A particularly striking feature of cluster headaches is that during the active cluster period, vasodilating substances such as alcohol, histamine, and nitroglycerin can reliably provoke cluster attacks. Interestingly, these agents are completely inactive in provoking cluster attacks during the remission period. The most reliable effect is achieved with histamine. Subcutaneous administration of 0.3 mg of histamine results in a throbbing, pulsating headache within ten minutes.
With nitroglycerin, the onset of headaches corresponds to the point of maximum vasodilatory effect of the substance. Only after approximately 30 to 45 minutes does a typical cluster attack occur during an active cluster period. Since the point of maximum vasodilation already passed , it cannot be assumed that the induction of cluster attacks is a direct consequence of the vasodilation . This is further supported by the fact that a cluster attack cannot be provoked with nitroglycerin at any given time . There is a refractory period of several hours is delayed by an experimentally provoked attack .
Similar to histamine, a latency period of 30 to 45 minutes observed before the onset of a cluster attack alcohol provoke a cluster attack in approximately 50% dose - effect delay the occurrence of further attacks and intervals of up to three days between individual cluster attacks during the active period. However, some patients then experience a rebound mechanism with a temporarily increased attack frequency.
Hypoxia also been considered a possible trigger for attacks. This observation is initially based on the fact that administering pure oxygen during a cluster headache attack can rapidly reduce the pain. The nocturnal occurrence of linked to reduced oxygen saturation at night and possible sleep apnea impaired central autoregulation a reduced oxygen supply to the central nervous system. This finding is supported by the observation that oxygen saturation after nitroglycerin administration is more pronounced and lasts longer in patients with cluster headache attacks than in control subjects.
Phospholipids
Evidence for a disturbance in phospholipid metabolism is provided by a significant reduction in choline concentration in erythrocytes of approximately 50% compared to healthy controls. Choline is generated from phosphatidylcholine in the cell membranes. Interestingly, a normalization of choline levels in erythrocytes occurs during a two-week course of lithium . This renormalization is facilitated by the inhibition of choline efflux from erythrocytes, thus offering a possible explanation for the mechanism of action of lithium in the treatment of cluster headaches.
Prostaglandins
The use of anti-inflammatory drugs , such as acetylsalicylic acid or indomethacin, has no significant therapeutic effect on cluster headaches. Since these substances belong to the group of prostaglandin synthesis inhibitors, it is unlikely that prostaglandins play a significant role in the pathogenesis of cluster headaches. Indeed, no significant differences in prostaglandin activity found in cluster headaches.
Leukotrienes
Leukotrienes play an important role in the induction of hyperalgesia, in increasing vascular permeability, and in reducing nociceptive reactions when bradykinin is administered . There is evidence that during the remission phase of cluster headache, the release of leukotriene B4 and leukotriene C4 is significantly reduced compared to healthy subjects .
In patients with cluster headaches, an increased number of mast cells was found in the skin ipsilateral to the painful side, but also on the pain-free side, compared to healthy controls. Mast cells are the main storage site of histamine . Histamine can be found in elevated concentrations during a cluster headache attack of the perivascular and cutaneous nerves. After a cluster headache attack, an increased number of mast cell degranulations observed, which are likely related to axon reflexes. Such increased degranulation processes are found both during a cluster headache episode and in the pain-free interval.
Monoamine
The monoamine oxidase (MAO) activity of platelets reduced in affected patients both during and between cluster attacks . The decrease is more pronounced within cluster attacks. Furthermore, MAO activity shows greater thermostability in cluster headache patients compared to healthy controls. This reduced MAO activity can be interpreted indication of impaired membrane function in
Significantly elevated concentrations of norepinephrine and epinephrine have also been described in cluster headache patients during the acute cluster period . However, such elevated concentrations were only found for conjugated norepinephrine and epinephrine , not for free norepinephrine and epinephrine. An increase in norepinephrine can be observed both during a spontaneous cluster attack and after attacks induced by nitroglycerin. This increase could be interpreted as a normal response to vasodilation . Overall, the changes in monoamines in cluster headache are not very specific . The changes could be attributed to physical activity, seasonal influences, or even treatment.
regarding serotonin uptake into platelets. Both reduced uptake and normal activity have been described.
Amino acids
Excitatory amino acids , particularly glutamate, aspartate, and glycine, exert important neurotransmitter functions in nociceptive transmission . The behavior of these excitatory amino acids in platelets is considered a model for their behavior in neurons. For example, glycine concentrations in platelets significantly reduced . However, glutamate and aspartate concentrations showed no altered levels compared to healthy individuals. The concentrations of these excitatory amino acids do not differ between the active and remission phases.
Neuropeptides and opioids
In patients with episodic cluster headache, elevated plasma concentrations of met-enkephalin were found during an acute cluster attack. Between attacks during a cluster period and during the remission period, however, normal levels . In chronic cluster headache, elevated plasma met-enkephalin levels were found before the generation of an acute attack compared to the time during an acute attack and the time after an attack . It can be assumed that the increase in plasma met-enkephalin is a secondary reaction to increased sympathetic activity shown reduced concentrations of met-enkephalin in the cerebrospinal of patients with cluster headache be interpreted as an indication of reduced endogenous antinociceptive activity
Analysis of inflammatory neuropeptides in cluster headache patients reveals elevated levels of calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide in the jugular vein during an acute cluster attack . In contrast, neuropeptide Y and substance P do not show elevated levels during the attack. Interestingly, treatment of the cluster attack—both with oxygen and subcutaneous sumatriptan— significantly reduces the elevated CGRP levels. Analgesic administration, however, does not induce any change in neuropeptide levels. These findings directly suggest activation within the trigeminovascular system , and successful treatment may directly block this increased activity. Furthermore, a case study observed that a patient who developed pseudoaneurysm of the cavernous sinus pain symptoms consistent with cluster headache . This finding suggests the importance of the cavernous sinus in the pathophysiology of cluster headache.
Substance P
Substance P are particularly important in the context of neurogenic inflammation , nociceptive transmission in neurons, and vasoactive reactions direct increase in pain sensitivity and can itself induce pain . For this reason, increased substance P activity in the neurons of the trigeminal and facial nerves has been suspected as a cause of pain during cluster attacks. The direct vasoactivity of this neuropeptide has also been interpreted as a cause of autonomic disturbances during cluster attacks. However, no altered concentration of substance P cerebrospinal fluid during the active cluster period compared to the remission period and compared to healthy subjects. In contrast, reduced substance P activity was observed in plasma . This could increased metabolism during a cluster attack. For the neuropeptide calcitonin gene-related peptide (CGRP), however, elevated concentrations were found in saliva during a cluster period. The same applies to vasoactive intestinal polypeptide (VIP).
The inhibitory neurotransmitter somatostatin is able to block release of substance P. Somatostatin can be found in the sympathetic ganglia. By blocking the release of substance P, somatostatin could be a potential candidate for the acute treatment of cluster headaches. However, it is associated with very pronounced tachyphylaxis, which is why the use of somatostatin for treating cluster headaches not very effective . Nevertheless, it has been shown that plasma somatostatin concentrations reduced during the cluster period , and that somatostatin injection alleviate acute cluster headaches .