Migraine in special populations

Treatment strategies for children and adolescents, pregnant women, and the elderly

Jonathan P. Gladstone, MD; Eric J. Eross, DO; David W. Dodick, MD

VOL 115 / NO 4 / APRIL 2004 / POSTGRADUATE MEDICINE

CME learning objectives

• To define the epidemiologic factors of migraine in children and adolescents, pregnant women, and the elderly
• To develop an approach to management of acute migraine in these populations
• To identify prophylactic treatment options for migraine in these populations

Dr Gladstone has received honoraria from GlaxoSmithKline. Dr Eross has received a research grant and honoraria from GlaxoSmithKline and has been a consultant for Ortho-McNeil. Dr Dodick has been on advisory panels for Merck, Pfizer, GlaxoSmithKline, Elan, and Ortho-McNeil. All treatments discussed in this article for migraine in children and adolescents and in pregnancy are off-label.

Preview: Although migraine is a common occurrence in children and adolescents, its diagnosis and treatment present unique challenges. Migraine management in pregnant women and the elderly can also be difficult and requires selection of appropriate and safe medications for patients in these special circumstances. In this article, Drs Gladstone, Eross, and Dodick provide pearls for both abortive and prophylactic treatments for migraine in these populations. Gladstone JP, Eross EJ, Dodick DW. Migraine in special populations: treatment strategies for children and adolescents, pregnant women, and the elderly. Postgrad Med 2004;115(4):39-50

Migraine is a common, often incapacitating headache disorder characterized by episodic attacks of moderate to severe headaches and various combinations of neurologic, gastrointestinal, and autonomic nervous system dysfunction. A recent report by the World Health Organization ranks migraine as one of the most disabling chronic conditions and equates a day of severe migraine to the disability associated with a day of quadriplegia, psychosis, or dementia (1).

The prevalence of migraine is influenced by chronologic and hormonal factors. Migraine occurs in up to 10% of children between ages 5 and 15 years (2), increases in prevalence to a peak of 18% between ages 30 and 49 (9% of men and 27% of women), and declines thereafter to rates of about 5% in persons older than 65 (2.5% of men and 7.5% of women) (3).

Migraines in children and adolescents

Migraine is a common cause of primary headache in children, and most affected patients experience their first migraine by the end of adolescence (4,5). Adolescents have more headaches during the week (specifically, Monday, Tuesday, and Wednesday) than on weekends, and attacks are more common during daytime hours (6 AM to 6 PM) (6). Consequently, migraine often results in school absences and impairs school performance (7). Interpersonal development may also be affected by limitations on recreational, family, and work-related activities. Although the clinical presentation of migraine in children is often similar to that in adults, the diagnosis can be challenging because attacks in children are often bilateral and shorter in duration (1 to 48 hours, compared with 4 to 72 hours in adults).

Abortive therapy
No medication, including those that provide headache relief in adults, is approved by the US Food and Drug Administration (FDA) for migraine treatment in the pediatric population. Nonetheless, several agents have demonstrated efficacy in clinical trials or clinical practice. The initial pharmacologic treatment of acute pediatric migraine begins with simple analgesics, such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) (8) (table 1). When used early in the course of a headache, over-the-counter analgesics can be quite effective. Patients should be educated to recognize the earliest symptoms of their migraines and to take an analgesic when pain is mild.

If simple analgesics are insufficient and if nausea or vomiting is a prominent symptom, then adding an antiemetic agent (eg, dimenhydrinate, metoclopramide, trimethobenzamide hydrochloride) may be helpful. Antiemetics assist with gastric absorption; relieve associated symptoms of nausea, vomiting, and abdominal pain; may help to directly relieve the headache; and may help the child fall asleep.

Evidence of the efficacy and tolerability of 5-HT₁ receptor agonists ("triptans") in the pediatric migraine population is limited but promising. Sumatriptan succinate (Imitrex) is the most extensively studied triptan in this population. Intranasal sumatriptan is well tolerated and, in multiple studies involving children and adolescents, has been shown to be superior to placebo for headache relief at 2 hours (9).

Even greater efficacy has been reported with subcutaneous sumatriptan (10). This preparation is a good choice for patients who desire immediate relief, do not like the taste of the nasal spray, or avoid pills because they are too nauseated or cannot swallow them (11). Oral formulations of sumatriptan, rizatriptan benzoate (Maxalt), and zolmitriptan (Zomig) have also been shown to be effective but to a lesser degree than the other formulations. Overall, triptans may be a good option, particularly for teenagers, who may require immediate relief in order to return to school or work-related activities.

Prophylactic therapy
Migraine prevention in the pediatric population requires lifestyle and behavior changes as well as drug therapy (4,5,12,13). Children and their parents should be educated to identify and avoid triggers (keep a migraine diary), normalize sleep schedules (get enough sleep and not sleep in), improve dietary habits (do not skip meals, limit caffeine intake), and participate in regular exercise. The role of food triggers is generally overestimated, and overly restrictive "migraine diets" should be avoided (12,13). Biofeedback, relaxation therapy, and stress management may be particularly useful in adolescents (14). Underlying psychiatric disorders and psychologic problems should be explored in patients suffering from frequent headaches.

Tolerability and efficacy data for prophylactic therapy are limited in the pediatric population (4,12). Beta-blockers and amitriptyline hydrochloride (Elavil) are considered first-line therapies and may be particularly useful in children with concomitant anxiety or insomnia. If sedation is a problem, nortriptyline hydrochloride (Aventyl HCl, Pamelor) or protriptyline hydrochloride (Vivactil) may be better tolerated than amitriptyline. Flunarizine, although not available in the United States, has been shown to be effective in children with migraine. Cyproheptadine hydrochloride, an antihistamine, is commonly used by pediatric headache specialists despite a lack of rigorous data supporting its efficacy. It is known to cause weight gain and sedation but can be beneficial even when other preventive agents have failed.

More recent evidence suggests that valproic acid (Depakene, Depakote) and topiramate (Topamax) are effective and safe prophylactic medications in children. Common side effects of valproic acid include dizziness, drowsiness, increased appetite, tremor, and hair loss. Although rare, hepatic toxicity and polycystic ovary disease have been reported with valproic acid for the treatment of epilepsy. The most frequent side effects of topiramate include cognitive difficulties, weight loss, and paresthesias.

Migraines in pregnancy

The relationship between migraine and sex hormones (particularly estrogen) is well accepted, because menarche, menstruation, oral contraceptive use, pregnancy, menopause, and hormone replacement therapy (15,16) often influence migraine. It is essential that primary care physicians be comfortable discussing migraine with pregnant patients, since the prevalence of migraine is highest among women during their childbearing years.

Migraine improves during pregnancy in 50% to 80% of patients, and attacks typically diminish by the end of the first trimester. However, attacks may remain unchanged, continue, or worsen (15,16). Infrequently, migraine may appear for the first time during pregnancy or, more commonly, during the postpartum period. Rising or sustained high estrogen levels during pregnancy may underlie the improvement during the later trimesters. Correspondingly, a rapid fall in the estrogen level may lead to menstrual migraine or migraine in the postpartum period.

When headache appears for the first time during pregnancy or peripartum, it may be the result of other conditions. Caution should be exercised to rule out secondary causes (16). These include:

• Stroke and cerebral venous sinus thrombosis, which occur at increased rates during pregnancy and peripartum
• Pituitary tumors and meningiomas, which may have estrogen receptors and can enlarge during pregnancy
• Eclampsia, which is often heralded by headache
• Inadvertent dural puncture during epidural anesthesia, which can lead to characteristic "post-lumbar-puncture headache"

When warranted, lumbar puncture, magnetic resonance imaging without gadolinium, and magnetic resonance venography or angiography are safe procedures to rule out secondary causes (15).

Migraine does not pose an increased risk for miscarriage, toxemia, congenital anomalies, or stillbirths (15). However, inadequately addressed and treated migraines can lead to poor nutritional intake, dehydration, sleep deprivation, increased stress, poor marital relations, and depression with associated adverse sequelae on maternal and fetal well-being. Correspondingly, in this population, the patient's familiarity and comfort with the treatment options are essential.

The risks and benefits of treatment must be weighed against the potential consequences to maternal and fetal well-being. Nonpharmacologic management is important to address with all patients. Because migraineurs are often exquisitely sensitive to changes in their internal and external environment, regulating daily activities (eg, maintaining regular mealtimes and sleep schedules) and avoiding identifiable triggers (eg, limiting caffeine intake) may be useful. Anxiety and attention to pain result in inhibition of antinociceptive brainstem structures. Correspondingly, training in relaxation, biofeedback, stress management, and cognitive-behavior therapy allows patients to exert control over physiologic responses that may influence pain transmission and can be particularly useful in pregnant women. Application of ice, direct compression, massage, and sleep may also be useful.

Abortive therapy
Pharmacologic treatment is often justified for headaches of moderate to severe intensity that are accompanied by significant disability, prominent nausea, or a combination of these (15,16). Treatment options are listed in table 2. First-line treatment consists of acetaminophen, NSAIDs, acetylsalicylic acid, caffeine-containing analgesics (with acetylsalicylic acid or acetaminophen), or codeine (alone or with acetaminophen). Other opioids may be used episodically and should be used with caution. NSAIDs and acetylsalicylic acid should be avoided after week 32 of gestation because of the risks of maternal or fetal bleeding and premature closure of the fetal ductus arteriosus.

Antiemetics, such as prochlorperazine (Compazine) and promethazine hydrochloride (Phenergan), can provide particularly useful adjunctive therapy. Ergotamine tartrate (Ergomar) and dihydroergotamine mesylate (D.H.E. 45, Migranal) are contraindicated. The triptans are not FDA-approved for use in pregnancy, but several studies and a pregnancy registry suggest no increased birth defects with sumatriptan, which can provide some reassurance for patients with inadvertent first-trimester exposure (17).

For protracted migraine attacks, treatment options include intravenous hydration and parenteral (usually intravenous) prochlorperazine, diphenhydramine hydrochloride, metoclopramide, or magnesium sulfate. In refractory cases, these drugs may be supplemented with parenteral opioids or corticosteroids (15).

Prophylactic therapy
Preventive therapy should be avoided because of potential teratogenicity. For patients with frequent, severe, and refractory migraines, various category C drugs, including propranolol hydrochloride (Inderal), amitriptyline, verapamil hydrochloride, and topiramate, can be used as preventive medications when the benefit outweighs the risk to the mother and fetus.

Physicians should be aware that since the majority of women with migraine stop their prophylactic medications when they contemplate pregnancy or find out that they are pregnant, some may substitute daily or near-daily use of analgesics for their daily preventive medication and risk the development of medication-induced (rebound) headache (16).

Migraines in the elderly

Persons older than 65 years are the fastest-growing segment of the US population. While headache is less common in the elderly, it still represents a frequently encountered and challenging problem. Headache is the 10th most common symptom in elderly women and the 14th most common in elderly men (18). The 1-year prevalence of headache in the elderly is 40% to 50%, and 2% to 4% of elderly persons have daily or near-daily headache (19-22). Migraine prevalence peaks at age 40 and decreases each decade thereafter; about two thirds of patients no longer have migraines by age 65. The prevalence of migraine in the elderly population has been estimated to be between 2.9% (23) and 10.5% (24), and women continue to be affected more often than men.

When migraine persists past age 65, attacks are typically less frequent, less severe, and less often associated with nausea than in adolescents and young adults. Nonetheless, the majority of elderly patients with migraine still experience considerable disability from their migraine attacks because of restricted treatment options, a failure of both patients and physicians to address the topic, and physician discomfort with treating attacks in this population.

Migraine in the elderly patient may be accompanied by aura or, as often recognized in clinical practice, recurrent attacks of painless aura (25). Aura without headache, referred to as a late-life migraine accompaniment, represents a reversible focal cortical dysfunction and may take the form of recurrent hemisensory disturbance (paresthesias) or scintillating visual scotoma. These episodic focal neurologic disturbances may be easily confused with transient ischemic attacks. A careful evaluation is important in this population, including a detailed history of prior migraine attacks, since the incidence and prevalence of cerebrovascular disease increase with advanced age. The key diagnostic features that differentiate late-life migraine accompaniments from transient ischemic attacks are listed in table 3.

Migraine beginning after age 65 is extremely uncommon (occurring in up to 2% of persons) and warrants thorough investigation (26,27). Since up to one third of headaches in the elderly are attributable to a secondary cause (26,28) (table 4), physicians should maintain a high index of suspicion for secondary headaches. A thorough history, medication history (including herbal and other supplements), physical examination, laboratory studies and, often, neuroimaging are therefore warranted to investigate new-onset headaches in this population (29,30) (table 5).

Table 4. Common causes of headache in elderly persons

Primary headache (two thirds of headaches) Tension-type headache Migraine Cluster headache Trigeminal neuralgia Hypnic headache Secondary headache (up to one third of headaches) Temporal arteritis Medication-overuse headache or medication side effect Ischemic or hemorrhagic stroke Subdural hematoma Primary or metastatic tumor Cervicogenic headache Meningitis or encephalitis Cardiac ischemia Postherpetic neuralgia Disorders of eyes, ears, nose, sinuses, teeth, or jaw Paroxysmal hypertension Metabolic disease: anemia, polycythemia, renal failure, hypothyroidism

Table 5. Red flags of headache

Acute onset of unusually severe headache Consider subarachnoid hemorrhage, infarct, intracerebral bleed, arterial dissection Presence of fever or systemic symptoms Consider: Meningitis/encephalitis (bacterial, viral, fungal, or parasitic infection, tuberculosis) Sinusitis (sphenoid sinusitis may occur without nasal symptoms) Vasculitis (primary central nervous system or secondary) Temporal arteritis (often constitutional symptoms, polymyalgia rheumatica) Focal neurologic symptoms or signs Look for optic disc swelling, field cut, focal weakness, and/or incoordination Age at onset >50 yr Consider temporal arteritis, brain tumor (primary or secondary), subdural hematoma, or heralding symptom of ischemic stroke Occurrence de novo in peripartum period Consider venous sinus thrombosis Change in headache pattern Be wary of change in quality, location, frequency, or severity Precipitated or exacerbated by positional changes, Valsalva maneuver, bending, or coughing If worse on standing, consider spontaneous intracranial hypotension If worse when supine or with Valsalva maneuver, consider increased intracranial pressure and/or posterior fossa abnormality Progressive headache or escalating medication requirements Reevaluate original diagnosis, consider a secondary cause Be wary of overuse of caffeine or medication History of cancer, immunocompromise, or HIV infection Be wary of metastatic disease or cerebral infection

Because of coexisting medical conditions and polypharmacy, abortive and prophylactic treatment strategies are challenging in the elderly (31). Altered drug distribution, metabolism, and elimination predispose geriatric patients to medication toxicity (29). Hence, migraine treatment in these patients requires both nonpharmacologic and pharmacologic treatment methods. Regulating daily activities (eg, maintaining regular mealtimes and sleep schedules) and avoiding identifiable triggers (eg, limiting caffeine intake) may assist those with frequent migraines. Training in relaxation, biofeedback, stress management, and cognitive-behavior therapy may be beneficial in some elderly migraineurs.

Abortive therapy
Options for abortive therapy and their contraindications and side effects are outlined in table 6. First-line therapy with acetaminophen, acetylsalicylic acid, and NSAIDs, while efficacious, should be used cautiously owing to the risks of gastrointestinal bleeding and renal and hepatic insufficiency. Adjunctive therapy with antiemetics can be particularly helpful. However, the elderly are vulnerable to the sedative and extrapyramidal (parkinsonian) side effects of antiemetics.

A useful strategy is to maximize drug efficacy by treating early in an attack and as aggressively as warranted to avoid the risks of repeated dosing. Close follow-up is crucial, and direct questioning should address use of over-the-counter medication to avoid rebound headache and to minimize the risks of adverse effects.

Clinical studies evaluating dihydroergotamine and the triptans have excluded patients older than 65 years. Furthermore, triptans are contraindicated in patients with a history of, or significant risk factors for, cardiovascular, cerebrovascular, or peripheral vascular disease. Patients who have tolerated triptans well over the years may continue taking triptans past age 65 only in the absence of new contraindications and in conjunction with periodic screening (eg, electrocardiogram, cardiac stress test) for silent cardiac disease.

There is no evidence from clinical experience that triptans are less safe after age 65 when prescribed appropriately. Therefore, in the absence of contraindications or significant risk factors for vascular disease, triptans are used in practice in the elderly with considerable efficacy. This is especially true for patients with severe migraine attacks that result in functional impairment and have not responded adequately to over-the-counter or prescription analgesics. Opioids should be used judiciously because of sedation and cognitive side effects but may be necessary for severe or disabling attacks.

Certain medications may exacerbate migraine, particularly in patients who are elderly. For example, vasodilating antihypertensive medications, such as nifedipine (Adalat, Nifedical, Procardia) and methyldopa, can worsen migraine or lead to an increase in its frequency. Similarly, nitrates may precipitate an attack of migraine in those who are predisposed.

Prophylactic therapy
Prophylactic options are limited in the geriatric population because of contraindications and side effects. In this population, the adage "start low and go slow" is particularly appropriate. Beta-blockers (eg, propranolol, nadolol [Corgard], timolol maleate [Blocadren]) may be helpful but are contraindicated with concomitant asthma, chronic obstructive pulmonary disease, congestive heart failure, and hypotension and can lead to unacceptable lethargy or confusion.

Tricyclic antidepressants are contraindicated with concomitant cardiac dysrhythmia, urinary retention, closed-angle glaucoma, and prostatic enlargement and can result in intolerable sedation, confusion, urinary retention, conduction block, or orthostatic hypotension. Nortriptyline and desipramine have fewer anticholinergic properties and are preferable. The anticonvulsants valproic acid, topiramate, and gabapentin (Neurontin) may be useful but can have significant cognitive and other central nervous system side effects (eg, sedation).

Botulinum toxin type A (Botox) is an emerging prophylactic therapy for migraine and may be particularly useful in the geriatric population because of the relative absence of systemic absorption and its excellent safety profile. Nonprescription and herbal alternatives with purported modest efficacy include magnesium, riboflavin, feverfew, Petasites hybridus (butterbur root), and coenzyme Q10.

Conclusion

Treating migraine in children and adolescents, pregnant women, and the elderly can be both extremely challenging and immensely rewarding. Failure to adequately treat migraine in these patients can lead to excessive disability and significant burden for both the patient and his or her family. An organized approach to migraine in these populations can lead to safe and effective therapy.

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Dr Gladstone is headache fellow, Dr Eross is associate consultant, and Dr Dodick is associate professor, department of neurology, Mayo Clinic College of Medicine, Scottsdale, Arizona. Correspondence: Jonathan P. Gladstone, MD, Department of Neurology, Mayo Clinic Scottsdale, 13400 E Shea Blvd, Scottsdale, AZ 85259. E-mail: gladstone.jonathan@mayo.edu.

Symposium Index

• EFFECTIVE TREATMENT OF MIGRAINE: Terminating acute attacks, reducing their frequency. By Tamara Pringsheim, MD, John Edmeads, MD
• MIGRAINE IN SPECIAL POPULATIONS: Treatment strategies for children and adolescents, pregnant women, and the elderly. By Jonathan P. Gladstone, MD, Eric J. Eross, DO, David W. Dodick, MD
• Clinical Commentary. IS THERE AN EASY WAY TO DIAGNOSE MIGRAINE? By John Edmeads, MD

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