Preventive treatment of migraine: an overview

The pharmacologic treatment of migraine may be acute (abortive, symptomatic) or preventive (prophylactic). Most migraine preventive medications were designed to treat other disorders (e.g., propranolol for hypertension, valproate for epilepsy, etc.). Preventive medication is usually given daily for months or years; however, treatment can be episodic, subacute, or chronic. The medications can be divided into two major categories: (i) Alternatives of high efficacy, which include β- blockers , tricyclic antidepressants , and divalproex , and of lower efficacy, which include selective serotonin reuptake inhibitors, calcium channel antagonists, and non-steroidal antiinflammatory drugs and (ii) second-line choices of high efficacy, which include methysergide and monoamine oxidase inhibitors. The choice of preventive treatment depends on the individual drug's efficacy and side effects, the patient's wants, needs, and response to prior treatment, and the presence of any comorbid or coexistent disease.     

Acute Migraine Treatment in Adults

There are many options for acute migraine attack treatment, but none is ideal for all patients. This study aims to review current medical office‐based acute migraine therapy in adults and provides readers with an organized approach to this important facet of migraine treatment. A general literature review includes a review of several recent published guidelines. Acetaminophen, 4 nonsteroidal anti‐inflammatory drugs (NSAIDs) (ibuprofen, acetylsalicylic acid [ASA], naproxen sodium, and diclofenac potassium), and 7 triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan) have good evidence for efficacy and form the core of acute migraine treatment. NSAID–triptan combinations, dihydroergotamine, non‐opioid combination analgesics (acetaminophen, ASA, and caffeine), and several anti‐emetics (metoclopramide, domperidone, and prochlorperazine) are additional evidence‐based options. Opioid containing combination analgesics may be helpful in specific patients, but should not be used routinely. Clinical features to be considered when choosing an acute migraine medication include usual headache intensity, usual rapidity of pain intensity increase, nausea, vomiting, degree of disability, patient response to previously used medications, history of headache recurrence with previous attacks, and the presence of contraindications to specific acute medications. Available acute medications can be organized into 4 treatment strategies, including a strategy for attacks of mild to moderate severity (strategy one: acetaminophen and/or NSAIDs), a triptan strategy for patients with severe attacks and for attacks not responding to strategy one, a refractory attack strategy, and a strategy for patients with contraindications to vasoconstricting drugs. Acute treatment of migraine attacks during pregnancy, lactation, and for patients with chronic migraine is also discussed. In chronic migraine, it is particularly important that medication overuse is eliminated or avoided. Migraine treatment is complex, and treatment must be individualized and tailored to the patient's clinical features. Clinicians should make full use of available medications and formulations in an organized approach.     

Comparative study of a combination of isometheptene mucate, dichloralphenazone with acetaminophen and sumatriptan succinate in the treatment of migraine

OBJECTIVE: To compare the safety and efficacy of isometheptene mucate, dichloralphenazone with acetaminophen to sumatriptan succinate for the treatment of mild-to-moderate migraine, with or without aura, when taken at the first sign of an attack. BACKGROUND: The Food and Drug Administration approved sumatriptan succinate and the combination of isometheptene mucate, dichloralphenazone with acetaminophen for the treatment of migraine. As part of the stratified treatment of migraine, those patients whose headaches are mild or moderate may benefit from nontriptan medications. Additionally, early treatment of acute migraine before the headache has become moderate or severe may improve response to treatment. METHODS: This was a multicenter, double-blind, randomized, parallel-group study to assess the safety and efficacy of the combination of isometheptene mucate, dichloralphenazone with acetaminophen and sumatriptan succinate in the early stages of a single migraine attack. Patients diagnosed with migraine, with or without aura, as defined by the International Headache Society diagnostic criteria were enrolled. RESULTS: One hundred thirty-seven patients were enrolled in the study. Data for efficacy were available for 126 patients; safety data were available for 128 patients. No statistically significant difference between the two active agents in the patient's response to treatment was demonstrated. Headache recurrence was not significantly different over the 24-hour evaluation period for those patients responding in the first 4 hours. In those with headache recurrence, it was statistically significantly more severe in those patients treated with sumatriptan succinate. Improvement in functional disability was, in general, better among those treated with isometheptene mucate, dichloralphenazone with acetaminophen. Global analysis of efficacy was similar in the two active groups. Patients treated with sumatriptan succinate were somewhat more likely to have adverse effects than the isometheptene mucate, dichloralphenazone with acetaminophen group. CONCLUSIONS: Both isometheptene mucate, dichloralphenazone with acetaminophen and sumatriptan succinate are safe and effective when used early in the treatment of an acute migraine. Several parameters suggest that isometheptene mucate, dichloralphenazone with acetaminophen may have a slight advantage compared with sumatriptan succinate in the early treatment of mild-to-moderate migraine.     

Zonisamide for migraine prophylaxis in refractory patients

Zonisamide is a new antiepileptic drug with multiple mechanisms of action and a favourable pharmacokinetic profile. Preliminary data suggest that zonisamide may be effective in migraine prophylaxis. We evaluated the efficacy and tolerability of zonisamide for migraine prophylaxis in refractory patients. We reviewed the charts of adult patients with International Headache Society-defined episodic migraine (EM) or with transformed migraine (TM) according to the Silberstein-Lipton criteria, who had been treated with zonisamide at our out-patient clinic for at least 60 days. Demographic data, zonisamide dosage and duration of treatment were collected and analysed. Headache frequency, attack duration, headache severity and headache-related disability before and after treatment initiation with zonisamide were compared. Thirty-three patients were included in the study (average age 43.9 +/- 8.4 years; 23 (70%) with TM and 10 (30%) with EM). The patients had failed an average of 6.2 migraine prophylactic drugs prior to zonisamide. The average zonisamide daily dose was 337.9 +/- 146.3 mg and the average duration of treatment was 186.4 +/- 174.0 days. The average number of days with headache per month was reduced in the entire study population from 20.7 +/- 9.5 before zonisamide treatment to 18.0 +/- 11.3 after its initiation (P = 0.06) [in TM from 24.7 +/- 7.3 to 21.0 +/- 10.7 (P = 0.06); in EM from 11.6 +/- 7.6 to 11.0 +/- 9.7 (P = NS)]. No significant changes in other headache parameters were found. Fourteen patients (42.4%) reported adverse events (AEs), the most common of which was fatigue. Most patients (12/14, 85.7%) rated AEs as mild or moderate. In this group of refractory migraine patients, zonisamide therapy did not result in a statistically significant beneficial effect on headache or on associated symptoms.     

Treating early versus treating mild: timing of migraine prescription medications among patients with diagnosed migraine

INTRODUCTION: Although research suggests that early treatment of migraine headache when the pain is mild results in better outcomes for patients, many patients delay taking their acute-migraine medication until their headaches are moderate or severe. Understanding when and why patients use their migraine medications is an important first step to improve migraine management. METHODS: A prospective observational study, conducted at a major national retail pharmacy chain with stores across the United States between April 2001 and November 2002, enrolled men and women between 18 and 55 years of age with a physician diagnosis of migraine with or without aura. Baseline data on 690 patients included patient demographics, migraine history, medication use, tendency to avoid or delay treatment of a migraine attack, and reasons for delaying treatment. Reasons for delaying treatment were assessed via a checklist of nine potential reasons. In the follow-up survey completed after treatment of the next migraine attack, patients reported the timing of medication use in relation to pain onset and the severity of the migraine headache at the time they took the medication. RESULTS: Despite the severity of their typical migraine attacks, approximately 49% of the respondents answered, "yes" to the question, "Do you often avoid or delay taking your migraine medications when you start to experience a migraine attack?" The two most common rationales for avoiding or delaying treatment were "wanting to wait and see if it is really a migraine attack" (69%) followed by "only want to take medications if it is a severe attack" (46%). In the follow-up survey, regardless of medication used, about 85% of patients did not treat their next migraine attack until the headache pain was moderate or severe, although 74% treated within 1 hour of pain onset. CONCLUSION: These results suggest that patients with migraine often delay their treatment until they have identified their attack as a migraine. In addition, while many patients treated their follow-up headache early, they did not treat when the pain was mild. This suggests that there is an opportunity for physicians to educate their migraine patients on how to differentiate migraine from other headache types and about when and how to use their acute-migraine medication.     

Subcutaneous Sumatriptan in a Clinical Setting: The First 100 Consecutive Patients With Acute Migraine in a Tertiary Care Center

SYNOPSIS
The first 100 consecutive patients at our center receiving subcutaneous sumatriptan (6 mg) were evaluated over a total of 455 migraine attacks. Parameters included overall efficacy, average time to relief, recurrence rate, average time to recurrence, adverse events, comparison to previous abortive agents, and subjective global ratings. Overall efficacy (defined as headache severity reduction from severe or moderate to mild or none) was 84%. Average time to relief was 40 minutes. Nine percent failed to respond at all. Recurrence rate was 46.5% with 36% of patients having no recurrence. Fourteen percent of patients reported 100% recurrence (minimum 3 attacks; average 5.4 attacks). Time to recurrence varied widely, but averaged 9.1 hours. Eighty-one percent rated the drug better or much better than previous abortive medications in terms of sumatriptan's ability to abort the attack. Seventy-seven percent reported some adverse event (generally mild and transient) with 23% reporting no adverse events, Sixty-nine percent reported a global rating of Good to Excellent and 31% rated Poor or Fair. The rate of recurrence and average time to recurrence were the most significant factors affecting the global ratings.
These parameters were further evaluated with respect to a variety of subgroups: 1) migraine alone 2) migraine with coexistent tension-type headache 3) drug-induced headache (analgesic rebound headache) 4) posttraumatic headache 5) preventive versus no preventive medication 6) presence or absence of adverse events 7) presence or absence of recurrence and 8) average duration of migraine with no medication.     

How to Apply the AHS Evidence Assessment of the Acute Treatment of Migraine in Adults to your Patient with Migraine

The “Acute Treatment of Migraine in Adults: The American Headache Society Evidence Assessment of Migraine Pharmacotherapies” provides levels of evidence for medication efficacy for acute treatment of migraine. The goal of this companion paper is to provide guidance on how to choose between evidence‐based treatment options, and, based on the clinical characteristics of the patient and their migraine attacks, to provide guidance on designing an individualized strategy for managing migraine attacks. The acute pharmacological treatments described in the American Headache Society evidence assessment can be divided into those initially taken by the patient during the headache phase of the migraine attack, those taken by the patient later in the attack when initial treatments fail, and those administered intravenously or intramuscularly in urgent care settings. Medications taken initially by patients in the headache phase include nonspecific analgesics such as acetaminophen and nonsteroidal anti‐inflammatory drugs (NSAIDs), triptans, and dihydroergotamine (DHE). A stratified approach to treatment is advised, with the choice of medication based on the patient's treatment needs, taking into consideration the attack severity, presence of associated symptoms such as nausea and vomiting, and the degree of migraine‐related disability. Individuals with migraine may find reassurance in having a “back‐up plan” in the event of an initial acute treatment failure. For those individuals who had a partial response to the initial acute treatment, a second dose might be indicated. When the initial treatment does not provide meaningful and sustained benefits, a treatment from a different medication class is typically chosen. Depending upon the initial treatment used, this might include NSAIDs, triptans, or DHE. Opioids or acetaminophen in combination with codeine or tramadol can be considered as part of the “back‐up plan,” provided they are used infrequently. When all patient administered treatments have failed and moderate to severe migraine symptoms remain, some individuals seek treatment in urgent care settings. The intravenous administration of antiemetics with or without an intravenous or intramuscular NSAID or DHE, or an intramuscular opioid can be considered. Patients with migraine should be encouraged to treat migraine pain early, and avoid overuse of medications.     

Practical Use of Topiramate for Migraine Prevention

When treating patients with migraine, clinicians should consider prescribing appropriate combinations of acute and preventive therapies. An effective migraine-preventive therapy should be prescribed to patients with frequent (≥2 migraines per month) or severe migraine. Topiramate has been shown to be an effective and generally well-tolerated migraine prophylaxis (preventive) therapy in adults, as demonstrated in several large, controlled trials. The most common adverse events in these trials were paresthesia, fatigue, anorexia, nausea, taste alteration, and diarrhea. Most adverse events were mild to moderate and transient in nature. Although patients should take migraine-preventive medications for approximately 2 to 3 months before evaluating effect, topiramate has shown efficacy as early as the first month of treatment. This article describes "real-world" approaches to using topiramate as a migraine-preventive therapy. Topiramate has received regulatory approval for the prophylaxis of migraine headache in adults in the United States and many other countries. The practical issues discussed in this article will enable clinicians to maximize the effectiveness while minimizing the side effects associated with this preventive agent.     

LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine

Glutamatergic hyperactivity is implicated migraine pathogenesis. Also, LY293558, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate (KA) receptor antagonist, is effective in preclinical models of migraine. We therefore tested LY293558 in acute migraine. We conducted a randomized, triple-blind, parallel-group, double-dummy, multicentre trial of 1.2 mg/kg intravenous (IV) LY293558, 6 mg subcutaneous (SC) sumatriptan, or placebo in the treatment of acute migraine. The primary efficacy variable was the headache response rate, i.e. headache score improvement from moderate/severe at baseline to mild/none at 2 h. Of 45 enrolled patients, 44 patients (20M:24F; mean age +/- SD = 40 +/- 9 years) completed the study. Response rates were 69% for LY293558 (P = 0.017 vs. placebo), 86% for sumatriptan (P < 0.01 vs. placebo) and 25% for placebo. LY293558 and sumatriptan were superior to placebo (P < 0.01 for all comparisons) on all other measures of improvement in pain and migraine associated symptoms. Fifteen percent of patients who took LY293558 reported adverse events (AEs) (n = 2; one mild, one severe). Fifty-three percent of patients who took sumatriptan (n = 8; seven mild, one moderate) and 31% of those who received placebo reported AEs (n = 5; four mild, one severe). The efficacy and safety results of LY293558 in this small migraine proof of concept trial, together with supportive preclinical data, provide evidence for a potential role of nonvasoactive AMPA/KA antagonists in treating migraine. Larger trials are needed to further test the hypothesis.     

Sumatriptan nasal spray in adolescent migraineurs: a randomized, double-blind, placebo-controlled, acute study

OBJECTIVE: To compare the efficacy and tolerability of sumatriptan nasal spray (NS) (5, 20 mg) versus placebo in the acute treatment of migraine in adolescent subjects. BACKGROUND: Currently, no triptan is approved in the United States for the treatment of migraine in adolescent subjects (12 to 17 years). In a previous randomized, placebo-controlled study of 510 adolescent subjects, sumatriptan NS at 5, 10, and 20 mg doses was well tolerated. However, the primary efficacy analysis for headache relief with 20 mg at 2 hours did not demonstrate statistical significance (P = .059). A second study was initiated to evaluate the efficacy of sumatriptan NS in this population. METHODS: This was a randomized (1:1:1), placebo-controlled, double-blind, parallel-group study. Overall, 738 adolescent subjects (mean age: 14 years) with > or = 6-month history of migraine (with or without aura) self-treated a single attack of moderate or severe migraine. The primary endpoints were headache relief at 1 hour and sustained relief from 1 to 24 hours. Pain-free rates, presence/absence of associated symptoms, headache recurrence, and use of rescue medications were also assessed. Tolerability was based on adverse events (AEs) and vital signs. RESULTS: Sumatriptan NS 20 mg provided greater headache relief than placebo at 30 minutes (42% vs. 33%, respectively; P = .046) and 2 hours (68% vs. 58%; P = .025) postdose, but did not reach statistical significance at 1 hour (61% vs. 52%; P = .087) or for sustained headache relief from 1 to 24 hours (P = .061). Significant differences (P < .05) in favor of sumatriptan NS 20 mg over placebo were observed for several secondary efficacy endpoints including sustained relief from 2 to 24 hours. In general, sumatriptan NS 5 mg percentages were slightly higher than placebo but the differences did not reach statistical significance. Both doses of sumatriptan NS were well tolerated. No AEs were serious or led to study withdrawal. The most common event was taste disturbance (2%, placebo; 19%, sumatriptan NS 5 mg; 25%, sumatriptan NS 20 mg). CONCLUSIONS: This study suggests that sumatriptan may be beneficial to some adolescents and is generally well tolerated in the acute treatment of migraine in this population.     

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

Botulinum toxins are promising preventive treatments for patients with moderate to severe episodic and chronic migraine and chronic daily headache. The recommended indications for botulinum toxins as preventive therapy lend themselves to the following patient types: those who demonstrate a lack of improvement from preventive (prophylactic) pharmacotherapy; those who experience severe and intolerable adverse events from preventive medications; those who refuse to use daily medications; those who have contraindications to acute migraine therapy, and elderly patients with chronic migraine. Both open-label and double-blind placebo-controlled studies using fixed-site, "follow the pain." or a combination approach have demonstrated significant reduction in migraine frequency, severity, and duration, as well as decreased use of acute medications. The most prominent reductions have been noted in those with reportedly the most severe migraine headaches. Large, well-designed, double-blind, placebo-controlled studies are recommended to further clarify optimum dosage and location of injection, reduce treatment frequency and duration, and address other primary headache disorders that may benefit from this therapy.     

Efficacy of eletriptan in migraineurs with persistent poor response to nonsteroidal anti-inflammatory drugs

BACKGROUND/OBJECTIVE: Nonsteroidal anti-inflammatory drugs continue to be one of the most widely used therapies for migraine, but their efficacy in treating moderate to severe migraine headache has not been well documented. In contrast, the efficacy of triptans in this group of patients is well documented, although no systematic research is available that evaluates the effectiveness of switching to a triptan in patients who respond poorly to nonsteroidal anti-inflammatory drugs. METHODS: One hundred thirteen patients who met International Headache Society criteria for migraine and who did not experience satisfactory response to nonsteroidal anti-inflammatory drugs, received open-label treatment with a 40-mg dose of eletriptan for one migraine attack. Efficacy assessments were made at 1, 2, 4, and 24 hours postdose and consisted of headache and pain-free response rates, absence of associated symptoms, and functional response. Global ratings of treatment effectiveness and preference were obtained at 24 hours. RESULTS: The pain-free response rate at 2 hours postdose was 25% and at 4 hours postdose, 55%; the headache response rate at 2 hours was 66% and at 4 hours, 87%. At 2 hours postdose, relief of baseline associated symptoms was achieved by 41% of patients with nausea compared to 82% of patients at 4 hours; for patients with phonophobia, 67% were relieved at 2 hours and 93% at 4 hours, and for patients with photophobia, 70% were relieved at 2 hours and 91% at 4 hours. Functional response was achieved by 70% of patients by 2 hours postdose. The high level of acute response was maintained over 24 hours, with only 24% of patients experiencing a headache recurrence and only 10% using rescue medication. At 24 hours postdose, 74% of patients rated eletriptan as preferable to any previous treatment for migraine. The most frequent reasons cited for this treatment preference were faster headache improvement (83%) and functional response (78%). Overall, eletriptan was well tolerated; most adverse events were transient and mild to moderate in severity. No serious adverse events were reported. CONCLUSION: Results of this open-label trial found the 40-mg dose of eletriptan to have a high degree of efficacy and tolerability among patients who responded poorly to nonsteroidal anti-inflammatory drugs.     

Practical use of topiramate for migraine prevention

When treating patients with migraine, clinicians should consider prescribing appropriate combinations of acute and preventive therapies. An effective migraine-preventive therapy should be prescribed to patients with frequent (> or = 2 migraines per month) or severe migraine. Topiramate has been shown to be an effective and generally well-tolerated migraine prophylaxis (preventive) therapy in adults, as demonstrated in several large, controlled trials. The most common adverse events in these trials were paresthesia, fatigue, anorexia, nausea, taste alteration, and diarrhea. Most adverse events were mild to moderate and transient in nature. Although patients should take migraine-preventive medications for approximately 2 to 3 months before evaluating effect, topiramate has shown efficacy as early as the first month of treatment. This article describes "real-world" approaches to using topiramate as a migraine-preventive therapy. Topiramate has received regulatory approval for the prophylaxis of migraine headache in adults in the United States and many other countries. The practical issues discussed in this article will enable clinicians to maximize the effectiveness while minimizing the side effects associated with this preventive agent.     

Management of the acute migraine headache

As many as 30 million Americans have migraine headaches. The impact on patients and their families can be tremendous, and treatment of migraines can present diagnostic and therapeutic challenges for family physicians. Abortive treatment options include nonspecific and migraine-specific therapy. Nonspecific therapies include analgesics (aspirin, nonsteroidal anti-inflammatory drugs, and opiates), adjunctive therapies (antiemetics and sedatives), and other nonspecific medications (intranasal lidocaine or steroids). Migraine-specific abortive therapies include ergotamine and its derivatives, and triptans. Complementary and alternative therapies can also be used to abort the headache or enhance the efficacy of another therapeutic modality. Treatment choices for acute migraine should be based on headache severity, migraine frequency, associated symptoms, and comorbidities.     

Almotriptan in migraine patients who respond poorly to oral sumatriptan: a double-blind, randomized trial

OBJECTIVE: To investigate the efficacy and tolerability of almotriptan 12.5 mg in migraine patients who respond poorly to sumatriptan 50 mg. BACKGROUND: Poor response to sumatriptan therapy for acute migraine attacks has been documented in the literature, but few controlled trials have investigated the efficacy of an alternative triptan in this subgroup of patients. METHODS: Patients with an International Headache Society diagnosis of migraine who self-described as experiencing at least two unsatisfactory responses to sumatriptan treated their first migraine attack with open-label sumatriptan 50 mg. Patients who did not achieve 2-hour pain relief (improvement of headache from moderate/severe to mild/no headache) were then randomized to treat their second attack with almotriptan 12.5 mg or placebo under double-blind conditions. RESULTS: In the first attack, 221 of 302 participants (73%) did not achieve 2-hour pain relief with sumatriptan and were randomized to treatment of their second attack with almotriptan 12.5 mg or placebo. Of the 198 sumatriptan nonresponders who treated their second attack (99 almotriptan; 99 placebo), 70% had severe headache pain at baseline. Two-hour pain-relief rates were significantly higher with almotriptan compared to placebo (47.5% vs 23.2%; P<.001). A significant treatment effect for almotriptan was also seen in pain-free rates at 2 hours (33.3% vs 14.1%; P<.005) and sustained freedom from pain (20.9% vs 9.0%; P<.05). In the second attack, 7.1% of patients in the almotriptan group experienced adverse events compared to 5.1% in the placebo group (P=.77). CONCLUSIONS: Almotriptan 12.5 mg is an effective and well-tolerated alternative for patients who respond poorly to sumatriptan 50 mg. A poor response to one triptan does not predict a poor response to other agents in that class.     

The medical management of migraine

Migraine is a common, chronic neurologic disorder that affects 11% of the adult population in Western countries. In this article, we review the current approaches to the pharmacologic treatment of migraine. Once migraine is diagnosed, and illness severity has been assessed, clinicians and patients should work together to develop a treatment plan based on the patient needs and preferences. The goals of the treatment plan usually include reducing attack frequency, intensity, and duration; minimizing headache-related disability; improving health-related quality of life; and avoiding headache escalation and medication misuse. Medical treatments for migraine can be divided into preventive drugs, which are taken on a daily basis regardless of whether headache is present, and acute drugs taken to treat individual attacks as they arise. Acute treatments are further divided into nonspecific and migraine-specific treatments. The US Headache Consortium Guidelines recommend stratified care based on the level of disability to help physicians individualize treatment. Simple analgesics are appropriate as first-line acute treatments for less disabled patients; if simple analgesics are unsuccessful, treatment is escalated. For those with high disability levels, migraine-specific acute therapies, such as the triptans, are recommended as the initial treatment, with preventive drugs in selected patients. A variety of behavioral interventions are helpful. The clinicians have in their armamentariums an ever-expanding variety of medications. With experience, clinicians can match individual patient needs with the specific characteristics of a drug to optimize therapeutic benefit.