Di Amerika Serikat, lebih dari 30 juta orang memiliki 1 atau lebih migren per tahun.

Hal ini kira-kira sesuai dengan sekitar 18% dari perempuan dan 6% laki-laki. [36] account Migraine untuk 64% dari sakit kepala parah pada perempuan dan 43% sakit kepala berat pada laki-laki. Sekitar 75% dari semua orang yang mengalami migrain adalah perempuan. Saat ini, 1 dari 6 wanita Amerika telah migren. Insiden migrain dengan aura di puncak anak laki-laki sekitar usia 5 tahun dan pada anak perempuan sekitar usia 12-13 tahun. Insiden migraine tanpa aura di puncak anak laki-laki pada usia 10-11 tahun dan pada anak perempuan pada usia 14-17 tahun. [37] Sebelum pubertas, baik prevalensi dan kejadian migrain lebih tinggi pada anak laki-laki dari pada anak perempuan. Pada individu yang lebih tua dari 12 tahun, peningkatan prevalensi di kedua pria dan wanita, mencapai puncak pada usia 30-40 tahun. Peningkatan rasio perempuan-ke-laki-laki dari 2,5:1 pada pubertas untuk 3,5:1 pada usia 40 tahun. Serangan biasanya penurunan keparahan dan frekuensi pada orang yang lebih tua dari 40 tahun, kecuali untuk perempuan di perimenopause. Onset migrain setelah usia 50 tahun jarang terjadi. Kejadian dilaporkan migrain pada perempuan usia reproduksi telah meningkat selama 20 tahun terakhir. Peningkatan ini mungkin mencerminkan kesadaran yang lebih besar dari kondisi tersebut. Prevalensi migrain tampaknya lebih rendah antara Amerika dan Afrika Amerika Asia dibandingkan orang kulit putih. Satu studi menunjukkan bahwa di antara perempuan, 20,4% dari kulit putih, 16,2% dari Afrika Amerika, dan hanya 9,2% dari Asia Amerika bertemu Klasifikasi Internasional Headache Disorders (ICHD) kriteria untuk migrain. Demikian pula, pada laki-laki, 8,6% dari kulit putih, 7,2% Afrika Amerika, dan 4,8% dari Asia Amerika tersebut dianggap sudah migrain. Sebuah studi oleh Wilper et al menemukan bahwa status asuransi mempengaruhi perawatan migrain di Amerika Serikat. Setelah mengontrol umur, jenis kelamin, ras, dan lokasi geografis, pasien dengan migrain dengan asuransi atau dengan Medicaid kurang mungkin dibandingkan secara pribadi diasuransikan untuk menerima terapi gagal. Jadi, berasuransi dan mereka yang kurang lancar Medicaid menerima terapi untuk migrain karena mereka menerima lebih perawatan di bagian gawat darurat dan kurang dalam pengaturan rawat jalan. [38] Ekonomi dampak migrain Dalam Amerika Migraine Study, lebih dari 85% wanita dan 82% laki-laki dengan migrain berat memiliki beberapa cacat sakit kepala yang berhubungan. laki-laki Migraineur dibutuhkan 3,8 hari tidur-istirahat per tahun, sedangkan wanita dibutuhkan 5,6 tempat tidur-sisa hari per tahun. Hilangnya waktu produktif dari tenaga kerja migrain di AS lebih dari $ 13000000000 per tahun, yang sebagian besar adalah dalam bentuk penurunan produktivitas di tempat kerja. [39] Internasional statistik Organisasi Kesehatan Dunia (WHO) memperkirakan prevalensi seluruh dunia migrain saat ini sebesar 10% dan prevalensi seumur hidup sebesar 14%. Prevalensi disesuaikan migraine tertinggi di Amerika Utara, diikuti oleh Amerika Selatan dan Tengah, Eropa, Asia dan Afrika. Sekitar 3000 serangan migrain terjadi setiap hari untuk setiap juta dari populasi umum di seluruh dunia. Menurut WHO migrain, yang 19 di antara semua penyebab tahun hidup dengan cacat. Di Amerika Serikat, prevalensi migren berkorelasi berbanding terbalik dengan pendapatan rumah tangga dan tingkat pendidikan. Namun, hubungan antara status sosial ekonomi migrain dan tidak ada internasional.

http://www.medscape.com/viewarticle/704767_3

From American Journal of Lifestyle Medicine

Modern Management of the Migraine Headache

Kimberly A. Pesaturo, PharmD; Fae G. Wooding, PharmD Authors and Disclosures Posted: 07/14/2009; Am J Lifestyle Med. 2009;3(2):147-159. 2009 Sage Publications, Inc.

Abstract and Introduction

Abstract Migraine headache is a debilitating disorder that affects millions of people in the United States and worldwide. The diagnosis of migraine can significantly affect quality of life, health care costs, and daily productivity. Hundreds of trials and many guidelines have documented various approaches to migraine management, whether via acute treatment or chronic migraine prophylaxis. Acute or abortive migraine management encompasses specific and nonspecific migraine therapeutics, including nonopioid and opioid analgesics, triptans, and ergotamines. Prophylactic migraine management data span the pharmacological spectrum from antiepileptic and antihypertensive agents to botulinum toxin type A. Special considerations for migraine management also must be applied in various populations, including children, pregnant women, and the elderly. The following review serves as an introduction to current therapeutic approaches for acute migraine treatment and provides an overview of available literature for pharmacological prophylaxis. Introduction Over the past 2 decades, an increase in migraine awareness has resulted in the introduction of new pharmacological treatment agents as well as additional indications and data on existing medications for prophylaxis. Migraine is defined as a unilateral headache with pulsating pain of a moderate to severe intensity, often accompanied by photophobia, phonophobia, and/or nausea, and may occur with or without aura.[1] The headaches exhibit a recurrent pattern and can significantly affect activities of daily living. Approximately 30 million people in the United States suffer from migraines, with 18% of women and 6% of men experiencing at least 1 migraine headache annually.[1] Because of its significant impact on quality of life and interpatient variability in treatment response, migraine management remains challenging for many health care professionals. Migraine has a significant societal burden resulting in costly medical bills and lost productivity, averaging about 64 to 150 million work days lost each year.[2,3] Consequently, migraine headache has been classified by the World Health Organization as one of the 19 most disabling diseases worldwide.[4] Migraine prevalence varies by age, sex, and ethnicity with the highest prevalence in whites, followed by African Americans and then Asians.[5] In the United States, the prevalence of migraine headache

decreases as household income increases.[6] Although hundreds of clinical trials are available regarding migraine treatment modalities, this review serves as an introduction to current accepted therapeutics for migraine treatment and an overview of pharmacological prophylaxis in the modern management of migraine.

Abortive Pharmacological Treatment

The main goal of acute migraine treatment is to abort an attack once it begins. The rate of therapeutic success during an acute attack is higher at onset than when the migraine is well established. According to the American College of Physicians-American Society of Internal Medicine (ACP-ASIM) and the American Academy of Family Physicians (AAFP), first-line treatments for migraine are nonsteroidal anti-inflammatory drugs (NSAIDs), followed by migraine-specific agents.[7] Because of interpatient variation in migraine presentation, management of migraine is often individualized because patient responses to therapy are not always predictable. The choice of treatment should be based on the frequency and severity of attacks, presence and degree of temporary disability, and the presence of associated symptoms such as nausea and vomiting. Acute treatment of migraine can be nonspecific (nonopioid analgesics, opioids, antiemetics) or specific (ergotamines and triptans). To establish an effective treatment plan for an acute migraine, the patient and his or her health care provider must identify specific goals of treatment. Specific goals for acute and long-term management of migraine are listed in Table 1 . These goals emphasize the importance of education and patient empowerment to meet the needs and expectations of the patient.[8] The choice of agent is just as important as the method used for managing migraine headaches. The "stepcare" and "stratified-care" approaches are 2 methods that have been used for the management of migraine. The stepcare approach involves initial treatment of acute attacks of any severity with safe, effective, and inexpensive therapies. Later use of more expensive, migrainespecific therapies may be required if initial treatment fails.[8] The stratified-care approach assigns treatment based on the severity of migraine-related disability, where nonspecific pharmacological agents are used in patients experiencing minimal or infrequent disability, and migraine-specific agents are reserved for patients with moderate to severe disability.[9] A higher degree of patient satisfaction has been demonstrated with migraine-specific (vs nonspecific) medications.[10] In addition, the stratified-care approach has shown to be more effective than the step-care method because the treatment is individualized and yields better clinical outcomes.[2] Nonspecific Abortive Migraine Therapy Nonspecific abortive agents include nonopioid and opioid analgesics. Nonopioid agents, including acetaminophen (APAP), aspirin, or acetylsalicyclic acid (ASA), and NSAIDs are effective options for mild migraine headache and may be used with or without an antiemetic.[10] Initiation of these agents at the onset of a migraine improves efficacy. However, close monitoring is required when using nonopioid analgesics because of the development of rebound headaches associated with overuse. If migraine symptoms do not subside within 40 to 60 minutes of initiating nonopioid analgesics, then migraine-specific agents should be added to the patient's current regimen.[11] Nonspecific abortive migraine therapies are summarized in Table 2 .

Acetaminophen. The use of APAP as monotherapy has not been shown to be effective for moderate- to severe-type migraine headaches.[7] However, its use in combination therapies with ASA plus caffeine has demonstrated efficacy for the acute treatment of migraines.[2,5] Acetaminophen combined with isometheptene and dichloralphenazone has also demonstrated efficacy in the treatment of mild migraine headaches.[12,13] Nonsteroidal Anti-Inflammatory Drugs. Because of the demonstrated efficacy and favorable tolerability of these agents, NSAIDs are considered the first-line treatment for managing migraine attacks and may be considered as an alternative option for prophylactic therapy. There is consistent evidence in the literature that demonstrates efficacy with ASA, ibuprofen, and naproxen sodium in migraine.[7] Trials comparing NSAIDs to placebo demonstrated effective pain relief of acute migraine headache. Combination analgesics consisting of APAP, ASA, and caffeine demonstrated significantly greater headache relief compared to placebo.[8] Barbiturates. The use of barbiturate hypnotics for the treatment of acute migraine attacks is not well established.[5] Butalbital-containing agents continue to be used in the United States but have been withdrawn from the European markets. Most of the clinical trials conducted using hypnotic barbiturates evaluate their efficacy in tension-type headaches.[8] Only one trial comparing a butalbital/ASA/caffeine/codeine combination to butorphanol nasal spray was conducted among patients with migraine.[14] Although the results of the trial demonstrated that butorphanol was superior in efficacy at 2 hours, the differences between treatment were insignificant at 4 hours. Opioids. Although opioids are well known for their analgesic properties, they are often reserved as rescue agents or as alternative agents for severe migraine sufferers who do not respond to nonopioid analgesics or cannot tolerate migrainespecific agents. These agents should be avoided for use of chronic daily headaches as they may lead to dependence, rebound headaches, or loss of efficacy.[2] In addition, opioid use should be restricted to less than twice a week in patients who experience severe, infrequent headaches.[5] Cyclooxygenase-2 Inhibitors. Selective cyclooxygenase-2 (COX-2) inhibitors have been studied in acute migraine treatment based on the theory of upregulation of COX-2 in the inflammation involved in migraine pathophysiology. One prospective, open-label trial randomized 60 patients with migraine to either celecoxib 400 mg or naproxen sodium 550 mg at migraine onset.[15] Both groups saw significant improvement in visual analog scores 2 hours from headache onset; however, no significant difference in magnitude of improvement was observed between groups. Other Nonspecific Pharmacological Agents. Additional agents that target symptoms associated with migraine such as nausea and vomiting have also been used as adjunctive treatment. The use of rectal and parenteral antiemetics has been evaluated, and only a few have demonstrated efficacy for the treatment of migraine and associated nausea and vomiting.[5] The use of prochlorperazine has demonstrated significant relief of headache pain compared to placebo.[3] Prochloperazine administered intravenously or intramuscularly (IM) has been shown to be significantly superior to metoclopramide in the corresponding forms for the treatment of acute migraine headache pain, nausea, and vomiting.[2,3] Although metoclopramide IM can be recommended as monotherapy for treatment of migraine pain, its use is primarily for treating the

associated nausea and improving gastric motility.[2] Finally, intranasal lidocaine and intravenous corticosteroids (dexamethasone and hydrocortisone) have been used to abort acute migraine attacks, but there is a lack of evidence demonstrating their effectiveness.[16-18] Specific-Migraine Abortive Therapy Triptans. The triptans consist of 7 approved medications that are currently available in the United States. This group of medications exhibits their effects on serotonin receptors 5HT1B and 5HT1D, resulting in a direct vasoconstrictive response. Triptans are effective for mild, moderate, or severe migraine attacks that do not respond to NSAIDs or other analgesics.[2,5] There is evidence available to support the effectiveness of oral, subcutaneous, and intranasal formulations.[7] Studies that demonstrated the efficacy of the different triptan formulations evaluated 2-hour headache response and therapeutic gain (the difference between active drug and placebo) as well as pain-free and recurrence rates.[5] Triptans are available in various formulations that allow for alternative dosing in patients who require alternative modes of drug delivery other than oral ingestion. Currently, no evidence exists demonstrating a quicker onset of action between the different oral triptan formulations.[19] The subcutaneous and intranasal forms of sumatriptan and the rizatriptan absorbable wafer are effective options for patients who experience significant nausea or vomiting.[7] Triptans are usually well tolerated and therefore are good options for patients with nausea and vomiting. Although all triptans have a similar mechanism of action, the different formulations vary in onset of action and half-life. Subcutaneous sumatriptan has the quickest onset of action and is most effective compared to other triptan formulations.[5] Sumatriptan and zolmitriptan nasal sprays provide quicker onset of action than oral triptans, but the use of sumitriptan nasal spray is limited by its disagreeable taste. Oral triptans (almotriptan, eletriptan, rizatriptan, sumtatriptan, and zolmitriptan) typically provide headache relief within 30 to 60 minutes without multiple headache recurrence.[5] Most of the triptans have similar contraindications and safety concerns, but response is unpredictable. Triptans are contraindicated in patients with vasospastic coronary disease, ischemic vascular conditions, uncontrolled hypertension, or other significant cardiovascular diseases.[2,3] It is also important to note that although a patient may not respond to one triptan, he or she may respond to another. Therefore, choice of therapy should be based on the ability to restore a patient's functionality by relieving the pain and associated symptoms with minimal adverse effects. Sumatriptan, zolmitriptan, and rizatriptan should be avoided within 2 weeks of monoamine oxidase inhibitor (MAOI) use because of potential triptan toxicity.[20] In addition, the use of eletriptan should be avoided within 72 hours of ingestion of potent cytochrome P450 inhibitors such as ketoconazole, itraconazole, nefazodone, clarithromycin, and erythromycin because of potential increases in eletriptan plasma levels.[20,21] Ergotamines and Ergotamine Derivatives. Evidence documenting the efficacy of ergotamines and ergotamine-containing products is inconsistent. Although ergotamines have been considered standard abortive therapy in the past, their use has been limited because of their potential to cause medication-overuse headaches, increased frequency of headaches, toxicity, and adverse effects. These agents are available as combination oral preparations and rectal suppositories.[2]

Trials comparing ergotamine combinations with ergotamine alone demonstrated less incidence of nausea and vomiting with combination products.[8] Dihydroergotamine (DHE) is a semisynthetic ergot alkaloid and nonselective 5-HT1 receptor agonist that is often used for treating severe migraines. DHE has a low headache recurrence rate of less than 20% and demonstrates fewer adverse effects and a reduced incidence of rebound headaches than ergotamine.[22] DHE is available in parenteral and nasal preparations. In addition, chronic use of ergot alkaloids is restricted because of their ability to cause peripheral vasoconstriction. 2 All specific abortive migraine therapies are summarized in Table 3 .

Preventative Pharmacological Treatment

Preventative pharmacological treatment for migraine should be considered in patients experiencing symptoms at least twice per month, with disability that lasts at least 3 days per month.[23] Patients with uncommon migraine presentation or those experiencing adverse effects from abortive therapy may also benefit from preventative treatment. The past 3 decades have seen the evolution of drug therapy for prophylaxis of migraine, beginning with propranolol and the betablockers in the early 1970s. To date, antidepressant agents, antiseizure agents, angiotensin-converting enzyme inhibitors (ACEIs), calcium channel blockers, and botulinum toxin type A, among others, have been studied for their potential roles in preventative management of migraine. Although no definitive treatment is universally supported as an allencompassing migraine preventative, several agents have shown evidencebased efficacy and safety. Many studies have been conducted on this topic, but the following data represent a cross section of current literature, with specific drugs discussed in Table 4 . Beta-Blockers Propranolol has long been studied in the prophylaxis of migraine and, along with timolol, has been recommended as first line for migraine prophylaxis.[7] A Cochrane Database Systematic Review conducted in 2004 examined 58 trials (propranolol vs placebo and vs other agents) and demonstrated the significant benefit of propranolol versus placebo in the short-term prophylaxis of migraine.[24] Many studies have been conducted comparing propranolol to other beta-blocker agents. One such study examined 96 patients with 2 to 6 migraines per month and randomized patients to propranolol 80 mg twice daily, timolol 10 mg twice daily, or placebo.[25] This 36week, 3-way crossover trial showed clinically meaningful reductions in mean frequency of migraine attacks per 28 days in the timolol and propranolol groups versus placebo (3.35 and 3.69 vs 4.83, respectively). This study also calculated headache index (frequency multiplied by severity) and noted statistically significantly lower indices in timolol and propranolol groups versus placebo. In 2008, Schellenberg and colleagues[26] evaluated metoprolol in migraine prophylaxis via a double-blinded study in which 30 patients in Germany were randomized to metoprolol 47.5 to 142.5 mg or nebivolol 5 mg over 18 weeks. Patients were included in the study if they had at least 2 migraines per month, with the final endpoint being a reduction in migraine frequency. A sample size calculation could not be conducted; however, the researchers were able to show a mean reduction of 3.4 to 1.3 migraines per month in the full-dose metoprolol group at 14 weeks, with similar results noted in the nebivolol group. However, the incidence of treatment-related

adverse effects was almost 50% decreased in those receiving nebivolol, a third-generation cardioselective beta-blocker. These data lend themselves to further research on the appropriateness of using less selective beta-blockers in migraine prophylaxis with regard to the adverse effect profile. Several other studies examining metoprolol, timolol, and nadolol also noted similar results in efficacy versus placebo.[27-30] Beta-blockers were well tolerated in these studies. Common reported adverse effects included dizziness, fatigue, and shortness of breath. Of note, 1 trial in 1997 examined the possible interaction between zolmitriptan (a selective 5HT1B/1D agonist) and propranolol.[31] Here, authors reported that propranolol increased the mean zolmitriptan area under the curve and concentration maximum by 37% and 56%, respectively. However, it was concluded that no clinically significant effect resulted from these alterations. Such trials are necessary to shed light on the increasing variety of treatments available for rescue and prophylactic therapy, as well as the need for providers to remain vigilant for potential problems that may arise with combination therapy. Antiepileptics Antiepileptic-type agents may be referred to as "neuromodulators," which include all of the classes of drugs that appear to inhibit cortical excitability.[32] Topiramate, an antiepileptic drug first approved for adjunct seizure treatment in 1996, has exhibited consistent migraine preventative efficacy results in many large-scale clinical trials. A 26-week, double-blind, placebo-controlled study randomized 487 patients with 3 to 12 migraines per month to placebo or topiramate at doses ranging from 50, 100, or 200 mg/d, with titration as tolerated.[33] A significant reduction was observed in the primary endpoint of mean monthly migraine frequency by approximately 2 migraines in the 100- and 200-mg/d groups versus placebo (P < .001). Responder rates that showed at least a 50% reduction in migraines per month were 35.9% in the 50-mg/d group (P = .04), 54% in the 100-mg/d group (P < .001), and 52.3% in the 200-mg/d group (P < .001). A significant reduction in use of acute treatments was also observed in the 100and 200-mg/d topiramate groups (P = .005 and P = .002, respectively). Furthermore, the improvements noted were observed as early as the first month of treatment. A second placebo-controlled trial from 2004 examined similar patients to the previous study and also included a washout period followed by a randomization to 50, 100, or 200 mg/d of topiramate.[34] Within the 26 weeks of the study, patients receiving doses of 100 or 200 mg/d of topiramate saw an average reduction in monthly migraines of 2.1 (P = .008) and 2.4 (P < .001), respectively, versus a reduction of 1.1 migraines/month with placebo. One study examined low-dose topiramate versus lamotrigine and each agent versus placebo in adults with 4 to 10 migraines per month.[35] Sixty patients were enrolled to receive topiramate 50 mg/d, lamotrigine 50 mg/d, or placebo in a 4-phase crossover design with washout periods. Achievement of at least a 50% reduction in migraine frequency was observed for topiramate versus placebo (63% vs 30%, P < .001), lamotrigine versus placebo (46% vs 34%, P < .93), and topiramate versus lamotrigine (P < .019). Reduction in migraine intensity was significantly

observed in the topiramate versus placebo or lamotrigine groups (P < .001 and P < .019, respectively). Topiramate is believed to act via statedependent sodium channel blockade, gamma-aminobutyric acid (GABA) enhancement, glutamate antagonism, and inhibition of 1-type calcium channels.[34] Each of these mechanisms, alone or in combination, may contribute to the prevention of migraine via the proposed neuronal excitability pathology hypothesis.[36] All topiramate studies examined allowed for the use of rescue medications when necessary and concluded that topiramate is an effective preventative therapy for migraine at doses of 100 to 200 mg/d.[33,34] Consistent adverse effects were observed across trials, including paresthesias, nausea, fatigue, difficulty concentrating, anorexia, and weight loss, with the greatest number of side effects occurring at the 200-mg/d dose. Divalproex sodium is another neuromodulator studied to assess efficacy and safety versus placebo for prophylaxis against migraine headache.[37] A doubleblind, parallel-group study randomized patients with at least 2 migraine headaches per month to receive divalproex sodium extended release 500 mg/d, which was titrated to 1000 mg/d as tolerated, or placebo. The primary efficacy endpoint of the study was migraine reduction from baseline in participants over 4 weeks. Mean reductions in baseline were 1.2 headaches in the treatment group versus 0.6 headaches for placebo (P = .006). Divalproex has also been studied for long-term outcomes; one open-label study showed a decrease in 4-week migraine rates at 3- and 6-month intervals. Initial benefit achieved was observed for over 360 days of treatment for some patients.[38] Divalproex sodium and sodium valproate act via increased availability or mimic GABA in the central nervous system; common adverse effects include somnolence, dizziness, gastrointestinal symptoms, and thrombocytopenia. When compared to topiramate, sodium valproate has been shown to be equivalent in terms of migraine reduction per month, decrease in headache intensity, and incidence of adverse effect.[39] Other neuromodulators continue to be assessed for efficacy and the possibility of added therapeutic indication. Small trials with zonisamide, levetiracetam, and gabapentin have shown varying degrees of efficacy in the prevention of migraine as first-line or refractory treatment.[4042] The role of tiagabine and lamotrigine in migraine prophylaxis has yet to be fully elucidated. Larger clinical trials are still necessary to determine the true place of these agents in migraine therapy. Antidepressants Amitriptyline is a tricyclic antidepressant that has been used for migraine prophylaxis since the 1970s.[43,44] In 1987, Ziegler et al[45] compared amitriptyline, propranolol, and placebo in 30 participants in a crossover fashion and found that although neither drug was superior to the other, both were favored over placebo, as reported in the participants' daily headache diaries. Of note, divalproex has been shown to increase the area under the curve for amitriptyline, suggesting that a lower dose of amitriptyline may be used when patients are concomitantly receiving divalproex.[46]

Fluoxetine is an antidepressant that was studied for its ability to downregulate presynaptic autoreceptors in the brain, which selectively inhibits serotonin reuptake.[47] Following a 30-day washout period, 52 adult patients were placed on fluoxetine 20 mg/d or placebo for 6 months.[47] A statistically significant decrease in study-derived total pain index (based on pain intensity and hours of headache) was observed in the fluoxetine group beginning in the third month of the study. No patients dropped out of the study because of adverse effects. Similar to fluoxetine and the selective serotonin reuptake inhibitors, venlafaxine is a serotoninnorepinephrine reuptake inhibitor that has been studied in the prophylaxis of migraine. One study enrolled 60 patients with migraine without aura and randomized the patients to extendedrelease (XR) venlafaxine 75 mg or 150 mg or placebo daily.[48] Patients were only allowed to use naproxen, flurbiprophen, or aspirin for acute headache. At the end of the 2-month study period, the venlafaxine XR 150-mg/d group noted a significant decrease in frequency of migraine, and a significant decrease in severity was noted in all 3 groups. Venlafaxine was well tolerated at all doses used in the study. Another study compared venlafaxine with amitriptyline in a 36-week crossover design that examined 52 patients.[49] Although migraine frequency, duration, and intensity were significantly decreased within treatment groups after 4 weeks, the endpoints were not shown to be different between groups. Study trends showed that venlafaxine was better tolerated than amitriptyline. Duloxetine, another serotonin-norepinephrine reuptake inhibitor, has shown minimal effectiveness as a prophylactic agent.[50] Other Antihypertensives Antihypertensives, including ACEIs, angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs), have been studied for their potential role in prophylaxis against migraine. The use of these agents has long relied on anecdotal evidence of their efficacy, as well as the theory that they can be used to manage migraine with patients who also have hypertension.[51] Lisinopril was among the first ACEIs studied, when Schrader et al[52] randomized 60 adult patients with migraine to lisinopril 10 mg daily or placebo via a crossover design. In the lisinopril group, days with headache were reduced by 17% (95% confidence interval [CI]: 5-30), as were hours with headache and headache severity. Patients in this trial experienced more adverse effects in the lisinopril group, including coughing and fainting (P = .07). After lisinopril was shown to be successful in patients who experienced migraine, other classes of antihypertensives were investigated. Trovnik and colleagues[53] recruited 60 patients with migraines occurring 2 to 6 times per month. Using a crossover design, patients were randomized to candesartan cilexetil 16 mg (an ARB) or placebo. Over the 12-week study, 13.6 mean headache days were observed with candesartan versus 18.5 days with placebo (P = .001). The candesartan group saw significant reductions in headache severity and level of disability. Olmesartan, another ARB, has a slightly longer half-life than candesartan and was also studied in migraine prophylaxis. Twenty-four adult patients with migraine and hypertension were treated with doses of olmesartan ranging from 10 to 40 mg in 1 trial.[51] Authors reported a reduction of 82.5% in frequency of headache, as well as a 45% reduction in migraine intensity, with no statistical data provided. Verapamil, a CCB, has shown similar efficacy versus placebo in older trials.[54] ACEIs have been associated with cough and angioedema; ARBs may cause orthostatic hypotension; CCBs can produce constipation, headaches, and flushing. All antihypertensive

agents have the potential to produce hypotension, and patients should be monitored appropriately. Botulinum Toxin Type A Botulinum toxin type A has been investigated in migraine prophylaxis for its potential antinociceptive effects via blockade of substance P and glutamate.[55] In a randomized, doubleblind, multicenter, parallel group study, 369 patients received a placebo run-in, followed by up to 3 rounds of botulinum toxin (110-260 units) or placebo over 11 months.[55] Pooled data of placebo nonresponders and placebo responders showed that both treatment groups experienced a clinical response in efficacy, as determined by a mean decrease in migraine frequency over 30 days. Adverse event rate was significantly higher in the active treatment group versus placebo and included events such as muscular weakness, neck pain, and blepharoptosis. Twenty-five units or 75 units of botulinum toxin type A injected into multiple sites also have been studied previously with safety and efficacy reported at the 25-unit dose.[56] A standard dose and treatment regimen for botulinum toxin type A in migraine prophylaxis has not yet been established.

Table 3. Specific Medications for Acute Treatment of Migraines[2,70]