Advances in Migraine Treatment
http://www.100md.com
《美国整骨期刊》
Migraine is a common, incapacitating disorder that is underdiagnosed in clinical practice. Early and correct diagnosis of migraine is essential and can lead to significant improvements in a patient's quality of life. In the clinical practice setting, a screening tool can be used that can help differentiate migraine from other headache disorders. New research into the development of central sensitization and cutaneous allodynia in chronic migraine sufferers has led to an early treatment approach with triptans and other agents for acute migraine episodes. This approach results in greater 2-hour headache pain-free results. The use of botulinum toxin type A in the prophylaxis of migraine and mixed-headache types offers an alternative treatment in patients who may not have responded to other currently available migraine prophylactic agents.
Migraine is one of the most prevalent disorders seen in clinical practice today, affecting nearly 28 million Americans. Migraine is also a major cause of disability in the workplace, leading to indirect costs to society greater than 13 billion dollars a year.1 The prevalence of migraine is highest during the years of peak productivity, ie, between the ages of 25 and 55 years.
More than half of all patients meeting the International Headache Society (IHS) criteria for migraine,2(pp24-25) have migraine that remains undiagnosed.3 Several new advances in migraine management have been made in regard to the recognition of the disease, the pathogenesis of migraine, and the phenomenon of central sensitization, the emphasis on the early treatment of patients with acute migraine and prevention modes of therapy, and the use of botulinum toxin type A as a prophylactic agent for chronic migraine.
Recognition of Migraine
The American Migraine Study II revealed the number of patients who meet the IHS criteria (Table 1) for migraine, yet had their headache diagnosed as sinus headache, tension-type headache, headache due to temporomandibular joint dysfunction (TMJ), and other headache types.4 The study observed that of the patients who met the IHS criteria for migraine, 32% reported a physician's diagnosis of tension-type headache. Among the difficulties in differentiating tension-type headache from migraine is that at least 10% of patients with migraine have bilateral pain and up to 82% have neck pain,5 symptoms that are commonly associated with tension-type headache. Additionally, up to 50% of the patients who met IHS criteria for migraine reported nonpulsating pain, and up to 84% identified stress or tension as a precipitant of their headache.
The importance of early recognition of migraine can lead to significant improvement in the patient's quality of life. It is important to remember that by the time patients present with the complaint of headache, they have likely been suffering for many years. Prompt clinical recognition of migraine can prevent unnecessary procedures and tests such as lumbar puncture, electroencephalography (EEG), and repeated computed tomography (CT) scans of the sinuses. Months and even years can be wasted in pursuing inappropriate treatment when patients meeting the clinical criteria for migraine have their headaches diagnosed as "sinus headache" or headache due to "stress," depression, or anxiety.
Because migraine is believed to be a chronic and progressive disease,6 delay in appropriate treatment may lose crucial time in halting progression of the disease and may hasten the development of central sensitization within and between attacks. Although this situation has not been fully investigated scientifically, poor migraine hygiene is widely believed to lower the threshold for attacks and, for patients at risk, potentiate the development of chronic migraine. This progression from episodic migraine to chronic migraine occurs in approximately 5% of the population.6 Many clinicians do not screen for migraine as they find it time-consuming and another problem to add to "the list"; yet, early and effective intervention allows episodic migraine to be successfully managed.
When patients present to a primary care physician's office with a complaint of headache, it is essential that the physician obtain a thorough history. The interview should include questions about family history as well as the location, frequency, and severity of the headaches. The history should reveal the presence of premonitory symptoms (prodrome), an aura, associated symptoms, and whether the headache is exacerbated by exertion. Neck pain, though not a part of the IHS diagnostic criteria,2(pp24-25) is frequently present and contributes to the misdiagnosis as tension-type headache.7
The presence of bilateral nasal drainage with the headache is often mistakenly labeled as "sinus headache." The presence of autonomic symptoms, including lacrimation and rhinorrhea, is important in the migraine history. Patients with frequent migraine, multiple comorbidities, or analgesic overuse (or a combination of these situations), underscore the importance of a detailed history.
In a busy primary care practice, easy screening devices are vital tools, and several are currently available. ID Migraine is a validated tool useful in migraine screening. Impact-based questions can also help differentiate the patients with migraine from that small percentage of patients presenting to a primary care office with organic disorders.8 This test includes three screening questions that can help identify candidates who are likely migraine sufferers:
Do you have recurrent headaches that interfere with work, family, or social functions
Do your headaches last at least 4 hours
Have you had new or different headaches in the past 6 months
A migraine diagnosis is established if patients reply "Yes" to the first two questions and "No" to the third question.
Other tools are impact based. If the clinical history is strongly suggestive of migraine, it is important to establish the diagnosis and initiate treatment early with therapy for acute attacks and lifestyle education (diet, relaxation exercises, and coping methods). Preventive treatment (-blockers, anticonvulsants, tricyclic antidepressants, etc) should be started if patients have one of the following alone or in combination: a high frequency of migraine attacks, their abortive medications are not reliably effective, or they have a high level of disability.
Pathogenesis of Migraine/Central Sensitization
The theories of migraine pathophysiology have traditionally fallen into two categories: vasogenic and neurogenic. For many years, the vascular theory of migraine was supported by the following observations:
Visual auras transiently resolved with cerebral vasodilation using amyl nitrate or by inhalation of a gas mixture of 10% carbon dioxide and 90% oxygen.
The superficial temporal artery increased in pulse amplitude with an increased throbbing quality of pain.
Ergotamine, which is a vasoconstrictor, relieved the pulsations of the superficial temporal artery and the pain.9
Based on these observations, it was hypothesized that intracranial vasoconstriction was responsible for the migraine aura and that head pain resulted from reactive vasodilation.
The neurogenic theory of migraine offers the hypothesis that migraine originates from neuronal dysfunction. Based on the concept of the cortical spreading depression of Leao,10 the aura is characterized by a wave of reduced cerebral blood flow (oligemia) that passes across the cerebral cortex at a rate of 2 mm to 6 mm per minute. Oligemia is a response to depressed neuronal function and is present even when the headache begins.
Recent research focusing on the physiologic causes of migraine has revealed a neurovascular etiology, which includes neurochemical imbalances, the trigeminal system, and meningeal blood vessels. The neurovascular theory proposes that migraine attacks are generated in the brain rather than in the vasculature. The threshold for the initiation of cortical excitation is lowered because of neuronal hyperexcitability. Migraine aura is thought to occur when normally nonnoxious stimuli trigger spontaneous depolarization. Neuronal function is subsequently suppressed, and this suppression spreads across the cortex.
The phenomenon of central sensitization is an important component in the pathogenesis of migraine. This mechanism proposes that changes in neural physiology lead to increased sensitivity to normal sensations that occur during migraine. These sensations occur when performing activities such as combing the hair, bending, and wearing tight clothing. Over time, it is believed that cranial nociceptors are sensitized by multiple migraine attacks. Neuropeptides such as substance P and calcitonin gene-related peptide (cGRP) are released during the migrainous state and produce perivascular neurogenic inflammation. The inflammatory state likely sensitizes cranial nociceptors and subsequently lowers their threshold for activation and expands their receptive field.11 Second- and third-order neurons are then activated.12 Exposure to repeated pain episodes ultimately results in increased hyperalgesia (lowered pain threshold) and cutaneous allodynia at both the painful and remote body regions.
Cutaneous allodynia refers to the generation of a painful response by normally innocuous stimuli.13 In a recent study of 42 patients with migraine, mechanical and thermal pain thresholds were repeatedly measured in the periorbital and forearm skin during and between acute headache attacks. Nearly 79% of the subjects exhibited cutaneous allodynia.14 It is important to emphasize the need to treat acute migraine attacks early to prevent the occurrence of cutaneous allodynia.
In a study of 100 patients with neck pain during migraine, the subjects were stratified into 50 with neck pain prior to head pain and 50 with head pain prior to neck pain.7 Each subject was then treated with sumatriptan succinate, 100 mg, at the first sign of neck pain. The primary endpoint was headache-free at 2 hours. The secondary endpoints were neck pain-free at 2 hours—a clinical marker for allodynia (neck muscle soreness)—and incidence of triptan sensations. The results were highly significant statistically. For those subjects who initially had neck pain, both 2-hour pain-free (headache and neck pain) results were tremendous (89.4% and 82.9%, respectively). For those subjects who had neck pain after head pain, only 7.3% achieved headache-free results at 2 hours and only 4.9% had neck-pain–free results.
What does this mean for practicing physicians in the approach to early intervention of acute migraine attacks The marker for triptan responsiveness in this case is early neck pain prior to the development of headache. If the neck pain occurs after the headache, then allodynia has already developed and central sensitization has occurred. This situation renders the triptans more likely to be ineffective in treating patients for the pain of headache. Physicians should encourage patients with migraine to use the triptan early in the course of the headache prior to the development of allodynia.
The triptans, which are administered in injectable, oral, and nasal formulations, achieve significant 2-hour headache-free results when used early in the pre-allodynia stage. It is also important to emphasize to patients that they should not use a triptan to treat an acute migraine more frequently than 2 days a week to decrease the possible development of rebound headaches.
Preventive Intervention
The decision to undertake preventive treatment in patients with migraine remains significantly controversial. Issues in preventive treatment include:
when to initiate therapy and for how long,
which agents to use,
whether a patient who requires preventive therapy will always require preventive therapy, and
number of migraines per month that indicate the need for preventive therapy.
For many of these issues, definitive answers are still pending. What is known is that few patients with migraine receive preventive treatment, and no consensus has been established as to when to initiate treatment. With the advent of triptan therapy and the limited efficacy of some preventive agents, we have experienced a decade of more hesitancy in committing patients to preventive therapy. Definite guidelines, such as those published by the Headache Consortium,27 may be used as a reference (Tables 2, 3, and 4).
Patients who have a high frequency of migraine attacks are typically good candidates for preventive treatment as are those individuals with infrequent, yet prolonged, attacks. Attacks that are poorly controlled with appropriately used modes of therapy for acute attacks may indicate that the patient is a likely candidate for preventive treatment. Patients with multiple comorbidities in addition to migraine seem to be at risk for more frequent attacks15 and should be considered for preventive treatment.
As the population with migraine ages, some patients will achieve a reduction in the frequency and severity of attacks; however, some modes of therapy for acute attacks may be contraindicated because of cardiovascular risk factors as seen with the triptans and ergotamine, or gastrointestinal and renal issues with nonsteroidal anti-inflammatory drugs (NSAIDs). For these older patients who are having frequent and severe migraine episodes, preventive treatment may be necessary. Some patients prefer to prevent attacks and would like to avoid therapy for acute episodes. Other patients may be successful with using therapy for acute attacks but have intermittent episodes in which prevention is warranted. It is important to remember migraine escalates during the late thirties and into the forties, especially in women.16
A thorough assessment of risk factors for exacerbation of migraine is useful before considering migraine prevention. A careful evaluation of analgesic and caffeine use is also helpful. Maintaining regular sleep and eating patterns, as well as exercising, may improve the patient's overall outcome. Reviewing headache diaries or calendars are useful for both the patient and physician to determine any progress. These headache calendars can often facilitate monitoring of patient compliance with early intervention and determining migraine triggers, as well as yielding information about timing of attacks. For example, patients with early morning migraine,17 may require injectable medications to successfully abort and manage their attacks. A significant feature to be considered is that about 25% of female migraineurs may become pregnant during their headache course. Therefore, the safety of the mother and the fetus must be given special consideration.
Currently, five agents are approved by the US Food and Drug Administration (FDA) for migraine prophylaxis, and include divalproex sodium, propranolol hydrochloride, timolol maleate, topiramate, and methysergide (which is no longer available in the United States). Over the years, many other medications have been used to prevent migraine with varying success. Since the 1960s, the tricyclic antidepressants have been used in migraine prophylaxis. Other agents used for migraine prevention include other antiepileptic drugs, NSAIDs, selective serotonin-reuptake inhibitors, calcium channel blockers, and muscle relaxants. None of these alternative agents has either applied for, or received, FDA approval. To evaluate their efficacy, the Headache Consortium again evaluated the quality of the evidence regarding these medications and has rated them in terms of evidence and efficacy. Adding the patient presentation to the evidence-based information can be a highly useful tool in selecting potential medications for tolerability and appropriate indication. Recognizing comorbidity may also be a useful tool in determining therapeutic options. Other important factors are dosing and adequate trials to assess the benefits of the medication.
Topiramate
The newest prophylactic agent approved by the FDA is topiramate, which garnered approval during 2004. This antiepileptic drug has been available for a few years but was used off-label for migraine prevention. In clinical trials,18,19 the drug decreased migraine attacks by 50% and was well tolerated. The experience from the clinical trials with topiramate showed efficacy at doses between 100 mg and 200 mg. Most patients tolerated the medication well and were able to remain in the study.
Clinically, some important teaching points are necessary for patients using this medication. Patients should be cognizant that some tiredness or cognitive dysfunction can occur but are usually transient and mild. Topiramate therapy should be started at a dose of 25 mg and increased by 25-mg increments every week to 10 days as tolerated. Some patients will not require 100-mg doses to achieve a significant response. Typical side effects include transient peripheral paresthesias and a distaste for carbonated beverages. Acute glaucoma has rarely occurred with initiation of this agent. Symptoms of renal colic may exacerbate with topiramate. Topiramate is a category C drug in pregnancy and, at doses of 200 mg/d or greater, it can decrease the efficacy of oral contraceptives.
Patients have found excellent results with this agent, and unlike many other migraine preventive medications, it is often weight neutral. Also, some patients can lose weight during topiramate therapy, though it is usually a modest loss. This agent should be used cautiously in patients with a history of eating disorders.
Botulinum Toxin Type A and Chronic Migraine
With botulinum toxin type A, pain relief has been reported frequently in the treatment of cervical dystonia and spasticity.20,21 The results of the initial studies revealed significant benefits to the quality of life of patients with cervical dystonia and spasticity,22 benefits that could extend to patients with chronic migraine and chronic daily headache. It is also currently FDA-approved for the treatment of blepharospasm, strabismus, and severe primary hyperhydrosis that is inadequately managed with topical agents. Botulinum toxin type A is a novel prophylactic headache treatment that, through its actions on the neuromuscular junction, has muscular actions without vascular or systemic effects.
The number of clinical trials has increased in the evaluation of the efficacy of botulinum toxin type A in the prophylactic treatment of migraine. In a study of 123 patients who met the IHS criteria for migraine,2(pp24-25) the patients were randomly assigned to receive either 0 U, 25 U, or 75 U of botulinum toxin type A.23 Each sample was injected symmetrically into the glabellar, frontalis, and temporalis muscles. While patients assessed both active treatments favorably compared with placebo, only the 25-U treatment group fared significantly better than placebo in several endpoints, including reduction in mean frequency of moderate to severe migraine attacks during days 31 to 60 (P = .008) and then days 61 to 90 (P = .04) postinjection. Patients receiving 25 U also had a reduced number of days using acute migraine medications at month 2 (P = .03). No serious treatment-related adverse events were reported.
A 3-year retrospective study was conducted in 271 patients who had headache diagnosed according to IHS criteria2(pp24-25) as either chronic daily headache (headache for more than 15 days per month), episodic tension-type headache, episodic migraine, or "mixed" headache (headache less than 15 days per month, a combination of migraine and tension-type headaches).24 The main reasons given for patients seeking botulinum toxin type A treatment were a refractory response to oral medications (77%) and overuse of medication for acute episodes (48%).
Depression, which is commonly observed in patients with "refractory" migraine, was a frequent comorbidity in the patient population (34%). The mean total treatment period was 8.6 months, during which time patients received an average of 3.4 treatments of botulinum toxin type A. All patients were treated at least twice, approximately 3 months between treatments. The results of the study revealed that botulinum toxin type A treatment significantly reduced headache frequency regardless of headache type (all, P < .001). The number of headache days per month decreased from 18.9 at baseline to 8.3 at last treatment, a 56% reduction (P < .001). Headache intensity decreased significantly from 2.4 points at baseline to 1.8 points at last treatment (P < .001), and was highly significant in patients with episodic migraine, chronic daily headache, and mixed headache. Approximately 95% of the patients reported no adverse events.24
Although results such as these are encouraging, more placebo-controlled studies will need to demonstrate consistent efficacy data. Additionally, the high placebo response rate will need to be evaluated further. The precise mechanism by which head pain is reduced by this treatment modality is unclear. A possible hypothesis is that treatment with botulinum toxin type A may reduce the local release of nociceptive neuropeptides.25 Also, it is postulated that the nerves may be stimulated by the strong contraction of the corrugator supercilii and the temporalis muscles.26
The question that most physicians ask is, what type of patient who has headaches is a suitable candidate for preventive treatment with botulinum toxin type A If the patient has localized pain in the neck associated with the headache, or if the headaches persist despite adequate headache preventive treatment (or both), then treatment with botulinum toxin type A may be considered. Patients may have rebound headaches if excessive amounts of prescription and over-the-counter analgesics, including acetaminophen, ibuprofen, naproxen, and aspirin, are used. This type of patient may also benefit from a trial of botulinum toxin type A to decrease the use of these medications.
Serious adverse reactions to botulinum toxin type A include anaphylaxis, severe dysphagia, focal facial paralysis, and dysphonia (very rare). More common reactions include irritation and pain at the injection sites, neck pain, flulike symptoms, and ptosis. Caution is advised with concomitant use of neuromuscular blockers, succinylcholine, quinidine, parenteral aminoglycosides, and clindamycin hydrochloride as each of these agents may potentiate the neuromuscular effect of the botulinum toxin. Also, concomitant use of chloroquine phosphate and hydroxychloroquine sulfate should be monitored as these drugs may interfere with the activity of botulinum toxin type A because of an unknown mechanism.
Comment
Migraine is a commonly seen medical disorder in primary care practice that can be incapacitating and is a major cause of workplace disability in the United States. Early and accurate diagnosis of migraine is important, because patients who are given incorrect diagnoses of sinus headache or tension-type headache tend to have long delays in receiving appropriate prophylaxis and treatment of acute migraine attacks. A screening tool can be used in the office setting to help distinguish between migraine and other headache disorders. Current research has revealed the necessity to treat acute migraine attacks early and to use a triptan prior to the development of central sensitization and cutaneous allodynia.
Migraine prophylaxis should be considered in patients who have at least three moderate to severe headache days per month, or in patients who have renal or cardiovascular risk factors alone or in combination with other comorbidities that contraindicate the use of triptans or other agents for acute migraine. Botulinum toxin type A treatment can be considered in patients with neck pain associated with migraine or those with mixed headache disorders. Further research into migraine pathogenesis and treatment continues to evolve and will provide greater insight into the selection of patients with migraine for treatment with botulinum toxin type A.
Footnotes
Dr Nissan has served as a consultant to and/or conducted research with Ortho-McNeil Pharmaceutical, Inc. Dr Diamond has served as a speaker for AstraZeneca; GlaxoSmithKline; Merck & Co, Inc; Ortho-McNeil Pharmaceutical, Inc; and Pfizer Inc. She has served as a consultant for GlaxoSmithKline and Merck & Co, Inc; and she has conducted research for Abbott Laboratories; AstraZeneca; GlaxoSmithKline; Merck & Co, Inc; Ortho-McNeil McNeil Pharmaceutical, Inc; Pfizer Inc; Pozen, Inc; and Winston Laboratories.
This continuing medical education publication supported by an unrestricted educational grant from Merck & Co, Inc
Dr Nissan is a staff physician at the Diamond Headache Clinic, and Dr Diamond is associate director of the Diamond Headache Clinic in Chicago, Ill. Dr Diamond is also a clinical assistant professor in the Department of Medicine at The Chicago Medical School at Rosalind Franklin University of Medicine and Science, in North Chicago, Ill.
References
1. Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML. Burden of migraine in the United States: disability and economic costs. Arch Intern Med. 1999;159:813 -818.
2. The International Classification of Headache Disorders, 2nd edition. Cephalalgia.2004; 24(Suppl 1):9 -160.
3. Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache. 2001;41 : 646-657.
4. Lipton RB, Diamond S, Reed M, Diamond ML, Stewart WF. Migraine diagnosis and treatment: results from the American Migraine Study II. Headache. 2001;41:638 -645.
5. Kaniecki RG. Diagnostic challenges in headache: migraine as the wolf disguised in sheep's clothing. Introduction. Neurology. 2002;58 : S1-S2.
6. Lipton RB, Pan J. Is migraine a progressive brain disease JAMA. 2004;291:493 -494.
7. Kaniecki RG. Migraine and tension-type headache: an assessment of challenges in diagnosis. Neurology.2002; 58(Suppl 6):S15 -S20.
8. Cady RK, Borchert LD, Spalding W, Hart CC, Sheftell FD. Simple and efficient recognition of migraine with 3-question headache screen. Headache. 2004;44:323 -327.
9. Wolff HG. Headache and Other Pain. 2nd ed. New York, NY: Oxford University Press; 1963.
10. Leao AA. Spreading depression of activity in the cerebral cortex. J Neurophysiol.1944; 8:379 -390.
11. Burstein R, Yamamura H, Malick A, Strassman AM. Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons. J Neurophysiol. 1998;79:964 -982.
12. Yamamura H, Malick A, Chamberlin NL, Burstein R. Cardiovascular and neuronal responses to head stimulation reflect central sensitization and cutaneous allodynia in a rat model of migraine. J Neurophysiol. 1999; 81:479 -493.
13. Cutrer FM. Pain-sensitive cranial structures: chemical anatomy. In: Silberstein SD, Lipton RB, Dalessio DJ, eds. Wolff's Headache and Other Head Pain. 7th ed. New York, NY: Oxford University Press;2001 : 50-56.
14. Burstein R, Yarnitsky D, Goor-Aryeh, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol. 2000;47:614 -624.
15. Scher AI, Lipton RB, Stewart W. Risk factors for chronic daily headache. Curr Pain Headache Rep.2002; 6:486 -491.
16. Lipton RB, Scher AI, Kolodner K, Liberman J, Steiner TJ, Stewart WF. Migraine in the United States: epidemiology and patterns of health care use. Neurology.2002; 58:885 -894.
17. Giffin NJ, Ruggiero L, Lipton RB, Silberstein SD, Tvedskov JF, Olesen J, et al. Premonitory symptoms in migraine: An electronic diary study. Neurology.2003; 60:935 -940.
18. Brandes JL, Saper JR, Diamond M, Couch JR, Lewis DW, Schmitt J, et al. Topiramate for migraine prevention: a randomized controlled trial. JAMA. 2004;291:965 -973.
19. Silberstein SD, Neto W, Schmitt J, Jacobs D; MIGR-001 Study Group. Topiramate in migraine prevention: results of a large controlled trial. Arch Neurol.2004; 61:490 -495.
20. Greene P, Kang U, Fahn S, Brin M, Moskowitz C, Flaster E. Double-blind, placebo-controlled trial of botulinum toxin injections for the treatment of spasmodic torticollis. Neurology.1990; 40:1213 -1218.
21. Jankovic J, Schwartz K. Botulinum toxin injections for cervical dystonia. Neurology.1990; 40:277 -280.
22. Jankovic J, Esquenazi A, Fehlings D, Freitag F, Lang AM, Naumann M. Evidence-based review of patient-reported outcomes with botulinum toxin type A. Clin Neuropharmacol.2004; 27:234 -244.
23. Silberstein S, Mathew N, Saper J, Jenkins S. Botulinum toxin type A as a migraine preventive treatment. For the BOTOX Migraine Clinical Research Group. Headache.2000; 40:445 -450.
24. Blumenfeld A. Botulinum toxin type A as an effective prophylactic treatment in primary headache disorders. Headache.2003; 43:853 -860.
25. Ishikawa H, Mitsui Y, Yoshitomi T, Mashimo K, Aoki S, Mukuno K, et al. Presynaptic effects of botulinum toxin type A on the neuronally evoked response of albino and pigmented rabbit iris sphincter and dilator muscles. Jpn J Ophthalmol.2000; 44:106 -109.
26. Guyuron B, Varghai A, Michelow BJ, Thomas T, Davis J. Corrugator supercilii muscle resection and migraine headaches. Plast Reconstr Surg. 2000;106:429 -434.
27. Silberstein SD, for the US Headache Consortium. Practice parameter: Evidence-based guidelines for migraine headache (An evidence-based review). American Academy of Neurology; 2004. Available at: http://www.neurology.org/cgi/reprint/55/6/754.pdf. Accessed March 4, 2005.(George R. Nissan, DO; Mer)
Migraine is one of the most prevalent disorders seen in clinical practice today, affecting nearly 28 million Americans. Migraine is also a major cause of disability in the workplace, leading to indirect costs to society greater than 13 billion dollars a year.1 The prevalence of migraine is highest during the years of peak productivity, ie, between the ages of 25 and 55 years.
More than half of all patients meeting the International Headache Society (IHS) criteria for migraine,2(pp24-25) have migraine that remains undiagnosed.3 Several new advances in migraine management have been made in regard to the recognition of the disease, the pathogenesis of migraine, and the phenomenon of central sensitization, the emphasis on the early treatment of patients with acute migraine and prevention modes of therapy, and the use of botulinum toxin type A as a prophylactic agent for chronic migraine.
Recognition of Migraine
The American Migraine Study II revealed the number of patients who meet the IHS criteria (Table 1) for migraine, yet had their headache diagnosed as sinus headache, tension-type headache, headache due to temporomandibular joint dysfunction (TMJ), and other headache types.4 The study observed that of the patients who met the IHS criteria for migraine, 32% reported a physician's diagnosis of tension-type headache. Among the difficulties in differentiating tension-type headache from migraine is that at least 10% of patients with migraine have bilateral pain and up to 82% have neck pain,5 symptoms that are commonly associated with tension-type headache. Additionally, up to 50% of the patients who met IHS criteria for migraine reported nonpulsating pain, and up to 84% identified stress or tension as a precipitant of their headache.
The importance of early recognition of migraine can lead to significant improvement in the patient's quality of life. It is important to remember that by the time patients present with the complaint of headache, they have likely been suffering for many years. Prompt clinical recognition of migraine can prevent unnecessary procedures and tests such as lumbar puncture, electroencephalography (EEG), and repeated computed tomography (CT) scans of the sinuses. Months and even years can be wasted in pursuing inappropriate treatment when patients meeting the clinical criteria for migraine have their headaches diagnosed as "sinus headache" or headache due to "stress," depression, or anxiety.
Because migraine is believed to be a chronic and progressive disease,6 delay in appropriate treatment may lose crucial time in halting progression of the disease and may hasten the development of central sensitization within and between attacks. Although this situation has not been fully investigated scientifically, poor migraine hygiene is widely believed to lower the threshold for attacks and, for patients at risk, potentiate the development of chronic migraine. This progression from episodic migraine to chronic migraine occurs in approximately 5% of the population.6 Many clinicians do not screen for migraine as they find it time-consuming and another problem to add to "the list"; yet, early and effective intervention allows episodic migraine to be successfully managed.
When patients present to a primary care physician's office with a complaint of headache, it is essential that the physician obtain a thorough history. The interview should include questions about family history as well as the location, frequency, and severity of the headaches. The history should reveal the presence of premonitory symptoms (prodrome), an aura, associated symptoms, and whether the headache is exacerbated by exertion. Neck pain, though not a part of the IHS diagnostic criteria,2(pp24-25) is frequently present and contributes to the misdiagnosis as tension-type headache.7
The presence of bilateral nasal drainage with the headache is often mistakenly labeled as "sinus headache." The presence of autonomic symptoms, including lacrimation and rhinorrhea, is important in the migraine history. Patients with frequent migraine, multiple comorbidities, or analgesic overuse (or a combination of these situations), underscore the importance of a detailed history.
In a busy primary care practice, easy screening devices are vital tools, and several are currently available. ID Migraine is a validated tool useful in migraine screening. Impact-based questions can also help differentiate the patients with migraine from that small percentage of patients presenting to a primary care office with organic disorders.8 This test includes three screening questions that can help identify candidates who are likely migraine sufferers:
Do you have recurrent headaches that interfere with work, family, or social functions
Do your headaches last at least 4 hours
Have you had new or different headaches in the past 6 months
A migraine diagnosis is established if patients reply "Yes" to the first two questions and "No" to the third question.
Other tools are impact based. If the clinical history is strongly suggestive of migraine, it is important to establish the diagnosis and initiate treatment early with therapy for acute attacks and lifestyle education (diet, relaxation exercises, and coping methods). Preventive treatment (-blockers, anticonvulsants, tricyclic antidepressants, etc) should be started if patients have one of the following alone or in combination: a high frequency of migraine attacks, their abortive medications are not reliably effective, or they have a high level of disability.
Pathogenesis of Migraine/Central Sensitization
The theories of migraine pathophysiology have traditionally fallen into two categories: vasogenic and neurogenic. For many years, the vascular theory of migraine was supported by the following observations:
Visual auras transiently resolved with cerebral vasodilation using amyl nitrate or by inhalation of a gas mixture of 10% carbon dioxide and 90% oxygen.
The superficial temporal artery increased in pulse amplitude with an increased throbbing quality of pain.
Ergotamine, which is a vasoconstrictor, relieved the pulsations of the superficial temporal artery and the pain.9
Based on these observations, it was hypothesized that intracranial vasoconstriction was responsible for the migraine aura and that head pain resulted from reactive vasodilation.
The neurogenic theory of migraine offers the hypothesis that migraine originates from neuronal dysfunction. Based on the concept of the cortical spreading depression of Leao,10 the aura is characterized by a wave of reduced cerebral blood flow (oligemia) that passes across the cerebral cortex at a rate of 2 mm to 6 mm per minute. Oligemia is a response to depressed neuronal function and is present even when the headache begins.
Recent research focusing on the physiologic causes of migraine has revealed a neurovascular etiology, which includes neurochemical imbalances, the trigeminal system, and meningeal blood vessels. The neurovascular theory proposes that migraine attacks are generated in the brain rather than in the vasculature. The threshold for the initiation of cortical excitation is lowered because of neuronal hyperexcitability. Migraine aura is thought to occur when normally nonnoxious stimuli trigger spontaneous depolarization. Neuronal function is subsequently suppressed, and this suppression spreads across the cortex.
The phenomenon of central sensitization is an important component in the pathogenesis of migraine. This mechanism proposes that changes in neural physiology lead to increased sensitivity to normal sensations that occur during migraine. These sensations occur when performing activities such as combing the hair, bending, and wearing tight clothing. Over time, it is believed that cranial nociceptors are sensitized by multiple migraine attacks. Neuropeptides such as substance P and calcitonin gene-related peptide (cGRP) are released during the migrainous state and produce perivascular neurogenic inflammation. The inflammatory state likely sensitizes cranial nociceptors and subsequently lowers their threshold for activation and expands their receptive field.11 Second- and third-order neurons are then activated.12 Exposure to repeated pain episodes ultimately results in increased hyperalgesia (lowered pain threshold) and cutaneous allodynia at both the painful and remote body regions.
Cutaneous allodynia refers to the generation of a painful response by normally innocuous stimuli.13 In a recent study of 42 patients with migraine, mechanical and thermal pain thresholds were repeatedly measured in the periorbital and forearm skin during and between acute headache attacks. Nearly 79% of the subjects exhibited cutaneous allodynia.14 It is important to emphasize the need to treat acute migraine attacks early to prevent the occurrence of cutaneous allodynia.
In a study of 100 patients with neck pain during migraine, the subjects were stratified into 50 with neck pain prior to head pain and 50 with head pain prior to neck pain.7 Each subject was then treated with sumatriptan succinate, 100 mg, at the first sign of neck pain. The primary endpoint was headache-free at 2 hours. The secondary endpoints were neck pain-free at 2 hours—a clinical marker for allodynia (neck muscle soreness)—and incidence of triptan sensations. The results were highly significant statistically. For those subjects who initially had neck pain, both 2-hour pain-free (headache and neck pain) results were tremendous (89.4% and 82.9%, respectively). For those subjects who had neck pain after head pain, only 7.3% achieved headache-free results at 2 hours and only 4.9% had neck-pain–free results.
What does this mean for practicing physicians in the approach to early intervention of acute migraine attacks The marker for triptan responsiveness in this case is early neck pain prior to the development of headache. If the neck pain occurs after the headache, then allodynia has already developed and central sensitization has occurred. This situation renders the triptans more likely to be ineffective in treating patients for the pain of headache. Physicians should encourage patients with migraine to use the triptan early in the course of the headache prior to the development of allodynia.
The triptans, which are administered in injectable, oral, and nasal formulations, achieve significant 2-hour headache-free results when used early in the pre-allodynia stage. It is also important to emphasize to patients that they should not use a triptan to treat an acute migraine more frequently than 2 days a week to decrease the possible development of rebound headaches.
Preventive Intervention
The decision to undertake preventive treatment in patients with migraine remains significantly controversial. Issues in preventive treatment include:
when to initiate therapy and for how long,
which agents to use,
whether a patient who requires preventive therapy will always require preventive therapy, and
number of migraines per month that indicate the need for preventive therapy.
For many of these issues, definitive answers are still pending. What is known is that few patients with migraine receive preventive treatment, and no consensus has been established as to when to initiate treatment. With the advent of triptan therapy and the limited efficacy of some preventive agents, we have experienced a decade of more hesitancy in committing patients to preventive therapy. Definite guidelines, such as those published by the Headache Consortium,27 may be used as a reference (Tables 2, 3, and 4).
Patients who have a high frequency of migraine attacks are typically good candidates for preventive treatment as are those individuals with infrequent, yet prolonged, attacks. Attacks that are poorly controlled with appropriately used modes of therapy for acute attacks may indicate that the patient is a likely candidate for preventive treatment. Patients with multiple comorbidities in addition to migraine seem to be at risk for more frequent attacks15 and should be considered for preventive treatment.
As the population with migraine ages, some patients will achieve a reduction in the frequency and severity of attacks; however, some modes of therapy for acute attacks may be contraindicated because of cardiovascular risk factors as seen with the triptans and ergotamine, or gastrointestinal and renal issues with nonsteroidal anti-inflammatory drugs (NSAIDs). For these older patients who are having frequent and severe migraine episodes, preventive treatment may be necessary. Some patients prefer to prevent attacks and would like to avoid therapy for acute episodes. Other patients may be successful with using therapy for acute attacks but have intermittent episodes in which prevention is warranted. It is important to remember migraine escalates during the late thirties and into the forties, especially in women.16
A thorough assessment of risk factors for exacerbation of migraine is useful before considering migraine prevention. A careful evaluation of analgesic and caffeine use is also helpful. Maintaining regular sleep and eating patterns, as well as exercising, may improve the patient's overall outcome. Reviewing headache diaries or calendars are useful for both the patient and physician to determine any progress. These headache calendars can often facilitate monitoring of patient compliance with early intervention and determining migraine triggers, as well as yielding information about timing of attacks. For example, patients with early morning migraine,17 may require injectable medications to successfully abort and manage their attacks. A significant feature to be considered is that about 25% of female migraineurs may become pregnant during their headache course. Therefore, the safety of the mother and the fetus must be given special consideration.
Currently, five agents are approved by the US Food and Drug Administration (FDA) for migraine prophylaxis, and include divalproex sodium, propranolol hydrochloride, timolol maleate, topiramate, and methysergide (which is no longer available in the United States). Over the years, many other medications have been used to prevent migraine with varying success. Since the 1960s, the tricyclic antidepressants have been used in migraine prophylaxis. Other agents used for migraine prevention include other antiepileptic drugs, NSAIDs, selective serotonin-reuptake inhibitors, calcium channel blockers, and muscle relaxants. None of these alternative agents has either applied for, or received, FDA approval. To evaluate their efficacy, the Headache Consortium again evaluated the quality of the evidence regarding these medications and has rated them in terms of evidence and efficacy. Adding the patient presentation to the evidence-based information can be a highly useful tool in selecting potential medications for tolerability and appropriate indication. Recognizing comorbidity may also be a useful tool in determining therapeutic options. Other important factors are dosing and adequate trials to assess the benefits of the medication.
Topiramate
The newest prophylactic agent approved by the FDA is topiramate, which garnered approval during 2004. This antiepileptic drug has been available for a few years but was used off-label for migraine prevention. In clinical trials,18,19 the drug decreased migraine attacks by 50% and was well tolerated. The experience from the clinical trials with topiramate showed efficacy at doses between 100 mg and 200 mg. Most patients tolerated the medication well and were able to remain in the study.
Clinically, some important teaching points are necessary for patients using this medication. Patients should be cognizant that some tiredness or cognitive dysfunction can occur but are usually transient and mild. Topiramate therapy should be started at a dose of 25 mg and increased by 25-mg increments every week to 10 days as tolerated. Some patients will not require 100-mg doses to achieve a significant response. Typical side effects include transient peripheral paresthesias and a distaste for carbonated beverages. Acute glaucoma has rarely occurred with initiation of this agent. Symptoms of renal colic may exacerbate with topiramate. Topiramate is a category C drug in pregnancy and, at doses of 200 mg/d or greater, it can decrease the efficacy of oral contraceptives.
Patients have found excellent results with this agent, and unlike many other migraine preventive medications, it is often weight neutral. Also, some patients can lose weight during topiramate therapy, though it is usually a modest loss. This agent should be used cautiously in patients with a history of eating disorders.
Botulinum Toxin Type A and Chronic Migraine
With botulinum toxin type A, pain relief has been reported frequently in the treatment of cervical dystonia and spasticity.20,21 The results of the initial studies revealed significant benefits to the quality of life of patients with cervical dystonia and spasticity,22 benefits that could extend to patients with chronic migraine and chronic daily headache. It is also currently FDA-approved for the treatment of blepharospasm, strabismus, and severe primary hyperhydrosis that is inadequately managed with topical agents. Botulinum toxin type A is a novel prophylactic headache treatment that, through its actions on the neuromuscular junction, has muscular actions without vascular or systemic effects.
The number of clinical trials has increased in the evaluation of the efficacy of botulinum toxin type A in the prophylactic treatment of migraine. In a study of 123 patients who met the IHS criteria for migraine,2(pp24-25) the patients were randomly assigned to receive either 0 U, 25 U, or 75 U of botulinum toxin type A.23 Each sample was injected symmetrically into the glabellar, frontalis, and temporalis muscles. While patients assessed both active treatments favorably compared with placebo, only the 25-U treatment group fared significantly better than placebo in several endpoints, including reduction in mean frequency of moderate to severe migraine attacks during days 31 to 60 (P = .008) and then days 61 to 90 (P = .04) postinjection. Patients receiving 25 U also had a reduced number of days using acute migraine medications at month 2 (P = .03). No serious treatment-related adverse events were reported.
A 3-year retrospective study was conducted in 271 patients who had headache diagnosed according to IHS criteria2(pp24-25) as either chronic daily headache (headache for more than 15 days per month), episodic tension-type headache, episodic migraine, or "mixed" headache (headache less than 15 days per month, a combination of migraine and tension-type headaches).24 The main reasons given for patients seeking botulinum toxin type A treatment were a refractory response to oral medications (77%) and overuse of medication for acute episodes (48%).
Depression, which is commonly observed in patients with "refractory" migraine, was a frequent comorbidity in the patient population (34%). The mean total treatment period was 8.6 months, during which time patients received an average of 3.4 treatments of botulinum toxin type A. All patients were treated at least twice, approximately 3 months between treatments. The results of the study revealed that botulinum toxin type A treatment significantly reduced headache frequency regardless of headache type (all, P < .001). The number of headache days per month decreased from 18.9 at baseline to 8.3 at last treatment, a 56% reduction (P < .001). Headache intensity decreased significantly from 2.4 points at baseline to 1.8 points at last treatment (P < .001), and was highly significant in patients with episodic migraine, chronic daily headache, and mixed headache. Approximately 95% of the patients reported no adverse events.24
Although results such as these are encouraging, more placebo-controlled studies will need to demonstrate consistent efficacy data. Additionally, the high placebo response rate will need to be evaluated further. The precise mechanism by which head pain is reduced by this treatment modality is unclear. A possible hypothesis is that treatment with botulinum toxin type A may reduce the local release of nociceptive neuropeptides.25 Also, it is postulated that the nerves may be stimulated by the strong contraction of the corrugator supercilii and the temporalis muscles.26
The question that most physicians ask is, what type of patient who has headaches is a suitable candidate for preventive treatment with botulinum toxin type A If the patient has localized pain in the neck associated with the headache, or if the headaches persist despite adequate headache preventive treatment (or both), then treatment with botulinum toxin type A may be considered. Patients may have rebound headaches if excessive amounts of prescription and over-the-counter analgesics, including acetaminophen, ibuprofen, naproxen, and aspirin, are used. This type of patient may also benefit from a trial of botulinum toxin type A to decrease the use of these medications.
Serious adverse reactions to botulinum toxin type A include anaphylaxis, severe dysphagia, focal facial paralysis, and dysphonia (very rare). More common reactions include irritation and pain at the injection sites, neck pain, flulike symptoms, and ptosis. Caution is advised with concomitant use of neuromuscular blockers, succinylcholine, quinidine, parenteral aminoglycosides, and clindamycin hydrochloride as each of these agents may potentiate the neuromuscular effect of the botulinum toxin. Also, concomitant use of chloroquine phosphate and hydroxychloroquine sulfate should be monitored as these drugs may interfere with the activity of botulinum toxin type A because of an unknown mechanism.
Comment
Migraine is a commonly seen medical disorder in primary care practice that can be incapacitating and is a major cause of workplace disability in the United States. Early and accurate diagnosis of migraine is important, because patients who are given incorrect diagnoses of sinus headache or tension-type headache tend to have long delays in receiving appropriate prophylaxis and treatment of acute migraine attacks. A screening tool can be used in the office setting to help distinguish between migraine and other headache disorders. Current research has revealed the necessity to treat acute migraine attacks early and to use a triptan prior to the development of central sensitization and cutaneous allodynia.
Migraine prophylaxis should be considered in patients who have at least three moderate to severe headache days per month, or in patients who have renal or cardiovascular risk factors alone or in combination with other comorbidities that contraindicate the use of triptans or other agents for acute migraine. Botulinum toxin type A treatment can be considered in patients with neck pain associated with migraine or those with mixed headache disorders. Further research into migraine pathogenesis and treatment continues to evolve and will provide greater insight into the selection of patients with migraine for treatment with botulinum toxin type A.
Footnotes
Dr Nissan has served as a consultant to and/or conducted research with Ortho-McNeil Pharmaceutical, Inc. Dr Diamond has served as a speaker for AstraZeneca; GlaxoSmithKline; Merck & Co, Inc; Ortho-McNeil Pharmaceutical, Inc; and Pfizer Inc. She has served as a consultant for GlaxoSmithKline and Merck & Co, Inc; and she has conducted research for Abbott Laboratories; AstraZeneca; GlaxoSmithKline; Merck & Co, Inc; Ortho-McNeil McNeil Pharmaceutical, Inc; Pfizer Inc; Pozen, Inc; and Winston Laboratories.
This continuing medical education publication supported by an unrestricted educational grant from Merck & Co, Inc
Dr Nissan is a staff physician at the Diamond Headache Clinic, and Dr Diamond is associate director of the Diamond Headache Clinic in Chicago, Ill. Dr Diamond is also a clinical assistant professor in the Department of Medicine at The Chicago Medical School at Rosalind Franklin University of Medicine and Science, in North Chicago, Ill.
References
1. Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML. Burden of migraine in the United States: disability and economic costs. Arch Intern Med. 1999;159:813 -818.
2. The International Classification of Headache Disorders, 2nd edition. Cephalalgia.2004; 24(Suppl 1):9 -160.
3. Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache. 2001;41 : 646-657.
4. Lipton RB, Diamond S, Reed M, Diamond ML, Stewart WF. Migraine diagnosis and treatment: results from the American Migraine Study II. Headache. 2001;41:638 -645.
5. Kaniecki RG. Diagnostic challenges in headache: migraine as the wolf disguised in sheep's clothing. Introduction. Neurology. 2002;58 : S1-S2.
6. Lipton RB, Pan J. Is migraine a progressive brain disease JAMA. 2004;291:493 -494.
7. Kaniecki RG. Migraine and tension-type headache: an assessment of challenges in diagnosis. Neurology.2002; 58(Suppl 6):S15 -S20.
8. Cady RK, Borchert LD, Spalding W, Hart CC, Sheftell FD. Simple and efficient recognition of migraine with 3-question headache screen. Headache. 2004;44:323 -327.
9. Wolff HG. Headache and Other Pain. 2nd ed. New York, NY: Oxford University Press; 1963.
10. Leao AA. Spreading depression of activity in the cerebral cortex. J Neurophysiol.1944; 8:379 -390.
11. Burstein R, Yamamura H, Malick A, Strassman AM. Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons. J Neurophysiol. 1998;79:964 -982.
12. Yamamura H, Malick A, Chamberlin NL, Burstein R. Cardiovascular and neuronal responses to head stimulation reflect central sensitization and cutaneous allodynia in a rat model of migraine. J Neurophysiol. 1999; 81:479 -493.
13. Cutrer FM. Pain-sensitive cranial structures: chemical anatomy. In: Silberstein SD, Lipton RB, Dalessio DJ, eds. Wolff's Headache and Other Head Pain. 7th ed. New York, NY: Oxford University Press;2001 : 50-56.
14. Burstein R, Yarnitsky D, Goor-Aryeh, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol. 2000;47:614 -624.
15. Scher AI, Lipton RB, Stewart W. Risk factors for chronic daily headache. Curr Pain Headache Rep.2002; 6:486 -491.
16. Lipton RB, Scher AI, Kolodner K, Liberman J, Steiner TJ, Stewart WF. Migraine in the United States: epidemiology and patterns of health care use. Neurology.2002; 58:885 -894.
17. Giffin NJ, Ruggiero L, Lipton RB, Silberstein SD, Tvedskov JF, Olesen J, et al. Premonitory symptoms in migraine: An electronic diary study. Neurology.2003; 60:935 -940.
18. Brandes JL, Saper JR, Diamond M, Couch JR, Lewis DW, Schmitt J, et al. Topiramate for migraine prevention: a randomized controlled trial. JAMA. 2004;291:965 -973.
19. Silberstein SD, Neto W, Schmitt J, Jacobs D; MIGR-001 Study Group. Topiramate in migraine prevention: results of a large controlled trial. Arch Neurol.2004; 61:490 -495.
20. Greene P, Kang U, Fahn S, Brin M, Moskowitz C, Flaster E. Double-blind, placebo-controlled trial of botulinum toxin injections for the treatment of spasmodic torticollis. Neurology.1990; 40:1213 -1218.
21. Jankovic J, Schwartz K. Botulinum toxin injections for cervical dystonia. Neurology.1990; 40:277 -280.
22. Jankovic J, Esquenazi A, Fehlings D, Freitag F, Lang AM, Naumann M. Evidence-based review of patient-reported outcomes with botulinum toxin type A. Clin Neuropharmacol.2004; 27:234 -244.
23. Silberstein S, Mathew N, Saper J, Jenkins S. Botulinum toxin type A as a migraine preventive treatment. For the BOTOX Migraine Clinical Research Group. Headache.2000; 40:445 -450.
24. Blumenfeld A. Botulinum toxin type A as an effective prophylactic treatment in primary headache disorders. Headache.2003; 43:853 -860.
25. Ishikawa H, Mitsui Y, Yoshitomi T, Mashimo K, Aoki S, Mukuno K, et al. Presynaptic effects of botulinum toxin type A on the neuronally evoked response of albino and pigmented rabbit iris sphincter and dilator muscles. Jpn J Ophthalmol.2000; 44:106 -109.
26. Guyuron B, Varghai A, Michelow BJ, Thomas T, Davis J. Corrugator supercilii muscle resection and migraine headaches. Plast Reconstr Surg. 2000;106:429 -434.
27. Silberstein SD, for the US Headache Consortium. Practice parameter: Evidence-based guidelines for migraine headache (An evidence-based review). American Academy of Neurology; 2004. Available at: http://www.neurology.org/cgi/reprint/55/6/754.pdf. Accessed March 4, 2005.(George R. Nissan, DO; Mer)