Palmquist 1 Leah Palmquist Migraine Review Paper Dr. Strand 27 April 2009 Migraine is an episodic headache disorder which affects otherwise healthy individuals. This prevalent disorder has been deemed by the World Health Organization as 19th among all causes of years lived with disability, 12th in women. Thus, a great deal of research has been conducted on migraine triggers and forms of treatment for migraines. Migraine headaches can be divided into two categories based on the aura associated with one type. Migraines without aura are the most common, and include episodic disabling attacks of headache associated with nausea and photophobia. These symptoms can last anywhere between a couple of hours to about three days. The other category of migraine, migraine with aura, can be recognized by different symptoms over a shorter time range. Specific neurological symptoms gradually develop over 5- 20 minutes, last under an hour and almost always discontinue with the onset of the headache itself. Homonymous visual symptoms are the most common symptom of migraine with aura and are experienced in 99% of migraine cases (MacGregor, 2009). The symptoms of migraine without aura can be very severe and can also include nausea, numbness and tingling sensation in various parts of the body (especially the face). Migraine is often debilitating, uncomfortable and therefore life altering. Since this is such a widespread, devitalizing condition, the National Headache Foundation (NHF) published a list of some of the most common migraine triggers. They suggest foods high in tyramine, an organic compound occurring naturally in plants and animals, may trigger migraines. Unfortunately, tyramine is widespread in foods such as ripened cheeses, sourdough bread, lima beans, processed meats such Palmquist 2 as salami and pepperoni, etc. Alcohol is another migraine trigger. For some, the vasodilating effects and consequently a drop in blood pressure cause the headache. A combination of the dehydrating effect of alcohol and the resulting imbalance of electrolytes can also contribute to migraine onset. The NHF has mixed reviews about caffeine’s effect on migraines. Avid caffeine users can trigger a migraine by not consuming caffeine. On the other hand, the vasoconstricting affect of caffeine can actually help relieve headache pain. The American Headache Society (AHS) suggests an entirely new set of migraine triggers. In a recent survey of 200 patients with successive migraines, more than 90% identified one or more migraine triggers. Among these triggers were physical and emotional stress (77%), menses (72% of actively cycling females), exposure to bright or flickering light (65%), and various odors (61%). The AHS also suggests a change in one’s usual sleep pattern or weather changes may also cause migraine onset. One trigger may cause a migraine for one victim, while having no effect on the next. Likewise, migraine onset may not always occur in conjunction with the trigger, or one or more triggers may be needed to induce a migraine. Migraine triggers are various, circumstantial and also vary from individual to individual. It seems as though migraine symptoms are difficult to control since triggers are so various. However, one major migraine trigger is incredibly predictable—menses. “Around 50% of women report an association between migraine and menstruation during the reproductive years” (MacGregor, 2009). This is not surprising, since four out of every ten women, and only two out of every ten men experience migraines. Ovarian hormones elicit varying effects on neurons which may explain association with migraine. “Estrogen withdrawl, prostaglandin release, and magnesium deficiency during the late luteal and early follicular phases of the menstrual cycle all may contribute to the risk of migraine” (Newman, 2007). Palmquist 3 To further understand the role of menses in migraine onset, a study was conducted to compare the characteristics between menstrually related and nonmenstrually related migraines. The researchers describe women with menstrually related migraines (MRMs) as occurring in at least two out of three menstrual cycles. An MRM is defined as occurring in the 5-day period from 2 days before to 2 days after the first day of menstrual flow. A nonMRM is defined as occurring from the eighth day of the menstrual cycle to 3 days before the onset of menstrual bleeding with the next cycle. Out of 64 women who referred to a specialty headache center, those with MRMs experienced significantly greater pain intensity than those with nonMRMs. Another survey of 21 women who kept daily headache diaries reported greater pain intensity in the menstruation interval from the first to sixth day of menstruation. This demonstrates that women are more likely to have severe MRMs on the first day of menstruation and during the following two days. (Diamond et al, 2008). This sudden increase in pain intensity suggests a correlation with the sudden change in estrogen levels that occurs with the first days of menstruation. To test this correlation, another study was performed primarily to determine if the symptoms of migraine differ between different intervals of the menstrual cycle. Their second objective was to determine if differing hormone levels correlated with the severity of migraine symptoms during these stages of the menstrual cycle. They hoped to distinguish “hormonally defined” intervals throughout the menstrual cycle. By dividing the menstrual cycle into intervals, they were able to compare hormone levels in each interval. The two ovarian hormones of interest were estrogen and progesterone. They hypothesized that “the frequency, severity, and disability of headache would differ in female migraineurs between hormonally defined intervals of the menstrual cycle and that headache outcome measures would be greatest during perimenstrual time intervals” (Martin et al, 2005). Palmquist 4 To test this hypothesis, 21 women age 21 to 45 years of age were asked to document their migraine headaches in a diary during three menstrual cycles. Ovarian hormone levels were obtained through measuring estrogen and progesterone metabolites in the urine. Thus, daily urine samples were collected and assessed during the three menstrual cycles. The research group was, in fact, able to define menstrual intervals based on differing levels of progesterone and estrogen and was therefore able to compare this to the diaries of the participants. They were able to conclude that both headache symptoms and levels of ovarian hormones varied among the different menstrual intervals. They could not confidently conclude, however, that the differing ovarian hormone levels directly caused the varying migraine symptoms. They explain their study “suggested that progesterone metabolites play a role in the modulation of migraine headache during luteal intervals of the menstrual cycle” (Martin et al, 2005). Since more direct correlations and mechanisms are yet to be discovered, they admit “future studies are needed to define the precise mechanisms through which ovarian hormones modulate and trigger migraine headaches” (Martin et al, 2005). Another conclusion was made in this experiment. The two abovementioned studies were not related or conducted in conjunction. Though different groups of females were asked to document their menstrual cycles, their results are similar. In this study they found “the first six days of the menstrual cycle represented a time period during which headaches were more frequent, disabling, and severe in the patient population” (Martin et al, 2005). It is important to note that both groups of women reported a greater intensity of migraine symptoms during the beginning of the menstrual cycle. It seems abnormal that the human body has an adverse reaction to such a normal physiological process. Severe and debilitating symptoms are arising in otherwise perfectly Palmquist 5 healthy women simply due to their menstruation cycle. A group of researchers at the Roby Institute in Austin, Texas hypothesized there is a “connection between symptoms associated with hormone changes to a hormone antibody response” (Roby et al, 2006). This hormone antibody response was thought to induce allergy, thus resulting in adverse symptoms. Since menstruation is an obvious time of hormone fluctuation, 270 patients who experience changes in symptoms during menstruation were examined. The symptoms of interest were not only those associated with migraine, but joint pain and asthma as well. As in the previously mentioned studies, the ovarian hormones of interest were progesterone and estrogen. The participants were divided into two groups—symptomatic and asymptomatic. Blood levels of IgG, IgM and IgE antibodies to progesterone and IgE antibodies to both progesterone and estrogen were measured in both groups. Their hypothesis was supported by evidence of increased blood levels of antibodies during menstruation in the symptomatic group. The asymptomatic group was not without these antibodies of interest, however their blood levels of IgG, IgM and IgE were significantly lower than the symptomatic group. Therefore, they were able to conclude there was, in fact, evidence of antibodies to estrogen and progesterone. They suggest “progesterone, estrogen and their metabolites, after binding to human tissue proteins, such as albumin or globulin, may act as antigens and promote Type 2 helper cell development, thereby regulating antibody synthesis and allergy”(Roby et al, 2006). This resulting allergy is thought to be the cause of symptoms relating to hormone fluctuation during the menstrual cycle—joint pain, asthma and MRM. If this is the case, health care professionals may be able to provide relief to suffering patients through “determining the presence of hormone allergy and (using) hormones as antigens to diminish symptoms by desensitization” (Roby et al, 2006). Palmquist 6 There are many hypotheses regarding the etiology of MRM. The symptoms associated with MRM, however, are not only obvious but life altering. So, whatever the cause of these unfortunate occurrences, finding a cure is crucial for migraine sufferers. Using hormones as antigens may be one way to help treat MRM. As shown earlier, however, migraine symptoms and triggers vary greatly among individuals. Fluctuating hormone levels during menstruation may elicit a completely different set of symptoms for two individuals. This makes treating MRMs and their symptoms a difficult task. NSAIDs such as aspirin and ibuprofen and acetaminophen are often used to treat migraine symptoms. A problem arises, however, when desensitization occurs due to regular use and an unhealthy dosage is needed to relieve migraine symptoms. These drugs also do not treat all symptoms relating to migraine. Photophobia may or may not be alleviated and nausea may actually be worsened by NSAIDs. Currently, a heavily marketed drug for acute migraine relief with or without aura is IMITREX ( sumatriptan succinate). The primary mechanism of action of IMITREX is vasoconstriction. According to the FDA, this is effective in relieving migraine pain due to vasoconstriction in the basilar artery. Certain animal trials have shown IMITREX binds to 5-HT1 receptors which is thought to diminish certain migranous symptoms such as photophobia. IMITREX has provided migraine relief for some patients, however has provided little to no relief for others. Some patients actually reported adverse side effects; paresthesia and warm and cold sensations being the most common. These side effects occurred in less than 10% of IMITREX users (FDA, 2000). Many drugs used for migraine symptom treatment are either specific to one symptom, ineffective for some patients, or elicit undesirable side effects. These undesirable qualities of synthetic drugs make a study on the effect of vitamin E on MRM especially interesting. The Palmquist 7 purpose of the study was to determine “the effect of vitamin E as a prophylactic agent on women with menstrual migraine” (Ziaei, 2009). 165 women age 20-30 with at least a six month history of menstrually related migraine participated in this double-blind placebo-controlled trial. In the past three months, they had not undergone any preventative strategies for migraine relief. The women were divided into two groups—one group receiving a placebo and the other receiving a vitamin E supplement. Both agents were in the form of a pill and similar in appearance. The participants were evaluated by a neurologist and were asked to rate the severity of the following symptoms: headache, photophobia, phonophobia, nausea and functional disability. Only the women who had a MRM according to the criteria of he International Headache Society (an attack of migraine without aura occurring on day 1 of menstruation (day-2 to day + 3) in two of three menstrual cycles) were identified as having a MRM. The results showed “statistically significant reductions in pain severity, functional disability and ibuprofen consumption dose in both treatment methods, but the magnitude of the reduction was significantly greater in the vitamin E treatment group than in the placebo group” (Ziaei, 2009). Though the placebo group was receiving only a placebo, they still experienced a decrease in these migraine symptoms. However, “vitamin E was superior to placebo regarding photophobia, phonophobia, and nausea in women with menstrual migraines” (Ziaei, 2009). These results are exciting to health care providers and migraine sufferers. If relief from menstrual migraine could be obtained from a vitamin E supplement, this could provide a relatively inexpensive, simple treatment method. Also, no negative side effects due to the vitamin E supplement were discussed in this study. This is not surprising since vitamin E is present in many common foods and therefore is not a foreign substance to the body. A substance not found in the diet—NSAIDs are briefly discussed in this paper and compared to vitamin E Palmquist 8 with regards to menstrual migraine relief. They explain that NSAIDs reduce headache temporarily, but “many patients experience an increase in headaches when the short-term preventative treatment is stopped. However, the patients did not experience breakthrough headache when five days of vitamin E was stopped” (Ziaei, 2009). This information provides another potential benefit of using vitamin E for menstrual migraine relief over commonly used synthetic drugs. Migraines are experienced by a very significant amount of people. This potentially debilitating condition can be life altering and unpredictable. MRMs allow us to more accurately predict when a migraine is going to occur, and to explore the physiological changes that occur during the migraine. Numerous hypotheses exist regarding which specific physiological changes associated with menstruation trigger a menstrual migraine. Since various symptoms are associated with menstrual migraine, it is difficult to pinpoint which alteration is causing which symptom. It would be helpful to isolate menstrual migraine patients who experience one predominant symptom and monitor bodily changes during an attack. This could lead us to information regarding treatment of the migraine itself, instead of solely the symptoms. It could potentially lead us to information about not only menstrual migraines, but nonmenstrually related migraines as well. This is an important condition that debilitates many people; more research needs to be done on the root of the problem and how to treat it. Palmquist 9 References 8 things you need to know about nutrition & your aching head.(2008). Tufts University Health & Nutrition Letter, 26(4), 6-6. Diamond, M. L., Cady, R. K., Mao, L., Biondi, D. M., Finlayson, G., Greenberg, S. J., et al. (2008). Characteristics of migraine attacks and responses to almotriptan treatment: A comparison of menstrually related and nonmenstrually related migraines. Headache, 48(2), 248-258. Diamond, M., & Cady, R. (2005). Initiating and optimizing acute therapy for migraine: The role of patient-centered stratified care. American Journal of Medicine Supplement, 118(Supplement 1), 18-27. Food and Drug Administration. (2000). IMITREX product information. MacGregor, E. A. Estrogen replacement and migraine. Maturitas, In Press, Corrected Proof Martin, V. T., Wernke, S., Mandell, K., Ramadan, N., Kao, L., Bean, J., et al. (2005). Defining the relationship between ovarian hormones and migraine headache. Headache, 45(9), 1190- 1201. Newman, L. C. (2007). Understanding the causes and prevention of menstrual migraine: The role of estrogen. Headache, 47 Suppl 2, S86-94. Roby, R. R., Richardson, R. H., & Vojdani, A. (2006). Hormone allergy. American Journal of Reproductive Immunology (New York, N.Y.: 1989), 55(4), 307-313. Palmquist 10 The truth about triggers.(2008). Headache: The Journal of Head & Face Pain, 48(3), 499-500. Ziaei, S., Kazemnejad, A., & Sedighi, A. (2009). The effect of vitamin E on the treatment of menstrual migraine. Medical Science Monitor : International Medical Journal of Experimental and Clinical Research, 15(1), CR16-9.