This presentation briefly introduces the plausibility of studying the cannabis-derived compounds for the treatment of chronic pain.

2. 2
Treating Chronic Pain
With Cannabis-Derived Compounds
AR Mohammad, S Pagliazzi

3. 3
Definition
Edition 1.00
• Chronic pain is defined as pain which persists for
more than 12 weeks, arising from injury or illness
(National Institute of Health)
• There are two generalised sub-classifications for
Chronic Pain, nociceptive and neuropathic pain.
• Nociceptive Pain: Caused by Inflammation or tissue
damage, which activate nociceptors (specialised
pain receptors)
• Neuropathic Pain: Caused by malfunction or
damage to Central Nervous System e.g.
neuropathic injury or psychological injury

4. 4
Epidemiology
Edition 1.00
• Chronic Pain affects ~20% European Population
which is approximately 148 Million people! (van
Hecke et al., 2013)
• WHO collaborative study estimates worldwide
prevalence of ~22%(Gureje et al., 1998), which
amounts to approximately 1.5 Billion People who
suffer from chronic pain!
• The Market for Chronic Pain can be estimated at
$7.5 Trillion and upwards (setting a baseline $5,000
per annum treatment cost per person)

5. 5
Current pain treatments and their shortfalls
Edition 1.00
• Opioids e.g. morphine, codeine, fentanyl, oxycodone,
hydrocodone have a market share of $12 Billion
However they are riddled with side effects such as nausea, vomiting,
constipation and respiratory depression. There are also the complications of
tolerance and abuse associated with opioids(Compton and Volkow, 2006).
Opioids are overused and inappropriately prescribed. This is an epidemic in
Australia, North America and Europe.
There are also many pain conditions which are opioid resistant! (MacDonald,
1991)
• Gabapentenoids e.g. Gabapentin
Only useful for neuropathic pain treatments
• NSAIDS e.g. Paracetamol, Ibuprofen, Aspirin
Only efficacious in Inflammatory conditions, often provide minimal relief in
many chronic pain conditions

6. 6
Cannabis for Chronic Pain: Historical Perspective
Edition 1.00
• Ancient Roman Physician Claudius Galen
(ethnically Greek) mentioned the use of
Cannabis for treating pain associated with
various conditions
• William Brooke O'Shaughnessy brought the
use of Cannabis into Western Medicine after
his time in India, where it was frequently
used. He was impressed by the favourable
toxicology (after the toxicity experiments on
goats and dogs) and cannabis preparations as
analgesics in pain
• Queen Victoria’s personal Phyisician J. Russell
Reynolds called “Indian hemp, when pure
and administered carefully, is one of the
most valuable medicines we possess” and
reported hemp treatment to be the only
successful treatment for a patient with
“neuralgia of the lower branches of the
nerve”(Reynolds, 1890).

7. 7
Targeting the Endocannabinoid System (1)
Edition 1.00
• CB1 receptor is prevalent in Central Nervous System.
• In the context of Pain, CB1 is distributed in supraspinal
(thalamus, amygdala, and periaqueductal grey matter),
spinal (dorsolateral funiculus, in the surroundings of the
central canal and in the superficial dorsal horn) and
peripheral areas involved in the pain pathway
• CB1 activation attenuates primary nociceptive synaptic
transmission (Manzanares et al., 2006) and increases the
descending inhibitory pain modulation stemming from the
Periaqueductal grey matter (Finn et al., 2003).
• CB1 upregulation in chronic neuropathic pain pathologies
(Siegling et al., 2001)-scope for increased analgesic effect!

8. 8
Targeting the Endocannabinoid System (2)
• CB2 receptors are majorly
present on inflammatory cells
• In inflammatory states,
immune cells are activated and
release inflammatory
mediators that sensitize
nociceptors.
• CB2 activation causes the
decrease in pro-inflammatory
cytokines (Rice et al.) and
subsequently the suppression
of persistent pain states which
arise from inflammation.

9. 9
Other Targets
• Cannabinoids can activate or block many other
receptors and ion channels
• Ca2+ Channels: L-type, N-type, P/Q type, T-type
• Na2+ Channels: Nav1.1, Nav1.2, Nav1.5
• Serotonin: 1a, 2a and 3
• K+ Channels: K-ATP, TASK-1, TASK-3, TREK-1, Kv1.2, Kv1.5, Kv3.1, Kv4.3
• Nuclear: PPARα, PPARβ/δ, PPARγ
• TRPs:TRPV1-4, TRPA1, TRPM8
• Opioid Receptors: μ, δ
• Orphan Receptors: GPR55, GPR119, GPR18, GPR30
• More research with Cannabinoids could help to
characterize orphan receptors

10. 10
Δ9-THC
• CB1 and CB2 partial agonist
• Synthetic preparations of Δ9-THC
(Nabilone and Dronabinol) have
been tried for chronic pain.
• Nabilone produced significant
analgesic effects in spinal pain,
fibromyalgia and spasticity related
pain. (Lynch and Campbell, 2011)
• Dronabinol led to significant
reduction in central pain in
Multpile Sclerosis (Lynch and
Campbell, 2011)
• However due the risks of cognitive
impairment in administering pure
Δ9-THC (debatable), Nabilone and
Dronabinol have very restricted
access (mainly for anorexia
treatment in HIV/AIDS patients)

11. 11
Cannabidiol-rationalizing Δ9-THC use
• Cannabidiol (CBD) has shown to reverse
the cognitive affects of Δ9-THC
(Bhattacharyya et al., 2010)
• Cannabidiol also has anti oxidant and
anti-inflammatory properties which are
valuable properties to treat pain (Booz,
2011).
• Sativex: a 1:1 formulation produced by
GW Pharmaceuticals, approved in
Canada for the treatment of Neuropathic
Pain. It is Phase II and III for some other
pain conditions
• Sativex has shown favourable efficacy in
various chronic pain conditions (Russo et
al., 2007), and Δ9-THC and CBD
compliment therapy.

12. 12
Other Cannabinoids and Cannabis derived compounds (1)
• Currently 105 phytocannabinoids have been isolated from Cannabis, many with
different affinities to the Cannabinoid receptors. In total there are 545 compounds
that have been isolated from Cannabis.
• Examples of the pharmacological actions of other compounds
• CBDA TRPA1 partial agonist, TRPV1 partial agonist, TRPM8
antagonist
• CBG CB1 and CB2 partial agonism, TRPA1 agonist, TRPV1α,
TRPM8 antagonist
• THCA TRPA1 partial agonist, TRPM8 antagonist
• THCV CB1 antagonist, CB2 partial agonist
• CBC TRPA1 agonist
• CBN CB1, CB2 and possibly more
• There is a need to study the actions of each compound in more
depth, particularly in experimental models of chronic pain

13. 13
Other Cannabinoids and Cannabis derived compounds (2)
• Other than the cannabinoids, active Terpenes and Flavonoids are present in Cannabis.
• These compounds are also present in other plants, and are often used in other herbal
remedies and medicines.
• Beta-Myrcene is a compound also present basil essential oil, with anti-inflammatory
properties and analgesic properties.
• Limonene is a compound present in lemon extracts, shown to have anti-inflammatory
and gastro-protective properties.
• Alpha-pinene is a compound present in ginseng plants from China, has anti-
inflammatory and antioxidant properties.
• There is anecdotal evidence suggesting Terpenoids enhance central Cannabinoid
action, possibly by facilitating greater Blood Brain Barrier intrusion of Cannabinoids
Cannabinoids and Terpenoids in could be used in synergic therapies to provide
therapeutic relief to many various diseases and disorders, particularly chronic pain

14. 14
Botanical Drug Discovery Pathway
Investigation of
Anecdotes, Herbal
Remedies and
Historical Medical
Uses
Pharmacological, pre-
clinical and clinical
rationale
Registered therapies with
controlled dosage and
administrative properties

15. 15
Future Directions
• Throughput analysis of Cannabis, the various strains and the
omnipresent active compounds present in the plant
• Screening of each potential compound (affinity to the right
receptors) within various experimental models of pain,
examining synergic affects as well
• Cell based assays (GPCRs, TRPs etc) as well as pain assays to
evaluate components.
• Large Scale clinical trials? Possibly using Cannabis-derived
therapeutics as conjunctive or replacement drugs.
• Favourable interactions have been seen with opioids, with
increases in efficacy (Abrams et al., 2011) More
investigation is required in the form of large scale clinical
trials

16. 16
Bibliography
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• BOOZ, G. W. 2011. Cannabidiol as an Emergent Therapeutic Strategy for Lessening the Impact of Inflammation on Oxidative Stress.
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• COMPTON, W. M. & VOLKOW, N. D. 2006. Major increases in opioid analgesic abuse in the United States: Concerns and strategies.
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