Several peptides have been studied in TTH, and the endogenous opioid peptides β-endorphin and methionine-enkephalin (met-enkephalin) received much attention for a period. The idea was that headache was a hypoendorphin-syndrome (66). It appears from Table 75-1 that the data are inconsistent with regard to this idea. Furthermore, because circulating endogenous opioid peptides are not vasoactive or have access to the central nervous system, the role of circulating opioid peptides in relation to headache is obscure (4). Plasma neuropeptide Y (NPY) concentrations were normal in patients suffering from episodic TTH (ETTH) and did not differ between headache episodes and pain-free periods (33). Endothelin-1 concentrations in plasma were normal in ETTH and chronic TTH (CTTH) (32).

Adrenocorticotropic hormone (ACTH) and cortisol were normal in daily chronic headache (24) and CTTH (43). Melatonin is synthesized in the pineal gland from serotonin, but possesses negligible serotoninlike activity. Nocturnal levels are high, whereas diurnal concentrations are low or undetectable. Nocturnal plasma melatonin levels have been found to be reduced in a group of female tension headache patients (16). It was not clear from the patient description whether this group also included depressed patients. The pathophysiologic interpretation of these
preliminary findings is not simple, but they were suggested to reflect global sympathetic hypofunction.

Ferrari et al. (26) studied plasma amino acids in migraine patients and used TTH patients and healthy normal individuals as controls. Whereas the neuroexcitatory amino acids glutamic and aspartic acid were clearly elevated in migraine patients, no abnormalities could be demonstrated in TTH patients. Also, homocysteine levels were normal in a study examining 20 patients with episodic TTH (23).

Shimomura et al. (62) found that plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), which seem to reflect central noradrenergic metabolism, predict the clinical response of TTH patients to tizanide hydrochloride. Those patients who showed the best clinical response after 4 weeks of treatment had the highest pretreatment MHPG plasma levels and presumably the highest central noradrenergic activity. Several methodologic reservations, however, apply to this interesting observation, most importantly the way the clinical response was measured (undefined criteria, open uncontrolled evaluation), how clinical outcome groups were formed and related to the MHGP levels (open or blinded), and lack of clinical information on the patients (use of medication, diet, and depression). Furthermore, those patients who improved most also had by far the shortest duration of the illness, suggesting that other factors were involved. Nevertheless, this approach is most promising and should be confirmed in a prospective, placebo-controlled, double-blind design.

Dopamine β-hydroxylase catalyzes the conversion of dopamine to norepinephrine, and serum levels of this enzyme were found to be reduced in 10 patients with TTH compared with control subjects (31). The same reduction was also seen in migraine patients. Gallai et al. (31) consider serum activity of dopamine β-hydroxylase a useful indicator of sympathetic activity, considering the instability of serum norepinephrine concentrations. Suggesting a reduced noradrenergic tonus in TTH (and migraine), this study should be reproduced on larger groups of patients and the status of headache at the time of sampling made clear.

Castillo et al. measured plasma concentrations of epinephrine, norepinephrine, and dopamine under standardized conditions in 30 patients with ETTH in headache phase. Pain and depression were rated on separate scales. Plasma concentrations of all three catecholamines were lower than in control persons, supporting the idea of reduced sympathetic activity in TTH (15). There was no association between depression scores and catecholamine concentrations. Reduced plasma norepinephrine concentrations also were found in 15 patients with muscle contraction headache (69).

Urinary excretion of 5-hydroxytryptamine (5-HT), noradrenaline, adrenaline, and dopamine and their acidic metabolites have been studied in female, chronic daily headache patients (28). Preliminary data suggested that in these patients the 24-hour excretion of dopamine was reduced and the circadian rhythmicity of the excretion of the metabolites was disturbed. Thus, the normally existing difference between diurnal and nocturnal excretion (diurnal > nocturnal) was absent in the headache patients. Chronic daily headache patients were similar to migraine patients in this respect. More studies are needed.

Martignoni et al. (47) found that baseline β-endorphin plasma levels and the β-endorphin plasma response to clonidine were significantly lower in patients with combined migraine without aura and tension headache than in healthy controls. This was interpreted as evidence for failure of central noradrenergic activity. It is not clear whether similar results could be obtained in patients with pure tension headache without associated migraine.

Link and colleagues (45) have investigated several immunologic parameters in cerebrospinal fluid (CSF) and plasma of patients with chronic headache (of unspecified and undefined type). However, in these studies the headache patients were used as controls for patients with multiple sclerosis, and no healthy, normal controls were included. Accordingly, no qualitative conclusions regarding these observations can be drawn.

Nagasawa et al. (51) found slightly higher serum levels of complement C3 and C4 in patients with muscle contraction headache compared with normal individuals. However, the patient group was a mean of 10 years older than the control group, and both C3 and C4 levels increased with age. Accordingly, the conclusion of Nasagawa et al. that inflammatory aspects are involved in muscle contraction headache is interesting but should be confirmed in a study with a matched control group.

Diaz-Mitoma et al. (20) reported that significantly more patients with so-called new daily persistent headaches had evidence of active Epstein-Barr infection (84% versus 25% in controls). It is unknown how frequent this headache syndrome is and how it relates to TTH. We are unaware of similar studies conducted with TTH patients.

Interleukin-2 is a cytokine activating T-lymphocytes. Shimomura et al. found reduced serum levels of interleukin-2 in 46 patients with TTH and similarly reduced levels in migraine (61).

The importance of connections between the immune and nervous systems is becoming increasingly clear, not the least in the field of pain. In a series of experiments, Christoph Stein et al. have provided evidence that β-endorphin may be synthesized in immunocytes and, following stimulation by inflammatory mediators such as corticotropin-releasing hormone and interleukin-1, released into inflamed tissue. Here, β-endorphin may bind to opioid receptors on nociceptive fibers and reduce nociception (14). Three independent groups have measured decreased β-endorphin concentrations in peripheral blood mononuclear cells in patients with episodic TTH during a headache-free period (10,44,48). Although the results are premature in the sense that β-endorphin was not characterized on the molecular level, these data are interesting in the light of development within the field. However, speculations about β-endorphin concentrations in peripheral blood mononuclear cells reflecting central nervous system concentrations of the same substance (44) have no support in scientific data (3).