Prophylactic activity of increasing doses of intravenous histamine in refractory migraine: Retrospective observations of a series of patients with migraine without aura

Background: Histamine is thought to play a pivotal role in the modulation of peripheral and central pain. The administration of increasing doses of histamine may lead to desensitization of receptors of histamine types 1 and 2, causing meningeal vasodilation, and to depletion of neuropeptides in the trigeminal ganglion, thus inhibiting the initiation of migraine.Objective: In this study, the efficacy and tolerability of increasing doses of IV histamine in migraine prophylaxis were investigated.Methods: This single-center, open-label, retrospective, controlled study was conducted at the Headache Center (Department of Internal Medicine, University of Florence, Villa Monna Tessa, Italy). Patients included in the study had 3 to 6 migraines without aura per month that were refractory to common symptomatic and prophylactic agents in the 6 months preceding the study. Patients were treated with IV histamine hydrochloride for 21 days starting with a dosage of 0.5 mg/d and increasing to 4.0 mg/d. To assess the efficacy of the treatment, these patients were matched for age; sex; and frequency, duration, and severity of attacks with untreated migraineurs. Clinical benefit was defined as ⩽ 1 migraine of mild intensity per month. Tolerability was assessed during the hospitalization period, and patients were instructed to contact the Headache Center to report any adverse effects after hospital discharge.Results: The histamine group comprised 47 patients (40 women, 7 men; mean [SD] age, 42.0 [8.6] years) and the control group comprised 23 patients (20 women, 3 men; mean [SD] age, 38.8 [8.4] years). The histamine-treated patients showed a clinical benefit lasting for a mean of 10.4 (4.2) months, while the patients in the control group showed a clinical benefit of 3.8 (1.9) months. The difference in the duration of the clinical benefit between the 2 groups was 6.6 months (95% CI, 5.15-7.99). Adverse effects consisted of flushing, heat sensation during infusion, headache, and palpitations.Conclusions: In this study, histamine showed lasting prophylactic efficacy in migraineurs. If further research confirms this preliminary finding, histamine could be considered when established prophylactic drugs, such as betablockers, calcium antagonists, antidepressants, and antiepileptics, have not been effective.     

Experimental toothclenching in common migraine

The effect of 30 min voluntary toothclenching was studied in 48 patients with common migraine, randomized in two groups. Group 1 performed low-level tension at 5% and group 2, high-level tension at 30% of the individual maximum, as judged by surface EMG from the temporal muscle. Pericranial muscle tenderness was evaluated by manual palpation and a four-point verbal scale. Headache, nausea, and soreness of the chewing muscles were scored on visual analogue scales. Although surface EMG, soreness, blood pressure, heart rate and difficulty in completing the toothclenching session all showed that group 2 patients were subjected to significantly higher levels of muscle tension than group 1 patients, headache developed equally often in both groups (63%). Headache was even more pronounced in group 1 (n.s.). Five patients in group 1 and none in group 2 developed an attack of migraine during the following 24 h. Pericranial muscle tenderness was unaffected by the experimental procedure. There was no significant correlation between headache intensity and pericranial muscle tenderness. Muscle ischemia, muscle "fatigue", and strain on muscle insertions are thus unlikely to cause attacks of common migraine.     

Personality and memory in childhood migraine

A series of neuropsychological tests were administered to a group of healthy children and another group suffering from common migraine. The tests demonstrated that children with common migraine do not have definitely abnormal personality traits even though inhibition of aggressivity and greater anxiety levels following certain environmental stimuli were seen. We also observed a decreased short- and long-term memory function in children with common migraine.     

Alterations of nonspecific immunity in patients with common migraine

In 23 patients with common migraine (CM), immune responsiveness and frequency of immunocompetent cells were investigated. In particular, phagocytosis and killing of Candida albicans by polymorphs (PMNs) and monocytes were analyzed. Also, the percentages of CD3+, CD4+, CD8+, natural killer, and CD15+ cells were evaluated by direct immunofluorescence using specific monoclonal antibodies. The results showed deficits of phagocytosis or killing exhibited by PMNs and monocytes. These immunological findings are discussed in terms of perturbation of immune status in CM patients during migraine attacks.     

Histamine release from leucocytes in migraine

The spontaneous histamine release (SHR) from leucocytes in migraine patients during symptom-free periods has been investigated, and also the influence of migraine sufferer serum on histamine release (HR) from blood donor leucocytes. The leucocytes were isolated according to the Day method and histamine assay was made by the Shore spectrofluorometric method modified by Bergendorff and Uvnäs (1). SHR in the 17 female migraine patients was significantly higher (39.7% ± 13.1%) than in 8 controls (25.4% ± 4.2%). Migraine serum increased HR from blood donor leucocytes by 14.6% ± 20.2% compared with the SHR of these cells.     

β-endorphin and ACTH in plasma during attacks of common and classic migraine

Plasma levels of beta-endorphin and ACTH were measured during and outside migraine attacks in 17 patients with common migraine and 11 patients with classic migraine. Specific radioimmunoassays for beta-endorphin and ACTH were used. The beta-endorphin assay did not cross-react with beta-lipotropin. In common migraine, median plasma beta-endorphin was 3.3 pmol/l (95% confidence limits: 2.5-4.0 pmol/l) during attacks and 2.9 (2.4-3.2) pmol/l in the headache-free period. In classic migraine, plasma beta-endorphin was 3.2 (1.4-4.3) pmol/l during attacks and 2.4 (1.1-3.6) pmol/l outside attacks. ACTH plasma levels were 15 (10.5-20) pmol/l during and 15.7 (13.4-17) pmol/l outside attacks in common migraine. In classic migraine, plasma ACTH was 16 (7-36) pmol/l and 12.3 (8-28) pmol/l respectively. No significant differences were found between attacks and headache-free periods in common or classic migraine. Accordingly, we could not add evidence to the theory of a dysfunction of the endogenous opioid system in migraine.     

Contingent negative variation and efficacy of beta-blocking agents in migraine

Thirty-three patients with common migraine underwent contingent negative variation (CNV) recordings before receiving prophylactic beta-blocker treatment with either metoprolol (27 patients) or propranolol (6 patients) at mean daily dosages of 110 mg and 122 mg, respectively. After 3 months the therapeutic efficacy of the beta-blocker was assessed in each patient by means of a global severity score and compared with the initial CNV recordings. The mean clinical improvement was 62%. A significant positive correlation was found between CNV amplitude before prophylaxis and the clinical response to beta-blockers: patients with higher CNV tended to respond better to therapy. Eight of 10 patients with a CNV amplitude higher than -25 microV had a more than 50% reduction of the severity score--that is, a good or excellent response to the beta-blocking agent--whereas only 2 of 9 patients with an amplitude lower than -20 microV had a good response.     

Intracellular and plasma magnesium in familial hemiplegic migraine and migraine with and without aura

Familial hemiplegic migraine (FHM) is an autosomal dominant type of migraine and probably represents the most extreme end of migraine with aura. Reduced magnesium facilitates the development of spreading depression and possibly aura. Cellular magnesium levels are under genetic control. We hypothesized that FHM patients would have significantly reduced intracellular magnesium levels. We determined intracellular and plasma magnesium levels in blood of 38 afflicted and 11 non-afflicted members of three families with FHM and, in 32 migraine patients (9 with and 23 without aura) and 32 age and sex matched healthy controls. We found no significant differences between the magnesium levels in the five study groups. We conclude that reduced blood magnesium is unlikely to be related to migraine pathophysiology.     

Histamine inhalation is a specific but insensitive laboratory test for migraine

Migraine is a subjective complaint and no laboratory test has until now been of value. The aim of the present study is to evaluate whether histamine inhalation may be used as a diagnostic test for migraine. In a double blind study design, 15 migra neurs and 15 control subjects scored headache intensity and characteristics before, during, and in the subsequent 12 h after inhalation of increasing doses of histamine (0, 2, 4, 8, 16, 32 and 64 mg/ml). During the histamine inhalations, headaches increased dose-dependently in both groups Eleven of the migraineurs and eight of the healthy controls experienced headaches after the inhalations These headaches fulfilled the IHS criteria for migraine without aura in six of the migraineurs, but in none of the control subjects. Using this as a test parameter, the specificity of the test was 1, but the sensitivity was only 0.4. Our results indicate that histamine inhalation is a specific but insensitive laboratory test for migraine. Migraineurs should be informed about the risk of a migraine attack being provoked before histamine inhalation in pulmonary laboratories.     

Platelet catecholamines in migraine

We measured platelet levels of norepinephrine (NE), epinephrine (E), and dopamine (DA) in migraine patients. Platelet NE was selectively increased in common migraine. This is attributed to platelet dense body hyposecretion.     

Familial hemiplegic migraine type 2 does not share hypersensitivity to nitric oxide with common types of migraine

Familial hemiplegic migraine type 2 (FHM-2) and common types of migraine show phenotypic similarities which may indicate a common neurobiological background. The nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway plays a crucial role in migraine pathophysiology. Therefore, we tested the hypothesis that ATP1A2 mutations in patients with FHM-2 are associated with hypersensitivity to NO-cGMP pathway. Eight FHM-2 patients with R202Q, R763C, V138A and L764P mutations and nine healthy controls received intravenous infusions of 0.5 mug kg(-1) min(-1) glyceryl trinitrate (GTN) over 20 min. We recorded the following variables: headache intensity on a verbal rating scale; mean flow velocity in the middle cerebral artery (V(meanMCA)) by transcranial Doppler; diameter of the superficial temporal artery (STA) by ultrasound. The primary end-points were differences in incidence of migraine headache and area under the curve (AUC) for headache score during an immediate phase (0-120 min) and a delayed phase (2-14 h) after start of infusion. We found no difference in the incidence of reported migraine between FHM-2 patients, 25% (two out of eight), and controls, 0% (0 out of nine) (95% confidence interval -0.06, 0.56) (P = 0.21). The AUC(headache) in the immediate (P = 0.37) and delayed (P = 0.09) phase was not different between patients and controls. The GTN infusion resulted in a biphasic response in patients. During the immediate phase, the median peak headache occurred at 30 min and tended to be higher in patients, 1 (0, 3.8), than in controls, 0 (0, 1) (P = 0.056). During the delayed phase, the median peak headache occurred 4 h after the start of the infusion and was significantly higher in patients, 2.5 (0, 3), than in controls, 0 (0, 0) (P = 0.046). We found no difference in the AUC(VmeanMCA) (P = 0.77) or AUC(STA) (P = 0.53) between FHM-2 patients and controls. GTN infusion failed to induce more migraine in FHM-2 patients than in controls. The pathophysiological pathways underlying migraine headache in FHM-2 may be different from the common types of migraine.     

Chemical mediators of migraine: preclinical and clinical observations

Migraine is a neurovascular disorder, and although the pathophysiology of migraine has not been fully delineated, much has been learned in the past 50 years. This knowledge has been accompanied by significant advancements in the way migraine is viewed as a disease process and in the development therapeutic options. In this review, we will focus on 4 mediators (nitric oxide, histamine, serotonin, and calcitonin gene-related peptide) which have significantly advanced our understanding of migraine as a disease entity. For each mediator we begin by reviewing the preclinical data linking it to migraine pathophysiology, first focusing on the vascular mechanisms, then the neuronal mechanisms. The preclinical data are then followed by a review of the clinical data which support each mediator's role in migraine and highlights the pharmacological agents which target these mediators for migraine therapy.     

Red blood cell magnesium levels in migraine patients

In the last few years, it has been suggested that magnesium plays a central role in establishing a threshold for migraine attacks and in intervening with the pathogenetic mechanisms involved in their onset. Accordingly, we determined red blood cell magnesium levels in adult migraine patients with and without aura interictally and in some of them also ictally. In comparison with normal subjects, migraineurs with and without aura had significantly lower red blood cell magnesium levels in the interictal period. Ictal red blood cell magnesium levels did not differ from the interictal values. Low red blood cell magnesium levels could be a peripheral expression of the reduced brain magnesium concentration observed in migraine patients.     

Common migraine attacks preceded by focal hyperemia and parietal oligemia in the rCBF pattern

Regional cerebral blood flow (rCBF) was measured in the dominant hemisphere with the xenon-133 injection method, using the 254 multidetector gamma camera. Two patients developed a common migraine attack during the rCBF studies. The headache was preceded by focal oligemia in the occipitoparietal region in one of the patients and in the parietocentral region in the other. Neurological examination was normal. These results indicate that the initiating cerebral hemodynamics in common migraine are, at least in particular patients, the same as in patients with classic migraine.     

Elevation of plasma vasopressin in spontaneous migraine

Vasopressin is a vasoactive hormone secreted from the posterior pituitary. At low concentration its role is in regulating renal water excretion, but at higher concentrations it has a number of extrarenal actions, including effects on blood flow. To investigate the role of vasopressin in spontaneous migraine, paired samples were collected from 14 subjects (a) during an acute attack of spontaneous migraine, and (b) when symptom-free for at least seven days. During an attack, vasopressin was consistently raised (median (range) 3.5 (1.2-9.6) pg/ml v 0.5 (0.5-1.1) pg/ml, p less than 0.001). The highest vasopressin concentration occurred in the only patient who vomited. The results suggest vasopressin rises during an attack of spontaneous migraine, and this may, in part, be related to emesis. In the majority, vasopressin levels only rose sufficiently to have some renal antidiuretic effect, although in some these levels could have been sufficient to cause alteration in peripheral blood flow. Release of vasopressin may be responsible for the facial pallor and antidiuresis observed in migraine.     

Raised plasma endothelin during acute migraine attack

Endothelins are the most potent vasoconstrictor peptides known. Plasma endothelin (ET-1) concentrations were measured in eight migraine patients (mean age 44.5 years), two during an acute migraine attack with aura and six during an attack without aura. The mean ET-1 values were elevated in all migraine patients above the range of normal subjects, and were 10.6 (range 6.0-16.0) pg/ml in migraine patients and 3.8 (range 0.7-5.8) pg/ml in controls. We hypothesize that ET-1 may constrict cerebral vessels during the initial stage of the migraine attack.     

Increased plasma histamine levels in migraine patients

Whole blood and plasma histamine levels, peripheral basophil and eosinophil counts and serum immunoglobulins have been measured in a group of eighteen patients with migraine in remission and in twelve of these patients during a headache attack. Plasma histamine levels were significantly elevated (P less than 0.0005) in patients with migraine both during headache attacks and symptom-free periods.     

The prophylactic effect of timolol versus propranolol and placebo in common migraine: beta-blockers in migraine

A multicentre double-blind, cross-over trial was planned to evaluate the prophylactic effect of timolol in migraine. The effectiveness of the drug was compared to propranolol and placebo. In the Norwegian part of the trial described in this paper, 18 patients completed the study. The data suggest that timolol is equivalent in effectiveness to propranolol in migraine prophylaxis. Firm conclusions should not be drawn until the results from the multicentre trial are available.     

Triptans in the treatment of basilar migraine and migraine with prolonged aura

OBJECTIVE: To report on the use of triptans in migraine with prominent neurologic symptoms. BACKGROUND: As stated in their package inserts, the triptans are contraindicated in patients with basilar or familial hemiplegic migraine, and physicians are reluctant to prescribe these drugs to other patients with prominent or prolonged aura. METHODS: We evaluated 13 patients with basilar migraine, familial hemiplegic migraine, or migraine with prominent or prolonged aura who had received triptans. RESULTS: Excellent; no adverse events. CONCLUSION: The contraindication of triptans in basilar migraine should be reconsidered. Similarly, prominent or prolonged aura may not represent a reasonable contraindication to triptan therapy.     

Histamine as a therapeutic alternative in migraine prophylaxis: a randomized, placebo-controlled, double-blind study

This study was undertaken to test the efficacy of the subcutaneous administration (twice a week) of consecutively increasing doses of histamine (0.1 to 1 ng) in the prophylaxis of migraine, compared to placebo, under a controlled, double-blind, clinical trial for 12 weeks. Sixty patients were selected, under criteria established by the International Headache Society (both sexes, 18 to 65 years of age, a migraine history of more than 1 year, one to six headache attacks per month), having no additional neurological or cardiovascular pathologies, and after a complete clinical and laboratory examination including computer-assisted tomography. Comparison between the groups treated with placebo (n = 30) and histamine (n = 30), on data collected for the 4th, 8th, and 12th weeks of treatment, revealed that histamine exerted a significantly (P < .0001) greater reduction (compared to placebo) in the frequency, intensity, and duration of migraine attacks, as well as on the use of rescue medication. No significant (P > .05) adverse experiences or side effects in either group developed to impede the blinding of the study or the planned order of events. We conclude that the subcutaneous administration of histamine (at very low doses) constitutes a novel and effective therapeutic approach in migraine prophylaxis, aimed at limiting excessive inflammatory responses involved in the pathophysiology of migraine through the activation of H3 receptors.