Vivid Dreams and Nightmares as an Adverse Effect of Beta‐Blockers in the Treatment of Episodic Migraine

CGRP as a new target in prevention and treatment of migraine

The Future of Migraine: Beyond Just Another Pill

Migraine, including episodic migraine (EM) and chronic migraine (CM), is a common neurological disorder that imparts a substantial health burden. Understand the characteristics and treatment of EM and CM from a population-based perspective. This retrospective population-based cross-sectional study utilized administrative data from Alberta. Among those with a migraine diagnostic code, CM and EM were identified by an algorithm and through exclusion, respectively; characteristics and migraine medication use were examined with descriptive statistics. From 79,076 adults with a migraine diagnostic code, 12,700 met the criteria for CM and 54,686 were considered to have EM. The majority of migraineurs were female, the most common comorbidity was depression, and individuals with CM had more comorbidities than EM. A larger proportion of individuals with CM versus EM were dispensed acute (80.6%: CM; 63.4%: EM) and preventative (58.0%: CM; 28.9%: EM) migraine medications over 1 year. Among those with a dispensation, individuals with CM had more acute (13.6 ± 32.2 vs. 4.6 ± 10.9 [mean ± standard deviation], 95% confidence interval [CI] 7.7-8.3), and preventative (12.6 ± 43.5 vs. 5.0 ± 12.6, 95% CI 6.9-8.4) migraine medication dispensations than EM, over 1-year. Opioids were commonly used in both groups (proportion of individuals dispensed an opioid over 1-year: 53.1%: CM; 25.7%: EM). Individuals with EM and CM displayed characteristics and medication use patterns consistent with other reports. Application of this algorithm for CM may be a useful and efficient means of identifying subgroups of migraine using routinely collected health data in Canada.

The treatment of migraine is complex, and non-pharmacological methods are useful and necessary complements or alternatives to pharmacotherapy. We reviewed techniques that can be recommended for the treatment of episodic and chronic migraine attacks and prevention, and described methods for which there is no evidence of effectiveness. The most important of the therapies that can be recommended for migraine prevention are the elimination of provoking factors, lifestyle modification and regular exercise, and some diets have also been suggested to be beneficial. Based on the available evidence, supplementing preventive treatment with acupuncture or psychological therapy reduces the frequency of headaches in episodic migraine, and some psychological techniques may also be recommended for chronic migraine or attack therapy. Among the nutritional supplements, the effectiveness of riboflavin, magnesium and Q10 have been clinically proven to be effective in the preventive treatment of migraine. Interventional and invasive neuromodulation techniques are not widespread due to specific equipment requirements and increased risk of complications, however, based on good tolerability, some non-invasive methods can be recommended in the treatment of chronic migraine attacks and prevention. A large proportion of patients try other complementary or alternative methods, the efficacy or ineffectiveness of which has not been clinically proven, and therefore cannot be recommended.

Objective: At the time of this study, there were no systematic reviews to evaluate phase III RCT`s of CGRP monoclonal antibodies on migraine characteristics, migraine related disability, impact and quality of life after 3 months. This meta-analysis is aimed to systematically review available data on the effect of anti-CGRP monoclonal antibodies on migraine characteristics, migraine related disability, impact and quality of life after 3 months of treatment. Methods: A systematic literature search was performed to identify phase III randomized-controlled trials on anti-GCRP monoclonal antibodies on migraine prevention. The primary outcome was the change in migraine characteristics monthly migraine days, monthly acute migraine specific medication days and 50 % responder rate. Secondary outcome was change in patient functioning and quality of life assessed through Migraine- Specific Quality of Life Questionnaire (MSQ) Migraine Disability Assessment Questionnaire (MIDAS), Headache Impact test (HIT -6) and Migraine Physical Function Impact Diary (MPFID). We calculated the mean difference (MD), standard deviation (SD), and 95 % confidence intervals for the outcomes. Results: Four trials showed effect of anti-CGRP monoclonal antibodies on migraine characteristics and quality of life after 3 months, named EVOLVE 1, EVOLVE 2, STRIVE, HALO_LTS. These trials present data on galcanezumab (120mg, 240 mg, monthly), erenumab (70 mg, 140 mg, monthly) and fremanezumab (225 mg, 675 mg, quarterly, monthly), respectively. The trials included 4625 patients with migraine, 3515 with episodic migraine and 1110 with chronic migraine. Just three of them were included in the meta-analysis because HALO_LTS had no placebo-controlled group. In the included trials, anti-CGRP monoclonal antibodies (galcanezumab and erenumab) were superior to placebo for MMDs, 50% reduction rate, MSQ_RFR and MIDAS beyond a 3-month treatment period. Conclusion: Galcanezumab and erenumab demonstrated improvement in migraine characteristics and quality of life above and beyond those seen with placebo after 3-months of treatment in episodic migraine, providing placebo-controlled evidence. There is a need to perform good RCT`s to evaluate the efficacy of all anti-CGRP monoclonal antibodies on migraine characteristics, impact and quality of life on longer time frame (beyond 12 months) and on different migraine populations such as chronic migraine, medication overuse headache and refractory migraine. Keywords: CGRP, Antibodies, Migraine, Disability

Monoclonal antibodies targeting the calcitonin gene-related peptide pathway (anti-CGRP mAbs) have shown promising efficacy in randomised clinical trials for the prevention of episodic and chronic migraine, but no head-to-head comparisons with established treatments are available. We aimed to examine absolute differences in benefit-risk ratios between anti-CGRP mAbs, topiramate and propranolol for the prevention of episodic migraine and between anti-CGRP mAbs, topiramate and onabotulinumtoxinA for the prevention of chronic migraine using a likelihood to help versus harm analysis. The number of patients needed to be treated for a patient to achieve ≥ 50% reduction in migraine days (NNTB50%) was used as an effect size metric of efficacy. The number of patients needed to be treated for a patient to experience an adverse event that led to treatment discontinuation (NNTHD-AE) was used as a measure of risk. Likelihood to help versus harm values - which are the ratios of NNTH:NNTB - were calculated using data from phase 3 randomised clinical trials. All agents tested were more likely to be beneficial than harmful (likelihood to help versus harm > 1) with the exception of topiramate at 200 mg per day for the prevention of episodic migraine. Anti-CGRP mAbs in all tested doses had higher LHH values than propranolol or topiramate for episodic migraine and onabotulinumtoxinA or topiramate for chronic migraine prevention. Fremanezumab had the highest LHH ratio in episodic migraine and galcanezumab in chronic migraine. This analysis showed that anti-CGRP mAbs exhibit a more favourable benefit-risk ratio than established treatments for episodic and chronic migraine. Head-to-head studies are needed to confirm these results.

The objective of this study was to compare the societal direct and indirect costs of chronic and episodic migraine in the United States. Episodic and chronic migraine are distinguished by the frequency of headache-days. Chronic migraine has a greater overall impact on quality of life than does episodic migraine. Individuals with chronic migraine also use more healthcare resources (resulting in higher direct costs) and experience greater decreases in productivity (resulting in higher indirect costs) than those with episodic migraine as shown in the American Migraine Prevalence and Prevention (AMPP) Study. The International Burden of Migraine Study utilized a web-based questionnaire to elicit data on several topics related to the burden of migraine illness, including health resource utilization and productivity losses. Potential survey participants were identified by Synovate Healthcare (Chicago, IL, USA) from a pool of registered panelists from various countries. The panelists were screened online to determine eligibility and to identify individuals with migraine (episodic or chronic), based on reported symptoms. Participants from the United States were divided into episodic and chronic migraine groups, based on reported headache-day per month frequency. Direct and indirect costs were estimated by applying estimated unit costs to reported headache-related productivity losses and resource use. Costs were compared between participants with episodic and chronic migraine. Mean [standard deviation] total annual cost of headache among people with chronic migraine ($8243 [$10,646]) was over three times that of episodic migraine ($2649 [$4634], P < .001). Participants with chronic migraine had significantly greater direct medical costs ($4943 [$6382]) and indirect (lost productivity) costs ($3300 [$6907]) than did participants with episodic migraine (direct, $1705 [$3591]; indirect, $943 [$2084]) (P < .001 for each). Unlike previous findings, direct medical costs constituted the majority of total headache-related costs for both chronic migraine (60.0%, $4943 of $8243) and episodic migraine (64.3%, $1705 of $2649) participants. A large portion of direct medical costs are attributable to pharmaceutical utilization among both chronic migraine (80%, $3925 of 4943) and episodic migraine (70%, $1196 of $1705) participants. The results of this study build on previous results of the AMPP Study, demonstrating that headache-related direct, indirect, and total costs are significantly greater among individuals with chronic migraine than with episodic migraine in the United States.

The aim of the study was to evaluate the effectiveness of sphenopalatine ganglion blockade in the treatment of episodic migraine (EM). episodic migraine is a neurological disorder characterized by frequent, severe headache episodes with significant functional impairment and reduced quality of life. Despite pharmacological treatment, many patients do not experience any improvement. The study included 31 patients (26 women and 4 men) within an age range and were diagnosed with episodic migraine. Participants were aged 22-55 years, with a median age of 35 years. The sphenopalatine ganglion (SPG) block was performed using a soft, needleless Sphenocath applicator (Curonix) with 4% lidocaine. The same procedure was performed in each patient after 6 weeks. Each patient was assessed using 3 scales: the visual analogue scale (VAS), the migraine disability assessment scale (MIDAS), and the headache impact test-6 (HIT-6). Patients rated their pain in VAS score and impact of headache on daily functioning as measured by the HIT-6 scale before the block, 6 weeks after the first block, 6 weeks after the second block, and 6 months after the second block. Moreover, the impact of migraine on a person's daily functioning and level of disa bility was assessed using the MIDAS scale 6 weeks after the second blockade and again 6 months after the second blockade. The first blockade had a significant effect (z = 5.47657, p = 0.000) reducing pain sensation in a VAS score. Improvement in patient functioning were also achieved, as confirmed by the MIDAS scale and the HIT-6. Preliminary results of analyses show that blockade of sphenopalatine ganglion can be an effective method of treating episodic migraine. For patients who suffer from migraine headaches, it may be an alternative or a complement to pharmacological treatment.

Historically, therapies for migraine have generally involved pharmacological treatments using non-selective or selective analgesics and preventive treatments. However, for many patients these treatments are not effective, while others prefer to use non-pharmacological-based therapies. To fill this need, over the last 15years, neuromodulatory devices have entered the market for migraine treatment. Here, we will review the most recent findings for the use of these devices in the treatment of migraine. Non-invasive vagus nerve stimulation and spring-pulse transcranial magnetic stimulation are both cleared for the treatment of migraine, supported by preclinical studies that validate efficacy and mechanism of action, and complemented with clinical trial data. Other options also authorized for use include transcutaneous supraorbital nerve stimulation and remote electrical neuromodulation. Various options are available to treat migraine using authorized neuromodulatory devices. These data support their efficacy in the treatment of episodic migraine, although further studies are necessary to elucidate their mechanism of action and to provide rigor to clinical trial data.

BackgroundThe reimbursement of erenumab in Spain and other European countries is currently restricted because of the cost of this novel therapy to patients with migraine who have experienced previous failures to traditional preventive treatments. However, this reimbursement policy should be preferably based on cost-effectiveness studies, among other criteria. This study performed a cost-effectiveness analysis of erenumab versus topiramate for the prophylactic treatment of episodic migraine (EM) and versus placebo for chronic migraine (CM).MethodsA Markov model with a 10-year time horizon, from the perspective of the Spanish National Healthcare System, was constructed based on data from responder and non-responder patients. A responder was defined as having a minimum 50% reduction in the number of monthly migraine days (MMD). A hypothetical cohort of patients with EM with one or more prior preventive treatment failures and patients with CM with more than two treatment failures was considered. The effectiveness score was measured as an incremental cost per quality-adjusted life year (QALY) gained and cost per migraine day (MD) avoided. Data from clinical outcomes and patient characteristics were obtained from erenumab clinical trials (NCT02066415, STRIVE, ARISE, LIBERTY and HER-MES). Deterministic and probabilistic sensitivity analyses were performed to validate the robustness of the model.ResultsAfter a 10-year follow-up, the estimated QALYs were 5.88 and 6.11 for patients with EM treated with topiramate and erenumab, respectively. Erenumab showed an incremental cost per patient of €4,420 vs topiramate. For CM patients, erenumab resulted in 0.756 QALYs gained vs placebo; and an incremental cost of €1,814. Patients treated with erenumab achieved reductions in MD for both EM and CM (172 and 568 MDs, respectively). The incremental cost per QALY gained with erenumab was below the Spanish threshold of €30,000/QALY for both health and societal perspectives (EM €19,122/QALY and CM €2,398/QALY).ConclusionsErenumab is cost-effective versus topiramate as a preventive treatment for EM and versus placebo for patients with CM from the perspective of the Spanish National Health System.

Complicated decisions on new migraine-prevention therapies

We have updated the migraine prevention guideline of the Canadian Headache Society from 2012, as there are new therapies available, and additionally, we have provided guidelines for the prevention of chronic migraine, which was not addressed in the previous iteration. We undertook a systematic review to identify new studies since the last guideline. For studies identified, we performed data extraction and subsequent meta-analyses where possible. We composed a summary of the evidence found and undertook a modified Delphi recommendation process. We provide recommendations for treatments identified and additionally expert guidance on the use of the treatments available in important clinical situations. We identified 61 studies that were included in this evidence update and identified 16 therapies we focused on. The anti-calcitonin gene-related peptide (CGRP) agents were approved by Health Canada between 2018 and 2024 and provide additional options for episodic and chronic migraine prevention. We also summarize evidence for the use of propranolol, topiramate and onabotulinumtoxinA in addition to anti-CGRP agents as treatments for chronic migraine. We have downgraded topiramate to a weak recommendation for use and gabapentin to a weak recommendation against its use in episodic migraine. We have weakly recommended the use of memantine, levetiracetam, enalapril and melatonin in episodic migraine. Based on the evidence synthesis, we provide updated recommendations for the prevention of episodic and chronic migraine utilizing treatments available in Canada. We additionally provided expert guidance on their use in clinical situations.

The authors conducted a systematic literature review of preventive pharmacological treatments for episodic childhood migraines searching several databases through May 20, 2012. Episodic migraine prevention was examined in 24 publications of randomized controlled trials that enrolled 1578 children in 16 nonrandomized studies. Single randomized controlled trials provided low-strength evidence that propranolol would result in complete cessation of migraine attacks in 713 per 1000 children treated (95% confidence interval, 452-974); trazodone and nimodipine decreased migraine days, while topiramate, divalproex, and clonidine were no more effective than placebo in preventing migraines. Migraine prevention with multidisciplinary drug management was not sustained at 6 months. Divalproex resulted in treatment discontinuation due to adverse effects, and topiramate increased the risk of paresthesia, upper respiratory tract infection, and weight loss. Long-term preventive benefits and improvement in disability and quality of life are unknown. No studies examined quality of life or provided evidence for individualized treatment decisions.

Clinical Guidelines19 November 2002Pharmacologic Management of Acute Attacks of Migraine and Prevention of Migraine HeadacheFREEVincenza Snow, MD, Kevin Weiss, MD, Eric M. Wall, MD, MPH, and Christel Mottur-Pilson, PhD, for the American Academy of Family Physicians and the American College of Physicians–American Society of Internal Medicine*Vincenza Snow, MDFrom American Academy of Family Physicians, Leawood, Kansas; Hines Veterans Affairs Medical Center and Northwestern University Feinberg School of Medicine, Chicago, Illinois; and American College of Physicians–American Society of Internal Medicine, Philadelphia, Pennsylvania., Kevin Weiss, MDFrom American Academy of Family Physicians, Leawood, Kansas; Hines Veterans Affairs Medical Center and Northwestern University Feinberg School of Medicine, Chicago, Illinois; and American College of Physicians–American Society of Internal Medicine, Philadelphia, Pennsylvania., Eric M. Wall, MD, MPHFrom American Academy of Family Physicians, Leawood, Kansas; Hines Veterans Affairs Medical Center and Northwestern University Feinberg School of Medicine, Chicago, Illinois; and American College of Physicians–American Society of Internal Medicine, Philadelphia, Pennsylvania., and Christel Mottur-Pilson, PhDFrom American Academy of Family Physicians, Leawood, Kansas; Hines Veterans Affairs Medical Center and Northwestern University Feinberg School of Medicine, Chicago, Illinois; and American College of Physicians–American Society of Internal Medicine, Philadelphia, Pennsylvania., for the American Academy of Family Physicians and the American College of Physicians–American Society of Internal Medicine*Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-137-10-200211190-00014 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Migraine headache is a common disorder seen in primary care. It affects 18% of women and 6.5% of men in the United States, almost half of whom are undiagnosed or undertreated (1, 2). These guidelines, developed by the American Academy of Family Physicians and the American College of Physicians–American Society of Internal Medicine, with assistance from the American Headache Society, are based on two previously published papers (3, 4). The papers, titled "Evidence-Based Guidelines for Migraine Headache in the Primary Care Setting: Pharmacological Management of Acute Attacks," by Matchar and colleagues (3), and "Evidence-Based Guidelines for Migraine Headache in the Primary Care Setting: Pharmacological Management for Prevention of Migraine," by Ramadan and coworkers (4), can be found at www.aan.com/professionals/practice/guidelines.cfm. 1 The target audience for this guideline is primary care physicians. The guideline applies to patients with acute migraine attacks, with or without aura, and patients with migraine who are candidates for preventive drug therapy. Although these guidelines are all based on the articles by Matchar and Ramadan and colleagues, the recommendations may differ because different thresholds of evidence were needed for making a positive recommendation. Table 1 compares the AAFP/ACP–ASIM guideline and the U.S. Headache Consortium Guideline.Table 1. Summary of U.S. Headache Consortium Recommendations Compared with AAFP/ACP–ASIM RecommendationsThroughout the text, asterisks indicate drugs that are currently not available in the United States.DiagnosisHeadache has many potential causes. Most headaches are caused by the primary headache disorders, which include migraine, cluster, and tension-type headaches. Secondary headaches, which are those with underlying pathologic causes, are far less common. Migraine is a chronic condition with recurrent acute attacks whose characteristics vary among patients and often among attacks within a single patient. Migraine is a syndrome with a wide variety of neurologic and non-neurologic manifestations. The International Headache Society (6) has developed diagnostic criteria for migraine with and without aura (Appendix Table 1). This classification system serves to diagnose headache syndromes, not patients. Thus, one patient could have more than one type of headache disorder. For example, it is not uncommon for migraine patients to also have episodic tension-type headaches.Management of Acute AttacksEffective long-term management of patients with migraine is challenging because of the complexity of the condition. Experts suggest several goals for successful treatment of acute attacks of migraine. These include treating attacks rapidly and consistently to avoid headache recurrence, to restore the patient's ability to function, and to minimize the use of backup and rescue medications.Clinicians need to educate people with migraine about their condition and its treatment and encourage them to participate in their own management. The physician must help the patient establish realistic expectations by discussing therapeutic options and their benefits and harms. Patient input can provide the best guide to treatment selection and helps the physician to better understand and accommodate patient treatment goals. Developing an effective acute migraine management strategy can be complex, and an engaged patient is more likely to negotiate this process successfully. Encouraging patients to identify and avoid triggers (Table 2) and to be actively involved in their own management by tracking their own progress may be especially useful.Table 2. Some Commonly Reported Triggers of Migraine HeadacheOnce a diagnosis of migraine is established, patients and their health care providers should decide together how to treat acute attacks and whether the patient is a candidate for preventive medications. A wide range of acute treatments with varying efficacies is currently in use (Appendix Table 2). A comprehensive review of the scientific literature, especially the data from randomized, controlled trials, provides a list of treatments that have demonstrated efficacy in the management of acute migraine headache. It also provides a clear understanding of the adverse events associated with various agents.The Headache Consortium's review of the evidence on antiemetics, barbiturate hypnotics, ergot alkaloids and derivatives, nonsteroidal anti-inflammatory drugs (NSAIDs), combination analgesics and nonopiate analgesics, opiate analgesics, triptans, and other agents found good evidence of the efficacy of only a few agents in the treatment of acute migraine (3).Available AgentsNSAIDsTheir demonstrated efficacy and favorable tolerability make NSAIDs a first-line treatment choice for all migraine attacks, including severe attacks that have responded to NSAIDs in the past. Among the NSAIDs, the most consistent evidence exists for aspirin (8-10), ibuprofen (11, 12), naproxen sodium (13, 14), tolfenamic acid* (8, 15), and the combination agent acetaminophen plus aspirin plus caffeine for the acute treatment of migraine (16). The evidence shows that acetaminophen alone is ineffective (17).Serotonin1B/1D Agonists (Triptans)There is good evidence for the effectiveness of the oral triptans naratriptan (18, 19), rizatriptan (20-23), sumatriptan (24-31), and zolmitriptan (32-34). In addition, there is good evidence for the effectiveness of subcutaneous (35-38) and intranasal (39-41) sumatriptan, making it an option for patients with nausea and vomiting. Adverse effects of the triptans include chest symptoms, but postmarketing data indicate that true ischemic events are rare. Triptans are contraindicated in patients with risk for heart disease, basilar or hemiplegic migraine, or uncontrolled hypertension. Subcutaneous sumatriptan is associated with a very rapid onset of action, and oral naratriptan is associated with a slower onset of action.ErgotaminesThere is good evidence for the efficacy and safety of intranasal dihydroergotamine (DHE) as monotherapy for acute migraine attacks (42-46). Placebo-controlled studies of intravenous DHE did not clearly establish its efficacy in the acute treatment of migraine (47, 48). The evidence was inconsistent to support efficacy of ergotamine or ergotamine–caffeine, and the studies documented frequent adverse events.OpioidsIt is well recognized that opiates are good analgesics, but there is good evidence only for the efficacy of butorphanol nasal spray (49, 50). Although opioids are commonly used, surprisingly few studies of opioid use in headache pain document whether overuse and the development of dependence are as frequent as clinically perceived. Until further data are available, these drugs may be better reserved for use when other medications cannot be used, when sedation effects are not a concern, or the risk for abuse has been addressed.Other AgentsFair evidence suggests that the antiemetic metoclopramide, given intravenously, may be an appropriate choice as monotherapy for acute attacks (51-53), particularly in patients with nausea and vomiting when the sedating side effect may also be useful. Isometheptene and isometheptene combinations obtained only borderline significance in relieving headache pain (17, 54, 55). Other agents used in practice, such as intravenous corticosteroids and intranasal lidocaine, are not effective.Choice of TreatmentSince patient responses to these therapies are not always predictable, individualized management is important. The choice of treatment should be based on, among other characteristics, the frequency and severity of attacks; the presence and degree of temporary disability; and the profile of associated symptoms, such as nausea and vomiting. The patient's history of, response to, and tolerance for specific medications must also be considered. Coexisting conditions (such as heart disease, pregnancy, and uncontrolled hypertension) may limit treatment choices.No studies document the effectiveness of specific treatment schedules, but experts suggest that acute therapy should be limited to no more than two times per week to guard against medication-overuse headache (or drug-induced headache). Medication-overuse headache is thought to result from frequent use of acute medication and has a pattern of increasing headache frequency, often resulting in daily headaches. In patients with suspected medication overuse or patients at risk for medication overuse, preventive migraine therapy should be considered.Although some use the term rebound headache interchangeably with the term medication-overuse headache, rebound headache is a distinct entity. Rebound headache is associated with withdrawal of analgesics or abortive migraine medication. There is no uniform agreement about which agents can cause rebound headache, although ergotamine (not DHE); opiates; triptans; and simple and mixed analgesics containing butalbital, caffeine, or isometheptene are generally thought to do so. There is less uniform opinion about other antimigraine agents.Another clinical consideration is the use of a self-administered rescue medication for patients with severe migraine attack that is not responding to (or failing) other treatments. A rescue medication is an agent such as an opioid or a butalbital-containing compound that the patient can use at home when other treatments have failed. Although rescue medications often do not completely eliminate pain and allow patients to return to normal activities, they permit the patient to achieve relief without the discomfort and expense of a visit to the physician's office or emergency department. A cooperative arrangement between provider and patient may extend to the use of rescue medication in appropriate situations.Summary of Treatment of Acute MigraineA body of evidence now points to effective first- and second-line agents for acute treatment of migraine. Beyond the choice of agent lies the choice of management strategy. Recently, interest and research in step care versus stratified care have increased. Step care refers to the initial use of safe, effective, and inexpensive medications as first-line agents in acute attacks of any severity. If the initial agent fails, a second-line, more expensive, migraine-specific medication is then used. The stratified care model initially stratifies migraine attacks by severity, advocating migraine-specific agents for moderate to severe attacks, regardless of previous response to or an unknown response to other agents. Which approach is more effective is still an open question (56).Management of Migraine with Preventive TherapyOnce patients and their health care providers decide how to treat acute attacks, use of preventive medications should be considered. 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) contraindication 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. Other factors to consider are adverse events with acute therapies, patient preference, and the cost of both acute and preventive therapies. (The U.S. Headache Consortium also produced a document on behavioral and other nonpharmacologic therapies for headache prevention, which can be found at www.aan.com/professionals/practice/guidelines.cfm.)A wide range of preventive treatments with varying efficacies is currently in use (Appendix Table 3). A comprehensive review of the scientific literature, especially the data from randomized, controlled trials, provides a list of treatments that have demonstrated efficacy in the prevention of migraine headache. It also provides a clear understanding of the adverse events associated with various agents. The Headache Consortium's review of the evidence on α2-agonists, anticonvulsants, antidepressants, β-blockers, calcium-channel blockers, NSAIDs, serotonergic agents (ergot derivatives, methysergide, and others), hormone therapy, feverfew, magnesium, and riboflavin found that there was good evidence of the efficacy of only a few agents in migraine prevention. A summary of these results follows.Available Agentsβ-BlockersEvidence consistently showed the efficacy of propranolol, 80 to 240 mg/d (57-63), and timolol, 20 to 30 mg/d (63-65), for the prevention of migraine. One trial comparing propranolol and amitriptyline suggested that propranolol is more efficacious in patients with migraine alone; amitriptyline was superior for patients with mixed migraine and tension-type headache (66). There is limited evidence of a moderate effect for atenolol (67, 68), metoprolol (69-71), and nadolol (72-74). β-Blockers with intrinsic sympathomimetic activity (acebutolol, alprenolol, oxprenolol, pindolol) seem to be ineffective for the prevention of migraine. Adverse effects reported most commonly with β-blockers were fatigue, depression, nausea, dizziness, and insomnia. These symptoms appear to be fairly well tolerated and seldom caused premature withdrawal from trials.AntidepressantsAmitriptyline has been more frequently studied than the other antidepressants and is the only one with consistent support for efficacy in migraine prevention (75-77). The dosages that were most efficacious in the clinical trials ranged from 30 to 150 mg/d. Drowsiness, weight gain, and anticholinergic symptoms were frequently reported with the tricyclic antidepressants studied, including amitriptyline. There is no evidence for the use of nortriptyline, protriptyline, doxepin, clomipramine, or imipramine. There is limited evidence of a modest effect for fluoxetine at dosages ranging from 20 mg every other day to 40 mg per day (78, 79). There is no evidence from controlled trials for the use of fluvoxamine, paroxetine, sertraline, phenelzine, bupropion, mirtazapine, trazodone, or venlafaxine.AnticonvulsantsFor the anticonvulsants, there is good evidence for the efficacy of divalproex sodium (80-82) and sodium valproate (83, 84). Adverse events with these therapies are not uncommon and include weight gain, hair loss, tremor, and teratogenic potential, such as neural tube defects. These agents may be especially useful in patients with prolonged or atypical migraine aura. Carbamazepine and vigabatrin* have been shown to be ineffective, and there is limited evidence for moderate efficacy of gabapentin (85).NSAIDsA meta-analysis (4) of five of seven placebo-controlled trials of naproxen or naproxen sodium showed a modest effect on headache prevention (62, 86-92). Similar trends were observed in single placebo-controlled trials of flurbiprofen, indobufen*, ketoprofen, lornoxicam*, and mefenamic acid and in two trials of tolfenamic acid*. Placebo-controlled trials of aspirin, aspirin plus dipyridamole, fenoprofen, and indomethacin were inconclusive. There is no evidence for the use of ibuprofen or nabumetone in the prevention of migraine.Side effect rates for naproxen were not significantly higher than those seen with placebo. The most commonly reported adverse events with all NSAIDs were gastrointestinal symptoms, including nausea, vomiting, gastritis, and blood in the stool. In the trials reviewed, such symptoms were reported by 3% to 45% of participants (86).Serotonergic AgentsOf these agents, time-released DHE* had the strongest support, with consistently positive findings in four placebo-controlled trials (93-96). Evidence is insufficient for the efficacy of ergotamine or ergotamine plus caffeine plus butalbital plus belladonna alkaloids or methylergonovine for migraine prevention. Limited information was reported on adverse events associated with these agents. The most commonly reported events for all the ergot alkaloids were gastrointestinal symptoms.There is strong evidence for the efficacy of methysergide (97-100), a semisynthetic ergot alkaloid. However, there are reports of retroperitoneal and retropleural fibrosis associated with long-term, mostly uninterrupted administration. The manufacturer suggests that methysergide therapy be discontinued for 3 to 4 weeks after each 6-month course of treatment. Other adverse events most commonly reported included gastrointestinal symptoms and leg symptoms (restlessness or pain).Other serotonergic agents that have been evaluated for the prevention of migraine include pizotifen*, lisuride*, oxitriptan*, iprazochrome*, and tropisetron*. Only lisuride (101-104) and pizotifen (87, 99, 105-110) have consistent evidence that supports their efficacy in the prevention of migraine. Published data on adverse events associated with lisuride are limited, and pizotifen is often associated with weight gain and drowsiness.Calcium-Channel BlockersThe evidence for nifedipine, nimodipine, cyclandelate*, and verapamil is poor quality and difficult to interpret, suggesting only a modest effect (see reference 4 for study references). There is no evidence for the use of diltiazem in the prevention of migraine. Symptoms reported with these agents included dizziness, edema, flushing, and constipation.Flunarizine*, 10 mg/d, has proven efficacy in the prevention of migraine and is commonly used in countries where it is available (111-115). Adverse events reported with flunarizine include sedation, weight gain, and abdominal pain. Depression and extrapyramidal symptoms can be observed, particularly in elderly persons.α2-AgonistsThere is good evidence for the lack of efficacy of the α2-agonist clonidine in the prevention of migraine (116-120). Limited evidence shows moderate efficacy of guanfacine (121).Hormone Therapy, Feverfew, Magnesium, and RiboflavinThere is fair evidence for modest efficacy of these agents in certain circumstances, but more trials need to be done. Most of the existing trials had small sample sizes, had self-referred or special patient samples, or had other methodologic flaws (see reference 4 for more details and references).Summary of Preventive TherapyTo alleviate the suffering of many patients with migraine, clinicians need to be aware of the commonly accepted indications for preventive therapy and initiate effective therapy in those patients. Although many agents are available for the preventive treatment of migraine, only a few have proven efficacy. Once an agent has been chosen, clinicians should initiate therapy with a low dose and titrate the dose slowly up until clinical benefits are achieved in the absence of adverse events or until limited by adverse events. Because a clinical benefit may take as long as 2 to 3 months to manifest, each treatment should be given an adequate trial. Once preventive treatment is under way, interfering medications, such as overused acute medications such as ergotamine, should be avoided. After a period of stability, clinicians should consider tapering or discontinuing treatment. Patient and clinician need to engage in an ongoing dialogue in which patient expectations and goals for therapy are taken into account when agents are chosen, titrated, or discontinued.RecommendationsRecommendation 1: For most migraine sufferers, nonsteroidal anti-inflammatory drugs (NSAIDs) are first-line therapy.To date, the most consistent evidence exists for aspirin, ibuprofen, naproxen sodium, tolfenamic acid*, and the combination agent acetaminophen plus aspirin plus caffeine. There is no evidence for the use of acetaminophen alone.Recommendation 2: In patients whose migraine attack has not responded to NSAIDs, use migraine-specific agents (triptans, DHE).There is good evidence for the following triptans: oral naratriptan, rizatriptan, and zolmitriptan; oral and subcutaneous sumatriptan; and DHE nasal spray. Few data in the literature demonstrate which triptans are more effective. Oral opiate combinations and butorphanol may be considered in acute migraine when sedation side effects are not a concern and the risk for abuse has been addressed.Recommendation 3: Select a nonoral route of administration for patients whose migraines present early with nausea or vomiting as a significant component of the symptom complex. Treat nausea and vomiting with an antiemetic.Evidence is limited, but in some patients, concomitant treatment with an antiemetic and an oral migraine medication may be appropriate. Antiemetics should not be restricted to patients who are vomiting or likely to vomit. Nausea itself is one of the most aversive and disabling symptoms of a migraine attack and should be treated appropriately.Recommendation 4: Migraine sufferers should be evaluated for use of preventive therapy.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) contraindication to, or failure of, acute treatments; 3) use of abortive medication more than twice per week; or 4) the presence of uncommon migraine conditions, including hemiplegic migraine, migraine with prolonged aura, or migrainous infarction.Recommendation 5: Recommended first-line agents for the prevention of migraine headache are propranolol (80 to 240 mg/d), timolol (20 to 30 mg/d), amitriptyline (30 to 150 mg/d), divalproex sodium (500 to 1500 mg/d), and sodium valproate (800 to 1500 mg/d).Medications with proven efficacy but limited published data on adverse events or frequent or severe adverse events include flunarizine*, lisuride*, pizotifen*, time-released and migraine sufferers about the of acute attacks and preventive therapy and engage them in the of a management should be on a is strong about the need for people with migraine. The physician must help the patient establish realistic expectations by discussing therapeutic options and their benefits and such as medication-overuse headache. Encouraging patients to be actively involved in their own management by tracking their own progress daily for example, may be especially useful. should attack frequency, severity, and resulting disability; response to type of and adverse effects of medication. Patient input can provide the best guide to treatment Table 1. International Headache Society Table 2. Summary of the Evidence for Acute Table Summary of the Evidence for Preventive M. and of migraine in the United data from the American Migraine Migraine diagnosis and results from the American Migraine Matchar guidelines for migraine headache in the primary care management of acute at www.aan.com/professionals/practice/guidelines.cfm. Ramadan guidelines for migraine headache in the primary care management for prevention of migraine. at www.aan.com/professionals/practice/guidelines.cfm. Matchar guidelines for migraine of and at www.aan.com/professionals/practice/guidelines.cfm. and diagnostic criteria for headache disorders, and pain. Headache of the International Headache and diagnosis of Headache in Clinical Medical acid is as effective as ergotamine migraine of an acetaminophen mg combination versus aspirin mg and in acute migraine and aspirin versus aspirin or for migraine a Treatment of acute migraine ibuprofen and A study of ibuprofen versus in the treatment of acute migraine a migraine naproxen sodium ergotamine plus caffeine. M. sodium in the treatment of migraine. metoclopramide, caffeine and their combinations in the treatment of migraine and safety of aspirin, and caffeine in migraine headache randomized, placebo-controlled Treatment of migraine with and a trial. is effective and well tolerated in the acute treatment of migraine. of a is effective and well tolerated in the acute treatment of migraine. of a The study of in migraine. sumatriptan in the acute treatment of migraine. A study of rizatriptan in the acute treatment of migraine.

Severe migraine affects more than 28 million Americans. It is associated with episodic as well as long-term disability and suffering, yet it is underdiagnosed and undertreated. Acute treatments have advanced considerably, ignited by sumatriptan and the subsequent triptans; unfortunately migraine prevention has lagged far behind. There are no great migraine preventives! No migraine preventive agent studied in good randomized, double blind, placebo-controlled trials proved to be 50% better than placebo. Migraine trials typically focus on episodic migraine, a milder, gentler type of migraine that is selected for low frequency, lack of daily headaches, no preventive need, and previous failure to no more than a few preventive agents. These features are not typical of the usual migraine patient seen in most neurologic practices, thus the results of clinical trials may not carryover to real world situations. Treatment of frequent, chronic, or pervasive migraine is inadequate, and never has been studied in randomized controlled trials. Traditional migraine preventives, eg, beta-blockers, calcium channel blockers, and tricyclic antidepressants, are often ineffective in difficult or complicated populations. The antiepileptic drugs represent a category of pharmaceutics that target the neuronal instability and central hyperexcitability of migraine, and, through these actions, may be more effective than traditional preventives. Episodic migraine attacks are associated with peripheral and central sensitization; however, if attacks are frequent, severe, or long lasting, this sensitization may increase the risk of developing daily headaches. If antiepileptic drugs have an effect on central sensitization, perhaps mediated via glutamate inhibition or gamma-aminobutyric acid potentiation, it is appropriate to use these agents early in migraine treatment, particularly in the highly comorbid patient, possibly in conjunction with agents that antagonize the 5HT2 receptor. This report reviews the best currently available evidence on antiepileptic drugs in the prevention of episodic migraine, and tabulates potential drug-drug and cytochrome P450 interactions. All antiepileptic drugs presented are effective in migraine prevention. However, deciding on the best agent for each individual patient will require recognizing comorbidity and assessing antiepileptic drug pharmacodynamics, tolerability, and safety.