Abstract
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.
Keywords
Introduction
Tension-type headache represents one of the most costly diseases in modern society because of its very high prevalence (1, 2). Very little research on this disease has actually been carried out and for a very long time tension-type headache has been the overlooked stepchild in headache research. Langemark and Olesen were the first to introduce systematic research into tension-type headache in the early 1980s (3, 4), at a time when most colleagues regarded tension-type headache as a purely psychological disorder and a confounder to the much more accepted migraine and cluster headaches. Another reason for this apparent ignorance was also the previous lack of a proper classification. Before 1988 no precise definition of tension-type headache was available, and several terms, such as muscle contraction headache, tension headache, psychogenic headache, psychomyogenic or stress headache, were used.
In the International Headache Classification of 1988 (5) tension-type headache was precisely classified and defined by means of operational criteria. The subdivision into an episodic and a chronic form and into types with and without a muscular factor was developed mainly on the basis of the experience of a group of experts and not on the basis of scientific evidence, which at that time was very limited. In the following, the current pathophysiological theories and evidence for a biological basis for tension-type headache will be presented.
Pathophysiological mechanisms
For decades it has been a matter of debate whether the pain in tension-type headache originates from myofascial tissues or from central mechanisms in the brain (3, 6 –9). Clinical and laboratory investigations to substantiate any of these hypothesis were few and Langemark and Olesen were the first to describe the clinical characteristics of these chronically affected patients and to demonstrate pronounced tenderness in their pericranial muscles (3, 4). This tenderness was later demonstrated to be the most pronounced and consistent finding in these patients and probably represents the activation of peripheral nociceptors (8 –10). Although the pain clinically resembles pain from the myofascial tissues, the findings of decreased mechanical, thermal and electrical pain thresholds (11 –13), combined with modern pain physiology, indicate that both peripheral and central mechanisms are involved.
The texture of pericranial, shoulder and chewing muscles is often altered in tension-type headache, with generalized increased consistency. Such findings have previously only been detected by manual palpation, but a newly invented and validated instrument, a hardness meter, has confirmed this observation (14 –16). A recent study of the stimulus-response function to mechanical pressure (17) demonstrated for the first time that chronic tension-type headache has a physiological basis and is caused at least partly by qualitative changes in the central processing of sensory information.
Several negative studies have been published in the last decennium and prior encouraging hypotheses have systematically been rejected (18). A defect either in the opioid system or in the production of neurotransmitters has been suspected as the nociceptive flexor reflex, a spinally organized reflex, was decreased in chronic tension-type headache (19), but no recent studies have confirmed these findings. Studies of neuropeptides and endorphins in these patients have mainly been negative (20, 21) and only one former study (22) has noted increased metenkephalin in the cerebrospinal fluid. These various abnormalities may result in or be a function of the disturbed balance between peripheral input and central modulation. The primary eliciting cause and the evolution of pain are, however, still unknown.
Nitric oxide (NO) plays an important role in the pathophysiology of primary headaches, including chronic tension-type headache. An NO synthase inhibitor thus reduced headache and muscle hardness in a recent study (23, 24), whereas the NO donor glyceryl trinitrate caused more headache in patients with chronic tension-type headache than in healthy controls. Patients also got a delayed headache of the tension-type (25). These findings suggest that glyceryl trinitrate-induced delayed headache can be used as a valuable human model of tension-type headache and that NO-related central sensitization may be an important factor in the underlying pathophysiology (25, 26).
Only very few experimental human models have otherwise been created and a characterization of the neurobiological basis of human muscle pain may be of crucial importance. Therefore, development of a local model of myofascial pain may lead the way to a systematic search for specific drugs, not only for tension-type headache but also for myofascial pain in general.
Headaches are generally reported to occur in relation to emotional conflict and psychosocial stress, but the cause-effect relationship is not clear. Stress and mental tension were the most frequently reported precipitating factors but they occurred with similar frequency in tension-type headache and migraine (27, 28). These results correspond with the findings of widely normal personality profiles in individuals with episodic tension-type headache, whereas studies of subjects with the chronic form often reveal a higher frequency of depression and anxiety (29 –31). As in other chronic pain disorders, psychological abnormalities in tension-type headache may rather be viewed as secondary rather than primary (29), and anxiety and depression are probably comorbid with chronic tension-type headache.
Is tension-type headache a separate entity?
Migraine was previously believed to be a heterogenous syndrome with many causes, but this is now less likely because the great majority of migraineurs respond to the highly specific 5-hydroxytryptamine-D agonists. This suggests that there is a common denominator in migraine, despite the numerous different trigger factors, and it cannot be excluded that a similar condition exists in tension-type headache.
In contrast to clinical observations, epidemiological studies document that migraine and tension-type headache are different disorders although they coexist in many patients (27, 32, 33). As episodes of tension-type headache are more pronounced and frequent in individuals with coexisting migraine than in non-migraineurs (28, 32), it indicates that migraine can be one of probably numerous precipitating factors to tension-type headache in genetically predisposed individuals. A genetic predisposition to chronic tension-type headache, reflected in a 3.18-fold increased risk in first-degree relatives compared with the general population, has been published (34, 35), but the mode of transmission seems to be complex.
On this basis, it can be concluded that the underlying pain mechanisms in tension-type headache are highly dynamic, as tension-type headache represents a wide variety of frequency and intensity, not only between individuals, but also within the individual subject over time. The initiating stimulus may be either a condition of mental stress, non-physiological motor stress, a local myofascial release of irritants or a combination of these. Secondary to the peripheral stimuli, the supraspinal pain perception structures may become activated, and because of the central modulation of the incoming stimuli, a self-limiting process will be the result in most individuals. In some genetically predisposed individuals the central processing of sensory information is permanently altered and the subsequent central sensitization may therefore be the physiological basis for chronic tension-type headache. As chronic tension-type headache usually evolves from the episodic form (36), an effective prevention of this evolution from a peripheral mechanism in episodic to a central mechanism in chronic tension-type headache will therefore be of major importance in future treatment strategies.
Perspectives
Fortunately, the lack of quantity in systematic research in tension-type headache is not paralleled by a lack of quality and it is actually promising that the relatively modest research investment has increased our knowledge about this previously enigmatic condition considerably. Regrettably, there have been no new developments in the treatment possibilities. As a result of this and the lack of scientific interest from the pharmaceutical industry, the treatment is widely nonspecific, very often ineffective and consists mainly of simple analgesics. If current progress in our understanding of the mechanisms of tension-type headache continues, this may lead to increased scientific interest and the development of more specific and more effective drugs in the future.