Posted by sdb on January 28, 2007, at 5:11:06
In reply to How can Atenolol be cardioselective?, posted by linkadge on January 18, 2007, at 17:47:57
> How can atenolol be cardioselective when it is used for migrane. Is migrane relief a property of lowered blood pressure?
>
> LinkadgeHi link,
If you have migraine, here's some basic information from harrison's internal medicine
warm regards
sdb
MIGRAINE
Migraine, the most common cause of headache, afflicts approximately 15% of women and 6% of men. A useful definition of migraine is a benign and recurring syndrome of headache, nausea, vomiting, and/or other symptoms of neurologic dysfunction in varying admixtures (Table 14-5). Migraine can often be recognized by its activators (red wine, menses, hunger, lack of sleep, glare, estrogen, worry, perfumes, let-down periods) and its deactivators (sleep, pregnancy, exhilaration, triptans). A classification of the many subtypes of migraine, as defined by the International Headache Society, is shown in Table 14-1.
TABLE 14-5 Symptoms Accompanying Severe Migraine Attacks in 500 Patients--------------------------------------------------------------------------------
Symptom Patients Affected, %--------------------------------------------------------------------------------
Nausea 87
Photophobia 82
Lightheadedness 72
Scalp tenderness 65
Vomiting 56
Visual disturbances 36
Photopsia 26
Fortification spectra 10
Paresthesias 33
Vertigo 33
Alteration of consciousness 18
Syncope 10
Seizure 4
Confusional state 4
Diarrhea 16--------------------------------------------------------------------------------
Source: From NH Raskin, Headache, 2d ed. New York, Churchill Livingston, 1998; with permission.
Severe headache attacks, regardless of cause, are more likely to be described as throbbing and associated with vomiting and scalp tenderness. Milder headaches tend to be nondescript—tight, bandlike discomfort often involving the entire head—the profile of tension-type headache.
Pathogenesis
GENETIC BASIS OF MIGRAINE
Migraine has a definite genetic predisposition. Specific mutations leading to rare causes of vascular headache have been identified (Table 14-6). For example, the MELAS syndrome consists of a mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes and is caused by an A → G point mutation in the mitochondrial gene encoding for tRNALeu(UUR) at nucleotide position 3243. Episodic migraine-like headaches are another
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common clinical feature of this syndrome, especially early in the course of the disease. The genetic pattern of mitochondrial disorders is unique, since only mothers transmit mitochondrial DNA. Thus, all children of mothers with MELAS syndrome are affected with the disorder.
TABLE 14-6 Migraine Genetics--------------------------------------------------------------------------------
Gene (Locus) Function of Gene Clinical Syndrome Comment--------------------------------------------------------------------------------
tRNALeu(UUR) (mitochondrial) Unknown MELAS syndrome Extremely rare syndrome
CACNL1A4 (19p13) P/Q calcium channel regulating neurotransmitter release Familial hemiplegic migraine (FHM) Mutations account for approximately 50% of FHM cases
DRD2 (11q23) G protein–coupled D2 receptor for dopamine Migraine Positive association reported in two independent laboratories--------------------------------------------------------------------------------
Note: MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.
Familial hemiplegic migraine (FHM) is characterized by episodes of recurrent hemiparesis or hemiplegia during the aura phase of a migraine headache. Other associated symptoms may include hemianesthesia or paresthesias; hemianopic visual field disturbances; dysphasia; and variable degrees of drowsiness, confusion, and/or coma. In severe attacks, these symptoms can be quite prolonged and persist for days or weeks, but characteristically they last for only 30 to 60 min and are followed by a unilateral throbbing headache.
Approximately 50% of cases of FHM appear to be caused by mutations within the CACNL1A4 gene on chromosome 19, which encodes a P/Q type calcium channel subunit expressed only in the central nervous system. The gene is very large (>300 kb in length) and consists of 47 exons. Four distinct point mutations have been identified within the gene (in five different families) that cosegregate with the clinical diagnosis of FHM. Analysis of haplotypes in the two families with the same mutation suggest that each mutation arose independently rather than representing a founder effect. CACNL1A4 is likely to play a role in calcium-induced neurotransmitter release and/or contraction of smooth muscle. Different mutations within this gene are the cause of two other neurogenetic disorders, spinocerebellar ataxia type 6 and episodic ataxia type 2 (Chap. 352).
In a genetic association study, a NcoI polymorphism in the gene encoding the D2 dopamine receptor (DRD2) was overrepresented in a population of patients with migraine with aura compared to a control group of nonmigraineurs, suggesting that susceptibility to migraine with aura is modified by certain DRD2 alleles. In a Sardinian population, an association between different DRD2 alleles and migraine has also been demonstrated. These initial studies suggest that variations in dopamine receptor regulation and/or function may alter susceptibility to migraine since molecular variations within the DRD2 gene have been associated with variations in dopaminergic function. However, since not all individuals with the implicated DRD2 genotypes suffer from migraine with aura, additional genes or factors must also be involved. Migraine is likely to be a complex disorder with polygenic inheritance and a strong environmental component.
THE VASCULAR THEORY OF MIGRAINE
It was widely held for many years that the headache phase of migrainous attacks was caused by extracranial vasodilatation and that the neurologic symptoms were produced by intracranial vasoconstriction (i.e., the “vascular” hypothesis of migraine). Regional cerebral blood flow studies have shown that in patients with classic migraine there is, during attacks, a modest cortical hypoperfusion that begins in the visual cortex and spreads forward at a rate of 2 to 3 mm/min. The decrease in blood flow averages 25 to 30% (insufficient to explain symptoms on the basis of ischemia) and progresses anteriorly in a wavelike fashion independent of the topography of cerebral arteries. The wave of hypoperfusion persists for 4 to 6 h, appears to follow the convolutions of the cortex, and does not cross the central or lateral sulcus, progressing to the frontal lobe via the insula. Perfusion of subcortical structures is normal. Contralateral neurologic symptoms appear during temporoparietal hypoperfusion; at times, hypoperfusion persists in these regions after symptoms cease. More often, frontal spread continues as the headache phase begins. A few patients with classic migraine show no flow abnormalities; an occasional patient has developed focal ischemia sufficient to cause symptoms. However, focal ischemia does not appear to be necessary for focal symptoms to occur.
The ability of these changes to induce the symptoms of migraine has been questioned. Specifically, the decrease in blood flow that is observed does not appear to be significant enough to cause focal neurologic symptoms. Second, the increase in blood flow per se is not painful, and vasodilatation alone cannot account for the local edema and focal tenderness often observed in migraineurs. Moreover, in migraine without aura, no flow abnormalities are usually seen. Thus, it is unlikely that simple vasoconstriction and vasodilatation are the fundamental pathophysiologic abnormalities in migraine. However, it is clear that cerebral blood flow is altered during certain migraine attacks, and these changes may explain some, but clearly not all, of the clinical syndrome of migraine.
THE NEURONAL THEORY OF MIGRAINE
Fortification spectrum is a migraine aura characterized by a slowly enlarging visual scotoma with luminous edges (see below). It is believed to result from spreading depression, a slowly moving (2 to 3 mm/min), potassium-liberating depression of cortical activity, preceded by a wavefront of increased metabolic activity. Spreading depression can be produced by a variety of experimental stimuli, including hypoxia, mechanical trauma, and the topical application of potassium. These observations suggest that neuronal abnormalities could be the cause of a migraine attack.
Physiologically, electrical stimulation near dorsal raphe neurons in the upper brainstem can result in migraine-like headaches. Blood flow in the pons and midbrain increases focally during migraine headache episodes; this alteration probably results from increased activity of cells in the dorsal raphe and locus coeruleus. There are projections from the dorsal raphe that terminate on cerebral arteries and alter cerebral blood flow. There are also major projections from the dorsal raphe to important visual centers, including the lateral geniculate body, superior colliculus, retina, and visual cortex. These various serotonergic projections may represent the neural substrate for the circulatory and visual characteristics of migraine. The dorsal raphe cells stop firing during deep sleep, and sleep is known to ameliorate migraine; the antimigraine prophylactic drugs also inhibit activity of the dorsal raphe cells through a direct or indirect agonist effect.
Positron emission tomography (PET) scan studies have demonstrated
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that midbrain structures near the dorsal raphe are activated during a migraine attack. In one study of acute migraine, an injection of sumatriptan relieved the headache but did not alter the brainstem changes noted on the PET scan. These data suggest that a “brainstem generator” may be the cause of migraine and that certain antimigraine medications may not interfere with the underlying pathologic process in migraine.
THE TRIGEMINOVASCULAR SYSTEM IN MIGRAINE
Activation of cells in the trigeminal nucleus caudalis in the medulla (a pain-processing center for the head and face region) results in the release of vasoactive neuropeptides, including substance P and calcitonin gene–related peptide, at vascular terminations of the trigeminal nerve. These peptide neurotransmitters have been proposed to induce a sterile inflammation that activates trigeminal nociceptive afferents originating on the vessel wall, further contributing to the production of pain. This provides a potential mechanism for the soft tissue swelling and tenderness of blood vessels that accompany migraine attacks. However, numerous pharmacologic agents that are effective in preventing or reducing inflammation in this animal model (e.g., selective 5-HT1D agonists, NK-1 antagonists, endothelin antagonists) have failed to demonstrate any clinical efficacy in migraine trials.
5-HYDROXYTRYPTAMINE IN MIGRAINE
Pharmacologic and other data point to the involvement of the neurotransmitter 5-hydroxytryptamine (5-HT; also known as serotonin) in migraine. Approximately 40 years ago, methysergide was found to antagonize certain peripheral actions of 5-HT and was introduced as the first drug capable of preventing migraine attacks. Subsequently, it was found that platelet levels of 5-HT fall consistently at the onset of headache and that drugs that cause 5-HT to be released may trigger migrainous episodes. Such changes in circulating 5-HT levels proved to be pharmacologically trivial, however, and interest in the humoral role of 5-HT in migraine declined.
More recently, interest in the role of 5-HT in migraine has been renewed due to the introduction of the triptan class of antimigraine drugs. The triptans are designed to stimulate selectively a particular subpopulation of 5-HT receptors. At least 14 specific 5-HT receptors exist in humans. The triptans (e.g., naratriptan, rizatriptan, sumatriptan, and zolmitriptan) are potent agonists of 5-HT1B, 5-HT1D, and 5-HT1F receptors and are less potent at 5-HT1A and 5-HT1E receptors. A growing body of data indicates that the antimigraine efficacy of the triptans relates to their ability to stimulate 5-HT1B receptors, which are located on both blood vessels and nerve terminals. Selective 5-HT1D receptor agonists have, thus far, failed to demonstrate clinical efficacy in migraine. Triptans that are weak 5-HT1F agonists are also effective in migraine; however, only 5-HT1B efficacy is currently thought to be essential for antimigraine efficacy.
DOPAMINE IN MIGRAINE
A growing body of biologic, pharmacologic, and genetic data supports a role for dopamine in the pathophysiology of certain subtypes of migraine. Most migraine symptoms can be induced by dopaminergic stimulation. Moreover, there is dopamine receptor hypersensitivity in migraineurs, as demonstrated by the induction of yawning, nausea, vomiting, hypotension, and other symptoms of a migraine attack by dopaminergic agonists at doses that do not affect nonmigraineurs. Conversely, dopamine receptor antagonists are effective therapeutic agents in migraine, especially when given parenterally or concurrently with other antimigraine agents. As noted above, genetic data also suggest that molecular variations within dopamine receptor genes play a modifying role in the pathophysiology of migraine with aura. Therefore, modulation of dopaminergic neurotransmission should be considered in the therapeutic management of migraine.
THE SYMPATHETIC NERVOUS SYSTEM IN MIGRAINE
Alterations occur within the sympathetic nervous system (SNS) of migraineurs before, during, and between migraine attacks. Factors that activate the SNS are all triggers for migraine. Specific examples include environmental changes (e.g., stress, sleep patterns, hormonal shifts, hypoglycemia) and agents that cause release and a secondary depletion of peripheral catecholamines (e.g., tyramine, phenylethylamine, fenfluramine, m-chlorophenylpiperazine, and reserpine). By contrast, effective therapeutic approaches to migraine share an ability to mimic and/or enhance the effects of norepinephrine in the peripheral SNS. For example, norepinephrine itself, sympathomimetics (e.g., isometheptene), monoamine oxidase inhibitors (MAOIs), and reuptake blockers alleviate migraine. Dopamine antagonists, prostaglandin synthesis inhibitors, and adenosine antagonists are pharmacologic agents effective in the acute treatment of migraine. These drugs block the negative feedback inhibition or norepinephrine release induced by endogenous dopamine, prostaglandins, and adenosine. Therefore, migraine susceptibility may relate to genetically based variations in the ability to maintain adequate concentrations of certain neurotransmitters within postganglionic sympathetic nerve terminals. This hypothesis has been called the empty neuron theory of migraine.
Clinical Features
MIGRAINE WITHOUT AURA (COMMON MIGRAINE)
In this syndrome no focal neurologic disturbance precedes the recurrent headaches. Migraine without aura is by far the more frequent type of vascular headache. The International Headache Society criteria for migraine include moderate to severe head pain, pulsating quality, unilateral location, aggravation by walking stairs or similar routine activity, attendant nausea and/or vomiting, photophobia and phonophobia, and multiple attacks, each lasting 4 to 72 h.
MIGRAINE WITH AURA (CLASSIC MIGRAINE)
In this syndrome headache is associated with characteristic premonitory sensory, motor, or visual symptoms. Focal neurologic disturbances are more common during headache attacks than as prodromal symptoms. Focal neurologic disturbances without headache or vomiting have come to be known as migraine equivalents or migraine accompaniments and appear to occur more commonly in patients between the ages of 40 and 70 years. The term complicated migraine has generally been used to describe migraine with dramatic transient focal neurologic features or a migraine attack that leaves a persisting residual neurologic deficit.
The most common premonitory symptoms reported by migraineurs are visual, arising from dysfunction of occipital lobe neurons. Scotomas and/or hallucinations occur in about one-third of migraineurs and usually appear in the central portions of the visual fields. A highly characteristic syndrome occurs in about 10% of patients; it usually begins as a small paracentral scotoma, which slowly expands into a “C” shape. Luminous angles appear at the enlarging outer edge, becoming colored as the scintillating scotoma expands and moves toward the periphery of the involved half of the visual field, eventually disappearing over the horizon of peripheral vision. The entire process lasts 20 to 25 min. This phenomenon is pathognomonic for migraine and has never been described in association with a cerebral structural anomaly. It is commonly referred to as a fortification spectrum because the serrated edges of the hallucinated “C” seemed to resemble a fortified town with bastions around it; spectrum is used in the sense of an apparition or specter.
BASILAR MIGRAINE
Symptoms referable to a disturbance in brainstem function, such as vertigo, dysarthria, or diplopia, occur as the only neurologic symptoms of the attack in about 25% of patients. A dramatic form of basilar migraine (Bickerstaff's migraine) occurs primarily in adolescent females. Episodes begin with total blindness accompanied or followed by admixtures of vertigo, ataxia, dysarthria, tinnitus, and distal and perioral paresthesias. In about one-quarter of patients, a confusional state supervenes. The neurologic symptoms usually persist for 20 to 30 min and are generally followed by a throbbing occipital headache. This basilar migraine syndrome is now known also to occur in children and in adults over age 50. An altered sensorium may persist for as long as 5 days and may take the form of confusional states superficially resembling psychotic reactions. Full recovery after the episode is the rule.
CAROTIDYNIA
The carotidynia syndrome, sometimes called lower-half headache or facial migraine, is most common among older patients,
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with the incidence peaking in the fourth through sixth decades. Pain is usually located at the jaw or neck, although sometimes periorbital or maxillary pain occurs; it may be continuous, deep, dull, and aching, and it becomes pounding or throbbing episodically. There are often superimposed sharp, ice pick–like jabs. Attacks occur one to several times per week, each lasting several minutes to hours. Tenderness and prominent pulsations of the cervical carotid artery and soft tissue swelling overlying the carotid are usually present ipsilateral to the pain; many patients also report throbbing ipsilateral headache concurrent with carotidynia attacks as well as between attacks. Dental trauma is a common precipitant of this syndrome. Carotid artery involvement also appears to be common in the more traditional forms of migraine; over 50% of patients with frequent migraine attacks are found to have carotid tenderness at several points on the side most often involved during hemicranial migraine attacks.
TREATMENT
Nonpharmacologic Approaches for All Migraineurs
Migraine can often be managed to some degree by a variety of nonpharmacologic approaches (Table 14-7). The measures that apply to a given individual should be used routinely since they provide a simple, cost-effective approach to migraine management. Patients with migraine do not encounter more stress than headache-free individuals; overresponsiveness to stress appears to be the issue. Since the stresses of everyday living cannot be eliminated, lessening one's response to stress by various techniques is helpful for many patients. These include yoga, transcendental meditation, hypnosis, and conditioning techniques such as biofeedback. For most patients, this approach is, at best, an adjunct to pharmacotherapy. Avoidance of migraine trigger factors may also provide significant prophylactic benefits. Unfortunately, these measures are unlikely to prevent all migraine attacks. When these measures fail to prevent an attack, pharmacologic approaches are then needed to abort an attack.
TABLE 14-7 Nonpharmacologic Approaches to Migraine--------------------------------------------------------------------------------
Identify and then avoid trigger factors such as:
Alcohol (e.g., red wine)
Foods (e.g., chocolate, certain cheeses, monosodium glutamate, nitrate-containing foods)
Hunger (avoid missing meals)
Irregular sleep patterns (both lack of sleep and excessive sleep)
Organic odors
Sustained exertion
Acute changes in stress levels
Miscellaneous (glare, flashing lights)
Attempt to manage environmental shifts such as:
Time zone shifts
High altitude
Barometric pressure changes
Weather changes
Assess menstrual cycle relationship--------------------------------------------------------------------------------
Pharmacologic Treatment of Acute Migraine
The mainstay of pharmacologic therapy is the judicious use of one or more of the many drugs that are effective in migraine. The selection of the optimal regimen for a given patient depends on a number of factors, the most important of which is the severity of the attack (Table 14-8). Mild migraine attacks can usually be managed by oral agents; the average efficacy rate is 50 to 70%. Severe migraine attacks may require parenteral therapy. Most drugs effective in the treatment of migraine are members of one of three major pharmacologic classes: anti-inflammatory agents, 5-HT1 agonists, and dopamine antagonists.
TABLE 14-8 A Staged Approach to Migraine Pharmacotherapy--------------------------------------------------------------------------------
Stage Diagnosis Therapies--------------------------------------------------------------------------------
Mild migraine Occasional throbbing headachesNo major impairment of functioning
NSAIDsCombination analgesics
Oral 5-HT1 agonists
Moderate migraine Moderate or severe headachesNausea common
Some impairment of functioning
Oral, nasal, or SC 5-HT1 agonistsOral dopamine antagonists
Severe migraine Severe headaches >3 times per month SC, IM, or IV 5-HT1 agonists
Significant functional impairment IM or IV dopamine antagonists
Marked nausea and/or vomiting Prophylactic medications--------------------------------------------------------------------------------
Note: NSAIDs, nonsteroidal anti-inflammatory drugs; 5-HT, 5-hydroxytryptamine.
Table 14-9 lists specific drugs effective in migraine. In general, an adequate dose of whichever agent is chosen should be used as soon as possible after the onset of an attack. If additional medication is required within 60 min because symptoms return or have not abated, the initial dose should be increased for subsequent attacks. Migraine therapy must be individualized for each patient; a standard approach for all patients is not possible. A therapeutic regimen may need to be constantly refined and personalized until one is identified that provides the patient with rapid, complete, and consistent relief with minimal side effects.
NONSTEROIDAL ANTI-INFLAMMATORY AGENTS
Both the severity and duration of a migraine attack can be reduced significantly by anti-inflammatory agents. Indeed, many undiagnosed migraineurs are self-treated with nonprescription anti-inflammatory agents (Table 14-4). A general consensus is that NSAIDs are most effective when taken early in the migraine attack. However, the effectiveness of anti-inflammatory agents in migraine is usually less than optimal in moderate or severe migraine attacks. The combination of acetaminophen, aspirin, and caffeine (Excedrin Migraine) has been approved for use by the U.S. Food and Drug Administration (FDA) for the treatment of mild to moderate migraine. The combination of aspirin and metoclopramide has been shown to be equivalent to a single dose of sumatriptan. Major side effects of NSAIDs include dyspepsia and gastrointestinal irritation.
5-HT1 AGONISTS
Oral
Stimulation of 5-HT1 receptors can stop an acute migraine attack. Ergotamine and dihydroergotamine are nonselective receptor agonists, while the series of drugs known as triptans are selective 5-HT1 receptor agonists. A variety of triptans (e.g., naratriptan, rizatriptan, sumatriptan, zolmitriptan, almotriptan, frovatriptan) are now available for the treatment of migraine (Table 14-9).
TABLE 14-9 Treatment of Acute Migraine--------------------------------------------------------------------------------
Drug Trade Name Dosage--------------------------------------------------------------------------------
NSAIDS--------------------------------------------------------------------------------
Acetaminophen, aspirin, caffeine Excedrin Migraine Two tablets or caplets q6h (max 8 per day)
5-HT1 AGONISTS--------------------------------------------------------------------------------
Oral
Ergotamine Ergomar One 2 mg sublingual tablet at onset and q1/2h (max 3 per day, 5 per week)
Ergotamine 1 mg, caffeine 100 mg Ercaf, Wigraine One or two tablets at onset, then one tablet q1/2h (max 6 per day, 10 per week)
Naratriptan Amerge 2.5 mg tablet at onset; may repeat once after 4 h
Rizatriptan MaxaltMaxalt-MLT
5 to 10 mg tablet at onset; may repeat after 2 h (max 30 mg/d)
Sumatriptan Imitrex 50 to 100 mg tablet at onset; may repeat after 2 h (max 200 mg/d)
Zolmitriptan ZomigZomig Rapimelt
2.5 mg tablet at onset; may repeat after 2 h (max 10 mg/d)
Nasal
Dihydroergotamine Migranal Nasal Spray Prior to nasal spray, the pump must be primed 4 times; one spray (0.5 mg) is administered followed, in 15 min, by a second spray
Sumatriptan Imitrex Nasal Spray 5 to 20 mg intranasal spray as 4 sprays of 5 mg or a single 20 mg spray (may repeat once after 2 h, not to exceed a dose of 40 mg/d)
Parenteral
Dihydroergotamine DHE-45 1 mg IV, IM, or SC at onset and q1h (max 3 mg/d, 6 mg per week)
Sumatriptan Imitrex Injection 6 mg SC at onset (may repeat once after 1 h for max of two doses in 24 h)
DOPAMINE ANTAGONISTS--------------------------------------------------------------------------------
Oral
Metoclopramide Reglan,a generica 5–10 mg/d
Prochlorperazine Compazine,a generica 1–25 mg/d
Parenteral
Chlorpromazine Generica 0.1 mg/kg IV at 2 mg/min; max 35 mg/d
Metoclopramide Reglan,a generic 10 mg IV
Prochlorperazine Compazine,a generica 10 mg IV
OTHER--------------------------------------------------------------------------------
Oral
Acetaminophen, 325 mg, plus dichloralphenazone, 100 mg, plus isometheptene, 65 mg Midrin, Duradrin, generic Two capsules at onset followed by 1 capsule q1h (max 5 capsules)
Nasal
Butorphanol Stadola 1 mg (1 spray in 1 nostril), may repeat if necessary in1–2 h
Parenteral
Narcotics Generica Multiple preparations and dosages; see Table 11-1.--------------------------------------------------------------------------------
a Not specifically indicated by the U.S. Food and Drug Administration for migraine.
Note: NSAIDs, nonsteroidal anti-inflammatory drugs; 5-HT, 5-hydroxytryptamine.
Each of the triptan class of drugs has similar pharmacologic properties but varies slightly in terms of clinical efficacy. Rizatriptan and almotriptan are the fastest acting and most efficacious of the triptans currently available in the United States. Sumatriptan and zolmitriptan have similar rates of efficacy as well as time to onset, whereas naratriptan and frovatriptan are the slowest acting and the least efficacious. Clinical efficacy appears to be related more to the tmax (time to peak plasma level) than to the potency, half-life, or bioavailability (Table 14-10). This observation is in keeping with a significant body of data indicating that faster-acting analgesics are more efficacious than slower-acting agents.
TABLE 14-10 Comparative Pharmacology of Oral Triptansa--------------------------------------------------------------------------------
Drug and Dose, mg tmax, h t1/2, h Oral Bioavailability, % Clinical Efficacy at 2 h, %--------------------------------------------------------------------------------
Rizatriptan, 10 1–2 2–3 45 71
Zolmitriptan, 2.5 2 2.5–3 44 65
Sumatriptan, 50 2–3 2 14 61
Naratriptan, 2.5 2–4 5–6 68 45
Frovatriptan, 2.5 2–3 26 25 43
Almotriptan, 12.5 2–3 3 70 58--------------------------------------------------------------------------------
a Data adapted from package inserts approved by the U.S. Food and Drug Administration.
Unfortunately, monotherapy with a selective oral 5-HT1 agonist does not result in rapid, consistent, and complete relief of migraine in all patients. Triptans are not effective in migraine with aura unless given after the aura is completed and the headache initiated. Side effects, although often mild and transient, occur in up to 89% of patients. Moreover, 5-HT1 agonists are contraindicated in individuals with a history of cardiovascular disease. Recurrence of headache is a major limitation of triptan use, and occurs at least occasionally in 40 to 78% of patients.
Ergotamine preparations offer a nonselective means of stimulating 5-HT1 receptors. A nonnauseating dose of ergotamine should be sought since a dose that provokes nausea is too high and may intensify head pain. Except for a sublingual formulation of ergotamine (Ergomar),
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oral formulations of ergotamine also contain 100 mg caffeine (theoretically to enhance ergotamine absorption and possibly to add additional vasoconstrictor activity). The average oral ergotamine dose for a migraine attack is 2 mg. Since the clinical studies demonstrating the efficacy of ergotamine in migraine predated the clinical trial methodologies used with the triptans, it is difficult to assess the clinical efficacy of ergotamine versus the triptans. In general, ergotamine appears to have a much higher incidence of nausea than triptans, but less headache recurrence.
Nasal
The fastest acting nonparenteral antimigraine therapies that can be self-administered include nasal formulations of dihydroergotamine (Migranal) or sumatriptan (Imitrex Nasal). The nasal sprays result in substantial blood levels within 30 to 60 min. However, the nasal formulations suffer from inconsistent dosing, poor taste, and variable efficacy. Although in theory the nasal sprays might provide faster and more effective relief of a migraine attack than oral formulations, their reported efficacy is only approximately 50 to 60%.
Parenteral
Parenteral administration of drugs such as dihydroergotamine (DHE-45 Injectable) and sumatriptan (Imitrex SC) is approved by the FDA for the rapid relief of a migraine attack. Peak plasma levels of dihydroergotamine are achieved 3 min after intravenous dosing, 30 min after intramuscular dosing, and 45 min after subcutaneous dosing. If an attack has not already peaked, subcutaneous or intramuscular administration of 1 mg dihydroergotamine suffices for about 80 to 90% of patients. Sumatriptan, 6 mg subcutaneously, is effective in approximately 70 to 80% of patients.
DOPAMINE ANTAGONISTS
Oral
Oral dopamine antagonists should be considered as adjunctive therapy in migraine. Drug absorption is impaired during migrainous attacks because of reduced gastrointestinal motility. Delayed absorption occurs in the absence of nausea and is related to the severity of the attack and not its duration. Therefore, when oral NSAIDs and/or triptan agents fail, the addition of a dopamine antagonist such as metoclopramide, 10 mg, should be considered to enhance gastric absorption. In addition, dopamine antagonists decrease nausea/vomiting and restore normal gastric motility.
Parenteral
Parenteral dopamine antagonists (e.g., chlorpromazine, prochlorperazine, metoclopramide) can also provide significant acute relief of migraine; they can be used in combination with parenteral 5-HT1 agonists. A common intravenous protocol used for the treatment of severe migraine is the administration over 2 min of a mixture of 5 mg of prochlorperazine and 0.5 mg of dihydroergotamine.
OTHER MEDICATIONS FOR ACUTE MIGRAINE
Oral
The combination of acetaminophen, dichloralphenazone, and isometheptene (i.e., Midrin, Duradrin, generic), one to two capsules, has been classified by the FDA as “possibly” effective in the treatment of migraine. Since the clinical studies demonstrating the efficacy of this combination analgesic in migraine predated the clinical trial methodologies used with
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the triptans, it is difficult to assess the clinical efficacy of this sympathomimetic compound in comparison to other agents.
Nasal
A nasal preparation of butorphanol is available for the treatment of acute pain. As with all narcotics, the use of nasal butorphanol should be limited to a select group of migraineurs, as described below.
Parenteral
Narcotics are effective in the acute treatment of migraine. For example, intravenous meperidine (Demerol), 50 to 100 mg, is given frequently in the emergency room. This regimen “works” in the sense that the pain of migraine is eliminated. However, this regimen is clearly suboptimal in patients with recurrent headache for two major reasons. First, narcotics do not treat the underlying headache mechanism; rather, they act at the thalamic level to alter pain sensation. Second, the recurrent use of narcotics can lead to significant problems. In patients taking oral narcotics such as oxycodone (Percodan) or hydrocodone (Vicodin), narcotic addiction can greatly confuse the treatment of migraine. The headache that results from narcotic craving and/ or withdrawal can be difficult to distinguish from chronic migraine. Therefore, it is recommended that narcotic use in migraine be limited to patients with severe, but infrequent, headaches that are unresponsive to other pharmacologic approaches.
Prophylactic Treatment of Migraine
A substantial number of drugs are now available that have the capacity to stabilize migraine (Table 14-11). The decision of whether to use this approach depends on the frequency of attacks and on how well acute treatment is working. The occurrence of at least three attacks per month could be an indication for this approach. Drugs must be taken daily, and there is usually a lag of at least 2 to 6 weeks before an effect is seen. The drugs that have been approved by the FDA for the prophylactic treatment of migraine include propranolol, timolol, sodium valproate, and methysergide. In addition, a number of other drugs appear to display prophylactic efficacy. This group of drugs includes amitriptyline, nortriptyline, verapamil, phenelzine, gabapentin, and cyproheptadine. Phenelzine and methysergide are usually reserved for recalcitrant cases because of their serious potential side effects. Phenelzine is an MAOI; therefore, tyramine-containing foods, decongestants, and meperidine are contraindicated. Methysergide may cause retroperitoneal or cardiac valvular fibrosis when it is used for >8 months, thus monitoring is required for patients using this drug; the risk of the fibrotic complication is about 1:1500 and is likely to reverse after the drug is stopped.
TABLE 14-11 Drugs Effective in the Prophylactic Treatment of Migraine--------------------------------------------------------------------------------
Drug Trade Name Dosage--------------------------------------------------------------------------------
β-Adrenergic agents
Propranolol InderalInderal LA
80–320 mg qd
Timolol Blocadren 20–60 mg qd
Anticonvulsants
Sodium valproate Depakote 250 mg bid (max 1000 mg/d)
Tricyclic antidepressants
Amitriptyline Elavil,a generic 10–50 mg qhs
Nortriptyline Pamelor,a generic 25–75 mg qhs
Monoamine oxidase inhibitors
Phenelzine Nardila 15 mg tid
Serotonergic drugs
Methysergide Sansert 4–8 mg qd
Cyproheptadine Periactina 4–16 mg qd
Other
Verapamil CalanaIsoptina
80–480 mg qd--------------------------------------------------------------------------------
a Not specifically indicated for migraine by the U.S. Food and Drug Administration.
The probability of success with any one of the antimigraine drugs is 50 to 75%; thus, if one drug is assessed each month, there is a good chance that effective stabilization will be achieved within a few months. Many patients are managed adequately with low-dose amitriptyline, propranolol, or valproate. If these agents fail or lead to unacceptable side effects, then methysergide or phenelzine can be used. Once effective stabilization is achieved, the drug is continued for 5 to 6 months and then slowly tapered to assess the continued need. Many patients are able to discontinue medication and experience fewer and milder attacks for long periods, suggesting that these drugs may alter the natural history of migraine.
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