Increased pain sensitivity is not a risk factor but a consequence of frequent headache: a population-based follow-up study

Altered pain sensitivity is believed to play an important role for chronification of headache. It has however mainly been evaluated in highly selected patients from headache clinics and never in longitudinal studies. The present study is a 12-year follow-up of a population-based study of primary headache disorders and pain perception, combining a diagnostic headache interview with examination of muscle tenderness and measurement of pressure pain thresholds in 1000 subjects drawn randomly from the general population in Denmark. The aim of the study was to explore the cause–effect relationship between the increased pain sensitivity and the development of headache. The pressure pain thresholds were normal at baseline but had decreased at follow-up in subjects who developed chronic tension-type headache over the 12-year period (p = 0.025). In subjects who developed frequent episodic tension-type headache the tenderness was normal at baseline but had increased at follow-up (p < 0.01) while the pain thresholds were normal both at baseline and at follow-up. The findings demonstrate that increased pain sensitivity is a consequence of frequent tension-type headache, not a risk factor, and support that central sensitization plays an important role for the chronification of tension-type headache.     

Central sensitization in tension-type headache--possible pathophysiological mechanisms

The aim of the present thesis was to investigate the pathophysiology of chronic tension-type headache with special reference to central mechanisms. Increased tenderness to palpation of pericranial myofascial tissues is the most apparent abnormality in patients with tension-type headache. A new piece of equipment, a so-called palpometer, that makes it possible to control the pressure intensity exerted during palpation, was developed. Thereafter, it was demonstrated that the measurement of tenderness could be compared between two observers if the palpation pressure was controlled, and that the Total Tenderness Scoring system was well suited for the scoring of tenderness during manual palpation. Subsequently, it was found that pressure pain detection and tolerance thresholds were significantly decreased in the finger and tended to be decreased in the temporal region in chronic tension-type headache patients compared with controls. In addition, the electrical pain threshold in the cephalic region was significantly decreased in patients. It was concluded that the central pain sensitivity was increased in the patients probably due to sensitization of supraspinal neurones. The stimulus-response function for palpation pressure vs. pain was found to be qualitatively altered in chronic tension-type headache patients compared with controls. The abnormality was related to the degree of tenderness and not to the diagnosis of tension-type headache. In support of this, the stimulus-response function was found to be qualitatively altered also in patients with fibromyalgia. It was concluded that the qualitatively altered nociception was probably due to central sensitization at the level of the spinal dorsal horn/trigeminal nucleus. Thereafter, the prophylactic effect of amitriptyline, a non-selective serotonin (5-HT) reuptake inhibitor, and of citalopram, a highly selective 5-HT reuptake inhibitor, was examined in patients with chronic tension-type headache. Amitriptyline reduced headache significantly more than placebo, while citalopram had only a slight and insignificant effect. It was concluded that the blockade of 5-HT reuptake could only partly explain the efficacy of amitriptyline in tension-type headache, and that also other actions of amitriptyline, e.g. reduction of central sensitization, were involved. Finally, the plasma 5-HT level, the platelet 5-HT level and the number of platelet 5-HT transporters were found to be normal in chronic tension-type headache. On the basis of the present and previous studies, a pathophysiological model for tension-type headache is presented. According to the model, the main problem in chronic tension-type headache is central sensitization at the level of the spinal dorsal horn/trigeminal nucleus due to prolonged nociceptive inputs from pericranial myofascial tissues. The increased nociceptive input to supraspinal structures may in turn result in supraspinal sensitization. The central neuroplastic changes may affect the regulation of peripheral mechanisms and thereby lead to, for example, increased pericranial muscle activity or release of neurotransmitters in the myofascial tissues. By such mechanisms the central sensitization may be maintained even after the initial eliciting factors have been normalized, resulting in the conversion of episodic into chronic tension-type headache. Future basic and clinical research should aim at identifying the source of peripheral nociception in order to prevent the development of central sensitization and at ways of reducing established sensitization. This may lead to a much needed improvement in the treatment of chronic tension-type headache and other chronic myofascial pain conditions.     

Determinants of tension-type headache in children

The objective of this study was to study the prevalence, characteristics and predisposing factors of tension-type headache in children. An unselected population-based questionnaire study was carried out in 1409 Finnish schoolchildren aged 12 years. Of them, 1135 (81%) returned an acceptably completed questionnaire. The prevalence of episodic tension-type headache in children was 12% (138 of 1135). Children with episodic tension-type headache also often reported characteristics of pain typical for migraine. Children with frequent and persistent episodic tension-type headache reported stabbing and severe occipital pain, phonophobia and abdominal pain significantly more often than children with infrequent episodic tension-type headache. Neck-shoulder symptoms, symptoms of depression and oromandibular dysfunction were each independently associated with episodic tension-type headache. The father's occupation of a lower-level white-collar worker put the child at a four-fold risk for episodic tension-type headache. We conclude that episodic tension-type headache is as common as migraine in children. It can be associated with depression, oromandibular dysfunction and muscular stress. Especially children with frequent and persistent episodic tension-type headache report characteristics of pain typical for migraine.     

Mechanisms of tension-type headache

Despite tension-type headache represents one of the most frequent and costly diseases in modern society only very little research on this disease has actually been carried out. In contrast to former belief tension-type headache is a separate entity that can and should be separated from migraine. No specific biochemical abnormalities have yet been identified but a reliable human model of tension-type headache has been developed by means of infusion of a NO-donor, glyceryl trinitrate. Myofascial factors and peripheral sensitization of nociceptors play an important role in the episodic form, and central sensitization has been demonstrated in the chronic form. As chronic tension-type headache usually evolves from the episodic form, prevention and reversal of this central sensitization may be an important target for future pathophysiological studies and drug development.     

Prevalence and clinical characteristics of an experimental model of 'ice-cream headache' in migraine and episodic tension-type headache patients

This study was designed to compare the prevalence and clinical characteristics of 'cold-induced headache' between migraine and episodic tension-type headache patients. Seventy-six migraine and 38 episodic tension-type headache patients were included in the study. An experimental model of an 'ice-cream headache' was developed for the study. The pain occurrence period, its location and quality were recorded for each patient who felt pain in their head during the test procedure. Pain in the head occurred in 74% of migraine and 32% of 'tension-type headache' patients. Although the most frequent pain location was the temple in both groups of patients, this rate was greater than twofold in migraine patients when compared with episodic tension-type headache patients. While headache quality was throbbing in 71% of migraine patients, it was so in only 8% of the episodic tension-type headache patients. Considering all the results, it seems that 'cold-stimulus headache' is not only more frequent in migraine patients, but also its location and quality differ from 'tension-type headache'.     

Coping styles of headache sufferers

Psychological factors are important in the chronification and aggravation of headaches. We studied 90 patients suffering from migraine, chronic daily headache (CDH) evolved from migraine, and episodic or chronic tension-type headache (TTH). Emotional, cognitive, and behavioral pain coping were assessed using the Kiel Pain Inventory (KPI), Beck's Depression Inventory, the State-Trait-Anxiety Inventory, and Quality of Life Questionnaire. In addition, the clinical course of headache was analyzed using a validated headache diary. The results were as follows. Firstly, the KPI is reliable internally for the assessment of pain-coping strategy employment among headache patients. Secondly, migraine sufferers were characterized by pronounced psychological abnormalities during the headache phase, demonstrating a less adaptive coping behavior. This was in contrast to the TTH patients, who showed more general distress manifesting in elevated anxiety and lower quality of life. The only factor which appeared to be essential for differentiating between migraine and TTH was the intensity of headache. Thirdly, chronic TTH and CDH evolved from migraine demonstrated more pronounced psychological disabilities and more severe clinical courses of headaches than episodic TTH or nontransformed migraine. The predictor variable for transformation of migraine was impairment of well-being/quality of life, and for transformation of TTH, the frequency of headaches and depression. Finally, analgesic misuse seems to be less important for chronification and transformation of headaches than the degree of psychological disability. This study draws attention to the role of psychological factors in the chronification of TTH and transformation of migraine and provides some recommendations for the behavioral treatment of chronic headaches.     

Evidence of persistent central sensitization in chronic headaches: a multi-method study

The aim of this study was to investigate central sensitization (CS) in chronic headaches and compare this phenomenon between chronic migraine (CM) and chronic tension-type headache (CTTH). We recruited 69 patients with chronic headaches and 18 control subjects. Questionnaires of headache history, allodynia and the Hospital Anxiety and Depression scale were administered. We recorded thresholds for pinprick and pressure pain, blink (BR) and nociceptive flexion reflex (NFR) R3 component coupled with wind-up ratios. Thresholds for pressure and pinprick pain, BR and NFR R3 were lower and wind-up ratios higher in patients. No differences of CS parameters between CM and CTTH were observed. CS is persistent and prevalent in patients with various types of chronic headache. CS levels are unrelated to the predominant side of pain, disease duration or depression. Neither is CS related to the headache type, suggesting similar mechanisms of headache chronification and chronicity maintaining and possibly explaining clinical similarity of various forms of chronic headache.     

Cortical Excitability in Chronic Migraine

A proportion of episodic migraine patients experiences a progressive increase in attack frequency leading to chronic migraine (CM). The most frequent external factor that leads to headache chronification is medication overuse. The neurobiological bases of headache chronification and of the vicious circle of medication overconsumption are not completely elucidated. More recently, the same neurophysiological methods used to study episodic migraine were applied to CM and medication-overuse headache (MOH). Studies of cortical responsivity tend overall to indicate an increase in excitability, in particular of somatosensory and visual cortices, reflected by increased amplitude of evoked responses, decreased activity of inhibitory cortical interneurons reflected in the smaller magnetic suppression of perceptual accuracy, and, at least for visual responses, an increase in habituation. In MOH, overconsumption of triptans or NSAIDs influences cortical excitability differently. Generalized central sensitization is suggested to play an important role in the pathophysiology of headache chronification.     

Chronic Migraine: An Update on Physiology,Imaging, and the Mechanism of Action of Two Available Pharmacologic Therapies

Several lines of research support the hypothesis that migraine is a spectrum of illness, with clinical symptoms that vary along a continuum from episodic migraine to chronic migraine. Physiologic changes may result in episodic migraine evolving into chronic migraine over months to years in susceptible individuals. With chronification, headache frequency increases, becoming more disabling and less responsive to therapy. Neurophysiologic and functional imaging research has reported that chronic migraine may be associated with severity‐specific metabolic, functional, and structural abnormalities in the brainstem. Without longitudinal studies, it is unclear whether these changes may represent a continuum of individual progression and/or are reversible. Furthermore, chronic migraine is associated with larger impairments in cortical processing of sensory stimuli when compared with episodic migraine, possibly caused by more pronounced cortical hyperexcitability. Progressive changes in nociceptive thresholds and subsequent central sensitization due to recurrent migraine attacks in vulnerable individuals contribute to the chronic migraine state. This may result in changes to baseline neurologic function between headache attacks, evident in both electrophysiological and functional imaging research. Patients experiencing migraine chronification may report increased non‐headache pain, fatigue, psychiatric disorders (eg, depression, anxiety), gastrointestinal complaints, and other somatic conditions associated with their long‐term experience with migraine pain. Recent research provides a foundation for differentiating episodic and chronic migraine based on neurophysiologic and neuroimaging tools. In this literature review, we consider these findings in the context of models designed to explain the physiology and progression of episodic migraine into chronic migraine, and consider treatment of chronic migraine in susceptible individuals. Advances in pharmacotherapy provide treatment options for chronic migraine. Of the currently available treatment options, only onabotulinumtoxinA and topiramate have received regulatory approval and have demonstrated efficacy in patients with chronic migraine, although the exact mechanisms of action are not fully elucidated.     

Frequent migraine and migraine status without tension-type headaches: an unusual presentation of rebound headaches

Rebound headaches usually present as daily or almost daily, prolonged, generalized tension-type headaches with superimposed migraine-like attacks. The latter are more frequent, more intense, and longer than any episodic migraine that the patient might have experienced prior to the development of the chronic daily headaches. Rebound presenting as migraine without tension-type pain has been mentioned in a few previous articles on chronic daily headache, but there have been no previous articles stressing that frequent migraine might relate to the analgesics that are being used. These case histories are presented to illustrate that frequent migraine and migraine status without tension-type headaches may be manifestations of rebound and improve when the offending analgesic agents are stopped. If the clinician fails to recognize this unusual presentation of rebound headache, the patient might be placed on unnecessary and often ineffective medications for prophylaxis instead of stopping the offending pain relief medications.     

Are infrequent episodic,frequent episodic and chronic tension-type headache inherited? A population-based study of 11 199 twin pairs

The objective was to investigate the importance of genetic and environmental factors for infrequent episodic, frequent episodic and chronic tension-type headache. Twin pairs recruited from the population-based Danish Twin Registry received a posted questionnaire. Only twin pairs where both twins replied were included. A total of 3523 monozygotic (MZ), 4150 dizygotic (DZ) same-gender and 3526 DZ opposite-gender twin pairs were included. The prevalence of frequent episodic and chronic tension-type headache was significantly more frequent in women than men, and significantly higher in those with co-occurrence of migraine. The concordance rates were significantly higher in MZ than same-gender DZ twin pairs with no or frequent episodic tension-type headache, while the difference was not significant in chronic tension-type headache. The concordance rates of infrequent episodic tension-type headache in MZ and same-gender DZ twin pairs was significantly different in women but not in men, although the difference was small in both genders. We conclude that genetic factors play a role in no and frequent episodic tension-type headache, while infrequent episodic tension-type headache is caused primarily by environmental factors. The data regarding chronic tensiontype headache were limited, so no firm conclusion could be drawn. Greppi-Sicuteri Commitee: Giorgio Zanchin, Miguel J.A. Lainez, Marcello Fanciullacci, Paolo Martelletti, Arne May, Lorenzo Pinessi     

Comparative study with EMG, pressure algometry and manual palpation in tension-type headache and migraine

According to International Headache Society classification criteria, the presence of pericranial muscle disorder in tension-type headache should be evaluated using one of the following methods: EMG, pressure algometry or manual palpation. The purpose of this study was to compare the results of these three methods in 15 patients with episodic tension-type headache, 29 with chronic tension-type headache and 22 presenting migraine without aura compared to those obtained in healthy individuals. Algometric and EMG recordings at the frontalis muscle during mental arithmetic were more impaired in episodic and chronic tension headache patients than in controls and migraine patients. Chronic tension headache patients were significantly impaired at the trapezius muscle in all three tests compared to controls. Our data indicate that when two or three tests were carried out the diagnostic capacity was significantly improved in comparison to only one test. Moreover, since a different pattern could be seen with pain and without pain, the existence of headache at the time of testing should be taken into consideration.     

Tension-type headache in children and adolescents

Although tension-type headache is at least as prevalent as migraine in children and adolescents, in contrast to migraine, childhood tension-type headache has received limited research attention. Follow-up studies have shown that migraine may reverse in tension-type headache and vice versa. In addition, children with frequent episodic tension-type headache may be at increased risk of chronic tension-type headache. It is very important to recognize these children and to intervene. Further studies are needed to clarify the pathophysiology of pediatric tension-type headache.     

Central mechanisms in tension-type headaches

Although tension-type headache is the most frequent primary headache, little is known about its pathophysiology. It is a matter of debate if the pain in tension-type headache originates from myofascial tissues or from central mechanisms in the brain. This article presents a summary of available data on the pathophysiology of tension-type headache and proposes a pathogenic model. From experimental research and clinical studies, it appears that myofascial nociception is important in episodic tension-type headache; however, central mechanisms (ie, central sensitization) are preponderant in the pathophysiology of the chronic form. Understanding the mechanisms of this central sensitization could allow for more efficient prophylactic treatments to emerge.     

Muscular Factors are of Importance in Tension-Type Headache

Recent studies have indicated that muscular disorders may be of importance for the development of increased pain sensitivity in patients with chronic tension-type headache. The objective of the present study was to investigate this hypothesis by examining the pain perception in tension-type headache with and without muscular disorders defined as increased tenderness. We examined 28 patients with episodic tension-type headache, 28 patients with chronic tension-type headache, and 30 healthy controls. Pericranial myofascial tenderness was recorded with manual palpation, and pressure pain detection and tolerances in cephalic and extracephalic locations with an electronic pressure algometer. In addition, thermal pain sensitivity and electromyographic activity were recorded. The main result was significantly lower pressure pain detection thresholds and tolerances in all the examined locations in patients with chronic tension-type headache with a muscular disorder compared to those without a muscular disorder. There were no such differences in any of the examined locations when the two subgroups of patients with episodic tension-type headache were compared. Thermal pain sensitivity did not differ between patients with and without a muscular disorder, while electromyographic activity levels were significantly higher in patients with chronic tension-type headache with than in those without a muscular disorder. Our results strongly indicate that prolonged nociceptive stimuli from the pericranial myofascial tissue sensitize the central nervous system and, thereby, lead to an increased general pain sensitivity. Muscular factors may, therefore, be of major importance for the conversion of episodic into chronic tension-type headache. The present study complements the understanding of the important interactions between peripheral and central factors in tension-type headache and may lead to a better prevention and treatment of the most prevalent type of headache.     

Genetics of tension-type headache

Abstract The objective of this study was to investigate the importance of genetics in tension-type headache. A MEDLINE search from 1966 to December 2006 was performed for “tension-type headache and prevalence” and “tension-type headache and genetics”. The prevalence of tensiontype headache varies from 11 to 93%, with a slight female preponderance. Co-occurrence of migraine increases the frequency of tension-type headache. A family study of chronic tension-type headache suggests that genetic factors are important. A twin study analysing tension-type headache in migraineurs found that genetic factors play a minor role in episodic tension-type headache. Another twin study analysing twin pairs without co-occurrence of migraine showed a significantly higher concordance rate among monozygotic than same-gender dizygotic twin pairs with no or frequent episodic tension-type headache, while the difference was minor in twin pairs with infrequent episodic tensiontype headache. Frequent episodic and chronic tension-type headache is caused by a combination of genetic and environmental factors, while infrequent episodic tensiontype headache is caused primarily by environmental factors. 1 This is a “Springer Open Choice” article. Unrestricted non-commercial use, distribution, and reproduction in any medium is permitted, provided the original author and source are credited.     

Amitriptyline Is Effective in Chronic But Not in Episodic Tension-Type Headache: Pathogenetic Implications

The tricyclic antidepressant amitriptyline, is an effective drug for the treatment of chronic tension-type headache and for other chronic pain syndromes, but it is also effective in the prophylaxis of an episodic type of headache such as migraine. However, its efficacy in episodic tension-type headache has not yet been clarified. We compared the efficacy of amitriptyline (25 mg/day) in 82 nondepressed patients with either chronic or episodic tension-type headache in an open-label study. Amitriptyline significantly reduced ( P <0.05) frequency and duration of headache as well as analgesic consumption in chronic, but not in episodic, tension-type headache. Further placebo-controlled trials, possibly with higher doses of amitriptyline, might confirm if the different pattern of response to amitriptyline can be explained in terms of different involvement of central nociception and of peripheral myofascial factors in the chronic and in the episodic forms of tension-type headache.     

Serum levels of N-acetyl-aspartate in migraine and tension-type headache

Serum levels of N-acetyl-aspartate (NAA) may be considered a useful marker of neuronal functioning. We aimed to measure serum NAA in cohorts of migraine and tension-type headache patients versus controls, performing correlations with main clinical features. A total of 147 migraine patients (including migraine without aura, with aura and chronic migraine), 65 tension-type headache (including chronic and frequent episodic tension-type headache) and 34 sex- and age-matched controls were selected. Serum was stored at −80 °C. Quantification of NAA was achieved by the standard addition approach and analysis was performed with liquid-chromatography–mass-spectrometry (LC/MS) technique. The NAA levels were significantly decreased in migraine group (0.065 ± 0.019 mol/L), compared with both tension-type headache patients (0.078 ± 0.016 mol/L) and controls (0.085 ± 0.013 mol/L). Control subjects were significantly different from migraine with and without aura and chronic migraine, who differed significantly from episodic and chronic tension-type headache. Migraine with aura patients showed lower NAA levels when compared to all the other headache subtypes, including migraine without aura and chronic migraine. In the migraine group, no significant correlation was found between NAA serum levels, and headache frequency, allodynia and interval from the last and the next attack. The low NAA in the serum may be a sign of neuronal dysfunction predisposing to migraine, probably based on reduced mitochondria function.     

Psychosocial Functioning in Schoolchildren With Recurrent Headaches

The psychosocial functioning of 113 schoolchildren (8 to 15 years old) reporting headaches at least once a month was compared to a group of headache-free control subjects matched for sex and age. Thirteen percent of the headache sufferers had migraine headaches, 28% had episodic tension-type headaches, 30% had chronic tension-type headaches, and 29% had migraine coexisting with tension-type headaches.
Overall, the headache sufferers experienced more somatic complaints, stress, and psychological symptoms, in addition to being absent from school (due to illness), more often and reported fewer caring persons as compared to headache-free controls. Although few differences between the four headache groups emerged in the children's psychosocial functioning levels, children with migraine coexisting with tension-type headaches had significantly more frequent somatic complaints than those having episodic tension-type headaches. In addition, children with migraine or migraine coexisting with tension-type headaches were more often absent from school than those having tension-type headaches only. A significant but weak relationship between children's headache severity and their somatic complaints was noted.