Sandler Family Trust. UCSF Medical Center. Headache A Review and Update. Headache The burden. Headache Group, UCSF Disclosure- by proportion*

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1 1 Headache A Review and Update Advances in Internal Medicine June 29 Professor Peter J. Goadsby Peter.Goadsby@headache.ucsf.edu Headache Group, UCSF Disclosure- by proportion Sandler Family Trust UCSF Medical Center Governments: California, Korea, Germany, Turkey Industry MSD/Neuralieve/Medtronic/GSK/MAP/Boston Scientific/JnJ Department of Neurology Font scale in proportion to contribution Q28 to Q19 (Font ~ {Contribution/Total Group Income} 1) Headache The burden Population Neurology OPD RA asthma diabetes OA Headache Epilepsy Alzheimers Stroke Parkinsons (sources: CDC, US Census, Neurology Ambassadors Program) 3 1 Headache International Headache Society Classification Primary 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 24;24:1-16)

2 2 Landmark Study How often are physicians wrong when they diagnose non-migraine in a patient complaining of primary headache? Age Specific Prevalence in the United States Prospective, open-label study Patients tracked for three months or six attacks Assigned IHS diagnoses by experts % Patients with non-migraine, Migrainous >6 7 female male (Tepper et al., Headache 24;44: ) (Lipton et al., Headache 21; 41: ) Update in Classification & Diagnosis Pathophysiology Treatment 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)

3 3 with aura Classification Is there Medication Overuse? Analgesics ten days or more per month Episodic Feature full headache Throbbing, unilateral, photophobia, phonophobia, movement effect without aura Is there headache on 15 days or more per month? Chronic (15+ days/month) Attacks The Attacks & the Disorder 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 1 days/month Triptans at 13 days/month NSAIDs are protective if used more than five days a month & Stroke Risk General risks Specific issues Brain lesions Patent foramen ovale (PFO) Bigal et al., Headache 28;48:1157

4 4 & Stroke Risk General risks Case-control Study (Tzourio et al., BMJ 1995;31:83) n = 72; females <45 yr without aura OR 3. ( ) with aura OR 6.2 ( ) Bonus- o/c, 13.9; Ciggs (>2/day) 1.2 Women s Health Study (Kurth et al., Neurology ;64:12) n = 39,754 females >45 yr MWOA, non-migraine-> no risk MWA OR 1.53 ( ) 3.8 cases per 1, women & Stroke Risk Specific issues Brain lesions (JAMA 24;291:427) N = 435; populationbased MRI study Patent foramen ovale (PFO) Autopsy studies M.I.S.T. PFO Closure- MIST-I- is this the answer? Update in % Elimination of attacks Primary endpoint PFO closure does not eliminate headache 4 5 sham n = closure Classification & Diagnosis Pathophysiology Genetics Aura Pain Treatment Dowson et al., Circulation 28;117:1397

5 5 as an Ionopathy not a Vascular Problem The tentorial nerve is a branch of V 1 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 23;33:192 FHM-III SCN1A: Voltage-gated Na + channel chr 2 Dichgans et al., Lancet ;366:371 (Feindel et al., Neurology 196;1:555) and the Neck Referred Pain in the Trigeminocervical Complex (TCC) Neck and Headache dura mater V ganglion trigeminal nucleus Cervical input C 1 C 2 }TCC Bartsch & Goadsby Current Pain and Headache Reports 23;7:

6 6 and the pons a systems disorder Nitroglycerin-triggered Spontaneous Bahra et al Lancet 21;357: Afridi et al. Arch Neurol ;62, (after Goadsby et al., NEJM 22; 346:7-27) Update in 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

7 7 Choice of treatment in acute migraine Acute attack treatments Trigeminovascular System & Non-specific aspirin or acetaminophen NSAIDS ibuprofen naproxen tolfenamic acid opioids Specific ergotamine derivatives ergotamine dihydroergotamine Triptans sumatriptan almotriptan eletriptan frovatriptan naratriptan rizatriptan zolmitriptan (Goadsby et al., NEJM 22; 346:7-27) %patients Acute Treatment of with Sumatriptan and Naproxen Double-blind randomized parallel group single attack adult migraineurs Placebo Naproxen 5 mg SumaRT 85 mg SUMA+Npx Study I Study II Meta-analysis n = pain free 2hr pain free 2hr Sumatriptan 1 mg Brandes et al., JAMA 27;297:1443 SumaRT/Nap Ferrari et al., Lancet 21;358:1668 sumatriptan %patients Acute Treatment of with Sumatriptan and Naproxen Double-blind randomized parallel group single attack adult migraineurs Placebo Naproxen 5 mg SumaRT 85 mg SUMA+Npx n = Sustained pain free Sustained pain free Sumatriptan 1 mg Brandes et al., JAMA 27;297:1443 SumaRT/Nap 19 Ferrari et al., Lancet 21;358:1668 sumatriptan AEs Nausea Somnolence Dizziness Paresthesia Dyspepsia

8 8 Trigeminovascular System & 5-HT 1D CGRP Trigeminal Activation & CGRP (Goadsby et al., NEJM 22; 346:7-27) Hou et al., Brain Res 21;99: (pmol/l) Trigeminal ganglion Superior Sagittal Sinus CGRP Substance P Cat CGRP Substance P CGRP Substance P Human Cat Ann Neurol 1988;23:193 Neuropeptides 199;16:69 (pmol/l) Calcitonin Gene-Related Peptide (CGRP) and CGRP is released in the cranial circulation in migraine 1 BIBN496BS (olcegepant), a CGRP receptor antagonist, is effective in migraine 2 CGRP Sub P control MWA MWOA HA response placebo BIBN496BS 2.5mg 12 Aes gepants Calcitonin/Calcitonin gene-related peptide (CGRP) Receptor Family Ian Dickersonwww.urmc.rochester.edu CLR CTR Ramp Agonist Telcagepant nm 1 CGRP.77 2 adrenomedullin 1, 3 adrenomedullin 29, 1 amylin 19 Calcitonin-like receptor (CLR) CGRP binds to CLR when it is co-expressed with receptor activity modifying protein 1 (RAMP1); Adrenomedullin (AM) binds to CLR when CLR when RAMP2 or RAMP3 expressed; Calcitonin Receptor (CTR) Calcitonin (CT) binds to the CTR); Amylin binds to CTR in the presence of RAMP1, RAMP2, or RAMP amylin 1, 1 Goadsby et al., Ann Neurol 199;28:183 2 Olesen et al NEJM 24;35:114

9 9 CGRP receptor antagonist telcagepant is effective in the treatment of acute migraine CGRP receptor antagonist telcagepant is effective in the treatment of acute migraine 5 Double-blind parallel group randomised controlled trial 2 Hour pain free Placebo T-15 T-3 Z5 Z2.5 5 Double-blind parallel group randomised controlled trials 2 Hour pain free Placebo T-15 T-3 Z5 (% patients) (% patients) N = Ho et al., Ferrari et al., Lancet 28;372:2115 Lancet 21;358;1668 N = Ho et al., Ho, AAN 29 Lancet 28;372:2115 CGRP receptor antagonist telcagepant is effective in the treatment of acute migraine CGRP receptor antagonist telcagepant is effective in the treatment of acute migraine Sustained pain free (SPF) at 24 and 48 hr 3 SPF 2-24 SPF Placebo T-15 T-3 Z5 5.7 (% patients) Placebo T-15 T-3 Zolmitriptan-5 (% patients) Aes Triptan-like Aes?Gepant-class AEs- dry mouth, fatigue (Ho et al., Lancet 28;372:2115 ) (Lancet 28;372:2115)

10 1 Preventives By mechanism Amine modulation 5-HT 2 : cyproheptadine, methysergide β- blockers: propranolol Tricylics: amitriptyline MAOI s: Phenelzine Channel modulation Gabapentin Topiramate Valproate Other - Neutriceuticals: riboflavin - Botulinum toxin % Reduction in headache days placebo Topiramate in Chronic topiramate 1mg/day 23.2 n = Diener et al., Cephalalgia 27;27: Silberstein et al., Headache 26;46:838 P < Reduction in migraine days How long does the effect of a preventive last? Topiramate PROMPT Study yrs, baseline one month- 8.9 attacks/month Six month open label Rx, then randomised to placebo or topiramate for six months Open Baseline Placebo withdrawal Month six Month six n = Diener et al., Cephalalgia 27;27:757; P < topiramate 5-2 mg placebo Botulinum Toxin and Headache χ Chronic tension-type headache No difference in frequency; n = 3 Silberstein et al., Cephalalgia 26;26:717 χ (episodic) No differences; n = 232 Saper et al., J Neurol ; 2: II-58 No differences; n = 495 Relja et al., J Neurol ; 2: II-62. Reduced frequency (?primary endpoint); n = 128 Chankrachang et al., Cephalalgia ; : 992 χ Chronic Daily Headache No reduction in headache frequency; n = 72 Silberstein et al., Mayo Clin Proc ; 8: No reduction in headache free days; n = 355 Mathew et al., Headache ; 45: ? Chronic Reduced headache frequency on no other preventive (sub-group ) Dodick et al., Headache ; 45: 315 Two RCTs Positive for reduction in headache days (Press release)

11 11 Transcranial magnetic stimulation for Randomised double-blind placebo controlled study Include: 3% aura episodes, aura leads to headache 9% Exclude: Prolonged aura, MOH TMS-.9T for 18 µs; 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 % Patients Sham Active TMS & CSD in the rat TMS (rise time 17µs; T) blocked 5 of 9 needle prick (NP) induced CSD s when pulsed 3s post-np 1 n = pain free 2 hr Sustained pain free 2-24 hr (Lipton et al., AHS Late-breaking abstract) (Holland et al., Neurology 29;72-Suppl 3:A) dura mater Vg pterygopalatine ganglion trigeminal nucleus C 2 nausea

12 12 Infarctions in the Migrainous Brain? Occipital nerve stimulation in chronic migraine ONSTIM Double-blind randomized parallel group sham stimulation controlled study Note- occipital pain, fail 2 preventives, exclude MOH 5 Pre-set Adjustable Medically managed 18Jan6 % 4 3 NS Kruit et al., Brain ;128:268 3Feb6 Rozen Cephalalgia 27;27: n = reduction in headache days 5 % responder rate Adverse event: lead migration in 24 % (Saper et al., AHS 28 late-breaking) P =.32; P =.3 6