Medical Cannabis in the Treatment of Chronic Pain...For all other chronic pain conditions (cancer,...

Medical Cannabis in the Treatment of Chronic Pain______________________________________________________________________

Elon Eisenberg

Institute of Pain Medicine, Rambam Health Care Campus,

The Technion – Israel Institute of Technology, Haifa, Israel

Disclosure_________________________________________________________________________________________________________________

E. Eisenberg received research grants from: Mundipharma,

Rafa Laboratories, Taro, Dexcel Pharma, Pfizer, MSD,

Novartis, Syqe Medical Ltd., St. Jude Medical, Israel Pain

Association, Israel Scientific Foundation, Focused

Ultrasounds Surgery (FUS) Foundation & Teva.

2

Presentation scope____________________________________________________________________________________________________________________

▪ A glance on cannabis history

▪ Scientific aspects

▪ Basic science

▪ Clinical science

History of Cannabis___________________________________________________________________________________________________________________________

Chinese emperor Shen Nung

3500 or 2800 BCE

Ramses II’ tomb,

dating back to 1224 BCE.

Beit Shemesh 4th century AD

Zias et al. Nature 1993

Sir John R. Reynolds (1828-1896)_____________________________________________________________________________________________________________________________

• The house physician to Queen

Victoria

• President of the Royal College of

Physicians in London

Medicinal use of Cannabis___________________________________________________________________________________________________________________________

“The prohibition”________________________________________________________________________________________________________________

▪ Harry J. Anslinger (1892-1975) played a

pivotal role in cannabis prohibition.

▪ 1937: Marijuana Tax Act

▪ Cannabis is still considered schedule I drug

in the USA, similar to heroin and cocaine

▪ Federal law prohibit use or research

First Commissioner of the U.S. Treasury Department’s

Federal Bureau of Narcotics (1930-1962)




▪ Basic science


Cannabinoids and pain________________________________________________________________________________________________________________________________

▪ Cannabinoid receptors are localized in areas known as

the “pain matrix” in the CNS and in sites associated

with nociception outside of the CNS.

▪ Cannabinoids interact with non-cannabinoids receptors,

which are associated with pain processing (i.e. TRPV,

serotonin and more).

Spinal Cord

Brain Stem

Thalamus

Sensory Cortex

Limbic Cortex

Ascending pathwaysDescending pathway

CB1R

CB2R

DRG

Nociceptor

Preclinical studies with cannabis________________________________________________________________________________________________________________________________

• Activation of CB1R resulted in attenuation of

– Mechanical and thermal hyperalgesia

– Spontaneous visceral pain-like behavior (writhing test)

• Activation of CB2R resulted in

– Attenuation of inflammatory pain

Maldonado et al. Pain 2016




▪ Basic science


Ways of consuming herbal cannabis________________________________________________________________________________________________________________________________

FlowersOil drop extracts

Smoking

InhalingInhaling -Bung

Eating Edibles

Sublingual/swallowing

TopicalSwallowing

Cannabis based medications ________________________________________________________________________________________________________________________________

• Oral tablets/capsules of synthetic THC

– Nabilone

– Dronabinole

• Oral mucosal spray of 1:1 THC:CBD cannabis extract

– Nabiximols (Sativex®).

• More recently oil based cannabis extracts with various

THC:CBD concentration ratios

Medical cannabis and pain_____________________________________________________________________________________________________________________________

Headache

Bone pain

Muscle /widespread

pain

Neuropathic

pain

Visceral pain

Joint pain

Inhaled cannabinoids for NP - RCTs (1)________________________________________________________________________________________________________________________________

Main outcomeDurationIntake/

preparation

NIndicationStudy

Smoked or inhaled cannabis

*Cannabis > placebo5 daysSmoked34HIV painAbrams

*Cannabis > placebo5 days X 2Smoked55HIV painWilsey

*Cannabis > placebo6 hrs. x 3

sessions

Smoked38Mixed neuropathicWare

*Cannabis > placebo14 daysSmoked23Neuropathic post-

traumatic

Ellis

*Cannabis > placebo6 hrs.Vaporized39Painful neuropathiesWilsey

*Cannabis > placebo4 hrsInhaled16PDNWallace

Oral /SL CBM for NP - RCTs (2)________________________________________________________________________________________________________________________________

Main outcomeDurationIntake/

preparation

NIndicationStudy

Oral intake of cannabinoid based medications

*Cannabis med > placebo1 weekCT324Chronic NPKarst

Cannabis med < DHC18 weeksNabilone96Chronic NPSvendsen

*Cannabis med > placebo3 weeksDronabinol24Central (MS)Frank

Cannabis med =

diphenydramine

4 weeksDronabinol7Central (SCI)Rintala

*Cannabis med > placebo8 weeksNabilone26PDNToth

Cannabis med = placebo16 weeksDronabinol240MSSchimrigk

*Cannabis med > placeboSingle doseTHC (extract)15Radicular painSharon

CBM for NP – High-Quality RCTs (3)________________________________________________________________________________________________________________________________

Main outcomeDuration

(weeks)

Intake/

preparation

NIndicationStudy

Oral mucosal spray

*Cannabis ext. > placebo8Spray24Mixed (central &

peripheral)

Wade

Cannabis ext. = placebo6Spray48Brachial plexus

injury

Berman

*Cannabis ext. > placebo4Spray63Central (MS)Rog

*Cannabis ext. > placebo5Spray125Painful neuropathiesNumikko

Cannabis ext. = placebo12Spray30PDNSelvarrah

Cannabis ext. = placebo14Spray339Central (MS)Longford

*Cannabis ext. > placebo15Spray246Peripheral

neuropathies

Serpell

Cannabis ext. = placebo10Spray16CIPNLynch

Cannabinoids for neuropathic pain________________________________________________________________________________________________________________________________

▪ The most extensively studied type of pain

▪ Six low-quality RCTs on smoked cannabis point to efficacy

▪ Seven higher-quality RCTs on cannabinoid based oral/S.L.

medications & eight high-quality RCTs on oral-mucosal

THC/CBD spray show equivocal results

Meta-analysis____________________________________________________________________________________________________________________________

Placebo Preference

Acti

ve T

reatm

en

t

Pre

fere

nce

http://www.google.co.il/url?url=http://www.hayadan.org.il/970-million-potential-new-drugs-2307092&rct=j&frm=1&q=&esrc=s&sa=U&ei=837IVIyVKoG2UNmTgrAL&ved=0CBUQ9QEwAA&sig2=CA5Ccp5hmOIZRfVQCuOFJQ&usg=AFQjCNFA2TO-1supSCxGDm2IgIwfbfzckg

• % of responders

Whiting et al. JAMA 2015

Average magnitude of change:

−0.46 points (on a 0-10- scale)

(OR, 1.41 [95%CI, 0.99-2.00]; 8 trials)

[95%CI, −0.80 to −0.11]; 6 trials]


Bone pain

Muscle /widespread

pain

Neuropathic

pain

Visceral pain

Joint pain

Headache

Cannabinoids for headaches________________________________________________________________________________________________________________________________

Lochte et al. Cannabis & Cannabinoids Research 2017

Cannabinoids for headaches________________________________________________________________________________________________________________________________

Lochte et al. Cannabis & Cannabinoids Research 2017

▪ Currently, there is not enough evidence from well-

designed clinical trials to support the use of cannabis for

headache.

▪ There are anecdotal and preliminary results, as well as

plausible neurobiological mechanisms, to warrant properly

designed clinical trials.


Bone pain

Muscle /widespread

pain

Neuropathic

pain

Visceral pain

Joint pain

Headache

➢ A single-center, double-blind, placebo-controlled, 4-way crossover

study.

➢ 20 FM patients received a single inhalation of:

➢ THC 22% and CBD < 1%

➢ THC 6.3% and CBD 8%

➢ THC 1% and CBD 9%

➢ Placebo

Spontaneous pain 30% pain relief 50% pain relief

van de Donk et al., Pain 2019

CBD ↑ THC plasma

concentration

Cannabis registries ____________________________________________________________________________________________________________

Hoggart B et al. J Neurol 2015 Ware M et al. J Pain 2015

Haroutounian S et al. Clin J Pain 2016 Abuhasira R, et al., Eur J Intern Med 2018

• A prospective, multicenter, longitudinal questionnaire-based

cohort study

• Data collection before and at 1, 3, 6, 9 and 12 months

following HC treatment initiation.

• In total, 843 patients completed at least one follow-up

questionnaire, providing a total of 2,965 observations

following treatment initiation.

The Israeli prospective cohort study (registry)____________________________________________________________________________________________________________________

Percent of change from baseline in weekly pain intensity________________________________________________________________________________________________________________

Percent of change from baseline in related symptoms________________________________________________________________________________________________________________

Reduction in opioid consumption________________________________________________________________________________________________________________

Prediction of response (Alluvial plot)____________________________________________________________________________________________________________________

“Treatment success” was defined as > points reduction in pain

Prediction of response____________________________________________________________________________________________________________________

▪ Significant predictors for “treatment success” were:

▪ Severe baseline pain intensity

▪ Age under 65

▪ Normative anxiety and sleep

▪ Mild disability

▪ Preserved quality of life

▪ The total proportion of variance explained by the mixed

effect model was 61% (random= 39% & fixed= 22%).

▪ Notably, pain diagnosis, pain duration & route of

cannabis consumption did not predict response.

Attitudes towards medical use of cannabis for chronic pain

_____________________________________________________________________________________________________________________________

D'Souza and Ranganathan, JAMA 2015 (Editorial)

• Medical marijuana is not a life-saving intervention.

• It may be prudent to wait before widely adopting its use

until high-quality evidence is available.

• Perhaps it is time to place the horse back in front of the

cart.

“The mandated transition to limit use of opioids, paired

with the current climate around liberalizing cannabis, may

lead to patients’ formal and informal substitution of

cannabis for opioids.”

Travis I. Lovejoy; JAMA 2016

▪ The quantity and quality of evidence are such that cannabis-

based medicines may be reasonably considered for chronic

neuropathic pain.

▪ For all other chronic pain conditions (cancer, non-

neuropathic noncancer pain), the use of cannabis-based

medicines should be regarded as an individual therapeutic

trial.

Hauser Et al., EJP 2018

European Pain Federation (EFIC) position paper on appropriate

use of cannabis-based medicines and medical cannabis for

chronic pain management_______________________________________________________________________________________________________________________

• Cannabis is becoming an integral part of pain medicine.

• Although controversial - it is here to stay!

• Cannabis seems to have some medical advantages but

moderate analgesic properties at best.

• Rigorous research is still ahead of us.

• Regulatory, social and educational considerations need to be

addressed along with continued medical research.

Conclusions____________________________________________________________________________________________________________________

For more information visit:

www.coursera.org

Medical Cannabis for Pain Control

from Technion - Israel Institute of Technology

Thank You

Medical Cannabis in the Treatment of Chronic Pain...For all other chronic pain conditions (cancer,...

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