The New England Journal of Medicine
Review Article
Drug Therapy
Volume 346:257-270
January 24, 2002
Number 4
Migraine — Current Understanding and Treatment
Peter J. Goadsby, M.D., D.Sc., Richard B. Lipton, M.D., and Michel D.
Ferrari, M.D., Ph.D.
Migraine is a common, chronic, incapacitating neurovascular disorder,
characterized by attacks of severe headache, autonomic nervous system
dysfunction, and in some patients, an aura involving neurologic symptoms. 1
<http://content.nejm.org/cgi/content/short/346/4/#R1> , 2
<http://content.nejm.org/cgi/content/short/346/4/#R2> Recent advances in
basic and applied clinical neuroscience 3
<http://content.nejm.org/cgi/content/short/346/4/#R3> have led to the
development of a new class of selective serotonin (5-hydroxytryptamine
[5-HT]) receptor agonists that activate 5-HT1B and 5-HT1D (5-HT1B/1D)
receptors and are known as the triptans; these agents have changed the lives
of countless patients with migraine. Despite such progress, migraine remains
underdiagnosed and the available therapies underused. 4
<http://content.nejm.org/cgi/content/short/346/4/#R4> In this article, we
review the current understanding of the epidemiology, pathophysiology, and
treatment of migraine.
Clinical Manifestations
Migraine is characterized by episodes of head pain that is often throbbing
and frequently unilateral and may be severe. In migraine without aura
(previously known as common migraine), attacks are usually associated with
nausea, vomiting, or sensitivity to light, sound, or movement. 5
<http://content.nejm.org/cgi/content/short/346/4/#R5> When untreated, these
attacks typically last 4 to 72 hours. 6
<http://content.nejm.org/cgi/content/short/346/4/#R6> A combination of
features is required for the diagnosis, but not all features are present in
every attack or in every patient ( Table 1
<http://content.nejm.org/cgi/content/short/346/4/#T1> ).
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Table 1. Modified Diagnostic Criteria for Migraine.
These symptoms distinguish migraine from tension-type headache, the most
common form of primary headache, which is characterized by the lack of
associated features. Any severe and recurrent headache is most likely to be
a form of migraine and to be responsive to antimigraine therapy. 8
<http://content.nejm.org/cgi/content/short/346/4/#R8> In 15 percent of
patients, migraine attacks are usually preceded or accompanied by transient
focal neurologic symptoms, which are usually visual; such patients have
migraine with aura (previously known as classic migraine). 9
<http://content.nejm.org/cgi/content/short/346/4/#R9> In a recent large,
population-based study, 64 percent of patients with migraine had only
migraine without aura, 18 percent had only migraine with aura, and 13
percent had both types of migraine (the remaining 5 percent had aura without
headache). Thus, up to 31 percent of patients with migraine have aura on
some occasions, 10 <http://content.nejm.org/cgi/content/short/346/4/#R10>
but clinicians who rely on the presence of aura for the diagnosis of
migraine will miss many cases.
We find it useful to assess the severity and effects of migraine by asking
about time lost because of migraine at work or school, in performing
household work or chores, or in family, social, and leisure activities. One
can ask patients directly about temporary disability, have them keep a
diary, or get a quick but accurate estimate with the use of the Migraine
Disability Assessment Scale (MIDAS) ( Table 2
<http://content.nejm.org/cgi/content/short/346/4/#T2> ), a well-validated
five-item questionnaire that is easy to use in practice. 11
<http://content.nejm.org/cgi/content/short/346/4/#R11>
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Table 2. Migraine Disability Assessment Scale (MIDAS) Questionnaire.
Although attacks of migraine may start at any age, the incidence peaks in
early to mid-adolescence. In the United States and Western Europe, the
one-year prevalence of migraine is 11 percent overall: 6 percent among men
and 15 to 18 percent among women. 12
<http://content.nejm.org/cgi/content/short/346/4/#R12> , 13
<http://content.nejm.org/cgi/content/short/346/4/#R13> , 14
<http://content.nejm.org/cgi/content/short/346/4/#R14> The median frequency
of attacks is 1.5 per month, and the median duration of an attack is 24
hours; at least 10 percent of patients have weekly attacks, and 20 percent
have attacks lasting two to three days. 12
<http://content.nejm.org/cgi/content/short/346/4/#R12> Thus, 5 percent of
the general population have at least 18 days of migraine per year, and at
least 1 percent — that is, more than 2.5 million persons in North America —
have at least 1 day of migraine per week. The lifetime prevalence of
migraine is at least 18 percent, 13
<http://content.nejm.org/cgi/content/short/346/4/#R13> although among older
subjects the figures are deflated by recall bias. In the United States, most
patients with migraine have not seen a physician for headache during the
previous year, have never received a medical diagnosis of migraine, and use
over-the-counter medications to the exclusion of prescription drugs. 15
<http://content.nejm.org/cgi/content/short/346/4/#R15> A recent survey by
the World Health Organization (WHO) rates severe migraine, along with
quadriplegia, psychosis, and dementia, as one of the most disabling chronic
disorders. 16 <http://content.nejm.org/cgi/content/short/346/4/#R16> This
ranking suggests that in the judgment of the WHO, a day with severe migraine
is as disabling as a day with quadriplegia.
Pathophysiology
Migraine is best understood as a primary disorder of the brain. 17
<http://content.nejm.org/cgi/content/short/346/4/#R17> It is a form of
neurovascular headache: a disorder in which neural events result in the
dilation of blood vessels, which, in turn, results in pain and further nerve
activation. 18 <http://content.nejm.org/cgi/content/short/346/4/#R18>
Migraine is not caused by a primary vascular event. Migraine attacks are
episodic and vary within and among patients. We may best explain this
variability by considering the basic biologic problem in migraine to be the
dysfunction of an ion channel in the aminergic brain-stem nuclei that
normally modulates sensory input and exerts neural influences on cranial
vessels. 17 <http://content.nejm.org/cgi/content/short/346/4/#R17>
In patients with familial hemiplegic migraine, missense mutations in the
{alpha}1 subunit of the voltage-gated P/Q-type calcium channel have been
identified. 19 <http://content.nejm.org/cgi/content/short/346/4/#R19> It is
possible that other ion-channel mutations contribute to migraine without
aura, since it is primarily cases of migraine with aura that have been
linked to the familial-hemiplegic-migraine locus. 20
<http://content.nejm.org/cgi/content/short/346/4/#R20> It thus seems
possible that the aura of migraine is separate from the headache, 21
<http://content.nejm.org/cgi/content/short/346/4/#R21> with aura
susceptibility genes as its determinant 22
<http://content.nejm.org/cgi/content/short/346/4/#R22> ; the pain and
associated features of migraine itself may be determined by another gene or
genes.
Migraine and the Brain
As noted above, migraine probably results from a dysfunction of brain-stem
or diencephalic nuclei that are involved in the sensory — particularly
nociceptive — modulation of craniovascular afferents. Activation in the
brain stem during attacks of migraine has been detected with the use of
positron-emission tomography. 23
<http://content.nejm.org/cgi/content/short/346/4/#R23> , 24
<http://content.nejm.org/cgi/content/short/346/4/#R24> Moreover, the aura
of migraine is likely to be the human counterpart of the animal phenomenon
of Leão's spreading depression. 25
<http://content.nejm.org/cgi/content/short/346/4/#R25> Aura is
characterized by a wave of oligemia that passes across the cortex 26
<http://content.nejm.org/cgi/content/short/346/4/#R26> , 27
<http://content.nejm.org/cgi/content/short/346/4/#R27> , 28
<http://content.nejm.org/cgi/content/short/346/4/#R28> , 29
<http://content.nejm.org/cgi/content/short/346/4/#R29> at the
characteristically slow rate of 2 to 6 mm per minute. 30
<http://content.nejm.org/cgi/content/short/346/4/#R30> A short phase of
hyperemia precedes this oligemia 31
<http://content.nejm.org/cgi/content/short/346/4/#R31> and is likely to be
a correlate of such symptoms as flashing, jagged lights. Oligemia is a
response to depressed neuronal function and is still clearly present when
the headache starts. 29
<http://content.nejm.org/cgi/content/short/346/4/#R29> , 32
<http://content.nejm.org/cgi/content/short/346/4/#R32> These findings,
together with direct evidence that the local oxygen supply is more than
adequate, 33 <http://content.nejm.org/cgi/content/short/346/4/#R33> make
the notion that migraine is simply a vascular headache untenable ( Figure 1
<http://content.nejm.org/cgi/content/short/346/4/#F1> ).
<http://content.nejm.org/cgi/content/full/346/4/257/F1>
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Figure 1. Pathophysiology of Migraine.
Migraine involves dysfunction of brain-stem pathways that normally modulate
sensory input. The key pathways for the pain are the trigeminovascular input
from the meningeal vessels, which passes through the trigeminal ganglion and
synapses on second-order neurons in the trigeminocervical complex. These
neurons, in turn, project through the quintothalamic tract, and after
decussating in the brain stem, form synapses with neurons in the thalamus.
There is a reflex connection between neurons in the pons in the superior
salivatory nucleus, which results in a cranial parasympathetic outflow that
is mediated through the pterygopalatine, otic, and carotid ganglia. This
trigeminal–autonomic reflex is present in normal persons 34
<http://content.nejm.org/cgi/content/short/346/4/#R34> and is expressed
most strongly in patients with trigeminal–autonomic cephalgias, such as
cluster headache and paroxysmal hemicrania; it may be active in migraine.
Brain imaging studies suggest that important modulation of the
trigeminovascular nociceptive input comes from the dorsal raphe nucleus,
locus ceruleus, and nucleus raphe magnus.
Pain Mechanisms
We do not completely understand the pathogenesis of pain in migraine, but
three key factors merit consideration: the cranial blood vessels, the
trigeminal innervation of the vessels, and the reflex connections of the
trigeminal system with the cranial parasympathetic outflow. The substance of
the brain is largely insensate; pain can be generated by large cranial
vessels, 35 <http://content.nejm.org/cgi/content/short/346/4/#R35> proximal
intracranial vessels, 36
<http://content.nejm.org/cgi/content/short/346/4/#R36> , 37
<http://content.nejm.org/cgi/content/short/346/4/#R37> or by the dura
mater. 38 <http://content.nejm.org/cgi/content/short/346/4/#R38> , 39
<http://content.nejm.org/cgi/content/short/346/4/#R39> , 40
<http://content.nejm.org/cgi/content/short/346/4/#R40> These vessels are
innervated by branches of the ophthalmic division of the trigeminal nerve,
40 <http://content.nejm.org/cgi/content/short/346/4/#R40> whereas the
structures of the posterior fossa are innervated by branches of the C2 nerve
roots. 41 <http://content.nejm.org/cgi/content/short/346/4/#R41>
In nonhuman primates, stimulation of vascular afferents leads to the
activation of neurons in the superficial layers of the trigeminal nucleus
caudalis in the region of the cervicomedullary junction and the superficial
layers of the dorsal horns of the C1 and C2 levels of the spinal cord 42
<http://content.nejm.org/cgi/content/short/346/4/#R42> , 43
<http://content.nejm.org/cgi/content/short/346/4/#R43> — the trigeminocervi
cal complex. Similarly, stimulation of branches of C2 activates neurons in
the same regions of the brain. 44
<http://content.nejm.org/cgi/content/short/346/4/#R44> , 45
<http://content.nejm.org/cgi/content/short/346/4/#R45> , 46
<http://content.nejm.org/cgi/content/short/346/4/#R46> The involvement of
the ophthalmic division of the trigeminal nerve and the overlap with
structures innervated by C2 explain the common distribution of migraine pain
over the frontal and temporal regions, as well as the involvement of
parietal, occipital, and high cervical regions by what is, in essence,
referred pain.
Peripheral trigeminal activation in migraine is evidenced by the release of
calcitonin-gene–related peptide, a vasodilator, 47
<http://content.nejm.org/cgi/content/short/346/4/#R47> but the mechanism of
the generation of pain is not clear. Studies in animals suggest that the
pain may be caused by a sterile neurogenic inflammatory process in the dura
mater, 48 <http://content.nejm.org/cgi/content/short/346/4/#R48> but this
mechanism has no clearly demonstrated correlate in humans. 49
<http://content.nejm.org/cgi/content/short/346/4/#R49> The pain may be a
combination of an altered perception — as a result of peripheral or central
sensitization — of craniovascular input that is not usually painful 34
<http://content.nejm.org/cgi/content/short/346/4/#R34> and the activation
of a feed-forward neurovascular dilator mechanism that is functionally
specific for the first (ophthalmic) division of the trigeminal nerve. 50
<http://content.nejm.org/cgi/content/short/346/4/#R50>
Drug Therapy
Approaches to treating migraine can be divided into nonpharmacologic
therapies and pharmacologic therapies. Nonpharmacologic therapies include
education of the patient about the disorder, its mechanisms, approaches to
treatment, and changes in lifestyle involved in the avoidance of triggers of
migraine. In patients with migraine, the brain does not seem to tolerate the
peaks and troughs of life well. Thus, regular sleep, regular meals,
exercise, avoidance of peaks of stress and troughs of relaxation, and
avoidance of dietary triggers can be helpful. The crucial message is that
the patient should aim for a certain regularity of habits, rather than
adhere to a long list of prohibitions of foods and activities. What cannot
be known is the sensitivity of the brain to such triggers at any given time.
This uncertainty leaves many patients frustrated by the fact that the same
manipulations intended to avoid triggering migraine will lead to different
outcomes on different days. It can be helpful to explain the nature of this
variability to patients. An evidence-based review of nonpharmacologic
approaches to treatment of migraine was recently published. 51
<http://content.nejm.org/cgi/content/short/346/4/#R51>
Drugs for the treatment of migraine can be divided into drugs that are taken
daily whether or not headache is present to reduce the frequency and
severity of attacks 52
<http://content.nejm.org/cgi/content/short/346/4/#R52> and drugs that are
taken to treat attacks as they arise. Treatments for attacks can be further
divided into nonspecific and migraine-specific treatments. Nonspecific
treatments, such as aspirin, acetaminophen, nonsteroidal antiinflammatory
drugs, opiates, and combination analgesics, are used to treat a wide range
of pain disorders. Specific treatments, 7
<http://content.nejm.org/cgi/content/short/346/4/#R7> including ergotamine,
dihydroergotamine, and the triptans, are effective for treating
neurovascular headaches, such as migraine and cluster headache, but not for
treating other types of pain, such as pure tension-type headache 53
<http://content.nejm.org/cgi/content/short/346/4/#R53> or atypical facial
pain. 54 <http://content.nejm.org/cgi/content/short/346/4/#R54> Given that
there are responses to placebo in patients with migraine, 55
<http://content.nejm.org/cgi/content/short/346/4/#R55> that there is a
significant rate of nonresponse to oral drugs, and that triptans have not
been studied systematically in patients with such problems as subarachnoid
hemorrhage or meningitis, triptans should not be used as diagnostic testing
agents in patients with headache.
Preventive Therapy
The decision to start a preventive therapy in a patient with migraine is
best made collaboratively. On the basis of a combination of the frequency,
duration, severity, and tractability of acute attacks, as well as the
preference of the patient, a sensible selection can be made. Patients who
have attacks that are unresponsive to acute-attack medications and that
cause substantial disability are candidates for preventive therapy. If
attacks occur at least twice a month, if the patient may be at risk for
rebound headache, or if the migraine diary kept by the patient reveals a
clear trend toward an increasing frequency of attacks, it is probably better
to consider prevention than to wait for the problem to become more
troublesome. It is not clear how preventive therapy works, although it seems
likely that it modifies the sensitivity of the brain that underlies
migraine.
In general, if headaches occur one to two days per month, there is usually
no need for preventive therapy; if they occur three to four days per month,
preventive therapy should be considered; if the patient has five or more
attacks per month, preventive therapy should be considered seriously. The
available options are listed in Table 3
<http://content.nejm.org/cgi/content/short/346/4/#T3> , and the evidence
regarding their use has been extensively reviewed. 50
<http://content.nejm.org/cgi/content/short/346/4/#R50> Often, the doses
required to reduce the frequency of headache cause marked and intolerable
side effects. Each drug should be started at a low dose, and the dose should
be gradually increased to a reasonable maximum; patients should be reminded
that this approach often entails some delay in achieving efficacy.
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Table 3. Preventive Therapy for Migraine.
On average, about two thirds of the patients given any of the drugs listed
in Table 3 <http://content.nejm.org/cgi/content/short/346/4/#T3> will have
a 50 percent reduction in the frequency of headaches. It is our practice to
explain the side effects of these drugs and engage the patient in the
decision-making process. We avoid methysergide, at least initially, because
of its fibrotic complications, 58
<http://content.nejm.org/cgi/content/short/346/4/#R58> , 59
<http://content.nejm.org/cgi/content/short/346/4/#R59> and we carefully
explain the teratogenicity of divalproex (valproate). 60
<http://content.nejm.org/cgi/content/short/346/4/#R60>
Treatment of Acute Attacks
Analgesic and Nonsteroidal Antiinflammatory Drugs
In many patients, migraine responds well to simple treatment at the time of
an attack. There are several key features of the successful use of such
treatments, after the preference of the patient and any contraindications
have been taken into consideration. The drug should be taken as soon as the
headache component of the attack is recognized. 61
<http://content.nejm.org/cgi/content/short/346/4/#R61> The dose of drug
should be adequate; for example, 900 mg of aspirin, 62
<http://content.nejm.org/cgi/content/short/346/4/#R62> , 63
<http://content.nejm.org/cgi/content/short/346/4/#R63> 1000 mg of
acetaminophen, 64 <http://content.nejm.org/cgi/content/short/346/4/#R64>
500 to 1000 mg of naproxen, 65
<http://content.nejm.org/cgi/content/short/346/4/#R65> 400 to 800 mg of
ibuprofen, 66 <http://content.nejm.org/cgi/content/short/346/4/#R66> or
appropriate doses of a combination of these drugs. 67
<http://content.nejm.org/cgi/content/short/346/4/#R67> , 68
<http://content.nejm.org/cgi/content/short/346/4/#R68> The administration
of antiemetic drugs or drugs that increase gastric motility is likely to
facilitate the absorption of the primary drug and thus help to ameliorate
the attack. 63 <http://content.nejm.org/cgi/content/short/346/4/#R63> , 69
<http://content.nejm.org/cgi/content/short/346/4/#R69> , 70
<http://content.nejm.org/cgi/content/short/346/4/#R70> Overuse of these
drugs should be avoided; for example, intake should be restricted to no more
than two to three days a week, and a headache diary should be kept and
monitored for any escalation in drug use. It is important to remember that
the severity of migraine attacks and their response to treatment may vary;
patients may therefore require only one drug for some attacks but several
drugs for more bothersome attacks.
As a rule, we avoid the use of opiates. These drugs seem to mask the pain
without suppressing the pathophysiologic mechanism of the attack, often
leaving the patient cognitively impaired. Their use may lead to addiction,
and for most patients, they offer no advantages over more migraine-specific
therapy.
Ergot Derivatives
The main advantages of the ergotamine and dihydroergotamine ergot
derivatives are their low cost and the long experience with their use. 71
<http://content.nejm.org/cgi/content/short/346/4/#R71> , 72
<http://content.nejm.org/cgi/content/short/346/4/#R72> The major
disadvantages are their complex pharmacology, their erratic
pharmacokinetics, the lack of evidence regarding effective doses, their
potent and sustained generalized vasoconstrictor effects, which are
associated with adverse vascular events, and the high risk of overuse
syndromes and rebound headaches. 72
<http://content.nejm.org/cgi/content/short/346/4/#R72>
The Triptans
In comparison with the ergot derivatives, the triptans ( Table 4
<http://content.nejm.org/cgi/content/short/346/4/#T4> ) have distinct
advantages — notably, selective pharmacology, simple and consistent
pharmacokinetics, evidence-based prescription instructions, established
efficacy based on well-designed controlled trials, moderate side effects,
and a well-established safety record. 5
<http://content.nejm.org/cgi/content/short/346/4/#R5> , 87
<http://content.nejm.org/cgi/content/short/346/4/#R87> The most important
disadvantages of the triptans are their higher cost and the restrictions on
their use in the presence of cardiovascular disease.
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Table 4. Pharmacokinetic Characteristics of Triptans.
Pharmacology and Mechanisms of Action
The triptans are serotonin 5-HT1B/1D–receptor agonists. They were discovered
88 <http://content.nejm.org/cgi/content/short/346/4/#R88> as a result of
studies of serotonin and migraine 89
<http://content.nejm.org/cgi/content/short/346/4/#R89> , 90
<http://content.nejm.org/cgi/content/short/346/4/#R90> , 91
<http://content.nejm.org/cgi/content/short/346/4/#R91> , 92
<http://content.nejm.org/cgi/content/short/346/4/#R92> , 93
<http://content.nejm.org/cgi/content/short/346/4/#R93> that led to the
identification of an atypical 5-HT receptor. Activation of the novel
receptor can close cranial arteriovenous anastomoses, 94
<http://content.nejm.org/cgi/content/short/346/4/#R94> and its anatomical
distribution is restricted in vivo. 95
<http://content.nejm.org/cgi/content/short/346/4/#R95> Seven major
subclasses of 5-HT receptors — classes 1 through 7 — are now recognized. 96
<http://content.nejm.org/cgi/content/short/346/4/#R96> , 97
<http://content.nejm.org/cgi/content/short/346/4/#R97> The triptans all
activate the 5-HT1B/1D receptor and, to a lesser extent, the 5-HT1A or
5-HT1F receptor. It is likely that the 5-HT1B/1D–agonist activity is the
primary mechanism of the therapeutic effects of these drugs, although a
therapeutic action at the 5-HT1F receptor has not been excluded. 98
<http://content.nejm.org/cgi/content/short/346/4/#R98> Exclusively
5-HT1D–mediated effects were studied with the use of PNU142633, 99
<http://content.nejm.org/cgi/content/short/346/4/#R99> but the results were
inconclusive. 100 <http://content.nejm.org/cgi/content/short/346/4/#R100>
This compound, which has exclusively neural action, produced some chest
symptoms remarkably similar to those that occur with triptans. 101
<http://content.nejm.org/cgi/content/short/346/4/#R101> We define a triptan
as a 5-HT1B/1D–receptor agonist. 102
<http://content.nejm.org/cgi/content/short/346/4/#R102>
Triptans have three potential mechanisms of action: cranial
vasoconstriction, 88 <http://content.nejm.org/cgi/content/short/346/4/#R88>
peripheral neuronal inhibition, 48
<http://content.nejm.org/cgi/content/short/346/4/#R48> and inhibition of
transmission through second-order neurons of the trigeminocervical complex.
102 <http://content.nejm.org/cgi/content/short/346/4/#R102> Which mechanism
is the most important is as yet unclear. 103
<http://content.nejm.org/cgi/content/short/346/4/#R103> These actions
inhibit the effects of activated nociceptive trigeminal afferents and, in
this way, control acute attacks of migraine ( Figure 2
<http://content.nejm.org/cgi/content/short/346/4/#F2> ).
<http://content.nejm.org/cgi/content/full/346/4/257/F2>
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Figure 2. Possible Sites of Action of Triptans in the Trigeminovascular
System.
There are five triptans in routine clinical use: sumatriptan, naratriptan,
rizatriptan, zolmitriptan, and almotriptan. Eletriptan was recently approved
in Europe; frovatriptan is awaiting approval; and donitriptan is in
preclinical development. 104
<http://content.nejm.org/cgi/content/short/346/4/#R104> During migraine
attacks, the oral absorption of many drugs is delayed, 69
<http://content.nejm.org/cgi/content/short/346/4/#R69> so there may be an
advantage to nonoral methods of administration, such as the use of nasal
sprays, inhalers, suppositories, or injections. Most patients, however,
prefer oral formulations, 105
<http://content.nejm.org/cgi/content/short/346/4/#R105> which account for
80 percent of all triptan prescriptions; we therefore focus on the oral
formulations. Sumatriptan is also available in subcutaneous, 106
<http://content.nejm.org/cgi/content/short/346/4/#R106> rectal, 107
<http://content.nejm.org/cgi/content/short/346/4/#R107> and intrana-sal 108
<http://content.nejm.org/cgi/content/short/346/4/#R108> formulations; these
will be discussed separately. The pharmacokinetic properties of the triptans
are summarized in Table 4
<http://content.nejm.org/cgi/content/short/346/4/#T4> .
Safety and Tolerability
It is crucial to distinguish between safety and tolerability in discussing
studies of treatments for acute migraine. Tolerability refers to the extent
of medically unimportant but clinically irritating side effects of drugs,
such as tingling, flushing, and sensations of pressure; safety is assessed
on the basis of records of medically important side effects. Because the
latter type of effects may be rare, safety is best assessed after
large-scale clinical exposure. The triptans differ from one another in terms
of tolerability but not in terms of safety. The most frequent side effects
are tingling, paresthesias, and sensations of warmth in the head, neck,
chest, and limbs; less frequent are dizziness, flushing, and neck pain or
stiffness. Triptans can constrict coronary arteries and may cause chest
symptoms, sometimes closely mimicking angina pectoris. Such symptoms may
cause alarm, so the cardiovascular issues warrant discussion. When patients
are warned about these symptoms, they rarely cause problems.
In rare instances, however, triptan therapy has been associated with
myocardial infarction. 87
<http://content.nejm.org/cgi/content/short/346/4/#R87> There has thus been
general concern about the safety of triptans. This concern is supported by
in vitro pharmacologic studies that demonstrate the potential of the
triptans to constrict the coronary vessels of humans, although ergotamine
and dihydroergotamine have a more potent and longer-lasting effect than the
triptans. 109 <http://content.nejm.org/cgi/content/short/346/4/#R109> It is
clear from anatomical studies using antibodies selective for human 5-HT1B or
5-HT1D receptors 110 <http://content.nejm.org/cgi/content/short/346/4/#R110>
that 5-HT1B receptors are located primarily in the cranial circulation but
are also found in the coronary circulation. 111
<http://content.nejm.org/cgi/content/short/346/4/#R111> There have been
relatively few reports of clinically important myocardial ischemia or
infarction, despite the now very substantial human exposure to triptans,
particularly to sumatriptan. 87
<http://content.nejm.org/cgi/content/short/346/4/#R87> However, all
triptans are 5-HT1B agonists, and thus the sensible contraindications of
ischemic heart disease, uncontrolled hypertension, and cerebrovascular
disease apply to the entire class.
Meta-Analysis of Studies of Oral Triptan Therapy
Most trials of triptans have been similar in design 112
<http://content.nejm.org/cgi/content/short/346/4/#R112> and in the
population of patients studied — factors that facilitate meta-analysis. We
recently performed such a meta-analysis, using data from 24,089 patients in
53 controlled clinical trials of triptans. 113
<http://content.nejm.org/cgi/content/short/346/4/#R113> , 114
<http://content.nejm.org/cgi/content/short/346/4/#R114> We subtracted the
rate of response in the placebo group from that in the active-drug group and
used this difference, the therapeutic gain, as another means of comparing
the results of the trials. 115
<http://content.nejm.org/cgi/content/short/346/4/#R115> All doses of all
drugs have been compared with the standard of sumatriptan at a dose of 100
mg.
Improvement at Two Hours
The headache (pain) response at two hours was the primary end point in
nearly all trials of triptans. As compared with 100 mg of sumatriptan, 10 mg
of rizatriptan and 80 mg of eletriptan were significantly more effective,
whereas 2.5 mg of naratriptan, 20 mg of eletriptan, and 2.5 mg of
frovatriptan were less effective (data were obtained from abstracts only)
( Figure 3A <http://content.nejm.org/cgi/content/short/346/4/#F3> ).
<http://content.nejm.org/cgi/content/full/346/4/257/F3>
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Figure 3. Effects of the Various Triptans in Patients with Migraine.
The mean rates and 95 percent confidence intervals of improvement in
headache pain at two hours (Panel A) and freedom from headache pain at two
hours (Panel B) are shown for each triptan at each dose tested. The box
represents the 95 percent confidence interval for 100 mg of sumatriptan —
the reference treatment. Adapted from Ferrari et al. 113
<http://content.nejm.org/cgi/content/short/346/4/#R113>
Although the freedom from pain is the currently recommended primary end
point, 116 <http://content.nejm.org/cgi/content/short/346/4/#R116> it was a
secondary end point in most trials. In terms of this end point, 80 mg of
eletriptan, 12.5 mg of almotriptan, and 10 mg of rizatriptan were more
effective than 100 mg of sumatriptan, whereas 25 mg of sumatriptan, 2.5 mg
of naratriptan, and 20 mg of eletriptan were less effective than 100 mg of
sumatriptan ( Figure 3B
<http://content.nejm.org/cgi/content/short/346/4/#F3> ).
Sustained Freedom from Pain
The percentages of patients with sustained freedom from pain (freedom from
pain at 2 hours with no rescue medication and with no recurrence of headache
within 24 hours) are shown in Figure 4
<http://content.nejm.org/cgi/content/short/346/4/#F4> . These rates were
higher with 10 mg of rizatriptan, 80 mg of eletriptan, and 12.5 mg of
almotriptan than with 100 mg of sumatriptan, and lower with 20 mg of
eletriptan than with 100 mg of sumatriptan.
<http://content.nejm.org/cgi/content/full/346/4/257/F4>
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Figure 4. Effects of the Various Triptans in Inducing Sustained Freedom from
Headache Pain.
The mean rates and 95 percent confidence intervals of sustained freedom from
headache pain (defined as freedom from pain at 2 hours, no use of rescue
medication, and no recurrence of headache within 24 hours) are presented.
The box represents the 95 percent confidence interval for 100 mg of
sumatriptan.
Intrapatient Consistency of Response
Efficacy in at least two out of three treated attacks can be considered a
reasonable estimate of consistency. Such consistency was found in 67 percent
of patients given 100 mg of sumatriptan and 65 percent of those given 50 mg
of sumatriptan. The consistency of 10 mg of rizatriptan was evaluated in a
novel double-blind, crossover study encompassing four attacks in each
patient, with placebo given during one randomly chosen attack in four of
five groups of patients; the fifth group received 10 mg of rizatriptan for
each of four attacks. 117
<http://content.nejm.org/cgi/content/short/346/4/#R117> The unusual design,
with the inclusion of placebo, makes it difficult to compare this study with
others, but it seems unlikely that the inclusion of placebo would increase
consistency. The rates of consistency in the three attacks for which
patients received rizatriptan were the highest for any of the triptans; the
rates of response and freedom from pain were 86 percent and 48 percent,
respectively, in at least two out of three attacks and 60 percent and 20
percent, respectively, in three of three attacks.
Tolerability
Differences among studies in the methods of collecting data on adverse
events and in the definitions of such events complicate comparisons. The
rates of adverse events with most triptans other than sumatriptan overlap
with those found with 100 mg of sumatriptan; there were lower values for 2.5
mg of naratriptan and 12.5 mg of almotriptan. The rates in the latter
instances did not differ from those found with placebo.
Direct Comparisons
In general, trials involving direct comparisons provide the optimal
comparison between drugs, although encapsulation of treatments, selection
bias, and population size may influence results. Some direct comparisons
between triptans have been conducted, and the overall results of those to
which we had access were consistent with the results of the studies of
single triptans. 113 <http://content.nejm.org/cgi/content/short/346/4/#R113>
Comparisons between the main pharmacologic and clinical characteristics of
the new oral triptans and those of 100 mg of oral sumatriptan are summarized
in Table 5 <http://content.nejm.org/cgi/content/short/346/4/#T5> ;
information on these characteristics is derived from a synthesis of both
types of studies. 113
<http://content.nejm.org/cgi/content/short/346/4/#R113>
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Table 5. Pharmacologic and Clinical Characteristics of Oral Triptans, in
Comparison with 100 mg of Sumatriptan.
Parenteral Sumatriptan
Subcutaneous sumatriptan, at a dose of 6 mg, has the best pharmacokinetic
profile (time to maximal concentration, 10 minutes; bioavailability, 96
percent), 118 <http://content.nejm.org/cgi/content/short/346/4/#R118>
clinical efficacy (a response rate of 76 percent and a rate of freedom from
pain of 48 percent at 60 minutes after administration), 106
<http://content.nejm.org/cgi/content/short/346/4/#R106> and intrapatient
consistency in multiple attacks (up to 90 percent). 119
<http://content.nejm.org/cgi/content/short/346/4/#R119> The main
limitations are that patients must inject themselves and that the incidence
of adverse events is higher and their intensity is greater than with oral
sumatriptan. This adverse-event profile may be related to the fixed 6-mg
dose, among other factors, since 3 to 4 mg may suffice in many patients. 120
<http://content.nejm.org/cgi/content/short/346/4/#R120> Subcutaneous
sumatriptan is also highly effective in the treatment of acute attacks of
cluster headache. 121
<http://content.nejm.org/cgi/content/short/346/4/#R121> The efficacy and
tolerability profiles of rectal and intranasal sumatriptan are very similar
to those of the oral formulation. 107
<http://content.nejm.org/cgi/content/short/346/4/#R107> , 108
<http://content.nejm.org/cgi/content/short/346/4/#R108> These formulations
may be useful in patients with nausea. Intranasal sumatriptan in a dose of
20 mg is the only triptan with demonstrated efficacy in adolescents, 122
<http://content.nejm.org/cgi/content/short/346/4/#R122> , 123
<http://content.nejm.org/cgi/content/short/346/4/#R123> in whom migraine
attacks are usually of relatively short duration and are associated with
more prominent gastrointestinal symptoms and a high rate of response to
placebo. 124 <http://content.nejm.org/cgi/content/short/346/4/#R124> , 125
<http://content.nejm.org/cgi/content/short/346/4/#R125>
Selecting Initial Treatment for Acute Attacks
Migraine is a heterogeneous disorder, so the selection of initial treatment
for acute attacks depends on the severity and frequency of the attacks, the
associated symptoms, the preference of the patient, and the history of
treatment. In patients with little headache-related disability, it is
usually appropriate to initiate treatment with one or more analgesic drugs
and to escalate treatment as needed. In a recent clinical trial, the
probability of successful treatment with aspirin and metoclopramide
decreased as the severity of headache-related disability increased. Among
the most disabled 25 percent of patients (MIDAS grade IV 126
<http://content.nejm.org/cgi/content/short/346/4/#R126> ), the attacks were
controlled successfully with a combination of aspirin and metoclopramide in
only 26 percent of the patients. 127
<http://content.nejm.org/cgi/content/short/346/4/#R127> It is critical to
establish realistic expectations and to advise patients to seek follow-up
care if treatment fails. In patients with substantial disability, it is
appropriate to prescribe a triptan early in the course of treatment, in
keeping with a stratified approach to care. 127
<http://content.nejm.org/cgi/content/short/346/4/#R127>
The Future of Migraine Treatment
Although the triptans represent an important advance, they are ineffective
in some patients. A crucial improvement would be a treatment for acute
attacks that had no vascular effects — in other words, an antimigraine
treatment with exclusively neural action.
If the hypothesis that neurogenic inflammation caused the pain was correct,
selective neuronally active compounds with peripheral action should be
effective. 128 <http://content.nejm.org/cgi/content/short/346/4/#R128>
Unfortunately, antagonists of neurokinin-1 receptors (which mediate the
biologic actions of substance P), 129
<http://content.nejm.org/cgi/content/short/346/4/#R129> , 130
<http://content.nejm.org/cgi/content/short/346/4/#R130> , 131
<http://content.nejm.org/cgi/content/short/346/4/#R131> , 132
<http://content.nejm.org/cgi/content/short/346/4/#R132> , 133
<http://content.nejm.org/cgi/content/short/346/4/#R133> an endothelin
antagonist, 134 <http://content.nejm.org/cgi/content/short/346/4/#R134> a
neurosteroid, 135 <http://content.nejm.org/cgi/content/short/346/4/#R135>
and two specific inhibitors of the extravasation of plasma protein
(CP122,288 136 <http://content.nejm.org/cgi/content/short/346/4/#R136> and
4991W93 137 <http://content.nejm.org/cgi/content/short/346/4/#R137> ) have
proved ineffective in clinical trials. The selective 5-HT1F–receptor agonist
LY334370 98 <http://content.nejm.org/cgi/content/short/346/4/#R98> was
effective, but it may act on both peripheral and central trigeminal targets.
102 <http://content.nejm.org/cgi/content/short/346/4/#R102> However, purely
neural compounds do work. The {alpha}-amino-3-hydroxy-5-methyl-4-isoxazole
propionic acid–kainate antagonist LY293558 138
<http://content.nejm.org/cgi/content/short/346/4/#R138> and GR79236, a
selective adenosine-A1–receptor agonist, 139
<http://content.nejm.org/cgi/content/short/346/4/#R139> , 140
<http://content.nejm.org/cgi/content/short/346/4/#R140> have proved
effective in acute attacks of migraine. Another nonvascular approach would
be to block the effects of calcitonin-gene–related peptide, 47
<http://content.nejm.org/cgi/content/short/346/4/#R47> and suitable
compounds that do so are now available. 141
<http://content.nejm.org/cgi/content/short/346/4/#R141> Another approach is
blockade of nitric oxide synthesis, which has proved effective in one
preliminary study. 142
<http://content.nejm.org/cgi/content/short/346/4/#R142>
There are novel clinical-trial designs and end points that are expected to
reflect clinical practice more accurately. These end points include efficacy
over the course of multiple attacks (intrapatient consistency), sustained
freedom from pain over a 24-hour period, and the preference of the patient.
Furthermore, so-called ASAP (as soon as possible) trials, in which patients
are allowed to treat their attacks as soon as they are sure migraine is
developing, will better reflect the nature of migraine treatment in real
life. 143 <http://content.nejm.org/cgi/content/short/346/4/#R143>
Finally, patients prefer not to have attacks at all. Current prophylactic
therapies for migraine are relatively nonspecific, their efficacy is
moderate, and they have substantial side effects. 52
<http://content.nejm.org/cgi/content/short/346/4/#R52> Studying the
mechanisms involved in the onset of migraine 23
<http://content.nejm.org/cgi/content/short/346/4/#R23> , 24
<http://content.nejm.org/cgi/content/short/346/4/#R24> and the
predisposition to attacks 144
<http://content.nejm.org/cgi/content/short/346/4/#R144> is likely to lead
to more specific, more efficacious, and better-tolerated prophylactic drugs.
We are very optimistic about the future for persons with migraine.
Dr. Goadsby is a Wellcome Senior Research Fellow.
Dr. Goadsby has received research grants from or served as a consultant to
Abbott, Allergan, Almirall Prodesfarma, AstraZeneca, Bristol-Myers Squibb,
Elan, Glaxo SmithKline, Merck, Ortho-McNeil, Pfizer, Pharmacia, Pierre
Fabre, and Vanguard.
Dr. Lipton has received research grants or served as a consultant to Abbott,
Allergan, American Home Products, AstraZeneca, Bristol-Myers Squibb, Elan,
Glaxo SmithKline, Johnson & Johnson, Merck, Pfizer, Pharmacia, and Vanguard.
Dr. Ferrari has received research grants from or served as a consultant to
Abbott, Allergan, Almirall Prodesfarma, AstraZeneca, Elan, Glaxo SmithKline,
Merck, Pfizer, Pharmacia, and Pierre Fabre.
Source Information
From the Institute of Neurology, National Hospital for Neurology and
Neurosurgery, London (P.J.G.); the Departments of Neurology, Epidemiology,
and Social Medicine, Albert Einstein College of Medicine and the Montefiore
Headache Unit, New York (R.B.L.); Innovative Medical Research, Towson, Md.
(R.B.L.); and the Department of Neurology, Leiden University Medical Center,
Leiden, the Netherlands (M.D.F.).
Address reprint requests to Professor Goadsby at the Institute of Neurology,
Queen Sq., London WC1N 3BG, United Kingdom, or at [log in to unmask]
<mailto:[log in to unmask]> .
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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.
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