Migraine PathophysiologyAn Update
Professor Peter J. [email protected]
BASH Teaching MeetingHull
22 January 2009
Department of Neurology
Migrainea systems disorder
(after Goadsby et al., NEJM 2002; 346:257-270)
Migraine and the pons
Bahra et alLancet 2001;357:1016-1017
Afridi et al.Arch Neurol 2005;62,1270-1275
Nitroglycerin-triggered Spontaneous
Brainstem activations in right and left-sided headache with PET
Left-sided headache Right-sided headache
Afridi et al., Brain 2005; 128:932-939
MigraineThe Attacks & the Disorder
• Premonitory symptoms• Pain
– unilateral– throbbing– movement worse
• Nausea• Sensory sensitivity
– photophobia– phonophobia– osmophobia
• Aura
• 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
Attacks Disorder
“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
MigraineClassification
Feature full headacheThrobbing, unilateral, photophobia,
phonophobia, movement effect
Episodic Migraine Chronic Migraine(15+ days/month)
Is there Medication Overuse?Analgesics ten days or more per month
Migraine with aura Migraine without aura
Is there headache on 15 daysor more per month?
Migraine Pathophysiolgy- Update
• Genetics
• Pain mechanisms
• Treatment
Genetics of Migraine Familial Hemiplegic Migraine- an ionopathy
FHM-II ATP1A2:Na+/K+ ATPase chr 1q23
FHM-I CACNA1A:P/Q voltage-gated Ca2+ channel chr 19
Ophoff et al. Cell 1996; 87:543
De Fusco et al. Nat Gen 2003;33:192
FHM-III SCN1A:Voltage-gated Na+ channel chr 2
Dichgans et al., Lancet 2005;366:371
FHM-IV ?:
Infarctions in the Migrainous Brain?
Kruit et al., Brain 2005;128:2068Rozen Cephalalgia 2007;27:557-560
18Jan06
3Feb06
Migraine aura
Silberstein et al.,Headache in Clinical Practice 2nd Ed
2002
Secretin/Glucagon Superfamily Peptides and Migraine
MCAVEL Migraine
VIP2 16% 0/12
PACAP3 16% 7/11
VIP1 PACAP
VPAC1 ++ ++
VPAC2 ++ ++
PAC1 +
VIP, vasoactive intestinal polypeptide; PACAP, pituitary adenylate cyclase activating peptide
1. Jansen-Olesen et al., Peptides 2004;25:21052. Rahmann et al., Cephalalgia 2008;28:2263. Henrik et al., Brain 2009; in press
Migraine Pathophysiolgy- Update
• Genetics
• Disease mechanismsPremonitory symptoms
– The neck
– Allodynia
– Medication overuse
• Treatment
When does migraine start?
Time (hours)
-100 -50 0 50 100
VA
S r
atin
g of
sta
te o
f hea
lth
0
20
40
60
80
100
headache
premonitory
(Giffin et al., Neurology 2003; 60:935-940)
Are there Phases of a Migraine Attack?
0
20
40
60
80
100 premonitoryheadachepostdrome
(Giffin et al., Neurology 2003;60:935-940)
% p
atie
nts
Dose-dependent dopaminergic modulation of trigeminocervical complex neurons
Bergerot et al. Ann Neurol 2007;61:251-262
MMA: middle meningeal artery
D1
D2
D2
Dopamine NeuN
A11 Neurons are Dopaminergic
Charbit et al.,
A11 neurons contain tyrosine hydroxylase (green) but not dopamine -hydroxylase
(red)
A11 Stimulation is Anti-Nociceptive through a dopaminergic mechanism
MMA
MMA + A11
Charbit, Akerman & Goadsby
A11 lesioning is Pro-Nociceptive
MMA
MMA + A11 lesion
Pe
rce
nta
ge
of
ba
se
lin
e f
irin
g
0
20
40
60
80
100
120
140
160 MMAnoxious pinchinnocuous brush
Baseline response
5-40mins post lesion A11
or control
Le
sion
A11
(n
= 8
)
Sha
m
(n =
5)
*
*
Sha
m
(n =
5)
Sha
m
(n =
5)
Le
sion
A11
(n
= 8
)
Le
sion
A11
(n
= 8
)
Charbi, Akerman & Goadsby
Migraine Pathophysiolgy- Update
• Genetics
• Disease mechanisms– Premonitory symptoms The neck
– Allodynia
– Medication overuse
• Treatment
dura mater
V ganglion
trigeminalnucleus
C2
C1
Migraine and the NeckReferred Pain in the Trigeminocervical Complex (TCC)
Cervical input
}TCC
Neck and Headache
Bartsch & Goadsby Current Pain and Headache Reports 2003;7:371-376
Migraine Pathophysiolgy- Update
• Genetics
• Disease mechanisms– Premonitory symptoms
– The neckAllodynia
– Medication overuse
• Treatment
Allodynia and migraine• Allodynia
– pain from non-noxious heat, cold or pressure• Incidence
– …now and then extensive pain over the head may be accompanied by some general tenderness of the hairy scalp…
– Two-thirds of 500 patients• Selby & Lance JNNP 1960;23:23-32
– 71% of 44 patients• Burstein et al., Ann Neurol 2000;47:614
– 63% of 16,573• higher for frequency & BMI
– Bigal et al., Neurology 2008;70:1525
• Site– Trigeminal– Cervical– Rest of body
Burstein et al.Ann Neurol 2004;55:19
“Act when Mild” StudyAllodynia did not predict outcome
(Goadsby et al., Cephalalgia 2008; 28383-391)
2517
54
38
93 96
0
20
40
60
80
100
Pain Free 2hr mild Pain free 2hrMod/severe
PlaceboAlmotriptanAllodynia
- Randomised Double-Blind Placebo Controlled Parallel Group- Allodynia surrogate: cutaneous sensitivityOutcome
- Patients treating at mild pain did better- The presence of allodynia did not determine outcome
Migraine Pathophysiolgy- Update
• Genetics
• Disease mechanisms– Premonitory symptoms
– The neck
– AllodyniaMedication overuse
• Treatment
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 10 days/month– Triptans at 13 days/month
• NSAIDs are protective if used more than five days a month
Bigal et al., Headache 2008;48:1157
Migraine Pathophysiolgy- Update
• Genetics
• Disease mechanisms– Premonitory symptoms
– The neck
– Allodynia
– Medication overuse
• Treatment
Trigeminovascular System & Migraine
(Goadsby et al., NEJM 2002; 346:257-270)
9 10 9
15 16
30
2523
3430
0
10
20
30
40
50
pain free 2hr pain free 2hr Sumatriptan 100 mg
Placebo Naproxen 500 mg SumaRT 85 mg SUMA+Npx
%pa
tient
sAcute Treatment of Migraine with
Sumatriptan and Naproxen
• Double-blind randomized parallel group single attack adult migraineurs
n = 360 356 361 364 382 364 362 362 799 1751
Study I Study II Meta-analysis
Ferrari et al.,Lancet 2001;358:1668
sumatriptan
Brandes et al., JAMA 2007;297:1443
SumaRT/Nap
8 7 710 10
1916 14
25 23
0
10
20
30
40
50
Sustained pain free Sustained pain free Sumatriptan 100 mg
Placebo Naproxen 500 mg SumaRT 85 mg SUMA+Npx
%pa
tient
sAcute Treatment of Migraine with
Sumatriptan and Naproxen
• Double-blind randomized parallel group single attack adult migraineurs
n = 360 356 361 364 382 364 362 362 799 1751
AEs•Nausea•Somnolence•Dizziness•Paresthesia•Dyspepsia
Ferrari et al.,Lancet 2001;358:1668
sumatriptan
Brandes et al., JAMA 2007;297:1443
SumaRT/Nap
Trigeminovascular System & Migraine
(Goadsby et al., NEJM 2002; 346:257-270)
5-HT1D CGRP
Hou et al., Brain Res 2001;909:112-120
Trigeminal ganglion stimulation increases CGRP
in the cranial circulation
(Goadsby, Edvinsson & Ekman Ann Neurol 1988;23:193)
(pm
ol/l)
0
20
40
60
80
100
120
CGRP Substance P CGRP Substance P
control VG stimulation
**
*
*
Cat Human
Superior sagittal sinus (SSS) stimulation in cat
Neuropeptide changes
0
50
100
150
200
CGRP Substance P VIP Neuropeptide Y
control
SSS
(Zagami, Goadsby & Edvinsson, Neuropeptides 1990;16:69-74)
(pm
ol/l)
*
*
Calcitonin Gene-Related Peptide (CGRP) and Migraine
0
20
40
60
80
CGRP Sub P
control MWA MWOA
1Goadsby et al., Ann Neurol 1990;28:183 2Olesen et al NEJM 2004;350:1104
(pm
ol/l)
* *27
12
66
25
0
10
20
30
40
50
60
70
HA response Aes
placebo
BIBN4096BS 2.5mg
• CGRP is released in the cranial circulation in migraine1
• BIBN4096BS (olcegepant), a CGRP receptor antagonist, is effective in migraine2
Gepants & the Calcitonin Receptor Family
• Calcitonin receptor-like receptor (CLR)• Calcitonin gene-related peptide (CGRP) binds to CLR when it is co-expressed with receptor activity modifying protein 1 (RAMP1);• Adrenomedullin (AM) binds to CLR when RAMP2 or RAMP3 expressed;• Intermedin (IM) binds to CLR when RAMP1 or RAMP3 are expressed.• Receptor component protein (RCP) for efficient signal transduction at CLR.
• Calcitonin Receptor (CTR)• Calcitonin (CT) binds to the CTR;• Amylin binds to CTR in the presence of RAMP1, RAMP2, or RAMP3.
Ian Dickerson- www.urmc.rochester.edu/smd/cgrp
14
9
45
3032 33
0
10
20
30
40
50
Placebo
%pa
tient
sCGRP receptor antagonists are effective in
acute migraine• Double-blind randomized parallel group single attack adult migraineurs Pain Free at 2 hours
n = 115 38 40 34 799 1751
300 600 R10 S100
Ferrari et al.,Lancet 2001;358:1668
sumatriptan
Ho et al.,Neurology 2008;70:1004
telcagepant
CGRP receptor antagonist telcagepant is effective in the treatment of acute migraine
9.67.2
17.2
26.931.3 32.4
29.1
0
10
20
30
40
50
Ho et al., Ferrari et al.,
Placebo T-150 T-300 Z5 Z2.5
(% p
atie
nts)
• Double-blind parallel group randomised controlled trial 2 Hour pain free
Lancet 2009;372:2115 Lancet 2001;358;1668
N = 348 333 354 345 553 1135 1219
CGRP receptor antagonist telcagepant is effective in the treatment of acute migraine
5
10.7
20.218.2
3.8
7.4
18
12.4
0
10
20
30
Placebo T-150 T-300 Zolmitriptan-5
SPF 2-24 SPF 2-48
(Ho et al., Lancet 2009;372:2115 )
(% p
atie
nts)
• Sustained pain free (SPF) at 24 and 48 hr
CGRP receptor antagonist telcagepant is effective in the treatment of acute migraine
32.1
3.2
31.4
2.1
37.2
4.3
50.7
10.4
0
20
40
60
Aes Triptan-like Aes
Placebo T-150 T-300 Z5
(Headache 2008;48:S7-S8)
(% p
atie
nts)
?Gepant-class AEs- dry mouth, fatigue
Ergot Alkaloid (tetracylic ergolene) Family Tree
D ih yd roerg o tam in e
zo lm itrip tan e le trip tan
riza trip tan a lm otrip tan
n ara trip tan frova trip tan
d o n itrip ta n
trip tan s
C P 1 2 2 ,2 8 8 4 9 9 1 w 9 3
an ti-P P Ecom p ou n d s
C O L -1 4 4
L Y 3 3 4 3 7 0
5 H T1 F ag on is ts
P N U 1 4 2 6 3 3
5 H T1 D ag on is ts
n on -trip tan s
S u m atrip tan
E rg o tam in e
NH
NMe2MeNHSO2
NHO
O
NH
NMe2(4991W93)
CH3
H H
Plasma protein extravasation, CP122,288
and migraine
32 28
0
20
40
60
80
100
intravenous
Placebo
CP122,288
(Roon et al., Ann Neurol 2000;47:238-241 response at 2 hours)
%pa
tient
s0
0.5
1
1.5
2
control sumatriptan CP122,288
70,000pmol/kg 100pmol/kg
(Lee & Moskowitz Brain Res 1993;626:303)
Rat Human
Dural Plasma Protein Extravasation
Buzzi et al., Brain Res 1999;583:137
iNOS and the dura mater iNOS protein co-localizes in macrophages after GTN treatment
Reuter et al. Brain 2001;124:2490
GTN
Ctrl
Macrophages iNos Macrophages/iNOS
iNOS in the treatment of migraineGW274150*
• Randomised, single-blind placebo-controlled adaptive design
• Acute attacks• *NOS inhibition at 120mg > 80%
0
10
20
30
40
Placebo 30 60 120 180
2 hr
pai
n fr
ee
Palmer at al., EHMTIC2008 Hoye et al., EHMTIC2008
0
10
20
30
40
Placebo 60 120
• Randomised, double-blind placebo-controlled• Migraine headache days base vs Rx• Prevention
n = 22 6 8 15 24 n= 111 37 36
Ergot Alkaloid (tetracylic ergolene) Family Tree
D ih yd roerg o tam in e
zo lm itrip tan e le trip tan
riza trip tan a lm otrip tan
n ara trip tan frova trip tan
d o n itrip ta n
trip tan s
C P 1 2 2 ,2 8 8 4 9 9 1 w 9 3
an ti-P P Ecom p ou n d s
C O L -1 4 4
L Y 3 3 4 3 7 0
5 H T1 F ag on is ts
P N U 1 4 2 6 3 3
5 H T1 D ag on is ts
n on -trip tan s
S u m atrip tan
E rg o tam in e
NH
NMe2MeNHSO2
NHO
O
NH
NMe2(4991W93)
CH3
H H
COL-144, 5-HT1F receptor agonist, in the acute treatment of migraine
• Randomised, single-blind placebo-controlled adaptive design• Specific agonist- 500 fold less affinity at 5-HT1B/1D than 5-HT1F receptors• No detectable 5-HT1B receptor agonist activity in vivo, eg., rabbit saphenous vein
0
10
20
30
40
Placeb
o2.
5 5 10 20 30
2 hr
pai
n fr
ee
Reuter at al., EHMTIC2008
0
10
20
30
40
50
60
Placebo 5 10 20 30
42 24 28 16 24 h
r S
PF
96
27
39
40
0
10
20
30
40
50
reduction in headache days 50 % responder rate
Pre-set Adjustable Medically managed
(Saper et al., AHS 2008 late-breaking) *P = 0.032; **P = 0.003
%Occipital nerve stimulation in chronic migraine
ONSTIM• Double-blind randomized parallel group sham stimulation controlled study• Note- occipital pain, fail 2 preventives, exclude MOH
***
n = 16 29 17
NS
* Adverse event: lead migration in 24 %
22
16
39
29
0
10
20
30
40
50
pain free 2 hr Sustained pain free 2-24 hr
Sham Active
(Lipton et al., AHS Late-breaking abstract)
% P
atie
nts
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 s; 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
n = 82 82
*
Botulinum Toxin and Headache
Cui et al., Pain 2004; 107: 125-133
after Aoki
Botulinum Toxin and Headacheχ Chronic tension-type headache
– No difference in frequency; n = 300• Silberstein et al., Cephalalgia 2006;26:717
χ Migraine (episodic)– No differences; n = 232
• Saper et al., J Neurol 2005; 252: II-58
– No differences; n = 495• Relja et al., J Neurol 2005; 252: II-62.
– Reduced frequency (?primary endpoint); n = 128• Chankrachang et al., Cephalalgia 2005; 25: 992-993.
χ Chronic Daily Headache– No reduction in headache frequency; n = 702
• Silberstein et al., Mayo Clin Proc 2005; 80: 1126-37– No reduction in headache free days; n = 355*
• Mathew et al., Headache 2005; 45: 293-307? Chronic Migraine
– Reduced headache frequency on no other preventive (sub-group *)• Dodick et al., Headache 2005; 45: 315
– Two RCTs Positive for reduction in headache days (Press release)
(after Goadsby et al., NEJM 2002; 346:257-270)
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