Migraine 2008 Controversies in Women s Health 5 December 2008 Professor Peter J. Goadsby Peter.Goadsby@headache.ucsf.edu Department of Neurology
Headache International Headache Society Classification Primary 1. Migraine 2. Tension-type headache 3. Trigeminal autonomic cephalalgias 3.1 Cluster headache 3.2 Paroxsymal hemicrania 3.3 SUNCT 4. Other Headaches 4.1 Primary Stabbing 4.2 Cough Headache 4.3 Exertional headache 4.4 Sex headache 4.5 Hypnic headache 4.6 Primary Thunderclap Headache 4.7 Hemicrania continua Secondary infection hemorrhage trauma tumour CSF pressure change (Cephalalgia 2004;24:1-160)
Migraine Age Specific Prevalence in the United States % patients 40 35 27.3 26 female male 30 25 21.5 19.7 20 15 10 5 0 7.1 9.7 8.1 7.5 7 7.2 5.2 2.5 12-17 18-29 30-39 40-49 50-59 >60 (Lipton et al., Headache 2001; 41:646-657)
Landmark Study How often are physicians wrong when they diagnose non-migraine in a patient complaining of primary headache? Prospective, open-label study Patients tracked for three months or six attacks Assigned IHS diagnoses by experts % Patients with non-migraine, 100 80 60 40 20 0 76 Migraine 18 Migrainous (Tepper et al., Headache 2004;44:856-864)
Update in Migraine Classification & Diagnosis Pathophysiology Treatment
Migraine Classification Feature full headache Throbbing, unilateral, photophobia, phonophobia, movement effect Is there Medication Overuse? Analgesics ten days or more per month Is there headache on 15 days or more per month? Episodic Migraine Chronic Migraine (15+ days/month) Migraine with aura Migraine without aura
International Headache Society Migrene Vanligvis episodisk hodepine (4-72 timer) med visse kjennetegn (& ingen annen årsak): Minst 2 av- ensidig pulserende Moderat til alvorlig Forverrelse ved aktivitet Minst en av- kvalme/brekninger foto/fonofobia (after International Headache Society, 1988)
Migraine The Attacks & the Disorder Attacks Premonitory symptoms Pain unilateral throbbing movement worse Nausea Sensory sensitivity photophobia phonophobia osmophobia Aura Disorder 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 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
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: in press
Update in Migraine Classification & Diagnosis Pathophysiology Genetics Aura Pain Treatment
Genetics of Migraine Familial Hemiplegic Migraine- an ionopathy FHM-I CACNA1A: P/Q voltage-gated Ca 2+ channel chr 19 FHM-II ATP1A2: Na + /K + ATPase chr 1q23 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 FHM-IV?:? Dichgans et al., Lancet 2005;366:371
Silberstein et al., Headache in Clinical Practice 2nd Ed 2002 Migraine aura
Infarctions in the Migrainous Brain? 18Jan06 3Feb06 Kruit et al., Brain 2005;128:2068 Rozen Cephalalgia 2007;27:557-560
Migraine a systems disorder (after Goadsby et al., NEJM 2002; 346:257-270)
The tentorial nerve is a branch of V 1 (Feindel et al., Neurology 1960;10:555)
Migraine and the Neck Referred Pain in the Trigeminocervical Complex (TCC) dura mater V ganglion trigeminal nucleus C 1 TCC Cervical input C 2
Neck and Headache Bartsch & Goadsby Current Pain and Headache Reports 2003;7:371-376
Cranial Autonomic Features and Experimental Head Pain 8 6 4 2 patients 0 lacrimation conjunctival injection nasal congestion ptosis miosis (Frese et al., Cephalalgia 2003;23:67-68)
Trigeminal Autonomic Cephalalgias trigeminal-autonomic activation dura mater V ganglion pterygopalatine ganglion C1 SSN trigeminal nucleus C2
When does migraine start? 100 (Giffin et al., Neurology 2003; 60:935-940) VAS rating of state of health 80 60 40 20 premonitory headache 0-100 -50 0 50 100 Time (hours)
%patients 100 80 60 40 20 Migraine A11 and the Premonitory Phase premonitory headache postdrome A11 neurons contain tyrosine hydroxylase (green) but not dopamine β-hydroxylase (red) Charbit, Akerman 0 tiredness stiff neck yawn polyuria hunger thirst emotional (Giffin et al., Neurology 2003;60:935-940)
Update in Migraine Classification & Diagnosis Pathophysiology Treatment - Current - Recent - Future
Therapy in migraine Non-drug Behavioural modification relaxation therapy meditation biofeedback Acupuncture Natural remedies feverfew Non-proven options homeopathy Proven not to work chiropractic osteopathy
Choice of treatment in acute migraine Acute attack treatments Non-specific aspirin or acetaminophen NSAIDS ibuprofen naproxen tolfenamic acid opioids Specific ergotamine derivatives ergotamine dihydroergotamine Triptans sumatriptan almotriptan eletriptan frovatriptan naratriptan rizatriptan zolmitriptan
λ Migraine Preventives By mechanism Amine modulation 5-HT 2 : cyproheptadine, methysergide β- blockers: propranolol Tricylics: amitriptyline MAOI s: Phenelzine λ Channel modulation Gabapentin Topiramate Divalproex Other - Neurtriceuticals: riboflavin 400mg daily - Botulinum toxin
Migraine frequency and CVS risk in females Women s Health Study: 5083 females 45 years Risk adjusted for BP, age, smoking, BMI, cholesterol, family history 3 <monthly monthly weekly 2.74 Odds ratios 2 1 1.54 0.97 1.9 1.42 0.54 1.64 0.94 0.64 0 Major CVS disease Stroke MI (Kurth et al., Neurology 2008;)
Randomised Double-Blind Placebo-Controlled Trial of Estradiol Gel in Menstrual Migraine Estradiol gel from peak fertility to day two of menses Placebo three cycles/active three cycles Migraine triggered when gel stopped Headache days 200 150 100 171 * 133 placebo estradiol 50 0 n = 27 32 MacGregor et al., Neurology 2006;67:2159; * P < 0.03
Trigeminovascular System & Migraine (Goadsby et al., NEJM 2002; 346:257-270)
50 Acute Treatment of Migraine with Sumatriptan and Naproxen Double-blind randomized parallel group single attack adult migraineurs Placebo Naproxen 500 mg SumaRT 85 mg SUMA+Npx %patients 40 30 20 10 Study I Study II Meta-analysis 34 30 30 25 23 15 16 9 10 9 n = 360 356 361 364 382 364 362 362 799 1751 0 pain free 2hr pain free 2hr Sumatriptan 100 mg Brandes et al., JAMA 2007;297:1443 SumaRT/Nap Ferrari et al., Lancet 2001;358:1668 sumatriptan
Acute Treatment of Migraine with Sumatriptan and Naproxen Double-blind randomized parallel group single attack adult migraineurs %patients 50 40 30 20 10 Placebo Naproxen 500 mg SumaRT 85 mg SUMA+Npx 25 23 16 14 10 10 8 7 7 19 AEs Nausea Somnolence Dizziness Paresthesia Dyspepsia n = 360 356 361 364 382 364 362 362 799 1751 0 Sustained pain free Sustained pain free Sumatriptan 100 mg Brandes et al., JAMA 2007;297:1443 SumaRT/Nap Ferrari et al., Lancet 2001;358:1668 sumatriptan
Trigeminovascular System & Migraine 5-HT 1D CGRP Hou et al., Brain Res 2001;909:112-120 (Goadsby et al., NEJM 2002; 346:257-270)
Trigeminal ganglion stimulation increases CGRP in the cranial circulation (pmol/l) 120 100 80 60 * control * VG stimulation * * 40 20 0 CGRP Substance P CGRP Substance P Cat Human (Goadsby, Edvinsson & Ekman Ann Neurol 1988;23:193)
Superior sagittal sinus (SSS) stimulation in cat Neuropeptide changes 200 (pmol/l) 150 100 * control SSS 50 * 0 CGRP Substance P VIP Neuropeptide Y (Zagami, Goadsby & Edvinsson, Neuropeptides 1990;16:69-74)
Calcitonin Gene-Related Peptide (CGRP) and Migraine CGRP is released in the cranial circulation in migraine 1 BIBN4096BS (olcegepant), a CGRP receptor antagonist, is effective in migraine 2 70 66 (pmol/l) 80 60 40 20 * * 60 50 40 30 20 10 27 placebo BIBN4096BS 2.5mg 25 12 0 0 CGRP Sub P HA response Aes control MWA MWOA 1 Goadsby et al., Ann Neurol 1990;28:183 2 Olesen et al NEJM 2004;350:1104
CGRP receptor antagonists are effective in acute migraine Double-blind randomized parallel group single attack adult migraineurs Pain Free at 2 hours 50 %patients 40 30 20 10 0 45 Placebo 32 33 30 14 9 n = 115 38 40 34 799 1751 300 600 R10 S100 Ho et al., Neurology 2008;70:1004 telcagepant Ferrari et al., Lancet 2001;358:1668 sumatriptan
CGRP receptor antagonist telcagepant is effective in the treatment of acute migraine 50 Double-blind parallel group randomised controlled trial 2 Hour pain free Placebo T-150 T-300 Z5 Z2.5 (% patients) 40 30 20 17.2 26.9 31.3 32.4 29.1 10 9.6 7.2 0 N = 348 333 354 345 553 1135 1219 Ho et al., Ferrari et al., Headache 2008;48:S7-S8 Lancet 2001;358;1668
CGRP receptor antagonist telcagepant is effective in the treatment of acute migraine Sustained pain free (SPF) at 24 and 48 hr 30 SPF 2-24 SPF 2-48 (% patients) 20 10 5 3.8 10.7 7.4 20.2 18 18.2 12.4 0 Placebo T-150 T-300 Zolmitriptan-5 (Headache 2008;48:S7-S8)
CGRP receptor antagonist telcagepant is effective in the treatment of acute migraine 60 Placebo T-150 T-300 Z5 50.7 (% patients) 40 20 0 32.1 31.4 37.2 3.2 2.1 4.3 10.4 Aes Triptan-like Aes?Pant-class AEs- dry mouth, fatigue (Headache 2008;48:S7-S8)
Migraine and the pons Nitroglycerin-triggered Spontaneous Bahra et al Lancet 2001;357:1016-1017 Afridi et al. Arch Neurol 2005;62,1270-1275
Brainstem activations in right and left-sided headache with PET Left-sided headache Right-sided headache Afridi et al., Brain 2005; 128:932-939
dura mater Vg pterygopalatine ganglion trigeminal nucleus C 2 nausea