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
Episodic
Primary Headache
disorders
Secondary
Headache disorders
Chronic
Paroxysmal Headache
Long lasting Headache
Attack Duration < 4 hours +/or
Daily or near daily headache
Discrete episodes
Duration > 4 hours per day
Chronic Migraine
Chronic Tensiontype headache
Adapted from Silberstein et al., Neurology (1996) 47: 871-
Hemicrania
Continua
With or without
medication overuse
New Daily
Persistent
headache
EPISODIC VERSUS CHRONIC

EPISODIC
 MIGRAINE



TENSION HEADACHE
CLUSTER HEADACHE
CHRONIC




CHRONIC MIGRAINE
CHRONIC TENSION TYPE HEADACHE
MEDICATION OVERUSE HEADACHE
CHRONIC CLUSTER HEADACHE
09/04/2015
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
100
Percent of Patients
80
60
40
20
0
Stress Hormones
Not
Weather Sleep Perfume/
Eating
Disturb. Odor
Neck
Pain
Lights
Alcohol
Smoke Sleeping
Late
Heat
Food
Triggers
09/04/2015
*Percentage of patients reporting depends on how the question is asked.
1. Kelman L Cephalalgia 2007;27:394–402. 2. Radat F et al. Cephalalgia 2009;29:338–350.
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
09/04/2015
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)
09/04/2015
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
09/04/2015
1. Lipton RB et al. Neurology 2007;68:343–349.
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
09/04/2015
2007;8:S1–47. 2. Lipchik GL. American Headache Society, 2008.
www.achenet.org/education/BiofeedbackRelaxationTrainingforHeadaches.asp Accessed April 2012.
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
09/04/2015
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
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
09/04/2015
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
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
09/04/2015
1. Linde K et al. Cochr Database of Syst Rev 2004, Issue 2. Art. No.: CD003225.
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
09/04/2015
1. Amitriptyline Summary of Product Characteristics 2009. Rosemount Pharmaceuticals Limited.
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
09/04/2015 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.
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
09/04/2015
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
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
No evidence that they are effective in CM
ACE inhibitors and ARBs
No evidence that they are effective in CM
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.
09/04/2015
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.
22
EPISODIC VERSUS CHRONIC

EPISODIC




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
management
Dodick DW N Engl J Med 2006;354:158–165.
26
CM and MOH: Controversy




1.
3.
5.
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
ICHD II 2006
Lovell Curr Opin Neurol 2010
Hagen Cephalalgia 2009
2. Hagen J Headache Pain 2010
4. Rossi Euro J of Neurol 2010
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
4. Tobin & Fitman Headache 2009
3. Shields Neurology 2004
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
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
PREEMPT POOLED ANALYSIS: MEAN CHANGE
FROM BASELINE IN FREQUENCY OF
MIGRAINE DAYS
Mean change in frequency migraine days
(days/28-day
baseline
period)
from
of migraine
in frequency
change
Mean
days from baseline (days/28-day period)
Double-blind phase:
BOTOX® vs. placebo
0
4
8
0
12
Open-label phase:
All patients on BOTOX®
Study week
16
20
24
28
32
36
40
44
48
52
56
BOTOX® (n=688)
Placebo (n=696)
-2
-4
-6
-8
-10
p<0.001
p<0.001
p<0.001
p<0.001
p<0.001
p<0.001
-12
p<0.001
p=0.006
p=0.024
p=0.003
p=0.003
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.

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
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
Transcranial Magnetic Stimulation for Migraine:
A safety Review: Dodick et al Headache
2010;50(7):1153-63
09/04/2015
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
50
*
Active
39
40
% Patients
Sham
29
30
22
20
16
10
0
n=
82
82
pain free 2 hr
(Lipton et al., Lancet Neurol 2010;9:373-380)
Sustained pain free 2-24 hr
Occipital Nerve Stimulator: St Jude’s device
 CE
Marked
 Chronic Migraine
and intractable TAC
09/04/2015
35
Occipital nerve stimulation in chronic migraine
ONSTIM
• Double-blind randomized parallel group sham stimulation controlled study
50
Pre-set
Adjustable
Medically managed
39
40
NS
27
30
%
Failed two
preventive Rx
*P = 0.032; **P = 0.003
20
9
10
0
4
n=
16
29
17
reduction in headache days
Single Blind,
Prospective Feasibility
Study N = 66
(Saper et al., AHS 2008)
6
*
0
**
50 % responder rate
Occipital nerve stimulation in migraine &
chronic migraine- PRISM
migraine days
migraine days- no MOH
migraine days- +MOH
0
Prospective
DB
controlled
N = 132
-2
n=
-4
62
63
-2.6
-3.9
days
-4.8
-6
-5.5
-5.9
NS
-8
-5
Sham- 1us, 10Hz, <1mA, 1s on 90min off
Active- 250usec/60Hz, 0-12mA
Double blind randomised parallel group sham
stimulation controlled study on patients failed
two preventative treatments
(Lipton et al., Cephalalgia 2009;29:30- IHC2009)
Trial Stimulation
Negative Study
Gamma Core Vagal Nerve Stimulator
 Received
CE Marked
 Low ampere
Stimulation
 Prophylaxis as well
as acute Treatment.
09/04/2015
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?

Where?
IP or OP
 OP as first line and brief IP if no motivation or failed
OP2,3
Before or after preventive
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



23% COMBINATION
ANALGESICS
85% TRIPTANS
ONE YEAR

23%
57%
35-60%
85%

5 YEARS

50% RELAPSE
EPISODIC VERSUS CHRONIC

EPISODIC


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

THANKS





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