Catherine
Dold
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Cutting Edge Tools for
Managing Migraines
Hippocrates
(written for
Dr. John Rothrock)
A new understanding of migraine has produced an array of effective treatments that give primary care physicians powerful ways to treat this common but widely misunderstood affliction.
Migraine is extremely common, affecting about 10% of American adults (Lipton 1993), yet it is also one of the most misunderstood and poorly managed conditions, despite the availability of effective therapies.
Many patients still accept such long-standing myths as the belief that migraine is caused by stress or personal inadequacy or that no effective therapy exists. Consequently, most migraineurs never seek treatment (Lipton 1993). Of those who do, many are treated inadequately because their physicians also have misconceptions about migraine. Some physicians are hesitant to diagnose migraine without a battery of expensive tests to rule out other conditions. Others are unfamiliar with current treatments. The impact of undertreatment can be devastating: The functional impairment of patients with migraine is comparable to that of patients with active cardiac disease (Adelman 1995). Some 64 million workdays are lost each year in the U.S. due to migraine, at an indirect cost of $17 billion annually (Adelman 1995; Peroutka 1996).
Our understanding of migraine has improved substantially in the last decade, and this new knowledge has led to the introduction of highly effective therapies. A new model of migraine’s biogenesis has emerged, replacing the decades-old primary vascular hypothesis and opening the door to new approaches to treatment (Noack 1996). There is still no cure for migraine, but today, with education and treatment, most patients can achieve some measure of control over the frequency and intensity of their migraines.
New Theories on Migraine
For more than 40 years, most physicians accepted the theory that migraine was primarily a vascular phenomenon. The vascular theory held that the aura that accompanies some migraines was caused by cerebral vasoconstriction and that the throbbing, intense pain was due to intracranial and extracranial vasodilation. Although many still adhere to this idea, it has largely given way to a new model in which migraine is understood to result from genetically induced abnormalities in neurotransmission within the brain, brainstem, and trigeminovascular system.
While the location of the primary generator of migraine attacks remains unknown, recent evidence suggests that the brains of migraineurs are sensitive (Aurora 1999). Specifically, genetic polymorphisms may induce the occipital (visual) cortex to persist in a hyperexcitable state; in response to changes in the internal and external environments (such as estrogen levels or barometric pressure), these inherently unstable neurons may depolarize and initiate an electrical event in the cortex known as “spreading depression.’ Spreading depression in turn is believed to be the source of migrainous aura and may in fact play a role in producing the headache and associated autonomic symptoms of migraine.
Activation of central-head pain pathways may provoke the trigeminal nucleus to fire impulses that travel in the opposite direction from the usual flow along the ophthalmic division of cranial nerve V to bombard pain receptors located on arteries and veins within the meninges. Neuropeptides released at the trigeminovascular junction incite the target artery to swell and leak, producing sterile perivascular inflammation. This inflammation sensitizes trigeminal nerve endings, sending more messages of head pain back to an already overwrought brainstem and brain. And so it goes, back and forth, from the central nervous system to meningeal blood vessels—an accelerating and self-perpetuating volley of neurotransmission that is expressed clinically as a migraine attack. A variety of chemicals fuel this process—serotonin, glutamate, dopamine, and calcitonin gene-related peptide among them. The stereotypical phenotype of migraine may represent the clinical expression of a wide variety of genetic polymorphisms, each with its own unique neurochemistry. If this is true, it is impossible to expect any given abortive or prophylactic agent to be effective for all migraineurs, no matter how similar their histories.
When Is It Migraine?
When a patient presents with a history of severe headache, how can the physician determine if it is migraine or something else entirely?
Given the confusing array of symptoms that can accompany migraine headache, and the threat, albeit small, that the headache is a symptom of a more serious disorder, many physicians hesitate to quickly diagnose migraine. Instead, they rely on tests— especially brain-imaging studies—to rule out all other possible conditions. It needn’t be that complicated. Has the patient had five or more attacks of headache, each lasting 4 to 72 hours, that were severe enough to inhibit or prohibit routine activity and that were accompanied by either nausea or sensitivity to light and sound? Is the exam normal? If the answer to each is yes, it is most likely migraine, and treatment—not diagnosis—is the issue (Table 1).
Symptoms that may accompany migraine headache include aura (neurological symptoms—most often visual, but at times involving numbness, tingling, weakness, speech/language difficulties, or confusion) or more general symptoms such as osmophobia, polyuria, sleep disturbances, food cravings, depression, euphoria, and drowsiness. Some patients have migraine pain on only one side of the head, but in others the pain is bilateral. About one-third report being bedridden or otherwise disabled during an attack (Silberstein 1996). Some patients have attacks only a few times during their lives, while others report daily migrainous symptoms (Guitera 1997; Lipton 1993).
A migraine attack may include as many as five distinct phases:
• Prodrome phase: This phase can last for hours or days before pain begins, and it may include sensitivity to light and noise, dyspepsia, drowsiness, euphoria, increased appetite (including a craving for sweets), and other symptoms.
• Aura phase: Visual or other neurological disturbances may occur, arising before or during the headache phase.
• Headache phase: Pain (often, but not always, pulsatile) occurs, often with nausea or vomiting, and may last as long as 72 hours.
• Resolution phase: The pain starts to subside.
• Postdrome phase: The patient may feel hungover, fatigued, hungry, depressed, or euphoric.
Migraine is more common in females than in males—about 17% of women and 6% of men have active migraine (Capobianco 1996; Silberstein 1997)—and young adult women are the most likely to be actively afflicted. Hormones seem to have some influence; many women report a link to the menstrual cycle, and migraine is more common after puberty and before menopause (Fettes 1997; Russell 1996). Migraine is less common in children than in adults but has been reported to afflict between 1.2% and 11% of the pediatric population (Lipton 1997; Maytal 1997; Sillanpaa 1996).
The International Headache Society (IHS) diagnostic guidelines (Table 2) describe migraine without aura (formerly, “common” migraine), migraine with aura (formerly, “classical” migraine), and pediatric migraine without aura. These descriptions have some limitations: For example, headaches change over time and may not fit easily into a category. Some people have more than one type of headache. And those who use drugs to treat headaches may be masking symptoms. The IHS guidelines also have a rather narrow definition of pediatric migraine; one study found that less than 30% of children diagnosed by pediatric neurologists as having migraine met the strict IHS definition (Maytal 1997).
Making a Diagnosis
If you
suspect migraine, structure the patient interview to cover the individual
components of the IHS definition. The patient history, along with physical
and neurological screening exams, will often lead to an accurate diagnosis
without the
need for further testing.
The patient history should include:
Location of pain: lateralized versus generalized
Frequency, intensity, and duration of headache attacks
Effect on activities
Associated symptoms, such as gastrointestinal, neurological, or ophthalmological problems
Triggering (Table 3) or ameliorating factors
Recent change, if any, in headache pattern
History of head injury
Age of onset
Current medications
Imaging results, if any
Family history of headache.
The history and physical exam will help rule out other conditions that can mimic migraine (Table 4). In the neurological exam, one should pay particular attention to the optic fundi, pupils, visual fields, and ocular excursions. In some cases, of course, more extensive testing will be needed. If a patient presents with the worst headache of her life, eye pain (especially if accompanied by eye signs), fever, chronic headaches that recently have changed in character, or headaches that began after age 50 or after head trauma, more investigation may be necessary.
If a patient has trouble recalling symptoms, ask her to keep a headache diary. She should note the day and time of each headache, its duration and severity, its relation to her menstrual cycle, medications she has taken and their effectiveness, symptoms other than pain, and any possible triggers such as foods or weather changes. Keeping such a diary may also help patients recognize premonitory symptoms, enabling them to take abortive medication earlier and to better effect.
Treatment Options
Patients who have suffered from migraine for some time may be resigned to chronic symptoms. They often have been misdiagnosed or treated ineffectively, and may consequently feel frustrated and inclined to misuse medications. To counter patients’ pessimism, emphasize that you will work with them to find the best treatment strategy, and that with the new medications available, at least some control is likely. Stress that finding a solution may take some time: identifying the right medication will involve some trial and error. The preventive drugs typically require a few weeks to be fully effective, and side effects may occur but are likely to subside with continued treatment. If you prescribe preventive medication, emphasize to your patients that they are unlikely to need that medication indefinitely; typically, less than a year of therapy is necessary.
Patients who have relatively infrequent migraines can often control them with abortive therapy alone. Those who find that migraine continues to disrupt their lives, despite optimal abortive therapy, should consider a course of prophylactic therapy. Those on prophylactic therapy should also receive abortive therapy for treatment of breakthrough headaches. Urge all patients to carry at least one dose of abortive medication at all times: early treatment is often the most effective. Instruct them to take medications only as prescribed. No abortive agent should be taken more than three times a week, and patients should be advised to inform you if the drugs seem to be losing their effectiveness. Such management can help prevent progression to medication-induced rebound headaches.
Little information is available to help us predict which medications will be most effective for a given patient. In most cases, you will need to try a few of the medications discussed next.
Abortive Therapy
Mild-to-moderate migraine may be treated with simple analgesics, such as acetaminophen; nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, indomethacin, naproxen sodium, meclofenamate, mefenamic acid, tolfenamic acid (not available in the U.S.), flurbiprofen, ketorolac, and aspirin; or a combination analgesic containing isometheptene, acetaminophen, and dichloralphenazone. These work best if taken as close to the onset of an attack as possible.
Moderate-to-severe migraine may be treated with a simple analgesic plus codeine, with or without caffeine, or with one of the serotonin agonists: the triptan drugs, dihydroergotamine mesylate (DHE), or ergotamine tartrate. The prototypic triptan, sumatriptan (Imitrex), is available in injectable, intranasal, and oral formulations; the subcutaneously administered formulation is best taken later in the attack, when the headache is moderate or severe, and in fact will not prevent subsequent headache if taken during the aura phase. However, the oral triptans—sumatriptan, zolmitriptan (Zomig), rizatriptan (Maxalt), and naratriptan (Amerge)—appear to be more effective if taken earlier in the attack, when headache is mild to moderate; recent data indicate that early treatment is more likely to produce complete headache relief and prevent early recurrent headache. Naratriptan has a slower onset of action than other triptans, but its side effects are fewer and its therapeutic effect is longer. If one triptan does not work, try another. DHE may be administered intravenously along with an antiemetic to treat acute headache and also to help patients with rebound headache to withdraw from the offending agent. Some patients administer DHE to themselves subcutaneously with a syringe, and it is also available in a nasal spray (Migranal). Although the clinical trial data regarding Migranal were quite encouraging, results in clinical practice have been somewhat disappointing. Subcutaneous DHE, on the other hand, acts almost as rapidly and effectively as subcutaneous Imitrex and is much less likely to be associated with early recurrent headache.
Ergotamine tartrate is also effective, but given its tendency to produce nausea and its potential for causing arterial vasoconstriction and rebound headaches if prescribed in excess, it is not used as often as it once was. Isometheptene may be better tolerated than ergotamine tartrate, but it is probably less effective; it is sold in combination with an analgesic and a sedative as Midrin. Narcotic analgesics are also sometimes used to treat migraines, but they are only moderately effective, are sedating, and may increase nausea and vomiting.
Migraine-associated nausea may be treated with the dopamine antagonists prochlorperazine, chlorpromazine, droperidol, and metoclopramide; all of these may also help to treat the headache itself.
Prophylactic Therapy
The goal of prophylactic therapy is to desensitize an unstable biological system, thereby decreasing headache frequency. Prophylactic therapy is usually reserved for those who have migraine attacks that are refractory to abortive therapy, and it should always be considered when a patient has a headache more days than not, regardless of that patient’s response to abortive medication. Treatment usually lasts 6 to 12 months and is then withdrawn as migraines become less frequent. The process can be frustrating; given the latency period associated with these drugs and the possibility that the initial treatment chosen may not be effective, finding an effective therapy may take months.
To increase patient compliance with this process, make sure your patient understands that migraine attacks are still likely to occur, especially in the early stages of treatment, but should subside over time. Make sure she understands how to effectively use abortive therapy for breakthrough attacks. Ask her to keep a simple headache diary, both to encourage her compliance and to provide an objective measurement of the therapy’s effectiveness.
To get the most benefit from prophylactic therapy, try to start with a clean brain (one that is free of other brain-active medications). Start low, but strive for a therapeutic dose. Discourage patients from taking daily analgesics, as these can render the prophylactic drugs less effective. Continue the medication for at least a few months after the migraine stabilizes; if stabilization persists, consider tapering off the drug. If the frequency of attacks then increases, resume treatment.
Divalproex sodium (Depakote), a drug that promotes brain gammaaminobutyric acid (GABA), is the best choice for many patients. Side effects include nausea, weight gain, tremor, and alopecia. A rarer side effect is liver toxicity; the Physicians’ Desk Reference mandates that liver-function studies should be done prior to treatment and at intervals thereafter, but clinically significant hepatotoxicity is extremely rare. Of greater concern is the fact that divalproex is teratogenic and thus should not be used if the patient is pregnant or expects to become pregnant.
Propranolol (Inderal), a beta-blocker, also works for some patients. Side effects include insomnia, depression, and lethargy. Other beta-blockers used for migraine prophylaxis that may be effective include atenolol, metoprolol, timolol, and nadolol.
Amitriptyline, a tricyclic antidepressant, is modestly effective for migraine prophylaxis, but side effects— dry mouth, urinary retention, vision problems, and cardiovascular effects —limit its use. Amitriptyline modifies serotonin and norepinephrine, but its mechanism of action in migraine is still unclear. The antidepressants nortriptyline and doxepin, as well as phenelzine, a monoamine oxidase inhibitor, also have been commonly prescribed for migraine.
Several NSAIDs have been shown to be effective in reducing the frequency of attacks. These include aspirin, naproxen sodium, flurbiprofen, indobufen, ketoprofen, mefenamic acid, lornoxicam, and tolfenamic acid. Drugs that have long been prescribed for migraine prophylaxis, but for which convincing evidence of efficacy is lacking, include cyproheptadine (commonly prescribed for pediatric migraine), methysergide, clonidine, and verapamil. Of the newer anticonvulsants, gabapentin and topiramate appear to be the most potentially effective for migraine prophylaxis, but relatively little information from clinical trials is yet available.
A consortium of seven medical organizations, among them the American Academy of Family Physicians, the American Academy of Neurology, and the American Headache Society, recently released evidence-based guidelines for diagnosis and treatment of headache (Silberstein 2000). My clinical practice largely mirrors these new guidelines, albeit with some modifications that reflect my interpretation of the medical literature and my experience in treating migraine. For example, the guidelines list divalproex sodium as possessing a “clinical impression of effect” equivalent to amitriptyline and propranolol. My experience with the latter two drugs has been decidedly uninspiring, so in my clinic divalproex typically is the drug of first choice for migraine prophylaxis. Results from clinical trials evaluating propranolol or amitriptyline have been disturbingly mixed, whereas divalproex consistently produced efficacy in each of its major multicenter studies.
Nonpharmacologic Therapy
Patients should also be advised on the various nonpharmacologic methods they may employ to prevent migraine. Some require a significant commitment, but others are fairly easy to implement. Nonpharmacologic therapies that have proven useful for some patients include biofeedback, stress management, acupuncture, and relaxation therapy (such as guided imagery and massage). Also helpful to some are daily doses of vitamin B2 (400 mg), magnesium oxide (400 mg), or the herb feverfew (100 mg). Keeping a headache diary may also help patients identify and avoid triggers.
Table 1. Rapid Migraine Diagnosis and Management
Migraine is caused by abnormal neurotransmission within the brain, brainstem, and trigeminovascular system. Blood vessel vasoconstriction/dilation, long considered the primary mechanism, is more likely an epiphenomenon.
Two questions are essential:
1. Has the patient had five or more attacks of headache, each lasting 4 to 72 hours, that were severe enough to inhibit or prohibit routine activity and that were accompanied by either nausea or sensitivity to light and sound? If yes, and the physical exam Is normal, the diagnosis is most likely migraine.
2. Does the patient need only abortive therapy, or is prophylactic therapy also indicated? If migraines occur only once or twice a month, abortive therapy may suffice.
• Try rizatriptan (Maxalt) for abortive therapy and divalproex sodium (Depakote) for prophylactic therapy (see p. 31 for caveats). If rizatriptan is ineffective, try another triptan. If divalproex falls, consult a neurologist.
Table 2. International Headache Society Diagnostic Criteria
Migraine without Aura (formerly, "common" migraine)
A. At least five attacks fulfilling B-D.
B. Headache lasting 4 to 72 hours (in children younger than age fifteen, 2 to 48 hours), untreated or unsuccessfully treated.
C. Headache with at least two of the following characteristics:
1. Unilateral location;
2. Pulsating quality;
3. Moderate or severe Intensity (Inhibits or prohibits daily activities);
4. Aggravation by walking up stairs or similar routine physical activity.
D. At least one of the following during headache:
1. Nausea or vomiting, or both;
2. Photophobia and phonophobia.
E. At least one of the following:
1. History, physical, and neurological examination suggest no organic disorder;
2. One or more of the following—history, physical, or neurological examination—suggest an organic disorder that is later ruled out;
3. Organic disorder is present, but migraine attack doesn’t occur for the first time in close temporal relation to the disorder.
Migraine with Aura (formerly, "classical” migraine)
A. At least two attacks fulfilling B.
B. At least three of the following characteristics:
1. One or more fully reversible aura symptoms indicate focal cerebral cortical or brainstem dysfunction, or both;
2. At least one aura symptom develops gradually over longer than four minutes, or two or more symptoms occur In succession;
3. No aura symptoms last longer than one hour, and if more than one aura symptom are present, the accepted duration is proportionally increased;
4. Headache precedes, coincides with, or follows the aura symptoms by less than 60 minutes.
C. At least one of the following:
1. No evidence of organic disorder based on history, physical, or neurological examination;
2. Evidence of organic disorder that is later ruled out;
3. Evidence of organic disorder, but no first-time occurrence of migraine attack in close temporal relation to the disorder.
Pediatric Migraine without Aura
A. At least five attacks fulfilling B-D.
B. Headache lasting 2 to 48 hours (untreated or unsuccessfully treated).
C. Headache having at least two of the following characteristics:
1. Unilateral location;
2. Pulsating quality;
3. Moderate or severe intensity (inhibits or prohibits normal activity);
4. Aggravation by walking up stairs or similar routine physical activity.
D. During headache, at least one of the following:
1. Nausea or vomiting, or both;
2. Photophobia and phonophobia.
E. At least one of the following:
1. History: physical, and neurological examination suggest no organic disorder;
2. One or more of the following—history, physical, or neurological examination—suggest an organic disorder that is later ruled out;
3. Organic disorder is present, but migraine attack doesn’t occur for the first time in close temporal relation to the disorder.
Source: Headache Classification Committee of the international Headache Society 1988.
Table 3. Migraine Triggers
Foods:
Aged cheese
Alcohol
Caffeine (or caffeine withdrawal)
Dairy products
Chocolate
Pickled or fermented food
Citrus fruits
Onions, bananas, raisins, and nuts
Yeast-containing foods
Processed meats
Food additives, such as saccharin, aspartame, sulfites, nitrites, and monosodium glutamate
Drugs:
Cimetidine (Tagamet)
Nifedipine (Adalat, Procardia)
Theophylline (TheoDur, Theo-24)
lndomethacin (lndocin)
Nitroglycerin (Nitrostat)
Withdrawal of pain medications
Estrogen
Reserpine-containing medications
Environmental and Other Factors:
Weather changes
High altitude
Bright or flickering light
Noise
Odors and air pollution
Excessive activity
Emotions and stress
Disrupted sleep patterns
Irregular eating patterns
Hormonal changes associated with birth control pills, menstruation, pregnancy, hormone-replacement therapy, and menopause
Table 4. Migraine Mimickers
Subarachnoid hemorrhage
Meningitis
Ischemic stroke/transient ischemic attack
Arteriovenous malformation
Tumor (primary or metastatic)
Arteritis
Subdural hematoma
Partial seizures
Sleep apnea headaches
Dr. Rothrock is a professor of neurology at the University of South Alabama, where he served as chair of neurology from 1994 through 1999. Previously, he served on the neurosciences faculty at the University of California, San Diego, where he established and directed the UCSD stroke and headache centers.
July 2000
Catherine Dold
PO Box 4424
Boulder, Colorado 80306
303-543-2390
1/14/03