54: Antimigraine Medications

A migraine headache is a neurovascular disorder often initiated by a trigger and characterized by a headache, which is preceded by a visual aura 20% of the time. The headache may be accompanied by a variety of multiple organ system symptoms, such as allodynia, nausea, vomiting, and urinary frequency. There are various types of migraine, the diagnostic criteria for which are established by the International Headache Society.⁴ The types of migraine are divided into two groups: migraine without aura (“common migraine”) and migraine with aura (“classic migraine”). Further subdivisions include migraine with typical aura with or without headache, familial hemiplegic migraine, sporadic hemiplegic migraine, basilar type migraine, and retinal migraine.⁴

The initiation of migraines is not fully understood, but likely involves genetic abnormalities in central nervous system (CNS) ion channels that predispose patients to specific triggers. Patients with familial hemiplegic migraine, an autosomal dominant disorder, have missense mutations in the α₁ subunit of brain specific P/Q voltage-gated calcium channels resulting in altered function of these channels. During migraines, the upper brainstem has increased blood flow and is implicated as a “migraine generator.” After activation, a wave of cortical depression spreads across the cortex from a caudal to rostral fashion followed by a spreading wave of oligemia, which can produce the auras that occur in 20% of migraineurs.^26,36,86 Current theories suggest that this spreading wave also occurs in patients who do not experience visual auras but spares the visual cortex.

Cephalalgia begins during vasoconstriction prior to vasodilation. Antidromic activation of the afferent neurons of the ophthalmic division of the trigeminal nerve and branches of the C1 and C2 nerves (first order neurons) located on dural arteries at the base of the brain releases inflammatory neuropeptides such as calcitonin gene-related polypeptide (CRGP), vasoactive intestinal peptide (VIP), and neurokinase A. Vasoactive neuropeptides, including serotonin, nitric oxide, substance P, neurokinin A, and calcitonin gene-related peptide (CGRP), are released during this process, which exacerbates the vasodilation and irritates the meninges at the base of the brain, causing further pain. CGRP from trigeminal A-δ-fibers produces dural vasodilation, while substance P and neurokinin A from trigeminal C-fibers increase dural vessel permeability.^24,26 Pain impulses are relayed orthodromically to the trigeminal nucleus caudalis (second order neurons) in the lower medulla and upper cervical spinal cord, then to the thalamus (third order neurons) via the quintothalamic tract, and finally to higher cortical areas (fourth order neurons probably located in the limbi cortex).^26,34 The trigeminocervical complex also produces retrograde parasympathetic impulses from the sphenopalatine ganglion and the superior salivatory nucleus in the pons through the pterygopalatine, otic, and carotid ganglia to the cerebral vessels.³⁴

Treatment of migraines encompasses a wide variety of xenobiotics that can be broadly classified as prophylactic or abortive therapies (Table 54–1). Current abortive therapies include analgesics (nonsteroidal antiinflammatory drugs, acetaminophen {APAP}, opioids), antiemetics, ergots alkaloids, triptans, oxygen, magnesium sulfate, and intranasal lidocaine. Triptans are considered the drugs of choice for abortive migraine therapy. Prophylactic therapies with the evidence for established efficacy include antiepileptics (topiramate, valproic acid), β-adrenergic antagonists (metoprolol, propranolol, timolol) and triptans (for menstrually related migraines).⁷⁵

History and Epidemiology

Ergot is the product of Claviceps purpurea, a fungus that contaminates rye and other grains. The spores of the fungus are both windborne and transported by insects to young rye, where they germinate into hyphal filaments. When a spore germinates, it destroys the grain and hardens into a curved body called the sclerotium, which remains the major commercial source of ergot alkaloids.⁷¹ The C. purpurea fungus produces diverse substances, including ergotamine, histamine, lysergic acid, tyramine, isomylamine, acetylcholine, and acetaldehyde.

In 600 b.c. an Assyrian tablet mentioned grain contamination believed to be by C. purpurea. In the Middle Ages, epidemics causing gangrene of the extremities, with mummification of limbs, were depicted in the literature as blackened limbs resembling the charring from fire and caused a burning sensation expressed by its victims. The disease was called holy fire or St. Anthony’s fire, but the improvement that reportedly occurred when victims went to visit the shrine of St. Anthony was probably the result of a diet free of contaminated grain on the journey.³⁷ Abortion and seizures were also reported to result from this poisoning. On the other hand, as early as 1582, midwives used ergot to assist in the childbirth process. In 1818, Desgranges was the first physician to use ergot for obstetric care, and in 1822 Hosack reported that ergot could be used for the control of postpartum hemorrhage.⁸⁴ Since 1950, the clinical use of ergot derivatives is almost entirely limited to the treatment of vascular headaches. Ergonovine, another ergot derivative, is used in obstetric care for its stimulant effect on uterine smooth muscle and was formerly used in cardiac stress tests. Methylergonovine is used for postpartum uterine atony and hemorrhage. Cabergoline is used for hyperprolactinemia and in the treatment of Parkinson disease. Ergot derivatives were also used as “cognition enhancers,”⁸⁷ to help manage orthostatic hypotension,⁷⁸ and to prevent the secretion of prolactin.⁷¹

Currently in the US, human poisoning epidemics from ergot grain infestations are prevented by government inspections of grain fields. If a grain field contains more than 0.3% affected grain, then it is rejected for commercial sale; in some years, as much as 36% of the grain was rejected.⁷¹ However, elsewhere in the world ergot toxicity remains a problem predominantly in animals.^9,48

Pharmacology and Pharmacokinetics

All ergot alkaloids are derivatives of the tetracyclic compound 6-methylergoline. They can be divided into three groups: amino acid alkaloids (ergotamine, ergotoxine), dihydrogenated amino acid alkaloids, and amine alkaloids (Fig. 54–1).

The pharmacokinetics of the ergot alkaloids are well defined by controlled human volunteer studies, whereas the toxicokinetics are essentially unknown (Table 54–2). Almost all of the ergots are poorly absorbed orally and there is considerable first-pass hepatic metabolism, resulting in highly variable bioavailability. Intramuscular absorption is unpredictable and actions are often delayed.⁶³ Peak plasma concentrations with oral ergotamine occur within 45 to 60 minutes.⁶³ The volume of distribution of ergotamine is approximately 2 L/kg and the half-life varies from 1.4 to 6.2 hours. Ergot alkaloids are metabolized in the liver, probably by CYP3A4, and the metabolites are excreted in the bile.^7,71

The pharmacologic effects of the ergot alkaloids can be subdivided into central and peripheral effects (Table 54–3). In the CNS, ergotamine stimulates serotonergic receptors, potentiates serotonergic effects, blocks neuronal serotonin reuptake, and has central sympatholytic actions.^37,71 Ergotamine and dihydroergotamine interact with the 1A, 1B, 1D, 1F, 2A, 2C, 3, and 4 serotonin receptor subtypes, dopamine receptors and adrenergic receptors.⁸ The result is increased intrasynaptic serotonin activity in the median raphe neurons of the brainstem.⁶⁸ Ergotamine and dihydroergotamine decrease the neuronal firing rate and stabilize the cerebrovascular smooth musculature, which make them useful drugs for both abortive and prophylactic treatment of migraine headaches.

Peripherally, ergotamine and dihydroergotamine are α-adrenergic, 5-HT_2A and 5-HT_1B agonists and vasoconstrictors.⁷⁶ The amino acid ergot alkaloids (ergotamine, ergotoxine) exhibit α-adrenergic agonism, and dehydrogenation (dihydroergotamine) of the lysergic acid nucleus increases the potency of this effect.⁷¹ Ergotamine is a more potent constrictor of peripheral arteries, whereas dihydroergotamine is a more potent vasoconstrictor.¹⁶Table 54–3 summarizes the pharmacologic actions of selected ergot alkaloids currently used in clinical medicine. The spectrum of effects depends on dose, host response, and physiologic conditions.

The clinical effects following overdose are an extension of the therapeutic effects. At toxic doses, extreme vasoconstriction produces the characteristic ischemic changes that occur in ergotism.

The cerebrovascular effects of ergot alkaloids are not as clearly understood. In migraine treatment, for example, therapeutic doses of ergotamine produce mild vasoconstriction via α-adrenergic agonism. This may be more pronounced in intracranial vessels that are already dilated during a migraine. In toxic doses, cephalic vasodilation may occur but the mechanism for this effect is unknown. One hypothesis is that toxic doses initially produce cerebral vasoconstriction and ischemia, just as occurs in the periphery, but since the cerebral vasculature cannot tolerate hypoxia and hypercapnia, rapid vasodilation then ensues to improve local perfusion. In addition, α-adrenergic receptors in the CNS function differently from those in the periphery, and it may be that CNS vascular tone cannot be maintained in the setting of local tissue hypoxia.

Clinical Manifestations

Ergotism, a toxicologic syndrome resulting from excessive use of ergot alkaloids, is characterized by intense burning of the extremities, hemorrhagic vesiculation, pruritus, formication, nausea, vomiting, and gangrene (Table 54–4). Headache, fixed miosis, hallucinations, delirium, cerebrovascular ischemia, and convulsions are also associated with this condition, which has been called “convulsive” ergotism.³⁷ Chronic ergotism usually presents with peripheral ischemia of the lower extremities, although ischemia of cerebral, mesenteric, coronary, and renal vascular beds are well documented.^{3,27,28,69,70} Ergotism can also result from interactions of ergot derivatives with CYP3A4 inhibitors such as macrolide antibiotics and protease inhibitors, which increase bioavailability of ergots.^6,7

The vascular effects ascribed to ergot alkaloids are complex and sometimes conflicting (Table 54–3). Subintimal and medial fibrosis, vasospasm, and arteriolar and venous thrombi (stasis related) are all reported.⁵⁶ Angiography can demonstrate distal, segmental vessel spasm with increased collateralization in patients with chronic ergotism. The coronary, renal, cerebral, ophthalmic, and mesenteric vasculature,⁷⁰ as well as the vessels of the extremities, may also be affected.⁷³ Neuropathic changes may be secondary to ischemia of the vasa nervorum.

Bradycardia is a characteristic effect of the ergot alkaloids, and is believed to be a reflex baroreceptor-mediated phenomenon associated with vasoconstriction, but a reduction in sympathetic tone, direct myocardial depression, and increased vagal activity may also be factors.⁷¹

Myocardial valvular abnormalities are reported with ergot alkaloids. Ergotamine, methysergide, pergolide, and cabergoline cause mitral and aortic valve leaflet thickening and immobility resulting in valvular regurgitation.^29,69,90

Treatment

The treatment for a patient with ergot alkaloid toxicity depends on the nature of the clinical findings. Gastric emptying should rarely be used, if at all, because vomiting is a common early occurrence, and the ingestion may be complicated by seizures. After an acute oral overdose, 1 g/kg of activated charcoal should be administered orally. If emesis is present, antiemetics such as ondansetron or metoclopramide should be administered intravenously to facilitate the administration of activated charcoal. In mild cases, characterized by minimal pain of the extremities, nausea, or headache, supportive measures such as hydration and analgesia are all that are needed. Patients who develop mild symptoms of vasospasm, such as dysesthesias and minimal ischemic pain of the digits, should be treated with immediate release nifedipine 10 mg every 8 hours orally.¹⁵ With more serious cases, severe peripheral vasoconstriction may produce ischemic changes that include angina, myocardial infarction, cerebral ischemia, intermittent claudication, and internal organ/mesenteric ischemia. Intravenous sodium nitroprusside at a starting dose of 0.5 µg/kg/min is recommended and should be titrated until resolution of vasoconstriction.^3,12,62 Phentolamine should be considered as well. Immediate release oral nifedipine at a dose of 10 mg every 8 hours can be administered as a second line therapy. Methylprednisolone at a dose of 1 mg/kg was reported to reverse ergotamine induced lower extremity arterial vasospasm that was not responsive to sodium nitroprusside and heparin.⁶⁶

Heparin or low molecular weight heparins should be administered to prevent sludging and subsequent clot formation. Benzodiazepines should be used to treat seizures or hallucinations.

In 1974, investigations began on a new class of compounds that produced vasoconstrictive effects via 5-HT receptors. The first compound successfully used in this way was 5-carboxamidotryptamine (5-CT). When applied to an isolated dog saphenous vein, 5-CT caused potent venoconstriction and induced significant hypotension in vivo. The next compound develo­ped, AH25086 [(3–2-aminoethyl)-N-methyl-1-H-indole-5-acetamide], also constricted saphenous veins in dogs but had more 5-HT receptor selectivity. AH25086 was effective against acute migraine in human volunteers, but further research was stopped because it was deemed less suitable for development in humans, possibly owing to the fact that it was highly polar, lipophobic, and unsuitable for oral use.^41,72 In 1984, sumatriptan was synthesized and its clinical success led to the rapid development of six other triptans: almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan and zolmitriptan, and one triptan combination medication (sumatriptan/naproxen; Fig. 54–2; Table 54–5).

Pharmacology

The triptans are all primarily 5-HT_1B and 5-HT_1D receptor agonists and have less activity at 5-HT_1A and 5-HT_1F receptors³⁰ (Chap. 14). In the CNS, 5-HT_1B receptors are located on cerebral vessels.³⁵ Stimulation of these receptors results in cerebral vasoconstriction,¹⁷ reversing abnormal cerebral vasodilation. In contrast, the 5-HT_1D receptors are located presynaptically on trigeminal neurons, and act as “autoreceptors” to decrease neurotransmitter release from central trigeminal nerve terminals.⁴⁵ The triptans also inhibit dural neurogenic inflammation by preventing the release of vasoactive neuropeptides from peripheral trigeminal nerves.^58,74 Peripherally, triptans cause vasoconstriction systemically through the 5-HT_1B receptor^19,52 (Fig. 54–3).

Sumatriptan has poor oral bioavailability but good subcutaneous bioavailability (96%), and is therefore preferentially given by this route. The newer triptans differ substantially from sumatriptan with regard to oral bioavailability, plasma half-life, time to maximum effect, and recurrence rate of headaches. All triptans are pharmacodynamically similar but pharmaco­kinetically different (Table 54–5).

Clinical Manifestations

With appropriate therapeutic use, the common adverse effects associated with the triptans are less common and include nausea, vomiting, dyspepsia, flushing, and paresthesias.^18,71 However, the most consequential adverse effects are chest pressure and vasoconstriction. Chest pressure symptoms are reported in up to 15% of sumatriptan users.^11,65 Although triptans reduce coronary artery diameter by 10% to 15%, chest pressure symptoms are not believed to be secondary to cardiac ischemia. Alternate hypotheses for the chest pressure sensations include a generalized vasospastic disorder in migraineurs, esophageal spasm, bronchospasm, alterations of skeletal muscle energy metabolism, and central sensitization of pain pathways.²⁰ Although the triptans show some degree of coronary artery constriction in vitro, studies demonstrate, and hence recommendations state, that there is no need for routine stress tests in low-risk patients prior to therapy with triptans.^21,51,83

However, triptans can cause ischemia due to vasoconstriction. Therapeutic sumatriptan use is associated with myocardial ischemia and or infarction, dysrhythmias, renal infarction, splenic infarction, and ischemic colitis.^{1,5,14,46,53,59,61,64} Cephalic vasoconstriction is the desired effect of sumatriptan, but there are reports of strokes, hemorrhages, and infarctions.^13,44,50,57 Extrapyramidal symptoms, such as akathisia and dystonia, may also occur.⁴⁹ Therapeutic use of other triptans has caused spinal cord infarction, renal infarction, myocardial infarction, ischemic colitis, and seizures.^{32,47,55,85,88}

Animal studies showed a wide margin of safety with oral sumatriptan. Subcutaneous administration of 2 g/kg of sumatriptan to rats was lethal. Death was preceded by erythema, inactivity, and tremor.⁴² Dogs survived 20 mg/kg and 100 mg/kg subcutaneous doses, but developed hind limb paralysis, erythema, tremor, salivation, and loss of vocalization.⁴¹ Reactions in other animals include seizures, inactivity, reduced respiratory rate, cyanosis, ptosis, ataxia, mydriasis, salivation, and lacrimation.^42,79

Excessive triptan use is associated with vasoconstrictive adverse effects. A 43 year-old man who used 23 (25 mg) tablets of sumatriptan and 32 tablets of a combination preparation of isometheptene 65 mg, dichloralphenazone 100 mg, and APAP 325 mg over 7 days for headaches developed a left occipital infarction with a right hemianopsia. Digital subtraction angiography revealed segmental narrowing in multiple cerebral vessels. The hemianopsia and vessel findings resolved after cessation of the sumatriptan and Midrin and treatment with nicardipine.⁵⁷ A 35 year-old woman who used 300 mg of sumatriptan orally and 12 mg subcutaneously developed ischemic colitis.⁴⁰ Two patients who received four times and 10 times the recommended dose of naratriptan developed severe hypertension.⁶⁰ However, not all triptan overdoses result in toxicity. One 36 year-old man reportedly used 66 (6 mg) doses of sumatriptan subcutaneously over 4 weeks for his cluster headaches and had no adverse effects.⁸¹ The maximum recommended dosage of sumatriptan is 12 mg subcutaneously in a 24-hour period. Patients who took single doses of 100 to 150 mg of almotriptan did not have any adverse effects.²

In 2006, the US Food and Drug Administration (FDA) issued an alert, warning of an increased risk of serotonin toxicity with triptans used in combination with selective serotonin reuptake inhibitors (SSRIs) or selective serotonin-norepinephrine reuptake inhibitors. The alert was based on 27 cases reported to the FDA Adverse Events Reporting System between 1998 and 2002.²⁵ The cases involved triptan use in conjunction with SSRIs that were coded as serotonin syndrome or symptoms indicative of serotonin toxicity.⁷⁷ A case series of serotonin toxicity from migraine medications described three cases associated with sumatriptan use alone, sumatriptan with sertraline, and sumatriptan with methysergide, lithium, and sertraline.⁵⁴ Other medications that might precipitate serotonin toxicity when used in conjunction with triptans include monoamine oxidase inhibitors (Chaps. 73 and 75).

Treatment

Treatment of triptan-induced vasoconstriction is dependent on the route of exposure and the organ system affected. Decontamination is not feasible after subcutaneous exposures, but can be effective following overdose of oral preparations. Gastrointestinal decontamination should be performed with activated charcoal. Because vomiting is not as prominent with triptan exposure as with exposure to the ergot alkaloids, gastric emptying procedures, such as orogastric lavage, may be considered early, but only following massive ingestion. The oral forms of rizatriptan and zolmitriptan are formulated to dissolve on the tongue, limiting the effectiveness of gastrointestinal decontamination.

Many reported cases of triptan induced vasoconstriction compromise responded to intravenous hydration and analgesia.^46,32 Triptan-associated myocardial ischemia should be treated with aspirin, heparin, and intravenous nitroglycerin.⁶⁴ Coronary angiography should be performed for transmural myocardial infarctions with ST segment elevations on electrocardiography.^53,61

Isometheptene is a mild vasoconstrictor marketed as a combination preparation (Midrin) that includes dichloralphenazone, a muscle relaxant, and APAP. It has indirect α- and β-adrenergic agonist effects as well as minor direct α-adrenergic agonist effects on the peripheral vasculature.⁸² When administered early during a migraine exacerbation, it is as effective as sumatriptan in relieving migraine headache.³¹ Cerebral vasoconstriction is reported after therapeutic and excessive isometheptene use.^59,67 Autonomic dysreflexia, which presented as hypertension, headache, diaphoresis, and flushing, was also reported in a man with spinal cord injury who used isometheptene for treatment of a migraine headache.⁸⁹ Treatment of isometheptene-induced vasoconstriction should include discontinuation of the medication and reversal of the vasoconstriction with calcium channel blockers or vasodilators, such as sodium nitroprusside, nitroglycerin, or phentolamine.

During migraines, CGRP is among the many vasoactive peptides released from activated trigeminal nerves.³³ CGRP is a potent vasodilator¹⁰ and is involved in the transmission of nociceptive signals from cerebral vessels to the central nervous system.²² CGRP receptors are found in nerve fibers in cerebral and dural vessels and in multiple areas of the central nervous system postulated in migraine genesis—the cerebral cortex, periaqueductal gray, locus coeruleus, dorsal raphe nuclei, solitary tractus nucleus, spinal dorsal horn, dorsal root ganglia, and trigeminal ganglia.⁸⁰ Treatment of active migraine with sumatriptan decreased CGRP concentrations to normal.³³

Two CGRP antagonists were developed for migraine therapy—olcegepant and telcagepant—neither olcegepant nor telcagepant is available. Based on two high dosing administrations, olcegepant has a volume of distribution of 20 L in an adult with a terminal half-life of 2.5 hours and minor renal excretion.⁴³ Adverse events reported with olcegepant include paresthesia, flushing, fatigue, headache, abdominal pain, diarrhea, flatulence, rhinitis, dry mouth, and abnormal vision.^23,43 Adverse effects reported with telcagepant include nausea, dizziness, somnolence, dry mouth, fatigue, paresthesia, and asthenia.^38,39 Systemic vasoconstrictive adverse effects did not occur in the phase 2 and 3 trials with either olcegepant or telcagepant.

• Migraine therapies include many xenobiotics for prophylaxis or for abortive therapy. Triptans have supplanted ergots as the primary abortive treatment for patients with migraines.

• Ergots interact with multiple 5-HT, dopamine, and adrenergic receptors, which can cause severe vasoconstriction and end organ ischemia.

• Ergot and triptan induced peripheral ischemia should be managed with vasodilators, calcium channel blockers, and heparin anticoagulation.

• Triptans are more selective and interact only with 5-HT_1B/D/F receptors but can also cause peripheral vasoconstriction and end organ ­ischemia. Triptan induced myocardial ischemia should be treated with anticoagulation, nitrates, and coronary angiography for transmural infarctions.

• Triptan use in conjunction with other serotonin increasing xenobiotics can increase the risk of serotonin toxicity.

Acknowledgment

Neal A. Lewin, MD, contributed to this chapter in previous editions.

References