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A14 2002febGallagherS58 73 2
Pathophysiology of Migraine
The characteristics of migraine vary in
igraine is a primary headache dis- frequency, duration, and the extent of dis-
acute attack) and prophylactic (preven- tan drugs are highly effective when admin-
tion of headache by using medication istered early in this phase of migraine.
and/or nonpharmacologic measures to When migraine evolves into an advanced
lessen precipitating factors, such as stress stage (late headache) and first- and second-
or lifestyle). line treatments have failed, rescue therapy
must be considered. Intravenously admin-
Nonpharmacologic Measures of istered phenothiazines are often effective
Preventing Migraine. The suggestions and can be combined with dihydroergota-
below are recommended by a primary mine (DHE) or other serotonin agonists.
care physician for the nonpharmacologic Opioid analgesics are also used to treat late
management of migraine.18 headache.
lac are also effective treatments for mild- migraine.32 Suppression of the firing rate of
to-moderate migraine.25 Diclofenac, a pre- those serotonergic neurons and the subse-
scription-strength NSAID, reduced the quent stabilization of serotonergic neuro-
intensity of migraine pain and ameliorated transmission is thought to be one of the
associated symptoms such as photophobia modes of action of ET compounds.32
and phonophobia in a placebo-controlled, ET was first introduced for the treat-
double-blind, randomized clinical trial.26 If ment of migraine in the 1920s. However,
a moderate dose of an NSAID adminis- its bioavailability is poor and unpre-
tered at the onset of migraine is not com- dictable after oral administration.25 The
pletely effective within 1 hour, a triptan potent vasoconstrictor effect of ET, which
should be given.21 Cyclo-oxygenase-2 can last for up to 3 days, is undesirable.
inhibitors may be useful adjuncts for the When compared with ET, DHE is a more
treatment of migraine.27 potent α-adrenergic antagonist and is
therefore a potent vasoconstrictor. DHE is
Opioids. Opioids such as intramuscu- a more potent antiemetic than ET, has
larly or intravenously administered meperi- less effect on the uterus, and is not associ-
dine or orally administered codeine are used ated with rebound headache.25
because of their analgesic potential but may Caffeine in combination with analgesics
exacerbate nausea and vomiting and increase or ET improves the absorption of the med-
the risk of drug addiction.25 A clinical trial ication and also potentiates pain relief, pos-
involving patients treated in an emergency sibly as a result of its vasoconstrictor
department for acute migraine indicated effect.25 The combination of ET and caf-
that a combination of meperidine and feine, although effective in only 50% of
hydroxyzine reduced headache pain by patients, is a treatment option for acute
approximately 55%, ameliorated nausea, migraine.25 The efficacy of ET is enhanced
and was not statistically significantly differ- by the addition of pentobarbital and the
ent in effect (P < .05) from treatment with a levorotatory alkaloids of belladonna.
combination of DHE and hydroxyzine.28 Although complete evidence regarding the
efficacy of DHE is unavailable, intravenous
Antiemetics. Antiemetic drugs may be administration can abort approximately
used to treat acute migraine. Orally or 90% of attacks.33 In one study, DHE nasal
intravenously administered metoclo- spray significantly reduced the severity of
pramide, a dopamine antagonist that headache.34 In another double-blind, pla-
affects the 5-HT3 receptor, may provide cebo-controlled study of migraine patients,
relief from pain and nausea or vomiting.29 those who used an intranasal formulation
Patients should be advised that antiemet- of DHE as opposed to placebo experienced
ics often cause adverse events such as statistically significant migraine resolution
diarrhea, drowsiness, or restlessness. (ie, mild or no pain) within 4 hours of tak-
ing the drug (70% versus 28%, P < .001).35
Ergot Compounds. Ergot compounds In that study, the most common adverse
such as ergotamine (ET) or DHE were the events associated with intranasal DHE
first drugs used to treat migraine.25 Ergot were local, such as rhinitis (21% of
compounds are pharmacologically nonse- patients), nausea (4%), and taste perver-
lective but have been used successfully in sion (9%). Patients with ischemic heart dis-
patients with moderate-to-severe migraine ease, a history of myocardial infarction, or
since the turn of the century. Their clinical clinical signs of coronary artery disease
efficacy is at least equal to that of NSAIDs.30 should not take DHE.
They have agonist affinity for several Ergot compounds should not be pre-
different 5-HT receptors (5-HT1 A, B, D; scribed for pregnant patients or those with
5-HT2 A, B, C), dopamine receptors (DA2), peripheral vascular disease, hypertension,
and alpha-adrenergic receptors.31 The coronary heart disease, or impaired renal
great number of DHE-binding sites in the or hepatic function.25 The adverse events
dorsal raphe nuclei may precipitate produced by ergots include nausea, acro-
events reported in other clinical trials pharmacologic profile and an oral bio-
included dizziness, drowsiness, and availability of about 40%.40 Its half-life (2.5
malaise or fatigue (4% to 7%); paresthesia to 3 hours) is only slightly longer than that
(2% to 4%); and pain and pressure sensa- of sumatriptan. Rizatriptan has a more
tion (2% to 4%). The side effect of chest rapid onset (tmax < 1 hour) than other trip-
tightness is not mentioned on the product tans currently on the market.40 In clinical
label, which indicates that a low inci- trials, rizatriptan produced pain relief 2
dence of chest pain or pressure and throat hours after administration at doses rang-
or neck symptoms are associated with ing from 2.5 to 40 mg; a dose of 10 mg
naratriptan. It is important to note that produced the most benefit (52% of
the decreased frequency of chest symp- patients experienced relief from headache
toms associated with that drug does not and few adverse events).40 Common adverse
diminish the importance of alerting events included dizziness (in 4% of the
patients with active or potential coronary patients), nausea (3%), somnolence (3%),
artery disease or cardiac ischemia to their chest symptoms (2%), and fatigue (1%). As
potential occurrence. with other triptans, the number of adverse
events caused by rizatriptan was dose
Zolmitriptan. Zolmitriptan, the next dependent.
second-generation triptan to enter the
market, has an oral bioavailability of Newer Triptans. Eletriptan has an oral
approximately 50%, which exceeds that of bioavailability of almost 50%; it is rapidly
sumatriptan (14%).42 In addition, the half- absorbed (tmax < 1 hour) but has a half-life
life of zolmitriptan (3 hours) provided a of 5 hours.42 In 2 recent multicenter stud-
more prolonged therapeutic plasma con- ies, the efficacy and tolerability of eletrip-
centration than did sumatriptan. In a tan in acute migraine were examined. In
recent study, zolmitriptan was effective in the first study, doses of oral eletriptan 5,
relieving acute migraine 2 hours after 20, or 30 mg were studied in the treatment
administration at an oral dose of 2.5 mg of acute migraine in 365 patients.48 Two
(in 67% of the patients) or 5 mg (in 65%).44 hours after administration of the drug,
Patients using zolmitriptan 2.5 mg or 5 mg relief from headache was reported by 41%,
had a statistically significant 2-hour 47%, and 49% of patients who had received
response rate compared with that of eletriptan 5, 20, or 30 mg, respectively.
patients using sumatriptan 25 mg (P < Thirty-five percent of the patients had
.001). When compared with sumatriptan received placebo. In the second trial, the
50 mg, zolmitriptan 2.5 mg also pro- effect of oral eletriptan 20, 40, or 80 mg
duced a statistically significant 2-hour was compared with that of sumatriptan
response (P = .017). The rate of headache 100 mg or placebo in 270 patients.48
recurrence consistently associated with Relief from headache 2 hours after drug
zolmitriptan is about 30%.45 Adverse administration was reported by 44%, 67%,
events of zolmitriptan, including those 80%, and 57% of the patients who had
affecting the CNS, are similar to those of received eletriptan 20, 40, or 80 mg or
oral sumatriptan, although zolmitriptan sumatriptan 100 mg, respectively. In that
can cross the blood-brain barrier.42 The study, 25% of the patients had received
most common adverse events caused by placebo. The adverse events produced by
zolmitriptan 2.5 mg were nausea (in 8% to eletriptan were similar to those of suma-
11% of the patients), dizziness (8% to 9%), triptan. In another study, adverse events
paresthesia (6%), somnolence (5% to 7%), from doses of eletriptan 20 or 40 mg were
chest tightness (5%), and vomiting less than those produced by sumatriptan
(2%).46,47 In clinical practice, zolmitriptan 100 mg.49
2.5 mg is equivalent to sumatriptan 50 mg. Frovatriptan, another second-genera-
tion triptan, has a higher affinity for 5-
Rizatriptan. Rizatriptan, another sec- HT1B/1D receptors than does sumatriptan.
ond-generation triptan, has an improved In higher doses, frovatriptan is an agonist
of the 5-HT receptors that might cause pranolol, or timolol may be the most effec-
vasodilation on, for example, coronary tive initial therapy in patients who experi-
vessels.42 It is absorbed relatively slowly ence situational anxiety or “letdown”
and reaches its tmax 2 hours after adminis- migraine or in those with hypertension. A
tration; its pharmacokinetic properties are calcium channel blocker may be appropri-
similar to those of naratriptan. Thus, 2 ate for patients with peripheral vascular
hours after receiving frovatriptan 2.5 or 5 disease or hypertension. Doses of those
mg, 38% and 37% of the patients, respec- medications to prevent migraine often are
tively, reported headache relief. Four much lower than those used to treat a
hours after they received the drug, 68% comorbid disorder.
and 67% of patients, respectively, reported The amine ergot alkaloid methysergide
headache relief.50 Frovatriptan has a long is an effective prophylactic agent in
half-life (> 10 hours); this may result in a migraine therapy.53 Although the drug is
lower incidence of headache recurrence, devoid of α-adrenergic activity, long-term
which was reported by 7% to 25% of use may result in pleural, pericardial, or
patients.51 retroperitoneal fibrosis. However, those
problems can usually be avoided by close
Prophylaxis Against Migraine medical monitoring and by advising the
The objective of prophylactic treatment patient to take a 1-month “drug holiday”
of migraine is to reduce the frequency, every 6 months.
severity, and/or duration of attacks while Beta-blocking adrenergic drugs without
keeping adverse events to a minimum. intrinsic sympathomimetic activity are
No single prophylactic drug is superior the only class of beta-blockers effective for
when potential adverse events are also the prophylaxis of migraine.25 Their effect
considered.25 is observed within 4 weeks and seems to
Prophylactic therapy is indicated when increase with time. That group of drugs is
patients report that their acute migraines particularly useful for treating patients
are not adequately controlled or that whose attacks are triggered by stress.
they often use medication to treat an Propranolol and timolol have been studied
acute attack (Table 3). Prophylaxis should in numerous clinical trials and have also
be considered when nonpharmacologic been found to be effective.54 However, the
attempts have failed.25 Low doses of pro- adverse events caused by beta-blocking
phylactic medication should be used at drugs must be considered before they are
first and slowly titrated upward.25 Treat- prescribed. Propranolol is likely to pro-
ment can be administered for 3 months, duce adverse events on the CNS, which
reassessed before being continued for an may cause physicians to avoid prescribing
additional 6 months or more, and then it. Metoprolol, which has been shown to
gradually withdrawn after the frequency of decrease the number of migraine attacks
migraine attacks has been decreased. by 22% to 49%, is a useful alternative to
Prophylaxis is also indicated after the propranolol. A lack of adequate, controlled
diagnosis of comorbid conditions (such as clinical trials prevents conclusions with
depression) that can be treated with med- respect to the use of atenolol or nadolol as
ications effective in the treatment of alternatives to propranolol.25
migraine.52 Patients with sleep distur- Valproate, a gamma-aminobutyric acid
bances or depression may benefit most transaminase inhibitor and activator of
from treatment with a tricyclic antide- glutamic acid decarboxylase, was found to
pressant (eg, amitriptyline, doxepin, nor- be effective in double-blind, placebo-con-
triptyline, imipramine, protriptyline, trolled trials in reducing migraine fre-
desipramine). Those with agitation or quency in at least 48% to 65% of patients;
bipolar disorder or patients who have ter- the placebo-treated patients experienced
minated their drug therapy may benefit a reduction of 14% to 18%. Unlike other
from divalproate sodium. A beta-blocker prophylactic agents, valproate reduced
such as atenolol, nadolol, metoprolol, pro- the severity and duration of migraine
attacks.55,56 Adverse events of valproate the disability of the patient.62 It can also
include nausea, tremor, transient hair loss, interfere with the administration of oral
increase in appetite, and weight gain. medication. Exacerbation of nausea after
Hepatotoxicity was observed in patients the administration of oral medication can
treated with valproate who were younger indicate either the development of new
than 2 years of age. Women of childbearing nausea or a disease-related worsening of
age who consider treatment with valproate nausea, and alternative medications for
must be cautioned about the potential the treatment of migraine should be
increased risk of spina bifida in the newborn. explored.
The tricyclic antidepressant amitripty-
line may be effective because of its 5-HT2- Clinical Safety of Dihydroergota-
receptor-blocking and/or calcium-channel- mine and Ergotamine. The clinical safe-
blocking effect on cerebral blood vessels ty experience with DHE is based on 21
and its inhibitory effect on the dorsal raphe clinical studies; unfortunately, few of
nuclei.57 Amitriptyline, which reduces the those studies had clinical controls, many
frequency and duration of migraine attacks, were open label and unblinded, and most
is superior to placebo and more effective did not compare DHE with placebo.63
than propranolol in decreasing the severity Adverse events were often not document-
of migraine attacks.58,59 However, amitripty- ed systematically because the focus of the
line produces anticholinergic adverse studies was the efficacy of the medication.
events and causes increased appetite and No clinical studies evaluated the effects or
weight gain. Other tricyclic antidepressants efficacy of long-term intramuscular
with varying adverse-event profiles can administration of DHE, and only a few
also be tried. evaluated the results of repetitive intra-
The use of calcium antagonists in venous administration in hospital patients.
migraine prophylaxis has been disappoint- Although nausea was reported in a
ing.60 The dihydropyridine derivatives number of trials after treatment of migraine
nifedipine and nimodipine can actually with DHE, critical quantitative observa-
cause headache. Either verapamil or dil- tions demonstrated that the drug-induced
tiazem is usually used to prevent migraine symptom was difficult to differentiate
only after trials of the more effective beta- from nausea caused by migraine. Open
blockers or amitriptyline have failed. trials reported few adverse events of
According to 1 review, verapamil was 19% DHE. In summary, closed clinical trials
to 49% more effective than placebo in and open-label studies suggested that
decreasing the frequency of migraine serious adverse events occur very rarely
attacks.61 The most common adverse after a recommended dose of DHE has
events produced by verapamil are hyper- been taken, regardless of the route of
tension and constipation. Despite wide- administration.64
spread use for treatment of migraine, the The clinical safety experience with ET
results of clinical studies of diltiazem are indicates that it is much more likely than
“underwhelming.” DHE to produce nausea and vomiting,
uterine effects, and rebound headache.63
Tolerability and Safety of Most of the adverse events produced by
Migraine Treatment ET were associated with excessive dosage
Some adverse events (particularly nau- and/or long-term administration. The
sea) of drugs used to treat migraine can peripheral vasoconstrictor effect of ET is
mimic the signs or symptoms of the disor- considerably stronger than that of DHE.
der. It is therefore critical to distinguish When primary care physicians prescribe
drug-induced symptoms from those either DHE or ET, they must be aware that
caused by headache. Nausea, a common both are safe in the treatment of migraine
symptom of migraine, occurs in 78% of with or without aura when used in recom-
migraine sufferers. Because it is often mended doses and frequencies in adults
moderate to severe, nausea contributes to who have no contraindications to the
medications. When compared with ET, of risk (rather than the number of risk fac-
DHE causes less arterial constriction and tors) is the most important factor.67
(according to indirect comparisons) less “Therapeutic gain” refers to the propor-
frequent nausea and vomiting.63 tion of patients who respond to treatment
The Quality Standards Subcommittee with a drug tested minus the proportion of
of the American Academy of Neurology patients who respond to placebo. A review
appointed an advisory committee from of 30 clinical trials demonstrated that, 1
experts in its headache and facial pain hour after administration, subcutaneous
section to review the clinical literature on sumatriptan 6 mg administered for the
the appropriate use of DHE and ET in the acute treatment of migraine resulted in a
treatment of migraine.65 On the basis of greater therapeutic gain than did 100 mg
that thorough literature review, practice of orally administered sumatriptan or 20
guidelines were formulated to define the mg of intranasal sumatriptan 2 hours after
limits of ergot use. ET and DHE were administration.68 Although 6 mg of subcu-
found to be safe and effective for the treat- taneous sumatriptan is more effective
ment of migraine as long as recommended than the other doses and dosage forms
dosages were not exceeded and high-risk mentioned above, it causes more adverse
patients (those with uncontrolled hyper- events than does 100 mg of oral sumatrip-
tension, coronary or peripheral artery dis- tan, which appears to have the better ben-
ease, thyrotoxicosis, or sepsis) did not efit-to-risk ratio. However, most adverse
receive those drugs. The committee also events produced by the subcutaneous
recommended restricting the use of ET form of the drug were mild and short-last-
in some instances, because its overuse ing, and patients may find that the greater
has been associated with physical and efficacy and quicker onset of action of
psychological dependence. Drug-dependent subcutaneous sumatriptan outweigh the
patients often experience predictable higher incidence of adverse events.69
recurrent and/or rebound headaches, and Placebo-controlled studies have report-
subsequent medications are required to ed an incidence of chest-related adverse
alleviate the symptoms of withdrawal, events in up to 4% of patients treated with
such as nausea. None of those symptoms second-generation triptans, compared
has been associated with DHE. with an incidence ranging from less than
1% to 3% in placebo-treated patients.20 An
Clinical Safety of Triptans. First- and analysis of safety data indicates that
second-generation triptans represent a migraine patients seem to have a higher
breakthrough treatment for patients with level of risk for cardiovascular events
acute migraine. However, those drugs cause than does the general population; this
some degree of coronary vasoconstriction in implies that such events may be associat-
susceptible patients.66,67 At therapeutic doses, ed with the underlying condition rather
triptans are unlikely to cause myocardial than the treatment.70,71 However, those
ischemia in individuals with normal coronary agents should be used with caution in any
circulation.66 Although that effect is not patient with vascular risk factors.
clinically significant for patients who do Clinical judgment is key when the deci-
not have coronary artery disease, triptans sion to use triptans is made. If a patient
are contraindicated in those who have or has ischemic heart disease and uncon-
are at risk for that disorder.66 trolled high blood pressure, the primary
Adverse-event databases compiled for care physician or specialist should not pre-
the triptans show that the risk of life- scribe a triptan.70 A patient with a family
threatening cardiovascular events pro- history of heart disease and a high choles-
duced by those medications is probably terol level should first receive other med-
less than 1 in 1 million.67 The level of risk ications for migraine treatment before
associated with triptans is actually similar treatment with a triptan is initiated.
to (or perhaps even better than) that of Safety is indeed a viable concern in the
prescription NSAIDs.67 The patient’s level selection of appropriate migraine treat-
produced pain relief rates similar to those mouth, nausea, paresthesia, and somno-
of oral sumatriptan 100 mg in a random- lence. No adverse events in the groups
ized, double-blind, placebo-controlled who received the 6.25 or 12.5-mg dose
clinical study, almotriptan 12.5 mg was occurred at a rate of 1 or more percentage
associated with a significantly lower inci- points higher than that of the placebo
dence of treatment-related adverse events group. Dry mouth, paresthesia, and som-
(P < .05).81 In addition, almotriptan 12.5 nolence are adverse events produced by
mg and sumatriptan 50 mg were com- triptans, and nausea and headache are
pared in a randomized, double-blind often observed in migraine patients. Other
trial.83 Pain relief occurred 2 hours after adverse events associated with triptan use,
administration in 58% of patients treated such as asthenia, chest pain, localized
with almotriptan and in 57% of those pain, palpitation, vasodilation, and dizzi-
treated with sumatriptan. However, signif- ness, were not associated with almotriptan
icantly fewer patients in the almotriptan administered at recommended doses. For
group (P < .05) experienced treatment- both doses, the only adverse event that
related adverse events (9.1% versus 15.5%) occurred in 2% or more of the patients was
and chest symptoms in particular (0.3% nausea (2% in those who received
versus 2.2%). almotriptan 12.5 mg).
The tolerability of almotriptan was in The adverse-event profile for sumatrip-
most instances similar to that of placebo. tan in the studies cited above is consis-
In controlled clinical trials, nausea in 2% tent with data from other studies of that
of the patients was the only adverse event drug.85,86 Although the types of adverse
recorded in 2% or more of those treated events in the almotriptan-treated groups
with almotriptan.84 Headache was fre- were similar to those observed in the
quently noted when oral almotriptan 6.25 groups treated with sumatriptan, almotrip-
to 25 mg was administered. Infrequent tan 6.25 and 12.5 mg produced lower rates
adverse events, all of which were mild and of chest pain and nausea than did suma-
transient in nature, included abdominal triptan 50 mg. Vomiting occurred at a
cramps, vasodilation, palpitations, tachy- higher rate in the placebo-treated group
cardia, dry mouth, diarrhea, vomiting, and (1.6%) than in any of the other main treat-
dyspepsia. In those trials, the adverse ment groups (all > 1%). Adverse-event
events were similar to those attributed to rates (particularly for chest pain, nausea,
placebo.84 Patients who experienced migraine-
associated photophobia, phonophobia, nau-
sea, or vomiting at baseline had a decreased
incidence of those symptoms after the Table 4. Clinical Studies of Oral Almotriptan Demonstrating
administration of almotriptan as opposed to Pain Relief* in the Treatment of Acute Migraine
placebo.
In controlled clinical studies, a total of Placebo Almotriptan Almotriptan
2809 patients were treated with almotrip- Study Author(s) (%) 6.25 mg (%) 12.5 mg (%)
tan (527 with 6.25 mg, 1313 with 12.5 mg,
Dahlöf et al80 33.8 56.3† 58.5‡
and 387 with 25 mg) or sumatriptan (582
(n = 80) (n = 166) (n = 164)
with 50 mg).84 The overall adverse event
rates in those studies were 12.4% (those Dowson81 42.4 — 56.8§
who received placebo), 14% (almotriptan (n = 99) (n = 183)
6.25 mg), 15.4% (almotriptan 12.5 mg), Pascual et al82 33.0 55.6‡ 64.9‡
20.4% (almotriptan 25 mg), and 19.4% (n =176) (n = 374) (n = 370)
(sumatriptan 50 mg). The most common
adverse events associated with almotrip-
*Pain relief was noted at 2 hours after administration of the drug for initial
tan use (at a rate of at least 1%—a rate
headache.
greater than that of placebo) in the con- †P = .002 in comparison with placebo.
trolled studies at the recommended doses ‡P ≤ .001 in comparison with placebo.
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