MANAGING PRIMARY HEADACHES AN OVERVIEW FAYYAZ AHMED HULL & EAST YORKSHIRE HOSPITALS NHS TRUST

LEARNING OUTCOME The Current management strategy for common primary headache disorders Appraisal of currently available treatments New treatments on the horizon

Primary Headache Disorders: Frequency Classification Secondary Headache disorders Episodic Chronic Paroxysmal Headache Attack Duration < 4 hours +/or Discrete episodes Long lasting Headache Daily or near daily headache Duration > 4 hours per day With or without medication overuse Chronic Migraine Chronic Tension-type headache Hemicrania Continua New Daily Persistent headache Adapted from Silberstein et al., Neurology (1996) 47: 871-

EPISODIC VERSUS CHRONIC MIGRAINE TENSION HEADACHE CLUSTER HEADACHE CHRONIC CHRONIC MIGRAINE CHRONIC TENSION TYPE HEADACHE MEDICATION OVERUSE HEADACHE CHRONIC CLUSTER HEADACHE

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Episodic Migraine; How to manage? Identify any obvious triggers Infrequent attacks Acute treatment only Frequent attacks Acute and Preventative treatments

High Percentage of Migraine Patients Report Triggers 76% to 95% of patients report triggers*,1 The mean number of triggers per patient is 6.71 Stress has been shown to be even more important in chronic migraine than in episodic migraine2 20 40 60 80 100 Stress Hormones Not Eating Weather Sleep Disturb. Perfume/ Odor Neck Pain Lights Alcohol Smoke Sleeping Late Heat Food Percent of Patients Triggers In a headache referral patient sample, 76% of patients affirmed that at least some of their headaches were triggered by some sort of trigger factor that they had identified. However, when the same patient sample was provided with a list of potential migraine triggers, 95% confirmed that some of the listed triggers at least occasionally triggered their headaches.1 The mean number of triggers identified by individual patients was 6.7. The 5 most common triggers identified by patients were stress; missing meals or fasting; weather change; undersleeping; and, in women, hormonal changes.1 The frequency of individual triggers occurring at least occasionally varied enormously, from stress (79.7%) and hormones (in women; 65.1%) to, least frequently, sexual activity (5.2%). In diminishing order of frequency following stress and hormones, these were not eating (57.3%); weather (53.2%); sleep disturbance (49.8%); perfume or odor (43.7%); neck pain (specifically reported as not part of the headache but neck pain worsening and causing headache; 38.4%); lights (38.1%); alcohol (37.8%); smoke (35.7%); sleeping late (32.3%); heat (30.3%); food, not specificied what (26.9%); and exercise (22.1%). 1 Patients with episodic migraine had fewer triggers associated with stress, not eating, perfume/odor, neck pain, smoke, sleeping late, and exercise than patients with chronic migraine.1 Reference: 1. Kelman L. Cephalalgia. 2007;27:394-402. *Percentage of patients reporting depends on how the question is asked. 14/04/2017 1. Kelman L Cephalalgia 2007;27:394–402. 2. Radat F et al. Cephalalgia 2009;29:338–350. 7 7 7

ACUTE TREATMENT OF MIGRAINE ATTACK Ergot (1868) Salicylic acid (1870) Ergotamine Dihydroergotamine (DHE) Triptans in early 90’s (working on 5 HT1 receptors) Sumatriptan Rizatriptan Eletriptan Almotriptan Zolmitriptan Naratriptan Frovatriptan

Migraine; How to manage? Standard abortive therapy 14/04/2017 9 9

Acute Rx: Key Message Avoid opiates or combination analgesics with barbiturates, caffeine Restrict the use to no more than two days/doses per week NSAID has the lowest potential for medication overuse

New Rx on the Horizon CGRP antagonists or Gepants Glutamate Receptor Antagonists Vanilloid (TRPV1) receptor antagonists Nitric Oxide Synthetase inhibitors Prostanoid Receptor Antagonist

New ways of Established Rx Inhaled version of DHE (MAP-004 - LEVADEX©) Triptans Melts and sprays Needle free injection (intraject) Transdermal patches (Zelrix) Sumnap (sumatriptan Naproxen combination)

MIGRAINE PROPHYLAXIS When should I give migraine prophylaxis? Prophylaxis is used to reduce the number of attacks in circumstances when acute therapy, used appropriately, gives inadequate symptom control. (BASH GUIDELINES 2010) 14/04/2017 13

Consensus view on migraine prophylaxis Should be offered to patients with 6 or more headache days per month; 4 or more days with some impairment; or 3 or more days with severe functional impairment Should be considered with 4–5 days per month with normal functioning; 3 days with some impairment and 2 days with severe impairment Should not be given to patients with <4 days of headache per month with normal functioning; or no more than 1 day per month regardless of impairment 14/04/2017 1. Lipton RB et al. Neurology 2007;68:343–349. 14 14 14

Migraine prophylaxis treatment options Non-pharmacological1,2 Behavioural lifestyle changes Anxiety management, psychotherapy and physiotherapy Pharmacological Few agents specifically licensed for migraine prophylaxis 1. World Health Organization (WHO) in collaboration with the European Headache Federation (EHF). J Headache Pain 2007;8:S1–47. 2. Lipchik GL. American Headache Society, 2008. www.achenet.org/education/BiofeedbackRelaxationTrainingforHeadaches.asp Accessed April 2012. 14/04/2017 15 15 15 15

Non-drug interventions Acupuncture has little benefit, if any at all Physiotherapy for the neck as an adjunctive treatment may be useful Indian head massage may be useful but the evidence is anecdotal Relaxation therapy, stress reduction and coping strategies are helpful These interventions are in need of formal evaluation Yoga and meditation are said to enhance stress management and appeal to some people1 Homeopathy offers no value2 14/04/2017 1. BASH Guidelines 2010. http://216.25.88.43/upload/NS_BASH/BASH_guidelines_2010.pdf  Accessed March 2012. 2. Whitmarsh TE et al. Cephalalgia 1997;17:600–4. 16 16 16

Pharmacological options for migraine prophylaxis1,2 Amine modulation: Beta blockers 5-HT blockers (pizotifen, methysergide) Channel modulation: Anticonvulsants (topiramate, epilim*) Tricyclic Antidepressants Amitriptyline* ACE inhibition: Lisinopril* * Currently not licensed for migraine prophylaxis in the UK 14/04/2017 1. BASH 2010. http://216.25.88.43/upload/NS_BASH/BASH_guidelines_2010.pdf Accessed August 2011. 2. Scottish Intercollegiate Guidelines Network 2008. http://www.sign.ac.uk/guidelines/fulltext/107/index.html. 17 17 17

Beta blockers First-line if not contraindicated by asthma, heart failure, peripheral vascular disease or depression Use of propranolol in migraine prophylaxis1: 58 propranolol studies met the inclusion criteria, of which 26 were placebo controlled Overall relative risk of response to treatment was 1.94 (95% CI 1.61 to 2.35) 17 trials showed a significant superiority over placebo, 7 a trend for propranolol and 2 no difference Commonly reported adverse events include cold extremities, reduced exercise tolerance, nightmares and dizziness 14/04/2017 1. Linde K et al. Cochr Database of Syst Rev 2004, Issue 2. Art. No.: CD003225. 18 18 18 18

Amitriptyline Used widely second only to beta-blockers 3 small trials of amitriptyline (all before 1987) show 21–42% reduction in number of attacks May be used first-line when migraines co-exist with troublesome tension-type headache, another chronic pain condition, disturbed sleep or depression Commonly reported adverse events include dry mouth, sedation, dizziness and nausea1 Dose used ranges between 10 and 150 mg per day1 Individual tolerance to dosages varies and titration is highly dependent on side-effects experienced 14/04/2017 1. Amitriptyline Summary of Product Characteristics 2009. Rosemount Pharmaceuticals Limited. 19 19 19 19

Topiramate Clinical trials suggest efficacy equal to sodium valproate1 Use of topiramate in migraine prophyalxis2: 6 (of 6) topiramate studies showed overall superiority to placebo in the combined analysis (OR 3.34; 95% CI 2.36 to 4.73) with noticeable variation in the odds ratio across the studies2 A dose of 100 mg reports a 50% response rate3 Cognitive side effects and tingling sensation in fingers and toes often limit its use Around a quarter of patients report loss of weight of around 10% and can act as a mood stabiliser 1. Shaygannejad V et al. Headache 2006;46: 642–8. 2. Chronicle EP et al. Cochr Database of Syst Rev 2004, Issue 3. Art. No.: CD003226. 3. Mathew N et al. Neurology 2003;60(Suppl. 1): A336. 14/04/2017 20 20 20 20

Valproate Sodium valproate has a response rate of around 44%1 It does not reduce the efficacy of hormonal contraception Use of valproate in migraine prophyalxis2: 4 (of 4) valproate studies showed active treatment was superior to placebo in reduction in migraine frequency (OR 3.34; 95%CI 1.46 to 7.67)2 Adverse events reported include nausea, asthenia, somnolence, weight gain and alopecia Blood cell count, platelet count, bleeding time and coagulation tests are recommended prior to starting treatment and in case of spontaneous bruising or bleeding Liver dysfunction is reported rarely 14/04/2017 1. Klapper J Cephalalgia 1997;17: 103–8. 2. Chronicle EP et al. Cochr Database of Syst Rev 2004, Issue 3. Art. No.: CD003226. 21 21 21 21

Few Clinical Trials Have Focused on Preventive Pharmacotherapy in Chronic Migraine ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker. Treatment Evidence for Use in Chronic Migraine Anticonvulsants: Valproate Topiramate Gabapentin Small double-blind, placebo-controlled in CM1,2 Double-blind, placebo-controlled trials in CM3,4 One double-blind, placebo-controlled trial in CDH5 Antidepressants: Amitriptyline Fluoxetine Tizanidine Small open-label trial in TM6 Small double-blind, placebo-controlled trial in CDH7 Small double-blind, placebo-controlled trial in CDH8 Beta-blockers No evidence that they are effective in CM Calcium channel blockers ACE inhibitors and ARBs There is evidence for the use of many treatments as first line in episodic migraine,1,2 but few clinical trials have focused on chronic migraine specifically and there are no treatment guidelines available. Randomized trials of the use of preventive medications in chronic migraine are scarce, and available studies are limited by small numbers of patients.3 Only a few pharmacologic options have been tested in randomized, double-blind, placebo-controlled studies or active comparator-controlled trials and these include amitriptyline, topiramate, gabapentin, tizanidine, valproate, and fluoxetine.4   References: 1. Silberstein SD Neurology. 2000;55:754-762. 2. Evers S et al. Eur J Neurol. 2006;13:560-572. 3. Vargas BB et al. Neurol Clin. 2009;27:467-479. 4. Yurekli VA et al. J Headache Pain. 2008;9:37-41. 1. Yurekli VA et al. J Headache Pain 2008;9:37–41. 2. Bartolini M et al. Clin Neuropharmacol 2005;28:277–279. 3. Diener HC et al. Cephalalgia 2007;27:814–823. 4. Silberstein SD et al. Headache 2007;47:170–180. 5. Spira PJ et al. Neurology 2003;61:1753–1759. 6. Krymchantowski AV et al. Headache 2002;45:510–514. 7. Saper JR et al. Headache 1994;34:497–502. 8. Saper JR et al. Headache 2002;42:470–482. 14/04/2017 22 22 22

EPISODIC VERSUS CHRONIC MIGRAINE TENSION HEADACHE CLUSTER HEADACHE CHRONIC CHRONIC MIGRAINE (CM) CHRONIC TENSION TYPE HEADACHE MEDICATION OVERUSE HEADACHE (MOH) CHRONIC CLUSTER HEADACHE

Chronic Migraine The IHS 2006 Revised Classification previously Triptan/Ergot responsive? Headache on > 15 days month with features of Migraine type headache On > 8 days / month* for > 3 months without other cause of headache *ICHD-2 = Previously >15 With or without Analgesic Medication Overuse Headache?

CHRONIC MIGRAINE Under-diagnosed and Under-treated Most disabling form of headache disorder1 Co-morbidities are more common2 Trigger factors more pronounced than episodic variety3 50-80% overuse painkillers4 Patients may have low pain threshold and abnormal cortical processing5 1. Blumenfield, 2011 2. Buse 2009 3. Kelman 2007 4. Allena 2009

Chronic Migraine: Multifaceted Approach to Therapy Lifestyle modifications, behavioral therapy Education, support, managing expectations, and close follow-up Pharmacologic therapy Chronic migraine is a complex condition that requires a multifaceted multidisciplinary approach to care, including nonpharmacologic and pharmacologic therapy.1 We will walk through each of these approaches. Reference: 1. Dodick DW N Engl J Med. 2006;354:158-165. Chronic migraine management Dodick DW N Engl J Med 2006;354:158–165. 26 26

CM and MOH: Controversy IHS criteria exclude MO in defining CM1 Preventive treatment first or deal with MOH2,3,4 Does MO reduce efficacy of preventive agent?5 Topiramate trial showed equal response in both arms i.e. with or without MOH6 1. ICHD II 2006 2. Hagen J Headache Pain 2010 3. Lovell Curr Opin Neurol 2010 4. Rossi Euro J of Neurol 2010 5. Hagen Cephalalgia 2009 6. Deiner Cephalalgia 2007

GREATER OCCIPITAL NERVE BLOCK (GON) Local anaesthetic +/- Steroids 50% respond for up to 1 month1,2 20% no benefit3 Local discomfort and alopecia4 1. Afridi Pain 2006 2. Ashkenazi JNNP 2007 3. Shields Neurology 2004 4. Tobin & Fitman Headache 2009

Botox in Migraine 29

Botulinum Toxin A in Chronic Migraine PREEMPT Studies 2 Trials: PREEMPT1 and PREEMPT 2 Phase 3, parallel-group, placebo-controlled studies of Botulinum toxin A 155-195U in Chronic Migraine 1384 patients randomised (Botulinum toxin A 688, Placebo 696) 31 injections per treatment session CSR p89 Figure 11-2 Diener HC et al., Cephalalgia. 2010 Jul;30(7):804-14 Aurora SK et al., Cephalalgia. 2010 Jul;30(7):793-803 Dodick DW et al., Headache. 2010 Jun;50(6):921-36 30 30

PREEMPT POOLED ANALYSIS: MEAN CHANGE FROM BASELINE IN FREQUENCY OF MIGRAINE DAYS Double-blind phase: BOTOX® vs. placebo Open-label phase: All patients on BOTOX® Study week Nearly 70% of patients treated with BOTOX® throughout the entire study experienced ≥50% reduction in migraine days from baseline at Week 56 (67.8% vs. 59.6% for placebo; p=0.018)3 4 8 12 16 20 24 28 32 36 40 44 48 52 56 BOTOX® (n=688) Placebo (n=696) -2 -4 Mean change in frequency migraine days from baseline (days/28-day period) Mean change in frequency of migraine days from baseline (days/28-day period) -6 Notes Significant differences for BOTOX® versus placebo were observed at all time points in PREEMPT, starting at the first post-treatment study visit (Week 4) and including Week 24, for the secondary efficacy variable of mean change from baseline in frequencies of migraine days (p<0.001):1 Week 24 95% CIs: BOTOX®/BOTOX® –8.69, –7.70 Placebo/BOTOX® –6.69, –5.68 Week 56 95% CIs: BOTOX®/BOTOX® –11.71, –10.74 Placebo/BOTOX® –10.82, –9.80 Reference 1. Aurora SK et al. Poster presented at: 14th International Headache Congress, September 10-13, 2009, Philadelphia, PA. p<0.001 p<0.001 -8 p<0.001 p<0.001 p<0.001 p<0.001 -10 p<0.001 p=0.006 p=0.003 p=0.003 p=0.024 -12 p=0.018 p=0.013 p=0.01 -14 Mean ± standard error. The double-blind phase included 688 subjects in the BOTOX® group and 696 in the placebo group. Migraine days at baseline: 19.1 BOTOX® group vs 18.9 placebo group, p=0.328. 1. Dodick DW et al. Headache 2010;50:921–936. 2. Aurora SK et al. Presented at IHC 2009. 3. Allergan Data on File – 50% responder rate at Week 56. 31

TRANSCRANIAL MAGNETIC STIMULATION TMS devices deliver a brief magnetic pulse to the scalp and underlying cortex, altering firing patterns targets cortical spreading depression (CSD) CSD is a wave of excitation followed by a wave of inhibition 32

Transcranial Magnetic Stimulation for Migraine: A safety Review: Dodick et al Headache 2010;50(7):1153-63 14/04/2017 33

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 ms; 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 n = 82 82 (Lipton et al., Lancet Neurol 2010;9:373-380) 34 34

Occipital Nerve Stimulator: St Jude’s device CE Marked Chronic Migraine and intractable TAC 14/04/2017 35

Occipital nerve stimulation in chronic migraine ONSTIM Double-blind randomized parallel group sham stimulation controlled study Failed two preventive Rx NS *P = 0.032; **P = 0.003 % * ** n = 16 29 17 Single Blind, Prospective Feasibility Study N = 66 (Saper et al., AHS 2008) 36

Occipital nerve stimulation in migraine & chronic migraine- PRISM Prospective DB controlled N = 132 n = 62 63 days Trial Stimulation Negative Study NS Double blind randomised parallel group sham stimulation controlled study on patients failed two preventative treatments (Lipton et al., Cephalalgia 2009;29:30- IHC2009) 37 37

Gamma Core Vagal Nerve Stimulator Received CE Marked Low ampere Stimulation Prophylaxis as well as acute Treatment. 14/04/2017 38

MOH: Definition IHS 2004, Revised 2005*, Appendix Criteria 2006 Headache present on > 15 d/month for > 3 months Regular overuse for > 3 months of Triptan or ergot or opiates or combination analgesics > 10 d/month Simple analgesics or combination with above > 15 d/month Headache developed or worsened during overuse * Probable until headache improves after withdrawal

Which Medication? Combination analgesic 39-42% Simple Analgesic 29-38% Triptans 12-20% Opiates 6% Ergotamine 4-11% MOH develops faster with triptan than simple analgesics and similarly withdrawal symptoms are much milder with triptans Relja et al Headache 2004 Zeeberg et al Cephalalgia 2006 Katsarava et al 2000,2001

MOH: Rx Strategy How? Abrupt or Gradual Abrupt with simple analgesic/triptan Gradual with combination analgesic, opiates4 Worse before better; short duration for rebound with triptan than combination and opiates1 When? Before or after preventive Where? IP or OP OP as first line and brief IP if no motivation or failed OP2,3 1. Diener and Katsarava 2001 2. Hering and Steiner 1991 3. Rossi et al 2006 4. Everz & Marziniak 2010

What to expect after withdrawal? 70% get worse Withdrawal symptoms of nausea, vomiting, sleep disturbance and autonomic symptoms Katsarava et al 2002 Headache intensity worsens at day 2-4 before improvement

Rx for withdrawal symptoms Steroids: controversial1,2,3 Naproxen 500 mg bd 10-20 days4 IV DHE intermittent/continuous +/- metoclopramide5,6,7 IV Valproate8 IV clonidine9, Prochlorperazine10, Tizanidine11 1. Krymchantowski and Barbosa 2000 2. Pagelar et al 2008 3. Boe et al 2008 4. Mitsikostas and Jumah 2011 5. Boes et al 2006 6. Silberstein et al 1991 7. Ford and Ford 1997 8. Schwartz et al 2003 9. Silberstein et al 2006 10. Le et al 2000 11. Smith 2002

PROGNOSIS OF MOH 2 WEEKS ONE YEAR 5 YEARS 23% COMBINATION ANALGESICS 85% 57% 23% 2 WEEKS 23% COMBINATION ANALGESICS 85% TRIPTANS ONE YEAR 35-60% 5 YEARS 50% RELAPSE

EPISODIC VERSUS CHRONIC MIGRAINE TENSION HEADACHE CLUSTER HEADACHE CHRONIC CHRONIC MIGRAINE (CM) CHRONIC TENSION TYPE HEADACHE MEDICATION OVERUSE HEADACHE (MOH) CHRONIC CLUSTER HEADACHE

EPISODIC CLUSTER HEADACHE 100% oxygen 4-8 litres/min or immigran sc injection 6 mg or nasal spray for acute attack Steroids to induce remission Verapamil Methysergide Pizotifen Topiramate Gabapentin

CHRONIC CLUSTER HEADACHE Lithium Other drugs used in episodic Can be refractory GON injection ONS Deep Brain Stimulation

INDOMETACIN RESPONSIVE HEADACHE Absolute Response Paroxysmal Hemicrania Hemicrania Continua Partial Response Primary Stabbing headache Hypnic Headache Primary cough, exertional or coital headache

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