Alcohol as a dietary trigger of primary headaches: what triggering site could be compatible?

Alcoholic drinks (AD) have been known as migraine triggers in about one-third of migraine patients in retrospective studies. We have reviewed the studies concerning the role of AD in triggering the various types of primary headaches published after the International Headache Society classification of 1988. There are many studies showing that AD are triggers of migraine without aura (MO), migraine with aura (MA), cluster headache (CH) and tension-type headache (TH). About one-third of MO and half of CH patients reported AD as trigger factors. Some studies show that AD are triggers in MA and TH in a similar percentage to that found in MO, but there are also discordant findings. There are sparse reports that AD are also triggers of less frequent types of primary headache such as familial hemiplegic migraine, hemicrania continua and paroxysmal hemicrania. The mechanism of alcohol-provoking headache is debated and should be compatible with the principal pathogenetic theories of primary headaches. If AD are capable of triggering practically all primary headaches, they should act at a common pathogenetic level. Vasodilatation is unlikely to be compatible as common mechanism. An action at cortical or more likely at subcortical level is plausible.

Triptans: low utilization and high turnover in the general population.

Studies performed in selected populations have shown a poor utilization of triptans for migraine. Our study was aimed at establishing patterns of triptans utilization in a large community using the pharmaceutical prescriptions database of two consecutive years in a regional Health Authority in Italy. About 0.5% of the population observed received triptans prescriptions in a year, but > 50% of the cases received only one prescription. On the other hand, 46% of triptan users did not receive a triptan prescription in the following year (past users): in 80% of cases, patients received only 1-2 triptan packages. The evaluation of the discontinued triptan type has shown percentages varying between 30 and 70%. The percentage of triptan users who received a triptan prescription for the first time in the successive year of study (new users) was 52%. These findings together highlight a high turnover in triptans utilization. Less than 15% of subjects received more than one triptan product in the 2 years. In conclusion, we observed a low percentage of triptan users and a low rate of utilization, associated with a high percentage of discontinuation and new utilization (high turnover), without any substantial increase in triptans utilization during the years. All these data probably do not support optimal satisfaction with triptan therapy.

Patterns of triptans use: a study based on the records of a community pharmaceutical department.

Studies performed in selected populations show that the use of triptans for migraine is low. Our study was aimed at establishing patterns of triptan utilization in a large community using the drug prescription database of a regional Health Authority in Italy. In a population of 224,065 residents, 0.55% received at least one prescription of triptans in 1 year: 77.9% were female and 22.1% male. Oral dosage forms accounted for 94% of prescriptions. About 60% of patients received a single prescription (containing one or two packages) of one triptan in 1 year. Age distribution showed that 7% of patients were aged > 65 years. They received 14% of packages, prevalently sumatriptan and zolmitriptan (the two triptans with the longest commercialization in Italy); 5.7% of patients received 40% of packages. Moreover, 3.2% of triptans users received > 120 dosage units in the year in the form of tablets (>10 single doses/month), and were potential triptan abusers. Our data indicate suboptimal treatment of migraine patients and also incorrect treatment of some patients (potential triptans abusers, the elderly).

First Report of Diplodia Canker of Cypress Caused by Diplodia pinea f. sp. cupressi on Mediterranean Cypress in Tunisia.

Symptoms of decline were observed on Mediterranean cypress trees (Cupressus sempervirens L.) in Tunisia in 2003 and 2004; disease specimens were vouchered as FIAF 38649. The declining, windbreak trees in the Cap Bon Region were 25 to 30 years old. Severity of symptoms varied among trees. Thus, areas of reddish, withered foliage alternated with areas that were still green. Other trees were completely withered. The bases of withered branches and tree trunks bore slightly sunken cankers with longitudinal bark cracks that oozed drops of resin. When the outer layer of a cankered area was scraped away, dark brown inner bark tissue was seen to extend up to several centimeters around the canker. Cross sections through cankers on trunks and branches revealed extensive darkened, wedge-shaped sectors in the wood. The affected bark bore numerous black pycnidia. Conidia were mostly smooth, ovoid, hyaline, and aseptate; a few were brown with a medial septum. The mean conidial dimensions (n = 100) were 27 × 11 µm; the extreme range was 19 to 31 × 8 to 13 µm. Isolates obtained from affected host tissue and conidia developed mainly floccose colonies that were white, then greyish green, and finally dark gray black on potato dextrose agar (PDA) at 25°C. Blackish pycnidial fructifications containing typical conidia were produced after 5 weeks on autoclaved cypress seeds placed on the colonies under light. Pathogenicity was tested using five 3-year-old potted Mediterranean cypress trees. These were inoculated by placing 3-mm-diameter plugs of mycelium of isolate DF IMG86 (DAOM 234788) from the edge of a 15-day-old colony on PDA on 5-mm-diameter wounds made in the bark. The wounds were covered with cotton wool moistened with sterile water and wrapped in adhesive tape. Similar wounds on five control trees received a plug of sterile PDA. Symptoms occurred as early as the third week after inoculation. The leaves first became yellow and then turned amaranth red, after which they progressively withered. Two months after inoculation, cankers were clearly visible at the inoculation site. Isolates from these cankers were morphologically similar to those used for inoculation. The control plants did not show any disease symptoms and their wounds healed normally. Morphological, cultural, and pathological characteristics of the fungus isolated from cypress with decline symptoms were similar to those of the fungus referred to as Diplodia pinea f. sp. cupressi or Sphaeropsis sapinea f. sp. cupressi (1). Identification was confirmed by marker analysis by using intersimple sequence repeat polymerase chain reaction (2). Banding patterns for isolate DF IMG86 were produced using primers HYH(GY)7 and (CAG)5 and were identical to those for Diplodia pinea f. sp. cupressi isolates 94-3 (DAOM 229437) and 95-158 (DAOM 229439) and differed from those obtained for isolates of Diplodia pinea (S. sapinea A group), D. scrobiculata (S. sapinea B group), Botryosphaeria obtusa, and B. stevensii. To our knowledge, this is the first report of this pathogen in Tunisia. The development of D. pinea f. sp. cupressi on cypress windbreaks in the Cap Bon Region may be related to a drought that has afflicted Tunisia for the past 5 years. Reference: (1) Z. Solel et al. Can. J. Plant Pathol. 9:115, 1987. (2) S. Zhou et al. Mycol. Res. 105:919, 2001.

Susceptibility of cypress seedlings to the eriophyoid mite Trisetacus juniperinus.

In Italian nurseries and young groves of evergreen cypress (Cupressus sempervirens L.), the eriophyoid mite Trisetacus juniperinus (Nal.) is considered a very serious pest. A rating system of damage symptoms was developed to investigate the susceptibility of different cypress seedling families to the mite. Based on this system, the seedlings were evaluated for three years in the nursery and in two field locations after transplanting. Data obtained in the nursery allowed the cypress families to be allocated to at least two different levels of susceptibility. These levels of susceptibility were generally also maintained in the field. However, the environmental conditions of the two transplanting localities significantly affected the susceptibility of each family. In all families, scores for each of the damage categories were strongly correlated positively to each other and negatively with the average increment in the height of plant over the duration of the field experiment. Assessment of the intensity of the symptoms peculiar to damage category A (buds enlarged, deformed, russet and/or branch apex folded) was sufficient to give the same susceptibility evaluation as if data for all damage categories were used. The evaluation of susceptibility on the basis of injury pattern may return very useful information for selection and certification of families of known susceptibility to eriophyoid mites.

Serum beta-endorphin increase after intravenous histamine treatment of chronic daily headache.

Histamine is able to induce spontaneous-like headache attacks in migraine and cluster headache subjects. Therefore, it has been considered as a possible agent in the pathogenesis of headache. Histamine desensitization is used for the treatment of cluster and other chronic headaches like migrains with interparoxysmal headache. However, it is unknown whether desensitization plays a role in headache improvement. Since a disfunction of the opioid system has been considered responsible for idiopathic headache and since low beta-endorphin levels have been demonstrated in some idiopathic headaches, particularly in migraine with interparoxysmal headache, we planned this study to verify if histamine therapy is able to modify serum beta-endorphin concentrations. For this purpose, we studied 24 healthy control subjects and 36 patients suffering from migraine with interparoxysmal headache refractory to conventional therapies. Patients showed baseline serum beta-endorphin levels significantly lower than healthy control subjects and treatment with histamine for 15 days increased their beta-endorphin concentrations. We believe that histamine treatment can activate the opioid endogenous system. However, the therapeutic effect of histamine remains to be verified by evaluating the correlation between beta-endorphin levels and headache improvement.

Headache induced by serotonergic agonists--a key to the interpretation of migraine pathogenesis?

Serotonergic agonists such as m-chlorophenylpiperazine (m-CPP) and fenfluramine may induce migraine attacks. This has led to opposing theories concerning the role of 5-hydroxytryptamine (5HT) in triggering migraine attacks; is there hyperfunction or hypofunction of the central serotonergic system. Our review of the literature strongly suggests that m-CPP and fenfluramine provoke migraine attacks by stimulating, directly or indirectly, the 5HT2C/5HT2B receptors, although there is no total agreement with this interpretation. Central 5HT hypersensitivity in migraine patients, probably due to 5HT neuronal depletion, is proposed on the basis of review of electrophysiological tests and neuroendocrine challenge paradigms.

Painful vein overdistension in migraine patients: no relationship with serotoninergic parameters.

Overdistension of the hand-forearm veins after a period of ischaemia-induced stasis causes local pain in a high percentage of migraineurs, but never in healthy subjects. To investigate the mechanism of such pain, we compared 5-hydroxytryptamine (5HT) whole blood levels and hand vein 5HT reactivity of migraine subjects who did experience pain during venous overdistension to those who did not. No differences were found in whole blood 5HT levels or in the venoconstrictor activity of 5HT between subjects experiencing pain and those who did not. No correlation was found between whole blood 5HT levels and the degree of 5HT-induced venoconstriction. Our results suggest that, if platelets are considered as a model of central antinociceptive 5HT neurons, pain appearance is not due to reduced 5HT at a central level and, therefore, to increased perception of peripheral nociceptive stimuli. Moreover, the similar 5HT venoconstrictive effect (indirect marker of venous tone and, therefore, of venous distensibility) seems to indicate that a mechanical factor is not involved in pain appearance during the HAVD test.

Sex differences in headache sufferers' responsiveness to painful overdistension of the hand-forearm veins.

A short-lasting overdistension of the hand-forearm veins, through the application of the Hand Arm Vein Distension (HAVD) test was carried out on patients suffering from migraine (no. = 102) and females with chronic daily headache (no. = 26): chronic tension-type headache (CTH) and migraine with interparoxysmal headache (MIH). Comparisons were made with a group of healthy controls (no. = 20). The HAVD test induced pain more often in female (65%) than in male migraineurs (14%) and female controls (p < 0.01). No significant difference appeared between male migraineurs and male controls. No significant difference was evidenced between female migraineurs in headache and headache-free periods. Patients with CTH showed less sensitivity to HAVD than those with MIH and migraine (respectively p < 0.01 and p < 0.05) and even a longer latency before the onset of pain. The findings show a stronger extracephalic pain sensitivity in migraineurs than in healthy controls, but sex must be taken into account. The results suggest that pain sensitivity is not correlated with the presence of headache.

Comparison between venoconstrictor effects of sumatriptan and ergotamine in migraine patients.

The vasoconstrictor activity of sumatriptan and ergotamine were compared by injecting these drugs in the hand vein of migraine subjects. We used the "venotest method", which permits the evaluation of the venoconstrictor effect of small doses of drugs, acting locally in the hand vein. Sumatriptan injected at increasing doses in the hand vein provoked contraction only at high doses (500 micrograms): venoconstriction lasted 5-15 minutes and was similar in intensity and duration to that induced by 0.5-1 micrograms of 5-hydroxytryptamine (5-HT). Likewise, ergotamine induced contraction only at a dose of 50 micrograms: this venoconstrictor effect was long lasting (at least 1 hour). Ergotamine-induced hand vein contraction, almost completely inhibited by ketanserin, seems mediated at least in part by 5-HT2 receptors, like the one induced by 5-HT and sumatriptan, already observed in a previous study. Clinical doses of ergotamine (0.25 mg intramuscular) and of sumatriptan (6 mg subcutaneous) do not provoke hand vein contraction for at least 1 hour: this could be due to a low activity of these drugs on the 5-HT2 vein receptors or a technique that is unsuitable to detect the vasoconstrictor effect of drugs given by the systemic route. The long lasting venoconstrictor effect of ergotamine may be due to a slow dissociation from receptor sites. The short vasoconstriction induced by sumatriptan could account for the recurrence of headache in many sumatriptan-treated migraine subjects.

Amplifying effect of sumatriptan on noradrenaline venoconstriction in migraine patients.

The venoconstrictive activity of sumatriptan and its interaction with noradrenaline (NA)- and 5-hydroxytryptamine (5HT) venoconstriction was studied in vivo in the hand vein of migraineurs. Sumatriptan, injected at increasing doses into the vein, caused local venoconstriction after a 500 microgram dose, comparable to that induced by 0.5-1 micrograms of 5HT. This venoconstriction was completely inhibited by low doses of ketanserin (5 micrograms). Subcutaneous sumatriptan (6 mg) provoked a minor increase in vein tone, lasting less than 30 min. Non-venoconstrictive doses of sumatriptan (10-100 micrograms), injected in the hand vein, produced an amplification of NA-venoconstriction but not of 5HT-induced venoconstriction. A similar increased effect was displayed by subcutaneous sumatriptan (6 mg) for at least 1 h. Sumatriptan appears to cause peripheral venoconstriction only at high doses locally applied (in the hand vein), by acting on 5HT2 receptors. Clinical subcutaneous doses (6 mg) do not show significant venoconstrictive effects. The amplifying effect on NA venoconstriction, also caused by 5HT, ergotamine and dihydroergotamine in human cranial arteries, may be important in explaining the therapeutic action of sumatriptan in migraine attacks.

[Headache caused by analgesic and/or ergotamine abuse]. / Cefalee da abuso di analgesici e/o ergotamina.

Headache induced by ergotamine-abuse was described 40 years ago. More recently there is ample evidence suggesting that chronic headache may also be provoked by analgesic abuse. A recent Classification of the International Headache Society has defined this kind of headache as an autonomous disease. It consists in a daily chronic headache with paroxysmal attacks associated with daily or almost daily assumption of analgesics and/or ergotamine. It is debated whether the term "abuse" or "dependence" is correct. Almost 5% of patients of the Headache Centres in Italy were found to be drug abusers. Most of these patients originally suffered from migraine. The therapeutic approach consists in hospitalization, withdrawal of analgesics and/or ergotamine, treatment of the withdrawal headache (which appears within 48 hours and lasts even 1-2 weeks) and finally in a prophylactic therapy. Although several treatments have been suggested for the abstinence syndrome, only fluid replacement, antiemetics, hypnotic-sedative drugs and rarely mild analgesics are necessary. A review of the literature shows the following success rates in the relief of the headache: above 50% relief in more than 60% of patients within a follow up period of 1 to 3.5 years as mean. Even if caffeine and barbiturates, which are often contained in the analgesic and ergotamine preparations, might be considered the cause of the abuse and withdrawal syndrome, they don't seem to play a fundamental role in this syndrome. An impairment of the central antinociceptive system was hypothesized to be involved in the pathogenesis of the headache associated with analgesic and/or ergotamine abuse. Recently there has been evidence of a possible hyposensitivity of the adrenergic and serotoninergic receptors of the central nervous system. It is still to be proved whether drug abuse is the cause or the consequence of the headache chronicization. The remarkable improvement of headache after analgesic withdrawal suggests a causal factor.

Reduced serotonin vascular sensitivity in ergotamine abusers.

The action of ergotamine on the 5-hydroxytryptamine (5-HT) venous sensitivity was studied in ergotamine abuser and non-abuser migraine patients. Ergotamine abusers showed reduced 5-HT hand vein contraction during abuse, compared to seven days after ergotamine withdrawal. In non-ergotamine users, the 5-HT venoconstriction was not significantly modified 12 h after a single intramuscular ergotamine (0.25 mg) administration. Even the administration of ergotamine locally into the vein did not change the venospasm of 5-HT given acutely in the same vein. Therefore, it seems that the 5-HT antagonism does not contribute to the therapeutic effect of ergotamine during the migraine attack. Moreover, the reduced 5-HT responsiveness during ergotamine abuse may possibly be compatible with the chronic headache present in some abusers, the withdrawal headache attacks and the abuse itself.

Effects of calcium antagonists on serotonin and noradrenaline venoconstriction in humans.

The activity of some calcium antagonists on 5-hydroxytryptamine (5HT) and noradrenaline-induced venoconstriction has been evaluated in humans. Oral doses of nimodipine, 30 mg, and nifedipine, 10 mg, but not of verapamil, 80 mg, and flunarizine, 10 mg, inhibit 5HT-induced venoconstriction of the dorsal hand vein. Nimodipine, but not verapamil and flunarizine, inhibit noradrenaline-induced venoconstriction as well. Verapamil, locally administered into the hand vein, inhibits 5HT and noradrenaline-induced venoconstriction. These results suggest that only calcium antagonists of the dihydropyridine type have antivenoconstrictive activity in the hand vein at oral clinical doses, whereas verapamil is active only if administered by the intravenous route, which probably produces local plasma concentrations higher than those reached with the oral clinical doses.

Somatostatin: peripheral venoconstrictive activity and interaction with monoamines in man.

The mechanism of somatostatin venoconstriction and tachyphylaxis in the human hand vein in vivo has been investigated. No cross-tachyphylaxis was observed between somatostatin and 5-hydroxytryptamine, noradrenaline, adrenaline, dopamine or tyramine-induced venoconstriction. Somatostatin potentiates the venoconstrictive activity of noradrenaline, adrenaline and dopamine, but not that of 5-hydroxytryptamine and tyramine. Phentolamine antagonizes the somatostatin-induced venoconstriction, whereas methysergide, haloperidol and morphine do not. It is suggested that somatostatin could act on specific receptors in the hand vein, but the mechanism of somatostatin venoconstriction and interaction with vasoactive monoamines remains to be defined.

A pharmacological approach to the analgesizing mechanism of somatostatin in cluster headache.

Vasodilation, conjunctival and nasal edema as well as miosis are symptoms associated with cluster headache (CH) attacks. Similar symptomatology is caused by substance P (SP) release from peripheral trigeminal nerve endings. The symptomatic effect of somatostatin (SRIF) during CH attacks was attributed to the inhibition of SP release from trigeminal neurons. This study was designed to evaluate both the vascular effect of SRIF on the dorsal hand vein and SRIF plasma levels prior to and after subcutaneous and intranasal administration in CH patients. A powerful venoconstriction and tachyphylaxis were demonstrated when SRIF was administered both as bolus and infusion. Plasma levels of SRIF in CH sufferers were lower than in control subjects. Subcutaneous and intranasal SRIF administrations induced maximal plasma levels after 5 and 10 min, respectively. These data suggest that SRIF plays an important role during CH attacks; however, its exact mechanism of action is still to be defined.

Enkephalinase and angiotensin converting enzyme activities in human venous and arterial plasma.

Circulating opioids, particularly enkephalins, can act on specific receptors located on the neurovascular sympathetic junction. These peptides are quickly metabolized by enkephalinase and angiotensin converting enzyme (ACE). According to the parallel distribution of enkephalinase with opioid receptors in the rat brain, and its location in the vascular bed, putative differences of enkephalinase and ACE activity between arterial and venous plasma of the same subjects was researched. Venous enkephalinase activity was found to be greater than arterial activity. No arterovenous differences were present in ACE activity. The activities of both enzymes presented a positive correlation between venous and arterial plasma in the same subjects. The arterovenous difference in enkephalinase activity supports a release of the enzyme from microvessels.