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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.).
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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
# Blackwell Science Ltd Cephalalgia, 2000, 20, 486±508
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.).
Central sensitization in tension-type headache 489
# Blackwell Science Ltd Cephalalgia, 2000, 20, 486±508
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.
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# Blackwell Science Ltd Cephalalgia, 2000, 20, 486±508
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
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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
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# Blackwell Science Ltd Cephalalgia, 2000, 20, 486±508
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.
Central sensitization in tension-type headache 493
# Blackwell Science Ltd Cephalalgia, 2000, 20, 486±508
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
# Blackwell Science Ltd Cephalalgia, 2000, 20, 486±508
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.).
Central sensitization in tension-type headache 495
# Blackwell Science Ltd Cephalalgia, 2000, 20, 486±508
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
# Blackwell Science Ltd Cephalalgia, 2000, 20, 486±508
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
tension-type headache.
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.).
Central sensitization in tension-type headache 497
# Blackwell Science Ltd Cephalalgia, 2000, 20, 486±508
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
# Blackwell Science Ltd Cephalalgia, 2000, 20, 486±508
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.)
Central sensitization in tension-type headache 499
# Blackwell Science Ltd Cephalalgia, 2000, 20, 486±508
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
# Blackwell Science Ltd Cephalalgia, 2000, 20, 486±508
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
tension-type headache.
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.
Central sensitization in tension-type headache 501
# Blackwell Science Ltd Cephalalgia, 2000, 20, 486±508
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
# Blackwell Science Ltd Cephalalgia, 2000, 20, 486±508
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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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