Migraines: Treatment Options Report

Transcription

1 Migraines: Treatment Options Report April 2006

2 Migraines: Treatment Options Report Prepared for: CALIFORNIA HEALTHCARE FOUNDATION Prepared by: UC Davis Center for Health Services Research in Primary Care Authors: Erika D. Cutler, Pharm.D. Michelle Apperson, M.D., Ph.D. Senior Scientific Editor: Richard L. Kravitz April 2006

3 Acknowledgments The authors would like to thank Rich Wenzel, Pharm.D., and Charles Flippen, M.D., for their careful review and critique of an earlier draft of this document. Additional thanks are due to Diane Romac, Pharm.D. for scientific editing; to Robert Mowers, Pharm.D., BCPS, and Jeff King, Pharm.D. for their contributions and input; to Joanne Tang for technical editing; and to the PDIP for their consistent guidance and support. About the Authors Erika D. Cutler, Pharm.D., is a pharmacist at the University of California, Davis Health System. Michelle Apperson, M.D., Ph.D. is with the Department of Neurology at the University of California, Davis Health System. About the Foundation The California HealthCare Foundation, based in Oakland, is an independent philanthropy committed to improving California s health care delivery and financing systems. Formed in 1996, our goal is to ensure that all Californians have access to affordable, quality health care. For more information about CHCF, visit us online at ISBN Copyright 2006 California HealthCare Foundation

4 Contents 4 I. Description of Condition Definition Classification Epidemiology Cause and Risk Factors Pathophysiology Natural History and Prognosis Diagnosis 9 II. Treatment of the Condition Prophylactic Treatment Nonpharmacologic Prophylactic Treatment Options Prophylactic Prescription Drug Treatment Other Prophylactic Drug Treatment Options Acute Management of Migraines Nonpharmacologic Treatment Options Acute Prescription Drug Treatment Other Treatment Options Interclass Comparisons 26 III. Summary 27 References

5 I. Description of Condition Definition HEADACHES ARE AN UBIQUITOUS FEATURE OF the human condition. 1 Primary headache disorders are not linked to an underlying source. Secondary headaches are attributable to an underlying pathological condition (e.g., infectious, neoplastic, vascular, drug-induced, idiopathic). 2 Migraine is a primary headache disorder. Rarely, migraine may be mimicked by a secondary headache disorder. In a migraineur, secondary processes may worsen migraine initially. As defined by the International Headache Society (IHS), migraine is a common, chronic, disabling condition, characterized by episodic attacks of head pain and associated symptoms. 3 The associated symptoms differ among patients and among attacks in a single patient. Patients may experience visual changes (scintillating patterns or double vision), motor weakness, parasthesias ( pins and needles sensation and tingling), aphasia (difficulty with understanding or producing language), vertigo, ataxia (incoordination), nausea, vomiting, sensitivity to light and noise, and head pain. 2 Although migraines are common, the condition remains underdiagnosed, as only 50% of patients seek medical attention for migraines, of whom only two-thirds are properly diagnosed. 4 Classification Migraines are classified based on symptoms. There are six types of migraines recognized by the IHS. 3 The two most common types of migraine are migraine without aura and migraine with aura. Migraine without aura is the more common of the two, has a higher average attack frequency, and is usually more disabling. Debilitating symptoms include aggravation with routine activity, vomiting, and sensitivity to everyday lights and sounds. Some of the symptoms listed above (e.g., visual changes, parasthesias) occur with aura, which is a phenomenon seen inconsistently. Some of the other symptoms listed, such as aphasia, motor weakness, and ataxia, are rarely seen clinically and would suggest the presence of a potentially serious anatomical lesion. Other types of migraines include childhood periodic syndromes that are commonly precursors of migraines, retinal migraines, complicated migraines, probable migraines, and chronic migraines. 3 4 CALIFORNIA HEALTHCARE FOUNDATION

6 Epidemiology Migraines affect approximately 11% of the adult population in Western countries. 5 Prevalence is highest between the ages of 25 and 55 years, peaking between 35 and 45 years of age. In Europe and North America, migraines affect 6% of males and 15% to 18% of females. The incidence is higher among whites than blacks or Asians. Over the last decade, the prevalence and distribution of migraines in the United States have remained constant. 2 The prevalence of migraines in children and adolescents increases with age. 6 In 3- to 7-yearolds, the incidence is 3%; in 7- to 11-year-olds, 4% to 11%; and in 11-to 15-year-olds, 8% to 23%. Migraines affect both boys and girls equally until puberty. 7 After puberty, the incidence is higher in females. 7 The mean age of onset in children is 7.2 years in boys and 10.9 years in girls. 6 Economically, migraines are a large burden on society. The World Health Organization ranks migraines as the 19th leading cause of disability worldwide. 4 Approximately 58% of migraines require bed rest for symptom resolution. 8 The average length of bed rest per headache ranges from 4.5 hours in men to 6 hours in women, equating to million bedridden days annually by migraine sufferers. The overall economic impact to society is comparable with that of diabetes and more than that of asthma. A 1998 report estimated the annual total direct cost of migraine attacks to be $1 billion and the annual total indirect cost to be $13.3 billion. Cause and Risk Factors There is no consistent genetic explanation for migraines, although 50% of migraine sufferers report a family history. 7 Among children for whom both parents experience migraines, there is a 75% chance that they will also develop the condition. 1 Any single risk factor, or more commonly a combination of factors, can set off a migraine. 9 Food may be an important contributing factor, especially in children. A doubleblind, controlled trial of 88 children found that 93% of subjects no longer experienced migraines when following an oligoantigenic diet. 10 Women may suffer from hormone-triggered migraines; however, this incidence is low. Approximately 14% of women who suffer from migraines have true menstrual migraine (beginning 1 day before to 4 days after the onset of menses), whereas 60% of women report a relation between their migraines and menses. 11 Risk factors may be beyond a patient s control (e.g., weather, puberty, menopause, bright lights), may be difficult to alter (e.g., depression, high altitude), may be inevitable due to life changes (e.g., pregnancy), or may otherwise benefit the patient (e.g., physical activity). Table 1 lists the risk factors for migraine attacks. Migraines: Treatment Options Report 5

7 Table 1. Risk Factors That May Provoke Migraines 9,12-14 Emotional Anger Anxiety Depression Excitement Let down response Environmental Allergens Bright lights or glare Head or neck injury High altitude Motion Noise Physical strain Strong odors Tobacco smoke Weather changes Dietary Alcohol Caffeine Cheese Chocolate Citrus fruits Cured meats Chemicals Aspartame Benzene Insecticides Monosodium glutamate Nitrites Tyramine Lifestyle Changes in sleep pattern Chronic high levels of stress Physical activity Skipping meals or poor diet Smoking Drugs Atenolol Caffeine or caffeine withdrawal Cimetidine Danazol Diclofenac Hydralazine Indomethacin Nifedipine Nitrofurantoin Nitroglycerin Oral contraceptives Reserpine Hormonal Estrogen use Menarche Menopause Menstruation Pregnancy Pathophysiology The etiology of migraines is largely unknown, although the prevailing belief is that migraines result from neuronal dysfunction. 15 Initially, an event occurs in the brainstem, causing an unstable trigeminovascular reflex that leads to excessive discharge of the trigeminal nerve and basal thalamic nuclei, which in turn releases vasoactive peptides, such as substance P and calcitonin gene-related peptide, resulting in vasodilatation and pain. The pathways that link migraine pain with auras are not well understood. A phenomenon of cortical spreading depression has been described, wherein a selfpropagating wave of neuronal depolarization across brain tissue occurs, which in turn may cause the aura of migraine and activate trigeminal 6 CALIFORNIA HEALTHCARE FOUNDATION

8 nerve afferents. 15 Auras occur with progressive neurologic deficits or disturbances that recover completely. The imbalance in activity between brainstem nuclei regulating antinociception and vascular control contributes to the pathogenesis of migraines. Serotonin has direct action on the cranial vasculature and central pain control pathways, although its exact role in migraine pathophysiology is unclear. Natural History and Prognosis The information available on the natural history and prognosis of migraines is scarce. Over half of children who develop migraines will have remission following puberty. 7 However, adolescents who develop migraines typically continue to have less frequent but more severe migraines into adulthood. There are few long-term effects associated with acute migraines. Still, patients with chronic migraine have a poor quality of life and suffer from pain that can affect daily activities. Usually the disease is not progressive, and declines in frequency after the age of 45 to 50 years in female patients. 7 However, up to 4% of the migraine population may experience chronic daily migraines, 75% of whom had progressed and deteriorated from episodic migraines. 16 Improvement to baseline episodic migraines is rare, and this group of patients responds poorly to treatment. Repeat episodes of migraines and the severity of migraines is correlated with permanent changes in central nervous system (CNS) structure or function and disability. 16 Treatment to decrease attack frequency and severity can lead to decreased disability and, possibly, decreased CNS changes. Diagnosis The diagnosis of migraines may be difficult. 17 Evolving evidence suggests that in patients with a history of debilitating migraine, most, if not all, attacks arise from migraine pathology. 18 Thus, the tension headaches that these patients report are in reality a mild version of migraine. The important implications are that, for these patients, diagnosis is made easier and a tension headache should be treated as a migraine. To obtain a proper diagnosis, the clinical evaluation should include a detailed patient history, a thorough physical examination, and a focused neurologic examination. 17,19 The diagnosis of migraine involves ruling out secondary causes of headache. Diagnostic tests, such as neuroimaging (computed tomography or magnetic resonance imaging), electroencephalography, lumbar puncture, cerebrospinal fluid analysis, or blood studies, are indicated only in the presence of the following causes: subacute and/or progressive headaches that worsen over time; a new or different headache; any headache of maximum severity at onset; headaches of new onset after the age of 50 years; persistent headache precipitated by a Valsalva maneuver (e.g., cough, sneeze, bending, with exertion); evidence such as fever, hypertension, myalgias, weight loss, or scalp tenderness suggesting a systemic disorder; neurologic signs; or seizures. 17 Table 2 lists the IHS criteria for the classification and proper diagnosis of migraine, with or without aura. 3 Migraines: Treatment Options Report 7

9 Table 2. International Headache Society Criteria for the Classification and Diagnosis of Migraine, With and Without Aura 3 Migraine Without Aura A At least five attacks fulfilling criteria B-D Migraine With Aura At least two attacks fulfilling criteria B-D B Each attack, untreated or unsuccessfully treated, lasts 4-72 hours Aura consisting of at least one of the following, but with no motor weakness: Fully reversible visual symptoms, including positive features (flickering lights, spots, or lines) and/or negative features (loss of vision) Fully reversible sensory symptoms, including positive features ( pins and needles ) and/or negative features (numbness) Fully reversible dysphasic speech disturbance C The attack has at least two of the following characteristics: Unilateral location Pulsating quality Moderate-to-severe intensity Aggravation by or causing avoidance of routine physical activity At least two of the following: Homonymous visual symptoms and/ or unilateral sensory symptoms At least one aura symptom developing gradually over >_ 5 minutes and/or different aura symptoms occurring in succession over >_ 5 minutes Each symptom lasts >_ 5 minutes but <_ 60 minutes D During the headache, at least one of the following characteristics is present: Photophobia and phonophobia Nausea and/or vomiting Headache fulfilling criteria for migraine without aura beginning during the aura or following the aura within 60 minutes E Not attributed to another disorder Not attributed to another disorder 8 CALIFORNIA HEALTHCARE FOUNDATION

10 II. Treatment of the Condition THE MANAGEMENT OF MIGRAINES INVOLVES pharmacologic and nonpharmacologic intervention. It is important to remember that the objective is control, and not cure. Acute treatment will shorten the duration of individual headaches, whereas prophylactic therapy will decrease the frequency and severity of attacks. Goals of therapy include reducing attack frequency, severity, and duration, while reducing reliance on poorly tolerated, ineffective, or unwanted acute pharmacotherapies. 20,21 Other goals include improving quality of life and decreasing disability, and avoiding the escalation of acute headache medication. Providers should educate and enable patients to manage their disease so as to enhance personal control of their migraines. Finally, treatment should reduce headache-related distress and psychological symptoms. Knowing when to refer a headache patient to a specialist is important. Diagnostic uncertainty, treatment failure, suspicion of secondary headache syndrome, medication overuse, chronic migraine or chronic daily migraine, and patient reassurance are all good reasons for referral to a specialist. 2 Patient education is a necessary component of any treatment plan and is recommended to optimize patient care. 12 Clinicians should determine each patient s knowledge base and become aware of the individual s attitudes, beliefs, cultural background, environmental factors, and social context that can influence the treatment management plan. 13 The education given to the patient should include the diagnosis of migraine; basic pathophysiology; treatment options, including benefits and limitations; treatment expectations, describing the concept of control, and not cure; and use of a diary. 12 As the first step in proper migraine management, it is important to discuss known factors that precipitate acute migraine and how to avoid these factors. 12,13 Guidelines also advocate using printed materials to reemphasize the clinician s advice. 12 Diaries are an important tool in migraine management. They enable monitoring of treatment effect on the severity and frequency of attacks, as well as disability. 12 A diary is especially useful for identifying factors that precipitate migraine attacks in a patient. Migraines: Treatment Options Report 9

11 Prophylactic Treatment Most patients with migraine are treated effectively with various acute migraine medications. However, there are patients who suffer from migraines in whom prophylactic therapy is warranted to decrease the frequency and the severity of headaches. The goal of preventive treatment is to decrease the frequency of attacks as much as possible. 17,22 However, some guidelines only consider prophylactic therapy efficacious if pain and disability are decreased with each individual attack, or if the preventative therapy increases the response to acute migraine treatment. 17 The following criteria may help guide clinicians in their decision to initiate prophylactic therapy in migraineurs: 22,23 Headache frequency of more than 2 days per week or 8 days per month Use of acute medications, successfully or unsuccessfully, for more than 2 days per week Headache attacks that remain disabling despite aggressive acute intervention, as documented by lifestyle interference, ratings on disability scales, or use of rescue medications more than once a month Presence of prolonged aura lasting more than 1 hour, aura with negative neurologic symptoms (loss of function), or migraineinduced stroke The cost of acute and preventive therapies Nonpharmacologic Prophylactic Treatment Options Nonpharmacologic interventions, including behavioral or physical modifications, are usually reserved for preventing migraines rather than acute treatment. 21 However, some patients are able to use these techniques to modify the course of a current headache, decreasing or eliminating the use of acute medications. 12,24 Behavioral therapies are often used in combination with each other or with pharmacologic therapy, despite their effectiveness as monotherapy. 21 Patients may eschew pharmacologic treatment owing to poor tolerance, medical contraindication, cost, or inadequate response. Behavioral treatment may be preferred in patients who are pregnant, are planning a pregnancy, are breastfeeding, have a history of excessive analgesic use or other acute medications, complain of stress, or have defiant coping skills or comorbid psychological disorders. 24 The choices for nonpharmacologic preventive therapy include biofeedback, relaxation therapy, cognitive behavioral therapy (CBT), acupuncture, hypnosis, transcutaneous electrical stimulation, vagus nerve stimulation, psychiatric therapy, physical therapy, and exercise. 12 The goals of these therapies are to reduce the frequency and severity of headaches, reduce headache-related disability, reduce reliance on poorly tolerated or unwanted pharmacotherapies, enhance personal control of migraine, and reduce headache-related distress and psychological symptoms. 25 Contraindications to, failure of, overuse of, or adverse events with acute treatment Patient desire to reduce the frequency of acute attacks 10 CALIFORNIA HEALTHCARE FOUNDATION

12 Biofeedback Biofeedback is the use of monitoring equipment to detect, amplify, and display internal physiologic processes online so that patients may learn to control their nervous system, in order to respond to stressors through their parasympathetic nervous system. 12,24 Several different biofeedback types have been shown to be effective in the prophylaxis of migraines, including thermal control, electromyographic (EMG), and blood volume pulse biofeedback. A meta-analysis of 25 controlled trials found biofeedback to be as effective as prophylactic propranolol, with a 43% reduction in migraine headache activity. 26 Headache activity (a composite of headache frequency, intensity, and duration) has been found to be decreased by 40% to 50% with the use of EMG biofeedback. 24,25 Thermal biofeedback, in combination with relaxation therapy, can decrease headache activity by about 35% in migraine patients. Biofeedback is limited by its time commitment. It is recommended as an adjunct to pharmacologic therapy or as an alternative in patients who are intolerant of medications. 12 Relaxation Therapy Three types of relaxation therapy are widely used for migraine prophylaxis: progressive muscle relaxation (PMR), autogenic training, and meditation. Guidelines state that relaxation techniques can reduce headache activity by 40%. 24,25 Two meta-analyses, published in the 1980s, suggested that relaxation therapy, including PMR, breathing exercises, meditation, or directed imagery, is as effective as biofeedback. 12 Autogenic training is a form of relaxation therapy that involves self-instruction of bodily perceptions, such as warmth and heaviness. 24 A meta-analysis of seven randomized controlled studies involving 626 migraine patients found autogenic training to improve migraine headaches substantially. 27 Cognitive Behavioral Therapy CBT allows patients, with the help of a therapist, to recognize and modify maladaptive behaviors that may be exacerbating their headache. 12,24,28 It is designed to identify the feelings that can cause migraine, to develop a treatment action plan to improve these thoughts or perceptions, and to encourage long-term use of the method(s). CBT has been shown to be effective in reducing headache activity by 49%. 28 There are several types of CBT, including assertiveness training, cognitive restructuring, stress management, and coping skills. 24 Patient selection is critical as CBT is only minimally effective in chronic head pain and the therapy is limited by its time commitment, cost, and availability. 12,24 Transcutaneous Electrical Stimulation Transcutaneous electrical stimulation requires placement of electrodes that send low-intensity currents through the head to relieve pain. It is currently not recommended for migraine treatment as there is scarce information on efficacy and safety. 12,17,25,28 Vagus Nerve Stimulation Vagus nerve stimulation has been found to provide relief of severe chronic migraines in case reports and indirect evidence. It alters cerebral metabolism and blood flow in the limbic system, and may affect the neurotransmitter systems involved in migraine through stimulation of the vagus nerve. 29 Currently, there have been no controlled trials examining this invasive surgical procedure in the treatment of migraines; the procedure therefore is not recommended. 28 Migraines: Treatment Options Report 11

13 Acupuncture Acupuncture is the use of needles inserted strategically by trained professionals to provide pain relief. There is no consensus on the efficacy of this treatment for migraine, with varying reports of substantial to no pain relief. 12,17,25 One study, comparing acupuncture with control ( no treatment or wait-list), found a 53% reduction in the frequency of disabling headaches; however, the significance of between-group differences was not tested. 25 A meta-analysis of 14 controlled trials found a trend towards pain relief. 30 A Cochrane review of acupuncture in the treatment of primary headache concluded that additional well-designed, large, controlled studies are needed to prove the efficacy of this treatment, even though current evidence supports the use of acupuncture. 31 A 2005 randomized controlled trial of 302 patients (88% women) found acupuncture and sham acupuncture to decrease the mean number of days with headache (severeto-moderate pain) by 2.2 days, from a baseline of 5.2 days in the acupuncture group and 5.0 days in the sham acupuncture group. 32 In comparison, the wait-list group that received no acupuncture saw a decrease of only 0.8 days from a baseline of 5.4 days. The percentage of patients for whom headache days were reduced by 50% or more was 51%, 53%, and 15% in the acupuncture, sham acupuncture, and wait-list groups, respectively. There was no statistical difference between the sham acupuncture and acupuncture treatments. This procedure is limited by availability and cost. 17 The most notable risk from this treatment, although rare, is the risk of infection associated with contaminated needles. Physical Therapy Physiotherapy, osteopathy, chiropractic, and other physical treatments lack evidence from controlled clinical trials to support their use in the treatment of migraine headaches. 12,28 A small randomized controlled trial of 85 volunteers with migraines treated with chiropractic manipulations, performed in 1978, demonstrated a decrease in migraine frequency and severity. 12 Indeed, cervical mobilization or manipulation has been associated with rare cases of stroke and death. One uncontrolled trial reported marked improvements in post-treatment headache scores for frequency and severity, but no effect on duration. 17,25 Physical therapy has proven to be more effective than manipulative treatment in a few limited studies and in select patients. 28 Spinal manipulative treatment (SMT), defined as the application of high-velocity, low-amplitude, manual thrusts to the spinal joints, slightly beyond the passive range of joint motion, has been shown to be advantageous. 33 A metaanalysis of nine randomized controlled trials involving 683 patients found SMT to decrease pain intensity, disability scores, duration of attacks, and frequency of attacks in limited and small trials. 33 No serious complications or side effects were reported, and only 5% of patients undergoing SMT reported side effects, which primarily included neck stiffness and muscle soreness. The role or importance of these therapies in migraine treatment remains to be determined and requires further well-designed controlled trials. 12 CALIFORNIA HEALTHCARE FOUNDATION

14 Exercise In one small trial of 11 patients, exercise decreased the frequency but not the severity of migraine headaches. 34 The beneficial effects of exercise are thought to be due to central pain inhibition, as well as effects on sleep, which indirectly improves headaches. Although there is no direct link between exercise and headache, exercise is still a recommended treatment in the prevention of migraines. 12,28 Hypnosis Hypnosis has a limited role in the prophylactic management of migraines in patients who are willing to undergo the procedure. 12,28 It may reduce distressing sensory input and have a placebo effect. 12 A meta-analysis of 18 trials found hypnosis to be of additional benefit when combined with CBT, as compared with CBT alone. 35 One study in the U.S. Headache Consortium s guidelines compared biofeedback plus relaxation therapy with self-hypnosis, and found both groups to provide a marked reduction in headache frequency. 25 Alternative and Complementary Medicines Herbal Therapies Herbal remedies remain a very popular treatment option as they are often perceived by patients as natural and safer than prescription medications. However, since the Food and Drug Administration (FDA) does not regulate herbal or nutritional remedies, their safety and effectiveness are not tested and may not be known. Several herbal products have been found to be safe and possibly effective in the management of migraines, and under medical supervision, they may represent additional treatment options for patients with migraine. 28 Feverfew has been tested in a few randomized, double-blind trials, which reported mixed results for efficacy, with an extensive safety profile. 12,23,28,36 It decreases the frequency of migraines (one study reported 1.5 vs. 3.4 attacks per month compared with placebo; another study reported 3.6 vs. 4.7 attacks per 2 months compared with placebo). 36 A recent review examining five controlled trials of 343 patients found mixed results for the efficacy of feverfew in preventing migraines, concluding that there is insufficient evidence to recommend the use of feverfew. 37 The long-term effects of feverfew have not been studied, and therefore it is not recommended for use for longer than 4 months, without medical supervision. 36 Although the mechanism of action for the effect of feverfew is unknown, there are several hypotheses. 36 The dose found effective in studies contains 250 µg of the active ingredient parthenolide. 17,36 However, since these products are not regulated, the amount of active ingredient may vary among manufacturers, and so patients should select products made by large and reputable companies. The most common side effects reported in studies include gastric upset, mucosal ulcerations, lip swelling, and tongue irritation. 36 However, feverfew can increase bleeding time and enhance the effects of aspirin and warfarin, and therefore should be used with caution in patients taking these other medications. 28,36 Another herbal product, butterbur root extract (the only pure form is sold as Petadolex), has two trials supporting its safety and efficacy. 28 In the first study, 33 patients were given butterbur root extract, 50 mg twice daily, and after 3 months, headache frequency had decreased from 3.4 attacks to 1.8 attacks per month. 38 The second study, involving 245 patients, found butterbur root extract to decrease migraine frequency by 48%, 36%, and 26% in patients receiving 75 mg Migraines: Treatment Options Report 13

15 twice daily, 50 mg twice daily, and placebo, respectively. 39 The most frequently reported adverse event was gastrointestinal upset, primarily burping. Dietary Supplements A few dietary supplements have been shown to be effective for migraine prophylaxis, among which magnesium, at doses of 400 to 600 mg/day, is one. 12,17,23,28 Three of four double-blind published studies found magnesium to be effective in the prophylaxis of migraines. 23,28 One study, involving 81 subjects, found high-dose magnesium to significantly decrease the frequency of headache by 41.6%, and to reduce, although not achieving significance, the severity and duration of migraine attacks, as well as reduce drug usage. 40 The study that did not demonstrate any significant improvements with magnesium reported a high incidence of diarrhea and poor tolerance, possibly suggesting that the drug was not absorbed. The chelated version of magnesium and magnesium oxide are better tolerated. 28 Another dietary supplement is riboflavin (vitamin B2). Riboflavin, at doses of 400 mg daily, has been shown to decrease the frequency and severity of migraines in randomized placebocontrolled trials. 12,17,23,28 This treatment option has an excellent side-effect profile, with no drug interactions; 12 however, the onset of effect may take months to demonstrate efficacy. 28 Finally, Coenzyme Q10, at doses of 300 mg daily, has been shown to be effective in a double-blind controlled trial. 28 Homeopathy/Naturopathy Homeopathy has not been shown to be an effective means of therapy in any controlled clinical trial. 28 There is little, if any, evidence supporting the benefits or cost-effectiveness of homeopathy in the management of migraines. 12 Prophylactic Prescription Drug Treatment The selection of a prophylactic medication for migraines should be based on efficacy, concurrent medical conditions, possible adverse events, dosing regimen, and patient preference. 22 Prophylactic treatment strategies are classified as episodic, short-term, or chronic. Episodic prevention is utilized if the migraine trigger is known (e.g., exercise). Short-term prophylaxis is employed when the exposure to the trigger is time limited (e.g., menstruation). Chronic preventative therapy may be used in the longterm (months to years) when the trigger is unknown. The fundamental key to a successful prophylactic or preventative regimen is compliance. Medications are typically started at lower doses, titrated up as needed, and sustained for 4 to 8 weeks before any benefit is noticed by the patient. 17,22 Typically, doses for migraine prophylaxis are lower than doses for the primary indication of the drug. 22 A 50% reduction in headache frequency is considered successful, and once this is attained, the prophylactic regimen is continued for 6 to 12 months before a gradual taper is begun. Table 3 outlines the U.S. Headache Consortium s evidence-based guidelines for pharmacologic migraine prophylaxis. The guidelines were based on results from 300 controlled trials, and rank drugs based on their clinical efficacy, adverse events, safety, and clinical experience. The choices for prophylactic medications include neurostabilizers, antidepressants, beta-blockers, calcium channel blockers, nonsteroidal antiinflammatory drugs (NSAIDs), and serotonin antagonists. 23 Patient preferences regarding drug costs, delivery, dosing schedule, tolerability, and comorbidities should be evaluated and considered when choosing the appropriate prophylactic medication CALIFORNIA HEALTHCARE FOUNDATION

16 Neurostabilizers Neurostabilizers are an option for the continuous preventative treatment of migraines. As a drug class, neurostabilizers are 2.4 times more likely than placebo to decrease the frequency of migraines by 50% or more. 41 Compared with placebo, they also reduce the number of attacks by 1.4 every 28 days. 41 The exact mechanism by which neurostabilizers provide benefit in migraine prophylaxis is unknown. Anticonvulsants are typically dosed at much lower doses than when used for other conditions (see Table 3 for more dosing information). 22 Lower doses provide a better safety and tolerability profile. Variation exists among neurostabilizers. The number of studies examining these medications is small, and the number of patients in each study is also small. Two neurostabilizer medications, divalproex sodium (Depakote) and topiramate (Topamax), have been approved by the FDA for the indication of migraine prophylaxis. Among the neurostabilizers, divalproex sodium and sodium valproate are the most studied. These drugs were used in seven of the 15 trials evaluating neurostabilizers for migraine prophylaxis, in which they were shown to be more effective than placebo. 23,41 Unfortunately, a large percentage of patients report adverse events, including nausea, weight gain, hair loss, and tremor, while taking these medications. 14,19 Divalproex sodium and sodium valproate are known teratogens and should not be used during the first-trimester of pregnancy or in women of child-bearing age. 41 Topiramate has been studied in three randomized controlled trials, in which it was found to be of clinical benefit in migraine prevention. 23,41 Topiramate has been associated with weight loss; the most commonly reported adverse event is parasthesia. 22,41 Although there are very few studies in humans, topiramate is also thought to be a teratogen, and appropriate cautioning is warranted for its use in women of child-bearing age. 41 Topiramate also decreases the efficacy of estrogen-based birth control pills. Other neurostabilizers, including gabapentin, lamotrigine, clonazepam, and carbamazepine, have been evaluated for possible efficacy in migraine prophylaxis. Gabapentin has a good safety and tolerability profile, and has been found to be effective in migraine prophylaxis, although the two trials that demonstrated these benefits were poorly conducted. 23,41 Since the study results were questionable, gabapentin should be reserved for patients who do not respond to or cannot tolerate first-line agents. 23 The remaining neurostabilizers can not be recommended for prophylactic use as evidence is lacking to support their efficacy or safety. 41 Antidepressants Antidepressants can also be used for long-term migraine prevention, although none have received FDA approval for this indication. 22 Studies have shown that patients treated with an antidepressant were twice as likely to have headache improvement as compared with those taking placebo. 42 Indeed, subjects receiving an antidepressant had a 1 standard deviation (SD) unit improvement in headache burden and a 0.7 SD unit reduction in consumption of analgesic medications, as compared with placebo. The exact mechanism by which antidepressants improve migraines is unclear, but is unrelated to their mechanism for antidepressant activity. 19 Migraines: Treatment Options Report 15

17 Table 3. U.S. Headache Consortium Guidelines for Migraine Prophylaxis Medications 22 Group 1 Medium-to-high efficacy, good strength of evidence, mild-to-moderate side effects Amitriptyline ( mg/d) Divalproex sodium ( mg/d) Propranolol ( mg/d) Group 2 Sodium valproate ( mg/d) Timolol (20-30 mg/d) Topiramate ( mg/d)* Lower efficacy, limited strength of evidence, mild-to-moderate side effects Aspirin (1300 mg/d) Atenolol (100 mg/d) Botulinum toxin type A ( units/3 months)* Fenoprofen (600 mg TID) Feverfew (250 µg/d) Fluoxetine (10-40 mg/d) Flurbiprofen (200 mg QD) Gabapentin ( mg/d) Group 3 No scientific evidence of efficacy, but clinically efficacious based on consensus of experience a) low-to-moderate adverse events: Cyproheptadine Doxepin Nortriptyline Paroxetine Sertraline Venlafaxine Group 4 Medium-to-high efficacy, good strength of evidence, but concerns about side effect Methysergide Group 5 Ketoprofen (75 mg TID) Magnesium ( mg/d) Metoprolol ( mg/d) Nadolol ( mg/d) Naproxen ( mg BID) Nimodipine (30 mg TID) Riboflavin (400 mg/d) Verapamil ( mg/d) b) frequent-to-severe adverse events (or safety concerns), complex management issues: Methylergonovine Phenelzine Evidence indicating no efficacy over placebo Acebutolol Carbamazepine Indomethacin Nabumetone Nicardipine Nifedipine Pindolol *Based on evidence not available at the time of publication of the U.S. Headache Consortium guidelines. 16 CALIFORNIA HEALTHCARE FOUNDATION

18 Tricyclic antidepressants (TCAs) inhibit noradrenaline and serotonin reuptake, which attenuates beta-adrenergic and central serotonin receptor function, all of which modulate pain. 19,42 For information on dosing of individual agents with proven benefit in this class, see Table 3. A 2001 meta-analysis of 38 published trials found antidepressants as a class to be efficacious for long-term headache prophylaxis. 42 The metaanalysis examined efficacy for both tension and migraine headaches, and found antidepressants to be equally effective. When examining specific antidepressant classes, TCAs and serotonin antagonists were effective in reducing headache burden, with similar risk reduction. The TCA amitriptyline and the serotonin antagonist pizotifen (unavailable in the United States) have demonstrated efficacy in migraine prevention. 22,23,42 Amitriptyline s most common side effects include drowsiness, weight gain, and anticholinergic symptoms. 14 The most common side effects observed with pizotifen are weight gain and fatigue. 19 Another serotonin receptor antagonist, methysergide, was removed from the U.S. market owing to an extensive side-effect profile that included some potentially life-threatening adverse events. 19,23 There is no evidence supporting the use of other TCAs such as nortriptyline, doxepin, clomipramine, and imipramine. 14 The benefit of selective serotonin reuptake inhibitors (SSRIs) is not established, as only two of eight trials reported statistically significant headache improvement. 42 Most guidelines do not recommend SSRIs for migraine prophylaxis, unless the patient has a comorbid depressive or anxiety disorder. 19,22 However, some guidelines state that there is evidence supporting the use of fluoxetine, which has been shown to have a modest effect in migraine prevention. 14,23 There is no evidence supporting the use of fluvoxamine, paroxetine, sertraline, phenelzine, bupropion, mirtazapine, trazodone, or venlafaxine. 14,19 The most common adverse effects of SSRIs include sedation, insomnia, nausea, and sexual dysfunction. 22 Beta-Blockers Beta-blockers are the most studied and most commonly used medications for chronic migraine prophylaxis. 22 In general, beta-blockers are 60% to 80% effective at decreasing the frequency of migraine attacks by more than 50%. 22 The exact mechanism by which betablockers provide migraine prophylaxis is unknown. 19 For specific dosing information, see Table 3. The most common side effects include fatigue, light-headedness, bradycardia, nausea, dizziness, insomnia, exercise intolerance, depression, and sexual dysfunction. 14,22 Adverse effects are generally well tolerated and cause few discontinuations in therapy. Due to idiosyncratic drug effectiveness, a combination of betablockers or a trial of another drug in the class should be attempted before this medication class is considered ineffective in a patient. 19,22 The only two beta-blockers with FDA approval for use in migraine prophylaxis are propranolol and timolol. Other agents, such as atenolol, metoprolol, and nadolol, have evidence of moderate efficacy in migraine prevention. 14 Betablockers with intrinsic sympathomimetic effects have not been shown to have benefit in migraine prevention. 14,22 A 2004 review concluded that propranolol is more effective than placebo in short-term interval treatment, but long-term evidence was lacking. 23,43 No clear conclusions regarding the efficacy of propranolol in comparison with other agents (e.g., calcium channel blockers, other beta-blockers, other drugs) could Migraines: Treatment Options Report 17

19 be drawn owing to insufficient numbers of or poorly conducted trials. 43 Since timolol, atenolol, and nadolol have demonstrated beneficial effects when compared with placebo, or equivalent effects when compared with propranolol, the U.S. Headache Consortium guidelines have also included these beta-blockers as effective agents in migraine prevention. 23 Calcium Channel Blockers Although the use of calcium channel blockers in patients with migraines has been well studied, the evidence for their effectiveness is less persuasive than for anticonvulsants, antidepressants, and beta-blockers. 14,22 Verapamil was found to be markedly better than placebo in two of three controlled trials; however, there were high dropout rates. 23 Nimodipine was also found to be more effective than placebo in two of five placebo-controlled trials, with large and statistically significant differences favoring nimodipine. 23 When these two agents were individually compared with propranolol, no significant differences were found. 23 Nifedipine is usually not recommended as studies have reported mixed results that are difficult to interpret, and the vasodilatory effects of the drug may be detrimental in migraines. 23,44 No evidence supports the use of diltiazem for migraine prophylaxis. 14 The mechanism of action of calcium channel blockers is through modulation of neurotransmitters and cytoprotection, through the prevention of hypoxia and cellular influx of calcium ions. 19 For dosing information, see Table 3. This medication class is popular because of its tolerability and limited adverse events, which may include dizziness, hypotension, constipation, flushing, and edema. 22 NSAIDs NSAIDs have a modest effect on migraine prevention and are typically used in episodic or short-term migraine prophylaxis. 14,19,22,23 Naproxen has the most evidence for efficacy, especially for the prevention of perimenstrual migraine attacks. 19,23 However, similar trends have been seen in single placebo-controlled trials of flurbiprofen, ketoprofen, and mefenamic acid. 14,23 For migraine prophylaxis, the evidence is inconclusive for aspirin, aspirin with dipyridamole, fenoprofen, and indomethacin. 14 No evidence supports the use of ibuprofen or nabumetone. 14 The mechanism of benefit is through inhibition of cyclooxygenase action and prostaglandin biosynthesis and action. 19 The most common side effects involve gastrointestinal upset, in the form of nausea, vomiting, gastritis, and blood in the stool. 14 Concerns about peptic ulcer disease or erosive gastritis, coupled with adverse renal events, has limited the use of NSAIDs for migraine prophylaxis. 22 Other Prophylactic Drug Treatment Options Botulinum Toxin Type A The use of botulinum toxin type A (Btt A) in the prophylaxis of migraines is an emerging therapy that needs further study. 28 The efficacy of Btt A has been confirmed by controlled trials, with reports of effects lasting an average of 3 months. 28,45 A recent review article states that in one clinical trial of 123 patients, Btt A was better than placebo in reducing the frequency of attacks and decreasing the number of days during which acute pain medication was used. 45 Another trial, in which 77% of the 271 patients were refractory to oral medications and 48% reported overuse of acute medications, found Btt A to reduce headache frequency, the number of headache days per month (18.9 to 8.3 days), and 18 CALIFORNIA HEALTHCARE FOUNDATION

20 headache intensity. 45 Its mechanism of headache relief is unclear, but is thought to be through action at the neuromuscular junction reducing the local release of nociceptive neuropeptides, or through nerve stimulation. 45 The optimal dosage and location of injections is still under investigation. 28 Side effects associated with this treatment are mild and rare (95% report no side effects), and typically involve minimal discomfort at the injection site. 28,45 Hormones Hormonal therapy is a prophylactic treatment option in women in whom standard short-term prophylaxis with NSAIDs, triptans, or ergotamines around menses, perimenopause, or menopause is unsuccessful or contraindicated. 17 Hormonal prophylaxis can be in the form of oral estradiol, estradiol patches or gel, progestin, or estrogen-containing contraceptives. Estradiol is the preferred form of estrogen as it does not convert to other active forms of estrogen. 11 The efficacy of hormonal therapy has varied among trials, owing to small patient samples and variable dosing regimens. Ergotamines There is insufficient evidence to support migraine prophylaxis with ergotamine or ergotamine combinations with caffeine, butalbital, and belladonna alkaloids. 23 Methysergide, a semisynthetic ergot alkaloid, has been shown to be efficacious for the prophylaxis of migraines, although its use is limited by reports of retroperitoneal and retropleural fibrosis associated with uninterrupted, long-term use. 23 Acute Management of Migraines The successful management of an acute migraine requires a treatment plan that includes patient and physician agreement on goals. Patients need to be engaged in their own management by discussing treatment and medication preferences that are then tailored to their individual needs based on illness severity, comorbid conditions, and history of response to prior medications. 20 The goals identified by the U.S. Headache Consortium to help define successful treatment of acute migraine attacks are to treat attacks rapidly and consistently without recurrence, to restore the patient s ability to function, to minimize the use of backup and rescue medications, to optimize self-care and reduce subsequent use of resources, to be cost-effective for overall management, and to have minimal or no adverse effects. 20 Nonpharmacologic Acute Treatment Options Cold/Pressure Cold or pressure applications, as well reducing activity and sensory input by retreating to a quiet dark room and attempting to sleep, are established methods that migraine sufferers have found helpful. 12 Neural Blockade In small uncontrolled trials, nerve blockade with local anesthetics at the occipital or supraorbital nerve has been found to be effective in relieving acute migraines where pain is localized to the occipital or frontal regions. 12 The greatest risk, although rare, is the possibility of an allergic reaction to the local anesthetic. This form of therapy, however, is not practical, especially if needed on repeated occasions. Migraines: Treatment Options Report 19

21 Acute Prescription Drug Treatment The choice of agents used for an acute attack should be based on the frequency and severity of the attacks, the presence and degree of disability, the associated symptoms, the patient s history of response and tolerance to specific agents, and comorbid conditions. 14 All patients should be prescribed at least two acute medications: one as their primary drug and one to use if the primary drug fails. This can help avoid unnecessary patient suffering and emergency department visits. To avoid the associated problems of medication overuse, acute therapy should be limited to 2 days per week. 14 If medication overuse becomes an issue, a prophylactic migraine regimen should be considered. Medications that are effective in the treatment of an acute migraine include NSAIDs, dihydroergotamine (DHE), triptans, and combination drugs (e.g. aspirin, acetaminophen, caffeine). If severe attacks are not alleviated with these medications, opiates, corticosteroids, or intravenous DHE should be considered. 14,19 NSAIDs NSAIDs are considered first-line therapy in patients with acute migraines, and are even appropriate in severe attacks that have responded to them in the past. 14,19 Most evidence from randomized placebo-controlled trials supports the use of aspirin, ibuprofen, and naproxen. All three agents have been shown to be more effective than placebo. 7,19 However, over-thecounter NSAID trials consistently exclude patients who suffer from moderate-to-severe attacks (patients enduring morbidity with 50% or more of attacks and/or vomiting with 20% or more of attacks); thus, these trial results only apply to a minority of migraine sufferers. 46 Evidence from a randomized placebo-controlled trial of 351 migraine patients supports the use of acetaminophen alone in acute migraine attacks. 47 Two hours after dosing, the headache response rate for acetaminophen was 57.8%, compared with 38.7% for placebo (P = 0.002). Pain-free rates at 2 hours in the acetaminophen and placebo groups were 22.4% and 11.3%, respectively (P = 0.01). The combination product of acetaminophen, aspirin, and caffeine has also been shown to be beneficial. 20 Ketorolac represents a parenteral option that may have advantages in the patient who is vomiting; however, there are no placebo-controlled trials testing its efficacy at this time. 20 For information on dosing in patients with acute attacks, see Table Triptans Triptans are another treatment alternative for migraineurs who experience more severe headaches, or for those whose headaches respond poorly to NSAIDs or other combination analgesics (e.g., aspirin/acetaminophen/caffeine or isometheptene-containing products). 9,17,19,20 There are seven triptans available in the United States: almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan. None are approved for prophylactic migraine use, but all are FDA approved for acute use during a migraine attack. They work as agonists at the 5-hydroxytryptamine (5-HT1B/1D) receptors, and are available as oral tablets or capsules, sublingual wafers, intranasal sprays, or subcutaneous injections. The bulk of quality data comes from studies of oral triptans. 20 CALIFORNIA HEALTHCARE FOUNDATION