GUJHS. 2004 Dec; Vol. 2, No. 1
Elizabeth H. Newman, ‘05
Department of Human Science
School of Nursing and Health Studies
In the United States, 18% of women and 6.5 % of men suffer from migraines (Snow et al., 2002). The World Health Organization has listed migraine as one of the top 20 most debilitating diseases world wide, reflecting a Global Burden of disease ranking at par with active psychosis, dementia, and quadriplegia (Tronvik et al., 2003). The most disturbing statistic on migraine sufferers is that nearly half of the cases go undiagnosed and only one-third of migraine sufferers are being treated with prescription medications (Lipton et al., 2003).
In recent years, there has been an increase in research and development for migraine medications mainly due to the arrival of the triptan family of medications (which includes Imitrex). However, these efforts have primarily focused on therapeutic medications rather than on tools for proper diagnosis and prophylactic treatments. Although some research has been done on a variety of diagnostic methods and preventative medications, none of these methods have been put into practice and very few of the drugs have been approved by the FDA for use in migraine patients. Throughout this paper, recent research studies that focus on diagnosis and prevention will be analyzed for efficacy, safety, and future potential for the management of migraine.
Migraine headaches have been notoriously difficult to diagnose and treat because they have an unknown etiology. In addition, migraines manifest with a variety of neurologic and non-neurologic symptoms and these symptoms vary considerably between patients. Common symptoms of migraine include throbbing pain on one side of the head that worsens with exertion, photophobia (sensitivity to light), phonophobia (sensitivity to sound), visual disturbances, nausea, and vomiting. A headache is an extremely common ailment, preventing accurate diagnosis of migraines in two ways. The first is that many people do not seek consultation regarding their migraines because they assume they are ‘normal’ headaches. The second is that when primary care physicians ask about headache history during a routine check-up, once they have ruled out other causes (stroke, infection, tumor, etc), they often will stop asking questions at that point and never discover the severity or level of disability that the headaches may be causing the patient. Also, physicians often use the presence of aura prior to headache as the determining factor for migraine diagnosis, yet only 20% of migraineurs experience aura at all (Lipton et al., 2003). As a result of all these factors, the patient and the physician never realize that the pain is not merely a headache, but in fact a migraine.
An article in Neurology written by Doctor Merle Diamond explores a number of reasons why there is such widespread under-diagnosis of migraine. She found that migraines were often overlooked in diagnosis when the patient’s symptoms overlapped with another class of headache such as tension or cluster headaches. This has been attributed to the fact that International Headache Society’s (IHS) criteria for headache classification were meant to categorize different types of headaches (any number of which can occur in one person) rather than categorizing patients. Many health care providers make the mistake of assuming that a patient can experience just one kind of headache. The frequency of occasional cluster, tension, or sinus headaches among migraineurs is relatively high and often is the cause for the missed diagnosis of migraine (Diamond, 2002).
The alarming statistics that show how many Americans suffer from undiagnosed migraines inspired a number of researchers and doctors to find a way to address the problem. In the 2003 article in Neurology, researchers presented their findings from a study that tested the validity and reliability of a self-administered migraine screener. This study was performed in response to a number of failed efforts to create a similar screening system. The reasons for past failures included studies being performed in specialty rather than primary care settings, lack of expert confirmation of migraine diagnosis using IHS criteria, and the use of instruments (surveys, etc) that “were too time-consuming or burdensome for routine use in primary care” (Lipton et al., 2003).
The screening system used in this study was a three-question survey that was administered in the primary care setting, asking patients about disability, nausea, and photophobia. The results of the screening tool were compared against a longer nine-question survey as well as the IHS criteria for diagnosis and a physician’s assessment through conversation. It was found that the survey performed well in both sensitivity and specificity, i.e. the three question survey has the same sensitivity and specificity as the nine-question survey (Lipton et al., 2003). This data shows that a simple three-question survey administered in the primary care setting can be a highly effective screening mechanism for migraines.
Once a patient has been diagnosed with having migraines, steps should be taken to see if he/she is a candidate for prophylactic treatment. According to the American College of Physicians and American Society of Internal Medicine:
Generally accepted indications for migraine prevention include 1) two or more attacks per month that produce disability lasting 3 or more days per month; 2) contraindications to, or failure of, acute treatments; 3) the use of abortive medication more than twice per week; and 4) the presence of uncommon migraine conditions, including hemiplegic migraine, migraine with prolonged aura, or migrainous infarction (Snow et al., 2002).
If any of these conditions are present, preventative efforts should be taken by the patient and physician. Keeping a headache journal is not only beneficial in providing the physician with information about the patient’s condition, but it can also help the patient discover potential migraine triggers. There are three main categories of triggers: dietary triggers (alcohol, nitrates, MSG, aspartame, etc.), environmental triggers (loud noises, bright lights, certain odors, changes in barometric pressure, etc.), and physiological triggers (lack of sleep, hypoglycemia, menstruation, etc.). Although identifying and avoiding triggers will not usually prevent migraines completely, many migraine sufferers are able to reduce the frequency or severity of their headaches by avoiding their triggers. (Raymond, 2003)
If the patient still qualifies for preventative treatment after adjusting his/her lifestyle, he/she should begin a prophylactic treatment regimen under the supervision of a neurologist or primary care physician. Although there are not any medications available today with the specific function of migraine prevention, a number of vitamins and medications used for other purposes have been inadvertently found to relieve migraines. The treatments that will be discussed are magnesium, riboflavin, niacin, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, topiramate, and botulinum toxin type A.
High doses of certain vitamins are sometimes used as first-line prophylactic treatment of migraines because of their safety, lack of side effects, and low cost. The B vitamins and magnesium are most often prescribed in this capacity. Magnesium supplements have been found to be especially effective in staving off menstrual migraines. Studies have shown that many women who experience menstrual migraines are deficient in this mineral and should try supplementing their diets with magnesium rich foods, such as legumes, whole grain cereals, and dark green vegetables, or with magnesium supplements. (Raymond, 2003)
Preliminary studies have also shown that high doses of riboflavin (vitamin B2) (Mattimoe and Newton, 1998) and niacin (vitamin B3) (Velling et al., 2003) can be helpful in preventing migraines. Although studies on these vitamins are only in their infancy, clinicians have been using them for a number of years. These vitamins can be found in natural foods, however, the high doses that are recommended for migraine prevention are usually attained by taking supplements.
While vitamin and mineral supplements may be beneficial for some patients, often times other courses of treatment are necessary. Angiotensin-converting enzyme (ACE) inhibitors are one class of drugs that has been found to be effective in prophylactic treatment of migraines. Patients who were put on an ACE inhibitor for hypertension showed improvement in migraine status and this led to a number of clinical trials on the use of these drugs in migraine prevention. Studies found that ACE inhibitors are effective in the prophylaxis of migraine, but like many other preventative treatments the mechanism of action is unclear. The direct effect of inhibiting the conversion of angiotensin I to angiotensin II prevents the potent vasoconstriction of blood vessels, which may play a part in prevention (Schrader et al., 2001). In addition to this action, the ACE inhibitor studied also “alters sympathetic activity, increases prostacyclin synthesis, and blocks the degradation of bradykinin, encephalin, and substance P” (Schrader et al., 2001).
One benefit to these medications is that they reduce migraine frequency and severity as well as blood pressure and resting heart rate. This combination is ideal for anyone who suffers from migraines as well as hypertension. Also, patients with asthma, intermittent claudication, conduction defects, and pregnant women are all able to take this medication and are not able to take β-blockers (another heart medication that is used to treat migraines prophylactically) (Schrader et al., 2001).
Although lowered blood pressure is a benefit for some, it may be reason for contraindication for others. Anyone with low blood pressure, normally or due to medication would not be able to take this drug. Also, this medication occasionally causes a cough in some patients severe enough to stop further treatment. (Schrader et al., 2001) These limitations to the use of ACE inhibitors for migraine prevention led researchers to perform studies on other medications that also influence the effects of angiotensin in the body.
In the past few years, angiotensin II receptor blockers (ARBs) have been the main focus of research for ACE inhibitor alternatives. ARBs compete with angiotensin II at the level of the receptor and block the binding site. ARBs are sometimes seen as preferential to ACE inhibitors for two reasons – the first is that ARBs block the effects of angiotensin II in ACE and non-ACE pathways and the second reason is ARBs “do not interfere with bradykinin, substance P, or tachykinin metabolism, the usual potential adverse effects associated with ACE inhibitors, such as coughing, and angioneurotic edema, are greatly reduced” (Tronvik et al., 2003). The study found that Candesartan, an ARB, showed drastically different data than the placebo in relation to “number of days with headache, headache hours, number of days with migraine, migra ine hours, headache severity index, level of disability, doses of triptans, and doses of analgesics” (Tronvik, 2003). These results are promising and suggest that additional studies and clinical trials.
Topiramate is another drug that was put on the market for non-headache use but was found to be effective in preventing migraines. This medication is traditionally prescribed to epileptic patients as an anti-seizure medication, but it has been found to be effective in treating a number of other disorders such as binge-eating, bulimia, and essential tremor. Over time patients began reporting some relief from migraine symptoms as a side effect of continued use of this drug. The exact mechanism by which Topiramate reduces the severity and frequency of migraines is unknown; however, various mechanisms of action of the drug may contribute to its efficacy including state-dependent inhibition of voltage-gated sodium channels, inhibition of high-voltage-activated calcium channels and of glutamate-mediated neurotransmission as well as the enhancement of γ-aminobutyric-acid-receptor-mediated chloride flux (Brandes et al., 2004). Any one or combination of these pathways may be responsible for migraine relief (Brandes et al., 2004).
In 2004, a report on a study performed on the use of Topiramate in migraine prevention was published. This study found that low doses of this drug are effective for the purpose of migraine prevention and that the differences in outcome between Topiramate and placebo were statistically significant. Some adverse events were reported, suggesting that larger clinical studies should be performed (Brandes et al., 2004). Topiramate and other anti-seizure medications are currently used in practice, but additional studies should be done on this class of drugs so that proper dosing schedules, contraindications, etc. can be determined in a regulated clinical setting.
Although these daily medication regimens have proven efficacious, the most promising new prophylactic treatment of migraine and other headache disorders is Botulinum Toxin type A (Botox). A number of formal and informal studies have shown that Botox injections in the forehead, neck, and scalp greatly reduce migraine occurrence, and in some studies, even completely eliminate migraine attacks in over half of the study participants (Loder and Biondi, 2002).
Botox is a toxin harvested from the Clostridium Botulinum bacteria. It is the most deadly of all bacterial toxins. Purified and greatly diluted Botox can be injected locally to paralyze muscles. Botulinum toxins have been used since the 1980s in disorders such as strabismus, spacticity, and dystonias. Its recent FDA approval for use in wrinkle reduction led physicians to realize its potential in the treatment of migraine. The overwhelming number of patients who experienced coincidental reduction in headache inspired researchers to perform clinical trials on the use of the toxin in migraine prevention (Loder and Biondi, 2002).
The role of Botox in migraine prevention is not completely understood. There are a number of different mechanisms of action that are suspected to be responsible for its effectiveness. First, the toxin locally paralyzes muscles and although the cause of migraines is unknown, muscle tension has been recognized as a possible factor. The toxin also affects neurotransmitter release and parasympathetic output, and decreases the release of substance P and other inflammatory peptides. These secondary effects of the toxin on neurophysiology may play a large part in its efficacy since most migraineurs experience relief from Botox, yet not all necessarily have migraines caused by muscle tension (Loder and Biondi, 2002).
One major drawback to treatment with Botox is the expense. Injections must be performed every three to four months by a neurologist and the combined cost of the medication and injections is several hundred dollars. Since Botox has not been approved by the FDA for the treatment of migraines, most insurance companies will not cover the cost. More clinical trials need to be performed so that this treatment can become FDA approved.
The lack of research in the area of migraine diagnosis and prevention is a serious concern, especially considering the very high prevalence of this type of headache. Additional research like the studies presented here would be beneficial to health care providers as well as migraine sufferers. These studies have shown the safety and efficacy of a number of prophylactic treatments; however, nearly every study mentioned that additional research and larger clinical trials need to be performed so that standardized guidelines for treatment in this capacity can be created. Considering the high rates of under-diagnosis and under-treatment of migraines, more effort needs to be focused on researching these diagnostic and treatment options.
Brandes, J.L., Saper, J.R., Diamond, M., Couch, J.R., Lewis, D.W., Schmitt, J., Neto, W., Schwabe, S., & Jacobs, D. (2004). Topiramate for migraine prevention. Journal of the American Medical Association 291(8) 965-973.
Diamond, M. (2002). The role of concomitant headache types and non-headache co-morbidities in the underdiagnosis of migraine. Neurology 58(6) S3-S9.
Lipton, R.B., Dodick, D., Sadovsky, R., Kolodner, K., Endicott, J., Hettiarachchi, J., & Harrison, W. (2003) A self-administered screener for migraine in primary care. Neurology 61 375-382.
Loder, E. & Biondi, D. (2002). Use of botulinum toxins for chronic headaches: A focused review. The Clinical Journal of Pain 18 S169-S176.
Mattimoe, D., & Newton, W. (1998). High-dose riboflavin for migraine prophylaxis. The Journal of Family Practice 47(1) 11.
Raymond, J. (2003). Migraine. New York: Barnes & Noble Books.
Schrader, H., Stovner, L.J., Helde, G., Sand, T., & Bovim, G. (2001). Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): Randomized, placebo controlled, crossover study. British Medical Journal 322 1-5.
Snow, V., Weiss, K., Wall, E.M., & Mottur-Pilson, C. (2002). Pharmacologic management of acute attacks of migraine and prevention of migraine headache. Annals of Internal Medicine 137 840-849.
Tronvik, E., Stovner, L.J., Helde, G., Sand, T., & Bovim, G. (2003) Prophylactic treatment of migraine with an angiotensin II receptor blocker. Journal of the American Medical Association 289(1) 65-69.
Velling, D.A., Dodick, D.W., & Muir, J.J. (2003). Sustained-release niacin for prevention of migraine headache. Mayo Clinic Proc. 78 770-771.