Migraine Studies and References for Magnesium, Riboflavin and Feverfew.

CLINICAL APPLICATIONS OF NATURAL MEDICINE: MIGRAINE

Published by Natural Product Research Consultants

Donald Brown, N.D.
Alan Gaby, M.D.
Ronald Reichert, N.D.

CLINICAL APPLICATIONS OF NATURAL MEDICINE: MIGRAINE

Migraine has been a well known medical problem for over 5,000 years and represents one of the most investigated types of head pain. Research on large groups of people has shown that in the U.S. 18% of women and 6% of men suffer from migraine.1 This extrapolates to approximately 18 million females and 5.6 million males over the age of 12 with this disorder.2 The prevalence of migraine, according to the Center for Disease Control, has increased 60% from 1981 to 1989.3 4 The economic impact of migraine is staggering, with annual cost of the disease estimated at 18 billion dollars.5

CAUSES OF MIGRAINES
The basic cause of migraine is still unknown. Although genetics may play a role, with 50 to 70% of migraine sufferers reporting a familial occurrence, no consistent biochemical or physiological characteristic can be recognized in the relatives of those afflicted with the condition.6

PHYSICAL AND FUNCTIONAL CONCERNS
There are several theories as to what causes a migraine and what happens to us when they occur. One of these theories suggests that certain arteries in our brain contract and cause a reduction in blood flow to the visual area of our brain. It is suggested that this reduction of blood flow results in the visual and other symptoms that accompany a migraine.

This theory further suggests that the pain that often follows these symptoms was the result of dilation (expansion) of the carotid artery and pressure on the nerves in the artery wall. Yet another theory proposes that nerve cells in the brain begin to lose function which causes a reduction blood flow, which reduces levels of magnesium, which in turn adds to decreasing nerve cell function and that this dysfunction spreads in a wave like fashion to all effected areas.7 Many researchers feel that serotonin, an important brain chemical may fuel migraines.8 9 10 11 12 13 Platelets (components of our blood) contain all of the serotonin normally present in blood, and, after they aggregate, (clump together) serotonin is released, resulting in a potent constricting effect on the arteries.14 15 16 17

SIGNS AND SYMPTOMS
The two most important categories are migraine without aura (common migraine) and migraine with aura (classic migraine). A diagnosis of migraine without aura is made if the patient fulfills specific criteria. The patient must have a history of five previous similar episodes, with pain lasting between 4 and 72 hours. Additionally, they must meet two of the following four characteristic symptoms: (1) unilateral head pain; (2) pain must be throbbing or pulsing; (3) an experience of moderate to severe pain which inhibits or restricts the ability to function;(4) pain is made worse by routine physical activity. Furthermore, they must have one of the following two symptoms present: (1) nausea and/or vomiting; (2) adverse reactions to light or sound.18 In contrast, migraine with aura employs the same diagnostic criteria as common migraine with the following exceptions. Patients only need a history of two prior migraine attacks and must fulfill three of the following four criteria: (1) one or more aura symptoms; (2) aura symptoms that develop over more than 4 minutes; (3) aura lasts less than 60 seconds; (4) headache follows within 60 minutes of the aura ending. Auras represent several forms of visual disturbances that are described as dark or black point(s) that may or may not expand and obscure the patient’s vision. The black spot may be surrounded by lights with zigzag lines. Patients with classic migraine symptoms may exhibit stroke-like symptoms including symptoms affecting one hand, arm, or side of the face.19 It is interesting to note that migraine sufferers are more likely to experience specific headache variants including intense throbbing head pain, brought on by exertion (exert ional headache); ice-pick-like pains or electrical jabs, called stabbing headaches; and unilateral, intense eye pain.20 21

TREATMENT
For the migraine sufferer, there is a wide variety of therapeutic approaches both pharmacologic and non-pharmacologic. However, for practical reasons the management of migraine can be divided into two categories; abortive and preventative. As abortive treatment of migraine simply address the symptoms, via the use of drugs. Initial therapy for mild migraine headache is usually aspirin or other non-steroidal anti-inflammatory agents (e.g. ibuprofen and naproxen sodium). These pain relievers, along with sleep in a quiet, dark room, an ice pack on the head and an anti nausea drug.22 23

Certain drugs that constrict arteries are used with varying degrees of success and side effects. Your pharmacist can discuss them with you. Some of these drugs, though effective frequently result in rebound headache and other side effects.24 25
Another drug, sumatriptan (Imitrex (r)),has been shown to reduce the intensity of moderate to severe migraine headaches.27 Side effects from this type of drug include, tingling, heaviness, and a sensation of pressure. In contrast to abortive therapy, preventative drug strategies can be employed if the frequency of migraine attacks is sufficiently high. Propranolol is widely prescribed in the United States as a treatment for migraine prevention. Although it has proven to be effective in migraine prevention, its side effects include fatigue, depression, impotence, insomnia, dizziness, and cold extremities.28 Like drug intervention, non-pharmaceutical preventive therapies may also be effective. These include behavioral modification techniques such as stress management, biofeedback, exercise, acupuncture, trigger point injections and numerous physical therapy techniques (e.g. massage, manipulation and transcutaneous nerve stimulation).29

PHYTOMEDICINE CONSIDERATIONS

FEVERFEW

Feverfew (Tanacetum parthenium) is a member of the daisy family (Asteraceae) and is a short, bushy perennial that grows along fields and roadsides. Its yellow-green leaves and yellow flowers resemble those of chamomile, for which it is sometimes confused.

The flowers bloom from July to October. The leaves are used in medicinal preparations.30 The name “feverfew” is derived from the Latin for “chase away fevers.” It is mentioned in the Greek literature as a remedy for inflammation and swelling as well as menstrual cramps. Feverfew enjoyed wide use by British herbalists as an analgesic in the treatment of fevers and arthritis, but faded into obscurity.

Feverfew has enjoyed a revival over the past two decades due to approval of its use for treatment of migraine by both the Canadian and British governments.

ACTIVE CONSTITUENTS: The most important of these compounds is parthenolide . First identified in 1960, parthenolide is the portion of the leaf believed to be responsible for feverfew’s anti-migraine activity.31 A critical consideration in commercial feverfew products has been the highly variable content of parthenolide. An analysis of commercial feverfew products in Canada found about half are virtually devoid of this compound.32 As a minimal standard, the Health Protection Branch of the Health and Welfare Department of the Canadian Government has proposed that feverfew preparations should contain at least 0.2% parthenolide content.
Health care practitioners should also be aware that parthenolide is highly unstable and seek feverfew extracts that address this issue. Your pharmacist has identified one of the few sources of feverfew where the parthenolide content is assured.

MECHANISM OF ACTION: Feverfew, and specifically parthenolide, inhibits platelet aggregation (which if you remember can release serotonin which may fuel migraines) and histamine release. It has also been shown to inhibit release of serotonin from platelets 33,34 This is believed to reduce the severity, duration and frequency of migraine headaches and lead to an improvement in blood vessel tone.35,36 37

CLINICAL APPLICATIONS: Clinical studies with feverfew have focused on the treatment and prevention of migraine and have primarily taken place in Great Britain. These studies indicate the efficacy of feverfew as a useful tool in the long-term management of migraines.

The initial clinical study enrolled migraine patients who had been using feverfew for several years.38 Seventeen patients were enrolled and given either feverfew (50 mg daily) or placebo. Eight patients, who remained on feverfew, experienced continued relief of migraines over a six month period. The nine receiving placebo had an almost three-fold increase in migraines. Many of these headaches were incapacitating, and anxiety, insomnia and muscle and joint soreness were also reported. This has prompted some concern at the abrupt cessation of feverfew therapy. A second study enrolled 72 migraine sufferers.39 They received either 82 mg of feverfew daily or placebo.

Treatment with feverfew for four months led to a decreased incidence and severity of migraines. Feverfew also led to less vomiting attacks and fewer visual disturbances during migraine attacks. Adverse events were mild (primarily mild gastrointestinal upset and nervousness) and did not result in discontinuation of treatment.

RECOMMENDED DOSAGE: Appropriate dosing of feverfew leaf for migraine prevention is based on parthenolide content. The Canadian Health Protection Branch has granted a Drug Identification Number (DIN) for feverfew.40 They recommend a daily dosage of 125 mg of a dried feverfew leaf preparation from authentic Tanacetum parthenium containing a minimum of 0.2% parthenolide for migraine prevention. This translates to a daily parthenolide dosage of at least 250 mcg. This should be considered a minimum amount for efficacy. Results from studies that are not yet published indicate that 100 mg. per day of feverfew extract at .7% parthenolide content may be desirable. (Remember that over 50% of most feverfew extracts have little or no parthenolide content regardless of their label claims. Your pharmacist can help to avoid this problem. Continuous use for at least four to six weeks is recommended.

SIDE EFFECTS/CONTRAINDICATIONS: In addition to the adverse events listed in the clinical studies above, the most common side effect reported with feverfew has been mouth ulceration.41 This has predominantly been found in individuals chewing the leaves not with higher quality standardized extracts. Scattered reports of dermatitis have been reported with use of feverfew. To date, no long-term toxicity studies have been performed. Feverfew is contraindicated for pregnant or lactating women and should not be used in children under the age of two years.

MAGNESIUM

It has pointed out that various factors which are known to trigger migraines (namely stress, pregnancy, menstruation, alcohol ingestion, and some diuretics) also promote magnesium depletion.50 In addition, magnesium exerts many of the same effects as drugs that are helpful in the prevention or treatment of migraines.51 These effects include: (1) inhibition of spasm; (2) inhibition of platelet aggregation; (3) stabilization of cell membranes; (4) interference with the synthesis, release or action of inflammatory compounds; and (5) improvements in cerebral vascular tone. In addition, brain magnesium concentrations were significantly lower by 19% in patients during a migraine attack than in healthy controls. These observations suggest that magnesium may play a role in the prevention and/or treatment of migraine. Clinical trials have supported that possibility. In an open trial, more than 3,000 patients with common or classical migraine received magnesium (usually at a dose of 200 mg/day).52 Almost all of the patients were women and most were of childbearing age. The “success rate” was reported to be 80%, but the criteria for determining success were not specified.

CONDITION-SPECIFIC MONOGRAPH SERIES

MIGRAINE
That uncontrolled study was followed by a double-blind trial in which 20 patients with perimenstrual migraine received 360 mg/day of magnesium or a placebo.53 The treatments were given for two months, starting on the 15th day of each menstrual cycle and continuing until menstruation. At the end of the treatment period, the “Pain Total Index” (which measures duration and intensity of migraines) was significantly lower in the magnesium group than in the placebo group. The number of days with headaches was significantly reduced in patients receiving magnesium, but not in those given placebo. Prior to the start of treatment, white-blood-cell (WBC) magnesium concentrations were lower in the migraine patients than in healthy controls.

Magnesium treatment was followed by a significant increase in WBC magnesium levels. These data suggest that magnesium deficiency contributes to the dysfunction of perimenstrual migraine. In another double-blind study, 81 patients aged 18 to 65 years with migraines (mean attack frequency, 3.6 per month) were randomly assigned to receive magnesium (600 mg every morning) or a placebo for 12 weeks. 54 The frequency of attacks was significantly reduced in the magnesium group, compared with the placebo group (by 41.6%vs. 15.8%; p < 0.05). The duration and intensity of attacks also tended to decrease compared to placebo, but the difference was not statistically significant. Diarrhea occurred in 18.6% and gastric irritation in 4.7% of patients receiving magnesium. One study failed to find a beneficial effect of magnesium for migraine prevention. 55 In that study, 69 patients with migraines were randomly assigned to receive magnesium (242 mg twice daily) or a placebo, in double-blind fashion, for 12 weeks. Response to therapy was assessed according to the criterion of the International Headache Society; i.e. a reduction of at least 50% in the duration or intensity of migraines. Using that criterion, approximately 30% of patients in each group were considered responders, with no significant difference between groups. However, this negative finding should be interpreted cautiously. Only a few studies have measured improvement according to the protocol of the International Headache Society and most of those studies showed no significant benefit from the treatment being tested. Even beta-blockers (a class of drugs known to prevent migraine recurrences) were ineffective when tested by the International Headache Society criteria.

It is noteworthy that 33% of patients receiving magnesium (but only 11% of patients given placebo) felt that their treatment was superior to previously used migraine medications. Thus, the results of this study are not inconsistent with previous reports of a beneficial effect of magnesium.

Magnesium has also been given intravenously to treat acute episodes of migraine.56 Forty patients with an acute migraine attack were given 1 g of magnesium sulfate (in a 10% solution) over five minutes. Fifteen minutes after the infusion, 35 patients (87.5%) experienced at least a 50% reduction in pain. Nine patients (22.5%) had complete relief of pain. In 21 of the 35 patients who improved, relief persisted for 24 hours or more. The effectiveness of magnesium was related to the pre-treatment serum concentration of magnesium. This study suggests that intravenous administration of magnesium is an effective treatment for acute migraine attacks, particularly in patients whose serum magnesium concentrations are low. These studies provide a rationale for oral magnesium supplementation for migraine prophylaxis.

A reasonable dosage is 200 to 600 mg/day (the larger amounts should be taken in divided doses with meals to reduce the risk of diarrhea). Intravenous administration of magnesium may also be considered as a method of aborting acute migraine attacks. While measurement of serum ionized magnesium might be useful to predict which patients are most likely to respond to intravenous magnesium, this test is not yet commercially available.

A therapeutic trial with intravenous magnesium is usually acceptable, provided that the physician is trained in proper administration of this compound. Dr. Alexander Mauskop of the New York Headache clinic has lead the research in the use of magnesium and has been issued a patent on the subject. Dr. Mauskop is considered internationally to be one of the leading experts on all types of headaches including migraines. His book “The Headaches Alternative” is available from Dell Publishing, N.Y, N.Y.

RIBOFLAVIN

49 patients with recurrent migraines were given riboflavin, 400 mg/day with breakfast, for at least three months.57 The mean number of migraine attacks fell by 67% and mean migraine severity improved by 68%. One patient stopped treatment because of gastric intolerance (that person was also taking small amounts of aspirin), but no other side effects were reported. This study suggests that riboflavin supplementation may reduce the recurrence rate of migraines.

OTHER INGREDIENT CONSIDERATIONS

GINGER
Ginger (Zingiber officinale) contains constituents that inhibit platelet aggregation.42,43 44,45 While all of these actions point to the potential use of ginger with migraine, controlled clinical trials are lacking. One case study published in the Journal of Ethno pharmacology reported on a 42 year old female migraine sufferer who found relief taking 500 to 600 mg of ginger powder mixed with water every four hours for four days.46 The patient was instructed to begin ginger at the onset of visual aura. The authors report improvement within 30 minutes of beginning ginger. They also note that continued use of ginger by the woman led to decreased frequency and intensity of migraines.

GINKGO BILOBA EXTRACT
GBE has been shown to offer some promise for the management of migraines in two small French clinical trials.47 48 49 The daily dose ranged from 120 to 240 mg. Clearly, more research is needed on the potential use of GBE for migraine.

L-TRYPTOPHAN
It has been suggested that migraines are related to a deficiency of serotonin in the brain.58 As the precursor to serotonin, L-tryptophan might therefore play a role in migraine prevention.

To test that hypothesis, eight migraine patients who had been resistant to therapy received 500 mg of L-tryptophan every six hours or a placebo (L-leucine), each for three months, in a double-blind, crossover trial.59 The mean headache index(number of attacks multiplied by the intensity) was 32.8% lower with L-tryptophan than with placebo. Although that difference was not statistically significant, headache indices were markedly lower in four of the eight patients during L-tryptophan treatment, compared to placebo treatment. These results are consistent with the possibility that L-tryptophan is of value for a subset of migraine patients. In a double-blind study, migraine patients received 3 g/day of L-tryptophan or a placebo for one month.

60 Patients receiving L-tryptophan had significantly fewer migraines of significantly shorter duration than did patients receiving placebo. These observations suggest that L-tryptophan may have preventive value for a portion of migraine patients. L-tryptophan has not been reported to cause any severe side effects. However, in 1989 a contaminated batch of L-tryptophan was implicated as the cause of a severe and sometimes fatal disorder known as eosinophilia myalgia syndrome. Uncontaminated L-tryptophan, on the other hand, has not been associated with this disorder. Currently, uncontaminated L-tryptophan is available by prescription from compounding pharmacists.

FISH OIL
Interest in the relationship between fish oil and migraines was triggered by the observation that migraine patients had significantly lower concentrations of omega-3 fatty acids in platelet and red blood cell membranes, compared with healthy individuals.61 Omega-3 fatty acids (which are found primarily in fish oils, flaxseed oil and some other vegetable and nut oils) are known to inhibit platelet aggregation. This effect would presumably decrease platelet serotonin release, with an accompanying reduction in cerebral artery spasm and migraine attacks.
Fifteen patients with migraines that had failed to respond to anti-migraine drugs received (in random order) a fish-oil concentrate (vegetable oil) for six weeks, in a double-blind, crossover trial.62 Compared with placebo, treatment with the oils resulted in a significant reduction in mean headache intensity. Fish-oil concentrates can cause gastrointestinal side effects, but are otherwise usually well tolerated. Other sources of omega-3 fatty acids (such as flaxseed oil) might conceivably have a beneficial effect, as well.

[‘]
It is generally accepted that a small proportion of migraine patients will react to tyramine, a chemical found in aged cheese, yogurt, beer, wine, liver, yeast and certain other foods. In these patients, avoidance of tyramine-containing foods will often prevent recurrences of migraine. Abnormal glucose metabolism has been identified in some patients with migraines. In one study, a five-hour glucose tolerance test was performed on 74 patients who experienced migraines in the mid-morning or mid-afternoon.63 Six patients (8%) were classified as diabetic and 56 (76%) had a pattern consistent with reactive hypoglycemia (a large drop in blood sugar after a meal). Following dietary therapy with a low-sucrose, six-meal regimen, all patients with a diabetic glucose curve and 56% of those with reactive hypoglycemia (low blood sugar) had an improvement of greater than 75% in the frequency and severity of migraines.

Food allergy has also been implicated as an important factor in migraine. In one study, 60 patients who had been suffering from frequent migraines for a mean duration of about 20 years followed an exclusion diet for five days.64 During that time, only two low-risk foods (usually lamb and pears) and spring water were consumed. Migraines disappeared in most cases by the fifth day. Each patient then tested one to three common foods per day, looking for reactions. The mean number of foods causing symptoms was 10 per patient (range, 1 to 30). The foods most frequently causing symptoms and/or pulse changes were wheat (78%), orange (65%), egg (45%), tea and coffee (40% each), chocolate and milk (37% each), beef (35%), corn, cane sugar and yeast (33% each), mushrooms (30%), and peas (28%). When the offending foods were avoided, all patients improved. The number of headaches in the group fell from 402 to 6 per month, with 85% of the patients becoming headache free. This study provides strong evidence that identification and avoidance of allergy causing foods is an effective procedure for a large proportion of patients with chronic recurrent migraines. Patients with recurrent migraines should be evaluated for possible blood-sugar abnormalities and food allergies. When either of these abnormalities is found, appropriate dietary modifications should be made. In addition, a trial of a low-tyramine diet should be considered.

Series Editor
Donald Brown, N.D.
Dr. Brown is the founder and director of Natural Product Research Consultants and the editor of the Quarterly Review of Natural Medicine. He is a faculty member of Bastyr University in Seattle, Washington, where he teaches herbal medicine and therapeutic nutrition. Dr. Brown’s book, Herbal Prescriptions for Better Health, was published in February 1996 by Prima Publishing.

CONTRIBUTORS

Alan Gaby, M.D.
Dr. Gaby is past-president of the American Holistic Medical Association and medical editor of The Townsend Letter for Doctors. He served on the Ad Hoc Advisory Panel of the National Institutes of Health Office of Alternative Medicine. He is the author of Preventing and Reversing Osteoporosis and B6: The Natural Healer.

Ronald Reichert, N.D.
An expert in European phytotherapy, Dr. Reichert resides in Vancouver, B.C., where he has an active medical practice. Dr. Reichert contributes regular articles to lay and professional publications in Canada. In addition to his regular herbal research columns, Dr. Reichert provides professional review of German translations for the Quarterly Review of Natural Medicine.

ABOUT THIS PUBLICATION
The information presented in this Condition-Specific Monograph is intended for professional education and is obtained from published research, articles and books. This update is not intended to replace the care of a licensed health professional in the diagnosis and treatment of illness.

References:

1. Rapoport AM, Scheftell ED. Headache Disorders: A Management Guide for Practitioners. Philadelphia: WB Saunders Co., 1996, 1.
2. Noack H, Rothrock JF. Migraine: definitions, mechanisms, and treatment. South Med J 1996; 89: 762.
3. Rapoport AM, Scheftell ED. Headache Disorders: A Management Guide for Practitioners. Philadelphia: WB Saunders Co.,1996, 4.
4. Theisler CW. Migraine Headache Disease. Gaithersburg, MD: Aspen Publishers Inc., 1990, 2.
5. Noack H, Rothrock JF. Migraine: definitions, mechanisms, and treatment. South Med J 1996; 89: 762.
6. Ziegler DK, Friedman AP. Migraine. In: Rowland LP, ed. Meritt’s Textbook of Neurology, 8th ed. Philadelphia: Lea and Febiger, 1989, 773.
7. Rapoport AM, Scheftell ED. Headache Disorders: A Management Guide for Practitioners. Philadelphia: WB Saunders Co., 1996, 1, 37.
8. Campbell JK, Caselli RJ. Headache and other craniofacial pain. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD, eds. Neurology in Clinical Practice, Vol II. Boston: Butterworth-Heinemann, 1991: 1525_6.
9. Theisler CW. Migraine Headache Disease. Gaithersburg, MD: Aspen Publishers Inc., 1990, 42.
10. Campbell JK, Caselli RJ. Headache and Other Craniofacial Pain. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD,eds. Neurology in Clinical Practice, Vol II. Boston: Butterworth-Heinemann, 1991: 1526.
11. Noack H, Rothrock JF. Migraine: definitions, mechanisms,and treatment. South Med J 1996; 89: 764.
12. Rapoport AM, Scheftell ED. Headache Disorders: A Management Guide for Practitioners. Philadelphia: WB Saunders Co., 1996, 44.
13. Noack H, Rothrock JF. Migraine: definitions, mechanisms, and treatment. South Med J 1996; 89: 764.
14. Theisler CW. Migraine Headache Disease. Gaithersburg, MD: Aspen Publishers, 1990, 30_32.
15. Campbell JK, Caselli RJ. Headache and Other Craniofacial Pain. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD, eds. Neurology in Clinical Practice, Vol II. Boston: Butterworth-Heinemann, 1991: 1526.
16. Noack H, Rothrock JF. Migraine: definitions, mechanisms, and treatment. South Med J 1996; 89: 765.
17. Rapoport AM, Scheftell ED. Headache Disorders: A Management Guide for Practitioners. Philadelphia: WB Saunders Co., 1996, 39_40.
18. Rapoport AM, Scheftell ED. Headache Disorders: A Management Guide for Practitioners. Philadelphia: WB Saunders Co.,1996, 7_10.
19. Ziegler DK. Headache syndromes. In: Rosenberg RN, ed. Comprehensive Neurology. New York: Raven Press Ltd., 1991, 290.
20. Rapoport AM, Scheftell ED. Headache Disorders: A Management Guide for Practitioners. Philadelphia: WB Saunders Co., 1996, 12_13.
21. Ziegler DK, Friedman AP. Migraine. In: Rowland LP, ed. Meritt’s Textbook of Neurology, 8th ed. Philadelphia: Lea and Febiger, 1989, 776_7.
22. Campbell JK, Caselli RJ. Headache and Other Craniofacial Pain. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD, eds. Neurology in Clinical Practice, Vol II. Boston: Butterworth-Heinemann, 1991: 1528.
23. Spierings ELM. Migraine: diagnosis, pathogenesis, and treatment. In: Rapoport AM, Scheftell ED, eds. Headache: A Clinician’s Guide to Diagnosis, Pathophysiology and Treatment Strategies. Costa Mesa, CA: PMA Publishers, 1993, 92.
24. Campbell JK, Caselli RJ. Headache and other craniofacial pain. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD, eds. Neurology in Clinical Practice, Vol II. Boston: Butterworth-Heinemann, 1991: 1528.
25. Rapoport AM, Scheftell ED. Headache Disorders: A Management Guide for Practitioners. Philadelphia: WB Saunders Co., 1996, 84.
26. Noack H, Rothrock JF. Migraine: definitions, mechanisms, and treatment. South Med J 1996; 89: 767.
27. Spierings ELM. Migraine: diagnosis, pathogenesis, and treatment. In: Rapoport AM, Scheftell ED, eds. Headache: A Clinician’s Guide to Diagnosis, Pathophysiology and Treatment Strategies. Costa Mesa, CA: PMA Publishers, 1993, 93_4.
28. Rapoport AM, Scheftell ED. Headache Disorders: A Management Guide for Practitioners. Philadelphia: WB Saunders Co., 1996, 91_2.
29. Rapoport AM, Scheftell ED. Headache Disorders: A Management Guide for Practitioners. Philadelphia: WB Saunders Co., 1996, 105_6.
30. Feverfew. Lawrence Review of Natural Products, September, 1994.
31. Awang DVC. Herbal medicine, feverfew. Canadian Pharm J 1989; 122: 266_70.
32. Heptinstall S, Awang DVC, Dawson BA, et al. Parthenolide content and bio-activity of feverfew (Tanacetum parthenium). Estimation of commercial and authenticated feverfew products. J Pharm Pharmacol 1992; 44: 391_5.
33. Heptinstall S, White A, Williamson L, Mitchell JRA. Extracts of feverfew inhibit granule secretion in blood platelets and polymophonuclear leukocytes. Lancet 1985; I:1071_4.
34. Makheja AN, Bailey JM. A platelet phospholipase inhibitor from the medicinal herb feverfew (Tanacetum parthenium). Prostagland Leukortrienes Med 1982; 8:653_60.
35. Pugh WJ, Sambo K. Prostaglandin synthetase inhibitors in feverfew. J Pharm Pharmacol 1988; 40:743_5.
36. Sumner H, Salan U, Knight DW, Hoult JRS. Inhibition of 5-lipoxygenase and cyclo-oxygenase in leukocytes by feverfew.Biochem Pharmacol 1992; 43:2313_20.
37. Pattrick M, Heptinstall S, Doherty M. Feverfew in rheumatoid arthritis: a double-blind, placebo-controlled study. Ann Rheumatic Dis 1989; 48:547_9.
38. Johnson ES, Kadam NP, Hylands DM, Hylands PJ. Efficacy of feverfew as prophylactic treatment of migraine. BritishMed J 1985; 291:569_73.
39. Murphy JJ, Heptinstall S, Mitchell JRA. Randomized double-blind placebo-controlled trial of feverfew in migraine prevention. Lancet 1988; ii:189_92.
40. Awang DVC. Feverfew fever. HerbalGram 1993; 29:34.
41. Bradley PR, ed. British Herbal Compendium, Volume 1. Bournemouth, Dorset: British Herbal Medicine Association, 1992, 96_8.
42. Kiuchi F, Ikwakami S, Shibuya M, et al. Inhibition of prostaglandin and leukotriene bio-synthesis by gingerols and diarylheptanoids. Chem Pharm Bull 1992; 40:387_91.
43. Verma SK, Singh J, Khamersa R, Bordia A. Effect of ginger on platelet aggregation in man. Indian J Med Res 1994; 98:240_2.
44. Kawai T, Kinoshita K, Koyama K, Takahashi K. Anti-emetic principles of Magnolia obovata bark and Zingiber officinale rhizome. Planta Med 1994; 60:17_20.
45. Onogi T, Minami M, et al. Capsaicin-like effect of (6)_shogaol on substance P containing primary afferentsin rats: A possible mechanism of its analgesic action. Neuropharmacol1992; 31:1165_9.
46. Mustafa T, Srivastava KC. Ginger (Zingiber officinale) in migraine headache. J Ethnopharmacol 1990; 29:267_73.
47. Kovacs K, Herman F, Filep J, et al: Platelet aggregation of migraineurs during and between attacks. Cephalagia 1990;10:161_5.
48. Lamant V, Mauco G, et al. Inhibition of the metabolism of platelet activating factor (PAF-acether) by three specific antagonists from Ginkgo biloba. Biochem Pharmacol 1987; 36:2749_52.
49. DeFeudis FV. Ginkgo biloba Extract (EGb 761): Pharmacological activities and Clinical Applications. Paris: Elsevier, 1991, 142.
50. Altura BM. Calcium antagonist properties of magnesium: implications for anti-migraine actions. Magnesium 1985; 4:169_75.
51. Ramadan NM, Halvorson H, Vande-Linde A, et al. Low brain magnesium in migraine. Headache 1989; 29:590_3.
52. Weaver K. Magnesium and migraine. Headache 1990; 30:168.
53. Faccinetti F, Sances G, Borella P, et al. Magnesium prophylaxis of menstrual migraine: effects on intra-cellular magnesium. Headache 1991; 31:298_304.
54. Peikert A, Wilimzig C, Kohne-Volland R. Prophylaxis of migraine with oral magnesium: results from a prospective, multi center, placebo-controlled and double-blind randomized study. Cephalalgia 1996; 16:257_263.
55. Pfaffenrath V, Wessely P, Meyer C, et al. Magnesium in the prophylaxis of migraine a double-blind, placebo-controlled study. Cephalalgia 1996; 16:436_440.
56. Mauskop A, Altura BT, Cracco RQ, et al. Intravenous magnesium sulphate relieves migraine attacks in patients with low serum ionized magnesium levels: a pilot study. Clin Sci 1995; 89:633_6.
57. Schoenen J, Lenaerts M, Bastings E. High-dose riboflavin as a prophylactic treatment of migraine: results of an open pilot study. Cephalalgia 1994; 14:328_9.
58. Salmon S, Fanciullacci M, Bonciani M, et al. Plasma tryptophan in migraine. Headache 1978; 17:238_241.
59. Kangasniemi P, Falck B, Langvik V-A, et al. Levotryptophantreatment in migraine. Headache 1978; 18:161_6.
60. Steardo L, Sorge F, Florio C. Trattamento con L-triptofanonelle cefalee essenziali: dati preliminari. Acta Neurologica1977; 32:613.
61. Carswell H. On a scale of 1 to 10 vs. a variety of ills,fish oil maybe a 5. Med Tribune, July 16, 1986, 3. 62 McCarren T, Hitzemann R, Smith R, et al. Amelioration of severe migraine by fish oil (omega-3) fatty acids. Am JClin Nutr 1985; 41:874.
62. Dexter JD,Roberts J, Byer JA. The five hour glucose tolerance test and effect of low sucrose diet in migraine. Headache1978; 18:91_4.
63. Grant ECG. Food allergies and migraine. Lancet 1979;i:966_9.