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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 dysfunctional 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

Introduction

The majority of headaches are termed primary headache, which refers to head pain not attributable (i.e. secondary) 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 associated with significant socioeconomic cost and reduced quality of life (1,2). Indeed, based on worldwide prevalence, primary headache is in the World Health Organization’s top ten ranking of disability causes (3), with TTH specifically having the highest socioeconomic cost of all headaches (4). However, despite its prevalence and impact, the causes of TTH are not clearly understood, 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 in TTH sufferers (7). However, this hypothesis has not been supported in most research (8–10). Recent research suggests TTH pathophysiology may involve sensitization in myofascial innervation or the central nervous system (CNS), impaired pain inhibitory mechanisms and/or enhanced psychological processing of pain in TTH sufferers.

Animal and healthy human studies show that stress can increase pain sensitivity, and affect pain processing throughout the CNS. It has therefore been suggested that stress may contribute to TTH by aggravating abnormal pain processing in TTH sufferers (8,11,12). There is, however, little research directly examining this hypothesis in headache sufferers. To facilitate further research in this area, the present paper reviews and synthesises literature on (i) pain mechanisms of TTH, (ii) relationships between stress and pain, with particular reference to pain mechanisms subserving head pain and (iii) literature directly examining relationship between stress and pain processing in TTH sufferers. 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 sufferers. 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 electromyography (EMG) levels, is not increased or only minimally increased in most TTH sufferers, 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 sufferers (15,16). Indeed, some studies have indicated lower levels of muscle tension in headache sufferers compared to controls 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 sufferers, 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 difference between conditions in the number of subjects who developed subsequent headache. A similar finding was reported for headache development following static contraction of trapezius muscles in TTH sufferers (19). However, the latter study included healthy control subjects, with results indicating significantly more TTH subjects compared to controls developed a headache following both the experimental and placebo conditions. These results indicate that headache sufferers develop headache subsequent to voluntary static muscle contraction as a result of some factor other than the muscle contraction specifically. Muscle contraction, therefore, may be one mechanism of TTH, but is now considered not the primary mechanism by which stress triggers a TTH episode.

Myofascial tenderness

Increased tenderness in the muscles and tendon insertions around the head, neck and shoulders is evident in most TTH subjects (8,13). Increased myofascial tenderness (MT) correlates with headache history (years of suffering headache) (20) and clinical parameters (e.g. severity, intensity) (21). Increased MT has also been shown to precede headache subsequent to voluntary 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 sufferers are unclear at present. Increased MT may reflect a peripheral pathology causing sensitization in the myofascia, or a central pathology such as sensitization at spinal/trigeminal dorsal horns, supra-spinal sensitization, deficiency 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 find peripheral pathology at sites of tenderness in TTH sufferers (23). Interestingly, however, the majority of ETTH sufferers studied have increased MT in the absence of reduced pain thresholds to mechanical, thermal or electrical stimulation at cephalic or extra-cephalic locations (24,25). This indicates that central pain processing, as reflected in general pain sensitivity, is normal in most ETTH sufferers, and concords with suggestions that increased MT in ETTH sufferers reflects as yet unidentified peripheral pathology (8).

In contrast to ETTH subjects, reduced pain thresholds to various stimuli (i.e. mechanical, electrical and/or thermal stimuli) at cephalic and extra-cephalic sites have been more reliably found in CTTH sufferers (26,27,28). Additionally, recent studies have demonstrated increased response to supra-threshold experimental pain in CTTH sufferers (29,30). Together, these findings indicate that central mechanisms, as reflected in general pain sensitivity, may be abnormal in CTTH, but not ETTH. Importantly, however, a negative 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 consequence. A well-received model is that prolonged noxious 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 sufferers, it should be noted that some healthy controls report markedly increased muscle tenderness without headache, and some headache sufferers do not have increased muscle tenderness (21,31). Similarly, a number of studies have failed to find a correlation between pericranial muscle tenderness and headache frequency or duration (32,33,34), and Bove and Nilsson (35) found no difference in muscle tenderness between and during a headache episode in TTH sufferers. These results indicate that factors other than muscle tenderness, 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 control 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 prominent in TTH and vascular input being prominent in migraine.

Support for a spinal/trigeminal-level dysfunction in TTH sufferers comes from findings of decreased detection 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) reflex responses in CTTH sufferers. 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 pericranial musculature specifically.

One of the most compelling indications of spinal/trigeminal dysfunction in CTTH sufferers comes from findings of qualitatively altered (linear) pressure-pain response function to muscle palpation in TTH sufferers with increased MT (20,42). Further, the degree of tenderness was associated with the response function alteration, with least tender muscles approximating a power function, while the most tender muscles approximated a linear function. This finding indicates MT may reflect functional reorganization in spinal/trigeminal inter-neurons such that previously non-nociceptive low-threshold mechanoreceptors (LTMs) acquire nociceptive properties. Specifically, the response function in high-threshold mechanoreceptors (nociceptors) is exponential, while the response function of LTMs is linear (43). The linear response function of pressure pain to manual palpation of tender muscles in CTTH sufferers may therefore reflect 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 findings in CTTH sufferers of decreased cephalic and extra-cephalic pain detection and tolerance thresholds to mechanical, thermal and electrical stimuli (26–28,46,47). This indicates CTTH may involve a more generalized pain dysfunction than sensitization to mechanical stimulation in the cephalic muscles or trigeminal pathways. Specifically, the anatomically generalized and modality non-specific increase in pain sensitivity has been interpreted 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 studies examining laser-evoked event-related potentials (ERPs) in the cortex (32,33). This group reported increased MT in CTTH sufferers, 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 sufferers. 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 sufferers. This offers the first experimental evidence of abnormal supra-spinal processing of muscle pain in CTTH sufferers to date.

Additional support for supra-spinal sensitization in CTTH sufferers comes from recent neuro-imaging studies reporting abnormalities in cortical structures involved in pain processing in CTTH sufferers, particularly 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 (49–51). At present, it is unclear whether the cortical atrophy is primary or secondary in CTTH, and the clinical significance is unclear. May (50) suggests structural abnormalities could be involved in a permissive or triggering manner. Alternatively, cerebral atrophy could be due to 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 defined as an increase (summation) in pain rating for repetitive stimulations at constant stimulus intensity (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 predominantly reflects central mechanisms: (i) TS occurs even when the site of each stimulus in the train is changed (56); (ii) C-polymodal afferents decrease in activity following repeated noxious stimulation (57); (iii) peripheral 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 potentials in C-fibers (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 fiber (30).

Wind-up has been suggested as a mechanism by which prolonged myofascial noxious input leads to sensitization in TTH sufferers (8). Results in headache sufferers are conflicting. Both Fusco, Colantoni and Giacovazzo (62) and Filatova, Latysheva and Kurenkov (63) demonstrated increased TS of the RIII reflex to supra-threshold electrical stimulation in chronic headache sufferers compared to healthy controls. More recently, however, Ashina et al. (30) found only a non-significant trend toward increased TS of pain rating to supra-threshold electrical stimulation in CTTH sufferers, and Buchgreitz et al. (48) found no difference in TS to electrical stimulation in CTTH sufferers compared to healthy controls. In the only study to examine TS to pressure pain in TTH sufferers, Cathcart, Winefield, 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 deficiency in pain modulation and inhibitory mechanisms rather than, or in conjunction with, central sensitization (8,18,65). Indeed, it has been suggested 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 finger increased in subjects who did not develop a headache following experimentally 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 reflected impaired pain inhibitory (anti-nociceptive) response to the mechanical challenge and subsequent pain development.

The aforementioned findings of altered spinal and trigeminal nociceptive reflexes in CTTH sufferers has also been interpreted to indicate impairment in pain inhibitory networks, as spinal/trigeminal inhibitory inter-neurons are known to mediate these reflexes (68). Findings of a reduced temporalis exteroceptive second silent period (ES2) in CTTH sufferers are particularly relevant in this regard (69–72). 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 find reduced ES2 in CTTH sufferers (74–76). Furthermore, it remains unclear if ES2 is a nociceptive or a more general inhibitory motor reflex (77).

More recently, Pielsticker et al. (65) and Sandrini et al. (78) demonstrated that central pain inhibitory networks, as assessed by the diffuse noxious inhibitory control (DNIC) paradigm, are deficient in CTTH sufferers. In DNIC, nociceptive neurons in spinal and trigeminal dorsal horns are inhibited by noxious stimulation remote from the neurons’ excitatory receptive field (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 formation, subnucleus reticularis dorsalis (81).

Pielsticker et al. (65) compared CTTH and healthy control subjects on DNIC-like effects 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, indicating impaired DNIC in the CTTH sufferers. Sandrini et al. (2006) assessed RIII spinal nociceptive reflex threshold in CTTH and healthy control subjects before and during cold pressor test. The reflex was inhibited during cold pressor in controls, but facilitated in CTTH sufferers, again indicating impaired DNIC in CTTH. In the only study to examine inhibition of TS in CTTH sufferers, Cathcart and colleagues (64) reported an impaired DNIC like inhibition of TS to pressure pain in CTTH sufferers.

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 additional to, physiological sensitization or deficient modulation/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 hypervigilance and cognitive bias to pain related stimuli in TTH sufferers (86). Kikuchi et al. (87) reported a memory recall bias for pain in TTH sufferers, and a number of studies have demonstrated increased arousal and poorer use of pain coping strategies in TTH sufferers (88,89). Additionally, emotional factors known to influence pain such as anxiety, depression and anger, have been demonstrated as higher in TTH sufferers and related to both headache activity (90) and sensitivity to experimental pain in TTH sufferers (90–92).

Although the above studies indicate that psychological factors may contribute to increased pain sensitivity in CTTH sufferers, they do not elucidate the mechanisms underlying such relationships. For example, some studies have found increased pain report but not abnormal nociceptive reflex response in TTH sufferers (93). Such findings lend some support to the suggestion that increased pain sensitivity in TTH sufferers is due to psychological rather than physiological sensitization at the spinal/trigeminal level. However, such findings 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 studies by de Tommaso and co-workers (32,33) are noteworthy 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 sufferers. Importantly, MT anxiety and ERPs were all positively correlated. The authors suggested that pericranial tenderness contributes to sensitization in cortical areas involved in attention 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-specific hypervigilance at the cortical level (32).

The findings 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 artificial, if it is assumed that neural structures sub-serve psychological processing in the brain. Possible relationships between psychological and physiological pain sensitivity in TH sufferers are yet to be clarified in the literature.

The relationship between stress and pain

Overview

Stress and pain share common and closely related neural, endocrine, autonomic and behavioral mechanisms and features that are thought to form part of an integrated adaptive behavioral system (95–98).

Physiologically, stress can effect pain throughout the CNS. At the periphery, stress releases epinephrine, which can aggravate sensitized nociceptors (99). Conversely, nociceptive input from the periphery activates the stress system (97). At the mid-brain level, pain both influences and is influenced by activation in the hypothalamic pituitary adrenocortical (HPA) and sympathetic 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 influence 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, hypothalamus, hippocampus), ACC, pre-frontal cortex, fronto-medial and fronto-lateral cortices, somato-sensory cortices and an extensive network of cortico-cortico connections (103–107). Chapman et al. (97) notes that the dynamic interaction of these structures forms a system for processing all aversive stimuli, including but not limited to noxious input.

Psychologically, stress is proposed by various theories to have facilitatory or inhibitory effects on pain in certain circumstances, through effects 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 since (e.g. 114,115) suggested pain may be inhibited under conditions of stress when fleeing or fighting have priority over recuperation from injury. Subsequent empirical research has confirmed inhibitory effects of stress on experimental pain processing. Aspects of stress which have been associated with inhibitory effects 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-efficacy in meeting stress requirements (119), and positive affect (120). The type of stressor involved also appears important in determining whether the effect on pain is inhibitory: inhibitory effects 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 effects on experimental pain (120,123–129). The stressors shown to increase pain sensitivity are typically less intense than those associated with inhibitory effects, such as mental tasks in humans (117,120,125,130), and restraint or novel environments in animals (131,132).

Hyperalgesic effects are often discussed in psychological terms, such as stress increasing vigilance to further aversive stimuli (including pain), or effecting 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 effects are more commonly discussed in terms of a dysfunctional 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 descending pain inhibition (97,135,136). A recent suggestion is that chronic stress may evoke long-term neuro-inflammation and neuroimmune alterations, both of which have been recognized as potentially contributing to pain (137,138).

Stress as the genesis of pain

Additional to stress having facilitatory and inhibitory effects 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 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 particularly 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 anywhere within the common stress and pain circuitry could be interpreted as either stress or pain, depending on a multitude of factors, including physiological, affective, cognitive and social context.

Stress and mechanisms subserving head pain

Stress and myofascial tenderness

The increased muscle tenderness in TTH sufferers may reflect peripheral sensitization. Although, as earlier discussed, 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 sufferers. 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, Fernández-de-las-Peñas and Arendt-Nielsen (147) demonstrated that increased pain sensitivity in myofascial trigger points during sympathetic arousal is restricted to the trigger point but not a normal control point. The authors suggested the hyperalgesic effect was peripherally mediated rather than a generalized sympathetic hyperactivity.

It is well documented that chronic stress can contribute 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 primary nociceptive afferents to bradykinin, and Melzack (140) notes that long-term corticosteroid release may cause tissue damage leading to pain. Together, these findings provide evidence that stress could directly affect a putative peripheral dysfunction in TTH sufferers.

Stress and spinal/trigeminal level pain processing

Nociceptive reflexes reflect nociception in spinal and brainstem circuitry, and hence can be used to assess pain processing specifically at the spinal/trigeminal level. Early research by Willer and colleagues (116,121,150) used spinal nociceptive reflexes to demonstrate that induced stress affects pain processing in spinal dorsal horns. Such findings supported the gate-control theory of pain by Melzack and Wall (114), which proposed that stress could influence pain through descending controls at the spinal gating mechanisms. Using spinal (151,152) and brainstem (153,154) nociceptive reflexes, several subsequent studies confirmed the earlier findings. Additionally, chronic stress (restraint) in rodents caused increased spinal nociceptive reflex 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 effects on spinal nociceptive reflex (156). Similarly, in human subjects brief stress has been shown to have inhibitory effects on spinal nociceptive reflexes (116,157), while chronic and daily stress has been correlated with increased spinal reflex response (116,158). Further, stress reduction from biofeedback training has produced an increase in the spinal nociceptive reflex threshold (159). Additionally, in correlative studies using human subjects, negative affect (e.g. anxiety, anger) has been associated with increased spinal nociceptive reflex magnitude or reduced threshold (93,158) and increased temporal summation (160). Together, these findings support the proposition that stress could contribute to spinal/trigeminal sensitization, or aggravate existing pain sensitivity resulting from the same, in TTH sufferers.

A number of studies, however, have failed to find relationships between stress or negative affect and spinal reflex magnitude, despite finding effects on pain report (161–164). Sarlani, Grace, Reynolds and Greenspan (165) found no correlation between temporal summation (TS) and anxiety or depression in healthy subjects, while Cathcart et al. (64) found no effect of induced stress on TS in healthy or chronic pain subjects. Such results suggest that stress may have differential effects on pain at spinal and supra-spinal levels.

Stress and supraspinal/cortical pain processing

At the mid-brain level, stress affects pain through activation in the HPA and SAM axes, PAG, RVM and the LC/noradrenergic systems (95,97,100–102). 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/noradrenergic mechanism, while Imbe et al. (101) demonstrated stress-induced hyperalgesia in rodents involved activation in the RVM and LC.

In higher structures, stress can affect 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) proposed that TTH pathophysiology may involve dysfunction 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 amplification system, even in the absence of peripheral tissue irritation. Similarly, Stoeter et al. (106) and others (104,139) suggest cortico-limbic connections common to stress and pain 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 particularly susceptible 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 influence pain (173–175). 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 affect 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 sufferers, either additional to or in the absence of effects on spinal processes. Consistent with this, some studies have failed to find effects of stress on spinal reflexes, but have found effects on cortical 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 differed on pain sensitivity but not thalamic activation in response to noxious stimulation. Together, such findings indicate that stress may have differential effects on pain at spinal and supra-spinal levels, and concords with suggestions that stress could contribute to putative supra-spinal sensitization in TTH sufferers (8).

Stress and pain modulation/inhibition

It is well documented in animal and healthy human studies that stress inhibits pain in certain circumstances via effects 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 effects of stress on pain may act via peripheral, spinal, supraspinal, and cortical networks putatively dysfunctional in TTH sufferers. Specifically, 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 effects on PAG (114), and activation of so-called ‘off cells’ in RVM and paraventricular nucleus (102), and at higher levels including thalamic and cortical structures (97,98), particularly orbito-frontal cortex (179), prefrontal cortex and rostral cingulate cortices (103). Therefore, because stress affects pain inhibitory mechanisms, and there is evidence of deficient pain inhibitory mechanisms in TTH sufferers, stress could contribute to TTH through effects on putative deficiency in pain inhibitory mechanisms in TTH sufferers at any of these levels, as hypothesized by others (8,12,36,106).

Pain inhibitory networks involved in diffuse noxious inhibitory controls (DNIC) have also been hypothesized to be potentially influenced by stress (180–182); however, results are conflicting to date: Sandrini et al. (183) found that reducing stress through hypnosis reduced the effectiveness of DNIC. Goffaux and colleagues (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. Larivière et al. (185) reported similar findings. 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 effect of experimentally induced stress on DNIC in healthy subjects. Interestingly, the finding that DNIC is not naloxone-reversible (97) indicates that DNIC operates independent of the HPA axis. Stress could, however, affect DNIC through neural mechanisms (94).

Additional to stress potentially aggravating an already impaired pain modulatory mechanism in TTH sufferers, stress could potentially contribute to the development of impaired pain inhibition. For example, although acute stress activates pain inhibition, prolonged activation of this system may exhaust the modulating system, resulting in central sensitization and hyperalgesia (187,188). Gameiro et al. (189) demonstrated that chronic stress decreased the efficiency of opioid analgesic systems in rodents. Stress may also increase receptor binding of CRH in mid-brain structures, possibly impairing descending pain inhibition (106,190). In TH sufferers, 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 effects on pain in certain circumstances, through effects on attention and vigilance to pain, arousal attribution, habituation, pain-related learning and memory and reporting behavior (109,112,118,134,191–193).

Physiological mechanisms sub-serving such effects could include descending modulation at mid-brain, brainstem or spinal mechanisms (94,118,133). However, a number of studies have found effects of stress on pain report but not spinal, brainstem or thalamic activity (151,161,162,177,178). Such findings demonstrate that stress can affect psychological aspects of pain processing (e.g. reporting behavior) in the absence of effects on spinal and brainstem processing. Additionally, the majority of studies examining the effects of stress on pain sensitivity in humans have examined subjective ratings of pain in the absence of measures assessing specific pain processing mechanisms (e.g. spinal reflexes). Such findings may reflect effects of stress on psychological (e.g. reporting behavior) rather than physiological processes (e.g. dorsal horn neuron activity).

Stress could therefore affect pain sensitivity in TTH sufferers through aggravating already increased psychological 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 sufferers due to strong memory of previous exposure and enhanced anticipation of new exposure to stress aggravating pain. Supporting this, Armstrong et al. (86) reported that headache sufferers reported a greater implicit association between negative events (e.g. stressors) and pain. Stress could also further challenge coping mechanisms, increasing pain reporting and sickness behavious in TTH sufferers (191,193).

Although we have presented a dichotomy between physiological and psychological aspects of pain processing, as noted by Edwards et al. (94) and others (177), such a dichotomy is somewhat artificial 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 generalized defense system (97,103,133), and neuroimaging studies show that psychological factors affecting 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 affect pain mechanisms proposed as dysfunctional in TTH. However, although numerous studies have demonstrated relationships between stress and clinical pain in TTH sufferers (11,15–17,194), fewer studies have examined both stress and pain sensitivity in TTH sufferers.

In a study by Lehrer and Murphy (92), TTH sufferers had a higher heart rate and increased negative affect (anxiety, anger and depression), and rated a tourniquet as more painful than did healthy controls. Similarly, Hatch et al. (91) found TTH sufferers 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 difference in self-reported stress levels in TTH sufferers. In regard to stress coping, Ukestad and Wittrock (89) reported increased use of catastrophizing as a coping strategy for stress and pain in TTH sufferers who also rated cold pressor as more painful than did healthy controls. Dawans et al. (196) reported increased subjective stress and reduced exteroceptive second silent period ES2 reflex in CTH sufferers, indicating both increased stress and impaired pain inhibitory mechanisms in CTTH. None of these studies reported examining for possible relationships between the increased pain sensitivity and the measures of affect or physiological arousal.

A number of studies have examined relationships between negative affect and pain sensitivity in TTH sufferers. De Tommaso et al. (33) and others (197,198) reported correlations between anxiety and muscle tenderness in CTH subjects; however, others found no such correlations (199). Similarly, Rollnik et al. (34) failed to find an association between coping strategy use and either muscle tenderness or cephalic pressure pain thresholds in TH sufferers, while Schoenen et al. (27) found no correlation between pressure 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 sufferers, which were both predictive of prospective headache activity.

Three studies reported examining relationships between affect and pain inhibition in TTH. Both Sandrini et al. (201) and Cathcart et al. (64) found impaired DNIC in TTH sufferers was not correlated with anxiety or depression, neither of which differentiated TTH sufferers from healthy controls. However, Wallasch, Reinecke and Langohr (202) reported a correlation between ES2 inhibitory reflex and self-reported tension, with the authors suggesting increased stress may contribute to TTH through affecting impaired pain inhibitory networks in CTTH sufferers.

Although temporal summation has been correlated with anxiety and stress coping style in healthy subjects (94,203), only two studies report examining relationships between TS and affect in headache sufferers. Filatova et al. (63) reported no correlation between RIII reflex wind-up ratios and depression in headache sufferers of mixed diagnoses, while Cathcart et al. (64) reported correlations between TS magnitude and both anxiety and depression in CTTH sufferers, but not healthy controls.

While the above studies examined correlations between stress and pain sensitivity, fewer studies have examined effects of stress on subsequent pain sensitivity in TTH sufferers. Leistad et al. (11) found pain to manual exertion of various pericranial muscles increased in TTH sufferers in response to stress induced by an hour-long mental task. The increased pain response was generalized to pericranial areas rather than specific 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 central pain mechanisms.

Janke et al. (204) examined pain thresholds and muscle tenderness in depressed and euthymic TTH sufferers before and after an hour-long stress task. Although stress-induced headache in the headache sufferers, 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 sufferers had increased 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 suggested that depression increases onset of stress-induced headache, and that this is associated with greater pain sensitivity in depressed TTH sufferers.

A recent series of studies by Cathcart and colleagues examined effects of induced stress on muscle tenderness, pain detection and tolerance thresholds, tonic pain rating, DNIC and TS in TTH sufferers (64,195,200,205–207). The results indicated that induced stress increased pain sensitivity more in TTH sufferers than in healthy controls, and that this was related to the development of stress-induced headache. However, while TTH sufferers had abnormal TS and DNIC responses, there was no effect of induced stress on either TS or DNIC in TTH sufferers or healthy controls. These results, although requiring replication and extension, support the proposition that stress contributes to TTH through aggravating already increased pain sensitivity in TH sufferers. Abnormal TS and/or DNIC may contribute to or result from increased pain sensitivity in the CNS. These propositions, and the literature reviewed herein, are summarized in the speculative model presented in Figure 1.

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.

Limitations to the literature and suggestions for future research

Research into TTH mechanisms indicates abnormal pain processing in TTH sufferers, while research in animal and healthy human demonstrates that mental stress may affect 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 affecting abnormal pain processing in TTH sufferers. 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 sensitivity 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 effects of stress on clinical pain (i.e. headache), very few studies have examined effects of stress on quantitative measures of experimental pain sensitivity in TTH sufferers. Such examinations are needed to clarify the nature of previously observed correlational 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 sufferers.

Another limitation and future direction is the need to better examine the particular aspects of pain affected by stress in TTH sufferers. There are now well-established techniques for examining such processes, such as TS and DNIC protocols, and assessments of multiple responses (e.g. detection and tolerance thresholds, tonic pain ratings) to multiple modalities (e.g. thermal and pressure pain). The studies by Cathcart and colleagues (64,195,200,205–207) and Janke et al. (204) represent initial work in this regard; however, a limitation common to their work is the reliance on self-reported pain measures. Techniques such as nociceptive reflexes and neuroimaging could be used not only to provide more objective measures of pain sensitivity, but also to better reveal the particular process and structures involved in stress affecting pain processing in TTH. Indeed, a current project by our group is using repetitive transcranial magnetic stimulation (rTMS) to examine cortical mechanisms in relationships between stress and headache.

Similarly, future research needs to elucidate the particular aspects of the stress process affecting pain processing 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 different pain processing abnormalities, with ETTH involving myofascial sensitivity 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 paper’s introduction, the present review is limited to TTH specifically. However, an overlap in symptoms and co-morbidity of different 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 findings indicating common pathophysiology, such as central sensitization (62,63,68,76), neurochemical anomaly (e.g nitric oxide, serotonin) (209,210) and common structural abnormalities in cortical 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, particularly migraine and CDH syndromes. Further research will be required to explore this notion.

Recent imaging studies, however, offer intriguing speculation on the relationship between stress and primary headaches other than TTH. A review by May (210) shows that an increase in ‘pain matrix’ activity is common to many primary headaches. As discussed above, these areas are also affected by stress—hence 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 conjunctival injection and tearing (SUNCT) (210,212). Speculatively, stress may contribute to these primary headaches via effects on specific brain regions related to their clinical presentation, additional to possible effects 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 affects pain processing throughout the CNS, including pain mechanisms proposed as dysfunctional in TTH sufferers. It has therefore been proposed that stress may contribute to TTH through aggravating abnormal pain processing in TTH sufferers. This hypothesis has not been adequately examined to date. However, initial findings suggest that stress aggravates already increased pain sensitivity in TTH sufferers, and this may be significant in the relationship 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.

Footnotes

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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Stress and tension-type headache mechanisms

Abstract

Keywords

Introduction

Mechanisms of tension-type headache

Muscle contraction

Myofascial tenderness

Central sensitization

Spinal/trigeminal sensitization:

Supra-spinal sensitization:

‘Wind-up’ and temporal summation

Pain modulation/inhibition

Psychological pain processing

The relationship between stress and pain

Overview

Inhibitory effects of stress on pain

Facilitatory effects of stress on pain

Stress as the genesis of pain

Stress and mechanisms subserving head pain

Stress and myofascial tenderness

Stress and spinal/trigeminal level pain processing

Stress and supraspinal/cortical pain processing

Stress and pain modulation/inhibition

Stress and psychological pain processing

Stress and pain processing in tension-type headache sufferers

Limitations to the literature and suggestions for future research

Other primary headaches

Summary

Footnotes

Acknowledgements

References