Transcript Headache Forum Treatment of Migraine Series

Headache Forum
Treatment of
Migraine Series
1.
2.
3.
4.
Preventative therapy
Acute therapy
Treatment in special populations
Advanced treatments for refractory
cases
Treatment of
Migraine Series
1.
Preventative Treatment
March 2006
Lucy Vieira MD
Preventative treatment

All patients require acute or abortive therapy,
many need preventative also.

Goals of preventative treatment:
–
–
reduce frequency, duration or severity of migraine
attacks.
Potentially reduce the risk of chronic forms of
migraine? (Limroth et al.,2007 Headache 47(1):13-21)
When do we consider using
preventative treatment?
Can be considered in any patient where there is significant disability
associated with migraine.
1.
2.
3.
4.
5.
6.
7.
8.
in the patients' opinion, migraines significantly interfere with their daily
routines, despite acute treatment
frequent headaches (increased risk of chronic forms if>4-5/month*)
contraindication to, failure of, or overuse of acute therapies
adverse events with acute therapies
the cost of both acute and preventive therapies
patient preference
the presence of uncommon migraine conditions, including hemiplegic
migraine, basilar
migraine, migraine with prolonged aura, or migrainous infarction (to
prevent neurologic damage)
US headache consortium guidelines 2000
*Katsarava Neurology 2004
Goals of Treatment for Prevention of
Migraine
1.
2.
3.
reduce attack frequency, severity, and
duration
improve responsiveness to treatment of
acute attacks
improve function and reduce disability
Reasonable goals for your patient

Reduce headache frequency by 50%
How to use prophylactic agents
A. Start low and go slow: try for usual effective dose (or
until limited by adverse events).
B. Give each treatment an adequate trial: usually
minimum of 2-3 months.
C. Avoid interfering medications (e.g., overuse of
certain acute medications such as ergotamine).
D. Use of a long-acting formulation may improve
compliance.
Patient education is essential for
success:
A. Maximize compliance: discuss with the patient the
rationale for a particular treatment, when and how to
use it, and what adverse events are likely.
B. Address patient expectations: discuss with the
patient the expected benefits of therapy and how
long it will take to achieve them.
C. Create a formal management plan
Evaluation:
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
A headache diary is essential:
-considered the “gold standard” in headache
evaluation.
-should be user-friendly
-should measure attack frequency, severity, duration,
disability, response to type of treatment, and adverse
effects of medication.
Re-evaluate therapy. After a period of stability,
consider tapering or discontinuing treatment.
Danish Headache Clinic
Diagnostic Headache
Diary
Russell MB, Rasmussen BK,
Brennum J, Iversen HK,
Jensen RA, Olesen J. Presentation
of a new instrument:
the diagnostic headache diary.
Cephalalgia 1992; 12:369–
74.
Choosing a prophylactic agent
1.
Consider coexisting conditions:
The Coexisting diseases present both treatment
opportunities and limitations.
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
Select a drug that will treat both disorders.
Establish that there are no contraindications
for the selected drugs (beta-blockers are
contraindicated with asthma)
Choosing a prophylactic agent
2. Establish that there are no contraindications
for treatment – pregnancy. Do not use or if
absolutely necessary use drug with lowest
teratogenic potential.
3. Beware of drug interactions
4. Choose a drug based upon highest clinical
efficacy and safety.
Group 1:
Med- high
efficacy, good
evidence, and
var. side effects
Amitriptyline
Propranolol
Timolol
Divalproex
Topiramate
Group 2:
Lower efficacy
or ltd evidence,
mild to moderate
side effects
Aspirin
Flurbiprofen
Ketoprofen
Mefenamic acid
Naproxen sodium
Tolfenamic acid
Gabapentin
Fluoxetine
Metoprolol
Atenolol,Nadolol
Nimodipine
Verapamil
Group 3:
Efficacious on consensus
and clinical experience, but no
scientific evidence
a. mild-to mod. side effects
Bupropion
Fluvoxamine
Paroxetine
Sertraline
Venlafaxine
Mirtazepine
Doxepin
Imipramine
Nortriptyline
Protriptyline
Trazodone
Group 4:
Med- high efficacy, good
strength of evidence, but
with side effect concerns
Methysergide
Flunarizine*
Pizotifen*
TR-DHE*
Cyproheptadine
b. side effect concerns
Methylergonovine
Phenelzine
Vitamin B2
Magnesium
Feverfew
US headache consortium guidelines and update Silberstein Headache Currents 2006
*N/A in USA
Recommended substances (drugs of first choice) for the prophylaxis
Substances
Betablockers
Metoprolol
Propranolol
Calcium channel blockers
Flunarizine
Antiepileptic drugs
Valproic acid
Topiramate
Daily dose
Level
50–200 mg
40–240 mg
A
A
5–10 mg
A
500–1800 mg
25–100 mg
A
A
Drugs of second choice for migraine prophylaxis (evidence of efficacy, but less
effective or more side effects)
Substances
Daily dose (mg)
Level
Amitriptyline
50–150
B
Naproxen
2 X250–500
B
Petasites
2 X 75
B
Bisoprolol
5–10
B
S. Eversa et al., EFNS guideline on the drug treatment of migraine. European Journal of Neurology 2006, 13: 560–572
Drugs of third choice for migraine prophylaxis (only probable efficacy)
Substances
Daily dose
Level
Acetylsalicylic acid
Gabapentin
Magnesium
Tanacetum parthenium
Riboflavin
Coenzyme Q10
Candesartan
Lisinopril
Methysergide
300 mg
1200–1600 mg
24 mmol
3 X 6.25 mg
400 mg
300 mg
16 mg
20 mg
4–12 mg
C
C
C
C
C
C
C
C
C
S. Eversa et al., EFNS guideline on the drug treatment of migraine. European Journal of Neurology 2006, 13:
560–572
Mechanisms of Action in Migraine
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
Generally uncertain; most were found by
accident.
Thought to generally raise the threshold of
migraine activation:
–
–
–
–
Inhibit CSD
Enhance antinociception
Inhibit peripheral and central sensitization
Modulate sympathetic, parasympathetic or
serotonergic tone.
B Blockers
1. inhibit central B receptors interfering with
vigilance-enhancing adrenergic pathways
2. interaction with 5HT receptors – increasing
5HT synthesis
3. inhibition of NO production by blocking
inducible NOS.
4. inhibition of kainate-induced currents
Beta-Blockers
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
Inhibition of B1 medicated mechanisms:
inhibition of NE release by blocking
presynaptic B receptors.
Delayed effects:
–
–
–
decr. Tyrosine hydroxylase activity (NE synthesis)
Delayed Decr. LC firing
Increased serotonin synthesis
Low serotonin synthesis/activity
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
The preactivation level of cortical excitability
may depend on the state-setting projections
from the brainstem (5HT,NA)
May reflect low interictal raphe-cortical 5HT
activity.
Megela and Taylor, J Comp Physiol Psychol1970; Schoenen J, Biomed Pharmacother1996
Figure 2. Whole-brain serotonin synthesis capacity (K-complex, mL/g/min) values before
and after prophylactic treatment with propranolol or nadolol in five migraine patients
Chugani, D. C. et al. Neurology 1999;53:1473
Antidepressants:
elavil has most evidence of efficacy
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TCAs, SSRI and SNRIs incr synaptic NE or 5HT by
inhibiting re-uptake---reduction in B adrenergic
receptor density.
Long-term treatment decreases 5HT2 receptor
binding - actually enhances 5HT neurotransmission.
TCAs up regulate GABA-B receptors, down-regulate
histamine receptors. Some are 5HT2 receptors
antagonists. Also interact with adenosine systems as
well as BDNF.
Topamax
Increase threshold of activation and decrease
excitability:
–
–
–
–
Inhibit VG sodium channels
Promote GABA neurotransmission
Inhibit Glutamate transmission at AMPA/Kainate receptors
Inhibit carbonic anhydrase
Serotonin Antagonists: Pizotofen and
methysergide metabolites
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5HT 2B and 2C antagonists
Methysergide – 5HT 1 receptor agonist and
also has activity on the 5HT 2 receptor.
–
–
Chronic administration attenuates dural plasma
extravasation after electric stimulation of the rat
trigeminal ganglion (Moskowitz)
Effect on reduction of CGRP release?
Theories of migraine pathogenesis
Hyperexcitability: Ion channels
 Reduced serotonin synthesis
 Energy Metabolism failure
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
CSD
Trigeminovascular system activation
(defense system??) –CGRP release
 Activation of certain brainstem nuclei
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CSD: Cortical spreading depression
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slowly progressive wave of neuronal and glial
depolarization.
–
–
–
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Decr membrane resistance
Incr ECF K+ and neurotransmitters
Incr ICF Na+, Ca+
Can be triggered by trauma, K+ or excitatory amino
acids, electrical stimulation, energy failure and
Na+/K+-ATPase inhibition.
FIG. 2. Leao's original illustration of spreading depression
Somjen, G. G. J Neurophysiol 94: 2-4 2005;
doi:10.1152/classicessays.00031.2005
Copyright ©2005 The American Physiological Society
Visual Aura
Wave of
hyperexcitability
(positive phase)
Followed by a
Wave of cortical
depression
(negative phase)
Ictal and interictal BOLD responses to checkerboard stimulation
in human visual cortex
1. INTERICTAL
Amplitude of
BOLD signal
induced
remains
constant
2. ICTAL
Hadjikhani, Nouchine et al. (2001) Proc. Natl. Acad. Sci. USA 98, 4687-4692
Copyright ©2001 by the National Academy of Sciences
-
↑ in mean MR
signal with ↓ in
oscillation
(scintillations)
-
↓ in mean MR
(scotoma) and
↓ in stimulus
response
Mechanisms of migraine aura revealed by
functional MRI in human visual cortex
Progression:
-3.5 ±1.1mm/min
-Does not cross the PO sulcus
-Does cross cytoarchitectonic boundaries (V1 to V2)
-Does not follow vascular territory
PNAS 2001;98:4687-92
Initial cortical hyperemia like in CSD
(3-4.5 min.)
With an amplified response to visual
stimulation
Followed by mild hypoperfusion(1-2h)
With an attenuated response to visual
stimulation
Characteristic duration and
velocity 3.5 ± 1.1 mm/min
Fig. 2. Time-dependent BOLD activity changes from a single region of interest in VI, acquired
before and during episodes of either spontaneous(C) or induced (B) visual aura
Copyright ©2001 by theNouchine
National Academy ofet
Sciences
Hadjikhani,
al. (2001) Proc. Natl. Acad. Sci. USA 98, 4687-4692
Cortical spreading depression
in the human brain
1- CSD liberates K+, H+,
NO in ECF→
depolarisation of
perivascular trigeminal
terminals on BVs
2- proinflammatory
peptides are released
from trigeminal axons
→local meningeal
inflammatory reaction
3- Activation of the SSN
and vasodilatation
4- Perception of pain
Iadecola C.Nature
Medicine 2002:8(2):110112
FHM 1 AND CSD
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Mouse knock in model (CACNA1A gene):
enhanced susceptibility to CSD through increased
Ca influx via increased channel opening and
subsequent neurotransmitter release (ie: glutamate)
at lower levels of depolarization.
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In vitro blockage of VGCC results in
suppression of KCL induced CSD
Neuron 2004:41(5):701-710
Neurosci Lett 2002;334(2):123-126
Mutations found in FHM
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Ca channel
Na/K ATPase
Glu Transporter
Na channel
Neuronal excitability, Glutamate transmission
and CSD
Preventative agents and CSD
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Rats were treated either over weeks and months,
with one of Topiramate, valproate, propranolol,
amitriptyline, or methysergide , vehicle, or Dpropranolol, a clinically ineffective drug.
The impact of treatment was determined on the
frequency of evoked CSDs after topical potassium
application or on the incremental cathodal
stimulation threshold to evoke CSD.
Ayata et al., 2006. Ann Neurol 2006;59:652–661
Suppression of CSD by chronic administration of migraine prophylactic agents
.
Dose
response
Duration
Ayata et al., 2006. Ann Neurol 2006;59:652–661
propranolol
The need to have long term
treatment
• suggests that these drugs may lead to long-term modulation of gene
expression or their encoded proteins.
– Ie: modulation of ion channels, pumps, neurotransmitter receptors, or
transporter genes
• For example, amitriptyline and methysergide, administered
chronically for 2 to 3 weeks, decreased 5-HT2 receptor expression
which may reduce the frequency of migraine attacks.
• long-term treatment with all five drugs can alter glutamatergic
transmission, either directly or indirectly.
– chronic valproate treatment:
• decr whole-brain glutamate levels after 2 weeks Valproate
• alters whole-brain expression of genes including ion channels (eg,
decreased aquaporin-4, K channel Kv3.2b, and gap junction protein)
• presynaptic Ca-binding proteins (eg, decreased synaptotagmins II and XI),
• and neurotransmitter receptors (eg, decreased metabotropic glutamate
receptor 3 and 5-HT2C receptor) after 30 days of treatment.
GTN model
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
Valproic acid but not propranolol inhibit
induced migraine
Other models are being sought after for the
development of prophylactic agents.
Some factors associated with
Chronification
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Obesity
Head injury
Low socioeconomic status and education
Caffeine overuse
Poor sleep quality (snoring)
Stressful life events
Co-morbid pain
Bigal et al.,Headache 2002;42:575-581,
Scher et al.,Curr Pain HeadacheRep.2002;6:486-91
Scher AI et al.,Pain 2003;106:81-9
Multivariable* risk factors for headache chronicity in patients
with episodic migraine
Risk factors
Odds ratio
95% CI p Value
Headache freq 5–9 d
6.2
1.7–26.6 0.005
Headache freq >10 d
20.1
5.7–71.5 0.001
Overuse
19.4
8.7–43.2 0.001
--------------------------------------------------------------------------------------------*Adjusted for all other variables in the model.
-30% patients developed CDH without medication overuse
Katsarava et al., headache 2004;62(5):788-90
Factors that may play a role in
chronification of migraine
1. Central sensitization after repeated bouts of
migraine
2. Damage to CNS pain modulation system
3. CNS changes due to medication overuse
4. Abnormal focal neurological activity (CNS
pain generators)
5. Persistent activity in a peripheral pain
generator (cervical pathology)
Can treatment with prophylactics
reduce the risk of chronification?
*p=.05
**p<.001
Limmroth,V. Headache 2007.
Change in headache rate. The mean change in the number of headache days per month
from the 4 week baseline period to the last 4 weeks of treatment – by subgroups acc. to
mean headache days per subgroup during baseline
References
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•
•
•
•
•
Cenk Ayata, MD,1,2 Hongwei Jin, PhD,1 Chiho Kudo, DDS, PhD,1 Turgay
Dalkara, MD, PhD,3 and Michael A. Moskowitz, Suppression of Cortical
Spreading Depression in Migraine Prophylaxis Ann Neurol 2006;59:652–
661
Volker Limmroth MD, David Biondi DO, Joop Pfeil MSc, Susanne Schwalen
MD (2007) Topiramate in Patients With Episodic Migraine: Reducing the
Risk for Chronic Forms of Headache. Headache 2007 Jan. 47 (1), 13–21.
Katsarava Z, Schneeweiss S, Kurth T Incidence and predictors of chronicity
of headache in patients with episodic migraine Neurology 2004;62:788-90
S. Eversa, J. A´ frab, A. Fresea, P. J. Goadsbyc, M. Linded, A. Maye and P.
S. Sa´ndorf. EFNS guideline on the drug treatment of migraine. European
Journal of Neurology 2006, 13: 560–572
Russell MB, Rasmussen BK, Brennum J, Iversen HK,Jensen RA, Olesen J.
Presentation of a new instrument: the diagnostic headache diary.
Cephalalgia 1992; 12:369–74.
Silberstein S. Current Preventative Therapy: preventative treatment
mechanisms. Headache Currents 2006; 3 (5/6): 112-119