cannabis: a medicine to treat pain? and scientific nomenclature to be referred to as...
TRANSCRIPT
Kalpna Gupta, PhD
Vascular Biology CentreDivision of Hematology, Oncology and
TransplantationDepartment of Medicine
University of Minnesota Medical SchoolMinneapolis, MN
Cannabis: A Medicine to Treat Pain?
MDH, Minnetonka, MN Sept 03, 2015
The starting point?
Medical and Scientific Nomenclature
To be referred to as Cannabis/cannabinoids and NOT Marijuana
To be called Medicine and NOT Drug
To be thought of as Plant NOT Weed
To treat the Sick NOT ----?
Calyx: comprise the female flowers with tiny nodules under the leaf with high concentration of glands or trichromes that secrete THC and other bioactive compounds in the highest concentration.
Trichromes: Crystal resins secreted through transluscent, mushroom shaped glands on leaves, stems and calyxes on the buds, containing cannabinoids and terpenes.
Schedule 1
Cannabis
Hallucinogenic amphetamine derivatives
Heroin
LSD
Barbiturates
Current Regulatory Status of Cannabis
1963 structure of Cannabidiol (CBD): Israeli Scientist Raphael Mechoulam
1964: Isolated the active ingredient delta-9 tetrahydrocannabinol (THC)
480 natural compounds and 66 are “cannabinoids” including CBD and THC.
Discovery of Cannabinoids
Cannabinoids
Endogenous
Anandamide(“Supreme bliss”)
Phytochemicals Synthetic
By binding to transmembrane G-Protein coupled receptors called cananbinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R)
How do Cannabinoids act?
Activation of signaling pathways by cannabinoid receptors
Elikottil J, Gupta P and Gupta K. The Analgesic Potential of Cannabinoids. J Opioid Management 2009
Role in central sensitization/intractable pain
Why do we want to use Cannabis as pain medicine?
PAIN
Compounds working better together than in isolation.Therefore the plant has greater beneficial effects as compared to an isolated cannabinoid.
Entourage effect
Pain
• Costs the nation >$635 billion/year.• 40% of the adult population in the United
States suffers with chronic pain.• Neuropathic pain such as that observed
in diabetes and sickle cell disease, remains a major challenge to treat.
Opioid and Cannabinoid use: side effects
Elikottil J, Gupta P and Gupta K. The Analgesic Potential of Cannabinoids. J Opioid Management 2009
Are opioids ideal analgesics to treat chronic pain?
Gupta K. Iatrogenic Angiogenesis. In, Morphine and Metastasis. Springer 2012.
Based on Experimental Studies
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Sickle Cell Anemia: Molecular Basis
Courtesy, Robert P Hebbel MD
Pain in sickle cell disease
• Pain can start during infancy and increases in severity throughout life, reaching levels considered higher than labor pain during childbirth.
• Long-term opioid usage, however, creates a high risk of addiction, tolerance and side effects that pose a major obstacle for pain management. Opioids may not even be effective always.
• Recurrent episodes of crises and pain lead to increased hospitalization, poor quality of life, morbidity and mortality, resulting in reduced lifespan of patients with sickle cell disease.
Des
cend
ing
pain
mod
ulat
ion
path
way
Ascending pathw
ay
TNFα IL6
gc
Skin
Peripheral nerve fibers
SPSpinal cord
Antidromic release
SP
SP
DRG
Nociceptive mechanisms involve peripheral and central nervous system and immune cells
BrainPAIN
Cannabinoids decrease the activity of nociceptors
Arachidonyl-2’-chloroethylamide (ACEA), a CB1R agonist,attenuated the response of A-delta nociceptors in inflamed skin.
Vehicle, ACEA, or ACEA + AM251(a CB1R antagonist) was injected into the plantar skin.
Line above each trace is the time of mechanical stimulation (156 mN).
Potenzieri et al., 2008CB1R mediates inhibition of nociceptor sensitization
Peripheral cannabinoids attenuate cancer pain
WIN 55,212-2 dose-dependently attenuates mechanical hyperalgesia in a murine model of cancer pain. Local injection of 2.5, 5, or 10 μg of WIN 55,212-2 into the tumor-bearing hindpaw reduced the mean paw withdrawal frequency evoked by a suprathreshold von Frey monofilament (3.4 mN). *Treatment Vsvehicle, p < 0.05. Potenzieri et al., 2008
Mouse model
Sickle (HbSS-BERK) and Control (HbAA-BERK) mice (Paszty et al., Science 1997): These mice recapitulate the hematologic disease, organ damage, reduced life-span and pain (Kohli et al, Blood 2010; Cain et al., Br J Hematol 2011).
Importantly, the chronic pain phenotypes observed in this mouse model have been validated in human sickle patients (Brandow et al., 2012 and 2015). Further escalation in hyperalgesia is evoked in these mice with hypoxia/reperfusion injury to simulate pain due to vasocclusive crises (Cain et al., 2012), a caharacteristic, recurrent and unpredictable feature of SCD, which remains a major challenge to treat.
Substance P and CGRP, mediators of pain are upregulated in the periphery (skin) via a centrally mediated mechanism in chronic pain.(Editorial Commentary: New Era dawns on pain in sickle cell disease)
Red, SP
Blue, CGRP
Green, blood vessel
Kohli et al., Gupta laboratory Blood 2010
HbAA-BERK (Control) HbSS-BERK (Sickle)
Substance P and CGRP are increased in the skin of sickle (BERK) mice
Red, SP; Blue, CGRP; Green, blood vessels
(Kohli et al. Blood, 2010)
A vicious cycle of mast cell degranulation and nociceptor activation leads to pain in SCD
(1) Mast cell-tryptase cleaves PAR2 on peripheral nociceptors
(2) Activation of PAR2 sensitizes TRPV1 channels on nerve endings
(3) Activation of PAR2 and TRPV1 leads to release of CGRP and SP from the sensory nerve endings
(4) CGRP may stimulate arteriolar dilatation.
(5) SP stimulates plasma extravasation leading to neurogenic inflammation
(6) SP acts in a paracrine and autocrinemanner by activating mast cells thus promoting a vicious cycle of mast cell degranulation and nocicepor activation.
6
Vincent et al.– Gupta K. “Plenary Paper” Blood 2013;122:1853-62. Editorial Commentary by Kutlar A “GLEE-ful for sickle pain?”
(0.3 mg/Kg)
Higher Grip Force = Less Pain
High dose of morphine is required to reduce hyperalgesia in sickle mice, but a relatively low dose of cannabinoids is effective
(Kohli et al. Blood, 2010)
Cannabinoid treatment ameliorates pain incited by hypoxia-reoxygenation in sickle mice
Higher Grip Force = Less Pain
Cain et al., Br J Hematology 2011
CP55,940 decreases deep hyperalgesia in sickle mice without causing tolerance
** p < 0.01 *** p < 0.001
3 wks treatment w/ CP55,940
Higher grip force = increased analgesiaTreatment for 3 weeks with CP55,940 (i.p. , 0.3 mg.kg-1) once daily.
Vincent et al., 2015, communicated
CP55,940 decreased cytokine expression in sickle mice
CYTOKINE RELEASE FROM SKIN
* p < 0.05 Vs. HbSS veh ** p < 0.01 Vs. HbSS veh
3 wks treatment w/ CP55,940
CP55,940 treatment for 3 weaks leads to a sustained inhibition of mast cell degranulation in the skin of sickle mice
HbSSVeh
HbSSCP55,940
HbAAVeh
C-kit/CD117 FCεRI Tryptase
Thus, cannabinoids reduce inflammation
CP55,940 decreases neorogenic inflammation following H/R injury in sickle mice
1 wk treatment w/ CP55,940 + H/R
Thus, cannabinoids attenuate the activation of peripheral nerve activity, which requires both CB1 and CB2R (data not shown)
Deep Mechanical
Thermal Catalepsy
Vincent et al., 2015 (communicated)
Requirement of CB1- and CB2-receptors for attenuation of hyperalgesia in sickle pain phenotypes
grip force,analgesia
PWF
analgesia
PWL,analgesia
Cannabinoids as potential analgesics to treat pain in SCD and other neuropathic pain conditions
• Cannabinoid receptors (CB1 & CB2) are located in the brain,nerve fibers & inflammatory cells in the periphery and CNS.
• Activation of peripheral cannabinoid receptors attenuatesinflammatory & neuropathic pain
• Potential therapeutic option to protect organs fromhypoxia/reperfusion injury (Fouad & Jresat, 2011; Gonzaleset al, 2011), oxidative stress (Booz, 2011; Cassol et al, 2010)and inflammation (Ribeiro et al, 2012
• Cannabinoids can be used via oral, oro-mucosal, respiratoryor systemic routes
• Some preparations like Sativex, an oro-mucosal spray, areapproved for clinical use in Canada & Europe.
• A retrospective study of Cannabis users showed that 52% of SCD patients reported decrease in pain, anxiety and depression. (Howard et al., Br J Hematology 2005)
University of Minnesota: Kalpna Gupta, PhD (lead PI) and John Connett, PhD with UCSF: Donald Abrams, MD
ClinicalTrials.gov (identifier:NCT01771731).
Funded by NHLBI, UO1 HL117664
Cannabis Provided by : NIDAVaporized Cannabis: 4.7% THC and 5.1% CBD
Proof of Principle Trial of Cannabis to Treat Pain in SCD
Cannabis Vaporizer
SCD: Study Design
1. Effect of 5-day treatment with vaporized Cannabis or Placebo on pain and other associated disorders (sleep. Anxiety, depression, etc) in patients with SCD.
2. Determine the short-term side effects associated with inhaled Cannabis treatment in association with opioids.
3. Examine the markers of pain, inflammation and disease progression.
From concept to realization
2010-2011: Gupta K, U of M, Efforts to obtain a license2011: Approached Donald Abrams, UCSF2012: Applied for funding to NHLBI, NIH2012-2013: Grant competed in the top ranks but funding delayed until Sept 2013 due to Government issues.7/19/2013: UCSF, CTSI approves the trial7/23/2013: UCSF General Hospital; IRB approves the trial (approval number 13-10526). 11/7/2103: IND 119158 for cannabis, FDA approval11/14/2013: DEA form submitted2/19/2014: DEA responds, field investigation required4/2014: Field investigation completedMay 2014: Research Advisory Panel of California, Approval.July 2014: Cannabis received from NIDA2017-18: Anticipated completion
Vaporization is a safe mode of delivery:Physiologic THC levels are comparableExpired carbon monoxide is decreased
Participants preferred vaporized Cannabis Vs smoked
Co-adminstration with opioids is safe and enhances analgesia in patients with chronic pain.
Abrams et al, Clin Pharm and Therap 2011
Safety and efficacy of vaporized Cannabis
HIV-associated Neuropathy
Smoked Cananbis effective in treating peripheral neuropathy
Smoked Cannabis effective in attenuating central sensitization
Effectiveness of smoked Cannabis comparable to trials with Gabapentin
Abrams et al., Neurology 2007
Abrams et al., Neurology, 2007
Analgesic effect of smoked Cannabis on HIV-neuropathy in a placebo controlled randomized clinical
trial
Abrams et al., Neurology, 2007
Date of download: 8/27/2014 Copyright © 2014 American Medical Association. All rights reserved.
From: Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in the United States, 1999-2010
JAMA Intern Med. 2014;():. doi:10.1001/jamainternmed.2014.4005
Association Between Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in Each Year After Implementation of Laws in the United States, 1999-2010Point estimate of the mean difference in the opioid analgesic overdose mortality rate in states with medical cannabis laws compared with states without such laws; whiskers indicate 95% CIs.
Figure Legend:
Randomized controlled trials examining cannabinoids in treatment of chronic non-cancer pain
Lynch et al., Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trialsBr J Clin Pharmacol 2011
Potential of Cannabis to treat pain and associated symptoms
• As an adjunct to opioids
• In opioid-induced tolerance
• For mood elevation?
• As an appetite stimulant
• Relieving nausea
• to relieve stress
•Sleep
Disease-specific research and appropriately designed clinical trials
Approval of these compounds by FDA and availability for analgesia through regulated pharmacies
Evidence based review and regulatory oversight should be similar for cannabis and other medications prescribed by physicians.
Safe route of administration (oral pills or inhalation in quantifiable amounts)
Database to record outcomes for objective assessment of pain and multiple symptoms and pathological outcomes.
Collaboration of a dedicated team of scientists, physicians, community participants, patient advocates, law makers and industry.
Funding and policies to facilitate fast-track research.
Future Directions
Lab MembersYing Wang, PhDHuy TranJianxun Lei, PhDLucile Vincent, PhDJinny A Paul, PhDYessenia V Guevara, PhDYann Lamarre, PhDMaureen Reidl, PhDJoe Cataldo, PhDMegan Uhelski, PhDAditya M Mittal
Lab MembersJulia NguyenBarbara BensonRitu JhaKathryn LukSusan ThompsonLindsey SkubitzThu DuongAditya MitalJonathan Luk PaulDeniz Arcan-FangSarita Jarret
ACKNOWLEDGEMENTS
NHLBI, UO1HL117664, RO1s HL6880, HL103733, HL68802-06S1; HL68802-7S1
Institute for Engineering in MedicineUniversity of Minnesota Foundation
Dean’s and Department of Medicine Funds
CollaboratorsDonald Abrams, MD, UCSFDonald A Simone, PhD
Acknowledgements
Collaborators
Donald A Simone, PhD
George Weiblen, PhD
Pankaj Gupta, MD
Donald Abrams, MD (UCSF)
Members of Gupta Laboratory
NIH RO1s HL68802 and HL103733; UO1HL117664Institute for Engineering in Medicine grant; University of Minnesota Foundation