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Clinical Endocannabinoid Deficiency Revisited

Clinical Endocannabinoid Deficiency Revisited. Ethan Russo, MD 20402 81 st Avenue SW Vashon Island, WA 98070 USA 001-206-408-7082 ethanrusso@comcast.net. Migraine. Tina Mérandon. Clinical Endocannabinoid Deficiency (CED) Diseases. Migraine Fibromyalgia Idiopathic bowel syndrome (IBS)

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Clinical Endocannabinoid Deficiency Revisited

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  1. Clinical Endocannabinoid Deficiency Revisited • Ethan Russo, MD • 20402 81st Avenue SW • Vashon Island, WA 98070 • USA • 001-206-408-7082 • ethanrusso@comcast.net • Migraine Tina Mérandon

  2. 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.

  3. 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.

  4. 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

  5. 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)

  6. 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 • Idiopathic • Bowel • Syndrome • Fibromyalgia

  7. 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?)

  8. 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

  9. 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. • 8.1 • N=4 • P<0.01 • 2.8

  10. 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 • 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).

  11. Study GWNP0101: 1° EndpointChange in BS-11 Pain Scores • Nurmikko TJ et al. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain. 2007;(in press).

  12. Study GWNP0101:Pain Scores: Responder Analysis • Nurmikko TJ et al. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain. 2007;(in press).

  13. Study GWNP0101Dynamic Allodynia Test ScoreImprovement 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).

  14. 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.

  15. 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)

  16. 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)

  17. 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.

  18. Sarchielli P et al. Endocannabinoids in chronic migraine: CSF findings suggest a system failure. Neuropsychopharmacology. 2007. 32(6):1384-90. • P<0.0001 • N=20 • N=15

  19. 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

  20. 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

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