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Home , Triptan

The new england journal of medicine

clinical therapeutics

Triptan in Elizabeth Loder, M.D., M.P.H.

This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the author’s clinical recommendations.

An otherwise healthy 23-year-old woman presents to her internist with a report of and associated symptoms that occur twice a month. A diagnosis of mi- graine without aura is made. The patient’s headaches last up to a day and cause her to miss work. The headaches have not responded reliably to analgesics or to combina- tions of analgesics with caffeine. Her internist has previously recommended the com- bination of aspirin and , which usually diminishes but does not elim- inate her . On one occasion, her headache progressed despite treatment, and the patient went to the emergency department. She received subcutaneous suma- triptan for a presumptive diagnosis of migraine. Her headache and nausea resolved, but she had a sensation of mild chest pressure for about 5 minutes, without associated symptoms. Her internist refers her to a headache specialist with the question of what therapy should be used to treat her headache episodes.

The Clinical Problem

Migraine is a genetically inf luenced chronic brain condition marked by paroxysmal From the Division of Headache and Pain, attacks of moderate-to-severe, throbbing headache with associated symptoms that Department of Neurology, Brigham and Women’s Hospital and Faulkner Hospi- may include nausea, vomiting, and photophobia or phonophobia. In up to a third tal — both in Boston. Address reprint re- of patients with migraine, the headaches are accompanied by focal neurologic quests to Dr. Loder at the John R. Graham symptoms (often visual) known as aura (Table 1).1 The World Health Organization Headache Center, Faulkner Hospital, Bos- ton, MA 02130, or at [email protected]. estimates that 324 million persons worldwide have .2 Migraine is both more common and more severe in women than in men.3 N Engl J Med 2010;363:63-70. Symptoms generally begin in adolescence or early adulthood. Disease activity Copyright © 2010 Massachusetts Medical Society. peaks during middle age, with a lifetime cumulative incidence of 43% in women and 18% in men.4 Although migraine is not life-threatening, it is associated with an increased risk of other vascular complications, including ischemic and preeclampsia.5,6 Almost a quarter of patients with migraines have more than 3 days of headache a month, and such headaches often interfere with work, social functioning, and overall quality of life.7 Episodes of headache, the majority of which are migraine headaches, account for almost 3% of visits to the emergency department in the United States8,9 and 1.3% of outpatient visits.10 Health care expenses associated with migraine include direct costs of roughly $11 billion among patients with health insurance and indirect costs of almost $12 billion.11,12

Pathophysiology and the Effect of Therapy

The pathophysiology of migraine is not completely understood. There is consider- able evidence that intracranial vasodilatation, long thought to be causal, in fact

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sensory nerve terminals that innervate meninge- Table 1. Diagnostic Criteria for Migraine.* al blood vessels. These peptides activate perivas- Migraine without aura cular trigeminal nerves and cause dilatation of Criterion A — At least five attacks fulfilling criteria B through D arteries in the meninges as well as perivascular Criterion B — Headache lasting 4 to 72 hours (untreated or unsuccessfully inflammation and extravasation of plasma pro- treated) teins. First-order terminate in the tri­ Criterion C — Headache having at least two of the following characteristics: gem­inal nucleus caudalis in the brain stem. They Unilateral location activate second-order neurons that ascend to the Pulsating quality thalamus, and from there, third-order neurons Moderate or severe intensity (inhibiting or prohibiting daily activities) project to higher cortical centers. If uninterrupt- Aggravation on using stairs or engaging in similar routine physical activity ed, this process causes pain and can lead to hy- Criterion D —Headache during which at least one of the following occurs: peralgesia and , both hallmarks of pro- 14 Nausea or vomiting longed migraine attacks. Activation of the sympathetic nervous system Photophobia and phonophobia is the likely cause of nausea, vomiting, and Criterion E — At least one of the following criteria is met: other autonomic symptoms associated with mi- History and physical and neurologic examination do not suggest an ­organic disorder graine. Sensitivity to light, sound, and smell is History or physical or neurologic examination suggests an organic dis­ theorized to result from abnormal brain-stem 15,16 order that is ruled out after appropriate investigation modulation of sensory information. There is Organic disorder is present, but initial migraine attacks do not occur close evidence that aura is caused by cortical spread- to the time at which the organic disorder began ing depression, a transient, spreading distur- Typical aura with migraine headache† bance in cortical function. Cortical spreading Criterion A — At least two attacks fulfilling criteria B through D depression is most easily triggered in the occipi- Criterion B — Aura consisting of at least one of the following criteria but no tal cortex, possibly explaining the predominance motor weakness: of visual forms of aura.15 Fully reversible visual symptoms, including positive features (e.g., seeing Triptans are (5-hydroxytryptamine, flickering lights or spots or lines), negative features (e.g., loss of vision), or 5-HT) with high affinity for 5-HT or both 1B and 5-HT receptors. Triptans were originally Fully reversible sensory symptoms, including positive features (e.g., feel- 1D ing of pins and needles, usually in the arms and legs, the face, or on thought to provide relief from migraine by caus- one side of the body), negative features (e.g., numbness), or both ing cranial , most likely through Fully reversible dysphasic speech disturbance action at postsynaptic 5-HT1B receptors on the Criterion C — At least two of the following criteria: smooth-muscle cells of blood vessels. It is now Visual symptoms on one or both sides of the visual field, or unilateral theorized that triptans also block the release of sensory symptoms vasoactive peptides from the perivascular trigem- At least one symptom of aura develops gradually over the course of 5 inal neurons through their action at presynaptic minutes or more, or other symptoms of aura occur in succession over 5-HT1D receptors on the nerve terminals. In ad- the course of 5 minutes or more dition, triptans bind to presynaptic 5-HT1D re- Each symptom lasts between 5 and 60 minutes ceptors in the dorsal horn, and this binding is Criterion D — Headache fulfilling criteria B through D for migraine without thought to block the release of neurotransmit- aura; migraine without aura begins during the aura or follows the aura within 60 minutes ters that activate second-order neurons ascend- 17 Criterion E — Symptoms cannot be attributed to another disorder ing to the thalamus. Triptans may also facili- tate descending pain inhibitory systems.18,19 * Adapted from the International Classification of Headache Disorders II (2004).1 More information on the classification of headache disorders is available at the International Headache Society Web site at www.i-h-s.org. Clinical Evidence † Typical aura with migraine headache is the most common subform of migraine with aura. Randomized, controlled trials have evaluated parenteral, oral, , and nasal formula- occurs in response to the neurologic events of tions of various triptans for short-term treatment migraine.13 The most widely accepted theory re- of migraine. In these trials, the most widely used garding the physiological mechanism of mi- measure of benefit is a reduction in the severity graine proposes that early in an attack, vasoac- of headache pain 2 hours after treatment, rated tive peptides are released from the primary on a four-point scale (no pain, mild pain, moder-

64 n engl j med 363;1 nejm.org july 1, 2010 clinical therapeutics ate pain, or severe pain). Headache “response” unclear whether additional unpublished com- has traditionally been defined as a reduction parative trials of other triptans have been con- from moderate or severe headache to mild or no ducted. This makes it difficult to draw definite headache 2 hours after administration of the conclusions about the overall place of orally ad- . The “therapeutic gain” is the differ- ministered triptans in the treatment of acute ence between the headache response with triptan migraine. therapy and the response with placebo. In a review of 13 randomized trials, a 6-mg Clinical Use dose of a subcutaneous formulation of sumatrip- tan was shown to have a mean therapeutic gain Triptans are first-line for individual at- of 51 percentage points (70% response with ac- tacks of migraine in patients whose attacks do tive treatment vs. 19% with placebo), which is not reliably respond to simple or combination the largest for all available triptans.20 Most pa- analgesics.26 Alternatives include ergot deriva- tients, however, prefer to use oral drugs to treat tives, opioids, and barbiturate-containing medi- migraine. A meta-analysis by Ferrari et al. sum- cations. A key advantage of triptans over most of marized 53 randomized, double-blind controlled these alternatives is their more favorable side- trials, involving more than 24,000 patients, in effect profile and more specific mechanism of which oral triptans were compared with place- action. Triptan therapy is most effective when bo.21 The 100-mg oral dose of was provided rapidly in adequate doses and when the reference dose, with a mean therapeutic gain used early, while headache pain is still mild.27 at 2 hours of 29 percentage points (59% re- Seven triptans are approved by the Food and sponse rate with active treatment vs. 30% with Drug Administration (FDA) for the treatment of placebo). Most of the other triptans evaluated acute migraine in adults (Table 2). The decision had similar therapeutic gain when administered about which triptan and which formulation to at doses recommended by the manufacturer. The use depends on the patient’s preference, the exceptions were , which was signifi- characteristics of the headache, convenience, cantly less effective, and , which was and cost. Only sumatriptan is available for par- marginally less effective. enteral administration. Fewer trials have compared the effectiveness Most patients have a strong preference for of triptans directly with that of nontriptan oral treatment of migraine. Oral triptans are ap- therapy. In a review of published trials in which propriate when nausea and vomiting are mild or oral triptans were used, Lipton et al. found that absent at the time of treatment. Naratriptan and the data suggested a significantly greater benefit frovatriptan are generally less effective in reliev- with triptans than with compounds, ing headache at 2 hours than the other agents, but no significant difference was detected be- although their longer half-lives may prove useful tween the effect of triptans and that of non- in some situations. The onset of action of most steroidal or other analgesics.22 In one study of oral triptans is within 20 to 60 minutes.20 If 733 patients, 54% of patients receiving 40 mg necessary, patients can take another dose of of oral had relief from headache at most oral triptans after 2 or 4 hours. The usual 2 hours, as compared with 33% of those receiv- initial dose and maximum daily dose for each ing a combination of 1 mg of ergotamine and agent are listed in Table 2. For patients who are 100 mg of caffeine (P<0.001).23 In another study, very sensitive to side effects of triptans, the dose involving 666 patients, which defined efficacy as may need to be lowered. a headache response in three of three migraine Subcutaneous sumatriptan has the fastest attacks, the efficacy was 33.4% with 2.5 mg of onset of action of all available triptans (approxi- oral as compared with 32.9% with mately 10 minutes) and is also the most effec- 900 mg of acetylsalicylic acid plus 10 mg of me- tive,20 making it the best choice for rapidly de- toclopramide (P = 0.72).24 veloping or well-established migraines or for Recently, new information has become avail- patients with prominent early nausea or vomit- able about unpublished comparative randomized ing. It is commonly used in the emergency de- trials of oral sumatriptan.25 The results of these partment, but it can also be self-administered in trials did not especially favor sumatriptan. It is the thigh or deltoid region with a reusable auto-

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5 mg 5 25 mg 25 mg 12 40 mg 40 mg 10 mg 10 80 mg 80 7.5 mg 7.5 200 mg 200 2 tablets 2 Dose per 24 Hr in which initial dose initial which in to reduced be must mg) 5 Highest Approved 30 mg (15 mg for cases for mg (15 mg 30

2 4 2 2 hr injection: 1 ­ injection: 2 tablet: naproxen Subcutaneous Sumatriptan– Minimum Interval before Repeating Dose Tablet: 2 Tablet: 2 Tablet: 2 spray: Nasal Tablet or wafer: 2 wafer: or Tablet 2 spray: Nasal

Selected Drug Interactions patients with sulfonamide allergies; dose allergies; sulfonamide with patients when suggested mg 6.25 to reduction such inhibitor, CYP3A4 potent with used nefazo ­ itraconazole, ketoconazole, as clarithromycin, troleandomycin, done, nelfinavir or ­ ritonavir, patients taking ; should not should propranolol; taking patients monoamine after wk 2 within used be inhibitor oxidase inhibitor oxidase amine not be used within 3 days after potent after days 3 within used be not ketoconazole, as such inhibitor, CYP3A4 troleandomy - , itraconazole, nelfinavir or ritonavir, clarithromycin, cin, amine oxidase inhibitor oxidase amine Contains a sulfa group — contraindicated in contraindicated — group sulfa a Contains Dose reduction to 5 mg recommended in recommended mg 5 to reduction Dose mono - after wk 2 within used be not Should Metabolized by CYP3A4 enzyme — should — enzyme CYP3A4 by Metabolized Should not be used within 2 wk after mono - after wk 2 within used be not Should

6 4 3 hr 26 2.5 Life 3–4 2–3 Half- 40 mg 40 2.5 mg 2.5 2.5 mg 2.5 12.5 mg 12.5 Initial Dose cartridge: 6 mg 6 cartridge: Commonly Prescribed Tablet: 10 mg 10 Tablet: mg 10 Wafer: Tablet: 5 mg 5 Tablet: mg 5 Wafer: mg 5 spray: Nasal Tablet: 50 or 100 mg 100 or 50 Tablet: mg 20 spray: Nasal injection Subcutaneous

Tablet: 2.5 mg 2.5 Tablet: Tablet: 1 and 2.5 mg 2.5 and 1 Tablet: Tablet: 20 and 40 mg 40 and 20 Tablet: Available Formulations Tablet: 6.25 and 12.5 mg 12.5 and 6.25 Tablet: and Recommended Doses device: 4 and 6 mg 6 and 4 device: mg 6 administration: taneous for subcutaneous for of mg 500 with sumatriptan of sodium naproxen Tablet: 5 and 10 mg 10 and 5 Tablet: mg 10 and 5 wafer: dissolving Orally Tablet: 2.5 and 5 mg 5 and 2.5 Tablet: mg 5 and 2.5 wafer: dissolving Orally mg 5 spray: Nasal Tablet: 25, 50, and 100 mg 100 and 50, 25, Tablet: mg 20 and 5 spray: Nasal solution of ml mg/0.5 6 vial: Single-dose subcu ­ for device single-use Needlefree, mg 85 tablet: combination Fixed-dose Cartridges used in reusable autoinjector reusable in used Cartridges Characteristics of Triptans Commercially Available in the United States.* United the in Available Commercially Triptans of Characteristics (Axert) (Relpax) (Amarge) (Maxalt) (Zomig) (Imitrex) (Frova) Table 2. Drug Eletriptan Naratriptan Zolmitriptan Sumatriptan Frovatriptan * Information on dosing is from package inserts.

66 n engl j med 363;1 nejm.org july 1, 2010 clinical therapeutics injector device into which medication cartridges or moderate increases in the risk of a particular are inserted. A needlefree, disposable device is birth defect.32-34 The risks of exposure are prob- also available; it uses a blast of air to create a ably very low, but because evidence is incom- small hole in the skin through which medication plete, triptans should not be used routinely dur- passes into the subcutaneous tissues.28 ing pregnancy. For some women whose severe Rectal formulations (available in Europe and headaches do not respond to other treatments, Asia) and intranasal or orally dissolving tablet the benefits of use may outweigh potential formulations of triptans offer clinically mean- harms. ingful advantages in some situations. Orally dis- When prescribing triptans, clinicians should solving wafers, intranasal triptans, and rectal be aware of several drug interactions (Table 2). formulations can be taken without water and Triptans should not be used within 24 hours may be useful for patients who have difficulty after receipt of ergotamine or ergot-type medica- swallowing tablets. However, the acceptability of tions. A 2006 FDA advisory alerted prescribers to rectal formulations to patients is low, and trip- the possible development of the serotonin syn- tan nasal sprays and orally dissolving tablets drome when triptans are used in combination have a bitter taste. with selective serotonin-reuptake inhibitors or Triptan monotherapy does not provide relief selective -reuptake inhibitors.35 from headache in about one third of patients.21 Migraine is often present in patients with affec- If the initial dose is ineffective, the dose should tive disorders, so it is not uncommon for pa- be increased within the approved limits (Table 2). tients to require treatment for both conditions. If an appropriate dose of a triptan is ineffective After several months of use, patients begin- for two headache attacks, or has unacceptable ning to take a triptan should be seen for a follow- side effects, a switch to a different triptan or up visit to evaluate the frequency of headaches triptan formulation should be considered.29 In and the completeness, duration, and consistency particular, patients with headache that does not of the response to the drug. To avoid causing respond to an oral triptan should be encouraged medication-overuse headache, treatment of mi- to consider subcutaneous sumatriptan. If triptan graine should generally be limited to an average monotherapy remains ineffective, triptans should of about 2 days per week.26 Triptans should be be tried in combination with other drugs, espe- combined with preventive treatment in patients cially antiemetics or nonsteroidal antiinflam- with frequent headache. In most cases treatment matory drugs (NSAIDs).23,30 Return of headache results are best monitored with the use of a after initial treatment success (recurrence) occurs headache diary, which can also be used to track in about one third of triptan-treated attacks. possible migraine triggers.36 A template for a Triptans are contraindicated in patients with simple headache diary is available at the Web poorly controlled , severe hepatic or site of the American Headache Society at www renal impairment, or basilar or hemiplegic mi- .americanheadachesociety.org. graine (uncommon forms of migraine with aura). Most triptans are expensive as compared with Patients with known vasospastic or ischemic alternative migraine treatments. The average should not use triptans. wholesale price for a single brand-name triptan Triptans also should be avoided in patients who tablet is in the range of $23 to $31.37 However, are at high risk for coronary artery disease on a generic formulation of sumatriptan is now the basis of risk-factor stratification. If the use available, and the average wholesale price of of triptans is contemplated despite the presence generic sumatriptan is as low as $2.55 per tab- of substantial coronary risk factors, cardiac evalu- let.37 Several triptans are available without a ation is recommended before use.31 prescription in some countries, but not the Because the majority of patients using trip- United States. tans are women of childbearing age, their safety in pregnancy is an important consideration. The Adverse Effects available data are sufficient to rule out a large increase in the overall risk of birth defects from Certain minor adverse events — including par- exposure to sumatriptan during the first trimes- esthesias, flushing, and mild, transient neck ter, but they are not adequate to rule out small tightness or chest pressure — occur commonly

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enough with the use of triptans that they are conservative limit on use to about 2 days per week. known as triptan sensations.38 In one study, However, many patients seen in specialty practice these sensations were reported by almost half of continue to have numerous, disabling headaches, patients who received subcutaneous sumatriptan despite aggressive preventive treatment. More and in about a quarter of those who took oral frequent use of triptans may be appropriate in formulations. These side effects may be more these circumstances, since good evidence is common in women and in younger people. They lacking with regard to individual susceptibility can sometimes be mitigated by switching to a and medication thresholds for the development different triptan or another route of administra- of medication-overuse headache.42,43 Triptans do tion. Some other mild adverse events, particu- not seem to lead to progression of migraine in larly effects such as som- those with relatively infrequent headache.44 nolence or asthenia, can be features of the Triptans do not prolong aura in the roughly underlying migraine attack that become appar- 30% of patients with migraine who are subject ent after successful treatment of the headache.39 to it, but it is uncertain whether efficacy is re- Neck or chest tightness occurring in associa- duced or absent when the drug is given during tion with triptan use may alarm patients and the aura. Thus, the optimal timing of triptan use doctors. When evaluated, most patients with in relation to aura is in doubt.45,46 In the absence triptan-induced neck or chest pain do not have of firm evidence, patients with aura who take electrocardiographic or other evidence of de- triptans should experiment with the timing of creased myocardial perfusion. Thus, in most use to find the timing that works for them. cases triptan-associated chest pain is not caused There has been interest in using triptans pre- by coronary vasoconstriction. ventively. A number of studies have investigated However, serious cardiovascular events, some the use of daily, scheduled doses of triptans for resulting in death, have been reported in asso- the prevention of highly predictable attacks of ciation with triptan use. Among the patients who migraine, such as those occurring in association died almost all those in whom a causal link was with menstruation.47,48 These studies have attrib- likely had cardiac risk factors and were found to uted modest benefits to triptans as compared have coronary artery disease on postmortem with placebo, but the long-term ratio of harm to examination. The authors of one study estimated benefit is not well established. No triptan has that the rate of serious cardiovascular events was been approved by the FDA for preventive use. lower than 1 event per 4 million uses.40 In a cohort study of almost 64,000 patients with mi- Guidelines graine who were receiving triptans as used in general practice, there was no observed associa- The 2000 U.S. Headache Consortium Guidelines tion between triptan use and coronary events.41 consider triptans an appropriate initial choice for A consensus statement issued by an expert panel the treatment of acute migraine in patients with of the American Headache Society concluded moderate-to-severe headaches and in patients that chest symptoms related to triptan use were with milder headaches that have previously failed “generally nonserious and are not explained by to respond to nonspecific treatment. The guide- ischemia” and noted that “the incidence of seri- lines propose that NSAIDs or combination anal- ous cardiovascular events with triptans in both gesics with caffeine are reasonable choices for clinical trials and clinical practice appears to be the treatment of less severe headaches that have extremely low.”31 previously responded to such drugs.26 In contrast, guidelines from the American Areas of Uncertainty College of Physicians and American Academy of Family Practice published in 2002 (which have As with other drugs used for the treatment of since expired) endorsed NSAIDs as first-line acute migraine, triptans have been associated with therapy for most patients and recommended the the development of headache caused by medica- use of an antiemetic in patients with nausea and tion overuse, in which frequent use of medica- vomiting. Triptans were recognized as an alter- tion leads to a cycle of increased headache and native treatment for attacks that failed to respond medication use. Most experts thus recommend a to NSAIDs.49

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Guidelines from the European Federation of formulation. In young, healthy patients who are Neurological Societies published in 2009 recom- at low risk for according mend either triptans or NSAIDs for the treatment to risk-factor stratification, there is no need to of acute migraine and suggest that treatment be perform baseline cardiovascular testing before preceded by the use of metoclopramide or dom- prescribing triptans. peridone (not available in the United States). Because it is the least expensive option, I The use of intravenous acetylsalicylic acid or sub- would prescribe a dose of 50 mg or 100 mg of cutaneous sumatriptan is recommended for very generic oral sumatriptan and advise the patient severe attacks.50 to take it early in the course of a headache, be- fore the pain becomes severe. I would ask her to Recommendations limit use of the medication to 2 days a week and to keep a diary of headache frequency, character- For the patient described in the vignette, it is rea- istics, and response to treatment. I would see sonable to recommend the use of an oral triptan. the patient in a follow-up visit several months She has not had a consistent benef it from NSAIDs later to assess treatment results. If sumatriptan or combination analgesics but obtained complete causes unpleasant side effects or is not helpful, relief of headache and associated nausea with I would consider trying a different triptan. subcutaneous sumatriptan. There is a good chance No potential conflict of interest relevant to this article was that her headaches will also respond to an oral reported. triptan. The chest symptoms she reported are en- Disclosure forms provided by the author are available with the full text of this article at NEJM.org. tirely consistent with nonserious triptan sensa- I thank Dr. Thomas Ward for his review of an earlier version tions and will be less likely to occur with an oral of the manuscript.

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collections o f a r t i c l e s o n t h e j o u r n a l ’s w e b s i t e The Journal’s Web site (NEJM.org) sorts published articles into more than 50 distinct clinical collections, which can be used as convenient entry points to clinical content. In each collection, articles are cited in reverse chronologic order, with the most recent first.

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