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

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

3. 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-

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

5. 14/04/2017 5

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

7. 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:
*Percentage of patients reporting depends on how the question is asked.
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1. Kelman L Cephalalgia 2007;27:394– Radat F et al. Cephalalgia 2009;29:338–350. 7 7 7

8. 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

9. Migraine; How to manage?
Standard abortive therapy
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10. 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

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

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

13. 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)
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14. 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
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1. Lipton RB et al. Neurology 2007;68:343–349. 14 14 14

15. 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– Lipchik GL. American Headache Society, Accessed April 2012.
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16. 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
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1. BASH Guidelines Accessed March Whitmarsh TE et al. Cephalalgia 1997;17:600–4. 16 16 16

17. 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
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1. BASH Accessed August Scottish Intercollegiate Guidelines Network 17 17 17

18. 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 (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
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1. Linde K et al. Cochr Database of Syst Rev 2004, Issue 2. Art. No.: CD 18 18 18 18

19. 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
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1. Amitriptyline Summary of Product Characteristics Rosemount Pharmaceuticals Limited. 19 19 19 19

20. 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.: CD Mathew N et al. Neurology 2003;60(Suppl. 1): A336.
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21. 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
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1. Klapper J Cephalalgia 1997;17: 103–8. 2. Chronicle EP et al. Cochr Database of Syst Rev 2004, Issue 3. Art. No.: CD 21 21 21 21

22. 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:
2. Evers S et al. Eur J Neurol. 2006;13: Vargas BB et al. Neurol Clin. 2009;27: Yurekli VA et al. J Headache Pain. 2008;9:37-41.
1. Yurekli VA et al. J Headache Pain 2008;9:37– Bartolini M et al. Clin Neuropharmacol 2005;28:277– Diener HC et al. Cephalalgia 2007;27:814– Silberstein SD et al. Headache 2007;47:170– Spira PJ et al. Neurology 2003;61:1753– Krymchantowski AV et al. Headache 2002;45:510– Saper JR et al. Headache 1994;34:497– Saper JR et al. Headache 2002;42:470–482.
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23. EPISODIC VERSUS CHRONIC
MIGRAINE
TENSION HEADACHE
CLUSTER HEADACHE
CHRONIC
CHRONIC MIGRAINE (CM)
CHRONIC TENSION TYPE HEADACHE
MEDICATION OVERUSE HEADACHE (MOH)
CHRONIC CLUSTER HEADACHE

24. 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?

25. 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, Buse Kelman Allena 2009

26. 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:
Chronic
migraine
management
Dodick DW N Engl J Med 2006;354:158–165. 26 26

27. 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 Hagen J Headache Pain 2010
3. Lovell Curr Opin Neurol Rossi Euro J of Neurol 2010
5. Hagen Cephalalgia Deiner Cephalalgia 2007

28. 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 Ashkenazi JNNP Shields Neurology 2004
4. Tobin & Fitman Headache 2009

29. Botox in Migraine 29

30. 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 U 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 Jul;30(7):804-14
Aurora SK et al., Cephalalgia Jul;30(7):
Dodick DW et al., Headache Jun;50(6):921-36 30 30

31. 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

32. 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

33. Transcranial Magnetic Stimulation for Migraine: A safety Review: Dodick et al Headache 2010;50(7):
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34. 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 =
(Lipton et al., Lancet Neurol 2010;9: ) 34 34

35. Occipital Nerve Stimulator: St Jude’s device
CE Marked
Chronic Migraine and intractable TAC
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36. 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 =
Single Blind, Prospective Feasibility Study N = 66
(Saper et al., AHS 2008) 36

37. Occipital nerve stimulation in migraine & chronic migraine- PRISM
Prospective DB controlled N = 132
n =
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

38. Gamma Core Vagal Nerve Stimulator
Received CE Marked
Low ampere Stimulation
Prophylaxis as well as acute Treatment.
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39. 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

40. 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

41. 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 Hering and Steiner Rossi et al Everz & Marziniak 2010

42. 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

43. Rx for withdrawal symptoms
Steroids: controversial1,2,3
Naproxen 500 mg bd days4
IV DHE intermittent/continuous +/- metoclopramide5,6,7
IV Valproate8
IV clonidine9, Prochlorperazine10, Tizanidine11
1. Krymchantowski and Barbosa Pagelar et al Boe et al Mitsikostas and Jumah Boes et al Silberstein et al Ford and Ford Schwartz et al Silberstein et al Le et al Smith 2002

44. 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

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

46. 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

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

48. 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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