central sensitization in tension-type headache possible ... · thesis central sensitization in...

THESIS

Central sensitization in tension-type headacheÐpossiblepathophysiological mechanisms

L Bendtsen.Department of Neurology N01, Glostrup Hospital, University of Copenhagen, Glostrup, Copenhagen, Denmark

Bendtsen L. Central sensitization in tension-type headacheÐpossible pathophysiologi-

cal mechanisms. Cephalalgia 2000; 20:486±508. London. ISSN 0333-1024

The aim of the present thesis was to investigate the pathophysiology of chronic tension-

type headache with special reference to central mechanisms. Increased tenderness to

palpation of pericranial myofascial tissues is the most apparent abnormality in patients

with tension-type headache. A new piece of equipment, a so-called palpometer, that

makes it possible to control the pressure intensity exerted during palpation, was

developed. Thereafter, it was demonstrated that the measurement of tenderness could

be compared between two observers if the palpation pressure was controlled, and that

the Total Tenderness Scoring system was well suited for the scoring of tenderness during

manual palpation. Subsequently, it was found that pressure pain detection and tolerance

thresholds were signi®cantly decreased in the ®nger and tended to be decreased in the

temporal region in chronic tension-type headache patients compared with controls. In

addition, the electrical pain threshold in the cephalic region was signi®cantly decreased

in patients. It was concluded that the central pain sensitivity was increased in the

patients probably due to sensitization of supraspinal neurones. The stimulus-response

function for palpation pressure vs. pain was found to be qualitatively altered in chronic

tension-type headache patients compared with controls. The abnormality was related to

the degree of tenderness and not to the diagnosis of tension-type headache. In support of

this, the stimulus-response function was found to be qualitatively altered also in patients

with ®bromyalgia. It was concluded that the qualitatively altered nociception was

probably due to central sensitization at the level of the spinal dorsal horn/trigeminal

nucleus. Thereafter, the prophylactic effect of amitriptyline, a non-selective serotonin

(5-HT) reuptake inhibitor, and of citalopram, a highly selective 5-HT reuptake inhibitor,

was examined in patients with chronic tension-type headache. Amitriptyline reduced

headache signi®cantly more than placebo, while citalopram had only a slight and

insigni®cant effect. It was concluded that the blockade of 5-HT reuptake could only

partly explain the ef®cacy of amitriptyline in tension-type headache, and that also other

actions of amitriptyline, e.g. reduction of central sensitization, were involved. Finally, the

plasma 5-HT level, the platelet 5-HT level and the number of platelet 5-HT transporters

were found to be normal in chronic tension-type headache. On the basis of the present

and previous studies, a pathophysiological model for tension-type headache is

presented. According to the model, the main problem in chronic tension-type headache

is central sensitization at the level of the spinal dorsal horn/trigeminal nucleus due to

prolonged nociceptive inputs from pericranial myofascial tissues. The increased

nociceptive input to supraspinal structures may in turn result in supraspinal

sensitization. The central neuroplastic changes may affect the regulation of peripheral

mechanisms and thereby lead to, for example, increased pericranial muscle activity or

release of neurotransmitters in the myofascial tissues. By such mechanisms the central

sensitization may be maintained even after the initial eliciting factors have been

normalized, resulting in the conversion of episodic into chronic tension-type headache.

Future basic and clinical research should aim at identifying the source of peripheral

486 # Blackwell Science Ltd Cephalalgia, 2000, 20, 486±508

nociception in order to prevent the development of central sensitization and at ways of

reducing established sensitization. This may lead to a much needed improvement in the

treatment of chronic tension-type headache and other chronic myofascial pain

conditions. u Tension-type headache, pathophysiology, central sensitization, tenderness, thesis

Dr Lars Bendtsen, Department of Neurology N01, Glostrup Hospital, University of

Copenhagen, DK-2600 Glostrup, Copenhagen, Denmark. Tel. 45 43233054, fax. 45 4323

3926, e-mail [email protected] Received 17 January 2000, accepted 18 May 2000

Introduction

Tension-type headache is the most common (1.) and, as

far as socio-economic impact is concerned, the most

important type of headache (2.). In spite of this, the

scienti®c interest in tension-type headache has pre-

viously been sparse, and knowledge about the patho-

physiological mechanisms leading to this disorder is

therefore limited. However, since the publication of the

International Headache Classi®cation (3.) an increasing

number of well-performed studies have been published.

Myofascial tissues have been extensively studied, and it

has been demonstrated that increased tenderness to

palpation of pericranial myofascial tissues is the most

apparent abnormality in patients with tension-type

headache (4, 5.). It is assumed that nociceptive impulses

from the pericranial muscles may be referred to the head

and perceived as headache, and that myofascial tissues

therefore do play an important role in tension-type

headache (6±8.).

The pathophysiological mechanisms leading to the

increased tenderness are poorly understood, which may

partially be caused by methodological dif®culties in the

quanti®cation of tenderness by manual palpation (9.).

Possible mechanisms leading to myofascial pain and

tenderness include: (i) sensitization of peripheral myo-

fascial nociceptors, (ii) sensitization of second order

neurones at the level of the spinal dorsal horn/

trigeminal nucleus, (iii) sensitization of supraspinal

neurones, and (iv) decreased anti-nociceptive activity

from supraspinal structures. Central mechanisms have

only been sparsely investigated in tension-type head-

ache, although it becomes increasingly evident that

central factors are involved in the pathophysiology of

this disorder (10±12.). Thus, one of the most exciting

developments in basic pain research over the past

decades has been the recognition that the response

generated by the somatosensory system to a de®ned

input is not ®xed or static. In particular, the increased

knowledge of central sensitization, i.e. increased excit-

ability of neurones in the central nervous system, has

been a major breakthrough in the understanding of

chronic pain (13.). Central mechanisms are complex and

often dif®cult to investigate in clinical studies. However,

it is necessary to do so in order to examine whether the

knowledge obtained from basic pain research is valid in

patients with chronic pain, and in order to increase our

understanding of the central mechanisms leading to

tension-type headache and other chronic pain disorders.

The aims of the present thesis were to evaluate and

improve the methodology used for manual palpation of

myofascial tissues, to investigate the mechanisms lead-

ing to myofascial tenderness, and to investigate central

pain mechanisms in patients with chronic tension-type

headache, with a special focus on the role of serotonin.

The thesis is based on a series of methodological and

clinical studies in patients with chronic tension-type

headache (14±20.) and in patients with other types of

chronic myofascial pain (21.).

Peripheral mechanisms: myofascialtenderness

Myofascial pain probably plays an important role in

tension-type headache. In this section, the methodology

used for the evaluation of myofascial tenderness, the

®ndings on pericranial tenderness in patients with

tension-type headache and possible peripheral mechan-

isms leading to myofascial pain will be discussed.

Evaluation of tenderness by manual palpation

Tenderness, which may be de®ned as pressure-induced

pain, is a very common sign in medical practice.

Tenderness may be a normal physiological sign, e.g.

following excessive muscle activity, or it may signal

underlying pathology, e.g. in¯ammation in a joint.

Manual palpation is the only clinically relevant

method for evaluation of tenderness, and it is also an

important tool in myofascial pain research including

studies of tension-type headache. A precise quanti®ca-

tion of tenderness by manual palpation is however,

dif®cult. Thus, the reliability of manual palpation has

been reported to be low (22, 23.) or acceptable (24±27.).

Among the factors which may contribute to the

variability in the evaluation of tenderness, the intensity

of the palpation pressure and the scoring of tenderness

are probably the most important (25, 28, 29.).

Central sensitization in tension-type headache 487

# Blackwell Science Ltd Cephalalgia, 2000, 20, 486±508

In order to be able to measure the pressure intensity

exerted during palpation a new piece of equipment, a so-

called palpometer, was developed (14.). The palpometer

consists of a thin pressure-sensitive plastic ®lm con-

nected to a meter, a principle ®rst described by Atkins

et al. (30.). The ®lm is attached to the tip of the second

®nger, and the pressure exerted during palpation is

measured in arbitrary units on the meter scale ..(Fig. 1.).

The relation between the forces applied to the plastic

®lm and the palpometer output was found to be

approximately linear, and the intra- and interobserver

variation of exerted force at given palpometer values

was found to be acceptably low (14.). The authors

concluded that the palpometer is a valuable tool for

the measurement of the pressure intensity exerted

during palpation. In the same study, it was demon-

strated that the palpation pressure was stable within

observers from week to week, while there was a

considerable difference in pressure intensities between

observers (14.).

In headache research, manual palpation is usually

performed according to the method described by

Langemark & Olesen (4.). Brie¯y, the palpation is

performed bilaterally with small rotating movements

of the second and third ®ngers, and the induced

tenderness is scored according to the Total Tenderness

b

a

Figure 1 (a) The palpometer consists of a Force Sensing Resistor connected to a meter. The force is recorded by the meter scale,which is divided into arbitrary units (U) from 60 to 200 U. (b) The Force Sensing Resistor is a thin polymer ®lm device, which isattached to the ®ngertip by means of thin adhesive tape (MicroporeH, not shown). Reproduced from (14.) with permission.

488 L Bendtsen


Scoring system. The validity of this method was recently

examined (15.). By the use of the palpometer it was

demonstrated that the measurement of tenderness

differed signi®cantly between two observers using

non-instrumental palpation, while this difference was

eliminated during pressure-controlled palpation. Ten-

derness scores did not differ signi®cantly within

observers from week to week even without control of

the palpation pressure. This supports that palpation

pressures are stable within observers over time as

previously suggested (14.). Thus, the intensity of the

palpation pressure has to be controlled if tenderness

scores have to be compared between research centres, or

if more than one observer is used in a study, while

palpation can be performed without control of the

pressure intensity if the same observer is used through-

out a study.

The Total Tenderness Scoring system scores tender-

ness on a four-point combined behavioural and verbal

scale as follows: 0 = denial of tenderness, no visible

reaction; 1 = verbal report of discomfort or mild pain, no

visible reaction; 2 = verbal report of moderate pain, with

or without visible reaction; 3 = verbal report of marked

pain and visible expression of discomfort. The values

from left and right sides are summed to a Total

Tenderness Score (TTS). The Total Tenderness Scoring

system is based on two important assumptions. First, the

four-point scale must re¯ect the pain perceived by the

subject. Second, it must be valid to summate the

individual tenderness scores to a total score, which is

not uncomplicated seen from a statistical point of view.

This requires, as a minimum, that the four-point ordinal

scale can be considered as a ratio scale, i.e. that increases

in tenderness scores from 0 to 1, 1 to 2 and 2 to 3 re¯ect

equal increases in pain perceived by the subjects. A

recent study (15.) indicated that each of the scores on the

four-point tenderness scale corresponded well with the

pain intensity recorded by the subjects on a visual

analogue scale ..(Fig. 2.). In addition, the pain recorded by

the subjects increased approximately linearly with

increasing tenderness score. Assuming the visual

analogue scale to be a ratio scale (31.), this indicates

that also the four-point tenderness scale roughly can be

considered as a ratio scale. This was con®rmed by the

®nding of a remarkably high correlation between the

sum of pain scores recorded by the subjects and the TTS

recorded by the observer (15.). This indicates that the

Total Tenderness Scoring system is well suited to the

recording of pain provoked by palpation. It should be

emphasized that the scoring is subjective, and that

blinding of the observer is important if tenderness has to

be compared between groups.

It can be concluded that the method for manual

palpation described by Langemark & Olesen (4.) makes it

possible to compare pericranial tenderness between

groups if the observer is blinded, and to compare

pericranial tenderness within subjects if only one

observer is used throughout a study. This method is

therefore a valuable tool for the evaluation of pericranial

tenderness.

Pericranial tenderness in patients with tension-typeheadache

The most prominent clinical ®nding in patients with

tension-type headache is a considerably increased

tenderness to palpation of pericranial myofascial tissues.

This abnormality was documented for the ®rst time in a

blinded study in 1987 (4.), and it has been con®rmed in

several blinded (5, 32, 33.) and unblinded (17, 34±39.)

studies. The increased pericranial tenderness has been

found both in patients with episodic and in patients with

chronic tension-type headache (5, 40.). The tenderness

seems to be uniformly increased throughout the

pericranial region and both muscles and tendon inser-

tions have been found excessively tender (4, 5, 17.)

..(Fig. 3.). In addition, it has been demonstrated that the

pericranial tenderness is positively associated with both

the intensity and the frequency of tension-type headache

(5.), and that evaluation of tenderness by manual

palpation is the most speci®c and sensitive test for

Tenderness score

0 1 2 3

Pai

n in

ten

sity

(m

m)

0

20

40

60

80

100

Figure 2 Tenderness scored by a blinded observer according toa four-point (0±3) scale vs. pain intensity recorded by thesubjects on a 100-mm visual analogue scale during palpation ofthe trapezius muscle. Thirty subjects were palpated, each withseven different pressure intensities. Boxes indicate quartiles andmedian of pain intensities recorded at each tenderness score.The number of observations was 79, 40, 40 and 51 fortenderness scores 0, 1, 2 and 3, respectively. Vertical linesextend to the 2.5th and 97.5th centiles. Outliers are indicatedseparately. Reproduced from (15.).



the subdivision (3.) of tension-type headache patients

into those with and those without a muscular disorder

(41.).

It is not known for certain whether the increased

tenderness in tension-type headache is a primary or a

secondary phenomenon to the headache. Migraineurs do

have increased pericranial tenderness during migraine

attacks (42.), which could indicate that the tenderness is

induced by the headache. The tenderness in the

migraineurs did not however, correlate with the

frequency of migraine attacks but with the frequency

of interval headaches (42.), and a large population study

has demonstrated that there is no difference in

pericranial tenderness between migraineurs studied

outside of attack and non-migraineurs (5.). Furthermore,

the pericranial tenderness in patients with tension-type

headache is increased not only on days with headache

but also on days without headache (33, 37, 39, 40.). This

indicates that tenderness is not solely a consequence of

an actual headache episode. A recent study (32.)

demonstrated that prolonged experimental tooth clench-

ing induced headache in 68% of tension-type headache

patients and in 16% of healthy controls. Shortly after

clenching, pericranial tenderness was increased in those

subjects who subsequently developed headache,

whereas the tenderness score was unchanged in patients

who remained headache-free. Experimental change of

bite function in healthy controls (43.) and experimental

tooth clenching in migraine patients (44.) also generated

tension type-like headaches in a large proportion of the

subjects. Together, these studies indicate that tenderness

precedes headache and that muscular factors are of

importance for the development of tension-type head-

ache.

Possible peripheral mechanisms leading tomyofascial tenderness

The term `myofascial pain' can be de®ned as pain

originating in striated muscle including its fascia and

tendon insertions. Under normal conditions, myofascial

pain is mediated by thin myelinated (Ad) ®bres and

unmyelinated (C) ®bres, while the thick myelinated (Aa

and Aû) ®bres normally mediate innocuous sensations

(45.). Various noxious and innocuous events such as

ischaemia, mechanical stimuli and chemical mediators

may excite and sensitize Ad ®bres and C ®bres (46.) and

thereby play a role in the increased tenderness in

tension-type headache.

It has been assumed for decades that contraction of

head and neck muscles is of importance for the

development of tension-type headache, as re¯ected in

the former term for this disorder, `muscle-contraction

headache' (47.). However, numerous laboratory-based

electromyographic (EMG) studies have reported normal

or, more often, only a slightly increased muscle activity

in tension-type headache (37, 48±55.). This probably

cannot give rise to generalized muscle ischaemia.

Alternatively, the increased muscle activity could be a

normal protective adaptation to pain rather than its

cause (56.). The ®nding of a slightly increased muscle

activity in patients with tension-type headache also on

days without headache (40.) however, makes this

explanation less likely. The above-mentioned studies

all used surface electrodes which record from relatively

large areas of the muscle. In a recent study, Hubbard &

Berkoff (57.) used needle electrodes and reported EMG

activity in so-called myofascial trigger points (7.) to be

signi®cantly increased compared with EMG activity in

Ten

der

nes

s sc

ore

(0–

3)

0

0.5

1

1.5

2

2.5

Fron Mast Mass Temp Coro Ster Neck Trap

Figure 3 Local tenderness scores ((right + left sides)/2) recorded by manual palpation at eight pericranial locations (mean ¡ SEM).Patients with chronic tension-type headache (&) (n=40) were signi®cantly more tender than healthy controls (u) (n=40) at alllocations, ***Pj0.0002. Fron, Frontal muscle; mast, mastoid process; mass, masseter muscle; temp, temporal muscle; coro, coronoidprocess; ster, sternocleidomastoid muscle; neck, neck muscle insertions; trap, trapezius muscle. Reproduced from (17.) withpermission.

490 L Bendtsen


adjacent non-tender muscle. Furthermore, EMG activity

in the trigger points was signi®cantly higher in patients

with chronic tension-type headache than in healthy

controls. The trigger point is apparently only a few

millimetres in diameter, which explains why the

increased EMG activity may only partially be detected

with surface electrodes. Continuous activity in a few

motor units over a long time may be suf®cient for the

development of myofascial pain and headache (58.).

Thus, it can be concluded that myofascial tenderness is

not caused by generalized excessive muscle contraction

leading to muscle ischaemia as was formerly believed

(59.). This is in agreement with a study demonstrating

normal blood ¯ow in the temporal muscle during rest as

well as during dynamic exercise in chronic tension-type

headache (60.). However, it cannot be excluded that a

slightly increased muscle activity may result in micro-

trauma of muscle ®bres and tendon insertions and

thereby to accumulation of metabolites, or that excessive

activity in a few motor units may excite peripheral

nociceptors.

During manual palpation it is often the clinical

experience that tender muscles are harder, i.e. have a

higher consistency than normal muscles. This was

con®rmed by Sakai et al. (61.) who found a signi®cantly

higher degree of trapezius muscle hardness in patients

with chronic tension-type headache than in healthy

controls. This ®nding was made possible by the

development of a new instrument for the measurement

of muscle hardness, a so-called pressure/displacement

transducer (62.). A recent study (39.) found a signi®cant

positive correlation between hardness and tenderness of

the trapezius muscle in patients with chronic tension-

type headache. Furthermore, there was no difference in

hardness recorded on days with and on days without

headache (39.), indicating that increased hardness is not a

direct consequence of actual pain. The mechanisms

contributing to increased muscle hardness are not

known, but may include slight tonic muscle contraction

and tissue swelling due to the accumulation of chemical

mediators (61.).

Chemical mediators may also sensitize the nociceptive

nerve endings. Particularly effective stimulants for

skeletal muscle nociceptors are endogenous substances

such as serotonin, bradykinin and potassium ions (63.).

These substances can be generated by numerous, not yet

clari®ed, mechanisms. Serotonin can, for example, be

released from platelets, bradykinin can be cleaved from

its precursor plasma molecule kallin and potassium can

be released from muscle cells, when pathologic condi-

tions occur (e.g. lowering of pH during ischaemia,

vascular damage, injury to muscle cells) (46.). The release

of neuropeptides, e.g. substance P and calcitonin gene-

related peptide, from muscle afferents may also play a

role in myofascial pain (64.). The mode of action of the

various mediators is complex and only poorly under-

stood. Thus, the peripheral sensitization induced by a

given mediator may be a rather speci®c process affecting

only some aspects of receptor function, i.e. the sensitivity

to local pressure (65.), and the various mediators may

interact and potentiate each other's effect. Thus, when

serotonin and bradykinin are injected separately into the

temporal muscle in healthy volunteers no pain is

induced, while a mixture of the two substances induces

both spontaneous muscle pain and tenderness (66.).

Much more research is needed to elucidate the role of

chemical mediators in myofascial pain.

Search for other peripheral mechanisms responsible

for sensitization of myofascial nociceptors has largely

been negative (67±69.), including temporal muscle biopsy

studies (70.) and studies on muscle metabolism (71.).

Thus, ®rm evidence for peripheral abnormalities as a

cause of myofascial tenderness is still lacking.

Central mechanisms I: central sensitization

Central mechanisms are probably far more important for

the pathophysiology of tension-type headache than

previously anticipated. In this section, the importance

of psychological stress and exteroceptive suppression

will be brie¯y reviewed. Thereafter, central pain

sensitivity in tension-type headache will be discussed

with special reference to supraspinal mechanisms and

mechanisms at the level of the spinal dorsal horn/

trigeminal nucleus. Finally, the important interactions

between peripheral and central mechanisms will be

discussed.

Psychological stress

To the clinician, it is obvious that tension-type headache

can be aggravated by psychological stress. In agreement

with this, it has recently been found that stress and

mental tension are the most conspicuous precipitating

factors in tension-type headache (72±74.), a series of

experimental studies has demonstrated that tension

type-like headaches can be induced by psychological

stress (75, 76.), and psychological and behavioural

therapies appear to be as effective for the treatment of

tension-type headache as pharmacotherapy (77.). The

mechanisms by which psychological stress plays a role

in tension-type headache are not known, but central

factors such as involuntary contractions of cephalic

muscles, a decrease in supraspinal descending pain-

inhibitory activity, and supraspinal hypersensitivity to

nociceptive stimuli may be involved (78, 79.). Thus, while

it is evident that psychological stress is of importance in

tension-type headache, the exact role of this factor in the



generation, exacerbation, and maintenance of headache

remains unclear (80.).

Exteroceptive suppression

In 1987 Schoenen et al. (81.) reported that the duration of a

brainstem re¯ex, the so-called late exteroceptive sup-

pression period (ES2) of temporal muscle activity, was

reduced in patients with chronic tension-type headache.

ES2 is probably mediated via inhibitory interneurones

located in the brainstem (82, 83.). These inhibitory

interneurones are strongly modulated by cortical struc-

tures (84, 85.), and it has therefore been suggested that

ES2 may provide information about the central mechan-

isms related to tension-type headache (51.). The original

paper by Schoenen et al. (81.) was received with great

interest, and the ®nding of reduced ES2 periods in

patients with chronic tension-type headache was later

con®rmed by two other research groups (86, 87.).

Unfortunately, the applied methodology, which is

crucial for the reliability of ES2 measurements (88±91.),

was far from optimal in most of the earlier ES2 studies. A

computerized method for recording and analysing ES2

was therefore developed (92.). The computerized aver-

aging method made it possible to analyse ES2 with low

intra- and interobserver variations (92.). By means of the

computerized method and a blinded design, Bendtsen

et al. then measured ES2 in 55 patients with chronic

tension-type headache and in 55 healthy controls.

Surprisingly, no difference in ES2 duration between

patients and controls could be detected (93.). The same

result was found by Zwart & Sand (94.) in a blinded

study including 11 patients with chronic tension-type

headache, and by Lipchik et al. (33.) in a blinded study

including 25 young women with chronic tension-type

headache. In addition, ES2 has been found normal in an

open study including 27 young women with chronic

tension-type headache (38.). Finally, it has not been

possible to detect any signi®cant correlations between

ES2 duration and either clinical characteristics or various

pain parameters in patients with tension-type headache

(33, 48, 93, 95.), and ES2 duration has been found to be

reduced, rather than increased, during prophylactic

treatment with amitriptyline in patients with chronic

tension-type headache (95.). Thus, while ES2 may be of

great interest, e.g. in the study of how experimental

stressors and drugs in¯uence central mechanisms (92,

95±97.), present knowledge indicates that ES2 is probably

not closely related to the pathophysiology of tension-

type headache (98.).

Central pain sensitivity

Supraspinal pain sensitivity

The abnormal pericranial tenderness in patients with

tension-type headache may be due to an increased

sensitivity in the central nervous system to nociceptive

stimuli from the periphery. Pain sensitivity has therefore

been extensively studied in tension-type headache. The

pressure pain detection threshold, i.e. the lowest

pressure stimulus that is perceived as painful, has

been found normal in patients with episodic tension-

type headache (5, 50.) and in groups of mixed episodic

and chronic tension-type headache patients (55, 99.). In

contrast, pressure pain detection thresholds have been

found decreased in patients with chronic tension-type

headache in two studies (12, 17.) ..(Fig. 4.). The same result

was indirectly found in an earlier study that compared

patients with chronic tension-type headache with

historical controls (10.). One population study found

normal pressure pain detection thresholds in 14 subjects

with chronic tension-type headache (5.). This study is

however, dif®cult to compare with the above-mentioned

studies because of the low number of subjects examined,

and, more important, because the subjects in the

population study probably were clinically less affected

than the patients in the three other studies, who were

recruited from specialized headache centres. The pres-

sure pain tolerance threshold, i.e. the maximal pressure

stimulus that is tolerated, has only been compared

between chronic tension-type headache patients and

healthy controls in one study (17.), although pain

tolerance is generally considered a better and more

reproducible correlate to clinical pain than pain detec-

tion (12, 100±101.). In this study (17.), pressure pain

tolerance thresholds in the ®nger were signi®cantly

lower in chronic tension-type headache patients than in

healthy controls (Fig. 4.). The lowered pressure pain

detection and tolerance thresholds indicate the presence

of both allodynia, i.e. pain elicited by stimuli which are

normally not perceived as painful, and hyperalgesia, i.e.

increased sensitivity to painful stimuli, in patients with

chronic tension-type headache.

Patients with chronic tension-type headache have also

been found hypersensitive to stimuli other than pres-

sure. Langemark et al. (10.) found signi®cantly decreased

pain detection thresholds to thermal stimuli in patients

with chronic tension-type headache, and both the pain

detection threshold (17.) (Fig. 4.) and the pain tolerance

threshold (102.) to electrical stimuli have been found

decreased in these patients. The sensitivity to the various

stimulus modalities (pressure, thermal and electrical)

has been found increased both at cephalic and extra-

cephalic locations (10, 12, 17, 102.). The fact that pain

hypersensitivity has been demonstrated for various

types of stimuli applied both at cephalic and at extra-

cephalic, non-symptomatic locations strongly indicates

that the pain sensitivity in the central nervous system is

increased in patients with chronic tension-type head-

ache. The widespread and unspeci®c nature of the

492 L Bendtsen


hypersensitivity indicates that the general pain sensitiv-

ity is affected at the supraspinal level rather than at the

segmental level of the spinal dorsal horn/trigeminal

nucleus. Thus, it can be concluded that the general pain

sensitivity in the central nervous system is increased in

patients with chronic tension-type headache, while the

central pain processing seems to be normal in patients

with episodic tension-type headache.

In the study by Bendtsen et al. (17.) pressure pain

detection and pressure pain tolerance thresholds were

decreased in parallel in chronic tension-type headache

patients compared with controls, and the two thresholds

were signi®cantly correlated both in the ®nger and in the

temporal region in the headache patients. In addition,

pressure pain thresholds recorded at cephalic and extra-

cephalic sites were highly correlated. These data indicate

that pain detection and pain tolerance, as well as pain

perception in different parts of the body, are modulated

by a common, probably supraspinal, factor in patients

with chronic tension-type headache. Moreover, pressure

pain detection and tolerance thresholds recorded both at

cephalic and extra-cephalic sites, as well as the pain

threshold to electrical stimuli, were signi®cantly and

negatively correlated to the TTS in patients with chronic

tension-type headache (17.). In agreement with this,

Langemark et al. (10.) found a signi®cant negative

correlation between pressure pain detection thresholds

in the temporal region and TTS in patients with chronic

tension-type headache, while Jensen et al. (40.) found a

signi®cant negative correlation between TTS and both

pressure pain detection and pressure pain tolerance

thresholds in patients with chronic tension-type head-

ache, but, importantly, not in patients with episodic

tension-type headache. These data demonstrate that

there is a relationship between the central hypersensi-

tivity and the increased pericranial myofascial tender-

ness in patients with chronic, but not in patients with

episodic, tension-type headache. However, the increase

in myofascial tenderness has been found much more

pronounced than the increase in general pain sensitivity,

as can be seen by comparing Figs 3 and 4., and the

correlation between pain thresholds and TTS was only

moderate in the above-mentioned studies (10, 17, 40.).

Thus, the general hypersensitivity can explain only a

minor part of the increased pericranial tenderness in

patients with chronic tension-type headache. It is there-

fore likely that other factors contribute to the increased

tenderness.

Pain sensitivity at the level of the spinal dorsal horn/

trigeminal nucleus

In 1990 it was suggested by Jensen (9.) that myofascial

tenderness may be the result of a lowered pressure pain

threshold, a stronger response to pressures in the

noxious range (as illustrated by a steeper stimulus-

response function) or a combination of both. However, it

was not possible to study the relation between palpation

pressure and pain until the development of the

palpometer (14.). By means of this instrument, the

stimulus-response function for pressure vs. pain was

investigated in 40 patients with chronic tension-type

headache and in 40 healthy controls (16.). The stimulus-

response function recorded from normal muscle was

well described by a power function. From highly tender

muscle, the stimulus-response function was displaced

towards lower pressures and, more important, it was

approximately linear, i.e. qualitatively different from

that of normal muscle ..(Fig. 5.). When the patients were

Pai

n t

hre

sho

ld (

kPa,

mA

x100

)

0

200

400

600

800

1200

PPDTFinger

1000

PPDTTemporal

PPTOFinger

PPTOTemporal

REPTComm

407

611

276333

801

1017

495579

359

544

Figure 4 Pain thresholds to mechanical and electrical stimuli in 40 chronic tension-type headache patients (&) and in 40 healthycontrols (u) (mean ¡ SEM). PPDT, Pressure pain detection threshold; PPTO, pressure pain tolerance threshold; REPT, relativeelectrical pain threshold; ®nger, index ®nger; temporal, temporal muscle; comm, labial commissure. ***Pj0.0009; *P=0.02.Reproduced from (17.) with permission.



subgrouped on the basis of their degree of tenderness, it

was found that the stimulus-response function was

almost perfectly linear in the most tender patients and

almost perfectly described by a power function in the

least tender patients. Thus, the abnormal stimulus-

response function was related to the degree of tender-

ness and not to the diagnosis of tension-type headache.

This was con®rmed in a subsequent study (21.) in

patients with ®bromyalgia, where the relation between

pressure and pain in the trapezius muscle was almost

perfectly linear and not slightly curved as in the patients

with chronic tension-type headache. This was in

accordance with the ®nding that the trapezius muscle

in patients with ®bromyalgia was more tender than in

the headache patients. The ®nding of a qualitatively

altered response to nociceptor stimulation in tender

muscle indicates that myofascial pain, at least in part, is

caused by qualitative changes in the processing of

sensory information. The question is whether these

changes are located in peripheral nerve endings, in the

spinal cord or in higher order neurones.

Spinal dorsal horn neurones that receive inputs from

deep myofascial tissues can be classi®ed as high-

threshold mechanosensitive (HTM) neurones requiring

noxious intensities of stimulation for activation, and as

low-threshold mechanosensitive (LTM) neurones, which

are activated by innocuous stimuli (63.). Yu & Mense

(103.) have shown that HTM dorsal horn neurones have a

positively accelerating stimulus-response function,

whereas the stimulus-response function of LTM neu-

rones is approximately linear. This suggests that the

linear stimulus-response function in tender human

muscle may be caused by activity in LTM afferents. At

®rst this seems unlikely, because LTM afferents nor-

mally mediate innocuous sensations. However, Woolf

(13.) has demonstrated that a prolonged noxious input

from the periphery is capable of sensitizing spinal dorsal

horn neurones, so that LTM afferents can mediate pain.

The original ®nding by Woolf on spinal dorsal horn

sensitization has later been con®rmed by numerous

independent laboratories (63, 104±107.), and a similar

sensitization of trigeminal brainstem nociceptive neu-

rones following stimulation of craniofacial muscle

afferents has been reported by Hu et al. (108.). While

the above-mentioned studies have been performed on

animal models, TorebjoÈrk et al. (109.) demonstrated

similar changes in the central processing of inputs

from LTM afferents in humans following intradermal

injection of capsaicin. It therefore seems likely that the

abnormal stimulus-response function in tender muscle

can be explained by changes in neuronal behaviour at

the spinal/trigeminal level. A decrease of the supra-

spinal descending inhibition probably does not explain

the ®nding, because it has been reported that the

descending inhibition acts via a parallel shift or via a

decreased slope of the stimulus-response curve (103,

110.), while it does not change the shape of the stimulus-

response curve. Sensitization or increased stimulation of

normally active peripheral nociceptors would probably

induce a quantitative rather than a qualitative change of

the stimulus-response curve (111.). However, activation

of a new class of peripheral nociceptors, e.g. silent

nociceptors, might result in a qualitatively changed

stimulus-response function. Although silent nociceptors

have not yet been identi®ed in skeletal muscle (63, 64.),

this might be an alternative explanation for the abnormal

stimulus-response function. In conclusion, the ®nding of

qualitatively altered nociception from tender human

muscles indicates that the central nervous system is

sensitized at the level of the spinal dorsal horn/

trigeminal nucleus in patients with chronic myofascial

pain.

It has long been a puzzle why patients with chronic

tension-type headache are much more tender to manual

palpation than controls, while there is only a slight

difference in pain thresholds between the two groups.

Pai

n in

ten

sity

(m

m)

0

20

40

60

20018016014012010080Pressure intensity (U)

Pai

n in

ten

sity

(m

m)

0

100

80

Pressure intensity (U)

100 120 140 160 180 200

10

Figure 5 Stimulus±response functions for pressure vs. pain inthe trapezius muscle in 40 patients with chronic tension-typeheadache ($) and in 40 healthy controls (m) (mean ¡ SEM).Patients were signi®cantly more tender than controls, P=0.002.In patients, the stimulus±response function was approximatelylinear with a slope (b)=0.50¡0.04 mm/U, P=0.00004. Incontrast, pain intensities increased in a positively acceleratingfashion with increasing pressure intensities in controls, arelation that was well described by a power function. This wasdemonstrated by obtaining an approximately linear relationbetween pressure and pain in a double logarithmic plot,b=3.8¡0.61 logmm/logU, P=0.002 (inset). Reproduced from(16.) with permission.

494 L Bendtsen


The abnormal stimulus-response function (16.) showing

that the largest difference between tender and normal

muscle is found at moderate pressure intensities,

together with the ®nding that most observers use a

moderate pressure intensity during manual palpation

(14.), explains this ..(Fig. 6.). Thus, the central sensitization

at the level of the spinal dorsal horn/trigeminal nucleus

probably accounts for a large part of the increased

tenderness in patients with chronic myofascial pain. This

does not necessarily imply that spinal mechanisms are

more important than supraspinal mechanisms in chronic

myofascial pain. A supraspinal dysfunction may, for

example, be a prerequisite for the development of

alterations at the level of the spinal dorsal horn/

trigeminal nucleus. Furthermore, the relative importance

of spinal and supraspinal pain mechanisms and the

interaction between these is only poorly understood. The

proposed separation between supraspinal and spinal

pain sensitivity in tension-type headache should there-

fore be regarded only as a working hypothesis.

Possible peripheral mechanisms leading to centralsensitization

As described above, the central nervous system is

probably sensitized both at the supraspinal level (10,

12, 17.) and at the level of the spinal dorsal horn/

trigeminal nucleus (16.) in patients with chronic tension-

type headache. Which factors are responsible for the

central sensitization? Basic pain research has, as

previously mentioned, demonstrated that central sensi-

tization can be generated by prolonged nociceptive

inputs from the periphery. This mechanism is particu-

larly liable to be of importance in patients with chronic

myofascial pain, because inputs from muscle nociceptors

are more effective in inducing prolonged changes in the

behaviour of dorsal horn neurones than are inputs from

cutaneous nociceptors (112.). The previously described

®nding of a relation between the increased tenderness

and the general pain hypersensitivity in patients with

chronic tension-type headache (17.) was recently inves-

tigated further by Jensen et al. (40.) by comparing pain

thresholds in tension-type headache patients with and in

tension-type headache patients without abnormal peri-

cranial tenderness. This study demonstrated that chronic

tension-type headache patients with abnormal tender-

ness had signi®cantly lower pressure pain detection and

tolerance thresholds than chronic tension-type headache

patients without abnormal tenderness. No such differ-

ence was detected in patients with episodic tension-type

headache. In addition, it was found that chronic tension-

type headache patients with abnormal tenderness

tended to have lower mechanical pain thresholds than

healthy controls, while patients without abnormal

tenderness had signi®cantly higher pain thresholds

than controls (40.). Thus, in agreement with previous

studies (16, 17.), this study indicates that central pain

sensitivity is increased only in chronic tension-type

headache patients with increased pericranial tenderness.

The demonstration of a relation between pericranial

Pai

n in

ten

sity

(m

m)

0

20

60

100

HighModerateLowPressure intensity

40

80

Paindifference

Patients Controls

Figure 6 Theoretical explanation for the markedly increased tenderness in patients with chronic tension-type headache. Thestimulus±response functions for pressure vs. pain in patients and in healthy controls have revealed that there is only a smalldifference between tender and normal muscles at low and high pressure intensities, while there is a considerable difference intenderness at moderate pressure intensities (16.). Together with the ®nding (14.) that most observers use a moderate pressure intensityduring manual palpation, this may explain the markedly increased tenderness but only slightly decreased pain detection andtolerance thresholds in patients with chronic tension-type headache (17.).



tenderness and central sensitization does not reveal the

cause±effect relationship between these factors. How-

ever, since patients with episodic tension-type headache

have increased pericranial tenderness but normal central

pain sensitivity, and since chronic tension type-headache

usually evolves from the episodic form (113.), it is most

likely that the central sensitization in patients with

chronic tension-type headache is induced by prolonged

nociceptive inputs from myofascial tissues, as previously

suggested (16, 17.). The central sensitization could

theoretically also be secondary to the chronic pain

condition itself, but this is most unlikely, because the

central nervous system is not sensitized in patients with

chronic tension-type headache who are not tender to

palpation (40.). However, until prospective studies have

investigated peripheral and central pain mechanisms in

episodic tension type-headache patients who later

develop the chronic form, this question cannot be

de®nitively answered. In conclusion, the central sensi-

tization in patients with chronic tension-type headache is

probably induced by prolonged nociceptive inputs from

pericranial myofascial tissues.

Central mechanisms II: biochemicalmechanisms

A disturbance in pain-modulating transmitters as well as

cellular changes in the central nervous system are likely

to be involved in the altered pain perception in patients

with chronic tension-type headache. Serotonergic

mechanisms in tension-type headache and the possible

synaptic and cellular events in the spinal dorsal horn/

trigeminal nucleus involved in central sensitization will

be discussed in this section.

Serotonergic mechanisms

Serotonin (5-hydroxytryptamine, 5-HT) is a widely

distributed neurotransmitter that has an important but

complex role in pain modulation. Thus, while 5-HT has

mainly algogenic actions on peripheral nerves as

previously described, it seems to have predominantly

anti-nociceptive effects in the central nervous system

(114.). 5-HT is an important transmitter in the anti-

nociceptive pathways descending from the brainstem to

the spinal dorsal horn, and it is probably also involved in

ascending anti-nociceptive pathways (115, 116.). The anti-

nociceptive effects of 5-HT are mediated via many

different 5-HT receptor subtypes, e.g. 5-HT1, 5-HT2 and

5-HT3 receptors (117.). The complexity of the 5-HT pain

modulatory system is underscored by the fact that the

effect of 5-HT may vary even within the same 5-HT

receptor subtype (118.). 5-HT may, for example, have

both a facilitatory and an inhibitory action on spinal

nociceptive processing when acting via the 5-HT1A

receptor (78.). In addition, 5-HT has effects on other

modalities than pain, i.e. vascular effects, that indirectly

may in¯uence pain mechanisms. This further compli-

cates the investigation of the role of 5-HT in pain. Thus,

while it is certain that 5-HT has important anti-

nociceptive effects, the exact role of 5-HT in pain

modulation is far from understood.

Ef®cacy of serotonergic drugs in tension-type headache

The prominent role of 5-HT in anti-nociception together

with the ®ndings of increased pain sensitivity in patients

with chronic tension-type headache render it probable

that 5-HT is of relevance for the pathophysiology of

tension-type headache. One way to test this assumption

is to examine the effect of various serotonergic drugs in

patients with tension-type headache. Lance & Curran

(119.) and Diamond & Baltes (120.) reported more than

two decades ago that the non-selective 5-HT reuptake

inhibitor amitriptyline had a prophylactic effect in

chronic tension-type headache. However, recent studies

have questioned these ®ndings. GoÈbel et al. (121.) found a

signi®cant effect of amitriptyline over placebo only in the

last week of a 6-week study, and Pfaffenrath et al. (122.)

found no signi®cant effect of amitriptyline compared

with placebo in a multicentre study. In the latter study

however, the frequencies of side-effects were similar in

amitriptyline and placebo. Usually, amitriptyline has

marked side-effects and the inability to detect these

suggests insensitivity of the trial for reasons which

remain obscure. In an attempt to clarify whether

amitriptyline has an effect in chronic tension-type

headache, and in order to investigate whether such an

effect could be attributed to blockade of 5-HT reuptake,

Bendtsen et al. (18.) conducted a double-blind, placebo-

controlled, three-way crossover study of the effect of

amitriptyline and of the effect of citalopram, a highly

selective 5-HT reuptake inhibitor, in patients with

chronic tension-type headache. The patients had been

resistant to numerous previous treatments and were not

suffering from depression. Amitriptyline reduced the

area under the headache curve (calculated as headache

duration times headache intensity) by 30% compared

with placebo, which was highly signi®cant, while

citalopram had only a slight (12%) and insigni®cant

effect ..(Fig. 7.). Amitriptyline also signi®cantly reduced

the secondary ef®cacy parameters headache duration,

headache frequency and intake of analgesics.

Previously it was assumed that the analgesic proper-

ties of the tricyclic antidepressants could be ascribed to

the blockade of serotonin reuptake in the central nervous

system (123±126.), but this has recently been questioned.

In an animal model, Ardid et al. (127.) found that

both noradrenaline reuptake inhibitors and selective

496 L Bendtsen


serotonin reuptake inhibitors had analgesic effects, but

that amitriptyline was more effective than both these

drugs. Watson & Evans (128.) found amitriptyline more

effective than the selective serotonin reuptake inhibitor

zimeldine in postherpetic neuralgia, and Sindrup et al.

(129.) and Max et al. (130.) have reported tricyclic anti-

depressants to be more effective than selective serotonin

reuptake inhibitors in painful diabetic neuropathy.

These results are in line with the ®nding of a clear

effect of amitriptyline but only a trend towards an effect

of citalopram in tension-type headache (18.). While

citalopram is an extremely speci®c serotonin reuptake

inhibitor (131.), amitriptyline also has effects on reuptake

of noradrenaline (132.) as well as effects on serotonergic

(133.), adrenergic (134.), cholinergic (133.), and histami-

nergic (135.) receptors. Of these effects, especially

inhibition of noradrenaline reuptake (132, 136.) and the

effects on various serotonin receptor subtypes (117, 137.)

have been considered important. The ef®cacy of the 5-

HT1D-like receptor agonist sumatriptan has recently

been examined in patients with tension-type headache,

but sumatriptan had only a minimal effect (138, 139.). In

addition to the above-mentioned properties of amitripty-

line, it is known that the drug potentiates the effect of

endogenous opioids (123, 140.). This may be of impor-

tance, because cerebrospinal ¯uid Met-enkephalin levels

have been found increased in chronic tension-type

headache patients (141.). However, the cerebrospinal

¯uid b-endorphin levels were found to be normal in the

same group of patients (142.). Most interestingly, it

has been demonstrated that amitriptyline may act

as a N-methyl-D-aspartate (NMDA) receptor antagonist

(143, 144.), and it has recently been suggested that the

analgesic effects of amitriptyline in chronic pain may be

due primarily to this effect (145.). Since the activation of

NMDA receptors plays a prominent role in the devel-

opment of sensitization in the spinal dorsal horn (see

below for further details), this supports the hypothesis

(16, 17.) of central sensitization in patients with chronic


In conclusion, our present knowledge on the effects

of serotonergic drugs in tension-type headache does not

allow de®nite conclusions on the role of 5-HT in

the pathophysiology of this disorder. It is likely that

the blockade of 5-HT reuptake plays some role in the

ef®cacy of amitriptyline in tension-type headache, but

that also other of the actions of amitriptyline, e.g.

blockade of noradrenaline reuptake or modulation of 5-

HT or NMDA receptors, are required in order to achieve

a clinically signi®cant reduction in headache.

Plasma and platelet 5-HT levels in tension-type headache

The role of 5-HT in tension-type headache may also be

investigated by studying 5-HT in the peripheral blood.

Platelets are considered a model for serotonergic

neurones, because there are several morphological,

biochemical and pharmacological similarities between

platelets and serotonergic nerve endings (146.). Platelets

themselves do not synthesize 5-HT but accumulate it

from the low concentrations which circulate free in the

plasma and which mainly originate from the entero-

chromaf®n tissue of the gastrointestinal tract (147.).

Platelet 5-HT is stored in dense granules and represents

a slow turnover reserve pool, which is pharmacologi-

cally inactive. In contrast, extracellular plasma 5-HT has

a rapid turnover and is pharmacologically active (148.).

The platelet and plasma levels of 5-HT may re¯ect the 5-

HT content in the serotonergic nerve endings and in the

synapses, respectively. The term plasma 5-HT has

previously been inconsistently de®ned (for a review

see (149.)). In the following, the term plasma 5-HT refers

to the extracellular platelet-poor plasma portion of 5-HT

in the blood.

The numerous studies on peripheral 5-HT metabolism

in tension-type headache have given very inconsistent

results. Platelet 5-HT has been reported to be reduced

(150±153.), normal (19, 154, 155.) or increased (156, 157.),

while plasma 5-HT has been found increased during

headache-free periods (156, 158.), normal during head-

ache (19, 155.), or normal during headache-free periods

and increased during headache (159.). These studies

seem con¯icting but are in fact incomparable because of

large clinical and methodological differences. In addi-

tion, the characterization of the patients has been

inadequate in many studies. If only studies including

Are

a u

nd

er t

he

hea

dac

he

curv

e

0

200

600

1200

Run-in

400

800

1000

Amitriptyline Citalopram Placebo

NS NS**

Figure 7 The prophylactic effect of amitriptyline, a non-selective 5-HT reuptake inhibitor, and of citalopram, a highlyselective 5-HT reuptake inhibitor, was compared in a double-blind, placebo-controlled, three-way crossover study including40 patients with chronic tension-type headache. The barsrepresent the area under the headache curve (duration3

intensity) during a 4-week run-in period and during the last4 weeks of treatment with amitriptyline, citalopram andplacebo. **P=0.002; NS, not signi®cant. Data from (18.).



patients with episodic or chronic tension-type headache

(3.) and excluding patients with concomitant serious

disorders, e.g. depression, are considered, a more simple

picture emerges. These studies indicate that patients

with episodic tension-type headache have increased

platelet 5-HT and plasma 5-HT levels (156.), while

patients with chronic tension-type headache have

normal or decreased platelet 5-HT and plasma 5-HT

levels (19, 152, 155.).

Simultaneous with the measurement of plasma and

platelet 5-HT levels, the plasma level of beta-thrombo-

globulin (b-TG) which is regarded as a marker of in vivo

platelet activation (160.), and the urinary excretion of the

main 5-HT metabolite 5-hydroxyindoleacetic acid (5-

HIAA) were measured in patients with chronic tension-

type headache (19.). Both of these parameters were found

to be normal. The normal levels of platelet 5-HT and

plasma b-TG suggest that the platelets are not con-

tinuously activated (161.). This is in line with the ®nding

of a normal urinary excretion of 5-HIAA, which

indicates that the systemic 5-HT turnover is not

increased (147.) in patients with chronic tension-type

headache. It can be concluded that present knowledge,

which is rather limited, indicates that plasma 5-HT and

platelet 5-HT levels are increased in patients with

episodic tension-type headache, while the peripheral 5-

HT metabolism seems to be largely normal in patients

with chronic tension-type headache.

Platelet 5-HT uptake in tension-type headache

The study of 5-HT uptake may be a more direct method

of investigating the role of 5-HT in tension-type head-

ache than the study of platelet 5-HT and plasma 5-HT

levels, because the presynaptic 5-HT uptake mechanism

is crucial for the regulation of 5-HT levels in the neuronal

synapses. 5-HT uptake can be measured indirectly by

measuring the number of 5-HT transporters in the

platelet membrane, because there is a high correlation

between the number of 5-HT transporters and 5-HT

uptake (162.). As mentioned above, human platelets have

for many years been considered a useful presynaptic

neurone model for the 5-HT nerve terminal in the central

nervous system (163.), and recent studies have con®rmed

that the amino acid sequence of the 5-HT transporter

protein expressed in platelets and in 5-HT neurones is

identical (164.). Thus, it is possible that some pathophy-

siological abnormalities linked to the 5-HT transporter

protein would occur in parallel in platelets and in the

brain (165.). As the 5-HT transporter contains speci®c

binding sites for several antidepressant drugs, receptor

binding analysis can be used to determine the number of

transporters. This subject has been investigated in only a

few tension-type headache studies. Marazziti et al. (166.)

reported decreased imipramine binding in patients with

episodic tension-type headache, while Jarman et al. (167.)

found no difference in this parameter between patients

with tension-type headache and healthy controls. Head-

ache frequency was not reported in the latter study.

Using tritiated paroxetine as the binding ligand, Bend-

tsen & Mellerup (20.) found the number of platelet 5-HT

transporters to be normal in patients with chronic

tension-type headache. From a methodological point of

view, tritiated paroxetine is a better ligand than

imipramine because the number of 5-HT transporters

can be determined with greater accuracy (162, 165, 168.).

In addition, the number of platelet 5-HT transporters in

the chronic tension-type headache patients did not

predict the outcome of subsequent treatment with

amitriptyline (20.). This is in agreement with a study

on patients with idiopathic pain (169.) and supports the

previous assumption that mechanisms other than

inhibition of serotonin reuptake are involved in the

analgesic effect of the tricyclic antidepressants (18.).

Using radioactively labelled 5-HT, platelet 5-HT uptake

has been reported increased (154.) in patients with

tension-type headache (headache frequency not

reported) and normal (170.) in patients with chronic

tension-type headache. Thus, the above-mentioned

studies indicate that platelet 5-HT uptake is decreased

in patients with episodic tension-type headache and

normal in patients with chronic tension-type headache.

This is in line with the ®ndings of increased, respec-

tively, normal plasma 5-HT levels in the two groups. It is

therefore possible that the increased plasma 5-HT level

in patients with episodic tension-type headache is

related to a decreased number of platelet 5-HT

transporters. However, further studies are needed to

con®rm these ®ndings.

In summary, present knowledge indicates that

patients with episodic tension-type headache have a

decreased platelet 5-HT uptake and increased plasma 5-

HT levels, while patients with chronic tension-type

headache have a normal platelet 5-HT uptake and

normal plasma 5-HT levels. Furthermore, it has been

found that plasma 5-HT increases during a headache

attack in a mixed population of episodic and chronic

tension-type headache patients (159.), while there is a

signi®cant negative correlation between plasma 5-HT

and headache frequency in patients with chronic

tension-type headache (19.). Thus, patients with chronic

tension-type headache may have an impaired ability to

increase plasma 5-HT, and therefore possibly also

synaptic 5-HT levels, in response to increased nocicep-

tive inputs from the periphery. Such a serotonergic

dysfunction could contribute to central sensitization at

the level of the spinal dorsal horn/trigeminal nucleus

and thereby to the conversion from episodic to chronic

tension-type headache. However, this must be regarded

498 L Bendtsen


as only a preliminary hypothesis. First, the above-

mentioned results should be con®rmed in future studies.

Second, we do not know whether the peripheral changes

in 5-HT actually do re¯ect similar mechanisms in central

neurones.

Possible synaptic and cellular mechanisms leadingto central sensitization

In the previous section, it was suggested that the central

sensitization in patients with chronic tension-type head-

ache may be induced by prolonged nociceptive inputs

from pericranial myofascial tissues. The recent progress in

basic pain research has increased our knowledge about

the mechanisms that may underlie the central neuroplas-

ticity. Thus, there is ample experimental evidence

showing that persistent activity in peripheral nociceptors

may lead to increased responsiveness of second order

dorsal horn neurones, and that neurotransmitters

released from C-®bres may be responsible for the altered

neuronal function (171.). Neurotransmitters known to be

involved in the development of central sensitization

include the tachykinins substance P and neurokinin A and

the excitatory amino acid glutamate (172.). Prolonged

release of these neurotransmitters may activate post-

synaptic receptors that are normally blocked, e.g. NMDA

receptors (173.). Activation of NMDA receptors leads to

increased in¯ux of calcium, which initiates a cascade of

biochemical events including increased production of

nitric oxide, prostaglandins, protein kinases and protein

products of immediate early genes (174, 175.). This may

lead to long-term metabolic changes and increased

excitability of the affected cell (176.).

The increased excitability of the dorsal horn neurones

signi®cantly alters the pain perception in the individual

patient. In the sensitized state, previously ineffective

low-threshold Aû-®bre inputs to nociceptive dorsal horn

neurones become effective (177.). This means that pain

can be generated by low-threshold Aû-®bres, which

clinically will manifest itself as allodynia. Woolf &

Doubell (171.) have suggested that the major cause of

increased pain sensitivity in the chronic pain condition is

an abnormal response to inputs from low-threshold Aû-

®bres. In addition, the response to activation of high-

threshold afferents is exaggerated, which clinically will

manifest itself as hyperalgesia.

Mechanisms other than increased excitability of

second order neurones that have been proposed to be

a

Supraspinalstructures

Brain stem/spinal cord

Pericranialmyofascialtissues

NORMAL PAIN PROCESSING

Supplementary motor areaLimbic system

Sensory cortexand thalamus

Normalpaintransmission

Inhibition Facilitation

RVMPAG Motor cortex

Motor neurons

Nociceptive second orderneurons: V, C2 and C3

Stimulation Inhibition

A-delta and C A-beta

Sensory afferents Muscle fibres

Figure 8 (See next page for caption.)



involved in central sensitization include: (i) structural

reorganization such that novel synapses between Aû-

®bres and nociceptive dorsal horn neurones are formed

(178.); (ii) decreased supraspinal inhibition of Aû-®bre

inputs to nociceptive dorsal horn neurones (171.); and

(iii) the formation of a presynaptic link between Aû-

®bres and nociceptive dorsal horn neurones as a

consequence of C-®bre-induced activation of spinal

interneurones (179.). Thus, in spite of the complexity of

the nociceptive system, our understanding of the

mechanisms involved in sensitization at the level of

the spinal dorsal horn has dramatically improved in

recent years. It is likely that similar mechanisms are

of importance at the supraspinal level, but present

knowledge on supraspinal neuroplasticity is very

limited.

A pathophysiological model for chronictension-type headache

On the basis of the previously described ®ndings in basic

pain and headache research, a simpli®ed pathophysio-

logical model for chronic tension-type headache can be

created. In healthy subjects, the processing of pain is

®nely regulated by multiple pathways, so that the degree

of perceived pain is appropriate for the actual situation

..(Fig. 8a.). The model shows two of the pain modulatory

structures: the periaquaductal grey (PAG) in the mid-

brain that gives rise to inhibitory pathways descending

to the spinal dorsal horn, and the rostral ventromedial

medulla (RVM) in the brain stem that, in addition to so-

called off-cells that inhibit nociceptive transmission, also

contains on-cells that facilitate nociceptive transmission

b

Supraspinalstructures

Brain stem/spinal cord

Pericranialmyofascialtissues

ABERRANT PAIN PROCESSING

Supplementary motor areaLimbic system

Sensory cortexand thalamus

Increased

paintransmission

Inhibition Facilitation

RVMPAG Motor cortex

Motor neurons

Sensitized nociceptive second

order neurons: V, C2 and C3

Stimulation Stimulation

A-delta and C A-beta

Sensory afferents Muscle fibres

Figure 8 (See previous page.) A simpli®ed theoretical model of chronic tension-type headache. The model states that the mainproblem in chronic tension-type headache is sensitization of dorsal horn neurones due to increased nociceptive inputs from peri-cranial myofascial tissues. (a) Normal pain processing. (b) Aberrant pain processing. Important alterations from the normal painstate are presented in bold: the nociceptive input from myofascial A-delta- and C-®bres is increased for unknown reasons, resultingin plastic changes in the spinal dorsal horn/trigeminal nucleus. As a consequence, the normally inhibitory effect of low-thresholdA-beta-®bres on pain transmission in the spinal dorsal horn is altered to a pain stimulatory effect, and the response to nociceptiveA-delta- and C-®bres is potentiated. The increased nociceptive stimulation of supraspinal structures may result in increased facilita-tion and decreased inhibition of pain transmission at the level of the spinal dorsal horn/trigeminal nucleus and in increased peri-cranial muscle activity. Together these mechanisms may induce and maintain the chronic pain condition. V, Trigeminal nerve; C2and C3, second and third cervical segment of the spinal cord; PAG, periaquaductal grey; RVM, rostral ventromedial medulla.

500 L Bendtsen


in the spinal dorsal horn (78.). The nociceptive system

allows the detection of potential harmful events and

enables the individual to react appropriately to these,

e.g. to avoid unphysiological working positions that

cause painful pericranial muscles and headache. The

painful stimulus from the periphery is usually elimi-

nated by actions from the individual and, if necessary,

by local reparative mechanisms in the myofascial tissues,

and the properties of the nociceptive system will

normally not be altered after a short-lasting painful

episode. This is termed `normal pain processing' in the

model and will probably be representative of the

nociceptive system in subjects with rare episodes of


Under some conditions, the painful stimulus from the

pericranial myofascial tissues may be more prolonged or

more intense than normal. As previously described, the

mechanisms behind this are not known but may include

increased muscle activity or the release of various

chemical mediators secondary to local pathological

conditions. Increased muscle activity secondary to

psychogenic stress is likely to be of relevance in this

respect, because the psychogenic stress condition may

cause a prolonged increase of muscle tone via the limbic

system and at the same time potentiate pain facilitation

from the brain stem to the spinal dorsal horn (79.). In

most subjects these conditions will be self-limiting due to

central pain modulatory mechanisms and local repara-

tive processes, and will be experienced as frequent

headache episodes for a limited period of time. How-

ever, in predisposed individuals the prolonged nocicep-

tive input from the pericranial myofascial tissues may

lead to sensitization of nociceptive second order

neurones at the level of the spinal dorsal/trigeminal

nucleus (Fig. 8b.). The pathophysiological basis for the

increased susceptibility to central sensitization is

unknown. Possible mechanisms include an impaired

supraspinal inhibition of nociceptive transmission in the

spinal dorsal horn due to a serotonergic dysfunction, as

proposed in the previous section. In the sensitized state,

the afferent Aû-®bres that normally inhibit Ad- and C-

®bres by presynaptic mechanisms in the dorsal horn will

on the contrary stimulate the nociceptive second order

neurones. In addition, the effect of Ad- and C-®bre

stimulation of the nociceptive dorsal horn neurones will

be potentiated, and the receptive ®elds of the dorsal horn

neurones will be expanded (173.). The nociceptive input

to supraspinal structures will therefore be considerably

increased, which may result in increased excitability of

supraspinal neurones (180.) as well as decreased inhibi-

tion or increased facilitation of nociceptive transmission

in the spinal dorsal horn (181.), i.e. in generalized pain

hypersensitivity. The central neuroplastic changes may

also increase the drive to motor neurones both at the

supraspinal and at the segmental level (13.), resulting in

slightly increased muscle activity and in increased

muscle hardness. It is possible that low-grade tension

that normally does not result in pain does so in the

presence of central sensitization (182.). Moreover, it is

possible that the biochemical changes in the dorsal horn

may alter the properties of the sensory afferents, so that

these release in¯ammatory mediators, i.e. substance P

and CGRP, from the receptive endings in the myofascial

tissues (64.), thereby creating a vicious cycle. For the sake

of simplicity this is not indicated in Fig. 8b.. By these

mechanisms the central sensitization may be maintained

even after the initial eliciting factors have been normal-

ized, and the individual will experience daily headaches.

CHRONIC TENSION-TYPE HEADACHE

Continuous nociceptive input from pericranial myofascial tissues

central sensitization at the level of the spinal dorsal horn/trigeminalnucleus so that stimuli that are normally innocuous are

misinterpreted as pain

induce and maintain

Figure 9 The proposed pathophysiological model of chronic tension-type headache delineates two major aims for future research:(i) to identify the source of peripheral nociception in order to prevent the development of central sensitization in patients withepisodic tension-type headache, and (ii) to reduce established central sensitization in patients with chronic tension-type headache.



The proposed model explains the sensitization at the

level of the spinal dorsal horn/trigeminal nucleus, the

slightly increased supraspinal hypersensitivity, the

slightly increased muscle activity, the increased muscle

hardness, the chronic pain and the absence of objective

signs of peripheral pathology in patients with chronic

tension-type headache with increased pericranial ten-

derness. The model is also compatible with the increased

pericranial tenderness but normal central pain proces-

sing in patients with episodic tension-type headache.

The model does not account for the mechanisms that

initiate the central sensitization or for the pain in the

minority (41.) of chronic tension-type headache patients

without abnormal pericranial tenderness (40.). The

proposed model is based mainly on experimental

animal studies and observational clinical studies. Head-

ache is however, a subjective feeling that cannot be

directly studied in animals, and in observational studies

it is dif®cult to clarify if an abnormal ®nding is a

consequence or a cause of the disorder. Experimental

human studies are therefore needed in order to bridge

the gap between basic animal and clinical research and

in order to study the cause±effect relationship between

myofascial nociception and central sensitization. Thus,

the proposed pathophysiological model of chronic

tension-type headache needs to be tested and probably

modi®ed, but it may be helpful in providing appropriate

directions for future research. To summarize, the model

states that the main problem in chronic tension-type

headache is central sensitization due to prolonged

nociceptive inputs from pericranial myofascial tissues,

and that this mechanism is of major importance for the

conversion of episodic into chronic tension-type head-

ache.

Future perspectives

An important implication of the proposed model is that

the future search for a satisfactory treatment for chronic

tension-type headache should have two major aims: (i)

to identify the source of peripheral nociception in order

to prevent the development of central sensitization in

patients with episodic tension-type headache, and (ii) to

reduce established central sensitization in patients with

chronic tension-type headache ..(Fig. 9.). The possibilities

for studying peripheral nociception have been greatly

improved with the recent development of experimental

human models of localized myofascial pain that allow

infusion of chemical mediators into muscles for pro-

longed periods of time (183, 184.). Similarly, experimental

human models of tension-type headache could be

extremely valuable, but so far only a few such models

have been developed (for a review see Bendtsen &

Jensen (185.)). Recently, a genetic predisposition to

chronic tension-type headache was reported (186.).

Future genetic studies may help to identify the mechan-

isms that make some individuals susceptible to the

development of central sensitization. Basic pain research

has demonstrated that NMDA receptor antagonists are

effective in preventing the development of central

sensitization as well as in reducing established central

sensitization (187.). In line with this, the NMDA receptor

antagonist ketamine inhibits central sensitization in

experimental human studies (188.) and reduces pain in

patients with ®bromyalgia (189.). Furthermore, an effect

of the nitric oxide synthase inhibitor NG-mono-methyl-L-

arginine in human experimental pain has been reported

(190.). With the development of more speci®c drugs with

higher ef®cacy and fewer side-effects it is likely that

compounds such as NMDA receptor antagonists and

nitric oxide synthase inhibitors may become of value in

the treatment of chronic tension-type headache. More-

over, the model of chronic tension-type headache can

probably be adapted to other chronic pain conditions in

which peripheral nociception may play a signi®cant role.

Thus, central sensitization may be involved in wide-

spread disorders such as ®bromyalgia (21, 191, 192.) and

rheumatoid arthritis (193.). Future research into the

mechanisms leading to central sensitization may there-

fore be bene®cial to a large number of patients with

chronic myofascial pain.

Acknowledgements

This thesis is based on work carried out at the Department ofNeurology, Glostrup Hospital from 1993 to 1996 during myappointment as a research fellow at the University ofCopenhagen. I express my profound gratitude to Dr RigmorJensen for continuous encouragement, innumerable fruitfuldiscussions and a valuable friendship, and to Professor JesOlesen for having provided me in every way with optimalworking conditions and continuous support and inspiration. Thepresent thesis would not have been possible without them. I amindebted to laboratory technician Hanne Andresen for herenthusiasm and skilful help during the studies. I also owethanks to Dr Messoud Ashina for constructive discussions and avaluable friendship. Furthermore, I wish to thank my co-authorsInge Hindberg, Jesper Nùrregaard, Niels Kristian Jensen, SteenGammeltoft and Erling Mellerup for their contributions in thespeci®c studies. My sincere gratitude is due to the headachepatients and healthy volunteers who participated in the studies.Without their participation it would have been impossible to dothis work. Last, but not least, I would like to thank my family fortheir patience throughout this study. The work was supportedby grants from the Lundbeck Foundation (145/91), thePharmaceutical Foundation of 1991, the Foundation of JacobMadsen and Olga Madsen, the Foundation of A.P. Mùller andChastine Mc-Kinney Mùller, the Oak Foundation, Danish HealthInsurance Foundation and the Foundation of Dr Eilif Trier-Hansen and Ane Trier-Hansen.

502 L Bendtsen


References

1 Rasmussen BK, Jensen R, Schroll M, Olesen J. Epidemiology

of headache in a general populationÐa prevalence study.

J Clin Epidemiol 1991; 44:1147±57.

2 Rasmussen BK, Jensen R, Olesen J. Impact of headache on

sickness absence and utilisation of medical services: a Danish

population study. J Epidemiol Community Health 1992;

46:443±6.

3 Headache Classi®cation Committee of the International

Headache Society. Classi®cation and diagnostic criteria for

headache disorders, cranial neuralgias and facial pain.

Cephalalgia 1988; 8 (Suppl. 7):1±96.

4 Langemark M, Olesen J. Pericranial tenderness in tension

headache. A blind, controlled study. Cephalalgia 1987; 7:249±

55.

5 Jensen R, Rasmussen BK, Pedersen B, Olesen J. Muscle

tenderness and pressure pain thresholds in headache. A

population study. Pain 1993; 52:193±9.

6 Kellgren JH. Observations on referred pain arising from

muscle. Clin Sci 1938; 3:175±90.

7 Travell JG, Simons DG. Myofascial pain and dysfunction. The

trigger point manual. Baltimore: Williams & Wilkins, 1983:1±

330.

8 Olesen J, Langemark M. Mechanisms of tension headache.

A speculative hypothesis. In: Olesen J, Edvinsson L, eds.

Basic mechanisms of headache. Amsterdam: Elsevier,

1988:457±61.

9 Jensen K. Quanti®cation of tenderness by palpation and use

of pressure algometers. In: Fricton JR, Awad E, eds. Adv Pain

Res Ther, Vol. 17. New York: Raven Press, 1990:165±81.

10 Langemark M, Jensen K, Jensen TS, Olesen J. Pressure pain

thresholds and thermal nociceptive thresholds in chronic

tension-type headache. Pain 1989; 38:203±10.

11 Olesen J. Clinical and pathophysiological observations in

migraine and tension-type headache explained by integra-

tion of vascular, supraspinal and myofascial inputs. Pain

1991; 46:125±32.

12 Schoenen J, Bottin D, Hardy F, Gerard P. Cephalic and

extracephalic pressure pain thresholds in chronic tension-

type headache. Pain 1991; 47:145±9.

13 Woolf CJ. Evidence for a central component of post-injury

pain hypersensitivity. Nature 1983; 15:686±8.

14 Bendtsen L, Jensen R, Jensen NK, Olesen J. Muscle palpation

with controlled ®nger pressure: new equipment for the study

of tender myofascial tissues. Pain 1994; 59:235±9.

15 Bendtsen L, Jensen R, Jensen NK, Olesen J. Pressure-

controlled palpation: a new technique which increases the

reliability of manual palpation. Cephalalgia 1995; 15:205±10.

16 Bendtsen L, Jensen R, Olesen J. Qualitatively altered

nociception in chronic myofascial pain. Pain 1996; 65:

259±64.

17 Bendtsen L, Jensen R, Olesen J. Decreased pain detection and

tolerance thresholds in chronic tension-type headache. Arch

Neurol 1996; 53:373±6.

18 Bendtsen L, Jensen R, Olesen J. A non-selective (amitripty-

line), but not a selective (citalopram), serotonin reuptake

inhibitor is effective in the prophylactic treatment of chronic

tension-type headache. J Neurol Neurosurg Psych 1996;

61:285±90.

19 Bendtsen L, Jensen R, Hindberg I, Gammeltoft S, Olesen J.

Serotonin metabolism in chronic tension-type headache.

Cephalalgia 1997; 17:843±8.

20 Bendtsen L, Mellerup ET. The platelet serotonin transporter

in primary headaches. Eur J Neurol 1998; 5:277±82.

21 Bendtsen L, Nùrregaard J, Jensen R, Olesen J. Evidence of a

qualitatively altered nociception in patients with ®bromyal-

gia. Arthritis Rheum 1997; 40:98±102.

22 Kopp S, Wenneberg B. Intra- and interobserver variability in

the assessment of signs of disorder in the stomatognathic

system. Swed Dent J 1983; 7:239±46.

23 Levoska S, Keinanen Kiukaanniemi S, Bloigu R. Repeatability

of measurement of tenderness in the neck-shoulder region

by a dolorimeter and manual palpation. Clin J Pain 1993; 9:

229±35.

24 Cott A, Parkinson W, Bell MJ et al. Interrater reliability of the

tender point criterion for ®bromyalgia. J Rheumatol 1992;

19:1955±9.

25 Fricton JR, Schiffman EL. Reliability of a craniomandibular

index. J Dent Res 1986; 65:1359±64.

26 Jacobs JW, Geenen R, van der Heide A, Rasker JJ, Bijlsma JW.

Are tender point scores assessed by manual palpation in

®bromyalgia reliable? An investigation into the variance of

tender point scores. Scand J Rheumatol 1995; 24:243±7.

27 Tunks E, McCain GA, Hart LE et al. The reliability of

examination for tenderness in patients with myofascial pain,

chronic ®bromyalgia and controls. J Rheumatol 1995; 22:944±

52.

28 Jensen R, Rasmussen BK, Pedersen B, Lous I, Olesen J.

Cephalic muscle tenderness and pressure pain threshold in a

general population. Pain 1992; 48:197±203.

29 Wolfe F, Smythe HA, Yunus MB et al. The American College

of Rheumatology 1990 criteria for the classi®cation of

®bromyalgia. Report of the Multicenter Criteria Committee.

Arthritis Rheum 1990; 33:160±72.

30 Atkins CJ, Zielinski A, Klinkhoff AV et al. An electronic

method for measuring joint tenderness in rheumatoid

arthritis. Arthritis Rheum 1992; 35:407±10.

31 Price DD, McGrath PA, Ra®i A, Buckingham B. The

validation of visual analogue scales as ratio scale measures

for chronic and experimental pain. Pain 1983; 17:45±56.

32 Jensen R, Olesen J. Initiating mechanisms of experimentally

induced tension-type headache. Cephalalgia 1996; 16:175±82.

33 Lipchik GL, Holroyd KA, Talbot F, Greer M. Pericranial

muscle tenderness and exteroceptive suppression of tempor-

alis muscle activity: a blind study of chronic tension-type

headache. Headache 1997; 37:368±76.

34 Lous I, Olesen J. Evaluation of pericranial tenderness and

oral function in patients with common migraine, muscle

contraction headache and `combination headache'. Pain 1982;

12:385±93.

35 Drummond PD. Scalp tenderness and sensitivity to pain in

migraine and tension headache. Headache 1987; 27:45±50.

36 Carlsson J, Fahlcrantz A, Augustinsson LE. Muscle tender-

ness in tension headache treated with acupuncture or

physiotherapy. Cephalalgia 1990; 10:131±41.

37 Hatch JP, Moore PJ, Cyr Provost M, Boutros NN, Seleshi E,

Borcherding S. The use of electromyography and muscle

palpation in the diagnosis of tension-type headache with

and without pericranial muscle involvement. Pain 1992;

49:175±8.

38 Lipchik GL, Holroyd KA, France CR et al. Central and



peripheral mechanisms in chronic tension-type headache.

Pain 1996; 64:467±75.

39 Ashina M, Bendtsen L, Jensen R, Sakai F, Olesen J. Muscle

hardness in patients with chronic tension-type headache:

relation to actual headache state. Pain 1999; 79:201±5.

40 Jensen R, Bendtsen L, Olesen J. Muscular factors are of

importance in tension-type headache. Headache 1998; 38:10±

17.

41 Jensen R, Rasmussen BK. Muscular disorders in tension-type

headache. Cephalalgia 1996; 16:97±103.

42 Jensen K, Tuxen C, Olesen J. Pericranial muscle tenderness

and pressure-pain threshold in the temporal region during

common migraine. Pain 1988; 35:65±70.

43 Magnusson T, Enbom L. Signs and symptoms of mandibular

dysfunction after introduction of experimental balancing-

side interferences. Acta Odontol Scand 1984; 42:129±35.

44 Jensen K, Bulow P, Hansen H. Experimental toothclenching

in common migraine. Cephalalgia 1985; 5:245±51.

45 Newham DJ, Edwards RHT, Mills KR. Skeletal muscle pain.

In: Wall PD, Melzack R, eds. Textbook of pain, 3rd edn.

Edinburgh: Churchill Livingstone, 1994:423±40.

46 Mense S. Peripheral mechanisms of muscle nociception and

local muscle pain. J Musculoskeletal Pain 1993; 1:133±70.

47 Ad hoc committee on classi®cation of headache.

Classi®cation of headache. JAMA 1962; 179:717±8.

48 Schoenen J, Gerard P, De Pasqua V, Sianard Gainko J.

Multiple clinical and paraclinical analyses of chronic tension-

type headache associated or unassociated with disorder of

pericranial muscles. Cephalalgia 1991; 11:135±9.

49 Hatch JP, Prihoda TJ, Moore PJ et al. A naturalistic study of

the relationships among electromyographic activity, psycho-

logical stress, and pain in ambulatory tension-type headache

patients and headache-free controls. Psychosom Med 1991;

53:576±84.

50 GoÈbel H, Weigle L, Kropp P, Soyka D. Pain sensitivity and

pain reactivity of pericranial muscles in migraine and

tension-type headache. Cephalalgia 1992; 12:142±51.

51 Schoenen J. Neurophysiology. In: Olesen J, Tfelt-Hansen P,

Welch KMA, eds. The headaches. New York: Raven Press,

1993:463±70.

52 Jensen R, Fuglsang Frederiksen A, Olesen J. Quantitative

surface EMG of pericranial muscles in headache. A popula-

tion study. Electroencephalogr Clin Neurophysiol 1994;

93:335±44.

53 Sandrini G, Antonaci F, Pucci E, Bono G, Nappi G.

Comparative study with EMG, pressure algometry and

manual palpation in tension-type headache and migraine.


54 Clark GT, Sakai S, Merrill R, Flack VF, McCreary C. Cross-

correlation between stress, pain, physical activity, and

temporalis muscle EMG in tension-type headache.


55 Jensen R. Mechanisms of spontaneous tension-type head-

aches: an analysis of tenderness, pain thresholds and EMG.

Pain 1996; 64:251±6.

56 Lund JP, Donga R, Widmer CG, Stohler CS. The pain-

adaptation model: a discussion of the relationship between

chronic musculoskeletal pain and motor activity. Can

J Physiol Pharmacol 1991; 69:683±94.

57 Hubbard DR, Berkoff GM. Myofascial trigger points show

spontaneous needle EMG activity. Spine 1993; 18:1803±7.

58 Henriksson KG, Lindman R. Morphologic, physiologic, and

biochemical changes in tender and painful muscle. In: Olesen

J, Schoenen J, eds. Tension-type headache: classi®cation,

mechanisms, and treatment. New York: Raven Press,

1993:97±107.

59 Wolff HG. Headache and other pain.Oxford, New York:

University Press, 1963:582±616.

60 Langemark M, Jensen K, Olesen J. Temporal muscle blood

¯ow in chronic tension-type headache. Arch Neurol 1990;

47:654±8.

61 Sakai F, Ebihara S, Akiyama M, Horikawa M. Pericranial

muscle hardness in tension-type headache. A non-invasive

measurement method and its clinical application. Brain 1995;

118:523±31.

62 Horikawa M, Ebihara S, Sakai F, Akiyama M. Non-invasive

measurement method for hardness in muscular tissues. Med

Biol Eng Comput 1993; 31:623±7.

63 Mense S. Nociception from skeletal muscle in relation to

clinical muscle pain. Pain 1993; 54:241±89.

64 Schmidt RF. Sensitization of peripheral nocisensors in

muscle. In: Olesen J, Schoenen J, eds. Tension-type headache:

classi®cation, mechanisms, and treatment. New York: Raven

Press, 1993: 47±59.

65 Mense S, Meyer H. Bradykinin-induced modulation of the

response behaviour of different types of feline group III and

IV muscle receptors. J Physiol (Lond) 1988; 398:49±63.

66 Jensen K, Tuxen C, Pedersen Bjergaard U, Jansen I,

Edvinsson L, Olesen J. Pain and tenderness in human

temporal muscle induced by bradykinin and 5-hydroxy-

tryptamine. Peptides 1990; 11:1127±32.

67 Simons DG. Muscle pain syndromesÐPart II. Am J Phys Med

1976; 55:15±42.

68 Langemark M, Jensen K. Myofascial mechanisms of pain. In:

Olesen J, Edvinsson L, eds. Basic mechanisms of headache.

Amsterdam: Elsevier, 1988:331±41.

69 Gerwin RD. Neurobiology of the myofascial trigger point.

Baillieres Clin Rheumatol 1994; 8:747±62.

70 Yunus MB. Research in ®bromyalgia and myofascial pain

syndromes: current status, problems and future directions.

J Musculoskel Pain 1993; 1:23±41.

71 Simms RW, Roy SH, Hrovat M et al. Lack of association

between ®bromyalgia syndrome and abnormalities in muscle

energy metabolism. Arthritis Rheum 1994; 37:794±800.

72 Rasmussen BK. Migraine and tension-type headache in a

general population: precipitating factors, female hormones,

sleep pattern and relation to lifestyle. Pain 1993; 53:65±72.

73 Scharff L, Turk DC, Marcus DA. Triggers of headache

episodes and coping responses of headache diagnostic

groups. Headache 1995; 35:397±403.

74 Ulrich V, Russell MB, Jensen R, Olesen J. A comparison of

tension-type headache in migraineurs and in non-migrai-

neurs: a population-based study. Pain 1996; 67:501±6.

75 Gannon LR, Haynes SN, Cuevas J, Chavez R.

Psychophysiological correlates of induced headaches.

J Behav Med 1987; 10:411±23.

76 Haynes SN, Gannon LR, Bank J, Shelton D, Goodwin J.

Cephalic blood ¯ow correlates of induced headaches. J Behav

Med 1990; 13:467±80.

77 Holroyd KA. Psychological and behavioral techniques. In:

Olesen J, Tfelt-Hansen P, Welch KMA, eds. The headaches.

New York: Raven Press, 1993:515±20.

504 L Bendtsen


78 Fields HL, Basbaum AI. Central nervous system mechanisms

of pain modulation. In: Wall PD, Melzack R, eds. Textbook

of pain, 3rd edn. Edinburgh: Churchill Livingstone,

1994:243±57.

79 Merskey H. Pain and psychological medicine. In: Wall PD,

Melzack R, eds. Textbook of pain, 3rd edn. Edinburgh:

Churchill Livingstone, 1994:903±20.

80 Andrasik F, Passchier J. Psychological aspects. In: Olesen J,

Tfelt-Hansen P, Welch KMA, eds. The headaches. New York:

Raven Press, 1993:489±92.

81 Schoenen J, Jamart B, Gerard P, Lenarduzzi P, Delwaide PJ.

Exteroceptive suppression of temporalis muscle activity in

chronic headache. Neurology 1987; 37:1834±6.

82 Godaux E, Desmedt JE. Exteroceptive suppression and motor

control of the masseter and temporalis muscles in normal

man. Brain Res 1975; 85:447±58.

83 Cruccu G, Agostino R, Fornarelli M, Inghilleri M, Manfredi

M. Recovery cycle of the masseter inhibitory re¯ex in man.

Neurosci Lett 1984; 49:63±68.

84 Mason P, Strassman A, Maciewicz R. Intracellular responses

of raphe magnus neurons during the jaw-opening re¯ex

evoked by tooth pulp stimulation. Brain Res 1986; 379:232±

41.

85 Hopf HC. Topodiagnostic value of brain stem re¯exes.

Muscle Nerve 1994; 17:475±84.

86 Nakashima K, Takahashi K. Exteroceptive suppression of the

masseter, temporalis and trapezius muscles produced by

mental nerve stimulation in patients with chronic headaches.


87 Wallasch TM, Reinecke M, Langohr HD. EMG analysis of the

late exteroceptive suppression period of temporal muscle

activity in episodic and chronic tension-type headaches.

Cephalalgia 1991; 11:109±12.

88 Hellsing G, Klineberg I. The masseter muscle: the silent

period and its clinical implications. J Prosthet Dent 1983;

49:106±12.

89 De Laat A. Re¯exes elicitable in jaw muscles and their role

during jaw function and dysfunction: a review of the

literature. Part III. Re¯exes in human jaw muscles during

function and dysfunction of the masticatory system. Cranio

1987; 5:333±43.

90 Lavigne G, Frysinger R, Lund JP. Human factors in the

measurement of the masseteric silent period. J Dent Res 1983;

62:985±8.

91 Schoenen J. Wolff Award 1992. Exteroceptive suppression of

temporalis muscle activity in patients with chronic headache

and in normal volunteers: methodology, clinical and

pathophysiological relevance. Headache 1993; 33:3±17.

92 Bendtsen L, Jensen R, Brennum J, Arendt-Nielsen L, Olesen J.

Exteroceptive suppression periods in jaw-closing muscles.

Variability and relation to experimental pain and sustained

muscle contraction. Cephalalgia 1993; 13:184±91.

93 Bendtsen L, Jensen R, Brennum J, Arendt-Nielsen L, Olesen J.

Exteroceptive suppression of temporal muscle activity is

normal in patients with chronic tension-type headache and

not related to actual headache state. Cephalalgia 1996;

16:251±6.

94 Zwart JA, Sand T. Exteroceptive suppression of temporalis

muscle activity: a blind study of tension-type headache,

migraine, and cervicogenic headache. Headache 1995;

35:338±43.

95 Bendtsen L, Jensen R, Olesen J. Amitriptyline, a combined

serotonin and noradrenaline re-uptake inhibitor, reduces

exteroceptive suppression of temporal muscle activity in

patients with chronic tension-type headache. Electro-

encephalogr Clin Neurophysiol 1996; 101:418±22.

96 GoÈbel H, Ernst M, Jeschke J, Keil R, Weigle L. Acetylsalicylic

acid activates antinociceptive brain-stem re¯ex activity in

headache patients and in healthy subjects. Pain 1992; 48:187±

95.

97 Wang W, Schoenen J. Reduction of temporalis exteroceptive

suppression by peripheral electrical stimulation in migraine

and tension-type headaches. Pain 1994; 59:327±34.

98 Bendtsen L. Exteroceptive suppression periods in tension-

type headache. PhD-Thesis. Copenhagen: Private Press: 1±60,

1997.

99 Bovim G. Cervicogenic headache, migraine, and tension-type

headache. Pressure-pain threshold measurements. Pain 1992;

51:169±73.

100 Petersen KL, Brennum J, Olesen J. Evaluation of pericranial

myofascial nociception by pressure algometry. Repro-

ducibility and factors of variation. Cephalalgia 1992; 12:

33±37.

101 Wolff B. Methods of testing pain mechanisms in normal man.

In: Wall PD, Melzack R, eds. Textbook of pain. London:

Churchill Livingstone, 1984:186±94.

102 Langemark M, Bach FW, Jensen TS, Olesen J. Decreased

nociceptive ¯exion re¯ex threshold in chronic tension-type

headache. Arch Neurol 1993; 50:1061±4.

103 Yu XM, Mense S. Response properties and descending

control of rat dorsal horn neurons with deep receptive ®elds.

Neuroscience 1990; 39:823±31.

104 Cervero F, JaÈnig W. Visceral nociceptors: a new world order?

Trends Neurosci 1992; 15:374±8.

105 McMahon SB, Lewin GR, Wall PD. Central hyperexcitability

triggered by noxious inputs. Curr Opin Neurobiol 1993;

3:602±10.

106 Mayer EA, Gebhart GF. Basic and clinical aspects of visceral

hyperalgesia. Gastroenterology 1994; 107:271±93.

107 Hoheisel U, Sander B, Mense S. Myositis-induced functional

reorganisation of the rat dorsal horn: effects of spinal

superfusion with antagonists to neurokinin and glutamate

receptors. Pain 1997; 69:219±30.

108 Hu JW, Sessle BJ, Raboisson P, Dallel R, Woda A. Stimulation

of craniofacial muscle afferents induces prolonged facilita-

tory effects in trigeminal nociceptive brain-stem neurones.

Pain 1992; 48:53±60.

109 TorebjoÈrk HE, Lundberg LE, LaMotte RH. Central changes in

processing of mechanoreceptive input in capsaicin-induced

secondary hyperalgesia in humans. J Physiol (Lond) 1992;

448:765±80.

110 Ness TJ, Gebhart GF. Quantitative comparison of inhibition

of visceral and cutaneous spinal nociceptive transmission

from the midbrain and medulla in the rat. J Neurophysiol

1987; 58:850±65.

111 Koltzenburg M, Kress M, Reeh PW. The nociceptor

sensitization by bradykinin does not depend on sympathetic

neurons. Neuroscience 1992; 46:465±73.

112 Wall PD, Woolf CJ. Muscle but not cutaneous C-afferent

input produces prolonged increases in the excitability of

the ¯exion re¯ex in the rat. J Physiol (Lond) 1984; 356:443±

58.



113 Langemark M, Olesen J, Poulsen DL, Bech P. Clinical

characterization of patients with chronic tension headache.

Headache 1988; 28:590±6.

114 Roberts MHT. 5-Hydroxytryptamine in nociception and

antinociception. In: Olesen J, Saxena PR, eds. 5-

Hydroxytryptamine mechanisms in primary headaches.

New York: Raven Press, 1992:69±76.

115 Le Bars D. Serotonin and pain. In: Osborne NN, Hamon M,

eds. Neuronal serotonin. London: John Wiley and Sons,

1988:171±229.

116 Wang QP, Nakai Y. The dorsal raphe: an important nucleus

in pain modulation. Brain Res Bull 1994; 34:575±85.

117 Eide PK, Hole K. The role of 5-hydroxytryptamine (5-HT)

receptor subtypes and plasticity in the 5-HT systems in the

regulation of nociceptive sensitivity. Cephalalgia 1993; 13:75±

85.

118 Millan MJ. Serotonin and pain: evidence that activation of 5-

HT1A receptors does not elicit antinociception against

noxious thermal, mechanical and chemical stimuli in mice.

Pain 1994; 58:45±61.

119 Lance JW, Curran DA. Treatment of chronic tension head-

ache. Lancet 1964; 1:1236±9.

120 Diamond S, Baltes BJ. Chronic tension headacheÐtreated

with amitriptylineÐa double-blind study. Headache 1971;

11:110±6.

121 GoÈbel H, Hamouz V, Hansen C et al. Chronic tension-type

headache: amitriptyline reduces clinical headache-duration

and experimental pain sensitivity but does not alter

pericranial muscle activity readings. Pain 1994; 59:241±9.

122 Pfaffenrath V, Diener HC, Isler H et al. Ef®cacy and

tolerability of amitriptylinoxide in the treatment of chronic

tension-type headache: a multi-centre controlled study.

Cephalalgia 1994; 14:149±55.

123 Botney M, Fields HL. Amitriptyline potentiates morphine

analgesia by a direct action on the central nervous system.

Ann Neurol 1983; 13:160±4.

124 Tollison CD, Kriegel ML. Selected tricyclic antidepressants in

the management of chronic benign pain. South Med J 1988;

81:562±4.

125 Tura B, Tura SM. The analgesic effect of tricyclic antide-

pressants. Brain Res 1990; 518:19±22.

126 Sacerdote P, Brini A, Mantegazza P, Panerai AE. A role for

serotonin and beta-endorphin in the analgesia induced by

some tricyclic antidepressant drugs. Pharmacol Biochem

Behav 1987; 26:153±8.

127 Ardid D, Marty H, Fialip J, Privat AM, Eschalier A,

Lavarenne J. Comparative effects of different uptake

inhibitor antidepressants in two pain tests in mice.

Fundam Clin Pharmacol 1992; 6:75±82.

128 Watson CP, Evans RJ. A comparative trial of amitriptyline and

zimelidine in post-herpetic neuralgia. Pain 1985; 23:387±94.

129 Sindrup SH, Gram LF, Brosen K, Eshoj O, Mogensen EF. The

selective serotonin reuptake inhibitor paroxetine is effective

in the treatment of diabetic neuropathy symptoms. Pain 1990;

42:135±44.

130 Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R.

Effects of desipramine, amitriptyline, and ¯uoxetine on pain

in diabetic neuropathy. N Engl J Med 1992; 326:1250±6.

131 Hyttel J. Neurochemical characterization of a new potent

and selective serotonin uptake inhibitor: Lu 10-171.

Psychopharmacology (Berl) 1977; 51:225±33.

132 Taiwo YO, Fabian A, Pazoles CJ, Fields HL. Potentiation of

morphine antinociception by monoamine reuptake inhibitors

in the rat spinal cord. Pain 1985; 21:329±37.

133 Hyttel J. CitalopramÐpharmacological pro®le of a

speci®c serotonin uptake inhibitor with antidepressant

activity. Prog Neuropsychopharmacol Biol Psychiatry 1982;

6:277±95.

134 U'Prichard DC, Greenberg DA, Sheehan PP, Snyder SH.

Tricyclic antidepressants: therapeutic properties and af®nity

for alpha-noradrenergic receptor binding sites in the brain.

Science 1978; 199:197±8.

135 Sindrup SH, Gram LF, Skjold T, Grodum E, Brosen K, Beck

Nielsen H. Clomipramine vs desipramine vs placebo in the

treatment of diabetic neuropathy symptoms. A double-blind

cross-over study. Br J Clin Pharmacol 1990; 30:683±91.

136 Fasmer OB, Hunskaar S, Hole K. Antinociceptive effects

of serotonergic reuptake inhibitors in mice. Neuro-

pharmacology 1989; 28:1363±6.

137 Glaum SR, Proud®t HK, Anderson EG. Reversal of the

antinociceptive effects of intrathecally administered seroto-

nin in the rat by a selective 5-HT3 receptor antagonist.

Neurosci Lett 1988; 95:313±7.

138 Brennum J, Kjeldsen M, Olesen J. The 5-HT1-like agonist

sumatriptan has a signi®cant effect in chronic tension-type

headache. Cephalalgia 1992; 12:375±9.

139 Brennum J, Brinck T, Schriver L et al. Sumatriptan has no

clinically relevant effect in the treatment of episodic tension-

type headache. Eur J Neurol 1996; 3:23±28.

140 Valverde O, Mico JA, Maldonado R, Mellado M, Gibert

Rahola J. Participation of opioid and monoaminergic

mechanisms on the antinociceptive effect induced by tricyclic

antidepressants in two behavioural pain tests in mice. Prog

Neuropsychopharmacol Biol Psychiatry 1994; 18:1073±92.

141 Langemark M, Bach FW, Ekman R, Olesen J. Increased

cerebrospinal ¯uid Met-enkephalin immunoreactivity in

patients with chronic tension-type headache. Pain 1995;

63:103±7.

142 Bach FW, Langemark M, Secher NH, Olesen J. Plasma and

cerebrospinal ¯uid beta-endorphin in chronic tension-type

headache. Pain 1992; 51:163±8.

143 Watanabe Y, Saito H, Abe K. Tricyclic antidepressants block

NMDA receptor-mediated synaptic responses and induction

of long-term potentiation in rat hippocampal slices.

Neuropharmacology 1993; 32:479±86.

144 Reynolds IJ, Miller RJ. Tricyclic antidepressants block N-

methyl-D-aspartate receptors: similarities to the action of

zinc. Br J Pharmacol 1988; 95:95±102.

145 Eisenach JC, Gebhart GF. Intrathecal amitriptyline acts as an

N-methyl-D-aspartate receptor antagonist in the presence of

in¯ammatory hyperalgesia in rats. Anesthesiology 1995;

83:1046±54.

146 Stahl SM. Platelets as pharmacologic models for the receptors

and biochemistry of monoaminergic neurons. In:

Longenecker GL, ed. The platelets. New York: Academic

Press, 1985:307±40.

147 Fozard JR. Serotonin, migraine and platelets. Progress in

pharmacology. Stuttgart: Gustav Fischer-Verlag, 1982:4:135±

46.

148 Ferrari MD, Saxena PR. On serotonin and migraine: a clinical

and pharmacological review. Cephalalgia 1993; 13:151±65.

149 Ferrari MD. Biochemistry. In: Olesen J, Tfelt Hansen P, Welch

506 L Bendtsen


KMA, eds. The headaches. New York: Raven Press, 1993:455±

61.

150 Rolf LH, Wiele G, Brune GG. 5-Hydroxytryptamine in

platelets of patients with muscle contraction headache.

Headache 1981; 21:10±11.

151 Anthony M, Lance JW. Plasma serotonin in patients with

chronic tension headaches. J Neurol Neurosurg Psychiatry

1989; 52:182±4.

152 Shimomura T, Takahashi K. Alteration of platelet serotonin

in patients with chronic tension-type headache during cold

pressor test. Headache 1990; 30:581±3.

153 Nakano T, Shimomura T, Takahashi K, Ikawa S. Platelet

substance P and 5-hydroxytryptamine in migraine and

tension-type headache. Headache 1993; 33:528±32.

154 Shukla R, Shanker K, Nag D, Verma M, Bhargava KP.

Serotonin in tension headache. J Neurol Neurosurg

Psychiatry 1987; 50:1682±4.

155 Ferrari MD, Odink J, Tapparelli C, Van Kempen GM,

Pennings EJ, Bruyn GW. Serotonin metabolism in migraine.

Neurology 1989; 39:1239±42.

156 D'Andrea G, Hasselmark L, Cananzi AR et al. Metabolism

and menstrual cycle rhythmicity of serotonin in primary

headaches. Headache 1995; 35:216±21.

157 Leira R, Castillo J, Martinez F, Prieto JM, Noya M. Platelet-

rich plasma serotonin levels in tension-type headache and

depression. Cephalalgia 1993; 13:346±8.

158 Takeshima T, Shimomura T, Takahashi K. Platelet activation

in muscle contraction headache and migraine. Cephalalgia

1987; 7:239±43.

159 Jensen R, Hindberg I. Plasma serotonin increase during

episodes of tension-type headache. Cephalalgia 1994;

14:219±22.

160 Zahavi J, Kakkar VV. Beta-thromboglobulinÐa speci®c

marker of in-vivo platelet release reaction. Thromb

Haemost 1980; 44:23±29.

161 Kaplan KL, Owen J. Plasma levels of beta-thromboglobulin

and platelet factor 4 as indices of platelet activation in vivo.

Blood 1981; 57:199±202.

162 Langer SZ, Galzin AM. Studies on the serotonin transporter

in platelets. Experientia 1988; 44:127±30.

163 Pletscher A, Laubscher A. Blood platelets as models for

neurons: uses and limitations. J Neural Transm Suppl 1980;

16:7±16.

164 Lesch KP, Wolozin BL, Murphy DL, Reiderer P. Primary

structure of the human platelet serotonin uptake site: identity

with the brain serotonin transporter. J Neurochem 1993;

60:2319±22.

165 Coccaro EF, Kavoussi RJ, Sheline YI, Lish JD, Csernansky JG.

Impulsive aggression in personality disorder correlates with

tritiated paroxetine binding in the platelet. Arch Gen

Psychiatry 1996; 53:531±6.

166 Marazziti D, Bonuccelli U, Nuti A et al. Platelet 3H-

imipramine binding and sulphotransferase activity in pri-

mary headache. Cephalalgia 1994; 14:210±4.

167 Jarman J, Davies PT, Fernandez M et al. Platelet

[3H]imipramine binding in migraine and tension headache

in relation to depression. J Psychiatr Res 1991; 25:205±11.

168 Mellerup ET, Plenge P. Why some depressed patients may

have low platelet 3H-imipramine binding. Acta Psychiatr

Scand 1990; 82:330±4.

169 Eberhard G, Von Knorring L, Mellerup ET, Nilsson HL,

Plenge P, Sundequist U. [3H]imipramine binding in idio-

pathic pain syndromes. Basal values and changes after

treatment with antidepressants. Pain 1989; 38:261±7.

170 Hannah P, Jarman J, Glover V, Sandler M, Davies PT, Clifford

Rose F. Kinetics of platelet 5-hydroxytryptamine uptake in

headache patients. Cephalalgia 1991; 11:141±5.

171 Woolf CJ, Doubell TP. The pathophysiology of chronic

painÐincreased sensitivity to low threshold A beta-®bre

inputs. Curr Opin Neurobiol 1994; 4:525±34.

172 Yaksh TL, Malmberg AB. Central pharmacology of nocicep-

tive transmission. In: Wall PD, Melzack R, eds. Textbook of

pain, 3rd edn. Edinburgh: Churchill Livingstone, 1994:165±

200.

173 Coderre TJ, Katz J, Vaccarino AL, Melzack R. Contribution of

central neuroplasticity to pathological pain: review of clinical

and experimental evidence. Pain 1993; 52:259±85.

174 Meller ST, Gebhart GF. Nitric oxide (NO) and nociceptive

processing in the spinal cord. Pain 1993; 52:127±36.

175 Woolf CJ. Windup and central sensitization are not

equivalent. Pain 1996; 66:105±8.

176 Dickenson AH. Pharmacology of pain transmission and

control. In: Cambell J, ed. Pain 1996Ðan updated review.

Seattle: IASP Press, 1996:113±21.

177 Woolf CJ, Thompson SW. The induction and maintenance

of central sensitization is dependent on N-methyl-D-

aspartic acid receptor activation; implications for the

treatment of post-injury pain hypersensitivity states. Pain

1991; 44:293±9.

178 Woolf CJ, Shortland P, Coggeshall RE. Peripheral nerve

injury triggers central sprouting of myelinated afferents.

Nature 1992; 355:75±78.

179 Cervero F, Laird MA. Mechanisms of touch-evoked pain

(allodynia): a new model. Pain 1996; 68:13±23.

180 Lamour Y, Guilbaud G, Willer JC. Altered properties and

laminar distribution of neuronal responses to peripheral

stimulation in the SmI cortex of the arthritic rat. Brain Res

1983; 22:183±7.

181 Wall PD, Devor M. The effect of peripheral nerve injury on

dorsal root potentials and on transmission of afferent signals

into the spinal cord. Brain Res 1981; 23:95±111.

182 Henriksson KG. Chronic muscular pain: aetiology and

pathogenesis. Baillieres Clin Rheumatol 1994; 8:703±19.

183 Ashton-Miller JA, McGlashen KM, Herzenberg JE, Stohler

CS. Cervical muscle myoelectric response to acute experi-

mental sternocleidomastoid pain. Spine 1990; 15:1006±12.

184 Graven-Nielsen T, McArdle A, Phoenix J et al. In vivo model

of muscle pain: quanti®cation of intramuscular chemical,

electrical, and pressure changes associated with saline-

induced muscle pain in humans. Pain 1997; 69:137±43.

185 Bendtsen L, Jensen R. Experimental models of tension-type

headache. In: Olesen J, Moskowitz MA, eds. Experimental

headache models. New York: Raven Press, 1995:297±302.

186 éstergaard S, Russell MB, Bendtsen L, Olesen J. Increased

familial risk of chronic tension-type headache. Br Med J 1997;

314:1092±3.

187 Ma QP, Woolf CJ. Noxious stimuli induce an N-methyl-D-

aspartate receptor-dependent hypersensitivity of the ¯exion

withdrawal re¯ex to touch: implications for the treatment of

mechanical allodynia. Pain 1995; 61:383±90.

188 Arendt-Nielsen L, Petersen Felix S, Fischer M, Bak P, Bjerring

P, Zbinden AM. The effect of N-methyl-D-aspartate antago-



nist (ketamine) on single and repeated nociceptive stimuli: a

placebo-controlled experimental human study. Anesth Analg

1995; 81:63±68.

189 SoÈrensen J, Bengtsson A, Backman E, Henriksson KG,

Bengtsson M. Pain analysis in patients with ®bromyalgia.

Effects of intravenous morphine, lidocaine, and ketamine.

Scand J Rheumatol 1995; 24:360±5.

190 Kindgen-Milles D, Arndt JO. Nitric oxide as a chemical link

in the generation of pain from veins in humans. Pain 1996;

64:139±42.

191 Yunus MB. Towards a model of pathophysiology of

®bromyalgia: aberrant central pain mechanisms with per-

ipheral modulation. J Rheumatol 1992; 19:846±50.

192 Kosek E, Ekholm J, Hansson P. Sensory dysfunction in

®bromyalgia patients with implications for pathogenic

mechanisms. Pain 1996; 68:375±83.

193 Morris VH, Cruwys SC, Kidd BL. Characterisation of

capsaicin-induced mechanical hyperalgesia as a marker for

altered nociceptive processing in patients with rheumatoid

arthritis. Pain 1997; 71:179±86.

Note

This thesis is based on the following previous publications:I Bendtsen L, Jensen R, Jensen NK, Olesen J. Muscle palpation

with controlled ®nger pressure: new equipment for the study of

tender myofascial tissues. Pain 1994; 59:235±9.II Bendtsen L, Jensen R, Jensen NK, Olesen J. Pressure-controlled

palpation: a new technique which increases the reliability of

manual palpation. Cephalalgia 1995; 15:205-10.III Bendtsen L, Jensen R, Olesen J. Decreased pain thresholds and

tolerances in chronic tension-type headache. Arch Neurol 1996;

53:373±6.IV Bendtsen L, Jensen R, Olesen J. Qualitatively altered

nociception in chronic myofascial pain. Pain 1996; 65:259±64.

V Bendtsen L, Nùrregaard J, Jensen R, Olesen J. Evidence ofqualitatively altered nociception in patients with ®bromyalgia.Arthritis Rheum 1997; 40:98±102.VI Bendtsen L, Jensen R, Olesen J. A nonselective (amitriptyline),but not a selective (citalopram), serotonin reuptake inhibitor iseffective in the prophylactic treatment of chronic tension-typeheadache. J Neurol Neurosurg Psych 1996; 61:285±90.VII Bendtsen L, Jensen R, Hindberg I, Gammeltoft S, Olesen J.Serotonin metabolism in chronic tension-type headache.Cephalalgia 1997; 17:843±8.VIII Bendtsen L, Mellerup ET. The platelet serotonin transporterin primary headaches. Eur J Neurol 1998; 5:277±82.

508 L Bendtsen


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