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Migraine is a common, chronic neurologic disorder that affects 11% of the adult population in
Western countries. In this article, we review the current approaches to the pharmacologic treatment
of migraine. Once migraine is diagnosed, and illness severity has been assessed, clinicians and
patients should work together to develop a treatment plan based on the patient needs and prefer-
ences. The goals of the treatment plan usually include reducing attack frequency, intensity, and
duration; minimizing headache-related disability; improving health-related quality of life; and
avoiding headache escalation and medication misuse. Medical treatments for migraine can be
divided into preventive drugs, which are taken on a daily basis regardless of whether headache is
present, and acute drugs taken to treat individual attacks as they arise. Acute treatments are further
divided into nonspecific and migraine-specific treatments. The US Headache Consortium Guide-
lines recommend stratified care based on the level of disability to help physicians individualize
treatment. Simple analgesics are appropriate as first-line acute treatments for less disabled patients;
if simple analgesics are unsuccessful, treatment is escalated. For those with high disability levels,
migraine-specific acute therapies, such as the triptans, are recommended as the initial treatment,
with preventive drugs in selected patients. A variety of behavioral interventions are helpful. The
clinicians have in their armamentariums an ever-expanding variety of medications. With experi-
ence, clinicians can match individual patient needs with the specific characteristics of a drug to
optimize therapeutic benefit.
attacks usually last from 4 to 72 hours and are associ- Table 2. Migraine Disability Assessment
ated with variable combinations of associated symp- (MIDAS) questionnaire
toms such as nausea, vomiting, photophobia, and pho-
MIDAS questionnaire Days
nophobia. Though a combination of features is re-
quired for the diagnosis,8 not all features are present 1. How many days in the last 3 months did
in every attack or in every patient (Table 1). Since two you miss work or school because of your
of four pain features are required, an attack with uni- headaches?
lateral throbbing pain or an attack with bilateral 2. How many days in the last 3 months was
severe pain aggravated by physical activity may your productivity at work or school reduced
be migraine. by half or more because of headaches. (Do
not include days you counted in question 1
Migraine with aura is characterized by aura, a com-
where you missed work or school.)
plex of focal neurologic symptoms that most often pre-
3. How many days in the last 3 months did
cedes or accompanies the headache attack; auras may you NOT do housework because of your
occur in the absence of headache. headaches?
In addition to diagnosis, the US Headache Consor- 4. How many days in the last 3 months was
tium9 recommends assessing the severity and disabil- your productivity in household work
ity of migraine. The Migraine Disability Assessment reduced by half or more because of your
(MIDAS) (Table 2) questionnaire is a well validated, headaches. (Do not include days you
five-item questionnaire that is easy to use in prac- counted in question 3 where you did not do
tice.10–13 The questions evaluate activity limitations in household work.)
three domains: paid work, household work or chores, 5. How many days in the last 3 months did
you miss family, social, or leisure activities
as well as family, social, and leisure activities. Patients
because of your headaches?
record days of missed activity (ie, absence from work
MIDAS score: Add the total number of days
due to headache), and days in which productivity was from questions 1–5.
reduced by at least at half. The MIDAS score is de- A. How many days in the last 3 months did
rived as the sum of missed days of activity and days in you have headache? (If headache lasted
which productivity was reduced by at least half (sum more than 1 day, count each day.)
of responses to questions 1 through 5) over a 3-month B. On a scale of 0–10, on average how painful
period. It is scored in units of lost days. Two addi- were these headaches (0 = no pain and 10 =
tional questions on the MIDAS questionnaire, not in- pain as bad as it can be)?
cluded in the score, assess frequency and intensity of
pain. The MIDAS questionnaire is used to assign pa- ranging from 11 to 20): moderate disability; grade IV
tients to 1 of 4 grades as follows: grade I (scores rang- (21 or greater): severe disability. As discussed below,
ing from 0 to 5): little or no disability; grade II (scores MIDAS grade predicts treatment needs.
ranging from 6 to 10): mild disability; grade III (scores
Migraine probably results from dysfunction of 5. If medication overuse or rebound headaches are
brainstem involved in the modulation of craniovascu- present, potentially offending medications [in-
lar afferents.16 Brainstem activation may also lead to cluding both prescription and over-the-counter
activation of ascending and descending pathways, (OTC) medications] and dietary caffeine should
with initiation of a perimeningeal vasodilatation and be tapered
neurogenic inflammation.17–20 The pain is understood 6. Institute a program of acute care and preventive
as a combination of altered perception (due to periph- pharmacologic therapy
eral or central sensitization) of stimuli that are usually
not painful,21 as well as the activation of a feed-
forward neurovascular dilator mechanism in the first OVERVIEW OF DRUG THERAPY
(ophthalmic) division of the trigeminal nerve.21 Corti-
cal spreading depression is the presumed substrate of Pharmacotherapy is usually divided into two catego-
migraine aura; spreading depression also occurs in ries: drugs that are taken whether or not headache is
migraine without aura. present to reduce the frequency and severity of attacks
(preventive therapy) and drugs that are acutely taken
to treat attacks (acute treatment).25,26 Acute treatment
THE TREATMENT OF MIGRAINE is subdivided into nonspecific treatments, useful for a
range of pain disorders [ie, aspirin, acetaminophen,
Once a clinical diagnosis of migraine is made and dis-
nonsteroidal antiinflammatory drugs (NSAIDS), opi-
ability and comorbidities have been assessed, the next
ates, and combination analgesics] and migraine-
task is to develop an individualized treatment plan.
specific treatments (ergotamine, dihydroergotamine,
This plan usually has a number of goals that vary in
and the triptans) The specific drugs are effective
priority with the patient’s headache characteristics
for treating neurovascular headaches, such as mi-
and treatment preferences. The goals usually include
graine and cluster headache, but not for treating other
educating the patient about their illness and its man-
types of pain, such as low back pain, painful neurop-
agement (eg, trigger avoidance and lifestyle changes);
athy, etc.27
reducing attack frequency, intensity, and duration;
While virtually every patient benefits from acute
minimizing disability, improving quality of life, and
treatment, preventive treatments are reserved for se-
avoiding headache escalation.22
lected migraine sufferers.
As with other chronic illnesses, several fundamental
management considerations are important for treat-
ment success in patients with migraine. Patients who PREVENTIVE TREATMENT
have suffering for years may be frustrated and may
not believe headache control is possible.23 Pharmaco- The U.S. Headache Consortium Guidelines9,28 suggest
logic and nonpharmacologic (behavioral and some- that preventive treatment should be considered in the
times physical) interventions may be necessary to pro- following circumstances:
duce a favorable outcome. Support programs and be-
havioral medicine techniques are an important part in • Recurring migraine that significantly interferes
ensuring treatment plan success. The essential features with the patient’s daily routine despite acute
of an effective treatment regimen include the follow- treatment. (eg, two or more attacks a month that
ing steps24: produce disability that lasts ⱖ3 days or head-
ache attacks that are infrequent but produce pro-
1. Educate the patient: adequate instruction about found disability)
the biology of migraine and deleterious effects of • Failure, contraindication to, or troublesome side
certain medications used in excessive quantities effects from acute medications
and too frequent intervals • Overuse of acute medications
2. Establish expectations and a follow-up plan • Special circumstances, such as hemiplegic mi-
3. Support the patient graine or attacks with a risk of permanent neuro-
4. Use nonpharmacologic therapies when necessary: logic injury
• Biofeedback and relaxation therapy • Very frequent headaches (more than two a week),
• Cognitive behavioral therapy or a pattern of increasing attacks over time, with
• Individual/family counseling as necessary the risk of developing rebound headache with
• Dietary instructions, chronobiologic therapy, and acute attack medicines
sleep hygiene • Patient preference (ie, the desire to have as few
• Daily exercise program acute attacks as possible)
American Journal of Therapeutics (2004) 11(2)
Medical Management of Migraine 133
channel antagonists, and antiepileptic agents. We will gain; cardiac toxicity and orthostatic hypotension oc-
briefly discuss these classes of drugs below. cur occasionally.
Calcium-channel blockers
Beta Blockers
The AHCPR Technical Report identified 45 controlled
The Agency for Health Care Policy and Research
trials of calcium antagonists.30 A metaanalysis sup-
(AHCPR) technical report analyzed 74 controlled tri-
ports the clinical benefits of flunarizine (not available
als of beta blockers for migraine prevention.30 Pro-
in the US). Nimodipine had mixed results in placebo-
pranolol. nadolol, atenolol, metoprolol, and timolol
controlled trials. The evidence for nifedipine was dif-
have been shown to be effective. The beta blockers that
ficult to interpret. Verapamil was more effective than
are partial agonists and have intrinsic sympathomi-
placebo in two of three trials, but both positive trials
metic activity have not been found to be effective for
had high dropout rates. Of the calcium channel block-
the prevention of migraine. As the relative efficacy of
ers available in the US, verapamil is the most widely
the different beta blockers has not been clearly estab-
used.29 Verapamil is especially useful for patients with
lished, decisions should be made based on beta selec-
comorbid hypertension or with contraindications,
tivity, convenience of drug formulation, side effects,
such as asthma and Raynaud disease, to beta blockers.
and the patient’s individual reaction.29,30 Since beta
Calcium channel blockers are also useful for patients
blockers can produce behavioral side effects such as
who have migraine with prolonged aura. Constipation
drowsiness, fatigue, lethargy, sleep disorders, night-
is verapamil’s most common side effect.
mares, depression, memory disturbance, and halluci-
nations, they are best avoided in patients with depres- Antiepileptic drugs
sion. Decreased exercise tolerance limits their use
Antiepileptic drugs (AEDs) are increasingly recom-
by athletes. Less common side effects include impo-
mended for migraine prevention because of placebo-
tence, orthostatic hypotension, significant bradycar-
controlled, double-blind trials that prove them effec-
dia, and aggravation of intrinsic muscle disease.
tive. Valproate or divalproex, topiramate, and gabap-
Beta blockers are especially useful for patients with
entin have demonstrated efficacy.31
comorbid angina or hypertension. They are relatively
Many patients find divalproex sodium to be effec-
contraindicated for patients with congestive heart
tive at a low dose (500–1000 mg/d). Side effects in-
failure, asthma, Raynaud disease, and insulin-
clude sedation, hair loss, tremor, and changes in cog-
dependent diabetes.
nitive performance. Nausea, vomiting, and indiges-
tion can occur, but these are self-limited side effects.
Antidepressants
Hepatotoxicity is the most serious side effect, but ir-
The currently available antidepressants consist of a reversible hepatic dysfunction is extremely rare in
number of different classes of drugs with different adults. Pancreatitis has also been reported. Baseline
mechanisms of action. The tricyclic antidepressants liver function studies should be obtained, but routine
(TCAs) most commonly used for migraine prophy- follow-up studies are probably not routinely needed
laxis include amitriptyline, nortriptyline, doxepin, and in adults on monotherapy. Follow-up is necessary to
protriptyline. Amitriptyline is the only antidepressant adjust the dose and monitor side effects. Silberstein32
with fairly consistent support for its efficacy in mi- published practical recommendations and clinical
graine prevention. Other agents have not been rigor- guidelines for using valproate for headache prophylaxis.
ously evaluated; their use is based largely on clinical Gabapentin (1800–2400 mg) was found to be supe-
experience and uncontrolled reports.30 Many head- rior to placebo in reducing the frequency of migraine
ache experts use nortriptyline in preference to amitrip- attacks in a controlled, double-blind trial, supporting
tyline because of its more favorable side effect profile. the results of previous open trials. The responder rate
TCAs are better used for patients who have sleep dis- was 36% for gabapentin and 14% for placebo.33 The
turbance or comorbid depression. Selective serotonin most common adverse events were dizziness and
reuptake inhibitors such as fluoxetine, paroxetine, and drowsiness. Relatively high patient withdrawal rates
sertraline can be used to treat coexistent depression due to adverse events were reported in some trials.
based on their favorable side effect profiles; their effi- Topiramate is a structurally unique anticonvulsant
cacy as migraine preventives has not been established. with rapid and almost complete oral absorption. Topi-
Side effects from TCAs are common. Most involve an- ramate has been associated with weight loss, not
timuscarinic effects, such as dry mouth and sedation. weight gain (a common reason to discontinue preven-
The drugs also cause increased appetite and weight tive medication) with chronic use. Topiramate should
be started at a dose of 15 to 25 mg/d at bedtime and or absence of coexisting or comorbid disease (Table 4).
increased weekly to 100 to 200 mg/d in divided doses. The clinician should select the drug with the best risk-
Adverse events include weight loss, paresthesias, and to-benefit ratio for the individual patient and mini-
cognitive dysfunction (which is often prevented by mize the side effects that are most important to
slow gradual dose escalation). Topiramate should be the patient.
used with caution in patients who have a history of
renal calculi. A recent double-blind, controlled study
showed that topiramate is superior than placebo in the
preventive treatment of migraine, supporting several TREATMENT OF ACUTE ATTACKS
previous open label trials.34
AEDs are especially useful when migraine occurs in Virtually every patient benefits from acute treatment,
patients with comorbid epilepsy, anxiety disorder, or which can be subdivided into nonspecific treatments
manic-depressive illness. They can be safely adminis- (ie, aspirin, acetaminophen, NSAIDS, opiates, and
tered to patients with depression, Raynaud disease, combination analgesics) and migraine-specific treat-
asthma, and diabetes, circumventing the contraindica- ments (ergotamine, dihydroergotamine, and the trip-
tions to beta blockers. With the exception of valproic tans) (Table 5).
acid and phenobarbital, many AEDs interfere with the
efficacy of oral contraceptives. Caution is therefore ad- Analgesic and nonsteroidal antiinflammatory drugs
vised in women on AEDs and oral contraceptives.
Many NSAIDs are more effective than placebo for the
acute treatment of migraine. Studies show that diclof-
enac (50–100 mg), flubiprofen (100–300 mg), ibuprofen
SETTING PREVENTIVE (200–800 mg) naproxen sodium (550 –1100 mg),
TREATMENT PRIORITIES piroxicam (40 mg), and tolfenamic acid (200–400 mg)
are effective in the acute treatment migraine. Ibupro-
The choice of a preventive drug is made based on its fen is approved for migraine as an OTC agent.35 The
proven efficacy, the patient’s preferences and head- administration of antiemetic drugs or drugs that in-
ache profile, the drug’s side effects, and the presence crease gastric motility is likely to facilitate the absorption
Comorbid condition
Adverse
Drug Efficacy events Relative contraindication Relative indication
Analgesics (monotherapy)
Aspirin tablets 325–650 mg
Acetaminophen tablets 325–1000 mg
Combination Analgesics
Aspirin plus acetaminophen plus caffeine tablets 250 mg plus 250 mg plus 65 mg
Isometheptene mucate plus acetaminophen plus 65 mg plus 325 mg plus 100 mg
dichloralphenazone tablets
Butalbital plus aspirin plus caffeine tablets 50 mg plus 325 mg plus 40 mg
Butalbital plus acetaminophen plus caffeine tablets 50 mg plus 325 mg plus 40 mg
Ergotamine Alkaloids
Erogotamine tartrate plus caffeine tablet 1 mg plus 100 mg
Ergotamine tartrate plus caffeine suppository 2 mg plus 100 mg
DHE nasal spray 0.5 mg/nostril (repeat in 15 min 1 × for 2 mg total dose)
DHE IM or SC 1 mg
NSAIDs
Diclofenac K tablets 50–100 mg
Flurbiprophen tablets 100–300 mg
Ibuprophen tablets 200–1200 mg
Naproxen tablets 250–500 mg
Naproxen sodium tablets 550–1100 mg
Piroxicam tablets 40 mg
Tolfenamic acid tablets 200–400 mg
Diclofenac sodium IM 50 mg
Opiate Analgesics
Butorphanol nasal spray 1–2 mg
Triptans
Almotriptan tablets 12.5 mg tablets
Naratriptan tablets 1 mg or 2.5 mg
Rizatriptan tablets 5 mg or 10 mg
Rizatriptan orally disintegrating tablets 5 mg or 10 mg
Sumatriptan tablets 25 mg, 50 mg or 100 mg
Sumatriptan nasal spray 5 mg or 20 mg
Sumatriptan sc self injection 6 mg
Zolmitriptan tablets 2.5 mg or 5 mg
Zolmitriptan orally disintegrating tablets 2.5 mg or 5 mg
Eletriptan tablets 40 mg
Frovatriptan tablets 2.5 mg
DHE, dihydroergotamine.
of the primary drug and thus help to ameliorate the side effects; they carry a risk of medication overuse
attack.36 Overuse of these drugs should be avoided, and rebound headache.
and the intake should be restricted to no more than 2
Ergotamine and dihydroergotamine
or at most 3 days a week.
The same principles apply to combination analge- The ergot alkaloids were the first available migraine-
sics. They seem to be most helpful in treating episodic specific therapy. The main advantages of the ergota-
tension-type headaches and migraines in patients mine and dihydroergotamine ergot derivatives are
who do not usually require bed rest with their head- their low cost and the long experience with their use.38
aches. The combination of aspirin, acetaminophen, They also have a number of disadvantages. Ergota-
and caffeine has been approved as an OTC mi- mine has a complex pharmacology, interacting with
graine treatment.37 many receptors. It has erratic oral absorption and vari-
As a rule, we avoid the use of butalbital or opiate able pharmacokinetics. It also has potent and sus-
compounds. These drugs cause sedation and cognitive tained generalized vasoconstrictor effects and is
American Journal of Therapeutics (2004) 11(2)
Medical Management of Migraine 137
proven to cause medication overuse as well as re- of treated patients report adverse events. For the most
bound headaches.38 part, adverse events are mild and transient. Most of
Ergotamine is still widely used in some countries the triptans show a modest increase in the incidence of
for the treatment of severe migraine attacks. It is adverse events at higher doses.43
generally regarded as a safe and useful drug when The triptans as a class produce modest coronary
prescribed in the correct dose.39 In randomized clini- artery vasoconstriction.44,45 Extensive use of triptans
cal trials, oral ergotamine was found superior to pla- over the past decade has provided substantial reassur-
cebo but inferior to oral triptans. In contrast, rectal ance that this physiologic effect carries minimal clini-
ergotamine was found to have higher efficacy (73% cal risk in appropriately selected patients. This is con-
headache relief) than rectal sumatriptan (63% head- sistent with pharmacologic data indicating that
ache relief). Dihydroergotamine is a less potent vaso- 5-HT1B receptors mediate less than 25% of the overall
constrictor then ergotamine and in useful in intrana- vasoconstrictive potential of the coronary arteries.45
sal, intramuscular, and intravenous treatment.40–42 Parenteral challenge with sumatriptan has been re-
Combined with metoclopramide, it is widely used for ported to result in approximately 14% coronary vaso-
status migrainous and intractable chronic migraine. constriction.44 It should be noted that the differential
vasoconstrictive selectivity of triptans is partly due to
The triptans the significantly higher density of 5-HT1B receptors in
The migraine-specific triptans have revolutionized the the meningeal arteries compared with the coronary
treatment of migraine. For patients who experience arteries.44–46 In patients with healthy coronary arter-
temporary disability with their migraine, they are usu- ies, this degree of vasoconstriction is hemodynami-
ally the drugs of choice to treat a migraine attack in cally insignificant. All of the triptans are, however,
progress (Table 6). They have several advantages contraindicated in the presence of significant coronary
when compared with the ergot derivatives, especially vascular disease.47–48
regarding their selective pharmacology, simple and In contrast with their similar safety profiles, the trip-
consistent pharmacokinetics, evidence-based dose rec- tans differ in tolerability. Overall, naratriptan, almo-
ommendations, and established efficacy based on triptan, and frovatriptan appear to have the most fa-
large, well designed, controlled trials. They are more vorable adverse event profiles.44 It should be empha-
expensive then ergotamine compounds and, like ergot sized, though, that tolerability problems as a reason
derivatives, they are contraindicated in the presence of for medication discontinuation are relatively low for
cardiovascular disease. all triptans. Nonetheless, for a patient in whom avoid-
Safety needs to be distinguished from tolerability. ing side effects is a priority, these agents may be bet-
Tolerability involves adverse events that cause short- ter choices.
term but not long-term harm, such as nausea or diz- A recent metaanalysis using data of 24,089 patients
ziness. Safety refers to medically significant adverse in 53 controlled clinical trials of triptans compared the
events, such as myocardial infarction, stroke, or he- oral triptans with 100 mg sumatriptan, and some re-
patic toxicity. sults are summarized below.46 The most important
The triptans as a class are both safe and well toler- conclusion of the metaanalysis is that all the triptans
ated in appropriately selected patients. Less than half are more effective than placebo in relieving the pain
When patients report that treatment is not working, 2. Stewart WF, Shechter A, Lipton RB. Migraine heteroge-
it is important to understand the nature of the treat- neity. Disability, pain intensity, and attack frequency
ment failure. The major categories include lack of ef- and duration. Neurology. 1994;44:24–39.
ficacy (pain relief is slow, incomplete, or both), head- 3. Lipton RB, Hamelsky SW, Stewart WF. Epidemiology
ache recurrence (the pain is relieved but comes back and impact of migraine. In: Silberstein SD, Lipton RB,
relatively quickly), or poor tolerability. For lack of ef- Dalessio DJ, eds. Wolff́s Headache and Other Head Pain. 7th
ed. Oxford, England: Oxford University Press; 2001:85–
ficacy, it may be useful to treat earlier in the attack,
107.
while pain is still mild. Both post hoc analysis and
4. Lipton RB, Stewart WF, Simon D. Medical consultation
specifically designed clinical trials show that acute mi-
for migraine: results from the American Migraine Study.
graine drugs work best when given early. Increasing
Headache. 1998;38:87–96.
the dose can be useful, especially if there is a partial
5. Stang PE, Von Korff M. The diagnosis of headache in
response. Switching to a non-oral form (nasal spray or
primary care: factors in the agreement of clinical and
injection) may help, especially if headaches are of standardized diagnoses. Headache. 1994;34:138–142.
rapid onset, present on awakening, or associated with
6. Richard A, Massiou H, Herrmann MA. Frequency and
prominent nausea or vomiting Anecdotally, switching profile of migraine patients seen by general practitio-
triptans or adding an NSAID or metoclopramide to ners. Semin Hosp Paris. 1999;75:440–446.
the triptan may help.
7. Lipton RB, Amatniek JC, Ferrari MD, et al. Migraine.
If recurrence is the problem, increasing the dose or Identifying and removing barriers to care. Neurology.
switching to a triptan with a favorable recurrence rate 1994;44:63–68.
is helpful. Examples of triptans with favorable recur- 8. Headache Classification Committee of the International
rence rates include naratriptan, frovatriptan, and Headache Society. Classification and diagnostic criteria
eletriptan. Adding adjunctive medication to the trip- for headache disorders, cranial neuralgias and facial
tan may be helpful. pain. Cephalalgia. 1988;8:1–96.
For problems with tolerability, naratriptan has ad- 9. Matchar DB, Young WB, Rosenerg J, et al. Multispecialty
vantages. In controlled clinical trials, it produces ad- consensus on diagnosis and treatment of headache:
verse events at a rate similar to placebo. pharmacological management of acute attacks. Neurol-
For many patients, if one triptan fails, other may ogy 2000;54: www.aan.com/professionals/prac-
well succeed. So, it is important to identify the nature tice/pdfs/gl0087.pdf.
and reason for failure and manage as appropriate.48 10. Stewart WF, Lipton RB, Kolodner K, et al. Reliability of
the migraine disability assessment score in a population-
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11. Stewart WF, Lipton RB, Kolodner KB, et al. Validity of
The selection of an antimigraine (acute or preventive) the Migraine Disability Assessment (MIDAS score in
drug for a patient depends upon the stratification of comparison to a diary-based measure in a population
sample of migraine sufferers. Pain. 2000;88:41–52.
the patient’s migraine attack by peak intensity, time to
peak intensity, level of associated symptoms such as 12. Stewart AL, Lipton RB, Whyte J, et al. A multi-national
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13. Stewart WF, Lipton RB, Kolodner K, et al. Validity of the
might cause drug interactions. The clinicians have in
Migraine Disability Assessment (MIDAS) score in com-
their armamentariums an ever-expanding variety of
parison to a diary-based measure in a population
medications, available in multiple formulations and sample of migraine sufferers. Pain. 2000;88:41–52.
dosages, with good safety and tolerability profiles.
14. Goadsby PJ. Pathophysiology of headache. In: Silber-
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