Comprehensive treatment of headache in children and adolescents may include a combination of stress management, counseling, physical therapy, prevention strategies, and pharmacotherapy. Generally, headache is best treated with as little medication as possible. When a prescription medication is used, it is important to remember the synergistic effects of placebo and active treatment and take full advantage of them.1 Reasonable goals and expectations also need to be established with the patient and the parents. Instruction in the use of any medication is always essential.
ABORTIVE MEDICATION FOR MIGRAINES
As discussed elsewhere in this issue of Pediatric Annals, the pathophysiology of acute, intermittent headache remains imperfectly understood, and hence the exact mechanisms of action of pharmacological agents are, to a great extent, presumptive. This article reviews the clinical basis of commonly used medications, discusses their benefits and major side effects, and recommends dosing regimens.
Most medications administered to children at home are given by mouth, but vomiting may be an early symptom in migraine and make oral administration impossible. Even in the absence of nausea or vomiting, reduced gastric motility and delayed absorption of orally administered medications commonly occurs. Thus, major therapeutic options for acute migraine in children include sublingual (ergotamine), rectal (promethazine, prochlorperazine, and ergotamine), intranasal (dihydroergotamine IDHE) and butorphanol), subcutaneous (sumatriptan) and intramuscular and intravenous routes (DHE and metoclopramide). The goal of these therapies is to terminate an acute attack quickly, eliminate vomiting, and improve gastric motility and absorption, which facilitates any necessary further oral treatment. Table 1 lists medications and doseages for abortive therapy of migraine.
Medications Used for Abortive Therapy off Migraine
Generally, one should start with low doses of medications that have the least toxic potential and proceed to stronger medications as needed. In rare instances, acute migraine can persist despite several attempts at treatment ("status migrainosus?). Aggressive early treatment is indicated in persons with a history of severe and prolonged attacks in order to abort the episode rather than provide treatment after the headache is fully established with profuse vomiting and prostration. Status migrainosus is a difficult condition to treat and may require hospitalization. Medications that are effective in the treatment of status migrainosus include prednisone, DHE, and sumatriptan.
Ergot Alkaloids: Ergotamine and DHE
Ergotamines remain the treatment oí choice for migraine when simple analgesics do not relieve headache. Ergotamine produces a powerful and selective vasoconstriction of the external carotid artery and its branches by a direct effect on arterial serotonin receptors and by a-adrenergic blockade. It is available as oral tablets or rectal suppositories in combination with caffeine (Cafergot, Sandoz Pharmaceuticals Corp, East Hanover, New Jersey and Wigraine, Organon Ine, West Orange, New Jersey) and as a sublingual preparation without caffeine (Ergostat, Parke-Davis, Morris Plains, New Jersey). Use of Ergostat may be limited in children because of its bad taste.
Highly variable bioavailability makes the precise titration of the oral ergotamine dosage difficult and the effectiveness of rectal preparations is much greater.2 One reason for apparent lack of success with ergotamines may be inadequate dosing. Therefore, determining the highest dose of ergotamine possible without producing nausea provides a therapeutic guideline.3
Dihydroergotamine is an ergot derivative with an action similar to ergotamine tartrate but with less side effects. It is effective once an acute migraine attack is established. Dihydroergotamine has less peripheral vasoconstrictive effects than ergotamine, produces less nausea, and if given with an emetic, is highly efficacious when a migraine attack is accompanied by vomiting.4 The patient should receive metoclopramide 5 to 10 mg (up to 1 mg/kg) or prochlorperazine 2.5 to 5 mg (or 0.1 mg/kg) prior to its administration. Dihydroergotamine is given intravenously or intramuscularly to older children and adolescents at an initial dose of 0.5 to 0.75 mg (no mg/kg dose has been established). It after an initial 0.5-mg dose, headache is not relieved and the patient is not nauseated, another 0.5 mg may be administered after i hour, if this does not relieve the headache, the patient may need admission to the hospital and a DHE protocol can be followed.3
Adolescents can be taught to administer subcutaneous DHE at home for severe migraine attacks. Several studies have shown intranasal DHE to be effective and well-tolerated. There is no commercial preparation for intranasal use, but some pharmacies will prepare it.
Ergotamine and DHE are safe and effective drugs for the short-term treatment of migraine. The maximum dose of ergotamine should not exceed 6 mg per day or 10 mg per week to avoid the problem of chronic ergotism, dependency, and withdrawal symptoms. In contrast, the use of DHE has not been associated with symptoms of dependence or withdrawal. Its principle adverse effects are nausea and vomiting, which occur in about 10% of patients. Weakness and muscle pains, together with numbness and tingling of the hands and feet, also may occur. Idiopathic hypersensitivity to ergotamines has been reported. All ergot derivatives should be avoided in patients with heart disease or hypertension. Ergot derivatives may have teratogenic properties and in addition are uterine stimulants, which make them contraindicated in pregnancy.
The combination of acetaminophen plus the mild vasoconstrictor isometheptene and the mild sedating agent dicloralphenazone has been used with success in the abortive treatment of migraine.5 Although there are no studies on its use in children, an isometheptene mucate (65 mg)/acetaminophen (325 mg)/dtchloralphenazone (100 mg) compound (Midrin, Carnrick Laboratories Ine, Cedar Knolls, New Jersey and others) is generally safe and often effective in some patients who cannot tolerate ergotamine or DHE. Its effectiveness in treating tension-type headache has not been demonstrated.
Phenothiazines (Prochlorperazine and Promethazine) and Metoclopramide
Controlled studies in adults have demonstrated that these groups of medications used as antiemetics/ antinauseants can provide complete or partial relief of migraine with prominent vomiting.6,7 Metoclopramide (Reglan, A. H. Robins Co Ine, Richmond, Virginia) is thought to have selective antagonism of 5-HT3 receptors, presumably located in the trigeminovascular system.8 An oral metoclopramide dose of 5 to 10 mg (up to 1 mg/kg) at the onset of symptoms may abort the headache. If headache relief is not complete, vomiting is often prevented and improvement in gastric motility facilitates the use of oral analgesic agents. When vomiting has supervened, one must resort to rectal or parenteral administration of these agents. Pretreatment with an antinauseant is an integral part of a regimen including DHE. Major side effects are sedation, dizziness, and confusion. All of these agents have the potential to produce acute or latent dystonic reactions that may require treatment with diphenhydramine (up to 5 mg/kg per 24 hours).
Based on the neurovascular theory of migraine, serotonin, or 5 -hydroxy tryptamine (5-HT), has long been suspected as being a primary mediator of migraine. Sumatriptan succinate (Imitrex) selectively stimulates vascular 5-HT1 receptors that constrict affected vessels, thus blocking nociceptive impulses and the subsequent inflammatory response, reducing extravasation of proteins, and consequently relieving pain.9 It can be administered both orally and subcutaneously, but Food and Drug Administration approval for oral sumatriptan is still pending. It is effective for established migraine attacks and improves migraine symptoms including visual changes, vomiting, and cephalgia. The 6-mg subcutaneous injection of sumatriptan may be effective several hours after the onset of headache, but patients should be instructed to administer the drug at the onset of pain. Sumatriptan is costly, but a therapeutic trial may be indicated for adolescents with severe migraine attacks and may prevent many emergency department visits. There are no published clinical trials in the pediatric age group.
Sumatriptan is easy to administer. Dispensed as a preloaded syringe (6 mg), it can be given subcutaneously either in the office or by the patient at home. The same injection may be repeated after 1 hour if necessary. Rebound headaches may be seen due to the short half-life, but oral sumatriptan administered as a rescue medication within 4 hours relieves moderate to severe recurrent headache in patients who showed improvement after an initial dose of sumatriptan.10
Sumatriptan is generally safe and well tolerated. It should not be given concomitantly with ergotamine derivatives. Common side effects include irritation at the injection site, flushing, tachycardia, disorientation, and chest tightness that lasts for several minutes following parenteral administration.
Although not tested in controlled trials, corticosteroids have been used in acute management of both cluster headaches and carotodynia.11 In the management of migraine, steroids should be reserved for use in patients with severe, intractable headaches (status migrainosus) who are unresponsive to DHE and sumatriptan. The recommended prednisone regimen is administered as a tapering course over 12 days given once daily in the morning. Dosage is given as 2 mg/kg per day (maximum 60 mg daily) tapered by 10 mg every 2 days.
ANALGESIC MEDICATION FOR BOTH MIGRAINE AND TENSION-TYPE HEADACHE
Prior to seeking medical care, the majority of children with headaches will receive a nonprescription analgesic. Simple analgesics may provide adequate relief particularly when headache is mild and infrequent. It is common to seek medical advice when headaches persist, increase in severity, or begin to interfere with daily routine.
In patients with recurrent tension- type headaches, there may be some underlying psychological or other predisposing factor that would cause persisting headache and motivate the patient to continue to seek medical help. The patients chief complaint may be that headaches have become refractory to this group of medications and alternative approaches to the headache problem are preferred. Table 2 lists analgesics and recommended doseages for treating migraine and tension- type headache.
Acetaminophen and Aspirin
Analgesics for recurrent headache should be administered in doses similar to those used in other pediatric pain conditions. A frequent problem is parental "underdosing" with repeated, low-dose administration of an analgesic preparation.
Acetaminophen is a cyclooxygenase inhibitor but does not cause prostaglandin inhibition. Its analgesic properties provide temporary relief If given for simple headache. An appropriate regimen should begin with doses of 10 to 15 mg/kg and not exceed a total dose of 90 kg/day. Rectal absorption oi acetaminophen is unpredictable and doses of 45 mg/kg may be required to achieve equianalgesia with oral administration.
Although difficult in the migraine patient with vomiting, aspirin should be given with ample liquids. Aspirin should be avoided in children with varicella or influenza symptoms, and in children with a history of certain metabolic problems (eg, mitochondrial cytopathies) because of the concern of idiopathic hepatotoxicity (eg, Reye's syndrome).
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
This group of medications has been used extensively for both acute and long-term preventive treatment of migraine as well as for tension-type headache. Nonsteroidal anti- inflammatory drugs comprise a heterogeneous group of compounds with certain common properties including variable prostaglandin inhibition, and analgesic and antipyretic action. The role of prostaglandins in the pathophysiology of migraine is tentative, but it has been observed that typical migraine attacks can be induced by intravenous infusion of prostaglandin El in healthy volunteers. Nonsteroidal anti-inflammatory drugs may be effective by the inhibition of prostaglandin synthesis and interference with substance P- mediated pain mechanisms.12
Most double-blind trials comparing a NSAID to placebo reveal significant superiority of the NSAiD for at least one of the criteria studied. In contrast, most NSAID versus reference drug (eg, ergotamine or acetaminophen) trials have not shown significant differences.13 Ibuprofen has been the most commonly used NSAID because of its over-the-counter availability. Naproxen (Naprosyn, Syntex Laboratories Ine, Palo Alto, California), a potent inhibitor of platelet aggregation and prostaglandin synthesis, is an NSAID effective in reducing the frequency, severity, and duration of migraines in adults when taken twice daily.14 Naproxen sodium (Anaprox, Syntex Laboratories Ine) recently has become available without prescription (Aleve) in a 220-mg tablet size. Side effects of NSAlDs include gastrointestinal distress, hypersensitivity skin reactions, and impaired platelet function with the potential for prolonged bleeding.
Ketorolac (Toradol, Syntex Laboratories Ine) is the first NSAID to be approved for intramuscular use in the United States for control of pain. It also may be given orally at home for refractory headaches. Although not studied in children, some evidence suggests that ketorolac is both safe and effective for emergency treatment of migraine in adults.15 Ketorolac is not recommended for use beyond 5 days because of the increased frequency of upper gastrointestinal and hematological side effects with longer administration.
Analgesic Medications Used for Treatment of Migraine and Tension-Type Headache
Opiates should be prescribed rarely, if ever, for home management of migraine or tension-type headache. In the short term, children may respond to codeine or oxycodone better than other oral medications, but regular administration may lead to both physical dependence and the analgesic-withdrawal syndrome. Parenteral meperidine or morphine sulfate has been used in the emergency management of moderate to severe migraine, but in recent years this practice largely has been supplanted by the combined use of an intravenous ant inausean t (eg, prochlorperazine or metoclopramide) followed by parenteral DHE, sumitriptan, or an NSAID (eg, intramuscular ketorolac) as needed. This regimen may be tried at home with a rectal antinauseant followed by an NSAID. Because these combinations of medications usually allow the patient to fall asleep and thus alleviate the migraine attack, they represent a preferred regimen over any narcotic.
Butorphanol (Stadol, Bristol Laboratories, Evansville, Indiana) is a mixed opioid agonist/antagonist. It theoretically offers less potential for abuse, but caution is needed because of the risk of overuse and dependency. It is used as an intranasal spray in the outpatient setting but can be given intramuscularly or intravenously in the emergency department. Because butorphanol is rapidly absorbed and avoids the gastrointestinal tract, it may be useful in patients with prominent vomiting. It is not recommended for use in pediatric patients because safety and efficacy have not been established.
Side effects of narcotics include hypotension, sedation, confusion, miosis, and constipation. In higher doses, respiratory depression and coma may be seen.
Rebound/Withdrawal Headache and the Overuse of Combination Preparations
Analgesic rebound headaches may occur, especially in persons receiving acetaminophen or ergot derivatives several times daily for prolonged periods.16 This is a frequent cause of chronic, daily headaches, and a careful history of medication usage should be documented. In treating recurrent headaches in pediatric patients, analgesics should not be given for more than 4 days in any single week. Prophylaxis should be considered in patients with frequent headache attacks or less frequent but disabling attacks that are unresponsive to analgesic or abortive medication.
Acetaminophen/butalbital/caffeine (Fiorcet, Sandoz Pharmaceuticals, East Hanover, New Jersey and Esgic, Forest Pharmaceuticals, St Louis, Missouri) is a combination tablet that has been used in the treatment of both tension-type and migraine-type headaches. Although the low-dose barbiturate (butalbital) may initially allow a patient with migraine to sleep, it is also associated with a predictable early morning rebound headache when taken in higher doses. Prescription medications containing butalbital, caffeine, and analgesic combination with or without codeine are among those most commonly overused for immediate relief. Drowsiness is another major limiting side effect of this preparation.
PROPHYLACTIC MEDICATION FOR MIGRAINE OR TENSION-TYPE HEADACHES
Prophylaxis may be considered for children and adolescents when 1) the frequency of headaches is more than two or three per month, 2) the headache episodes are extremely severe and disrupt school attendance and parental work patterns, 3) the patient is unable to cope with the attacks, or 4) abortive therapies produce serious side effects. Nonpharmacological preventive measures designed to avoid trigger factors identifiable through history and behavioral techniques emphasizing coping skills and relaxation training should be established in the therapeutic regimen.
Most of the drugs used in headache prophylaxis were discovered by chance (eg, propranolol) or were proposed on the basis of presumed migraine pathophysiology (eg, calcium-channel blockers). Most of the information presented here is derived from the adult headache literature, smaller studies in children, and anecdotal experience. There still remains a great need for well-designed, prospective, controlled studies of headache therapies in children. Table 3 lists medications and doseages for prophylactic treatment of migraine.
Prophylactic medications should be started at low dosage but regular follow-up with incremental dosage may be needed every 3 to 4 weeks. Patients may give up on a medication when there is no response to a small starting dose within a few days, but maximal effect often will not be seen for as long as 2 to 3 months. The duration of treatment should be as condensed as possible and will depend on the child's response, the benefit from adjunctive nonpharmacological treatments, and psychosocial factors. A convenient time to begin tapering medication in most children is at the end of the school year.
Antiserotonin Agents. Virtually all of the tricyclic antidepressant drugs (amitriptyline, desipramine, nortriptyline, Imipramine, and clomipramine) have been demonstrated to relieve neuropathic pain in placebocontrolled trials, probably by blocking the reuptake of both serotonin and norepinephrine.17 The migraine prophylaxis effect of the tricyclic antidepressant amitriptyline appears to be independent of its antidepressant actions. When used for migraine prophylaxis in adults, amitriptyline appears to be as effective as propranolol with which it may be given simultaneously.18 There are no controlled studies published on its use in children. In general, the optimal daily dose is lower in children than in adults, and the pediatric patient should be monitored closely for any evidence of intolerance at doses that exceed 1 mg/kg per day. Amitriptyline is best prescribed at a low starting dose (eg, 10 mg at bedtime in older children) with gradual increments if necessary. Because of great variability in its absorption and distribution, it is difficult to correlate plasma levels and therapeutic effect.
Common unwanted antimuscarinic effects of tricyclic antidepressants are orthostatic hypotension, drowsiness, blurred vision, weight gain, dry mouth, constipation, and urinary retention. Children with cardiomyopathy or conduction defects should not receive tricyclics. A baseline EKG should be obtained if the total daily dose of amitriptyline approaches 1 mg/kg to rule out a reduction of the P-R interval or a prolonged QT interval. Although a normal electrocardiogram is no guarantee against the appearance of cardiotoxic effects, periodic monitoring is recommended if higher doses of tricyclic antidepressants are used.19
Medications Used for Prophylactic Therapy of Migraine
Although its use in migraine is not FDA approved, cyproheptadine (Periactin, Merck Sharp &. Dohme, West Point, Pennsylvania) has been widely used in recent years. No controlled studies in children have been reported. Structurally, it bears resemblance to the tricyclics and the ergot compounds. Its action in migraine may be related to mild to moderate antiserotonin activities and an antiplatelet aggregation effect. Cyproheptidine also has been used to stimulate appetite, and weight gain has been the most consistent side effect when it is used to treat migraine. It has an atropine-like action and therefore should be used with caution in patients with asthma. The other main, dose-related, adverse effect of cyproheptadine is drowsiness, which may limit its use in school-aged children. Methysergide (Sansert, Sandoz Pharmaceuticals), a semisynthetic compound derived from the alkaloid ergonovine, has peripheral antiserotonin properties. Its use in children is not recommended because of the risk of retroperitoneal and endocardial fibrosis.
Beta-Adrenergic Receptor Blockers. The mechanism of action of this class of drugs for migraine prophylaxis is poorly understood. Their effectiveness does not result from 5-HT receptor blockade» there is no correlation between efficacy and beta receptor selectivity, and efficacy is unrelated to central nervous system entry. Possible mechanisms include blocking catecholamine-induced platelet aggregation and adhesiveness or decreasing prostaglandin formation. Although many effective beta-blockers have shown therapeutic benefit in adult migraine prevention, propranolol has been the main beta-blocker used in pediatric migraine.
Studies evaluating propranolol in the prevention of migraine in adults support its safety and efficacy.20 Three controlled studies on the use of propranolol in children have been published. One demonstrated a prophylactic effect of propranolol at dosages of approximately 3 mg/kg per day.21 The other two doubleblind, crossover studies used similar dosages of propranolol but failed to show any positive effect over placebo22 or self-hypnosis.23
With a plasma half-life of about 6 hours, propranolol can be taken on a twice-daily basis or can be prescribed once per day as Inderal LA (Wyeth-Ayerst Laboratories, Philadelphia, Pennsylvania). There is no appreciable tolerance to propranolol after long periods of use, and rebound headaches do not occur when it is discontinued gradually.
Important contraindications to beta blockers include asthma, congestive heart failure (it diminishes heart rate and contractility), renal insufficiency, and use of insulin (it may cause hypoglycemia). Adverse effects are due to excessive ß-adrenergic activity causing bradycardia, hypotension, insomnia, depression, gastrointestinal disturbances, and weight gain.
Calcium Channel Antagonists. The use of this heterogeneous group of drugs (eg, verapamil, nifedipine, and nimodipine) in migraine prophylaxis is based on the premise that their vasoconstricting inhibitory properties might be beneficial. The (act that vasoconstriction has not been proven to be an essential feature in the pathophysiology of migraine has raised doubts about the validity of the hypothesis. Because many central nervous system neurotransmitters are calcium dependent, other ways in which these drugs may exert their action are readily conceivable.
There was much initial enthusiasm for the use of calcium channel blockers, but recent studies in adults24 and children25 have not demonstrated significant prophylactic benefit comparing nimodipine and placebo. Calcium channel blockers have the advantage of minimal side effects and provide an alternative to those patients who are unable to tolerate other medications. A full effect may not be achieved before several weeks or months which is somewhat disadvantageous to patient compliance. Adverse effects include bradycardia and vasodilation.
Other Agents. Numerous medications may be effective but have not had adequate clinical trials in either adults or children. This miscellaneous group includes monoamine oxidase inhibitors (eg, phenelzine) and newer antidepressants (eg, fluoxetine and trazodone) and anticonvulsants (valproic acid).26
Tension-Type Headache Prophylaxis
Because the pathophysiologic mechanism of tensiontype headaches is largely unknown, treatment of the symptom complex, rather than the presumed cause, is undertaken. Coexisting conditions such as sleep disturbance or depression may be present. Stopping medications (eg, analgesics or ergotamines) is crucial if they are overused. Although it is important to use a variety of approaches to this headache problem, the inclusion of pharmacological treatment may be helpful in preventing tension-type headaches from becoming chronic.
The tricyclic antidepressants (eg, amitriptyline) have been shown to be useful in the management of chronic tension-type headache in adults.27 Their analgesic properties are thought to result from opiate and endorphin effects, as well as enhancement of inhibitory pain pathways. The doses of tricyclic antidepressants given for the treatment of chronic headache are smaller than those required for the treatment of major depression.
Sedative drugs that contain short-acting barbiturates and benzodiazepines are not recommended for treatment of chronic tension-type headaches. Overuse of simple analgesics can likewise contribute to a cycle of recurrent and chronic tension-type headache by rebound or withdrawal mechanisms.
Biofeedback, behavior therapy, lifestyle changes, and other adjunct therapies such as physical therapy or a program of daily stretching exercises may provide relief of muscle contraction in the neck and shoulders, which may contribute to the production of the headache. Stress management instruction is useful in older children and adolescents.
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Medications Used for Abortive Therapy off Migraine
Analgesic Medications Used for Treatment of Migraine and Tension-Type Headache
Medications Used for Prophylactic Therapy of Migraine