Cephalalgia

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Stress and tension-type headache mechanisms

Stuart Cathcart, Anthony H Winefield, Kurt Lushington and Paul Rolan
Cephalalgia 2010 30: 1250 originally published online 7 April 2010
DOI: 10.1177/0333102410362927

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Review
Cephalalgia
30(10) 12501267
Stress and tension-type headache ! International Headache Society 2010
Reprints and permissions:

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DOI: 10.1177/0333102410362927
cep.sagepub.com

Stuart Cathcart1, Anthony H Winefield1, Kurt Lushington1 and

Paul Rolan2

Abstract
Stress is widely demonstrated as a contributing factor in tension-type headache (TTH). The mechanisms underlying this
remain unclear at present. Recent research indicates the importance of central pain processes in tension-type headache
(TTH) pathophysiology. Concurrently, research with animals and healthy humans has begun to elucidate the relationship
between stress and pain processing in the central nervous system, including central pain processes putatively dysfunc-
tional in TTH. Combined, these two fields of research present new insights and hypotheses into possible mechanisms
by which stress may contribute to TTH. To date, however, there has been no comprehensive review of this literature.
The present paper provides such a review, which may be valuable in facilitating a broader understanding of the central
mechanisms by which stress may contribute to TTH.

Keywords
stress, headache, pain, tension-type, mechanisms
Date received: 1 October 2009; accepted: 18 January 2010

Introduction in TTH suerers (7). However, this hypothesis has not

The majority of headaches are termed primary headache,
which refers to head pain not attributable (i.e. second-
ary) to another disease process (e.g. brain tumor).
The most common primary headache, tension-type
headache (TTH), represents approximately 80% of all
headache diagnoses, is extremely prevalent and is asso-
ciated with signicant socioeconomic cost and reduced
quality of life (1,2). Indeed, based on worldwide preva-
lence, primary headache is in the World Health
Organizations top ten ranking of disability causes (3),
with TTH specically having the highest socioeconomic
cost of all headaches (4). However, despite its prevalence
and impact, the causes of TTH are not clearly under-
stood, precluding optimal treatment at present. There is
therefore a considerable need for greater understanding
of the causes of TTH, in order to improve treatment for
this common condition.
Psychological stress is a widely noted contributing
factor to TTH. Indeed, while many factors have
been reported as headache triggers, stress is by far the
most common (5,6). The mechanisms by which
stress contributes to TTH are not clearly understood.
It was previously thought that stress aggravated or
even caused abnormally high levels of muscle tension
been supported in most research (810). Recent research
suggests TTH pathophysiology may involve sensitiza-
tion in myofascial innervation or the central nervous
system (CNS), impaired pain inhibitory mechanisms
and/or enhanced psychological processing of pain in
TTH suerers.
Animal and healthy human studies show that stress
can increase pain sensitivity, and aect pain processing
throughout the CNS. It has therefore been suggested
that stress may contribute to TTH by aggravating
abnormal pain processing in TTH suerers (8,11,12).
There is, however, little research directly examining
this hypothesis in headache suerers. To facilitate fur-
ther research in this area, the present paper reviews and
synthesises literature on (i) pain mechanisms of TTH,
(ii) relationships between stress and pain, with
1
University of South Australia, Australia.
2
University of Adelaide, Australia.
Corresponding author:
Stuart Cathcart, Centre for Applied Psychological Research, School of
Psychology, University of South Australia, Adelaide 5000, Australia
Email: Stuart.Cathcart@unisa.edu.au

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Cathcart et al.
particular reference to pain mechanisms subserving
head pain and (iii) literature directly examining rela-
tionship between stress and pain processing in TTH
suerers. The review is limited to studies examining
TTH unless indicated otherwise. In studies where
other diagnoses were examined as well, only the TTH
results are discussed. Where possible, the review has
delineated episodic TTH (ETTH) and chronic TTH
(CTTH), and frequent and infrequent ETTH. Many
studies, however, have not reported or separated these
sub-groupings. In this case the review simply reports
the study as examining TTH suerers. The relationship
of the reviewed material to other primary headaches
and their potential overlap with TTH are discussed
further.
Mechanisms of tension-type headache
Muscle contraction
Sustained extra-fusal muscle contraction leading to
ischemia or trigger point activation was previously
thought the primary mechanism of TTH-like headache
(7). However, the majority of studies have found that
pericranial muscle tension, as measured by surface elec-
tromyography (EMG) levels, is not increased or only
minimally increased in most TTH suerers, and not
related to TTH activity (10,13,14). Additionally,
EMG levels do not reliably correlate with stress levels
or stress-induced headache in TTH suerers (15,16).
Indeed, some studies have indicated lower levels of
muscle tension in headache suerers compared to con-
trols and a negative relationship between EMG levels
and headache activity (17). Jensen and Olesen (18)
demonstrated that voluntarily sustained jaw muscle
contraction can precipitate headache activity in
CTTH suerers, and suggested the results showed
muscle contraction can cause headache. However, in
a later cross-over design study in which TTH subjects
were exposed to both a jaw clenching and a placebo
condition, Neufeld, Holroyd and Lipchik (9) found
no dierence between conditions in the number of sub-
jects who developed subsequent headache. A similar
nding was reported for headache development follow-
ing static contraction of trapezius muscles in TTH suf-
ferers (19). However, the latter study included healthy
control subjects, with results indicating signicantly
more TTH subjects compared to controls developed a
headache following both the experimental and placebo
conditions. These results indicate that headache suf-
ferers develop headache subsequent to voluntary
static muscle contraction as a result of some factor
other than the muscle contraction specically. Muscle
contraction, therefore, may be one mechanism of TTH,
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1251
but is now considered not the primary mechanism by
which stress triggers a TTH episode.
Myofascial tenderness
Increased tenderness in the muscles and tendon inser-
tions around the head, neck and shoulders is evident in
most TTH subjects (8,13). Increased myofascial tender-
ness (MT) correlates with headache history (years
of suering headache) (20) and clinical parameters
(e.g. severity, intensity) (21). Increased MT has also
been shown to precede headache subsequent to volun-
tary muscle contraction (18), and is increased during
the headache episode (13,14,22). This indicates
that increased MT is of clinical relevance to TTH.
The mechanisms of increased MT in TTH suerers
are unclear at present. Increased MT may reect a
peripheral pathology causing sensitization in the myo-
fascia, or a central pathology such as sensitization at
spinal/trigeminal dorsal horns, supra-spinal sensitiza-
tion, deciency in pain modulatory networks and/or
psychological factors (e.g. increased attention to pain,
increased pain reporting behavior). Muscle biopsy or
in vivo chemical challenges have failed to nd periph-
eral pathology at sites of tenderness in TTH suerers
(23). Interestingly, however, the majority of ETTH suf-
ferers studied have increased MT in the absence of
reduced pain thresholds to mechanical, thermal or elec-
trical stimulation at cephalic or extra-cephalic locations
(24,25). This indicates that central pain processing, as
reected in general pain sensitivity, is normal in most
ETTH suerers, and concords with suggestions that
increased MT in ETTH suerers reects as yet uniden-
tied peripheral pathology (8).
In contrast to ETTH subjects, reduced pain thresh-
olds to various stimuli (i.e. mechanical, electrical and/
or thermal stimuli) at cephalic and extra-cephalic sites
have been more reliably found in CTTH suerers
(26,27,28). Additionally, recent studies have demon-
strated increased response to supra-threshold experi-
mental pain in CTTH suerers (29,30). Together,
these ndings indicate that central mechanisms, as
reected in general pain sensitivity, may be abnormal
in CTTH, but not ETTH. Importantly, however, a neg-
ative correlation between pain thresholds and MT has
been found in both ETTH and CTTH subjects (24),
indicating that central sensitization may be related to
increased MT, either as a cause, concomitant or conse-
quence. A well-received model is that prolonged nox-
ious input from pericranial myofascia may sensitize the
CNS, causing increased general pain sensitivity and
facilitating the progression from ETTH to CTTH (8).
Although increased muscle tenderness is the most
commonly observed pain processing abnormality in
TTH suerers, it should be noted that some healthy
1252
controls report markedly increased muscle tenderness
without headache, and some headache suerers do not
have increased muscle tenderness (21,31). Similarly, a
number of studies have failed to nd a correlation
between pericranial muscle tenderness and headache fre-
quency or duration (32,33,34), and Bove and Nilsson
(35) found no dierence in muscle tenderness between
and during a headache episode in TTH suerers. These
results indicate that factors other than muscle tender-
ness, such as endogenous pain regulatory mechanisms,
may be involved in the pathogenesis of TTH.
Central sensitization
Spinal/trigeminal sensitization: Nerves in the head,
neck and shoulders synapse centrally at the spinal
dorsal horns and trigeminal nucleus caudalis. These
central nuclei receive convergent input from pericranial
musculature and vascular structures, trigeminal and
cervical nerves of the neck and shoulders, and are
also under descending facilitatory and inhibitory con-
trol from supra-spinal structures. Based on this,
Olesen (36) proposed a vascular-supra-spinal-myogenic
(VSM) model of migraine and TTH. The VSM model
suggests pain in TTH and migraine may result from
the combined input from myofascial, vascular
and supra-spinal structures to the trigeminal nucleus,
with myofascial and supra-spinal input being promi-
nent in TTH and vascular input being prominent in
migraine.
Support for a spinal/trigeminal-level dysfunction in
TTH suerers comes from ndings of decreased detec-
tion and tolerance thresholds to experimentally induced
pain at cephalic but not extra-cephalic locations
(26,37,38), and demonstration of abnormal spinal
(39), trigeminal (40) and trigemino-cervical (41) reex
responses in CTTH suerers. Of particular interest is
that increased pain sensitivity has been demonstrated at
both muscular and non-muscular pericranial locations
(30). This indicates that pain sensitivity is increased in
the pericranial region generally, supporting the notion
that spinal/trigeminal processing may be abnormal,
rather than or in addition to, sensitivity in the pericra-
nial musculature specically.
One of the most compelling indications of spinal/
trigeminal dysfunction in CTTH suerers comes from
ndings of qualitatively altered (linear) pressure-pain
response function to muscle palpation in TTH suerers
with increased MT (20,42). Further, the degree of ten-
derness was associated with the response function alter-
ation, with least tender muscles approximating a power
function, while the most tender muscles approximated
a linear function. This nding indicates MT may
reect functional reorganization in spinal/trigeminal
inter-neurons such that previously non-nociceptive
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Cephalalgia 30(10)
low-threshold mechanoreceptors (LTMs) acquire noci-
ceptive properties. Specically, the response function in
high-threshold mechanoreceptors (nociceptors) is expo-
nential, while the response function of LTMs is linear
(43). The linear response function of pressure pain to
manual palpation of tender muscles in CTTH suerers
may therefore reect recruitment of LTMs and/or their
inter-neuronal networks in tender muscles (20,42). Such
neuroplastic changes are a demonstrated component of
central sensitization (44,45).
Supra-spinal sensitization: There are ndings in
CTTH suerers of decreased cephalic and extra-cephalic
pain detection and tolerance thresholds to mechanical,
thermal and electrical stimuli (2628,46,47). This indi-
cates CTTH may involve a more generalized pain dys-
function than sensitization to mechanical stimulation in
the cephalic muscles or trigeminal pathways.
Specically, the anatomically generalized and modality
non-specic increase in pain sensitivity has been inter-
preted to indicate a supra-spinal sensitization in these
subjects (8,29,30).
Physiologically, supra-spinal sensitization refers to
sensitization of third order thalamic neurons or
higher structures (such as cortical structures). Recent
support for supra-spinal sensitization comes from stu-
dies examining laser-evoked event-related potentials
(ERPs) in the cortex (32,33). This group reported
increased MT in CTTH suerers, which was correlated
with an increased N2a-P2 amplitude (32) and R2 wave
(33) to painful laser evoked stimulation in the CTTH
group. Notably, ERP amplitudes were particularly
increased during laser stimulation at pericranial
regions. The authors suggested MT may be associated
with an increased sensitivity to pain at the cortical
level in CTTH suerers. Supporting this, Buchgreitz
et al. (48) recently used high-density electro-
encephalographic (EEG) mapping to demonstrate
abnormal pain processing response to induced muscle
pain in CTTH suerers. This oers the rst experimen-
tal evidence of abnormal supra-spinal processing of
muscle pain in CTTH suerers to date.
Additional support for supra-spinal sensitization in
CTTH suerers comes from recent neuro-imaging stu-
dies reporting abnormalities in cortical structures
involved in pain processing in CTTH suerers, partic-
ularly decreased tissue mass in several areas of the pain
matrix, including pons, anterior cingulate cortex
(ACC), insular cortex, temporal lobe, orbito-frontal
cortex and hippocampus (4951). At present, it is
unclear whether the cortical atrophy is primary or sec-
ondary in CTTH, and the clinical signicance is unclear.
May (50) suggests structural abnormalities could be
involved in a permissive or triggering manner.
Alternatively, cerebral atrophy could be due to
Cathcart et al.
prolonged activation due to input from lower structures
conveying pericranial noxious signals (48,52).
Wind-up and temporal summation
One mechanism leading to central sensitization is
wind-up, whereby repetitive noxious stimulation from
the periphery causes cumulative activity in central pain
neurons that does not return to baseline levels between
stimulations (53). The psychophysiological correlate
of wind-up is temporal summation (TS), which may
be dened as an increase (summation) in pain rating
for repetitive stimulations at constant stimulus inten-
sity (54), such as pain detection threshold (55). While
peripheral and central mechanisms may contribute
to TS, a number of features of TS suggest that it predo-
minantly reects central mechanisms: (i) TS occurs even
when the site of each stimulus in the train is changed
(56); (ii) C-polymodal aerents decrease in activity
following repeated noxious stimulation (57); (iii) periph-
eral nociceptors show fatigue from repeated noxious
stimulation (58); (iv) shorter inter-stimulus intervals
(compared to longer inter-stimulus intervals) elicit
greater pain ratings despite eliciting fewer action poten-
tials in C-bers (59); (v) N-methyl-D-aspartate
(NMDA) receptor antagonists inhibit wind-up in
dorsal horn neurons (60) and TS (61); and (vi) TS can
be induced using intra-muscular electrical stimulation,
which bypasses the nociceptor and directly activates the
nerve ber (30).
Wind-up has been suggested as a mechanism by
which prolonged myofascial noxious input leads to sen-
sitization in TTH suerers (8). Results in headache suf-
ferers are conicting. Both Fusco, Colantoni and
Giacovazzo (62) and Filatova, Latysheva and
Kurenkov (63) demonstrated increased TS of the RIII
reex to supra-threshold electrical stimulation in
chronic headache suerers compared to healthy
controls. More recently, however, Ashina et al. (30)
found only a non-signicant trend toward increased
TS of pain rating to supra-threshold electrical stimula-
tion in CTTH suerers, and Buchgreitz et al. (48) found
no dierence in TS to electrical stimulation in CTTH
suerers compared to healthy controls. In the only
study to examine TS to pressure pain in TTH suerers,
Cathcart, Wineeld, Lushington and Rolan (64)
reported increased TS to mechanical stimuli in CTTH
subjects.
Pain modulation/inhibition
Central mechanisms of TTH have also been suggested
to involve deciency in pain modulation and inhibitory
mechanisms rather than, or in conjunction with, central
sensitization (8,18,65). Indeed, it has been suggested
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1253
that sensitization through wind-up may be partially
controlled by inhibitory mechanisms (66,67).
Jensen and Olesen (18) found that pressure pain
detection thresholds at the nger increased in subjects
who did not develop a headache following experimen-
tally sustained jaw muscle contraction, compared to
subjects who did develop a subsequent headache, in
whom pressure pain thresholds were unchanged. The
authors suggested that the unchanged pain thresholds
may have reected impaired pain inhibitory
(anti-nociceptive) response to the mechanical challenge
and subsequent pain development.
The aforementioned ndings of altered spinal and
trigeminal nociceptive reexes in CTTH suerers has
also been interpreted to indicate impairment in pain
inhibitory networks, as spinal/trigeminal inhibitory
inter-neurons are known to mediate these reexes
(68). Findings of a reduced temporalis exteroceptive
second silent period (ES2) in CTTH suerers are
particularly relevant in this regard (6972). The ES2
is the momentary suppression of voluntary jaw closing
muscle activation during painful stimulation in the
trigeminal area. The ES2 is believed to be mediated
by a polysynaptic inhibitory inter-neuronal brainstem
network (73), and hence may index descending
inhibitory pathways from limbic system to brainstem
(70). However, several studies failed to nd reduced
ES2 in CTTH suerers (7476). Furthermore, it
remains unclear if ES2 is a nociceptive or a more gen-
eral inhibitory motor reex (77).
More recently, Pielsticker et al. (65) and Sandrini
et al. (78) demonstrated that central pain inhibitory
networks, as assessed by the diuse noxious inhibitory
control (DNIC) paradigm, are decient in CTTH suf-
ferers. In DNIC, nociceptive neurons in spinal and tri-
geminal dorsal horns are inhibited by noxious
stimulation remote from the neurons excitatory recep-
tive eld (79). Hence, pain from one part of the body
inhibits pain from elsewhere in the body. The exact
pathways are unclear, but are thought to involve a
spino-bulbo-spino loop encompassing the dorsolateral
and ventrolateral funiculi, and supraspinal circuits (80)
that include the brainstem medullary reticular forma-
tion, subnucleus reticularis dorsalis (81).
Pielsticker et al. (65) compared CTTH and healthy
control subjects on DNIC-like eects by measuring
cephalic and extra-cephalic electrical pain thresholds
before and during painful heat applied to the thigh.
Pain thresholds increased during heat application
more in healthy controls than in CTTH group, indicat-
ing impaired DNIC in the CTTH suerers. Sandrini
et al. (2006) assessed RIII spinal nociceptive reex
threshold in CTTH and healthy control subjects
before and during cold pressor test. The reex was
inhibited during cold pressor in controls, but facilitated
1254
in CTTH suerers, again indicating impaired DNIC in
CTTH. In the only study to examine inhibition of TS in
CTTH suerers, Cathcart and colleagues (64) reported
an impaired DNIC like inhibition of TS to pressure
pain in CTTH suerers.
Psychological pain processing
Finally, central mechanisms of TTH may involve
increased psychological response to pain, which could
occur in the absence of, as a consequence of, or addi-
tional to, physiological sensitization or decient modu-
lation/inhibition. Psychological factors possibly
increasing pain response include hypervigilance and
increased attention to pain (82), mis-attribution of
arousal as pain (83), increased pain related cognitions
(e.g. beliefs and meaning of the pain) (84), or increased
pain reporting behavior (85).
Supporting these propositions are reports of hypervi-
gilance and cognitive bias to pain related stimuli in TTH
suerers (86). Kikuchi et al. (87) reported a memory
recall bias for pain in TTH suerers, and a number of
studies have demonstrated increased arousal and poorer
use of pain coping strategies in TTH suerers (88,89).
Additionally, emotional factors known to inuence pain
such as anxiety, depression and anger, have been demon-
strated as higher in TTH suerers and related to both
headache activity (90) and sensitivity to experimental
pain in TTH suerers (9092).
Although the above studies indicate that psycholog-
ical factors may contribute to increased pain sensitivity
in CTTH suerers, they do not elucidate the mechan-
isms underlying such relationships. For example, some
studies have found increased pain report but not abnor-
mal nociceptive reex response in TTH suerers (93).
Such ndings lend some support to the suggestion that
increased pain sensitivity in TTH suerers is due to
psychological rather than physiological sensitization
at the spinal/trigeminal level. However, such ndings
do not rule out the possibility that a physiological
basis to the increased pain sensitivity may exist in
higher (e.g. thalamic, cortical) networks. The two stu-
dies by de Tommaso and co-workers (32,33) are note-
worthy in this regard. These authors found increased
MT, increased anxiety, and increased R2 wave and
N2a-P2 ERPs to laser-evoked pain stimulation at the
hand and head in CTH suerers. Importantly, MT anx-
iety and ERPs were all positively correlated. The
authors suggested that pericranial tenderness contri-
butes to sensitization in cortical areas involved in atten-
tion and emotional (i.e. anxiety) components of pain
(33). The authors also suggested that this may create
a self-perpetuating cycle such that the increased MT is
then aggravated by a pain-specic hypervigilance at the
cortical level (32).
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Cephalalgia 30(10)
The ndings by de Tommaso et al. (32,33) highlight
Edwards et al.s (94) assertion that the distinction
between psychological and physiological sensitivity to
pain may be somewhat articial, if it is assumed that
neural structures sub-serve psychological processing in
the brain. Possible relationships between psychological
and physiological pain sensitivity in TH suerers are
yet to be claried in the literature.
The relationship between stress and
pain
Overview
Stress and pain share common and closely related
neural, endocrine, autonomic and behavioral mechan-
isms and features that are thought to form part of an
integrated adaptive behavioral system (9598).
Physiologically, stress can eect pain throughout the
CNS. At the periphery, stress releases epinephrine,
which can aggravate sensitized nociceptors (99).
Conversely, nociceptive input from the periphery acti-
vates the stress system (97). At the mid-brain level, pain
both inuences and is inuenced by activation in the
hypothalamic pituitary adrenocortical (HPA) and sym-
pathetic adrenomedullary (SAM) axes, periaqueductal
grey (PAG), rostroventral medulla (RVM) and the locus
coeruleus (LC)/noradrenergic systems (95,100,101).
Descending projections from PAG and RVM inuence
pain in second-order synapses at spinal and trigeminal
dorsal horns (102). Sub-cortical and cortical structures
common to pain and stress include the limbic structures
(particularly the amygdala, basal ganglia, hypothala-
mus, hippocampus), ACC, pre-frontal cortex,
fronto-medial and fronto-lateral cortices, somato-
sensory cortices and an extensive network of
cortico-cortico connections (103107). Chapman et al.
(97) notes that the dynamic interaction of these struc-
tures forms a system for processing all aversive stimuli,
including but not limited to noxious input.
Psychologically, stress is proposed by various the-
ories to have facilitatory or inhibitory eects on pain
in certain circumstances, through eects on attention
and vigilance to pain (108,109), arousal attribution
(110), habituation (111), pain-related learning and
memory (106), and reporting behavior (112). These
relationships may be sub-served by the above structural
mechanisms, as indicated by others (97,98,104,105).
Inhibitory effects of stress on pain
Classic phenomenological work on stress inhibiting pain
was conducted by Beecher (113), who surveyed wounded
soldiers reporting low levels of pain despite severe
wounding during combat. Beecher (113) and others
Cathcart et al.
since (e.g. 114,115) suggested pain may be inhibited
under conditions of stress when eeing or ghting have
priority over recuperation from injury. Subsequent
empirical research has conrmed inhibitory eects of
stress on experimental pain processing. Aspects of
stress which have been associated with inhibitory eects
on experimental pain include acute physiological and
subjective stress (109,116), pain-irrelevant anxiety
(i.e. anxiety over something other than pain) (117),
attention focused on a stressor rather than pain (109),
adaptive coping (118), high self-ecacy in meeting
stress requirements (119), and positive aect (120).
The type of stressor involved also appears important
in determining whether the eect on pain is inhibitory:
inhibitory eects have typically been induced by stress
that is intense and involving fear, such as anticipation of
electrical shock in humans (e.g. 121), or exposure to
predators in animals (122).
Facilitatory effects of stress on pain
Poor stress coping, chronic stress, daily stress, sustained
physiological arousal, negative mood states and anxiety
related to pain have been associated with facilitatory
eects on experimental pain (120,123129). The stres-
sors shown to increase pain sensitivity are typically less
intense than those associated with inhibitory eects,
such as mental tasks in humans (117,120,125,130),
and restraint or novel environments in animals
(131,132).
Hyperalgesic eects are often discussed in psycho-
logical terms, such as stress increasing vigilance to fur-
ther aversive stimuli (including pain), or eecting the
mis-labeling of arousal as pain (118,133). Presumably
this acts as a warning of increasing challenge to the
organism, facilitating elaboration of coping behaviours
(133,134). Physiologically however, hyperalgesic eects
are more commonly discussed in terms of a dysfunc-
tional relationship. For example, chronic stress causes
long-term corticosteroid release, which may cause
tissue damage leading to pain, as well as increasing
receptor binding of corticotropin-releasing hormone
CRH in mid-brain structures, possibly impairing des-
cending pain inhibition (97,135,136). A recent sugges-
tion is that chronic stress may evoke long-term
neuro-inammation and neuroimmune alterations,
both of which have been recognized as potentially con-
tributing to pain (137,138).
Stress as the genesis of pain
Additional to stress having facilitatory and inhibitory
eects on pain signal is the theoretical possibility that
pain can be generated by stress, in the absence of an
incoming noxious signal (106,139). This possibility
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1255
arises due to the extensive overlap and inter-
connectedness of stress and pain systems, particularly
at sub-cortical and cortical levels (97,98,106,107,136).
For example, Stoeter et al. (106) and others (104,139)
suggest limbic connections may bind stress-regulating
and pain processing systems together, resulting in pain
perception being triggered by stress even in the absence
of any peripheral noxious input. The ACC appears par-
ticularly susceptible to this, being a center integrating
physical, emotional, and cognitive aspects of both pain
and stress (97,98,103,106). Moreover, Melzack (140)
and others (97,98,141,142) speculate that activity any-
where within the common stress and pain circuitry
could be interpreted as either stress or pain, depending
on a multitude of factors, including physiological, aec-
tive, cognitive and social context.
Stress and mechanisms subserving
head pain
Stress and myofascial tenderness
The increased muscle tenderness in TTH suerers may
reect peripheral sensitization. Although, as earlier dis-
cussed, muscle contraction per se has not been shown
as pathogenic in TTH, it should be noted that stress
may aggravate sensitive myofascial tissue by increasing
muscle contraction within normal ranges, and this
could lead to trigger-point activation in TTH suerers.
Muscle tone is further increased in response to pain,
eventually activating nociceptors (99). The increased
muscle contraction may be particularly evident at the
site of pain (143).
Additional to muscle contraction, catecholamines
(noradrenaline and epinephrine) released as part of
the sympathetic response to stress can aggravate
already sensitized nociceptors (144,145), and this may
be particularly evident at sites of trigger points (146).
Supporting this, Ge, Fernandez-de-las-Penas and
Arendt-Nielsen (147) demonstrated that increased
pain sensitivity in myofascial trigger points during sym-
pathetic arousal is restricted to the trigger point but not
a normal control point. The authors suggested the
hyperalgesic eect was peripherally mediated rather
than a generalized sympathetic hyperactivity.
It is well documented that chronic stress can contrib-
ute to peripheral sensitization through peripheral and
central release of epinephrine, cortisol, noradrenaline
and algogenic substances (144,145,148,149). Khasar
et al. (132) demonstrated in rodents that chronic
stress-induced release of epinephrine can sensitize pri-
mary nociceptive aerents to bradykinin, and Melzack
(140) notes that long-term corticosteroid release may
cause tissue damage leading to pain. Together, these
ndings provide evidence that stress could directly
1256
aect a putative peripheral dysfunction in TTH
suerers.
Stress and spinal/trigeminal level pain processing
Nociceptive reexes reect nociception in spinal and
brainstem circuitry, and hence can be used to assess
pain processing specically at the spinal/trigeminal
level. Early research by Willer and colleagues
(116,121,150) used spinal nociceptive reexes to dem-
onstrate that induced stress aects pain processing in
spinal dorsal horns. Such ndings supported the
gate-control theory of pain by Melzack and Wall
(114), which proposed that stress could inuence pain
through descending controls at the spinal gating
mechanisms. Using spinal (151,152) and brainstem
(153,154) nociceptive reexes, several subsequent stu-
dies conrmed the earlier ndings. Additionally,
chronic stress (restraint) in rodents caused increased
spinal nociceptive reex response (155), while acute
stress in rodents (e.g. anticipation of shock) has been
well documented to induce so-called stress induced
analgesia, through demonstration of inhibitory eects
on spinal nociceptive reex (156). Similarly, in human
subjects brief stress has been shown to have inhibitory
eects on spinal nociceptive reexes (116,157), while
chronic and daily stress has been correlated with
increased spinal reex response (116,158). Further,
stress reduction from biofeedback training has pro-
duced an increase in the spinal nociceptive reex thresh-
old (159). Additionally, in correlative studies using
human subjects, negative aect (e.g. anxiety, anger)
has been associated with increased spinal nociceptive
reex magnitude or reduced threshold (93,158) and
increased temporal summation (160). Together, these
ndings support the proposition that stress could con-
tribute to spinal/trigeminal sensitization, or aggravate
existing pain sensitivity resulting from the same, in
TTH suerers.
A number of studies, however, have failed to nd
relationships between stress or negative aect and
spinal reex magnitude, despite nding eects on pain
report (161164). Sarlani, Grace, Reynolds and
Greenspan (165) found no correlation between tempo-
ral summation (TS) and anxiety or depression in
healthy subjects, while Cathcart et al. (64) found no
eect of induced stress on TS in healthy or chronic
pain subjects. Such results suggest that stress may
have dierential eects on pain at spinal and
supra-spinal levels.
Stress and supraspinal/cortical pain processing
At the mid-brain level, stress aects pain through acti-
vation in the HPA and SAM axes, PAG, RVM and the
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Cephalalgia 30(10)
LC/noradrenergic systems (95,97,100102). Indeed, as
outlined in the gate-control theory (114), descending
projections from the PAG to dorsal horns may be a
principal mechanism by which stress facilitates and
inhibits nociception. Zhuo and Gebhart (166) and
others (167) have demonstrated that stress may increase
pain through activation of on-cells in the RVM.
Jorum (168) demonstrated stress induced hyperalgesia
in rodent partially operated through the LC/noradre-
nergic mechanism, while Imbe et al. (101) demonstrated
stress-induced hyperalgesia in rodents involved activa-
tion in the RVM and LC.
In higher structures, stress can aect pain through
increasing activity in circuitry common to stress and
pain, involving the amygdala, thalamus, hypothalamus,
ACC, frontal cortex and somatosensory cortex
(94,97,98,103,106,134,151). Schoenen et al. (70) pro-
posed that TTH pathophysiology may involve dysfunc-
tion in the limbic system. Suzuki and colleagues
(169,170) present evidence for a model of descending
facilitatory mechanisms whereby cortico-limbic activity
induced by stress can up-regulate the pain amplication
system, even in the absence of peripheral tissue irrita-
tion. Similarly, Stoeter et al. (106) and others (104,139)
suggest cortico-limbic connections common to stress
and pain may bind stress-regulating and pain process-
ing systems together, resulting in pain perception being
triggered by stress even in the absence of any peripheral
noxious input. The ACC appears particularly suscepti-
ble to this, being a center integrating physical,
emotional and cognitive aspects of both pain and
stress (98).
Stress may also induce reorganization of primary
and secondary cortical nociceptive representations
(171,172), as well as their modulation by fronto-
medial, fronto-lateral, and parietal cortex, which can
all inuence pain (173175). A study by Jasmin,
Boudah and Ohara (176) demonstrated that changes
in gamma-aminobutyric acid (GABA) in the rostral
agranular insular cortex (RAIC) can raise or lower
pain the threshold, producing hypo- or hyperalgesia.
The authors suggested that psychological stress could
aect pain through the RAIC, changing the set point of
the pain threshold in a top down manner.
Stress could therefore contribute to TTH through
aggravating putative mid-brain, sub-cortical or cortical
sensitization in TTH suerers, either additional to or in
the absence of eects on spinal processes. Consistent
with this, some studies have failed to nd eects of
stress on spinal reexes, but have found eects on cor-
tical level processing or pain report (151,161,162,164).
Similarly, Gracely et al. (177) and Seminowicz and
Davis (178) found that high and low catastrophizers
diered on pain sensitivity but not thalamic activation
in response to noxious stimulation. Together, such
Cathcart et al.
ndings indicate that stress may have dierential eects
on pain at spinal and supra-spinal levels, and concords
with suggestions that stress could contribute to putative
supra-spinal sensitization in TTH suerers (8).
Stress and pain modulation/inhibition
It is well documented in animal and healthy human
studies that stress inhibits pain in certain circumstances
via eects on endogenous pain modulatory systems
throughout the CNS (e.g. 109,115,117,119,120,121).
Pain inhibitory mechanisms have typically been
enhanced by stress that is intense and involving fear,
such as anticipation of electrical shock in humans
(116,121), and exposure to predators in animals (122).
Pain inhibitory mechanisms, and their activation by
stress, are thought to facilitate escape from immediate
danger (116,121,125).
Inhibitory eects of stress on pain may act via
peripheral, spinal, supraspinal, and cortical networks
putatively dysfunctional in TTH suerers. Specically,
stress has been shown to inhibit pain processing at
spinal/trigeminal levels through descending inhibitory
control of dorsal horn neurons (116), at sub-cortical
levels through eects on PAG (114), and activation of
so-called o cells in RVM and paraventricular nucleus
(102), and at higher levels including thalamic and cor-
tical structures (97,98), particularly orbito-frontal
cortex (179), prefrontal cortex and rostral cingulate
cortices (103). Therefore, because stress aects pain
inhibitory mechanisms, and there is evidence of de-
cient pain inhibitory mechanisms in TTH suerers,
stress could contribute to TTH through eects on puta-
tive deciency in pain inhibitory mechanisms in TTH
suerers at any of these levels, as hypothesized by
others (8,12,36,106).
Pain inhibitory networks involved in diuse noxious
inhibitory controls (DNIC) have also been hypothe-
sized to be potentially inuenced by stress (180182);
however, results are conicting to date: Sandrini et al.
(183) found that reducing stress through hypnosis
reduced the eectiveness of DNIC. Goaux and collea-
gues (184) found that stress induced by expectation of
pain reduced the magnitude of DNIC inhibition, while
the inhibition was enhanced in subjects who expected
less pain. Lariviere et al. (185) reported similar ndings.
In contrast, both Reinhert and colleagues (186) and
Mason et al. (182) demonstrated that inhibition of
pain during DNIC was not due to attention, vigilance
or arousal associated with the conditioning stimulus.
Similarly, Edwards et al. (181) found no correlation
between DNIC magnitude and scores on the
Perceived Stress Scale, while Cathcart et al. (64)
found no eect of experimentally induced stress on
DNIC in healthy subjects. Interestingly, the nding
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1257
that DNIC is not naloxone-reversible (97) indicates
that DNIC operates independent of the HPA axis.
Stress could, however, aect DNIC through neural
mechanisms (94).
Additional to stress potentially aggravating an
already impaired pain modulatory mechanism in TTH
suerers, stress could potentially contribute to the
development of impaired pain inhibition. For example,
although acute stress activates pain inhibition, pro-
longed activation of this system may exhaust the mod-
ulating system, resulting in central sensitization and
hyperalgesia (187,188). Gameiro et al. (189) demon-
strated that chronic stress decreased the eciency of
opioid analgesic systems in rodents. Stress may also
increase receptor binding of CRH in mid-brain struc-
tures, possibly impairing descending pain inhibition
(106,190). In TH suerers, then, stress could contribute
to the impairment of inhibitory mechanisms, aggravate
already impaired inhibitory mechanisms directly and
increase the excitability of nociceptive circuitry, further
challenging an already impaired pain modulatory
system.
Stress and psychological pain processing
Psychologically, stress is proposed by various theories
to have facilitatory or inhibitory eects on pain in cer-
tain circumstances, through eects on attention and
vigilance to pain, arousal attribution, habituation,
pain-related learning and memory and reporting behav-
ior (109,112,118,134,191193).
Physiological mechanisms sub-serving such eects
could include descending modulation at mid-brain,
brainstem or spinal mechanisms (94,118,133).
However, a number of studies have found eects of
stress on pain report but not spinal, brainstem or tha-
lamic activity (151,161,162,177,178). Such ndings
demonstrate that stress can aect psychological aspects
of pain processing (e.g. reporting behavior) in the
absence of eects on spinal and brainstem processing.
Additionally, the majority of studies examining the
eects of stress on pain sensitivity in humans have
examined subjective ratings of pain in the absence of
measures assessing specic pain processing mechanisms
(e.g. spinal reexes). Such ndings may reect eects of
stress on psychological (e.g. reporting behavior) rather
than physiological processes (e.g. dorsal horn neuron
activity).
Stress could therefore aect pain sensitivity in TTH
suerers through aggravating already increased psy-
chological pain processing factors, such as increased
reporting behavior. For example, Stoeter et al. (106)
and others (133) suggest that central processing of
pain and stress may be increased in chronic pain suf-
ferers due to strong memory of previous exposure and
1258
enhanced anticipation of new exposure to stress
aggravating pain. Supporting this, Armstrong et al.
(86) reported that headache suerers reported a greater
implicit association between negative events (e.g. stres-
sors) and pain. Stress could also further challenge
coping mechanisms, increasing pain reporting and sick-
ness behavious in TTH suerers (191,193).
Although we have presented a dichotomy between
physiological and psychological aspects of pain pro-
cessing, as noted by Edwards et al. (94) and others
(177), such a dichotomy is somewhat articial if we
assume that neural processes sub-serve psychological
processing of pain. For example, as discussed above,
both pain and stress are processed through common
and closely related neural structures comprising a gen-
eralized defense system (97,103,133), and neuroimaging
studies show that psychological factors aecting pain
processing are associated with alterations in brain
structures comprising this system.
Stress and pain processing in
tension-type headache sufferers
The literature reviewed so far indicates that stress can
increase pain sensitivity and aect pain mechanisms
proposed as dysfunctional in TTH. However, although
numerous studies have demonstrated relationships
between stress and clinical pain in TTH suerers
(11,1517,194), fewer studies have examined both
stress and pain sensitivity in TTH suerers.
In a study by Lehrer and Murphy (92), TTH suerers
had a higher heart rate and increased negative aect
(anxiety, anger and depression), and rated a tourniquet
as more painful than did healthy controls. Similarly,
Hatch et al. (91) found TTH suerers to have increased
levels of self-reported stress and increased rating of cold
pressor pain compared to healthy controls, while
Cathcart et al. (195) found increased rating of cold
pressor pain but no dierence in self-reported stress
levels in TTH suerers. In regard to stress coping,
Ukestad and Wittrock (89) reported increased use of
catastrophizing as a coping strategy for stress and pain
in TTH suerers who also rated cold pressor as more
painful than did healthy controls. Dawans et al. (196)
reported increased subjective stress and reduced extero-
ceptive second silent period ES2 reex in CTH suerers,
indicating both increased stress and impaired pain inhib-
itory mechanisms in CTTH. None of these studies
reported examining for possible relationships between
the increased pain sensitivity and the measures of
aect or physiological arousal.
A number of studies have examined relationships
between negative aect and pain sensitivity in TTH
suerers. De Tommaso et al. (33) and others
(197,198) reported correlations between anxiety and
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Cephalalgia 30(10)
muscle tenderness in CTH subjects; however, others
found no such correlations (199). Similarly, Rollnik
et al. (34) failed to nd an association between coping
strategy use and either muscle tenderness or cephalic
pressure pain thresholds in TH suerers, while
Schoenen et al. (27) found no correlation between pres-
sure pain thresholds and anxiety, depression or
self-reported stress levels. Cathcart and Pritchard
(200) reported correlations between daily hassles and
both pressure pain thresholds and muscle tenderness
in TH suerers, which were both predictive of prospec-
tive headache activity.
Three studies reported examining relationships
between aect and pain inhibition in TTH. Both
Sandrini et al. (201) and Cathcart et al. (64) found
impaired DNIC in TTH suerers was not correlated
with anxiety or depression, neither of which dieren-
tiated TTH suerers from healthy controls. However,
Wallasch, Reinecke and Langohr (202) reported a cor-
relation between ES2 inhibitory reex and self-reported
tension, with the authors suggesting increased stress
may contribute to TTH through aecting impaired
pain inhibitory networks in CTTH suerers.
Although temporal summation has been correlated
with anxiety and stress coping style in healthy subjects
(94,203), only two studies report examining relation-
ships between TS and aect in headache suerers.
Filatova et al. (63) reported no correlation between
RIII reex wind-up ratios and depression in headache
suerers of mixed diagnoses, while Cathcart et al. (64)
reported correlations between TS magnitude and both
anxiety and depression in CTTH suerers, but not
healthy controls.
While the above studies examined correlations
between stress and pain sensitivity, fewer studies have
examined eects of stress on subsequent pain sensitivity
in TTH suerers. Leistad et al. (11) found pain to
manual exertion of various pericranial muscles
increased in TTH suerers in response to stress induced
by an hour-long mental task. The increased pain
response was generalized to pericranial areas rather
than specic muscles, pain increased although stress
levels remained constant and pain continued after the
task ceased. The authors concluded that stress
increased head pain through aggravating sensitized cen-
tral pain mechanisms.
Janke et al. (204) examined pain thresholds and
muscle tenderness in depressed and euthymic TTH suf-
ferers before and after an hour-long stress task.
Although stress-induced headache in the headache suf-
ferers, it did not induce pre-post task change in pain
detection thresholds in any group. Muscle tenderness
appeared on visual inspection to increase following the
task; however, within-subject analyses were not
reported. However, TTH suerers had increased
Cathcart et al. 1259

overall MT compared to controls. Furthermore,
depressed TTH subjects had increased pain sensitivity
and were more likely to develop a headache following
task than euthymic TTH subjects. The authors sug-
gested that depression increases onset of stress-induced
headache, and that this is associated with greater pain
sensitivity in depressed TTH suerers.
A recent series of studies by Cathcart and colleagues
examined eects of induced stress on muscle tender-
ness, pain detection and tolerance thresholds, tonic
pain rating, DNIC and TS in TTH suerers (64,195,
200,205207). The results indicated that induced stress
increased pain sensitivity more in TTH suerers than in
healthy controls, and that this was related to the devel-
opment of stress-induced headache. However, while
TTH suerers had abnormal TS and DNIC responses,
there was no eect of induced stress on either TS or
DNIC in TTH suerers or healthy controls. These
results, although requiring replication and extension,
support the proposition that stress contributes to
TTH through aggravating already increased pain sen-
sitivity in TH suerers. Abnormal TS and/or DNIC
may contribute to or result from increased pain sensi-
tivity in the CNS. These propositions, and the literature
reviewed herein, are summarized in the speculative
model presented in Figure 1.
Limitations to the literature and
suggestions for future research
Research into TTH mechanisms indicates abnormal
pain processing in TTH suerers, while research in
animal and healthy human demonstrates that mental
stress may aect pain throughout the CNS, including
CNS pain processes recently proposed as dysfunctional
in TTH. This converging research indirectly supports
the suggestion that stress may contribute to TTH
through aecting abnormal pain processing in TTH
suerers. However, there has been little research to
date directly examining this hypothesis. Initially, then,
further research is needed to replicate and extend the
small number of studies examining stress and pain sen-
sitivity in TTH. Furthermore, while that research which
has been published has largely been supportive, it has
considerable limitations.
A major limitation in the research to date is that
while a number of studies have examined both stress
and pain sensitivity, or eects of stress on clinical pain
(i.e. headache), very few studies have examined eects
of stress on quantitative measures of experimental pain
sensitivity in TTH suerers. Such examinations are
needed to clarify the nature of previously observed cor-
relational relationships. Similarly, further research is
needed to determine the potential importance of stress
as an aggravator, concomitant and consequence of
increased pain sensitivity in TTH suerers.
Another limitation and future direction is the need
to better examine the particular aspects of pain aected
by stress in TTH suerers. There are now
well-established techniques for examining such pro-
cesses, such as TS and DNIC protocols, and assess-
ments of multiple responses (e.g. detection and
tolerance thresholds, tonic pain ratings) to multiple
modalities (e.g. thermal and pressure pain). The studies

Reduces pain detection

Increases peripheral STRESS threshold, and increases
activation / intensity of noxious signal in the
sensitization CNS

Myofascia CNS sensitivity Headache

Wind up

DNIC

Figure 1. A model for stress and headache mechanisms. The model suggests that stress may contribute to chronic tension-type
headache (CTTH) through peripheral and central mechanisms. The term stress in the model refers to the stress process, involving
stressors, appraisal/coping and resultant physiological and psychological levels of arousal. Peripherally, stress may enhance activation
and sensitization in the pericranial myofascia. Centrally, stress may lower threshold to, and increase intensity of, noxious signal in the
central nervous system (CNS). In CTTH sufferers, such effects may lower the threshold to, and increase the intensity of, painful input
from already tender pericranial musculature, thereby triggering or exacerbating an episode of head pain. Such effects could also
contribute to CNS sensitization in CTTH sufferers. Wind-up and impaired diffuse noxious inhibitory control (DNIC) are proposed as
underlying mechanisms in CTTH that are not directly affected by stress, but which may contribute to the development of central
sensitization by facilitating effects of prolonged noxious myofascial input to CNS.

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1260
by Cathcart and colleagues (64,195,200,205207) and
Janke et al. (204) represent initial work in this regard;
however, a limitation common to their work is the reli-
ance on self-reported pain measures. Techniques such
as nociceptive reexes and neuroimaging could be used
not only to provide more objective measures of pain
sensitivity, but also to better reveal the particular pro-
cess and structures involved in stress aecting pain pro-
cessing in TTH. Indeed, a current project by our group
is using repetitive transcranial magnetic stimulation
(rTMS) to examine cortical mechanisms in relation-
ships between stress and headache.
Similarly, future research needs to elucidate the par-
ticular aspects of the stress process aecting pain pro-
cessing in TTH. Various components of the stress
process, including stress events (e.g. daily hassles,
appraisal/coping and physiological and psychological
stress response, have all been related to TTH activity
(see (6,208) for comprehensive reviews). Recent
research on pain in healthy humans has independently
demonstrated that many of these aspects of stress
related to headache activity are also related to pain
processes recently proposed as dysfunctional in TTH
(e.g. 94). Furthermore, although stress is noted as a
contributing factor in both ETTH and CTTH, these
two diagnoses appear to have dierent pain processing
abnormalities, with ETTH involving myofascial sensi-
tivity predominantly, and CTTH involving additional
central sensitization (8). Further research is needed to
examine the mechanisms by which stress contributes to
ETTH compared with CTTH.
Other primary headaches
As noted in this papers introduction, the present
review is limited to TTH specically. However, an over-
lap in symptoms and co-morbidity of dierent primary
headaches has been well documented (4,11,13,14,36),
particularly for CTTH, migraine and other chronic
daily headache (CDH) syndromes. Stress is noted as a
contributing factor in all these headaches (87,88,148),
and there are ndings indicating common pathophy-
siology, such as central sensitization (62,63,68,76), neu-
rochemical anomaly (e.g nitric oxide, serotonin)
(209,210) and common structural abnormalities in cor-
tical areas involved in pain processing (50,51,210). It
may be, therefore, that putative relationships between
stress and TTH mechanisms reviewed herein are also
applicable to other primary headache disorders, partic-
ularly migraine and CDH syndromes. Further research
will be required to explore this notion.
Recent imaging studies, however, oer intriguing
speculation on the relationship between stress and pri-
mary headaches other than TTH. A review by May
(210) shows that an increase in pain matrix activity
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Cephalalgia 30(10)
is common to many primary headaches. As discussed
above, these areas are also aected by stresshence
stress could aggravate headache in these conditions
via common neural mechanisms. However, as noted
by May (210) other studies indicate additional distinct
functional neuroanatomy in some primary headaches,
particularly migraine (211), hemicrania continua (213)
and the trigeminal autonomic cephalalgias (TACs), as
well as in cluster headache, paroxysmal hemicrania
and short-lasting neuralgiform headache with conjuncti-
val injection and tearing (SUNCT) (210,212).
Speculatively, stress may contribute to these primary
headaches via eects on specic brain regions related
to their clinical presentation, additional to possible
eects on neural mechanisms common across primary
headaches. To our knowledge, this notion has not been
examined to date.
Summary
Stress is a widely accepted contributing factor to TTH;
however, the mechanisms underlying this relationship
are unclear. The previous model of increased muscle
contraction as the primary mechanism has not been
widely supported in the research literature. Recent
research suggests TTH pathophysiology involves
abnormal pain processing in the CNS. Concurrently,
animal and healthy human research demonstrates that
psychological stress aects pain processing throughout
the CNS, including pain mechanisms proposed as dys-
functional in TTH suerers. It has therefore been pro-
posed that stress may contribute to TTH through
aggravating abnormal pain processing in TTH suf-
ferers. This hypothesis has not been adequately exam-
ined to date. However, initial ndings suggest that
stress aggravates already increased pain sensitivity in
TTH suerers, and this may be signicant in the rela-
tionship between stress and headache activity. Further
research is needed to elucidate the relationships
between stress and pain in TTH. Such research may
facilitate the improvement of both pharmacological
and behavioral intervention for TTH.
Acknowledgements
The authors are sincerely grateful to the following people for
their generous and expert assistance with project design and
manuscript review: Dr John Petkov from the University of
South Australia, and Dr Don Pritchard from the University
of Adelaide.
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