NEW ADVANCES IN MIGRAINE
Edward Lichten, M.D.,PC
Director, Diamond Headache Clinic, Chicago, Illinois
Director, Inpatient Headache Unit, Columbus Hospital
Adjunct Professor of Pharmacology and Molecular Biology, The Chicago Medical School
Phone contact@ 1-800-HEADACH
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The non-steroidal anti-inflammatory agents (NSAIDs) have demonstrated efficacy in the abortive therapy of migraine. In a review of several investigations into the use of the NSAIDs in headache treatment, Pradalier observed that in the majority of studies, the NSAIDs were superior to placebo and equivalent to other reference drugs.15 Naprosyn (naproxen) and Anaprox (naproxen sodium) have demonstrated efficacy over placebo in several investigations of the abortive treatment of migraine. The patients also reported less side effects with the NSAIDs than with an agent containing ergotamine and caffeine.
S In treating the patient experiencing an acute migraine attack for several days or weeks (status migraine), certain complex therapeutic issues are faced. Ergot preparations should not be used on the second, third, or fourth day of an attack in order to m aintain the four day drug hiatus between days of use. The agents of choice in the treatment of status migraine are the corticosteroids. The intramuscular use of long-acting dexamethasone 16mg or methyprednisone 80 mg has been effective in treating patients with prolonged attacks. Raskin and Raskin reported on the successful use of dihydroergotamine 0.5 mg IV with metoclopramide 10 mg in repetitive doses every eight hours for two days.
Prophylactic Therapy: The primary goals of prophylactic therapy are to prevent the onset of the attacks and to reduce the frequency and severity of the attacks. Several types of drugs are used in migraine prophylaxis including the beta blockers, calcium channel blockers, al pha agonists, NSAIDs, tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), ergotamine derivatives, platelet antagonists, and antiserotinin agents. Only two drugs have been approved for long-term use in migraine prophylaxis, propranolol and ti molol. Both of these agents are non-selective beta blockers. Propranolol is a beta-adrenergic blocker and is considered the drug of choice in migraine preventive therapy. This drug is especially useful for migraineurs with concomitant hypertension, angina pectoris, and thyrotoxicosis. A long acting form of this drug (Inderal LA) has been introduced. Its once-daily dosage of 60, 80, 120 or 160 mg enhances patient compliance. This drug should not be withdrawn abruptly in patients with coronary heart disease as this action could exacerbate coronary ischemia and e ventually produce unstable angina or myocardial infarction. Propranolol is contraindicated in patients with asthma, chronic obstructive lung disease, congestive heart failure, or arterioventrcular conduction disturbances. Patients receiving concomitant treatment with insulin, oral hypoglycemic drugs, or MAOIs should not be treated with propranolol. If propranolol is contraindicated, treatment with another beta blocker may be considered. Timolol (Blockadren) can be administered in doses of 5 to 30 mg per day. Although not as yet approved by the FDA, nadolol has also been used successfully in migraine therapy, at doses of 80 to 160 mg per day. For patients with concurrent asthma, a cardioselective beta-blocker, such as metoprolol or atenolol, may be indicated in migraine prophylaxis. Metoprolol (Lopressor) has been used successfully in a slow-release dose of 200 mg per day. Atenolol (Tenormin) 100 mg daily, has also been efficacious in migraine prophylaxis. Clonidine (Catapres) as alpha-agonist, demonstrated efficacy in migraine treatment although not as successfully as propranolol. This drug has also been reported effective in patients sensitive to food triggers, such as tyramine. It is given in doses of 0.1 to 2.4 mg daily, in divided doses. Side effects associated with clonidine are usually mild and include drowsiness, dry mouth, constipation, and occasional disturbances of ejaculation. Mild orthostatic hypertension and depression may occur. Clonidine has been used successfully in treatment of opiate withdrawal. The calcium channel blockers are known to inhibit arterial vasospasm and to block platelet serotonin release and aggregation. These actions have triggered investigations into their use in migraine prophylaxis. Their effects of CBF, neurotransmission, and neuroreceptor blockade have also enhanced their efficacy. None of these agents have been approved for indication in migraine prophylaxis. Most headache experts concur that this class of drugs will not replace the betablockers in migraine therapy, and in particular, propranolol. Verapamil (Calan, Isotin) is a calcium ion influx inhibitor (slow-channel blocker or calicum ion antagonist) with antiplatelet effects. Its efficacy is attributed to its effect of CBV, arterial dilation, norepinephrine release, dopamine receptors, serot onin release from both brain and platelets, and opiate-withdrawal symptoms. The drug is orally active and has long-term effects which promote its efficacy in migraine prophylaxis. Verapamil is prescribed in doses up to 360mg per day, its most common side effect is constipation. Of the calcium channel blockers, nimodipine (Nimotop) has the highest marked selectivity for the cerebral vasculature. Investigations have demonstrated its usefulness in doses of 30 mg daily for migraine prophylaxis. However, in the United States, nimod ipine is only marketed for its indication for improvement of neurologic deficits due to spasm after subarachnoid hemorrhage resulting from ruptured congenital intracranial aneurysms. Other calcium channel blockers, available in the United States, have been investigated for migraine prophylaxis with little success. Nifedipine (Procardia) and diltiazem (Cardizem) are not used frequently in migraine therapy. Flunarizine, which is not available in the United States has been investigated in Europe in migraine prophylaxis. The results of these studies have been promising, and an extended response time has been observed. The tricyclic antidepressants have also been used successfully in migraine prevention. Their efficacy has been attributed to their analgesic properties instead of their antidepressant action. The MAOIs have also been identified as effective agents in migraine prophylaxis. Patients refractory to standard therapeutic agents have responded to phenelzine (Nardil) 15mg TID or isocarboxizid (Marplan) 10 mg q.i.d. These drugs must not be used concomitantly with medications containing a pressor agent nor narc otics, such as meperidine (Demerol). Hypertensive crises have been observed in patients on MAOIs who consume foods containing vasoactive substances. These patients must be instructed on the foods to avoid and to contact their physician before starting any other therapy, prescribed or over-the-counter. Several studies have focused on the use of the NSAIDs in migraine prophylaxis. Fenoprofen calcium (Nalfon), naproxen, ketoprofen (Orudis), and tolfenamic acid (Tolectin) have all been used successfully in migraine therapy. Indomethacin (Indocin), althOugh used successfully in cyclic migraine, may exacerbate or trigger a migraine in sensitive individuals. Cypropheptadine (Periactin) has been used successfully in the treatment of childhood migraine. Its antiserotonin and antihistamine effects have suggested its use for treatment of migraine in adults, with marginal results. For children, this drug us usua lly used in doses of 4mg at bedtime. The only other drug approved by the FDA for migraine prophylaxis is methysergide (Sansert). However, its long-term use is precluded by its adverse effects associated with prolonged use. Cardiopulmonary and retroperitoneal fibrosis have been reported aft er long-term use of methysergide. This drug is closely related to the ergots and has a variety of actions, including serotonin inhibition and mild vasoconstriction. Methysergine is usually prescribed in doses of 2 mg t.i.d., and should not be used for m ore than four to six consecutive months. A four to six week drug hiatus is required for patients on methysergide for four to six month intervals. During the treatment period, the patient should be examined at regular intervals to rule out fibrotic condi tions. At the end of 4-6 months of therapy, an intravenous pyelogram should be performed.
Seventy percent of female migraineurs will report a relationship between the acute attacks and their menstrual period. In treating menstrual migraine, the NSAIDs are the agents of choice. Mefenamic acid (Ponstel), ketoprofen, and fenoprofen have demons trated efficacy in treating menstrual migraine. The agent should be started three days prior to menses and continued through the flow. Bellergal-S which contains ergotamine, or ergonovine maleate (Ergotrate) have also been efficacious in this therapy. These agents should be administered in a similar manner, starting three days before the expected migraine episode.
Although migraine has been a recognized entity for centuries, debate continues over its pathogenesis. Wolff described migraine as a self-limited, neurogenic sterile inflammation He identified the occurrence of four dynamic events during a migraine attack: 1) initial cerebral vasoconstriction, which is correlated with the aura or warning of migraine; 2)the extracranial vasodilation (which Wolff considered the cause of migraine pain); 3)the sterile inflammation that increases the pain and prolongs the migraine attack; and 4)a secondary muscle contraction.
Wolff suggested that the vasoconstriction occurring during the aura involves either the retina (or the retinal or ophthalmic artery), or the occipital portion of the cerebral hemisphere. During his investigations, he attempted to determine if there was a causal relationship between the initial cerebral vasoconstriction to the cranial vasodilation of migraine. He observed that cerebral vasoconstriction had usually ended before the extracerebral vasodilatation had started. Wolff suggested that dilatation and the distention of large arteries, as well as an increase in pain-threshold-lowering substances, produce the headache. During a migraine attack, the pain usually radiates from the large subsurface cranial arteries and their branches. The patient will experience pain if the vessels are distended, pulled upon, or displaced.
Through further investigations, Wolff postulated that a sterile inflammation occurs in addition to the vasodilatation. A neurokinin and a proteolytic (neurokinin-forming) enzyme neurogenically induce the inflammatory reaction. Five groups of substances, and possibly more, have been implicated with the sterile inflammation. These substances include catecholamines, histamine and serotonin, peptikinins, prostaglandins, and the slow-reacting substances of anaphylaxis (SRSA), an acidic lipid. Contraction and relaxation of smooth muscle are caused by these substances, in addition to constriction or dilatation of arteries and veins, induction of water and sodium diuresis, fever, wheal and flare reactions, and triggering of pain, including headache. in his studies, Wolff noted that noxious stimulation of any part of the head triggers muscle contraction of the head and neck. Therefore, noxious stimulation triggered by vascular distention will also cause muscle contraction. Sustained muscle contraction of the muscles of the head and neck can be triggered by emotional tension. This sustained contraction may persist after the vascular aspects of the headache have diminished, and is considered a secondary feature of the migraine attack.
Wolff's theories have been disputed by several researchers, including Olesen's group. In their investigations, they injected a radioactive isotope, xenon-133, into the carotid artery, and induced migraine after arteriography in a series of subjects. They described a "spreading oligemia" which usually starts in the occipital regions and radiates anteriorly, reaching a primary sensorimotor area after the symptoms from that region had started. After the focal symptoms ceased, the oligemia continued. The authors, using this regional blood flow method, suggested that the painless pre-headache phase of migraine with aura was possibly secondary to a reaction similar to the spreading depression described by Leao and not secondary to oligemia.
In an earlier study, Olesen's group noted that the striking oligemia did not occur in migraine without aura. No significant change was demonstrated in cerebral or regional blood flow between the resting phase, the onset of migraine without aura, and the acute attack. Skyhoj Olsen reported on the limitations of these cerebral blood flow (CBF) studies He proposed the "spreading oligemia" observed in CBF studies during migraine with aura may be an artifact that reflects a gradual decrease of CBF in an area of constant size. His theory suggests that migraine with aura and migraine without aura may be due to the same disease process but differ in the intensity of vasospasm and CBF reduction.
Local and systemic biochemical changes also occur during the headache phase. The preceding vasoconstriction phase causes local anoxia and acidosis. A systemic decrease in serotonin levels occurs as serotonin is transported by the blood vessels and the perivascular tissues. In response to local metabolic changes, the noninnervated parenchymal arteries dilate (a reaction also potentiated by the drop in blood serotonin), increasing cerebral blood flow and provoking local vasomotor changes in the innervated system of blood vessels, particularly marked dilation of the ipsilateral extracranial and intracranial arteries. Vasoactive substances, including serotonin, sensitized the pain receptors in the blood vessels and produces sterile inflammation around the vessels. These changes and the vasodilatation, cause the pain of migraine. This observation explains the hemicranial aspect of migraine.
In 1969, Heyck suggested that migraine is caused by the opening of carotid arteriovenous anastomoses, shunts, in the head, When open, direct oxygenated blood will be diverted wastefully to the veins. The tissues requiring oxygen will be bypassed. The shunt vessels may divert large volumes of blood and become distended and pulsating. Heyck's theory helps support the effectiveness of a new specific subtype-selective serotonin agonist which terminates established migraine with minimal side effects. Recent investigations have advanced our understanding of 5-hydroxytryptamine (5-HT) receptors. These receptors are membranal "trigger" proteins with which 5-HT must interact to produce its various actions. It is possible to selectively stimulate only one type of 5-HT receptor by producing a selective synthetic 5-HT-like molecule, and thus mimic some actions of 5-HT.
For most migraine sufferers, the initial onset of their headaches occurred during adolescence or their twenties. Migraine does occur in childhood, as noted by Bille in this study of school children that the average age of onset was six years old. The initial onset of migraine rarely occurs after age 40. During the fifth and sixth decade of life, migraine usually disappears, often with the onset of menopause. Some patients with migraine with aura will experience the prodromes long after the headaches have stopped.
The higher incidence of migraine in females has long been recognized. In an earlier study by Linet's group, the authors noted the prevalence of migraine in the general population was 7.4% for females and 3% for men. In childhood migraine, there is an equal distribution between the sexes but after puberty, the predominance in females is obvious.
Migraine has long been considered a familial disorder. Selby and Lance reviewed the histories of 464 patients and noted a 55% family history of migraine. Researchers have not concluded if migraine is a hereditary or familial disorder. In my own clinical experience of over 30 years, a family history of headache is reported by at least 70% of migraine sufferers.
According to the definition established by the International Headache Society, migraine is "an idiopathic, recurring headache disorder manifesting in attacks lasting 4-72 hours. Typical characteristics of headache are unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity, and association with nausea, photo- and phonophobia." Migraine headaches do not occur on a daily basis, and the usual frequency is one to four per month. In some patients, the migraine may occur once yearly or as often as 15 to 20 times per month.
Characteristically, migraine affects one side of the head, and may switch sides. The headache can become generalized. Many patients indicated that the pain localizes around or behind the eyes, or in the front-temporal area. The pain may radiate towards the occiput or upper neck during an attack. The shoulder and lower portion of the neck may be involved. In some patients, the pain may radiate to the face.
The pain of migraine is often observed by the patient to start as a dull ache and develop into a throbbing and pulsating pain. Other patients will complain of a constant headache that is never pulsatile in nature. During the attack, the area over the dilated arteries may be tender, and this symptom may continue for several hours after the attack. The degree of severity is variable but migraine can be incapacitating. Migraine usually continues for 4 to 24 hours, although the attack may continue for one or more days. The patient may experience lethargy and fatigue for several days after an attack. Status migraine describes those attacks that are continuous for several days or weeks.
Migraine has often been described as a "sick" headache. Nausea and vomiting are frequent components of an acute attack. Other associated symptoms are anorexia, photophobia, phonophobia, constipation, diarrhea, dizziness, lightheadedness, blurred or double vision, chills, tremors, cold extremities, ataxia, and dysarthria. Difficulty in concentration and memory loss has been reported by some patients.
The prodromes occurring in patients with migraine with aura usually start one to two hours before the acute headache. The symptoms typically continue less than one hour. In order of frequency, the prodromes are: 1)scotoma (blind spots); 2) teichopsia (bright shimmering or wavy lines) or fortification spectra (a zigzag pattern resembling a fort); 3)flashing of lights (photopsia); 4)paresthesias; and 5)visual and auditory hallucinations (Alice in Wonderland Syndrome). The positive visual disturbances include photopsia, teichopsia, or the fortification spectra; the negative disturbances include scotomata; hemianopsia (partial visual field loss); or metamorphopsia (illusions of distorted size of shape). Other prodromal symptoms include paresthesias that occur as a "slow march" through the body.
Patients with migraine without aura may describe premonitions of an impending migraine attack. The vague symptoms may occur from two to 72 hours before an attack, and may occur four times as frequently as the prodromata of migraine with aura. These premonitions can occur in either type of migraine and include hunger, anorexia, drowsiness, depression, irritability, tension, restlessness, talkativeness, a surge of energy, and a feeling of well-being.
The Migraine Personality
The debate continues over the subject of "migraine personality." Wolff described migraine patients as ambitious, perfectionist, persistent, and unforgiving. The children included in Bille's study were described as fearful, tense, sensitive, and easily frustrated.6 These findings confirmed the observations of Wolff. In 1976, however, Phillips reviewed several investigations and noted that evidence was limited to support the theory that migraine sufferers were more neurotic than age-matched controls  Ross and McNaughton reviewed the Rorschach records of migraine patients, and observed a tendency towards rigidity, perfectionism, intolerance, conventionality, obsessive-compulsive features, persistence towards success, and difficulty in sexual adjustment. From my own clinical experience, I would agree with the findings of their study as well as that of Wolff.
Although many migraine patients will experience difficulty in identifying migraine triggers, the use of a headache diary will facilitate this process. On this diary, patients will be asked to record the frequency, duration, and severity of the migraine attack, as well as any provocative factors which may have triggered the headache. Migraine triggers can be divided into three categories: 1) external stimuli; 2)physiological; and 3)psychological.
Stress is probably the most readily identified trigger of an acute migraine attack. Curiously, many migraine patients will remain headache-free during a stressful period only to experience a severe headache when the stress has resolved. Many migraine patients will create an environment too great to handle, such as the working mother who attempts to go back to school, and juggle the demands of a career, raising a family, and pursuing a degree. An increase in migraine frequency is inevitable. Depression, fear, anger, anxiety, and repressed hostility have also been identified as migraine provocateurs. Although avoiding stress is difficult to achieve, instruction on coping methods may be beneficial for these patients.
The migraine sufferer is especially sensitive to any changes in sleep and eating patterns. Fasting or missing a meal is a known headache trigger. All migraine patients should be encouraged to maintain a strict meal schedule. Oversleeping or lack of sleep can also precipitate a migraine, although migraine rarely awakens a patient. The incidence of headaches occurring on weekends, holidays, or during vacations has been linked to oversleeping. Headache clinicians believe that the responsible mechanism is a relative hypoglycemia or an alteration in the level of carbon dioxide. In order to avoid these "weekend" headaches, patients should be instructed to maintain a regular sleeping schedule, and plan on arising at the same time each day. Lack of sleep and fatigue may also provoke an acute migraine attack.
The link between diet and migraine has long been a controversial subject. Most physicians who participated in a survey regarding "dietary migraine" believed that the acute attacks were triggered by certain foods that contain vasoactive substances. The term diet-precipitated migraine has been allotted to these headaches. The direct-acting vasoactive substances are the amines, including tyramine, nitrates, monosodium glutamate, and alcohol. Tyramine is found in aged cheese, pickled foods, fresh-baked yeast breads, and marinated foods. Another amine, phenylethylamine, is contained in chocolate. The nitrates, which cause migraine due to their vasodilating action, are found in cured meats. Monosodium glutamate is found in food additive and Chinese foods, and can cause a variety of symptoms, including pressure in both central and direct vasodilating properties. Migraine can be precipitated by a single glass of red wine.
Indirect-acting vasoactive substances include caffeine, nicotine, ergotamine, hypoglycemia, allergy, ingestion of ice cream, and monoamine oxidase inhibitors. Caffeine and nicotine are vasoconstrictors. However, rebound vasodilation may evolve from intemperate ingestion of these substances. Excessive consumption of caffeine-containing beverages, such as coffee, tea, or colas, can precipitate a migraine attack. Predictably, caffeine withdrawal, often associated with fasting, can trigger a severe headache.
Some migraine patients will describe a relationship between their headaches and weather. Rapid changes in barometric pressure as well as extreme variations in weather may provoke a migraine attack. During or subsequent to travel to areas of high altitude, a may report an increased frequency in their headaches. A diuretic, such as acetazolamide, used on the day of a flight may prevent these headaches.
A relationship between the menstrual cycle and migraine attacks is well documented. The increased incidence of migraine in women exemplifies this relationship. Of these female migraineurs, 60% to 70% will note a menstrual link to their migraine attacks, with severe headaches occurring immediately before, during, or after their period. Also, many of these women will note a remission in their headaches after the first trimester of pregnancy. Older patients will note a decrease or complete remission of their headaches after menopause. Oral contraceptives should be avoided in migraine patients as these drugs have been observed to increase the frequency, severity, duration, and complications of migraine. Also, estrogen replacement therapy should be avoiDed in post-menopausal migraineurs when giving these hormones exacerbates or restarts a migraine attack.
Drug therapy of migraine is difficult and will require frequent office visits and adequate lines of communication between the physician and the patient. Both the physician and the patient should have an adequate understanding of the complexities of treatment and the physician should be cognizant of drug interactions. Dependent on the patient's history, the physician must select the type of therapy indicated. If the patient is only experiencing occasional headaches, abortive treatment may be indicated. however, if the headaches are occurring two or more times per month, or if the attacks greatly impact on the patient daily life, due to absences from work or school, prophylactic therapy should be considered.
Recently, a serotonin receptor agonist, sumatriptan, has demonstrated success in the abortive treatment of migraine. Sumatriptan acts as an agonist at the 5-HT(1D) receptor. The net effect of this action appears to be important in migraine as it causes the constriction of dilated arteries in the brain. Compared to serotonin itself, sumatriptan is safer and better tolerated by patients because its effect are highly specific are highly specific for this receptor. Also, sumatriptan may be advantageous over currently available agents for the treatment of migraine because of this specific effect on the 5-HT(1D) receptor as an agonist.
This agent, administered subcutaneously in doses of 6mg produced beneficial effects in treating migraine attacks. This dose may be repeated after one hour if symptoms return. Side effects associated with this therapy included tingling, dizziness, warm-hot sensations, and injection-site reactions. Intravenous sumatriptan administration is contraindicated due to the potential of to cause coronary vasospasm. Sumatriptan should not be administered subcutaneously in patients with ischemic heart disease, prior history of myocardial infarction, documented silent ischemia, or patients with Prinzmetal's angina. Sumatriptan may cause increases in blood pressure and is therefore contraindicated in patients with uncontrolled hypertension. It should never be used concomitantly with ergotamine preparations. Studies are currently underway on the oral preparation of this drug in the treatment of acute migraine.
The ergotamine preparations have been used in migraine abortive therapy for several decades. These drugs are classified as vasoconstrictors that specifically counteract the dilation of some arteries and arterioles, primarily the branches of the external carotid artery. The success of ergot in a migraine attack impinges on early use of the drug during an attack or preferably during the prodromal phase. Ergotamine is available in preparations suitable for various routes of administration, including oral, sublingual, rectal, and parenteral. Selecting the route of administration is dependent on the following: 1)need for rapid action; 2)associated nausea and vomiting; 3)availability of the preparation; and 4)the patient's preference.
Nausea is a frequent side effect of ergot preparations and caffeine has been added to the oral and rectal preparations in order to facilitate absorption of the drug, and ergot and caffeine are believed to act synergistically. Sublingual preparations should be considered if the oral route is too slow or is not tolerated. The rectal suppository is the most effective of the non-parenteral preparations and is especially helpful for those patients with associated vomiting. However, its use may be awkward for the patient and should not be used in those migraineurs with associated diarrhea. The parenteral form of ergotamine is no longer available in the U.S. However, an ergotamine derivative, dihydroergotamine (DHE-45) may be used IV or IM.
In order to prevent ergotamine rebound phenomena, a four day hiatus must be maintained between days of use of these agents. Ergotamine should never be repeated on the second or third day of a migraine attack. If the drug is stopped abruptly, the patient will experience a severe rebound headache. Excessive consumption of the ergots may cause symptoms of vasoconstriction, such as cold, clammy extremities, and could lead to ergotism.
Patients with peripheral vascular disease, thrombophlebitis, severe hypertension, coronary ischemia, angina, renal or hepatic disease, or recent infection should not use an ergotamine preparation. These agents should not be used in the elderly, or during pregnancy because of the oxytocic effects of ergotamine. The us of a combination agent containing isometheptene mucate, dichloralphenazone, and acetaminophen (Midrin) may be indicated for those patients who cannot use the ergots. Isometheptene has cerebral vasoconstrictor action.
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|Revised: January 1, 2011|