1. Migraine Pathophysiology An Update Professor Peter J. Goadsby Peter.Goadsby@headache.ucsf.edu BASH Teaching Meeting Hull 22 January 2009 Department of Neurology

2. Migraine a systems disorder (after Goadsby et al., NEJM 2002; 346:257-270)

3. Migraine and the pons Bahra et al Lancet 2001;357:1016-1017 Afridi et al. Arch Neurol 2005;62,1270-1275 Nitroglycerin-triggered Spontaneous

4. Brainstem activations in right and left-sided headache with PET Left-sided headache Right-sided headache Afridi et al., Brain 2005; 128:932-939

5. Migraine The Attacks & the Disorder Premonitory symptoms Pain –unilateral –throbbing –movement worse Nausea Sensory sensitivity –photophobia –phonophobia –osmophobia Aura Repeated attacks –< 15 days/month: Episodic –≥ 15 days/month: Chronic Family history Triggers (biology) –Sleep: missing/excess –Food: skipping meals –Chemical: alcohol or nitroglycerin –Weather –Sensory: light, smells –Hormonal –Stress- relaxation AttacksDisorder “The simple headaches have the same characters, and occur under the same causal conditions of heredity &c, as those in which there are additional other sensory symptoms” Gowers 1893

6. Migraine Classification

7. Migraine Pathophysiolgy- Update Genetics Pain mechanisms Treatment

8. Genetics of Migraine Familial Hemiplegic Migraine- an ionopathy FHM-II ATP1A2: Na + /K + ATPase chr 1q23 FHM-I CACNA1A: P/Q voltage-gated Ca 2+ channel chr 19 Ophoff et al. Cell 1996; 87:543 De Fusco et al. Nat Gen 2003;33:192 FHM-III SCN1A: Voltage-gated Na + channel chr 2 Dichgans et al., Lancet 2005;366:371 FHM-IV ?:

9. Infarctions in the Migrainous Brain? Kruit et al., Brain 2005;128:2068 Rozen Cephalalgia 2007;27:557-560 18Jan06 3Feb06

10. Migraine aura Silberstein et al., Headache in Clinical Practice 2nd Ed 2002

11. Secretin/Glucagon Superfamily Peptides and Migraine  MCA VEL Migraine VIP 2 16%0/12 PACAP 3 16%7/11 VIP 1 PACAP VPAC 1 ++ VPAC 2 ++ PAC 1 + VIP, vasoactive intestinal polypeptide; PACAP, pituitary adenylate cyclase activating peptide 1.Jansen-Olesen et al., Peptides 2004;25:2105 2.Rahmann et al., Cephalalgia 2008;28:226 3.Henrik et al., Brain 2009; in press

12. Migraine Pathophysiolgy- Update Genetics Disease mechanisms  Premonitory symptoms –The neck –Allodynia –Medication overuse Treatment

13. When does migraine start? (Giffin et al., Neurology 2003; 60:935-940)

14. Are there Phases of a Migraine Attack? (Giffin et al., Neurology 2003;60:935-940) % patients

15. Dose-dependent dopaminergic modulation of trigeminocervical complex neurons Bergerot et al. Ann Neurol 2007;61:251-262 MMA: middle meningeal artery D1D1 D2D2 D2D2 Dopamine NeuN

16. A11 Neurons are Dopaminergic Charbit et al., A11 neurons contain tyrosine hydroxylase (green) but not dopamine  -hydroxylase (red)

17. A11 Stimulation is Anti-Nociceptive through a dopaminergic mechanism MMA MMA + A11 Charbit, Akerman & Goadsby

18. A11 lesioning is Pro-Nociceptive MMA MMA + A11 lesion Charbi, Akerman & Goadsby

19. Migraine Pathophysiolgy- Update Genetics Disease mechanisms –Premonitory symptoms  The neck –Allodynia –Medication overuse Treatment

20. dura mater V ganglion trigeminal nucleus C2C2 C1C1 Migraine and the Neck Referred Pain in the Trigeminocervical Complex (TCC) Cervical input } TCC

21. Neck and Headache Bartsch & Goadsby Current Pain and Headache Reports 2003;7:371-376

22. Migraine Pathophysiolgy- Update Genetics Disease mechanisms –Premonitory symptoms –The neck  Allodynia –Medication overuse Treatment

23. Allodynia and migraine Allodynia –pain from non-noxious heat, cold or pressure Incidence –…now and then extensive pain over the head may be accompanied by some general tenderness of the hairy scalp… –Two-thirds of 500 patients Selby & Lance JNNP 1960;23:23-32 –71% of 44 patients Burstein et al., Ann Neurol 2000;47:614 –63% of 16,573 higher for frequency & BMI –Bigal et al., Neurology 2008;70:1525 Site –Trigeminal –Cervical –Rest of body Burstein et al. Ann Neurol 2004;55:19

24. “Act when Mild” Study Allodynia did not predict outcome (Goadsby et al., Cephalalgia 2008; 28383-391) - Randomised Double-Blind Placebo Controlled Parallel Group - Allodynia surrogate: cutaneous sensitivity Outcome - Patients treating at mild pain did better - The presence of allodynia did not determine outcome

25. Migraine Pathophysiolgy- Update Genetics Disease mechanisms –Premonitory symptoms –The neck –Allodynia  Medication overuse Treatment

26. Medication Overuse and the evolution of chronic migraine AMPP Sample- 16,339 Progression to Chronic migraine in 2.5% over one year Acetaminophen use does not predict risk Predictors –Barbiturates at 5 day/month –Opioids at 10 days/month –Triptans at 13 days/month NSAIDs are protective if used more than five days a month Bigal et al., Headache 2008;48:1157

27. Migraine Pathophysiolgy- Update Genetics Disease mechanisms –Premonitory symptoms –The neck –Allodynia –Medication overuse Treatment

28. Trigeminovascular System & Migraine (Goadsby et al., NEJM 2002; 346:257-270)

29. %patients Acute Treatment of Migraine with Sumatriptan and Naproxen Double-blind randomized parallel group single attack adult migraineurs n = 360 356 361 364 382 364 362 362 799 1751 Study I Study II Meta-analysis Ferrari et al., Lancet 2001;358:1668 sumatriptan Brandes et al., JAMA 2007;297:1443 SumaRT/Nap

30. %patients Acute Treatment of Migraine with Sumatriptan and Naproxen Double-blind randomized parallel group single attack adult migraineurs n = 360 356 361 364 382 364 362 362 799 1751 AEs Nausea Somnolence Dizziness Paresthesia Dyspepsia Ferrari et al., Lancet 2001;358:1668 sumatriptan Brandes et al., JAMA 2007;297:1443 SumaRT/Nap

31. Trigeminovascular System & Migraine (Goadsby et al., NEJM 2002; 346:257-270) 5-HT 1D CGRP Hou et al., Brain Res 2001;909:112-120

32. Trigeminal ganglion stimulation increases CGRP in the cranial circulation (Goadsby, Edvinsson & Ekman Ann Neurol 1988;23:193 ) (pmol/l) * * * * Cat Human

33. Superior sagittal sinus (SSS) stimulation in cat Neuropeptide changes (Zagami, Goadsby & Edvinsson, Neuropeptides 1990;16:69-74) (pmol/l) * *

34. Calcitonin Gene-Related Peptide (CGRP) and Migraine 1 Goadsby et al., Ann Neurol 1990;28:183 2 Olesen et al NEJM 2004;350:1104 (pmol/l) * * CGRP is released in the cranial circulation in migraine 1 BIBN4096BS (olcegepant), a CGRP receptor antagonist, is effective in migraine 2

35. Gepants & the Calcitonin Receptor Family Calcitonin receptor-like receptor (CLR) Calcitonin gene-related peptide (CGRP) binds to CLR when it is co-expressed with receptor activity modifying protein 1 (RAMP1); Adrenomedullin (AM) binds to CLR when RAMP2 or RAMP3 expressed; Intermedin (IM) binds to CLR when RAMP1 or RAMP3 are expressed. Receptor component protein (RCP) for efficient signal transduction at CLR. Calcitonin Receptor (CTR) Calcitonin (CT) binds to the CTR; Amylin binds to CTR in the presence of RAMP1, RAMP2, or RAMP3. Ian Dickerson- www.urmc.rochester.edu/smd/cgrp

36. %patients CGRP receptor antagonists are effective in acute migraine Double-blind randomized parallel group single attack adult migraineurs  Pain Free at 2 hours n = 115 38 40 34 799 1751 300 600 R10 S100 Ferrari et al., Lancet 2001;358:1668 sumatriptan Ho et al., Neurology 2008;70:1004 telcagepant

37. CGRP receptor antagonist telcagepant is effective in the treatment of acute migraine (% patients) Double-blind parallel group randomised controlled trial  2 Hour pain free Lancet 2009;372:2115 Lancet 2001;358;1668 N = 348 333 354 345 553 1135 1219

38. CGRP receptor antagonist telcagepant is effective in the treatment of acute migraine (Ho et al., Lancet 2009;372:2115 ) (% patients) Sustained pain free (SPF) at 24 and 48 hr

39. CGRP receptor antagonist telcagepant is effective in the treatment of acute migraine (Headache 2008;48:S7-S8 ) (% patients) ?Gepant-class AEs- dry mouth, fatigue

40. Ergot Alkaloid (tetracylic ergolene) Family Tree CH 3 H H

41. Plasma protein extravasation, CP122,288 and migraine (Roon et al., Ann Neurol 2000;47:238-241 response at 2 hours) %patients 70,000pmol/kg 100pmol/kg (Lee & Moskowitz Brain Res 1993;626:303) Rat Human Dural Plasma Protein Extravasation Buzzi et al., Brain Res 1999;583:137

42. iNOS and the dura mater iNOS protein co-localizes in macrophages after GTN treatment Reuter et al. Brain 2001;124:2490 GTN Ctrl Macrophages iNos Macrophages/iNOS

43. iNOS in the treatment of migraine GW274150* Randomised, single-blind placebo- controlled adaptive design Acute attacks *NOS inhibition at 120mg > 80% 2 hr pain free Palmer at al., EHMTIC2008 Hoye et al., EHMTIC2008 Randomised, double-blind placebo- controlled Migraine headache days base vs Rx Prevention n = 22 6 8 15 24 n= 111 37 36

44. Ergot Alkaloid (tetracylic ergolene) Family Tree CH 3 H H

45. COL-144, 5-HT 1F receptor agonist, in the acute treatment of migraine Randomised, single-blind placebo-controlled adaptive design Specific agonist- 500 fold less affinity at 5-HT 1B/1D than 5-HT 1F receptors No detectable 5-HT 1B receptor agonist activity in vivo, eg., rabbit saphenous vein 2 hr pain free Reuter at al., EHMTIC2008 42 24 28 16 24 hr SPF

46. (Saper et al., AHS 2008 late-breaking) *P = 0.032; **P = 0.003 % Occipital nerve stimulation in chronic migraine ONSTIM Double-blind randomized parallel group sham stimulation controlled study Note- occipital pain, fail 2 preventives, exclude MOH ** * n = 16 29 17 NS * Adverse event: lead migration in 24 %

47. (Lipton et al., AHS Late-breaking abstract) % Patients Transcranial magnetic stimulation for Migraine Randomised double-blind placebo controlled study Include: 30% aura episodes, aura leads to headache 90% Exclude: Prolonged aura, MOH TMS- 0.9T for 180  s; Sham- click and vibrate Primary endpoint: 2 hr pain free plus non-inferiority for nausea/photo/phono Blinding: Thought they got active, 67% Sham and 72% active n = 82 82 *

48. Botulinum Toxin and Headache Cui et al., Pain 2004; 107: 125-133 after Aoki

49. Botulinum Toxin and Headache χChronic tension-type headache –No difference in frequency; n = 300 Silberstein et al., Cephalalgia 2006;26:717 χMigraine (episodic) – No differences; n = 232 Saper et al., J Neurol 2005; 252: II-58 –No differences; n = 495 Relja et al., J Neurol 2005; 252: II-62. –Reduced frequency (?primary endpoint); n = 128 Chankrachang et al., Cephalalgia 2005; 25: 992-993. χChronic Daily Headache –No reduction in headache frequency; n = 702 Silberstein et al., Mayo Clin Proc 2005; 80: 1126-37 –No reduction in headache free days; n = 355* Mathew et al., Headache 2005; 45: 293-307 ?Chronic Migraine –Reduced headache frequency on no other preventive (sub-group *) Dodick et al., Headache 2005; 45: 315 –Two RCTs Positive for reduction in headache days (Press release)

50. (after Goadsby et al., NEJM 2002; 346:257-270)