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Nocturnal plasma melatonin profile and melatonin kinetics during infusion in status migrainosus
Claustrat B.; Brun J.; Geoffriau M.; Zaidan R.; Mallo C.; Chazot G.
B. Claustrat, Serv. Radiopharmacie/Radioanalyse, Hopital Neurologique, 59 Boulevard Pinel, 69003 Lyon France
Cephalalgia (Norway), 1997, 17/4 (511-517)

The plasma melatonin profile was significantly disturbed (phase-shift of the maximum melatonin level) in four out of six female sufferers from status migrainosus, compared with nine healthy controls. The number of secretion peaks was similar in both groups. A nocturnal 20 pg melatonin infusion (from 21.00 to 01.00 h) evoked plasma melatonin levels slightly higher than a physiological secretion peak. During infusion, the episodes of secretion were reinforced and the endogenous plasma profile was phase-advanced in two patients displaying a phase-delay. These data suggest impaired pineal function in migraine. In the absence of side effects of melatonin infusion, the relief of certain migraine symptoms described by our patients might support a controlled trial of melatonin in migraine.

Pharmacology of serotonin as related to anesthesia
Gyermek L.
Department of Anesthesiology, Harbor-UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90509 USA
Journal of Clinical Anesthesia (USA), 1996, 8/5 (402-425)

Serotonin (5-hydroxytryptamine) is an important biogenic amine that fulfills the role of neurotransmitter and neuromodulator. It has been a focus of interest during the last decade. Its diversity of pharmacologic actions is related to a wide variety of receptors and effector mechanisms. Serum serotonin receptor families have been identified thus far. They are genetically different transmembrane proteins composed of several hundred amino acids. The majority of these are G-protein-coupled, except the 5-HT3 receptors, which are directly ligand gated to fast ion channels. Serotonin is widely distributed in the body within the central and peripheral nervous systems, smooth muscles, and platelets, in particular. Consequently, its effects manifest mainly in these organs and influence a wide variety of neural, vascular, smooth muscle, and platelet functions. (Melatonin, a physiologically active metabolite of serotonin, is also instrumental in affecting many neural and hormonal functions.) Several selective agonists and particularly many selective antagonists have been developed for serotonin, which helped the serotonin receptor subtype classification. Some of these drugs are also used therapeutically in the treatment of migraine (eg, sumatriptan, which is a 5-HT1 receptor agonist), vascular disorders (5-HT2 antagonists), and nausea and vomiting (5-HT3 antagonists, eg, dolasetron, granisetron, ondansetron, and tropisetron), and have been investigated in gastrointestinal motility disorders (5-HT4 antagonists) and behavioral psychopathologies (5-HT1 agonists and 5-HT2-4 antagonists). Serotonin reuptake inhibitors are of particular clinical importance in the treatment of psychological illnesses. Future use of these drugs is also envisioned in the treatment of certain types of pain syndromes. Awareness of the serotonergic drugs and the recognition of possible drug interactions among drugs that influence serotonergic mechanisms in humans are becoming increasingly important in the practice of anesthesiology.

Pathogenesis of posttraumatic headache and migraine: a common headache pathway?
Packard RC; Ham LP
Headache Management and Neurology, Pensacola, FL 32503, USA.
Headache (United States) Mar 1997, 37 (3) p142-52

In recent years, research implicating biochemical abnormalities in various pathological conditions has spiralled. Headache is an area in which numerous research studies have been conducted examining biochemical alterations. We have noticed several similarities in biochemical changes reported to occur in migraine and in experimental traumatic brain injury. The most common symptom in mild head injury or mild traumatic brain injury is headache which, in many instances, resembles migraine but has a poorly understood pathophysiology. Biochemical mechanisms believed to be similar in both conditions include: increased extracellular potassium and intracellular sodium, calcium, and chloride; excessive release of excitatory amino acids; alterations in serotonin; abnormalities in catecholamines and endogenous opioids; decline in magnesium levels and increase in intracellular calcium; impaired glucose utilization; abnormalities in nitric oxide formation and function; and alterations in neuropeptides. In this paper, these proposed biochemical alterations will be reviewed and compared. Very similar alterations suggest posttraumatic headache associated with mild head injury and migraine may share a common headache pathway. (114 Refs.)

[Migraine--diagnosis, differential diagnosis and therapy]
Diener HC
Klinik und Poliklinik fur Neurologie, Universitat Essen.
Ther Umsch (Switzerland) Feb 1997, 54 (2) p64-70

Migraine is caused by intermittent brain dysfunction. Attacks result in severe unilateral headache with nausea, vomiting, photophobia, phonophobia and general weakness. The prevalence of migraine is 12 to 20% in women and 8 to 12% in man. Treatment of an acute attack is done by antiemetics in combination with analgesics. Severe migraine attacks are treated with ergotamine or sumatriptan. Parenteral treatment is performed most efficiently and safely with i.v. ASA. Frequent and severe attacks require prophylaxis. Drugs of first choice are metoprolol, propranolol, flunarizine and cyclandelate. Substances of second choice are valproic acid, DHE, pizotifen, methysergide and magnesium. Homeopathic remedies are not superior to placebo. Nonpharmacological treatment consists of sport therapy and muscle relaxation techniques.

Magnesium taurate and fish oil for prevention of migraine.
McCarty MF
Nutrition 21, San Diego, CA 92109, USA.
Med Hypotheses (England) Dec 1996, 47 (6) p461-6

Although the pathogenesis of migraine is still poorly understood, various clinical investigations, as well as consideration of the characteristic activities of the wide range of drugs known to reduce migraine incidence, suggest that such phenomena as neuronal hyperexcitation, cortical spreading depression, vasospasm, platelet activation and sympathetic hyperactivity often play a part in this syndrome. Increased tissue levels of taurine, as well as increased extracellular magnesium, could be expected to dampen neuronal hyperexcitation, counteract vasospasm, increase tolerance to focal hypoxia and stabilize platelets; taurine may also lessen sympathetic outflow. Thus it is reasonable to speculate that supplemental magnesium taurate will have preventive value in the treatment of migraine. Fish oil, owing to its platelet-stabilizing and antivasospastic actions, may also be useful in this regard, as suggested by a few clinical reports. Although many drugs have value for migraine prophylaxis, the two nutritional measures suggested here may have particular merit owing to the versatility of their actions, their safety and lack of side-effects and their long-term favorable impact on vascular health. (94 Refs.)

Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study.
Peikert A; Wilimzig C; Kohne-Volland R
Department of Neurology and Clinical Neurophysiology, Munich-Harlaching Clinic, Germany.
Cephalalgia (Norway) Jun 1996, 16 (4) p257-63

In order to evaluate the prophylactic effect of oral magnesium, 81 patients aged 18-65 years with migraine according to the International Headache Society (IHS) criteria (mean attack frequency 3.6 per month) were examined. After a prospective baseline period of 4 weeks they received oral 600 mg (24 mmol) magnesium (trimagnesium dicitrate) daily for 12 weeks or placebo. In weeks 9-12 the attack frequency was reduced by 41.6% in the magnesium group and by 15.8% in the placebo group compared to the baseline (p < 0.05). The number of days with migraine and the drug consumption for symptomatic treatment per patient also decreased significantly in the magnesium group. Duration and intensity of the attacks and the drug consumption per attack also tended to decrease compared to placebo but failed to be significant. Adverse events were diarrhea (18.6%) and gastric irritation (4.7%). High-dose oral magnesium appears to be effective in migraine prophylaxis.

Electromyographical ischemic test and intracellular and extracellular magnesium concentration in migraine and tension-type headache patients.
Mazzotta G; Sarchielli P; Alberti A; Gallai V
Interuniversity (Perugia-Rome-Sassari-Bari) Centre for the Study of Headache and Neurotransmitter Disorders of the CNS, Italy.
Headache (United States) Jun 1996, 36 (6) p357-61

Headache has often been described in the hyperexcitability syndrome which recognizes an alteration of calcium and magnesium status in its etiopathogenesis. Moreover, in migraine patients magnesium has been shown to play an important role as a regulator of neuronal excitability and, therefore hypothetically, of headache. The present research involves a neurophysiological evaluation and magnesium status assessment of a group of headache patients. Nineteen patients (15 women and 4 men) with episodic tension-type headache and 30 patients (27 women and 3 men) with migraine without aura were examined. An ischemic test was carried out on the right arm with electromyographic (EMG) recording of motor unit potential activity during the interictal period. The determination of extracellular (serum and saliva) and intracellular (red and mononuclear blood cells) magnesium was also performed. The EMG test was positive in 25 of 30 migraine patients and in 2 of 19 tension-type headache patients. Between the two patient groups, there were no significant variations in the concentration of extracellular and white blood cell magnesium, while the red blood cell concentration of this mineral in the group of migraineurs was significantly reduced with respect to that in the group of tension-type headache patients (P < 0.05). The positive EMG test was significantly associated with a low concentration of red blood cell magnesium (P < 0.0001). These results confirm previous findings by demonstrating different etiopathogenic mechanisms as the basis of migraine and tension-type headache. Migraine seems to be related to an altered magnesium status, which manifests itself by a neuromuscular hyperexcitability and a reduced concentration in red blood cells.

Efficacy and tolerability of subcutaneous sumatriptan administered using the IMITREX STATdose System.
Mushet GR; Cady RK; Baker CC; Clements B; Gutterman DL; Davis R
Georgia Headache Treatment Center, Augusta, USA.
Clin Ther (United States) Jul-Aug 1996, 18 (4) p687-99

The efficacy and tolerability of subcutaneous (SC) sumatriptan administered with the IMITREX (sumatriptan succinate) STATdose System, which circumvents the need for patients or health care professionals to handle a syringe, were evaluated in two randomized, double-masked, parallel-group, placebo-controlled, multicenter studies. In the clinic, 158 adults with migraine diagnosed according to International Headache Society criteria received SC sumatriptan (6 mg) or placebo delivered with the IMITREX STATdose System for treatment of a migraine attack. By 120 minutes after SC dosing, 73% and 79% of sumatriptan-treated patients, compared with 28% and 37% of placebo-treated patients in studies 1 and 2, respectively, experienced headache relief (a statistically significant difference). Clinical disability scores 120 minutes after dosing showed that 75% and 85% of sumatriptan-treated patients, compared with 30% and 42% of placebo-treated patients, were normal or only mildly impaired (a statistically significant difference). Similar efficacy rates were observed for nausea, phonophobia, and photophobia. No serious or unusual adverse events occurred, and no clinically relevant abnormalities in laboratory test values were reported. Based on these results, we concluded that SC sumatriptan (6 mg) administered using the IMITREX STATdose System is effective for the treatment of migraine. The efficacy and tolerability profiles of SC sumatriptan administered with this device are similar to those reported for SC sumatriptan administered with a conventional syringe.

A double-blind study of subcutaneous dihydroergotamine vs subcutaneous sumatriptan in the treatment of acute migraine.
Winner P; Ricalde O; Le Force B; Saper J; Margul B
Palm Beach Headache Center, Fla, USA.
Arch Neurol (United States) Feb 1996, 53 (2) p180-4

OBJECTIVE: To assess the efficacy and tolerability of subcutaneous dihydroergotamine mesylate (DHE-45) vs subcutaneous sumatriptan succinate (Imitrex) for the treatment of acute migraine with or without aura.

DESIGN: Double-blind, randomized trial with parallel treatment arms.

SETTING: Clinics and private neurology practices.

SUBJECTS: Patients of either sex, with migraine with or without aura, between the ages of 18 and 65 years.

INTERVENTIONS: Patients with moderate or severe head pain were randomized to receive either 1 mg of subcutaneous dihydroergotamine mesylate or 6 mg of subcutaneous sumatriptan succinate. Patients rated head pain, functional ability, nausea, and vomiting at baseline and at 0.5, 1, 2, 4, and 24 hours after the injection. Presence or absence of headache at 3 hours was calculated from collected data. If pain persisted after 2 hours, a second injection of the same study medication was allowed, and self-ratings were repeated 30 and 60 minutes later. Follow-up data were collected at 24 hours.

MAIN OUTCOME MEASURES: Relief of head pain and recurrence of successfully treated headache.

RESULTS: There were 295 evaluable patients. At 2 hours, 73.1% of the patients treated with dihydroergotamine and 85.3% of those treated with sumatriptan had relief (P = .002). There was no statistical difference in headache relief between the groups at 3 or 4 hours. Headache relief was achieved by 85.5% of those treated with dihydroergotamine and by 83.3% of those treated with sumatriptan by 4 hours. By 24 hours 89.7% of dihydroergotamine-treated patients and 76.7% of sumatriptan-treated patients had relief (P = .004). Headache recurred within 24 hours after treatment in 45% of the sumatriptan-treated patients and in 17.7% of the dihydroergotamine-treated patients (P < or = .001).

CONCLUSIONS: Both sumatriptan and dihydroergotamine were effective in aborting migraine headaches. Headache recurrence was two and a half time as likely with sumatriptan as with dihydroergotamine.

Herbal products begin to attract the attention of brand-name drug companies.
Cottrell K
Can Med Assoc J (Canada) Jul 15 1996, 155 (2) p216-9

Many Canadians are interested in alternative medicine, and burgeoning public interest in herbal remedies has not gone unnoticed by Canada's drug companies. McNeil Consumer Products recently began selling a migraine prophylaxis made from the plant feverfew. Physicians who would like to see herbal medications subjected to outcome studies and quality-control standards, with evidence of risks and benefits being made available to consumers, welcome the interest the companies are showing. Meanwhile, physicians and pharmacists are trying to respond to consumer demand by increasing their own knowledge about herbal medications.

Long-time efficacy of cyclandelate and propranolol in prophylaxis of migraine following four months of treatment
Schellenberg R.; Schwarz A.; Niederberger U.; Bolsche F.; Schindler M.; Gerber W.-D.; Wedekind W.; Soyka D.
Dr. R. Schellenberg, Talstrasse 29, D-35625 Huttenberg Germany
Nervenheilkunde (Germany), 1997, 16/3 (183-187)

After a 4 months randomized double-blind study with cyclandelate versus propranolol all patients kept a miniaturized headache diary for one more year. Both duration of migraine attacks in hours and the number of additional analgetic medication were recorded monthly. Reduction of the duration of migraine attacks in the clinical responders of the cyclandelate treated patients remained nearly unchanged. In the propranolol responders the duration of migraine attacks in hours increased from the third month after finishing the medication and reached values comparable to those at the beginning of the active treatment. Intake of additional analgetic medication during the 1-year-follow-up was lower in the cyclandelate responders than in the propranolol-responders. Cyclandelate can be described as an effective long-lasting drug in migraine prophylaxis.

Sumatriptan use in a large group-model health maintenance organization
Greiner D.L.; Addy S.N.
Kaiser Permanente, Box 6182, 2101 East Jefferson Street, Rockville, MD 20849-6182 USA
American Journal of Health-System Pharmacy (USA), 1996, 53/6 (633-638)

The outcomes of sumatriptan use at a health maintenance organization (HMO) were studied. The study was conducted during one year beginning immediately after sumatriptan was added to the formulary of a large group-model HMO. Subjects were included on the basis of drug-use evaluation criteria, a positive response to the first dose of sumatriptan (administered at the HMO by a nurse), and ability to participate in a telephone survey. Responders to the first dose were eligible to receive up to six doses of sumatriptan for home use. The telephone survey was designed to assess sumatriptan's effects on migraine headache and to capture data on quality of life, perceived problems with sumatriptan, and patient satisfaction. Patients who received sumatriptan between April and September 1993 were interviewed in late September 1993; patients who received sumatriptan between September and April 1994 were interviewed in late April 1994. Of 180 patients surveyed, 160 (89%) had evaluable responses. Migraine headache improved in two thirds of the patients. Sumatriptan was more effective than previously used agents in three fourths. The mean number of migraine headaches per patient per month decreased from 7.4 to 4.2. Quality-of-life indicators, such as time spent with friends, improved in three fourths. Eighty-three percent reported missing fewer days from work. Ninety percent said they would continue to take the drug, despite a 44% incidence of drug-related problems. There were no unexpected problems. A retrospective review showed that utilization of the HMO's resources was reduced with sumatriptan. Placing sumatriptan on an HMO's formulary led to favorable effects on the frequency and severity of migraine headache, patient quality-of-life indicators and productivity, and resource utilization by the organization.

The effect of sumatriptan on brain monoamines in rats
Mitsikostas D.D.; Papadopoulou-Daifotis Z.; Sfikakis A.; Varonos D.
Department of Neurology, Athens Naval Hospital, 70 Dinokratous Street, Athens 115 21 Greece
Headache (USA), 1996, 36/1 (29-31)

Clinical data suggests that sumatriptan is effective in the acute treatment of migraine. The vascular effects of the drug have been invoked to explain this antimigraine efficacy. However, the effect of sumatriptan on brain monoamines has not previously been investigated. In order to study these hypothetical effects, we administered the drug to 24 male rats, subcutaneously, at three doses (0.3, 0.6, and 0.9 mg/kg of body weight), and 30 minutes later, all animals were decapitated. Dopamine, serotonin, and their metabolites 3,4 dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid, and homovanillic acid concentrations were measured in the frontal cortex, hypothalamus, striatum, and hippocampus, by high performance liquid chromatography. Plasma concentrations of the drug were also determined. The control group was treated with NaCl 0.9%, given subcutaneously. Sumatriptan, at the dose of 0.3 mg/kg did not alter the brain monoamine concentrations; however, at the dose of 0.6 mg/kg, sumatriptan decreased serotonin concentration in the hypothalamus and increased the turnover of dopamine and serotonin in the hypothalamus and striatum, while at the dose of 0.9 mg/kg, it augmented only the turnover of serotonin in the hypothalamus. No dose- dependent effect of the drug was found. This subcortical antidopaminergic end antiserotoninergic effect of sumatriptan may be involved in its antimigraine action.

In vivo administration of propranolol decreases exaggerated amounts of serum TNF-alpha in patients with migraine without aura. Possible mechanism of action.
Covelli V; Munno I; Pellegrino NM; Marinaro MR; Gesario A; Massari F; Savastano S; Jirillo E
Acta Neurol (Napoli); 14(4-6):313-9 1992

Patients with migraine without aura (MWA) display elevated amounts of Tumor Necrosis Factor (TNF)-alpha in their sera. In this study in 18 patients with MWA the in vivo effect of propranolol, a beta blocker agent, was evaluated with regard to the TNF serum levels before and after treatment. Results show that in 9 out 11 patients exaggerated serum concentrations of TNF reverted to normality after three months of therapy. Some hypotheses on the mechanisms of action of propranolol in terms of modulation of the immune response are formulated.

Concurrent use of antidepressants and propranolol: case report and theoretical considerations
Nemeroff CB; Evans DL
Biol Psychiatry; 18(2):237-41 1983

The therapeutic indications for propranolol have been steadily increasing in recent years. Propranolol and other beta-adrenergic blocking agents are now generally acknowledged to be helpful in the management of hypertension, certain cardiac arrhythmias, migraine, essential tremor, angina pectoris, and most recently, immediately after myocardial infarction (Frishman, 1981; Norwegian Multicenter Study Group, 1982). Because of the myriad clinical settings in which propranolol has been found to be of benefit, the interactions of these drugs with other commonly utilized pharmacological agents is of great pragmatic interest. In this report we describe the successful concomitant clinical use of propranolol and an antidepressant drug. This finding is also of interest because of recent theories concerning the mechanism of action of antidepressant drugs. Because propranolol readily penetrates into the CNS, it blocks beta-adrenergic receptors in both the periphery and the CNS (Weiner, 1980). Much attention has been focused recently on the effects of long-term antidepressant therapy on central beta-adrenergic receptors in the brain as a possible mechanism of action of these drugs. The concurrent use of propranolol and an antidepressant drug in the patient described in this report did not attenuate the therapeutic effects of the antidepressant.

Nocturnal melatonin excretion is decreased in patients with migraine without aura attacks associated with menses
Brun J.; Claustrat B.; Saddier P.; Chazot G.
Cephalalgia (Norway), 1995, 15/2 (136-139)

Nocturnal melatonin excretion was studied throughout a complete menstrual cycle in 10 women with migraine without aura attacks associated with menses and 9 women controls. Urine melatonin was determined by radioimmunoassay. The mean nocturnal melatonin excretion throughout the cycle was significantly lower in the migraine patients than in controls. In the control group, melatonin excretion increased significantly from the follicular to the luteal phase, whereas no difference was observed in the migraine group. Results are discussed in view of the role of the pineal gland in the organization of biological rhythms and homeostasis in relation to environmental conditions.

Urinary melatonin excretion throughoutthe ovarian cycle in menstrually related migraine
Murialdo G.; Fonzi S.; Costelli P.; Solinas G.P.; Parodi C.; Marabini S.; Fanciullacci M.; Polleri A.
Endocrinological/Metabol. Sci. Dept., Viale Benedetto XV, 6, I-16132 Genoa Italy
Cephalalgia 1994 Jun;14(3):205-9

Nocturnal urinary melatonin excretion was significantly decreased throughout an ovarian cycle in 12 migraine without aura patients compared to 8 healthy controls. Normal increases in urinary melatonin excretion during the luteal phase was less pronounced in the migraine patients. Melatonin excretion was further decreased during headache. The data indicate impaired pineal function in migraine.

Nocturnal plasma melatonin levels in migraine: A preliminary report
Claustrat B, Loisy C, Brun J, Beorchia S, Arnaud JL, Chazot G
Headache (United States) Apr 1989, 29 (4) p242-5

We determined by radioimmunoassay plasma melatonin levels on blood samples drawn at 11 p.m. in migraine patients and control subjects. Ninety-three cephalalgic outpatients (75 females, 18 males) were compared to a control group (24 females, 22 males) matched according to age. Patients were divided into subgroups presenting common migraine (n = 38); ophthalmic migraine (n = 12); and tension headache associated with ophthalmic or common migraine (n = 24), and associated depressive status (n = 19). Statistical analysis revealed a decrease in plasma melatonin levels for the entire migraine population, compared to the control one, and a heterogeneity in both controls and patients; this heterogeneity was found mainly in the depressive and tension headache subgroups. When the migraine population - from which the depressive patients were excluded - was divided into male and female subgroups, a decrease in plasma melatonin levels was observed only for the female subgroups. Results are discussed with reference to the role of the pineal gland in the synchronization of the organism with the environmental conditions.

Octopamine and some related noncatecholic amines in invertebrate nervous systems
Robertson H.A.; Juorio A.V.
Int. Rev. Neurobiol. (USA), 1976, Vol.19 (173-224)

In addition to the major monoamines (dopamine, noradrenaline, serotonin) there exists in the nervous tissue of all species examined a group of monoamines described as exotic amines, trace amines or microamines. Among the endogeneous microamines found in the mammalian brain are beta phenylethylamine, phenylethanolamine, m and p tyramine, octopamine and tryptamine. Despite their very low concentrations, microamines are interesting for several reasons: they are heterogeneously distributed within the brain; they are present in the same subcellular fraction as catecholamines and 5 HT; they have a high turnover rate; they release and/or replace catecholamines from storage sites and block reuptake; they may be excreted abnormally in the urine of patients with migraine, Parkinson's disease, schizophrenia and depression; some of them are behaviorally active. Analytical procedures for micramines are described and their biosynthesis and catabolism discussed. Out of them octopamine proved to be the most prospective candidate as a transmitter in the invertebrate nervous system as it fulfilled six of the seven criteria for identification of chemical transmitters (it has been shown to be present in neurons; presence of synthetic enzymes as well as precursors and intermediates has been demonstrated; it was released during nerve stimulation; exogeneous octopamine mimics the effect of the released transmitter; pharmacological agents interact with both the synaptically released transmitter and octopamine in an identical manner. The physiological means of inactivation and/or removal from the synapse, however, remain unknown). Among the other microamines, there is little evidence for a role in invertebrates.

The co-occurrence of multiple sclerosis and migraine headache: the serotoninergic link.
Sandyk R; Awerbuch GI
Int J Neurosci (England) Jun 1994, 76 (3-4) p249-57

The occurrence of migraine headaches in patients with multiple sclerosis (MS) has been recognized for quite some time but the significance of this association to the pathogenesis of MS largely has been ignored. Several reports have documented that migraine headaches may occur during exacerbation of symptoms and may even herald the onset of relapse in MS. We present three MS patients in whom migraine headaches developed during a period of relapse. As migraine has been linked to changes in serotonin (5-HT) functions, the emergence of migraine headaches coincident with the onset of relapse implicates dysregulation of the 5-HT system in the pathophysiology of MS. This hypothesis is plausible considering the evidence that MS patients are serotonergically depleted and that 5-HT is involved in maintaining the integrity of the blood brain barrier, disruption of which is believed to occur in the initial stages of exacerbation of MS symptoms. Furthermore, this hypothesis may have potential therapeutic implications in the treatment of exacerbations of MS and possibly in the prevention of relapse in the disease.

Urinary melatonin excretion throughout the ovarian cycle in menstrually related migraine
Murialdo G; Fonzi S; Costelli P; Solinas GP; Parodi C; Marabini S; Fanciullacci M; Polleri A
Cephalalgia (Norway) Jun 1994, 14 (3) p205-9

Nocturnal urinary melatonin excretion was significantly decreased throughout an ovarian cycle in 12 migraine without aura patients compared to 8 healthy controls. Normal increases in urinary melatonin excretion during the luteal phase was less pronounced in the migraine patients. Melatonin excretion was further decreased during headache. The data indicate impaired pineal function in migraine.

The influence of the pineal gland on migraine and cluster headaches and effects of treatment with picoTesla magnetic fields.
Sandyk R
Int J Neurosci (England) Nov-Dec 1992, 67 (1-4) p145-71

For over half a century the generally accepted views on the pathogenesis of migraine were based on the theories of Harold Wolff implicating changes in cerebral vascular tone in the development of migraine. Recent studies, which are based on Leao's concept of spreading depression, favor primary neuronal injury with secondary involvement of the cerebral circulation. In contrast to migraine, the pathogenesis of cluster headache (CH) remains entirely elusive. Both migraine and CH are cyclical disorders which are characterised by spontaneous exacerbations and remissions, seasonal variability of symptoms, and a relationship to a variety of environmental trigger factors. CH in particular has a strong circadian and seasonal regularity. It is now well established that the pineal gland is an adaptive organ which maintains and regulates cerebral homeostasis by "fine tuning" biological rhythms through the mediation of melatonin. Since migraine and CH reflect abnormal adaptive responses to environmental influences resulting in heightened neurovascular reactivity, I propose that the pineal gland is a critical mediator in their pathogenesis. This novel hypothesis provides a framework for future research and development of new therapeutic modalities for these chronic headache syndromes. The successful treatment of a patient with an acute migraine attack with external magnetic fields, which acutely inhibit melatonin secretion in animals and humans, attests to the importance of the pineal gland in the pathogenesis of migraine headache. (242 Refs.)

Is migraine due to a deficiency of pineal melatonin?
Toglia JU
Ital J Neurol Sci (Italy) Jun 1986, 7 (3) p319-23

Recent clinical observations favor the theory that migraine is caused by a primary injury of cerebral neurons with secondary involvement of intracranial and extracranial blood vessels. The primary injury is attributed to disruption of cerebral neurotransmitters and particularly the neuroadrenergic and serotonergic systems. These theories have not explained the importance of environmental factors, which so frequently trigger migraine. The author suggests that the pineal gland, which is outside the CNS unprotected by blood brain barrier and sensitive to external stimuli, could act as the intermediate causative factor of migraine, via a derangement of melatonin. (47 Refs.)

Melatonin in humans physiological and clinical studies.
Wetterberg L
J Neural Transm Suppl (Austria) 1978, (13) p289-310

Studies are reported of the variation of melatonin in serum, plasma urine and cerebrospinal fluid in normal subjects and in patients with various diseases. The diurnal variation of plasma and urine melatonin found in healthy controls on a regular dark-sleep pattern persisted when the subjects slept in light. The effect of sleep deprivation and of rapid light exposure at night is reported. There was a correlation between melatonin in morning urine and plasma at 2 a.m. Four hours of extended darkness in the morning as well as a 9-hour shift of sleep and activity cycles following travel affected the melatonin rhythm. The night increase in plasma melatonin preceeded both the cortisol and prolactin rise. A single oral dose of 4.3 X 10(5) nmol of melatonin given to a 44-year-old healthy male gave a peak plasma value of 624 nmol/l after 30 min. Plasma melatonin was not affected by electroconvulsive therapy, TRH-injection, L-Dopa or bromoergocryptine orally. Patients with alcoholism, migraine, postoperative pinealoma, panhypopituitarism, hereditary dystonia and schizophrenics on propranolol exhibited a decreased amplitude of their diurnal rhythm of melatonin. Two patients with pituitary tumors had occasional high levels of plasma melatonin. The change in melatonin secretion in human is apparently controlled by a mechanism which is at least party influenced by environmental lighting conditions, drugs and different disease states. (27 refs.)

FEVERFEW (Tanacetum pathenium):

Feverfew appears to work in the treatment and prevention of migraine headaches by inhibiting the release of blood vessel dilating substances from platelets (serotonin and histamine), inhibiting the production of inflammatory substances (leukotrienes, serine proteases, etc.), and re-establishing proper blood vessel tone. Commercial sources providing assurance of botanical identity and minimum required level of parthenolides are needed (Awang DVC. Feverfew. Car Pharm J 122:266-70, 1989).

In vitro Study: Feverfew was found to contain a factor that inhibits prostaglandin synthesis, but differs from salicylates by not inhibiting cyclo-oxygenase by prostaglandin (PG) synthase. "The ability of feverfew to inhibit PG production may account for its effectiveness as a herbal remedy in conditions responding to acetylsalicylate and like-acting drugs" (Collier HOJ, Butt NM, McDonald-Gibson WJ, Saeed SA. Extract of feverfew inhibits prostaglandin biosynthesis. Letter. lancet October 25, 1980).

The dosage of feverfew used in one double-blind study was one capsule containing 25 mg of the freeze-dried pulverized leaves twice daily; in another double-blind study it was one capsule containing 82 mg of dried powdered leaves once daily. While these low dosages may be effective in preventing an attack, a higher dose (I to 2 grams) may be necessary during an acute attack.

Note: The efficacy of feverfew is dependent upon adequate levels of parthenolide, the active ingredient. (The preparations used in successful clinical trials have a parthenolide content of 0.4-0.66%.)

Animal Ex vivo Study: Extracts of fresh feverfew caused a dose- and time dependent, irreversible inhibition of the contractile response of rabbit aortic rings to all receptor-acting agonists tested. The presence of potentially SH reacting parthenolide and other sesquiterpene alpha-methylenebutyrolactones in, these extracts, and the close parallelism of pure parthenolide, suggest that the inhibitory effects are due to these compounds. Extracts of the dry leaves were not inhibitory and actually caused potent and sustained contractions of aortic smooth muscle; these extracts were found to be devoid or parthenolide or butyrolactones (Barsby RWJ, Salan U, Knight BW, Hoult JRS. Feverfew and vascular smooth muscle: Extracts from fresh and dried plants show opposing pharmacological profiles, dependent upon sesquiterpene lactone content. Planta Medica 59:20-5, 1993).

Chemical Analysis: The parthenolide content of over 35 different commercial preparations of feverfew was determined by bioassay, 2 HPLC methods, and NMR. The results indicate a wide variation in the amts. of parthenolide in commercial preparations. The majority of products contained no parthenolide or only traces (Heptinstall S et al. Parthenolide content and bioactivity of feverfew (Tanacetum parthenium (L.) Schultz-Bip.). Estimation of commercial and authenticated feverfew products. J Pharm Pharmaco1 44:391-5, 1992).

WARNING: No long-term toxicity studies have been conducted. While feverfew is extremely well-tolerated and no serious side effects have ever been reported, chewing the leaves can result in small ulcerations in the mouth and swelling of the lips and tongue in about 10% of users (Awang DVC. Feverfew. Can Pharml 122:266-70, 1989).

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