Migraine Pathophysiology An Update Professor Peter J. Goadsby [email protected] BASH...

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


• 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


• Genetics

• Disease mechanisms– Premonitory symptoms The neck

– Allodynia


• 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


• Genetics

• Disease mechanisms– Premonitory symptoms

– The neckAllodynia


• 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


• Genetics


– 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


• Genetics


– The neck

– Allodynia


• 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


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


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


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


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)

Migraine Pathophysiology An Update Professor Peter J. Goadsby [email protected] BASH...

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