• Reduction in pain of 0.7 points on 10 point

scale• Statistically significant improvement in sleep• No difference in mood or QOL

34Ware MA, Wang T, Shapiro S, Robinson A, Ducruet T, Huynh T, Gamsa A, Bennett GJ, Collet JP, Smoked cannabis for chronic neuropathic pain: a randomized controlled trial, CMAJ October 5, 2010, 182(14): E694-701

• Well-designed study; rigorous methods• Outcomes carefully considered• Abuse monitored• All previous MJ smokers• low dose (25mg tid)• concentration THC 9.4%• Very small magnitude of effect• Effectively a five-day trial

Neuropathic pain: Ware et al

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Wilsey: mixed neuropathic pain

Wilsey, B., Marcotte, T., Deutsch, R., Gouaux, B. et al. (2012). Low-Dose Vaporized Cannabis Significantly Improves Neuropathic Pain. J.Pain. 14: 136-148.

• 2013 double-blind, placebo-controlled, crossover study

• N=39 (13 central, 26 peripheral NeP)• Previous cannabis use required “to reduce the

risk of adverse psychoactive effects in naıve individuals”

• Vapourized medium-dose (3.53%), low-dose (1.29%), or placebo cannabis

• Flexible dose – 4 puffs, then 4-8 puffs 2h later, to overcome “robust placebo response”

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Wilsey: mixed neuropathic pain


• Significant difference from placebo not evident until 120 minutes after initial dose, drops off 1-2 hours later

• 57% of cannabis patients saw >30% reduction in VAS, compared to 26% of placebo

• No difference in analgesia between low and medium doses

• Unblinded for 63% placebo, 61% low dose, 89% medium dose

• Analgesia not associated with feeling “high”; “high” and “stoned” more likely with medium dose

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Experimental pain: Wallace et al

Wallace M, Schulteis G, Atkinson JH, Wolfson T, Lazzaretto D, Bentley H, Gouaux B, Abramson I, Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers, Anesthesiology 2007; 107:785–96

• Randomized, double blind, placebo-controlled crossover trial

• N=15• Must have used cannabis within the prior 6

months• Concentration/response effects of smoked 0%,

2%, 4% and 8% THC• Pain and cutaneous hyperalgesia from

intradermal capsaicin

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• Given a “high dose trial” before the study period to make sure that they could tolerate it

• 4 dose-randomized testing sessions one week apart

• Blood samples to quantify exposure• Measures of neurocognition, sensory function,

and “highness.”

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• No effect 5 minutes after exposure• 45 minutes later, significant decrease in pain at

4%, significant increase in pain at 8%• No effect on hyperalgesia at any dose• No effect on neurocognitive testing

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• No assessment of blinding – but this should prejudice in favour of effect

• Acute pain studies do tend to show either lack of effect or increased pain

• Clearly state that the pain relief was modest and delayed, and that conclusions can’t be drawn about clinical pain states

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Benefit assessmentMS or HIV neuropathy: more likely

Palliative care: probably less riskSevere, disabling neuropathic pain, unresponsive to standard therapy: perhaps

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What do we know about dose?Hazekamp, A., and E.R. Heerdink (2013). The

prevalence and incidence of medicinal cannabis on prescription in The Netherlands. Eur. J. Clin. Pharmacol. Published online April 16, 2013. (average dose [various potencies] 0.68g/d)

Israel's medical marihuana program suggests that the average daily amount used by patients was approximately 1.5 grams of dried cannabis per day in 2011-2012 (Health Canada personal communication) website accessed March 27 2014.

Trials range from 0.5% THC to ~10%

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Max 150 grams or 30 times daily “rx” at a time, whichever is less.

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Is 3g the upper end of the dose range?

45Mark Ware, 2014 – used with permission

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- Prices ranging $5 – $12 / g- THC ranging 1 – 24 %- CBD often not stated- sativa; indica; often not stated- some websites offer tasting notes

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Meaningful consentIncluding the lack of evidence for safety or efficacy

Risk of addiction/dependence unclear

Consider at this point unsafe to drive or combine with ETOH

Mu-Chen Li, Joanne E. Brady, Charles J. DiMaggio, Arielle R. Lusardi, Keane Y. Tzong, and Guohua Li, Marijuana Use and Motor Vehicle Crashes, Epidemiologic Reviews Vol. 34, 2012

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Risk assessmentChildren/adolescents and significant mental health issues: NO

Cardiac, hepatic disease or risk of stroke: NO

Active substance abuse concerns: NO

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Risk assessmentSignificant anxiety or depression: CAUTION

Current unauthorized use: CAUTION

Concerns regarding cognition or memory: CAUTION

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A logical approachEnsure that evidence-based approaches have been tried – including non-pharmacologic approaches

Screen for history of substance abuseScreen for contraindications: heart and liver disease, pregnancy, psychotic disorders, age <21

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A logical approachTotal dose less than 3g/dNo way to Rx concentration of THC, but < 9.4% seems logical to suggest

Likely better to vaporize than smoke or consume orally

Consider at this point unsafe to drive or combine with ETOH

Mu-Chen Li, Joanne E. Brady, Charles J. DiMaggio, Arielle R. Lusardi, Keane Y. Tzong, and Guohua Li, Marijuana Use and Motor Vehicle Crashes, Epidemiologic Reviews Vol. 34, 2012

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www.lifeinnorway.net

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References Abrams DI, Vizoso HP, Shade SB, Jay C, Kelly ME, Benowitz NL.

Vaporization as a Smokeless Cannabis Delivery System: A Pilot Study. Clin Pharmacol Ther 2007.



Bostwick JM, Blurred boundaries: the therapeutics and politics of medical marijuana, Mayo Clinic Proceedings 87.2 (Feb. 2012): p172.

Crane NA, Schuster RM, Fusar-Poli P, Gonzalez R, Effects of Cannabis on Neurocognitive Functioning: Recent Advances, Neurodevelopmental Influences, and Sex Differences, Neuropsychol Rev (2013) 23:117–137

Ishida JH, Peters MG, Jin C, Louie K, Tan V, Bacchetti P, Terrault NA, Influence of Cannabis Use on Severity of Hepatitis C Disease, CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2008;6:69–75

Lee MHS, Hancox RJ, Effects of smoking cannabis on lung function Expert Rev. Respir. Med. 5(4): 2011, 537–547

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References Li MC, Brady JE, DiMaggio CJ, Lusardi AR, Tzong KY, Li G, Marijuana Use

and Motor Vehicle Crashes, Epidemiologic Reviews, Vol. 34, 2012 Singh NN, Pan Y, Muengtaweeponsa S, Geller TJ, Cruz-Flores S, Cannabis-

Related Stroke: Case Series and Review of Literature, Journal of Stroke and Cerebrovascular Diseases, Vol. 21, No. 7 (October), 2012: pp 555-560

Ste-Marie PA, Fitzcharles MA, Gamsa A, Ware MA, Shir Y, Association of Herbal Cannabis Use With Negative Psychosocial Parameters in Patients With Fibromyalgia, Arthritis Care & Research, Vol. 64, No. 8, August 2012, pp 1202–1208

Thurstone C, Lieberman SA, Schmiege SJ, Medical marijuana diversion and associated problems in adolescent substance treatment, Drug Alcohol Depend. 2011 November 1; 118(2-3): 489–492.


Wang T, Collet JP, Shapiro S, Ware MA, Adverse effects of medical cannabinoids: a systematic review, CMAJ June 17, 2008, 178(13):1669-78

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References Ware MA, Wang T, Shapiro S, Robinson A, Ducruet T, Huynh T, Gamsa A,

Bennett GJ, Collet JP, Smoked cannabis for chronic neuropathic pain: a randomized controlled trial, CMAJ October 5, 2010, 182(14): E694-701



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