Tina Mérandon

Migraine

Clinical Endocannabinoid Deficiency Revisited

Ethan Russo, MD20402 81st Avenue SWVashon Island, WA 98070USA

001-206-408-7082ethanrusso@comcast.net

Clinical Endocannabinoid Deficiency (CED) Diseases

• Migraine• Fibromyalgia• Idiopathic bowel syndrome (IBS)• Causalgia/allodynia/brachial plexopathy/phantom limb

pain• Infantile colic• Glaucoma• Dysmenorrhea• Hyperemesis gravidarum• Unexplained fetal wastage• Post-traumatic stress disorder (PTSD)• Bipolar disease

Russo EB. Clinical endocannabinoid deficiency (CECD): Can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuroendocrinol Lett. 2004.25(1-2):31-9.

Migraine Pathophysiology• AEA produced 89%

potentiation of 5-HT1A and 36% inhibition of 5-HT2A receptor responses (Boger 1998)

• Associated photophobia and phonophobia suggest a “sensory hyperalgesia”

• AEA is tonically active in periacqueductal grey matter, producing analgesia with CB1 agonist application, or hyperalgesia upon CB1R blockade (Walker 1999)

Walker JM et al. Pain modulation by the release of the endogenous cannabinoid anandamide. PNAS. 1999;96(21):12198-203.

Fibromyalgia• Controversial, but most frequent diagnosis for American

rheumatologists• Now commonly portrayed as a “central sensitization”

syndrome (Bennett 2002)• Produces “secondary hyperalgesia” suggesting need for

NMDA blockade for defect in serotonergic analgesia (Nicolodi 1998)

• Hyperalgesia related to central endocannabinoid hypofunction (Richardson 1998)

• Endocannabinoids at spinal level reduce hyperalgesia, suggesting cannabinoid Rx of disorders driven by primary afferent barrage (allodynia, visceral hyperalgesia, RSD/CRP) (Richardson 1998)

• Cannabis frequently employed by patients with the disorder

Idiopathic Bowel Syndrome (IBS)

• A “diagnostic wastebasket” that nevertheless is the top diagnosis in gastroenterology practices in USA

• A “visceral hypersensitivity” that fails to respond well to conventional treatment

• GI motility is under tonic control of ECS (Pertwee 2001)

• “The brain and the gut speak the same language” (Russo 2004)

• Cannabinoids suggested for Tx of IBS (Di Carlo & Izzo 2003)

Comorbidity: Migraine, Fibromyalgia, IBS

• Primary headache co-occurred in 97% of 201 fibromyalgia patients (Nicolodi 1996)

• 35.6% of 101 transformed migraine/CDH subjects had fibromyalgia (Peres 2001)

• 31.6% of IBS subjects had fibromyalgia; 32% of fibromyalgia subjects had IBS (Sperber 1999)

Migraine

Fibromyalgia

IdiopathicBowelSyndrome

Smid SD et al. The endocannabinoids anandamide and 2-arachidonoylglycerol inhibit cholinergic contractility in

the human colon. European J Pharmacol. 2007 Jul 26. • Examined normal colon longitudinal and circular

muscle from surgical specimens from 31 patients

• AEA co-localizes with cholinergic receptors in normal human colon and inhibits cholinergic contractile potency of circular and longitudinal muscle via a non-CB1 mechanism, or an alternative cannabinoid mechanism (non-CB1, non-CB2)

• Suggested that the EC system is augmented and more functionally important in disease and inflammatory states (including IBS?)

Schley M et al. Delta-9-THC based monotherapy in fibromyalgia patients on experimentally induced pain, axon reflex flare, and pain

relief. Current Medical Research and Opinion. 2006. 22(7):1269-76. • Uncontrolled study of 9 fibromyalgia

patients receiving 2.5-15 mg oral THC daily over 3 months (placebo not allowed by Ethics Committee)

• 5 of 9 dropped out due to AEs• 4 subjects who completed study showed

no change in touch-evoked allodynia or pinprick-induced hyperalgesia, but prominent reductions in perceived pain

Schley M et al. Delta-9-THC based monotherapy in fibromyalgia patients on experimentally induced pain, axon reflex flare, and pain relief. Current Medical

Research and Opinion. 2006. 22(7):1269-76. VAS Fibromyalgia Pain

1 2

Baseline vs. Post 3 Months

Pai

n V

AS

VAS Fibromyalgia Pain

8.1

2.8

P<0.01

N=4

• Multi centre, double-blind, randomised, placebo-controlled parallel group study of Sativex for the treatment of peripheral neuropathic pain characterised by allodynia

• N=125 (n=63 Sativex, n=62 placebo)

• Treatment duration: 5 weeks

• 6 study centres

• All patients remain on current medication throughout trial

• Primary endpoint– Change from baseline in average daily pain score after 5 weeks

of treatment, evaluated from daily pain diaries and measured on a Numerical Rating Scale (NRS, 0-10) of pain severity

• Range of secondary endpoints, including sleep disturbance, allodynia, Pain Disability Index

Phase III Trial: Peripheral Neuropathic

Pain

Nurmikko TJ et al. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised,

double-blind, placebo-controlled clinical trial. Pain. 2007;(in press).

Study GWNP0101: 1° EndpointChange in BS-11 Pain Scores

Study GWNP0101Improvement in BS-11 Pain Scores from Baseline

0

1

2

3

Sativex Placebo

Study Week

Ad

just

ed M

ean

BS

-11

Pai

n

Sco

re

SativexPlacebo

p=0.004*

*ANCOVA, ITTNurmikko TJ et al. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial.

Pain. 2007;(in press).

Study GWNP0101:Pain Scores: Responder Analysis

Study GWNP0101 BS-11 Pain Score: Responder Analysis

0

5

10

15

20

25

30

>= 30% >= 50%

% Improvement from Baseline

% o

f Pat

ient

s

SativexPlacebo

ITT PopulationNurmikko TJ et al. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain. 2007;(in press).

Study GWNP0101 - Improvement in Dynamic Allodynia Test Scores from Baseline (Patients with Score of Zero at Baseline Excluded)

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

Sativex Placebo

Ad

jus

ted

Mea

n C

ha

ng

e in

Dyn

amic

A

llod

yn

ia T

es

t S

co

re

p=0.042*

*ANCOVA, ITT

Study GWNP0101Dynamic Allodynia Test Score

Improvement from Baseline

Nurmikko TJ et al. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain. 2007;(in press).

Akerman, S et al. 2003. Anandamide is able to inhibit trigeminal neurons using an in vivo model of trigeminovascular-mediated

nociception. Journal of Pharmacology and Experimental Therapeutics 309 (1):56-63.

• AEA reduces dural vessel dilation by CGRP 30%, capsaicin 45% and NO 40%.

• AEA works presynaptically to prevent CGRP-induced NO release in SM of dural arteries.

• AEA is tonically released and has a modulatory role in trigeminovascular system.

Akerman S et al. Anandamide acts as a vasodilator of dural blood vessels in vivo by activating TRPV1

receptors. Br J Pharmacol. 2004. 142:1354-1360. • AEA caused a dose

dependent increase in dural vessel diameter attenuated by capsazepine (TRPV1

antagonist) and CGRP8-37 (CGRP antagonist)

• Doses of AEA required were much above those activating CB1

• Repetitive dosing (as with CBD, another TRPV1 agonist) might fatigue mechanisms (as with capsaicin in peripheral neuropathic pain)

Akerman S et al. Cannabinoid (CB1) receptor activation inhibits trigeminovascular neurons. J

Pharmacol Exp Ther. 2007 320(1):64-71. • WIN 55,212-2 inhibited

trigeminocervical complex A and C-fiber afferent activity (blocked by SR141716A)

• AEA did so only after TRPV1 blockade (by capsazepine)

• Data suggests CB1-agonists have therapeutic potential in migraine, cluster HA, etc. (although authors feared psychoactive effects)

Cupini, L.M., M. Bari, N. Battista, G. Argiro, A. Finazzi-Agro, P. Calabresi, and M. Maccarrone. 2003. Abnormal degradation of endocannabinoids in migrainous women. Cephalalgia 23:684.

• CBR levels were equivalent in groups.

• Increased AEA membrane transporter and AEA hydrolase (FAAH) activity were observed in platelets of female migraine without aura pts. (MoA) vs. episodic tension HA pts. (ETTH) and controls.

• Increased AEA degradation by platelets, and decreased blood levels may lower pain threshold in female migraineurs.

Sarchielli P et al. Endocannabinoids in chronic migraine: CSF findings suggest a system failure.

Neuropsychopharmacology. 2007. 32(6):1384-90.

AEA Levels in Cerebrospinal Fluid

0.39

0.21

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

Control Chronic Migraine

pm

ol/m

l

P<0.0001

N=20 N=15

Sarchielli P et al. Endocannabinoids in chronic migraine: CSF findings suggest a system failure.

Neuropsychopharmacology. 2007. 32(6):1384-90.

“Reduced AEA levels in the CSF of CM patients support the hypothesis of the failure of this endogenous CB system in the CM ---.”

p. 1387

Clinical Endocannabinoid Deficiency: Quo vadis?

• Further studies of IBS, fibromyalgia and migraine with serum EC (or better CSF) comparisons vs. controls

• Brain and spinal imaging for endocannabinoid levels in health and disease

• Genomic investigation of links between CED diseases and ECS regulation

• Controlled clinical trials of cannabinoid medicines in these three and other putative CED syndromes