Transcript Clinical Endocannabinoid Deficiency Revisited Ethan Russo, MD
Clinical Endocannabinoid Deficiency Revisited Ethan Russo, MD 20402 81 st Avenue SW Vashon Island, WA 98070 USA 001-206-408-7082 [email protected]
Migraine Tina Mérandon
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-HT 1A and 36% inhibition of 5-HT 2A receptor responses (Boger 1998) • Associated photophobia and phonophobia suggest a “ sensory hyperalgesia ” • AEA is tonically active in periacqueductal grey matter, producing analgesia with CB 1 agonist application, or hyperalgesia upon CB 1 R 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
Fibromyalgia Migraine Idiopathic Bowel Syndrome • 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)
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-CB 1 mechanism, or an alternative cannabinoid mechanism (non-CB 1 , non-CB 2 ) • 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 8.1
N=4
P<0.01
2.8
VAS Fibromyalgia Pain 1
Baseline vs. Post 3 Months
2
•
Phase III Trial: Peripheral Neuropathic Pain
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
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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
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
°
Endpoint Change in BS-11 Pain Scores
Study GWNP0101 Improvement in BS-11 Pain Scores from Baseline 3 p=0.004* 2 Sativex Placebo 1 0 Sativex Placebo Study Week
Nurmikko TJ et al. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial.
Pain.
2007;(in press).
*ANCOVA, ITT
Study GWNP0101: Pain Scores: Responder Analysis
Study GWNP0101 BS-11 Pain Score: Responder Analysis 30 25 20 15 10 Sativex Placebo 5 0 >= 30% >= 50% % 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).
ITT Population
Study GWNP0101 Dynamic Allodynia Test Score Improvement from Baseline
Study GWNP0101 - Improvement in Dynamic Allodynia Test Scores from Baseline (Patients with Score of Zero at Baseline Excluded) 7.0
6.0
5.0
4.0
3.0
2.0
p=0.042* 1.0
0.0
Sativex Placebo
Nurmikko TJ et al. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial.
Pain.
2007;(in press).
*ANCOVA, ITT
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
dural vessel diameter attenuated by capsazepine (TRPV 1 in antagonist) and CGRP 8-37 (CGRP antagonist) • Doses of AEA required were much above those activating CB 1 • Repetitive dosing (as with CBD, another TRPV neuropathic pain) 1 agonist) might fatigue mechanisms (as with capsaicin in peripheral
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 TRPV 1 blockade (by capsazepine) • Data suggests CB 1 -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.
0.45
0.4
0.35
0.3
0.25
0.2
0.15
0.1
0.05
0 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
P<0.0001
0.21
Control N=20 Chronic Migraine 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