The Use of Botulinum Toxin in the Management of Headache Disorders.

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.

Prevention of Migraine in Women Throughout the Life Span

BackgroundFollowing approval of fremanezumab for the prevention of migraine in adults, health care decision makers are interested in understanding real-world clinical characteristics and treatment patterns among patients initiating fremanezumab therapy.MethodsData were obtained for this retrospective (pre-post) study from the Veradigm Health Insights database. The study period was January 1, 2014, to June 30, 2019. Patients were included if they were aged ≥ 18 years; had ≥ 1 migraine diagnosis during the study period; and had a medication record for fremanezumab on or after diagnosis during the identification period (September 1, 2018–December 31, 2018). Treatment patterns, including adherence, persistence, and utilization of acute and preventive migraine medication prescriptions, were evaluated.ResultsOf 987 patients initiating fremanezumab during the study period, 738 (74.8%) were adherent to fremanezumab by proportion of days covered (PDC; ≥ 80%) and 780 (79.0%) were adherent by medication possession ratio (MPR; ≥ 80%). A total of 746 (75.6%) patients were persistent for ≥ 6 months. Quarterly fremanezumab (n = 186) was associated with higher rates of adherence versus monthly fremanezumab (n = 801) by PDC (quarterly, 91.3%; monthly, 84.9%; P < 0.001) and MPR (quarterly, 92.2%; monthly, 87.9%; P = 0.006) and higher persistence at ≥ 6 months (quarterly, 82.8%; monthly, 73.9%; P = 0.011). After fremanezumab initiation, patients who were persistent for ≥ 6 months experienced significant reductions from baseline in the mean monthly number of acute and preventive migraine medication prescriptions (P < 0.001). Subgroup analyses in patients with comorbid depression and anxiety showed meaningful real-world benefits based on significant reductions in the number of patients who were prescribed antidepressants (baseline, 68.6%; follow-up, 56.4%; P = 0.0025) and anxiolytic medications (baseline, 55.0%; follow-up, 47.2%; P = 0.037), respectively. In a subgroup of patients with comorbid hypertension at baseline, fremanezumab treatment resulted in nonsignificant reductions in blood pressure.ConclusionsOverall, adherence and persistence to fremanezumab in this real-world study was high in patients with migraine, with higher rates observed for quarterly fremanezumab. Patients who were persistent for ≥ 6 months experienced significant reductions in acute and preventive migraine medication use, while a subgroup of migraine patients with comorbid depression and anxiety at baseline showed significant reductions in antidepressant and anxiolytic medication use.

In the article by Dr. Paul Mathew published in Headache in January 2014, some questions were posed and many accusatory statements were made about our studies that merit clarification and response.1 Dr. Mathew writes “Given the high prevalence of migraine and inconsistent effectiveness of preventative treatment, a plastic surgeon, Bahman Guyuron, MD, devised 4 surgical procedures intended to deactivate migraine headache trigger sites.” This statement is not accurate. Neither I nor any other plastic surgeon was looking for a more effective migraine headache (MH) treatment. It evolved following the reports by a few patients who noticed that their MH stopped after forehead rejuvenation. Dr. Mathew has summarized the surgical techniques very accurately. He questions why the temple region is the only site in which a nerve is being lysed. This small branch of the trigeminal nerve has been sacrificed during craniofacial surgery and forehead rejuvenation procedures for decades. It was the latter procedure that resulted in patient reports of improvement or elimination of MH. We did not want to alter the technique that prompted the patients to report cessation of their MH until we have evidence that decompression will be effective in this site as well. We have just completed a randomized trial comparing avulsion to decompression of the zygomaticotemporal branch of the trigeminal nerve. Our results indicate that decompression and avulsion produce similar results and we have altered our technique. Our patient selection and use of headache terminology has been the subject of criticism by Dr. Mathew. He may have failed to realize that some of the terminology was coined after publication of our earlier articles. The patient selection for all of the clinical studies was done by the neurologists in the team. In fact, there were three different neurologists involved in our studies and all three were board certified specializing in headache. It is clearly stated in every publication that they used the International Headache Society criteria and classification for the diagnosis and patient selection. If the patient is diagnosed to have MH by these experts, surely medication overuse headache is ruled out. Dr. Mathew finds use of botulinum toxin A (BT-A) injection for patients screening flawed. BT-A was used for patient selection in our earlier studies to emulate the surgery effects by eliminating the muscle function through paralyzing the muscle. Since many of our patients are from out of town or out of the country, adherence to our initial algorithm became too cumbersome and often impossible. As Dr. Mathew mentioned, we have demonstrated that the constellation of symptoms can be reliably used for detection of trigger sites. Thus, BT-A is no longer routinely used as a screening tool by our team. Dr. Mathew states “It is unclear what is implied by therapeutic BTX, and why any patients in the control group received any BTX. In the review, there is no mention of how many units were utilized. The injections were performed at the sites deemed by the evaluating surgeon to be migraine trigger sites.” By therapeutic BT-A, we meant the Food and Drug Administration (FDA)-approved doses used for preventing chronic MH. Prevention with BT-A was not the purpose of our injection of BT-A and it has been indicated in our articles that we used 12.5 to 25 units based on the size of the muscle. The patients in the control group received BT-A for confirmation of their trigger sites and to assure that we had patients with matching trigger sites. His assumption that the decision is made merely based on response to BT-A injection and nerve block is incorrect. The candidacy for surgery is based on a number of factors including the type of MH, the severity and frequency of the headaches, failed previous medical treatments, constellation of symptoms, computed tomography (CT) findings, and, yes, response to a nerve block and BT-A, if indicated. The overwhelming majority of patients who undergo surgery have already undergone preventative BT-A injections following the FDA-approved guidelines for years and nerve blocks by several reputable neurologists prior to their visit to our office. A number of these patients have had a failed nerve stimulator removed and some of them still have the nonfunctional device in place. Regardless, before we proceed with the surgery, the patients will have an additional evaluation by the neurologists of our team to make sure that they have had sufficient medical management before surgery. Only a very small percentage of the patients who are treated in our headache center are referred to have surgery. Dr. Mathew questions the type of pathology that we are looking for in the CT of the nose and assumes that septal deviation and enlarged turbinates are the only types of pathology that we consider as migraine triggering elements. In reality, these two abnormal findings by themselves are not sufficient to make a patient a candidate for surgery on this site. We first confirm the presence of symptoms that are commonly associated with the intranasal trigger sites, such as retrobulbar pain that is triggered with weather change, MHs that awaken the patient in the morning or in the middle of the night, MHs that are aggravated by menstrual periods and worsen with allergies or are orgasmic. We look for contact points as we have indicated in many of the articles and book chapters. Other common pathology includes concha bullosa, Haller's cell, and paradoxical curl of the middle and superior turbinates. These findings on patients who have the diagnosis of MHs based on the criteria set forth by the IHS will lead us to suggest surgery on the septum and turbinates. Dr. Mathew discusses the value of high-resolution magnetic resonance imaging or ultrasound studies in detecting the trigger sites. These studies may demonstrate some pathology when assessing daily headaches. However, since most episodic headaches seem to be triggered peripherally and may have a dynamic muscle origin, documenting any static pathology may prove difficult. We are currently studying the role of vascular Doppler and infrared thermography in detection of the migraine trigger sites and are hopeful to share our findings with our neurology colleagues in the near future. Dr. Mathew questions why out of 317 patients initially screened in our study with a sham surgery group, only half of them received BT-A injection and 76 were included in the study. We were looking for the rare patients with a single trigger site or a single predominant site that required screening of many patients. Additionally, the patients with nasal trigger sites were excluded in this process since a strong placebo effect could not be generated for this group. Also, the patients with medication overuse headaches were excluded by the neurologist in the team. This was the reason that only 76 of the 317 patients qualified for the study. Dr. Mathew also questions why the number of control group patients was nearly half of the surgical group. This was based on a calculation by our bio-statistician considering the results of our previous studies and satisfaction of sufficient statistical power. He wanted to include the minimum number of patients in the sham surgery group that would still produce strong enough statistical evidence, for obvious reasons. This study indeed had sufficient statistical power, especially for a sham surgery study whereby committing more patients to sham surgery than was absolutely necessary would have been unprincipled. Dr. Mathew made some puzzling omissions that were important, were clearly stated in the articles, and empowered the study. He failed to mention that there were two neurologists involved in this particular study alone. Additionally, he failed to mention that all three MH components, including the frequency, severity, and duration, were independent end-points along with the Migraine Index. Therefore, Migraine Index being unreliable is not a reasonable argument since we took every major migraine component into consideration independently. Furthermore, Dr. Mathew did not mention that we used three different validated tools including Migraine Disability Assessment (MIDAS), Migraine Specific Quality-of-Life Questionnaire (MSQ), and Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) to make sure that we had assessments beyond the patient statements about their MH. I find Dr. Mathew's argument that the included patients in our studies may have had non-MHs specious since our neurologist strictly adhered to the definition by the IHS, as stated clearly in every article. Dr. Mathew questions who followed up the patients, and offers an opinion that these patients should have been followed by an independent neurologist. The patients were followed up by both the neurologist and the surgical team. Having an independent specialist follow the patients and collect detailed information for a study is not a common practice in surgery. I wonder if this is routine in neurology. If yes, are the independent physicians reimbursed? Who reimburses them? Dr. Mathew writes “Although all subjects were blinded as to which intervention they received, the retained movement of the corrugator supercilii, depressor supercilii, and procerus muscles in the sham group likely led to subjects in the sham group becoming aware that they received the sham procedure. In addition, it is assumed that the subjects in the frontal group received bilateral surgery for cosmetic reasons, but it is unclear whether subjects received bilateral or unilateral surgery in the temporal and occipital groups. This also draws into question whether bilateral or unilateral procedures are performed in clinical practice for patients with a unilateral headache origin.” Had Dr. Mathew's theory been correct about the muscle movement, we would not have seen as many positive changes in the sham surgery group as we did. Blinding was complete in the temporal and occipital sites and it was adequate in the frontal region since no matter how hard one tries, complete elimination of muscle function, and thus forehead movement, with the surgery is impossible without violating the nerves. Additionally, the frontalis and orbicularis oculi muscle function were never altered by surgery and, therefore, the patients in the treatment group did not have a completely motionless forehead. Meanwhile, sham surgery often resulted in some swelling and reduction in the muscle function temporarily, which was enough to give an impression of muscle removal to the patients with sham surgery. Regardless, the placebo effect in our sham surgery study was much more reliable than the Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) study where neither the patient nor the treating physician could miss the difference between those who received BT-A vs those who did not. To answer his question about whether the procedures were done unilaterally or bilaterally, none of the patients in this study had unilateral temporal or occipital headaches. However, since no muscle is removed to potentially cause asymmetry during the temple surgery and the removed muscle is insignificant during the occipital surgery, the procedure is performed unilaterally on these two sites in rare patients with unilateral headaches. Dr. Mathew points out that we did not indicate whether preventative or abortive medications were altered, and he sees post-surgery patients who received BT-A and whose preventative medications were changed postoperatively thus altering the surgical results on patients to whom he attends. The preventative medications were not altered for our study patients except for those who had elimination and no longer needed migraine medications, as indicated earlier, and none of the patients received BT-A injection after surgery while they were the subject of the study. Dr. Mathew outlines every adverse effect of the surgery and adds “Interestingly, only 2 of the adverse events were specifically cited to last for greater than 1 year, which would lead some readers to assume that the other events lasted for less than 1 year and resolved when in fact some of these adverse events may actually be ongoing.” This kind of distortion of facts is a reflection of a prejudicial assessment of our studies. Any fair reviewer would have concluded that since we recorded and reported every complication throughout the follow-up period, if only two adverse effects were cited to be present at the 1-year follow up, that means the remaining complications were all temporary and resolved over time, which indeed was the reality. Dr. Mathew's statement that I am attempting to discredit the trigeminovascular theory of MH is baseless. First, there is no such statement in any of our publications. I have advocated the role of peripheral mechanisms based on our findings and the efficacy of surgical procedures and BT-A, without dismissing any other theories. I do not believe that I am qualified to redefine the pathophysiology of the complex MH cascade. In the discussion paragraph, Dr. Mathew writes “The author once again lumps together these 4 procedures, and uses this collective weak data to reinforce these self-promoting curative surgical interventions.” This type of unsubstantiated remark with a baseless condescending tone is a clear indication of the bias frame within which Dr. Mathew has been expressing his tainted opinion. I have not claimed a cure and I do not need self-promotion. Dr. Mathew states that not including sham surgery in the 5-year follow up is a design flaw. Criticizing the methodology of a surgical study by someone who is not in the field of surgery and has never done a randomized prospective study or sham surgery is improper. In order for patients to participate in the control group (sham surgery), they were promised that they would be surgically treated if they served in the control group for 1 year. To expect the patient to participate in a study and serve as a control for 5 years is totally unrealistic. If Dr. Mathew does a literature search, he would find very few, if any, sham surgery studies being done today due to the extremely perplexing nature of this type of study and the difficulty in obtaining institutional review board approval. To expect a 5-year sham surgery study is unreasonable and no IRB is going to approve that kind of investigation. Related to our comprehensive study with 25 patients serving as controls, he did not see the value of this control group. He states, “As such, it is not clear why this ‘control group’ was part of the study other than possibly to convince the reader that there was a fair comparison to a ‘control group,’ which would artificially elevate the significance of the results from the active intervention group.” I am not sure why Dr. Mathew does not see the scientific merit in having a randomly selected group of patients who did not undergo surgery to compare with a group of patients who underwent surgery. Validated tools were used on both groups and meaningful data with statistical significance were collected. Had we not had a control group, the scientific value would have been open to more criticism. In an overwhelming majority of surgery-related studies, the control group consists of a number of patients who do not undergo surgery rather than sham surgery, which again is extremely rare. Dr. Mathew questions who evaluated the patients for our 5-year follow-up study. Here as well, the team, including a biostatistician, the surgeon, and the neurologist, designed the study; the neurologist selected the patients; the surgeon and neurologist detected the trigger sites; the nurse study coordinator collected, compiled, and delivered the data directly to the biostatistician who then analyzed the results without the involvement of the surgeon. Additionally, the surgical team never wrote a prescription for MH medication and therefore the patients who needed medications during the 5-year follow up had to visit the neurologists for medications in addition to the patient obligation to visit the neurologist by the design of the study. Dr. Mathew once more considers the fact that the patients were not followed up by an independent neurologist a flaw. Again, to expect an independent neurologist to follow the surgical patients for 5 years and to collect data is totally unreasonable. This is not what is done in the surgical field and, again, I wonder how often it is done in the neurology field. I sincerely hope that this type of distrust is not ubiquitous in the neurology field. We trust and respect our colleagues in the surgery field who devote their lives to research and believe in the scientific integrity of the researchers unless it is proven otherwise. Dr. Mathew writes, “Among the 79 patients who presented at the 5-year follow-up, 10 received additional procedures. These 10 subjects were not included in the final analysis. It is interesting to note that these 10 patients had ‘significant improvement’ of their migraines but still opted to proceed with additional procedures. One could assume that these patients had an outcome that would the final and not these 10 subjects were not included in the final I find this and this is the first that the integrity of what I do has been by I am not sure why he did not or to our clear statement in the article that the final results were analyzed with and without of those 10 subjects and there was no difference in the final patients who had additional surgery had a improvement in the sites where they had the surgery, but they still had pain in the sites and that is why they underwent additional surgery. We were to them pain by on the sites that we had not It would have been and totally to them additional improvement for 4 more years of the fact that we needed them to having some pain to prove a to the These patients had already served in the initial 1-year of the study. Additionally, I wonder how Dr. Mathew would have our study had we included the 10 patients who had undergone additional surgery. he not have claimed that the study was since some patients underwent additional Furthermore, had there been any of in our we would not have about the surgery, since the surgery was not being on the site. However, this type of and of patients who had undergone additional surgery is an obligation of any research team with integrity and should not be used the Dr. Mathew writes the subjects who did not present for follow-up, the for not may have included adequate treatment effect after the surgical to the or complications from the Dr. Mathew's that subjects did not present for a follow up is We on patients and 2 patients during the first year follow up and an additional 10 patients in the 4 for a of patients not being for a follow up at the of the year. Again, I find his assumption that they were potentially not included we wanted to only include patients with results very I would if he would for an However, that we may have excluded these patients they had is an to our team. We have included patients in the study who did not have a positive response than who has not done a 5-year it would be to how it is to in with to patients for 5 the that he has the likely reason for these patients in follow up is that many of these patients were and they did not need these patients would have needed medication from our would they not visit the neurologist and treatment without had they had this is not what we claimed in the study nor do we it and results should be about the not One a of the patients along the especially in a 5-year and that is a One more statement from Dr. Mathew his that our procedures are curative We have never stated during our or that the surgery is a To such a is totally and is on his Dr. Mathew writes is then made about and subjects which is the only the author on medications that are during the study. It is not that the only medications by the author are those that may study results overuse as there is no mention of preventative and abortive medications that can statistical This is of the facts to the significance of the study. Had the of the studies by to these medications been our we would have referred to them more and not just in the most study. The medication use was only on in our studies since we during the review process that this matter was to our neurology Dr. Mathew writes “The improvement of a pain with nerve blocks or could be used to a patient to proceed with an surgical treatment with unclear and potentially complications including of He our team as patients to do what they should not be he the facts that all of these patients are referred to us by their neurologists or by our neurologist and to be a candidate for surgery. These are the patients who are but are at the of their us are last I have no of and I may as not Dr. Mathew's that the is for a single trigger site is not the are physicians in every field. However, many of these patients have often undergone of nerve as I indicated earlier, which have a and much and these patients a I do not see Dr. Mathew this procedure in any of the of articles that he has Dr. Mathew that neurologists have been about the 4 surgical decompression techniques of unclear mechanisms of within the of migraine of migraine and of the is not an procedure to neurologists and those who have an open can see the for the efficacy of the surgical treatment of MH. The is similar to surgery or other nerve decompression the evidence for with the the pathophysiology is becoming more but we still have a to Dr. Mathew that many of these patients have episodic MH and may not have had adequate preventative treatment. First, I have indicated that these patients were selected by neurologists in every article that I have the which are very few, are not In fact, which is is actually a and when I this complication to the patients, their common response is I could the nerve I The only complication is of pain or of the surgical and this is extremely rare. of the patients that I currently on have daily pain with an of 10 a of 1 to and I am not sure how much it can We are studying these these complications and treatment for these patients. I do not migraine medications but from the articles, it that every migraine medication potentially can in some Dr. Mathew's comparison of what we do with Dr. surgery for trigeminal is His statement that it took years for the neurologists to and Dr. procedure is it has been years since I the peripheral trigger site and the fact that the headache the surgical decompression of migraine trigger sites is very believe that there is between what we do and what Dr. The role of a in the of the nerve that especially in the and occipital sites, is and we routinely find a Doppler in the most pain site in different To assume that some or many of the patients who have had a positive outcome from the nerve decompression may have as Dr. Mathew once more the of our headache of the team and this is not We have performed decompression surgery on those who had the diagnosis of with the study group. Dr. Mathew a remark about an article the complications of these I the publication of any failed or migraine symptoms to which Dr. Mathew has without of all of the First, this type of of patients who that their symptoms became be the surgical techniques are subject to the and The fact that a surgeon or a few do not produce results does not that the surgery is not as much as an abortive or preventative medication may not or may in while the medication would in most if there are a number of patients who are on such that if they do not these medications, they may that they are in order to more Furthermore, those who have failed the initial surgery or symptoms could be with additional by those of us who have an of in out the to this surgery. Additionally, not and only to or is totally if out of patients, a few results while from surgery, the may the We need to that the majority of the patients who undergo surgery have already been seen and treated by reputable and have most and often and are surgery as a last Therefore, the will not be We are the of pain after migraine surgery and we will report the the reason for and how or can be or I wonder how headache would if would research and an article about failed preventative and abortive medications or their This will not since we consider this kind of report and totally In the Dr. Mathew the nature of the treatment of the zygomaticotemporal branch of the trigeminal nerve. As I indicated earlier, this which is less than 1 in has been the subject of in many and procedures for decades. We are not aware of any patients a or pain after this surgery that was not present prior to the surgery. This nerve will be from on based on our study This will a for the patients, should decompression His that the patients who from the surgery may have had different types of headaches rather than MH is remark the headache who are of our research team. These neurologists have been in serving many patients and them to a of they had never between plastic and neurologists can serve a small group of migraine patients who are not from the preventative or abortive surgical decompression of migraine trigger sites is not different from or decompression of the different and nerves. The complications are extremely and the are altering for many of these patients. The patients who are are not going to their neurologist to report not having pain or visit their neurologist and for the visit when they do not need any These neurologists are not going to about the of the surgery, but they will about the I our neurology colleagues to with us to out how we can this small group of patients who from such a but do not from the or abortive of these patients who undergo surgery not only have migraine or less but they can often and commonly look the surgery will in patients being and by the of the few and with unreasonable which will have and Our neurology by this procedure and patients to can control the to some and these patients from who may have as their

Introduction: Migraine is a chronic neurological disorder marked by recurrent moderate to severe headaches with symptoms such as nausea, photophobia, and phonophobia. Chronic migraine, occurring on 15 or more days per month for over three months, significantly impairs daily functioning and creates a substantial health burden. Botulinum toxin type A (BoNT-A) is an effective preventive option for patients who do not respond to standard treatments. Aim of the study: The aim of this review is to summarize current evidence on the mechanism of action, clinical efficacy, safety profile, and practical use of botulinum toxin type A in the prevention of chronic migraine. Materials and methods: A literature search was mostly performed in PubMed and Google Scholar for studies published between 2015 and 2025, using the keywords: migraine, chronic migraine, botulinum toxin, onabotulinumtoxinA, PREEMPT trials, CGRP. Priority was given to randomized controlled trials, long-term observational studies, clinical guidelines, and mechanistic research. Discussion: OnabotulinumtoxinA (BoNT-A) is a well-established preventive treatment for chronic migraine supported by evidence from the PREEMPT trials and long-term studies such as COMPEL. BoNT-A significantly reduces headaches, improves quality of life and decreases disability with benefits sustained over multiple treatment cycles. Its mechanism blocking the release of CGRP, substance P, and glutamate from sensory nerves and modulating nociceptive receptors targets both peripheral and central sensitization, which distinguishes it from traditional oral medication. Injection protocols vary worldwide. The PREEMPT paradigm is evidence-based and standardized, while alternative approaches, such as the Saudi 5/20/100 protocol, offer lower doses and fewer injections but lack of large-scale validation. The safety profile is generally positive. Following recommended dosing intervals minimizes the risk of neutralizing antibodies. Emerging CGRP-targeting therapies provide additional options, and early data suggest potential benefits of combination therapy for refractory cases. Economic analyses indicate that despite higher upfront costs, BoNT-A reduces healthcare use and disability, making it cost-effective in the long term. Future research should focus on identifying predictors of response, optimizing injection protocols, and evaluating combination strategies with biologics. Results: Evidence from large randomized trials (PREEMPT 1 and 2) demonstrates that BoNT-A significantly reduces the number of headache days, improves quality of life, and decreases disability in patients with chronic migraine. Long-term studies show sustained benefits over multiple treatment cycles with a favorable safety profile. BoNT-A reduces peripheral and central sensitization by inhibiting the release of pain-related neuropeptides and modulating sensory nerve activity. Conclusion: OnabotulinumtoxinA is an effective and well-tolerated preventive treatment for chronic migraine. Standardized injection protocols and appropriate patient selection optimize therapeutic outcomes. Further research is needed to identify predictors of treatment response and to explore the potential of combination therapy with CGRP (calcitonin gene-related peptide)-targeting agents.

Managing Migraine

Background: The previously approved botulinum toxin and nowadays promising calcitonin gene-related peptide (CGRP) monoclonal antibody have shown efficacy for preventing chronic migraine (CM). However, there is no direct evidence for their relative effectiveness and safety. In this study, we conducted an indirect treatment comparison to compare the efficacy and safety of CGRP monoclonal antibody with botulinum toxin for the preventive treatment of chronic migraine.Methods: Up to August 31, 2020, we systematically searched PubMed, Embase, and Cochrane Library Central Register of Controlled Trials (Central). Weighted mean difference (WMD) and relative risk (RR) were used to evaluate clinical outcomes. Indirect treatment comparison (ITC) software was used to conduct indirect treatment comparison.Results: Ten studies were pooled with 6,325 patients in our meta-analysis. Both botulinum toxin and CGRP monoclonal antibody demonstrated favorable efficacy in the change of migraine days, headache days, HIT-6 score, and 50% migraine responder rate compared with placebo. In indirect treatment comparison, CGRP monoclonal antibody was superior to botulinum toxin in the frequency of acute analgesics intake (WMD = −1.31, 95% CI: −3.394 to 0.774, p = 0.02113), the rate of treatment-related adverse events (AEs) (RR = 0.664, 95% CI: 0.469 to 0.939, p = 0.04047), and the rate of treatment-related serious adverse events (RR = 0.505, 95% CI: 0.005 to 46.98, p < 0.001).Conclusion: For chronic migraine patients, CGRP monoclonal antibody was slightly better than botulinum toxin in terms of efficacy and safety. In the future, head-to-head trials would be better to evaluate the efficacy and safety between different medications in the prevention of chronic migraine.

Migraine is considered a common but under-diagnosed and untreated condition. Treatment patterns have pointed at frequent over-the-counter medication use and low use of preventive therapies. Studies exploring migraine prescription practice among doctors are few. A population-based study was carried out to examine the prescription practice in the use of acute and preventive migraine medications. The data covered 4864 working-age people reporting they have been diagnosed with migraine. Data on reimbursed prescription medicines from 1 January 1998 to 31 December 2006 were drawn from the registers of the Social Insurance Institute of Finland and compared with age- and sex-matched controls. Anti-inflammatory analgesics were prescribed for 71% of female and 62% of male migraine patients vs. 56% and 50% of controls. Triptans were prescribed for 21% of female and 10% of male patients. Combinations of analgesics and muscle relaxants were offered to 37% of female and 29% of male patients vs. 26% and 21% of controls, and antidepressants to 19% of women and 14% of men vs. 13% and 9% of controls. Although use of preventive medication among migraineurs was high, the prescription patterns in acute treatments showed that NSAIDS were used more often than triptans. Assimilation of national guidelines to treat migraine published in 2002 in Finland was not reflected in the prescription patterns up to 2006.

Headache disorders can be further classified as episodic (< 15 headache days per month) or chronic (≥ 15 headache days per month for more than 3 months). Chronic migraine (CM) requires that headaches occur on 15 or more days a month for more than 3 months. These headaches must be migraines on at least 8 days per month. There are seven botulinum toxin (BoNT) serotypes (A1, A2, A3, B, C1, D, E, F, and G). All serotypes inhibit acetylcholine release, although their intracellular target proteins, physiochemical characteristics, and potencies are different. Its mechanism of action in pain is being investigated. Botulinum toxin type A (BoNT-A) has been the most widely studied serotype for therapeutic purposes. A major clinical advantage of type A toxin arises from its prolonged duration of action due to the longevity of its protease (90 days in rats and probably much longer in human neurons). Clinical studies suggest that BoNT is a safe treatment and is efficacious for the prevention of some forms of migraine, such as CM, and perhaps high-frequency episodic migraine.

The ongoing Pan-European Real Life (PEARL) phase 4 study is evaluating fremanezumab effectiveness and safety for the prevention of episodic and chronic migraine. This interim analysis reports primary, secondary and exploratory endpoints from when 500 participants completed at least six months of treatment. Adults with episodic migraine or chronic migraine maintaining daily headache diaries were enrolled upon initiation of fremanezumab. Primary endpoint: proportion of participants with ≥50% reduction in monthly migraine days during the six-month period after fremanezumab initiation. Secondary endpoints: mean change from baseline across months 1-12 in monthly migraine days, acute migraine medication use, and headache-related disability. Exploratory endpoint: mean change in headache severity from baseline across months 1-12. Safety was assessed through adverse events reported. Overall, 897 participants were enrolled and 574 included in the effectiveness analyses (episodic migraine, 25.8%; chronic migraine, 74.2%). Of participants with data available, 175/313 (55.9%) achieved ≥50% monthly migraine days reduction during the six-month period post-initiation. Across months 1-12, there were sustained reductions in mean monthly migraine days, acute medication use, disability scores, and headache severity. Few adverse events were reported. PEARL interim results support the effectiveness and safety of fremanezumab for migraine prevention in a real-world population across several European countries.Trial registration: encepp.eu: EUPAS35111.

Our objective was to characterize patterns of preventive medication use in persons with episodic migraine (EM) and chronic migraine (CM). Several classes of medications are used both on- and off-label for the prevention of migraine, including β-blockers (eg, propranolol, timolol), tricyclic antidepressants (eg, amitriptyline), anti-epileptic drugs (eg, topiramate, valproic acid), and neurotoxins (eg, onabotulinumtoxinA). Preventive medication use and reasons for discontinuation were collected in an international, Web-based, cross-sectional survey of adults with migraine during 2010. Descriptive analyses were conducted on demographics and headache-related disability as measured by the Migraine Disability Assessment Scale, stratified by use of preventive medication, and EM or CM. Univariate and multivariate logistic regression models were constructed to assess predictors of preventive medication use. One thousand one hundred and sixty-five respondents completed the survey. Only 28.3% of EM and 44.8% of CM respondents were currently using preventive medication; any use of prophylaxis (prior or current) was reported by 43.4% of those with EM and 65.9% with CM. The mean number of prophylactic medications ever used was 2.92 for EM and 3.94 for CM. Antidepressants were used most frequently (EM 60.9%; CM 54.7%), followed by β-blockers (EM 35.4%; CM 36.8%) and anti-epileptics (EM 28.6%; CM 36.3%). Odds of preventive medication use were higher among CM than EM, adjusting for age, gender, race, years of daily headache, and country (odds ratio 2.72; 95% confidence interval 2.15 to 3.57). Greater headache-related disability and older age were also associated with greater odds of ever having used prophylaxis, regardless of headache frequency. Less than half the persons with EM and CM were currently using preventive medication for migraine, with treatment rates being higher for CM, as expected. Those with CM tried more medications than those with EM, possibly reflecting higher levels of treatment need.

In chronic migraine, botulinum toxin type A may reduce the number of migraine days per month by 2 days compared with placebo treatment. Non-serious adverse events were probably experienced by 60/100 participants in the treated group compared with 47/100 in the placebo group. For people with episodic migraine, we remain uncertain whether or not this treatment is effective because the quality of this limited evidence is very low. Better reporting of outcome measures in published trials would provide a more complete evidence base on which to draw conclusions.

In a population sample of persons with migraine treating with a single category of acute migraine medication, to identify rates and factors associated with acute treatment outcomes, including 2-hour pain freedom (2hPF), 24-hour pain response (24hPR), and 24-hour sustained pain response (24hSPR). Key predictors include acute treatment type (triptans and other medication categories), the influence of allodynia on response to medication, and the interaction between medication category and presence of allodynia in response to treatment among people with migraine. Cutaneous allodynia was previously associated with inadequate 2hPF, 24hPR, and 24hSPR (sustained response at 24 hours among those with adequate 2hPF) among people with migraine in the American Migraine Prevalence and Prevention (AMPP) Study. The AMPP Study obtained data from a representative US sample of persons with migraine by mailed questionnaire. The 2006 survey included 8233 people with migraine aged 18 or over who completed the Migraine Treatment Optimization Questionnaire (mTOQ). mTOQ was used to assess acute treatment outcomes including 2hPF, 24hPR, and 24hSPR. Eligible individuals used only a single category of acute prescription migraine treatments (n = 5236, 63.6%). This sample was stratified into 5 categories of type of acute prescription headache medication used (triptans, nonsteroidal anti-inflammatory drugs, barbiturate-combinations, opioids, and opioid combinations and ergot alkaloids). Separate binary logistic regression models evaluated: (1) triptans vs other medication types; (2) presence of allodynia vs no allodynia; and (3) the interaction of medication category with allodynia. Sociodemographic variables, health insurance status, over-the-counter and preventive medication use were included as covariates. Odds ratios (OR) and 95% confidence intervals (CI) were generated for each acute treatment outcome. Among eligible participants, the mean age was 46 years, and 82.5% were women. The triptan use group had better outcomes than other medication groups for 2hPF (OR range: 2.00-2.63, all significant except ergot alkaloids) and 24hPR (OR range: 2.10-6.22, all significant). No significant medication effects were found for the 24hSPR outcome. The presence of allodynia was associated with significantly worse outcomes for both 2hPF (OR range: 1.42-1.55, all significant) and 24hPR (OR range: 1.30-1.32, all significant, except for ergot alkaloids, P = .051). Allodynia effects were not significant for the 24hSPR. The interaction between medication and allodynia was also not significant (OR range for 2hPF: .68-2.02; OR range for 2hPR: .35-1.34; OR range for 24hSPR: 1.21-2.72) in any of the models, suggesting allodynia is an important predictor of treatment response regardless of the medication group prescribed. The use of triptan medication was associated with significantly better 2hPF (except vs ergot alkaloids) and significantly better 24hPR outcomes compared with other acute medication categories. The presence of allodynia significantly increased the likelihood of an inadequate treatment response for both of these outcomes. Triptan use was generally associated with the best outcomes. Because allodynia was associated with inadequate outcomes for all medication groups, we suggest that allodynia is an area of unmet treatment need.

IntroductionEarly discontinuation and poor adherence are common limitations of conventional preventive migraine medications that limit their long-term efficacy. Therefore, a migraine preventive medication with favorable long-term safety is warranted.ObjectiveThis study aimed to evaluate the long-term safety and tolerability of fremanezumab for the preventive treatment of chronic or episodic migraine in Japanese patients.MethodsIn this 52-week, randomized, open-label, parallel-group study, fremanezumab monthly or quarterly was administered in newly enrolled Japanese patients with chronic migraine or episodic migraine. Safety was assessed by monitoring of treatment-emergent adverse events, including injection-site reactions, laboratory and vital sign assessments. Newly enrolled patients and rollover patients from previous phase IIb/III trials who did not receive fremanezumab in this study were included in the immunogenicity testing cohort (n = 587). Efficacy outcomes included changes from baseline in the average monthly migraine days and headache days of at least moderate severity. Other efficacy outcomes included changes in disability scores.ResultsA total of 50 patients were enrolled with chronic migraine (monthly, n = 17; quarterly, n = 17) or episodic migraine (monthly, n = 8; quarterly, n = 8). The most commonly reported treatment-emergent adverse events were nasopharyngitis (64.0%) and injection-site reactions (erythema, 24.0%; induration, 10.0%; pain, 8.0%; pruritus, 6.0%). The discontinuation rate was low (4.0% from adverse events, 2.0% from a lack of efficacy) and no deaths were reported. The incidence of anti-drug antibody development was low (2.4%). Fremanezumab reduced monthly migraine days and headache days of at least moderate severity from 1 month after initial administration, and this effect was maintained with no worsening throughout 12 months. Fremanezumab also led to sustained reductions in any acute headache medication use and headache-related disability at 12 months.ConclusionsFremanezumab administered monthly and quarterly was well tolerated in patients with chronic migraine and episodic migraine and led to sustained improvements in monthly migraine days and headache days of at least moderate severity throughout 12 months.Clinical Trial RegistrationClinicalTrials.gov Identifier: NCT03303105.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40264-021-01119-2.

Botulinum toxins in the treatment of migraine and tension-type headaches