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Danish Headache Center

Tension-type headachePathophysiology

Lars BendtsenAssociate professor, MD, PhD, Dr Med Sci

Danish Headache Center, Department of NeurologyGlostrup Hospital, University of Copenhagen, Denmark

European Headache School, Belgrade, May, 2012

Pathophysiology of Tension-Type Headache

• Peripheral mechanisms

M l f t− Muscular factors

• Central mechanisms

− Altered central nociception

Bendtsen and Fernández-de-las-Peñas, Cur. Pain Head. Rep. 2011

2

Episodic Tension-Type HeadacheReferred pain from myofascial tissues

Travell and Simons, The Trigger Point Manual 1983

Muscle activity

2

3

4

5

Right Temp Left Temp

* *

Jensen et al., Electroenceph. clin. Neurophysiol. 1994

Never Migr ETH CTH0

1

3

Stress-induced pain and muscle activity in patients with migraine and tension-type headache

Leistad et al., Cephalalgia 2006

2.5

Chronic tension-type headacheHealthy controls

Local tenderness scores

1

1.5

2

rnes

s sc

ore

(0-3

)

***

Fron Mast Mass Temp Coro Ster Neck Trap0

0.5

Tend

er

*** ***

***************

Bendtsen et al., Arch Neurol 1996

4

Tenderness induced by static exercise

4

5

patients, activepatients, placebocontrols active

0

1

2

3

baseline 0 min 30 min 60 min 90 min 120 min

controls, activecontrols, placebo

Cha

nge

in T

TS

Time afterstatic work

Christensen et al., Cephalalgia 2005

Patients with frequent ETTH developed significantly more shoulder and neck tenderness in response to static exercise than healthy controls (P=0.04).

Pain induced by infusion of endogenous substances

800 ****

0

100

200300

400

500

600700

Patients Controls

mm

x m

in

CombinationPlacebo

***

Mork et al., Cephalalgia 2004

Patients with frequent ETTH experienced significantly more pain in response to infusion of endogenous substances in trapezius muscle than healthy controls (P≤0.05).

5

120

140

%) P = 0.03

MicrodialysisMuscle blood flow during exercise

80

100

120

-to-in

flow

Rat

io (%

CTTH patients

Controls

40

60

Out

flow

Baseline Ex 1 Ex 2 Pex 1 Pex 2

Ashina et al., Brain 2002

200P = 0.38

MicrodialysisNo in vivo signs of muscle ischemia or inflammation

140

160

180

ange

s in

lact

ate

(%)

CTTH patients

Controls

100

120Cha

Baseline Ex 1 Ex 2 Pex 1 Pex 2

Ashina et al., Brain 2002, Cephalalgia 2003

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Peripheral factors

• Summary – Tenderness and hardness is increased– Degree of tenderness is significantly related to

headache frequency, intensity and treatment outcome– Increased tenderness in response to static exercise– Experimental tenderness precedes headache– Decreased blood flow during exercise

• Conclusion– Muscular factors are probably of primary importance

Suprathreshold pain sensitivity in chronic TTH

20

25

30

S

0

5

10

15

20

CTTHControls

Pain

ratin

gs V

AS

Ashina et al., Cephalalgia 2006

Patients have considerably increased pain sensitivity both in skin and muscle and both in cephalic and extracephalic regions (P<0.05).

Temporalmuscle

Trapeziusmuscle

Ant. tibialmuscle

Temporalskin

Trapeziusskin

Ant. tibialskin

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Central factors in chronic TTH

• The hyperalgesia is generalized (found in all tissues

examined) and of comparable degree in all examined locations

• Increased central pain sensitivity in chronic, but not in

infrequent episodic, TTH

• Decreased antinociceptive activity in chronic TTH

(Sandrini et al. 2006)( )

Mirtazapine in chronic tension-type headache

8090

100

C

010203040506070

MirtazapinePlacebo

Impr

ovem

ent i

n A

UC

Bendtsen and Jensen, Neurology 2004

-100

Baseline

Week 1

Week 2

Week 3

Week 4

Week 5

Week 6

Week 7

Week 8

8

Tenderness in responders and non-responders to amitriptyline

15

5

10

0Responders Non-responders

(n=19) (n=14)Bendtsen and Jensen, Cephalalgia 2000

Stimulus-response function, trapezius muscle

60

20

40

ain

inte

nsity

(mm

)

Chronic tension-type headache

0

Pa

80 100 120 140 160 180 200

Pressure intensity (U)

headacheHealthy controls

Bendtsen et al., Pain 1996

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Chronic tension-type headache

Continuous painful input from pericranial myofascial tissues

induce and maintain

central sensitization such that normally innocuous stimuli become painfulstimuli become painful

Conversion from episodic to chronic tension-type headache

Bendtsen, Cephalalgia 2000

Central sensitization in chronic TTH

• How to test this hypothesis?

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D l tMUSCLE

Nitric oxide and nociception

D l h f th

C-fibre

Dorsal root ganglion

→→→Nociception→→

Central Sensitization

Dorsal horn of the spinal cord

C fibre→→

Activation of nNOS → NO ↑ ↑

Ashina 1999 Increased platelet NOS in CTTH (Sarchielli 2002)

Nitric oxide induced headache in CTTH

6 NitroglycerinPlacebo

S

2

4

dach

e in

tens

ity o

n V

RS

Sensitization of sensory afferents

or dilatation

Sensitization of trigeminal nucleus or

spinal dorsal horn

00 20 40 60 90 120 4 8 12

Infusion Minutes Hours

Hea

d

Ashina et al., Brain 2000

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Treatment with a NOS inhibitor in CTTH Headache intensity over time

00 15 30 60 90 120 minutes

20

-15

-10

-5

0

L-NMMAPlaceboVA

S (%

)

-35

-30

-25

-20 Placebo

Ashina et al., Lancet 1999

V

Voxel-based morphometry in chronic tension-type headache

MOH vs. controls: no changeMigraine vs controls: no changeMOH vs. migraine: no change

Chronic TTH vs. controls:Decrease in grey matter in theant. & post. cingulate cortex,insulae, brainstem, precuneus and parahippocampus

Decrease in grey matter positively correlated to

Schmidt-Wilcke et al., Neurology 2005

p yheadache duration in years

Most likely a consequence of central sensitization

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Cathcart et al., Cephalalgia 2010

CTTH at baseline P200 5th train Controls at baseline P200 5th train

+z

-z

-x +x

+y -y

Buchgreitz et al., Brain, 2008

13

+z

-z

-x +x

• Lack of reduction in brain activity during tonic muscle pain in patients with chronic TTH may be explained by impaired inhibition of the nociceptive input

Conclusions

+y -y

Buchgreitz et al., Brain, 2008

• Supraspinal response to muscle pain is abnormal in chronic TTH

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Developed CTTH (N=9)***

Change in Total Tenderness Score from 1989 to 2001

3

5

7

9

11Developed FETTH (N=20)

Developed Coexist. H (N=7)

Developed migr. (N=9)

ns

ns

ns

Diff

. TTS

-1

1

1No headache (N=62)

Buchgreitz et al., Pain 2008

14

60

80

100Developed CTTH (N=9)

Change in Pressure Pain Threshold from 1989 to 2001

-40

-20

0

20

40

60 Developed FETTH (N=20)

Developed Coexist H. (N=7)

Developed Migr. (N=9)

No headache (N=62)

Cha

nge

in P

PT

-100

-80

-60

*

Buchgreitz et al., Pain 2008

Tenderness and pain sensitivity in relation to development of TTH

• Subjects who developed episodic TTH had increased tenderness but normal pain sensitivity at follow-up

• Subjects who developed chronic TTH had normal pain sensitivity at baseline but developed increased central pain sensitivity at follow-up

• Conclusions─ Increased central pain sensitivity is not a risk factor but a─ Increased central pain sensitivity is not a risk factor but a

consequence of frequent headache─ Central sensitization plays an important role for the

chronification of TTH

Buchgreitz et al., Pain 2008

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Central factors in chronic TTHSummary

• The central nervous system is sensitized in chronic, but not inThe central nervous system is sensitized in chronic, but not in

episodic, tension-type headache

• Central sensitization may be induced by prolonged painful

input from pericranial myofascial tissues

• Descending pain inhibition may be deficient

Sensory cortex and thalamus

Supraspinal structures

ABERRANT PAIN PROCESSING

Supplementary motor area Limbic system

PAG RVM Motor cortex

Brain stem/ spinal cord

Sensitized nociceptive second order neurons: V, C2 and C3 Motor neurons

Increasedpain transmission

Inhibition Facilitation

Pericranialmyofascial tissues

A-delta and C A-beta Sensory afferents Muscle fibres

Stimulation

Bendtsen, Cephalalgia 2000

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Chronic tension-type headachePeripheral and central mechanisms

Deficient descending

Pain transmission

descending inhibition

Muscle

Increased activity

Release of inflammatory peptides

Central sensitization

Conversion of episodic to chronic headacheintensity of headache ?

Peripheral mechanism? Central mechanism?

Jensen et al., 1998

episodic chronic days with headache permonth

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• Identify source of peripheral nociception to prevent development of central sensitization and thereby conversion of episodic to chronic TTH

Future perspectives

of episodic to chronic TTH• Reduce established central sensitization• Animal model (Ellrich et al. 2005, 2006)• Muscular factors

– Abnormal activation or release of chemical mediators• Central factors

– Neuroimaging– Reduction of central sensitization, e.g., by nitric

oxide inhibitors or NMDA-antagonists