ISSN 0017-8748 doi: 10.1111/head.12273 Published by Wiley Periodicals, Inc.
Headache © 2013 American Headache Society
Views and Perspectives Preventive Pharmacotherapy in Migraine Paul Rizzoli, MD
Migraine prevention can be instrumental in the effective management of the migraine patient but remains underused in treatment of this common, chronic, and often debilitating condition. The development of methysergide as the first migraine preventive agent not only laid the groundwork for our current thinking about migraine prevention, but also created a paradigm shift away from migraine as a psychological issue and toward migraine as a legitimate medical condition. This short review is intended to help the reader select patients appropriate for prevention and to initiate, monitor, and adjust preventive treatment. Goals in discussing preventive management are to facilitate provider familiarity with and confidence in this therapy leading to improved clinical outcomes and to a reduced burden of headache-related disability. Optimal therapeutic success is best achieved in the setting of a strong therapeutic alliance. Medication options for prevention are reviewed. Continued educational efforts directed at both patient and provider may be required to improve treatment utilization and reduce headache impact. Key words: migraine, migraine therapy, prevention, methysergide, pharmacotherapy, therapeutic alliance (Headache 2014;54:364-369)
INTRODUCTION Migraine is a common chronic condition characterized by recurrent and often stereotyped headache events that recur with a marked variation in frequency within the population, from 1-2 events per year to several or more events per month. An individual patient’s headache frequency may also change over time. When events are infrequent, abortive therapy alone may be appropriate. When episodes occur frequently, however, an additional management approach that seeks to reduce or prevent headache events may be more desirable. As an example, a 40-year-old woman with migraine who reports an increase in headache fre-
quency to 3 or more events per month as a result of home and work stress may be a typical candidate for preventive migraine therapy. This discussion will include tips on how to recognize patients who might benefit from prevention, how to initiate and monitor treatment, and how to select the best preventive medication.
Address all correspondence to P. Rizzoli, Neurology, Brigham & Women’s/ Faulkner Hospital, 1153 Centre Street, #4970 Boston MA 02130, USA.
THE HISTORY OF MIGRAINE PREVENTION Although numerous treatments for migraine have been advocated throughout history, the preventive management of migraine can be seen as originating from the development of methysergide in the 1960s. Synthesized from lysergic acid, methysergide proved to be a potent and selective inhibitor of the actions of serotonin.1 Clinically, it was effective as a migraine preventive and was approved in 1962 by the US Food and Drug Administration (FDA) for this purpose. Subsequently, it was recognized that with
Accepted for publication October 6, 2013.
Conflict of Interest: None.
From the John R. Graham Headache Center, Department of Neurology, Brigham & Women’s/ Faulkner Hospital, Boston, MA, USA.
364
Headache chronic use, methysergide could cause fibrotic complications, especially retroperitoneal fibrosis, and it has since been removed from the market in the United States. For that period of time during which it was used, however, it created a paradigm shift in thinking about migraine management. This was described by Neil Raskin, a headache specialist working at the time: “It was quite astonishing how this drug changed physicians’ thinking about the nature of migraine. This drug’s ability to antagonize certain actions of serotonin abruptly transformed migraine from a psychosocial problem to a scientific one. It was the first of the stabilizers that could actually affect the mechanism in such a way that symptoms did not reappear. It didn’t simply suppress symptoms but actually reset the mechanism so that patients could go about their lives and forget about headaches.”2
THE NEED FOR MIGRAINE PREVENTION Thus, migraine, as of the 1960s, had become a legitimate and treatable medical condition. As such, interest began to develop in the classification of and research in the disease of migraine. More migraine preventive agents followed, and it might be expected that patients benefitted. However, almost 50 years after methysergide, the American Migraine Prevalence and Prevention Study3 investigated preventive migraine treatment in the United States and found disappointing results. In this large population study, using a validated self-administered questionnaire, the authors determined that although more than 25% of migraineurs surveyed would qualify for prevention, only a small proportion (3-13%) were actually receiving preventive therapy for migraine. Thus, as migraine prevention continues to be chronically underused, frequent but treatable headaches go unchecked and the migraine population remains underserved. One contributory factor may be patient unawareness, and this could improve with educational efforts. Other factors on the part of providers including lack of familiarity with the process of patient selection, medication initiation and monitoring, and assessment of outcomes could also play a role.
365
SELECTING THE PATIENT In general, migraine preventive therapy should be considered in a patient, like the one above, who reports frequent and limiting migraines. More specific recommendations suggest prevention be offered when migraine events exceed roughly 4 per month; fewer events qualify if the events are typically more severe and disabling and perhaps more events per month are acceptable if, although frequent, events are fairly easily treated.3 Patient preference may also influence the decision. Other important features to consider include a contraindication to, adverse reaction to, failure of, or overuse of acute abortive medications. In addition to reducing the frequency, duration, and severity of individual headache events, prevention may improve responsiveness to acute treatments and should lead overall to reduced disability and improved function. These practical goals are frequently attained with today’s preventive management approach, often a very satisfying outcome for both patient and provider. SELECTING THE TREATMENT A recent guideline (American Headache Society/ American Academy of Neurology 2012)4 addresses the efficacy of the currently used preventive agents. A change in methodology (now based entirely on published scientific data) used in the creation of this guideline resulted in an adjustment in ranking for some medications, compared with prior guidelines, and elimination from the list for some other previously included preventives (see Table 1). Still, other drugs, such as feverfew and 2 angiotensin receptor blockers, now appear in the main rankings for the first time. Level A drugs in the current ranking, such as divalproex sodium, sodium valproate, topiramate, metoprolol, and propranolol, possess established efficacy in the reduction of migraine frequency and severity, and should be offered to patients. Level B drugs, such as amitriptyline, venlafaxine, and atenolol, are considered probably effective and should be considered for patients. Level C drugs are considered possibly effective and may be considered for use in migraine prevention. These include lisinopril, candesartan, clonidine, and carbamazepine. Medications previously ranked as migraine preventives
366
February 2014 Table 1.—Classification of Selected Migraine Preventive Therapies (Available in the United States)
Level A: Medications with established efficacy (>2 Class I trials) Divalproex sodium Sodium valproate Metoprolol Propranolol
Topiramate Timolol
Level B: Medications are probably effective (1 Class I or 2 Class II studies) Amitriptyline Venlafaxine Nadolol
Atenolol
Level C: Medications are possibly effective (1 Class II study) Lisinopril Candesartan Guanfacine Carbamazepine
Clonidine
Level U: Inadequate or conflicting data to support or refute medication use Acetazolamide Anti-thrombotics (eg, Coumadin) Fluoxetine Gabapentin
Fluvoxamine Verapamil
Other: Medications that are established as possibly or probably ineffective Lamotrigine Clomipramine Clonazepam Nabumetone Telmisartan Montelukast
Acebutolol Oxcarbazepine
Adapted from American Headache Society/American Academy of Neurology 2012 guideline.
but now considered ineffective include lamotrigine, montelukast, oxcarbazepine, and telmisartan. The guideline provides an overview and distillation of the trial data about individual preventive medications. But how does one select a medication for an individual patient? Based on the guideline and in a routine setting without modifying features, treatment can be initiated with an FDA-approved preventive agent (see Table 2). Often, however, medication and dosage selection in the clinic setting
is dictated by features specific to the individual patient. For example, a patient with frequent migraine and poor sleep may benefit from use of amitriptyline nightly to treat both of these conditions. Verapamil in another example might be considered for a patient who has migraine with aura. Also, since many preventive agents have been associated with possible weight gain, topiramate could be considered in a patient with migraine and associated weight management concerns. Discussion with the
Table 2.—Common Migraine Preventive Medications5
A A A A B B B C U U
Name
Daily Adult Dose† Example (mg)
Comments
Propranolol‡ Metoprolol Divalproex sodium‡ Topiramate‡ Amitriptyline Atenolol Venlafaxine Cyproheptadine Gabapentin Verapamil
80-240 50-150 250-1500 25-150 10-150 50-150 37.5-150 2-8 300-1800 80-480
? Avoid in migraine with aura ? Avoid in migraine with aura FDA pregnancy category D FDA pregnancy category D Downgraded but clinical strong efficacy ? Avoid in migraine with aura Well tolerated, non-sedating Used in pedi population, sedating Downgraded, favorable AE profile Migraine with prolonged aura, vestibular migraine
†A lower initial starting dose may be used followed by titration to the working dose. ‡FDA indication. Adapted from Rizzoli PB. Acute and preventive treatment of migraine. Continuum (Minneap Minn). 2012;18:764-782. FDA = Food and Drug Administration.
Headache patient of the rationale for selection of a medication is of course appropriate, but discussion and documentation of the rationale for a medication not FDA approved for migraine prevention is perhaps even more desirable. Such discussion also provides opportunity for collaboration with the patient about treatment choices and goals. Lastly, migraine management is optimally viewed as an ongoing, creative, and interactive process picking up where the scientific trail leaves off; the process is a collaborative experience that can be equal parts marketing, coaching, advising, and educating.
SUCCESSFUL TREATMENT Principles to maximize success in the treatment process (see Box 1) include beginning with a low dose of a selected agent and increasing only slowly (eg, every 2 weeks) to help avoid or reduce adverse medication effects. A rapid titration that produces a dramatic adverse reaction can result in premature termination of what may otherwise have been a useful agent. Once a target dose of an agent is reached, an adequate trial of up to 2-3 months is often needed to determine whether the medication is effective. Especially early on, benefits may be slight and only develop slowly, thus necessitating use of a calendar, journal, or diary to help capture an early treatment response. These are widely available for download or online use.
Box 1.—Principles of Migraine Prevention5 Start with a low dose and increase slowly. Use an adequate trial of 2 to 3 months. Avoid medication interactions or contraindications. Monitor with calendar or diary. Monitor for medication overuse. Consider comorbid conditions. Consider preventive medication combinations in refractory patients. Taper when headaches are controlled. Adapted from Rizzoli PB. Acute and preventive treatment of migraine. Continuum (Minneap Minn). 2012;18:764-782.
367 Medication interactions are a potential concern, although clinical experience suggests a high level of safety in the use of most of the migraine preventives at suggested doses, either alone or in combination. Combinations of preventives may produce a strong therapeutic effect while minimizing adverse effects from the individual agents, which can each be used a lower than typical dose. An example might be a combination of a low dosage of amitriptyline with a low dosage of topiramate. Comorbid medical or psychiatric conditions should be factored into the decision making as warranted. Addition of a beta-blocker, for example, may be limited in a patient with preexisting hypotension. Conversely, addition of a beta-blocker in a migraine patient with coexistent hypertension often and for a variety of reasons will not result in adequate management of the hypertension, and discussion of this with the patient may help avoid confusion. In another example, tricyclic medication doses often used in migraine prevention would not typically be considered sufficient to treat depression. Since higher doses of these agents are often not well tolerated in this population, a separate antidepressant medication may be needed if a coexistent depression is to be adequately treated. A careful discussion with the patient as to rationale and goals of the particular medication choice is especially necessary under these circumstances but need not be overly time consuming. Medication overuse, usually of prescription or over-the-counter headache abortive agents, may complicate treatment. Depending on the agent and dose, regular exposure several times a week or more may expose the patient to this complication, leading to increased headache frequency and seeming failure of the prescribed abortive and preventive medication program. Although it is not always possible to diagnose medication overuse with confidence in advance, in retrospect, it becomes clear that removal of the overused medication alone has resulted in improvement of the overall headache pattern. Initiation of migraine preventive therapy has been noted to be effective even within the setting of medication overuse, thus this approach need not be withheld; however, slower, less dramatic improvement could be expected.
368 Clinical experience can provide a beneficial perspective for managing a challenging situation; for example, the patient who has unrealistic expectations, or is possibly suspicious of the medical process or medication aversive. Useful skills displayed by the experienced clinician in these settings include a creative, collaborative, and artful approach to medication selection, and guidance for the patient in avoiding misinformation from internet sources, family members, or even other providers. The experienced clinician also realizes the importance of adequate management of comorbid-associated conditions, such as sleep, anxiety, or obesity disorders, in the successful management of the patient with frequent migraine. Lastly, but to be stressed, is the importance of a strong therapeutic bond in successful migraine management.
SELECTED MIGRAINE PREVENTIVE AGENTS (SEE TABLE 2) A large number of medication classes (see Box 2), including anti-epileptic drugs, beta-blockers, calcium channel blockers, antidepressants, and serotonin antagonists, are represented in the list of commonly used preventive agents (see Table 2). Given this variety, it is not surprising that no unified mechanistic theory of action has been advanced for migraine preventives. Possible therapeutic mechanisms include stabilization of reactive central nervous system centers, enhancement of central antinociceptive pathways, inhibition of cortical spreading depression, and inhibition of peripheral sensitization.
Box 2.—Classes of Migraine Preventives5 Anti-epileptic drugs Antidepressants Beta-adrenergic blockers Calcium channel antagonists Nonsteroidal anti-inflammatory drugs Serotonin (5-hydroxytryptamine) antagonists Neurotoxins (eg, onabotulinumtoxinA) Other or miscellaneous Adapted from Rizzoli PB. Acute and preventive treatment of migraine. Continuum (Minneap Minn). 2012;18:764-782.
February 2014 Some of the more commonly used preventives as shown in the table are discussed below. Anti-Epileptic Drugs (AEDs).—Valproate and topiramate are both potent migraine preventives and both hold a US FDA indication for this use. Dosing can reach levels used in epilepsy, although typically the migraine doses are lower. Serious and significant side effects are possible with each, and nuisance side effects are common. A discussion in some detail with the patient is therefore warranted before use. Unfortunately, both are also categorized as Pregnancy Category D by the US FDA, thus limiting their use in pregnancy and indeed often limiting their selection in pregnancy-aged females as well. Tricyclic Antidepressants (TCAs).—Of the TCAs, the best evidence overall is for amitriptyline. In addition, there is a strong clinical impression of utility, especially in patients with coexistent sleep disruption, often characterized as fragmented sleep. Generally, low doses of 10-25 mg are used in migraine prevention, not the higher antidepressant doses. It may be helpful to emphasize this to the patient to avoid confusion on 2 issues. First, if comorbid depression is present, these doses may not be efficacious and another antidepressant agent may be needed for that condition. Second, some patients may suspect that, in making this drug recommendation, the provider believes that depression is the cause of the headache but may not mention this concern, thus emphasis of the reasons behind the recommendation can help ensure compliance. Adverse effects of amitriptyline include morning sedation that may be mitigated by dosing in the early evening instead of bedtime. Other limiting effects include tachycardia and vivid dreams. Weight gain and urinary retention seem less likely at these lower doses, but may nonetheless be reported rarely. Beta-Blockers.—Propranolol and timolol, which each hold a US FDA indication for migraine prevention are generally considered safe and effective. Dosing may be similar to or lower than those used in the treatment of hypertension. Although often mentioned as first choices in a patient with migraine and hypertension, in practice, achieving the ideal dose of 1 medication for 2 separate conditions is often not possible. One practical concern is that the patient may
Headache assume, because they are on a beta-blocker, that their hypertension need not be followed by their primary provider and may fail to obtain optimal care. Side effects of beta-blockers may include weight gain, somnolence, exercise intolerance, and symptomatic hypotension. Recent reports suggest an association between their use and the development of type 2 diabetes. These agents were originally considered first line in management of migraine with aura. More recently, case reports of prolonged aura in patients treated with beta-blockers or even stroke in such patients has tempered recommendations for use of these agents in the treatment of migraine with aura. Calcium Channel Antagonists.—Of the various members of this heterogeneous group, verapamil is probably the most commonly used in migraine prevention, and seems, based largely on clinical experience but with some research support, to have surpassed propranolol in the management of migraine with aura.6,7 Verapamil has also shown utility in vestibular migraine. Nonetheless, evidence cited in the recent guideline suggesting verapamil may not be of as much benefit as previously thought has resulted in a downgrade of the medication in this guideline. Dosing is typically between 80 mg and 480 mg daily and the medication is generally well tolerated. Constipation is a commonly reported side effect that may be managed by the coadministration of magnesium citrate or gluconate, 250-500 mg daily, an over-the-counter supplement that is also used separately in migraine management. At the higher end of the dosing range, cardiac conduction defects have been described and routine cardiograms may play a role in the monitoring of these patients.
CONCLUSION Advances in the preventive management of migraine have provided significant benefits to patients with this challenging and, at times, devastating condi-
369 tion. Medication management is discussed. Optimal therapeutic success is best achieved in the setting of a strong therapeutic alliance. Treatment options although limited and imperfect are nonetheless valuable in the reduction of symptoms and in the restoration of function, but are currently underused in the United States. Further educational efforts are necessary to increase utilization and improve care. The successful treatment of migraine is difficult but worth the effort. It taps every resource of the physician. Probably more hours of suffering are caused by migraine than by any other human affliction. Knowledge of its secrets is incomplete but increasing. For these reasons it presents a unique challenge. John R. Graham, MD The Treatment of Migraine, 1955
REFERENCES 1. Koehler PJ, Tfelt-Hansen PC. History of methysergide in migraine. Cephalalgia. 2008;28:11261135. London. ISSN 0333-1024. 2. Solomon S, Diamond S, Mathew N, Loder E. American headache through the decades: 1950 to 2008. Headache. 2008;48:671-677. 3. Lipton RB, Bigal ME, Diamond M, et al. Migraine prevalence, disease burden and the need for preventive therapy. Neurology. 2007;68:343-349. 4. Silberstein SD, Holland S, Freitag F, et al. Evidencebased guideline update: Pharmacologic treatment for episodic migraine prevention in adults: Report of the Quality Standards subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78:1337-1345. 5. Rizzoli PB. Acute and preventive treatment of migraine. Continuum (Minneap Minn). 2012;18:764782. 6. Evans RW, Rizzoli P, Loder E, Bana D. Betablockers for migraine. Headache. 2008;48:455-460. 7. Markley HG. Verapamil in migraine prophylaxis: Mechanisms and efficacy. Am J Med. 1991;90(5A): 48s-53s.
Headache © 2013 American Headache Society
Views and Perspectives Preventive Pharmacotherapy in Migraine Paul Rizzoli, MD
Migraine prevention can be instrumental in the effective management of the migraine patient but remains underused in treatment of this common, chronic, and often debilitating condition. The development of methysergide as the first migraine preventive agent not only laid the groundwork for our current thinking about migraine prevention, but also created a paradigm shift away from migraine as a psychological issue and toward migraine as a legitimate medical condition. This short review is intended to help the reader select patients appropriate for prevention and to initiate, monitor, and adjust preventive treatment. Goals in discussing preventive management are to facilitate provider familiarity with and confidence in this therapy leading to improved clinical outcomes and to a reduced burden of headache-related disability. Optimal therapeutic success is best achieved in the setting of a strong therapeutic alliance. Medication options for prevention are reviewed. Continued educational efforts directed at both patient and provider may be required to improve treatment utilization and reduce headache impact. Key words: migraine, migraine therapy, prevention, methysergide, pharmacotherapy, therapeutic alliance (Headache 2014;54:364-369)
INTRODUCTION Migraine is a common chronic condition characterized by recurrent and often stereotyped headache events that recur with a marked variation in frequency within the population, from 1-2 events per year to several or more events per month. An individual patient’s headache frequency may also change over time. When events are infrequent, abortive therapy alone may be appropriate. When episodes occur frequently, however, an additional management approach that seeks to reduce or prevent headache events may be more desirable. As an example, a 40-year-old woman with migraine who reports an increase in headache fre-
quency to 3 or more events per month as a result of home and work stress may be a typical candidate for preventive migraine therapy. This discussion will include tips on how to recognize patients who might benefit from prevention, how to initiate and monitor treatment, and how to select the best preventive medication.
Address all correspondence to P. Rizzoli, Neurology, Brigham & Women’s/ Faulkner Hospital, 1153 Centre Street, #4970 Boston MA 02130, USA.
THE HISTORY OF MIGRAINE PREVENTION Although numerous treatments for migraine have been advocated throughout history, the preventive management of migraine can be seen as originating from the development of methysergide in the 1960s. Synthesized from lysergic acid, methysergide proved to be a potent and selective inhibitor of the actions of serotonin.1 Clinically, it was effective as a migraine preventive and was approved in 1962 by the US Food and Drug Administration (FDA) for this purpose. Subsequently, it was recognized that with
Accepted for publication October 6, 2013.
Conflict of Interest: None.
From the John R. Graham Headache Center, Department of Neurology, Brigham & Women’s/ Faulkner Hospital, Boston, MA, USA.
364
Headache chronic use, methysergide could cause fibrotic complications, especially retroperitoneal fibrosis, and it has since been removed from the market in the United States. For that period of time during which it was used, however, it created a paradigm shift in thinking about migraine management. This was described by Neil Raskin, a headache specialist working at the time: “It was quite astonishing how this drug changed physicians’ thinking about the nature of migraine. This drug’s ability to antagonize certain actions of serotonin abruptly transformed migraine from a psychosocial problem to a scientific one. It was the first of the stabilizers that could actually affect the mechanism in such a way that symptoms did not reappear. It didn’t simply suppress symptoms but actually reset the mechanism so that patients could go about their lives and forget about headaches.”2
THE NEED FOR MIGRAINE PREVENTION Thus, migraine, as of the 1960s, had become a legitimate and treatable medical condition. As such, interest began to develop in the classification of and research in the disease of migraine. More migraine preventive agents followed, and it might be expected that patients benefitted. However, almost 50 years after methysergide, the American Migraine Prevalence and Prevention Study3 investigated preventive migraine treatment in the United States and found disappointing results. In this large population study, using a validated self-administered questionnaire, the authors determined that although more than 25% of migraineurs surveyed would qualify for prevention, only a small proportion (3-13%) were actually receiving preventive therapy for migraine. Thus, as migraine prevention continues to be chronically underused, frequent but treatable headaches go unchecked and the migraine population remains underserved. One contributory factor may be patient unawareness, and this could improve with educational efforts. Other factors on the part of providers including lack of familiarity with the process of patient selection, medication initiation and monitoring, and assessment of outcomes could also play a role.
365
SELECTING THE PATIENT In general, migraine preventive therapy should be considered in a patient, like the one above, who reports frequent and limiting migraines. More specific recommendations suggest prevention be offered when migraine events exceed roughly 4 per month; fewer events qualify if the events are typically more severe and disabling and perhaps more events per month are acceptable if, although frequent, events are fairly easily treated.3 Patient preference may also influence the decision. Other important features to consider include a contraindication to, adverse reaction to, failure of, or overuse of acute abortive medications. In addition to reducing the frequency, duration, and severity of individual headache events, prevention may improve responsiveness to acute treatments and should lead overall to reduced disability and improved function. These practical goals are frequently attained with today’s preventive management approach, often a very satisfying outcome for both patient and provider. SELECTING THE TREATMENT A recent guideline (American Headache Society/ American Academy of Neurology 2012)4 addresses the efficacy of the currently used preventive agents. A change in methodology (now based entirely on published scientific data) used in the creation of this guideline resulted in an adjustment in ranking for some medications, compared with prior guidelines, and elimination from the list for some other previously included preventives (see Table 1). Still, other drugs, such as feverfew and 2 angiotensin receptor blockers, now appear in the main rankings for the first time. Level A drugs in the current ranking, such as divalproex sodium, sodium valproate, topiramate, metoprolol, and propranolol, possess established efficacy in the reduction of migraine frequency and severity, and should be offered to patients. Level B drugs, such as amitriptyline, venlafaxine, and atenolol, are considered probably effective and should be considered for patients. Level C drugs are considered possibly effective and may be considered for use in migraine prevention. These include lisinopril, candesartan, clonidine, and carbamazepine. Medications previously ranked as migraine preventives
366
February 2014 Table 1.—Classification of Selected Migraine Preventive Therapies (Available in the United States)
Level A: Medications with established efficacy (>2 Class I trials) Divalproex sodium Sodium valproate Metoprolol Propranolol
Topiramate Timolol
Level B: Medications are probably effective (1 Class I or 2 Class II studies) Amitriptyline Venlafaxine Nadolol
Atenolol
Level C: Medications are possibly effective (1 Class II study) Lisinopril Candesartan Guanfacine Carbamazepine
Clonidine
Level U: Inadequate or conflicting data to support or refute medication use Acetazolamide Anti-thrombotics (eg, Coumadin) Fluoxetine Gabapentin
Fluvoxamine Verapamil
Other: Medications that are established as possibly or probably ineffective Lamotrigine Clomipramine Clonazepam Nabumetone Telmisartan Montelukast
Acebutolol Oxcarbazepine
Adapted from American Headache Society/American Academy of Neurology 2012 guideline.
but now considered ineffective include lamotrigine, montelukast, oxcarbazepine, and telmisartan. The guideline provides an overview and distillation of the trial data about individual preventive medications. But how does one select a medication for an individual patient? Based on the guideline and in a routine setting without modifying features, treatment can be initiated with an FDA-approved preventive agent (see Table 2). Often, however, medication and dosage selection in the clinic setting
is dictated by features specific to the individual patient. For example, a patient with frequent migraine and poor sleep may benefit from use of amitriptyline nightly to treat both of these conditions. Verapamil in another example might be considered for a patient who has migraine with aura. Also, since many preventive agents have been associated with possible weight gain, topiramate could be considered in a patient with migraine and associated weight management concerns. Discussion with the
Table 2.—Common Migraine Preventive Medications5
A A A A B B B C U U
Name
Daily Adult Dose† Example (mg)
Comments
Propranolol‡ Metoprolol Divalproex sodium‡ Topiramate‡ Amitriptyline Atenolol Venlafaxine Cyproheptadine Gabapentin Verapamil
80-240 50-150 250-1500 25-150 10-150 50-150 37.5-150 2-8 300-1800 80-480
? Avoid in migraine with aura ? Avoid in migraine with aura FDA pregnancy category D FDA pregnancy category D Downgraded but clinical strong efficacy ? Avoid in migraine with aura Well tolerated, non-sedating Used in pedi population, sedating Downgraded, favorable AE profile Migraine with prolonged aura, vestibular migraine
†A lower initial starting dose may be used followed by titration to the working dose. ‡FDA indication. Adapted from Rizzoli PB. Acute and preventive treatment of migraine. Continuum (Minneap Minn). 2012;18:764-782. FDA = Food and Drug Administration.
Headache patient of the rationale for selection of a medication is of course appropriate, but discussion and documentation of the rationale for a medication not FDA approved for migraine prevention is perhaps even more desirable. Such discussion also provides opportunity for collaboration with the patient about treatment choices and goals. Lastly, migraine management is optimally viewed as an ongoing, creative, and interactive process picking up where the scientific trail leaves off; the process is a collaborative experience that can be equal parts marketing, coaching, advising, and educating.
SUCCESSFUL TREATMENT Principles to maximize success in the treatment process (see Box 1) include beginning with a low dose of a selected agent and increasing only slowly (eg, every 2 weeks) to help avoid or reduce adverse medication effects. A rapid titration that produces a dramatic adverse reaction can result in premature termination of what may otherwise have been a useful agent. Once a target dose of an agent is reached, an adequate trial of up to 2-3 months is often needed to determine whether the medication is effective. Especially early on, benefits may be slight and only develop slowly, thus necessitating use of a calendar, journal, or diary to help capture an early treatment response. These are widely available for download or online use.
Box 1.—Principles of Migraine Prevention5 Start with a low dose and increase slowly. Use an adequate trial of 2 to 3 months. Avoid medication interactions or contraindications. Monitor with calendar or diary. Monitor for medication overuse. Consider comorbid conditions. Consider preventive medication combinations in refractory patients. Taper when headaches are controlled. Adapted from Rizzoli PB. Acute and preventive treatment of migraine. Continuum (Minneap Minn). 2012;18:764-782.
367 Medication interactions are a potential concern, although clinical experience suggests a high level of safety in the use of most of the migraine preventives at suggested doses, either alone or in combination. Combinations of preventives may produce a strong therapeutic effect while minimizing adverse effects from the individual agents, which can each be used a lower than typical dose. An example might be a combination of a low dosage of amitriptyline with a low dosage of topiramate. Comorbid medical or psychiatric conditions should be factored into the decision making as warranted. Addition of a beta-blocker, for example, may be limited in a patient with preexisting hypotension. Conversely, addition of a beta-blocker in a migraine patient with coexistent hypertension often and for a variety of reasons will not result in adequate management of the hypertension, and discussion of this with the patient may help avoid confusion. In another example, tricyclic medication doses often used in migraine prevention would not typically be considered sufficient to treat depression. Since higher doses of these agents are often not well tolerated in this population, a separate antidepressant medication may be needed if a coexistent depression is to be adequately treated. A careful discussion with the patient as to rationale and goals of the particular medication choice is especially necessary under these circumstances but need not be overly time consuming. Medication overuse, usually of prescription or over-the-counter headache abortive agents, may complicate treatment. Depending on the agent and dose, regular exposure several times a week or more may expose the patient to this complication, leading to increased headache frequency and seeming failure of the prescribed abortive and preventive medication program. Although it is not always possible to diagnose medication overuse with confidence in advance, in retrospect, it becomes clear that removal of the overused medication alone has resulted in improvement of the overall headache pattern. Initiation of migraine preventive therapy has been noted to be effective even within the setting of medication overuse, thus this approach need not be withheld; however, slower, less dramatic improvement could be expected.
368 Clinical experience can provide a beneficial perspective for managing a challenging situation; for example, the patient who has unrealistic expectations, or is possibly suspicious of the medical process or medication aversive. Useful skills displayed by the experienced clinician in these settings include a creative, collaborative, and artful approach to medication selection, and guidance for the patient in avoiding misinformation from internet sources, family members, or even other providers. The experienced clinician also realizes the importance of adequate management of comorbid-associated conditions, such as sleep, anxiety, or obesity disorders, in the successful management of the patient with frequent migraine. Lastly, but to be stressed, is the importance of a strong therapeutic bond in successful migraine management.
SELECTED MIGRAINE PREVENTIVE AGENTS (SEE TABLE 2) A large number of medication classes (see Box 2), including anti-epileptic drugs, beta-blockers, calcium channel blockers, antidepressants, and serotonin antagonists, are represented in the list of commonly used preventive agents (see Table 2). Given this variety, it is not surprising that no unified mechanistic theory of action has been advanced for migraine preventives. Possible therapeutic mechanisms include stabilization of reactive central nervous system centers, enhancement of central antinociceptive pathways, inhibition of cortical spreading depression, and inhibition of peripheral sensitization.
Box 2.—Classes of Migraine Preventives5 Anti-epileptic drugs Antidepressants Beta-adrenergic blockers Calcium channel antagonists Nonsteroidal anti-inflammatory drugs Serotonin (5-hydroxytryptamine) antagonists Neurotoxins (eg, onabotulinumtoxinA) Other or miscellaneous Adapted from Rizzoli PB. Acute and preventive treatment of migraine. Continuum (Minneap Minn). 2012;18:764-782.
February 2014 Some of the more commonly used preventives as shown in the table are discussed below. Anti-Epileptic Drugs (AEDs).—Valproate and topiramate are both potent migraine preventives and both hold a US FDA indication for this use. Dosing can reach levels used in epilepsy, although typically the migraine doses are lower. Serious and significant side effects are possible with each, and nuisance side effects are common. A discussion in some detail with the patient is therefore warranted before use. Unfortunately, both are also categorized as Pregnancy Category D by the US FDA, thus limiting their use in pregnancy and indeed often limiting their selection in pregnancy-aged females as well. Tricyclic Antidepressants (TCAs).—Of the TCAs, the best evidence overall is for amitriptyline. In addition, there is a strong clinical impression of utility, especially in patients with coexistent sleep disruption, often characterized as fragmented sleep. Generally, low doses of 10-25 mg are used in migraine prevention, not the higher antidepressant doses. It may be helpful to emphasize this to the patient to avoid confusion on 2 issues. First, if comorbid depression is present, these doses may not be efficacious and another antidepressant agent may be needed for that condition. Second, some patients may suspect that, in making this drug recommendation, the provider believes that depression is the cause of the headache but may not mention this concern, thus emphasis of the reasons behind the recommendation can help ensure compliance. Adverse effects of amitriptyline include morning sedation that may be mitigated by dosing in the early evening instead of bedtime. Other limiting effects include tachycardia and vivid dreams. Weight gain and urinary retention seem less likely at these lower doses, but may nonetheless be reported rarely. Beta-Blockers.—Propranolol and timolol, which each hold a US FDA indication for migraine prevention are generally considered safe and effective. Dosing may be similar to or lower than those used in the treatment of hypertension. Although often mentioned as first choices in a patient with migraine and hypertension, in practice, achieving the ideal dose of 1 medication for 2 separate conditions is often not possible. One practical concern is that the patient may
Headache assume, because they are on a beta-blocker, that their hypertension need not be followed by their primary provider and may fail to obtain optimal care. Side effects of beta-blockers may include weight gain, somnolence, exercise intolerance, and symptomatic hypotension. Recent reports suggest an association between their use and the development of type 2 diabetes. These agents were originally considered first line in management of migraine with aura. More recently, case reports of prolonged aura in patients treated with beta-blockers or even stroke in such patients has tempered recommendations for use of these agents in the treatment of migraine with aura. Calcium Channel Antagonists.—Of the various members of this heterogeneous group, verapamil is probably the most commonly used in migraine prevention, and seems, based largely on clinical experience but with some research support, to have surpassed propranolol in the management of migraine with aura.6,7 Verapamil has also shown utility in vestibular migraine. Nonetheless, evidence cited in the recent guideline suggesting verapamil may not be of as much benefit as previously thought has resulted in a downgrade of the medication in this guideline. Dosing is typically between 80 mg and 480 mg daily and the medication is generally well tolerated. Constipation is a commonly reported side effect that may be managed by the coadministration of magnesium citrate or gluconate, 250-500 mg daily, an over-the-counter supplement that is also used separately in migraine management. At the higher end of the dosing range, cardiac conduction defects have been described and routine cardiograms may play a role in the monitoring of these patients.
CONCLUSION Advances in the preventive management of migraine have provided significant benefits to patients with this challenging and, at times, devastating condi-
369 tion. Medication management is discussed. Optimal therapeutic success is best achieved in the setting of a strong therapeutic alliance. Treatment options although limited and imperfect are nonetheless valuable in the reduction of symptoms and in the restoration of function, but are currently underused in the United States. Further educational efforts are necessary to increase utilization and improve care. The successful treatment of migraine is difficult but worth the effort. It taps every resource of the physician. Probably more hours of suffering are caused by migraine than by any other human affliction. Knowledge of its secrets is incomplete but increasing. For these reasons it presents a unique challenge. John R. Graham, MD The Treatment of Migraine, 1955
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