PROJAP A14 Gallagher S58-S73€¦ · often delay taking medication, which ... The prevalence of a...

S58 THE AMERICAN JOURNAL OF MANAGED CARE FEBRUARY 2002

Migraine is a primary headache dis-order characterized by recurringattacks of throbbing (often unilat-

eral) headache, photophobia, phonopho-bia, nausea, and other symptoms. The

headache may be preceded by transientfocal neurologic symptoms known as aura.Migraine is the most common primaryheadache disorder for which patientspresent to primary care physicians, yetit remains underdiagnosed and under-treated.1,2 Migraine sufferers are often themost dissatisfied patients; less than 30% ofsufferers report that they are very satisfiedwith their usual migraine treatment.3,4

Almost two thirds of migraine sufferersexperience unwanted side effects fromantimigraine treatment. Those patientsoften delay taking medication, whichresults in prolonged pain and disability.5

The prevalence of a family history ofmigraine suggests that the disorder mayhave a genetic component.6 An estimated6% of men and 15% to 17% of women in theUnited States experience migraine, butonly 3% to 5% of that population receivepreventive therapy.7 The prevalence ofmigraine increased 60% (from 25.8 to 41per 1000 population) from 1981 to 1989.8

In addition, 2 studies conducted manyyears apart indicated that the incidenceof migraine in school children hasincreased.9 Those data suggest that theprevalence of migraine is increasing withtime; however, this increase could be theresult of increased awareness of the disor-der among physicians and patients.

Pathophysiology of Migraine

The characteristics of migraine vary infrequency, duration, and the extent of dis-ability produced among sufferers andbetween attacks. Some migraine patientsexperience fewer than 1 attack per month,and others suffer from 1 or more attacks

. . . REPORTS . . .

Migraine: Diagnosis, Management, and New Treatment Options

R. Michael Gallagher, DO; and F. Michael Cutrer, MD

AbstractObjective: The safety and tolerability of med-

ications used to treat acute migraine attacks aresummarized, the classification of headaches andthe causes of and diagnostic criteria for migraineare reviewed, and the clinical tolerability profilesand therapeutic benefits of second-generation trip-tans are presented.

Background: Migraine is a paroxysmal disor-der characterized by attacks of headache, nau-sea, vomiting, photophobia, and phonophobia.Drugs used to prevent migraine and those thateffectively treat acute migraine attacks are readilyavailable.

Methods: Mild or moderate migraines are oftentreated with aspirin, acetaminophen, nonsteroidalanti-inflammatory drugs, antiemetic drugs, orisometheptene. Triptans (5-HT1 receptor agonists) areused to treat moderate or severe migraine and whennonspecific medications have been ineffective.Because sumatriptan, the first triptan used, is effectivebut can induce adverse events, second-generationtriptans (zolmitriptan, naratriptan, rizatriptan, andalmotriptan) were developed to increase the bene-fit-to-risk ratio in migraine management.

Results: Important pharmacologic, pharmaco-kinetic, and clinical differences exist among thosedrugs, but the tolerability profile of the newer trip-tans is very good, and they provide rapid relieffrom headache and sustained duration of effect.

Conclusion: Primary care physicians must man-age migraine patients with treatments that demon-strate a balance between efficacy and tolerability.

(Am J Manag Care 2002;8:S58–S73)

per week.10 Some migraine patients aredisabled by their headaches; others arenot. Therefore, the care provided to thosewho suffer from migraine must be strati-fied by the frequency and severity of theheadache and by the resultant level ofdisability.11

Abnormalities in blood vessels may beimportant in the pathogenesis of migraineand the excessive muscle contraction oftension-type headaches, but currentresearch suggests that headaches are pro-duced by abnormalities in the central nerv-ous system (CNS) regulation of bloodvessels within pain-producing intracranialmeningeal structures.12,13 Evidence hasshown that changes in the level of serotoninprecede the changes in blood vessels andmuscle tone that occur during chronicheadaches.12 The influence of serotonin onheadache may also explain the effectivenessof medications used to treat migraine.

The nature of the CNS dysfunctionproduced in migraine patients is stillunclear and may involve spreadingdepression-like phenomena and the acti-vation of brain stem monoaminergicnuclei that are part of the central auto-nomic, vascular, and pain-control centers.A proposed mechanism for the generationof migraine is that of local vasodilation ofintracranial and extracerebral blood ves-sels and a consequent stimulation of sur-rounding trigeminal sensory nervous painpathways.13 This activation of the trigemi-novascular system is thought to cause therelease of vasoactive sensory neuropep-tides (substance P, calcitonin–gene-relatedpeptide, neurokinin A, and others) thatincrease the pain response.13 The activatedtrigeminal nerves convey nociceptive infor-mation to central neurons in the brain stemtrigeminal sensory nuclei, which in turnrelay the pain signals to higher centers thatmay become sensitized as a migraineattack progresses.13

Diagnosis of Migraine

International Headache SocietyClassification. The International HeadacheSociety (IHS) has developed the first clas-sification system for migraine and othertypes of headaches (Tables 1 and 2).14,15

The IHS user-friendly classification con-sists of 2 major categories: primary andsecondary headaches. Primary headaches(headache disorders in which an identifi-able pathologic factor is not present) con-sist of migraine (with or without aura),tension-type headaches (episodic or chron-ic), cluster headaches, posttraumatic head-aches, and rebound headaches caused bydrug use or withdrawal. Secondary head-aches are symptoms of organic diseasessuch as meningitis or cerebral tumors.

The IHS classification system providesvaluable information about the diagnosisand treatment of headaches, but primarycare physicians and neurologists are ulti-mately responsible for accurate diagnosisand effective treatment. Migraine pro-drome (phase 1 or preheadache period),which may occur hours to days before theonset of headache, consists of nonfocalconstitutional symptoms and can varywidely among patients. Some feel euphor-ic, and others may experience irritabilityor extraordinary fatigue. Migraine post-

VOL. 8, NO. 3, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S59


Table 1. The International HeadacheSociety Classification of Migraine

■ Migraine without aura

■ Migraine with auraMigraine with typical auraMigraine with prolonged auraFamilial hemiplegic migraineBasilar migraineMigraine aura without headacheMigraine with acute onset aura

■ Ophthalmoplegic migraine

■ Retinal migraineChildhood periodic syndromes that may be

precursors to or associated with migraineBenign paroxysmal vertigo of childhood Alternating hemiplegia of childhood

■ Complications of migraineStatus migrainousMigrainous infarction

■ Migrainous disorder not fulfilling above criteria

Source: Headache Classification Committee of theInternational Headache Society. Classification anddiagnostic criteria for headache disorders, cranialneuralgias and facial pain. Cephalalgia 1988;8(suppl 7):1-96. Adapted with permission.

drome appears as the pain wanes, afterwhich the patient feels tired and listless.

The clinical diagnosis of migraine with-out aura requires that the patient experi-ence at least 5 headaches with a duration of4 to 72 hours. During migraine withoutaura, unilateral pain of moderate-to-severeintensity seems to pulsate, and patientsmust experience at least 1 of the followingsymptoms: nausea, vomiting, photophobia,or phonophobia.14 Such headaches areoften exacerbated by routine physical activ-ity. However, during a migraine, approxi-mately 30% of migraine patients experiencean aura (usually visual) that precedes theheadache by 5 to 30 minutes, may reflect awide range of neural deficits, and fades with-in 30 minutes. It may first be noticed nearthe visual center as a small spot surround-ed by bright, jagged lines. An aura that per-sists for more than 1 hour may signal anischemic attack and should be evaluated.14

Medical History. Obtaining an accu-rate medical history is the first step in anevaluation for migraine. Informationobtained should include the patient’s age atfirst migraine; the site or sites of pain; thefrequency, intensity, and duration of pain;the presence of any associated symptom(eg, aura, dizziness); aggravating, precipi-tating, or ameliorating factors; prior med-ication use; caffeine intake; prior headtrauma; results of neuroimaging studies;and family history.16 The physician shouldencourage the patient to keep a headache“diary” in which the characteristics of eachheadache and the response to treatmentare recorded. That type of diary is also valu-able in helping the patient and physicianidentify factors such as lifestyle, diet, men-strual cycle, and the overuse of medicationor caffeine, all of which may precipitatemigraine.16

Physical Examination. After thepatient’s medical history has been obtained,a physical examination should be performedto evaluate (at the very least) blood pressure,heart rate, extracranial structures (eg,sinuses, scalp arteries, temporomandibularjoints), and the range of motion and pres-ence of pain in the cervical spine.17 Addi-tional laboratory tests and neuroimagingstudies should not be necessary unless thephysician observes the following danger sig-nals: the sudden onset of a new type ofsevere headache; headache onset duringexertion; first headache in a middle-agedpatient; headache accompanied by loss ofconsciousness or systemic illness (fever, stiffneck, rash); headache associated withmeningeal signs; an accelerating pattern ofheadache; new onset of headache inimmunocompromised patients or thosewith cancer; headache accompanied bysigns of disease or focal neurologic symp-toms atypical for aura; and papilledema(swelling of the optic disk).16 In those cases,referral for diagnostic imaging or neurologictesting is appropriate to rule out concomi-tant illness that may cause headache.

Treatment

Two types of treatment are available forheadaches: abortive (treatment of the


REPORTS

Table 2. Diagnostic Criteria for Migraine Without Aura

A. At least 5 attacks fulfilling the criteria of B to D below

B. Headache attacks lasting 4 to 72 hours (untreated or unsuccessfullytreated)

C. Headache with at least 2 of the following characteristics:

1. Unilateral location

2. Pulsating quality

3. Moderate or severe intensity (inhibits or prohibits daily activities).

4. Intensified when patient walks up or down stairs or performs a similar activity

D. During headache, at least 1 of the following must occur:

1. Nausea and/or vomiting

2. Photophobia or phonophobia

E. At least 1 of the following must apply:

1. History, physical, and neurologic examinations do not suggest another disorder*

2. History and/or physical and/or neurologic examinations do suggestsuch a disorder, but it is ruled out by appropriate investigations

3. Such a disorder is present, but migraine attacks do not occur for the first time in close temporal relation to the disorder

*Other disorders that may cause headache include head trauma; vascularand neurovascular disorders; substance use or withdrawal; noncephalicinfection; metabolic disorder; and disorders of the cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cranial structures.Source: Headache Classification Committee of the International HeadacheSociety. Classification and diagnostic criteria for headache disorders, cranialneuralgias and facial pain. Cephalalgia 1988;8(suppl 7):1-96. Adapted withpermission.

acute attack) and prophylactic (preven-tion of headache by using medicationand/or nonpharmacologic measures tolessen precipitating factors, such as stressor lifestyle).

Nonpharmacologic Measures ofPreventing Migraine. The suggestionsbelow are recommended by a primarycare physician for the nonpharmacologicmanagement of migraine.18

• Maintain regular sleeping, eating, andexercise habits.

• Avoid excessive stress-producingactivities.

• Practice relaxation techniques.• Avoid potential triggers such as trauma,

caffeine, and certain foods (eg, choco-late, aged cheeses, red wine, foods con-taining sodium nitrate).

• Address possible underlying depressionor anxiety.

Pharmacologic Treatment. Early inter-vention with appropriate medication cancompletely abort a migraine so that thepatient can function normally and arecurrence is prevented.19 Simple anal-gesics and nonsteroidal anti-inflammato-ry drugs (NSAIDs) may be used to treatmild-to-moderate headache or migrainethat does not increase in intensity.Triptans (5-HT1 receptor agonists) are thepreferred therapy for moderate-to-severeheadaches. In Table 3, therapies recom-mended by primary care physicians forpatients with specific headache patternsare presented.20,21

During prodrome, many interventionscan be effective. Over-the-counter (OTC)or nonprescription products such asNSAIDs, serotonin receptor agonists, aspirin,acetaminophen, or a combination of aspirinand acetaminophen may prevent theheadache.19 If prodromal warning signs donot occur or intervention fails to abort themigraine in its early stage, migraine-spe-cific medications such as triptans areindicated. Headache characterized by pho-tophobia, phonophobia, and/or nausea andvomiting suggests that the neurovascularinflammatory process has begun, and trip-

tan drugs are highly effective when admin-istered early in this phase of migraine.When migraine evolves into an advancedstage (late headache) and first- and second-line treatments have failed, rescue therapymust be considered. Intravenously admin-istered phenothiazines are often effectiveand can be combined with dihydroergota-mine (DHE) or other serotonin agonists.Opioid analgesics are also used to treat lateheadache.

Selecting Pharmacologic Agents

Simple Analgesics and NSAIDs. Simpleanalgesics, which may be used to treatmild-to-moderate acute migraine, are mosteffective as first-line treatments whenused before the pain becomes severe.22

Aspirin, which is both an analgesic and anNSAID, inhibits prostaglandin andleukotriene synthesis.23 Acetaminophencan also be used to treat mild-to-moderateacute migraine.24 Ibuprofen and OTC com-bination products containing aspirin, aceta-minophen, and caffeine have been approvedby the US Food and Drug Administration(FDA) for the treatment of mild-to-moder-ate migraine. Patients should be cautionedthat the overuse of all treatments formigraine, including triptans and OTC anal-gesics (especially combination productscontaining caffeine) may cause reboundheadache.22

Prescription-strength NSAIDs such asibuprofen, naproxen sodium, and ketoro-



Table 3. Medications Prescribed for Headaches by PrimaryCare Physicians

Headache Pattern Suggested Therapy

Mild-to-moderate migraine Nonspecific agents (eg, NSAIDs,combination medications)

Moderate or severe migraine; or Migraine-specific agentspoor response to NSAIDs and (eg, triptans, dihydroergotamine)combination medications

Migraine associated with severe Nonoral route of administrationnausea or vomiting

Severe migraine that fails to Self-administered rescue respond to other treatments medication

NSAIDs = nonsteroidal anti-inflammatory drugs.

Source: Reference 27.

lac are also effective treatments for mild-to-moderate migraine.25 Diclofenac, a pre-scription-strength NSAID, reduced theintensity of migraine pain and amelioratedassociated symptoms such as photophobiaand phonophobia in a placebo-controlled,double-blind, randomized clinical trial.26 Ifa moderate dose of an NSAID adminis-tered at the onset of migraine is not com-pletely effective within 1 hour, a triptanshould be given.21 Cyclo-oxygenase-2inhibitors may be useful adjuncts for thetreatment of migraine.27

Opioids. Opioids such as intramuscu-larly or intravenously administered meperi-dine or orally administered codeine are usedbecause of their analgesic potential but mayexacerbate nausea and vomiting and increasethe risk of drug addiction.25 A clinical trialinvolving patients treated in an emergencydepartment for acute migraine indicatedthat a combination of meperidine andhydroxyzine reduced headache pain byapproximately 55%, ameliorated nausea,and was not statistically significantly differ-ent in effect (P < .05) from treatment with acombination of DHE and hydroxyzine.28

Antiemetics. Antiemetic drugs may beused to treat acute migraine. Orally orintravenously administered metoclo-pramide, a dopamine antagonist thataffects the 5-HT3 receptor, may providerelief from pain and nausea or vomiting.29

Patients should be advised that antiemet-ics often cause adverse events such asdiarrhea, drowsiness, or restlessness.

Ergot Compounds. Ergot compoundssuch as ergotamine (ET) or DHE were thefirst drugs used to treat migraine.25 Ergotcompounds are pharmacologically nonse-lective but have been used successfully inpatients with moderate-to-severe migrainesince the turn of the century. Their clinicalefficacy is at least equal to that of NSAIDs.30

They have agonist affinity for severaldifferent 5-HT receptors (5-HT1 A, B, D;5-HT2 A, B, C), dopamine receptors (DA2),and alpha-adrenergic receptors.31 Thegreat number of DHE-binding sites in thedorsal raphe nuclei may precipitate

migraine.32 Suppression of the firing rate ofthose serotonergic neurons and the subse-quent stabilization of serotonergic neuro-transmission is thought to be one of themodes of action of ET compounds.32

ET was first introduced for the treat-ment of migraine in the 1920s. However,its bioavailability is poor and unpre-dictable after oral administration.25 Thepotent vasoconstrictor effect of ET, whichcan last for up to 3 days, is undesirable.When compared with ET, DHE is a morepotent α-adrenergic antagonist and istherefore a potent vasoconstrictor. DHE isa more potent antiemetic than ET, hasless effect on the uterus, and is not associ-ated with rebound headache.25

Caffeine in combination with analgesicsor ET improves the absorption of the med-ication and also potentiates pain relief, pos-sibly as a result of its vasoconstrictoreffect.25 The combination of ET and caf-feine, although effective in only 50% ofpatients, is a treatment option for acutemigraine.25 The efficacy of ET is enhancedby the addition of pentobarbital and thelevorotatory alkaloids of belladonna.Although complete evidence regarding theefficacy of DHE is unavailable, intravenousadministration can abort approximately90% of attacks.33 In one study, DHE nasalspray significantly reduced the severity ofheadache.34 In another double-blind, pla-cebo-controlled study of migraine patients,those who used an intranasal formulationof DHE as opposed to placebo experiencedstatistically significant migraine resolution(ie, mild or no pain) within 4 hours of tak-ing the drug (70% versus 28%, P < .001).35

In that study, the most common adverseevents associated with intranasal DHEwere local, such as rhinitis (21% ofpatients), nausea (4%), and taste perver-sion (9%). Patients with ischemic heart dis-ease, a history of myocardial infarction, orclinical signs of coronary artery diseaseshould not take DHE.

Ergot compounds should not be pre-scribed for pregnant patients or those withperipheral vascular disease, hypertension,coronary heart disease, or impaired renalor hepatic function.25 The adverse eventsproduced by ergots include nausea, acro-


REPORTS

paresthesia, ischemia, habituation, andergot-dependent headache. According tosome research, reports of serious adverseevents that occurred after recommendeddoses of DHE were much fewer thanthose associated with ET, and physicaldependence did not occur.36 The mostfrequently noted adverse events with theintravenous administration of DHE arenausea, vomiting, and leg cramps. However,after intramuscular or intranasal adminis-tration, the incidence of nausea and vomit-ing is low and concomitant administrationof an antiemetic is not warranted.

Newer Antimigraine Drugs

A new era in antimigraine drugs began in1973 with efforts to synthesize a moreselective 5-HT1 agonist. Prior research hadindicated that serotonin 5-HT (a potentvasoconstrictor and a pain modulator) wasa factor in the generation of migraine.37

Triptan antimigraine agents are serotoner-gic agonists that act selectively. They causevasoconstriction by affecting serotonin (5-HT1B) receptors in human intracranialarteries and inhibit nociceptive transmis-sion by their effect on 5-HT1D receptors onperipheral trigeminal sensory nerve termi-nals in the meninges and central terminalin brain stem sensory nuclei. Those com-plementary sites of action are the basis ofthe clinical effectiveness of those 2 types ofagonists in treating migraine pain and itsassociated symptoms.13

Sumatriptan. In 1991, sumatriptan, afirst-generation triptan, was introduced.Sumatriptan produces agonist effects at 35-HT receptors (5-HT1B, 5-HT1D, and 5-HT1F) and weaker effects at other 5-HT1

receptors.38 It is about 5-fold more potentat 5-HT1D receptors than at 5-HT1A recep-tors when compared with DHE, which isabout 10-fold more potent at 5-HT1A thanat 5-HT1D receptors.38 Sumatriptanrelieves migraine pain and associatedsymptoms of nausea, vomiting, photopho-bia, and phonophobia.39-41

Second-Generation Triptans. Nara-triptan, zolmitriptan, and rizatriptanentered the US market in late 1997 and

1998. Almotriptan became available in theUnited States in 2001, frovatriptan hasbeen approved by the FDA, and FDAapproval of eletriptan is pending. It washoped that those second-generation trip-tans would be superior in effect to suma-triptan by providing a shorter onset ofaction after oral administration, a longerhalf-life, greater oral bioavailability, andimproved tolerability.42 However, currentclinical trial data pertaining to 2-hour painrelief and pain-free endpoints suggest thatthe differences among triptans are subtlerather than dramatic. Some patientsfound sumatriptan ineffective or difficultto tolerate, especially when administeredsubcutaneously. Many of those patientsbenefit from treatment with a newer trip-tan or with the oral form of sumatriptan.The overall efficacy rates for all orallyadministered triptans is approximately65%.42 However, patients may prefer onetreatment as opposed to another.

Adverse events associated with triptansinclude nausea, paresthesia, fatigue, som-nolence, dizziness, pain, heaviness ortightness in the chest or throat, warm orcold sensations, and dry mouth. Triptans,like ergot-containing drugs, are con-traindicated or prescribed with caution forthose with uncontrolled blood pressure,coronary artery disease, or peripheral vas-cular disease.39

Naratriptan. Naratriptan is a second-generation drug approved for marketingas an oral formulation to abort migraine.The pharmacologic profile of naratrip-tan is superior to that of sumatriptan; itsbioavailability is about 60%, whichreduces the effective dose to 2.5 mg.42

The half-life of naratriptan is about 6hours (2 to 3 times longer than that ofsumatriptan), which seems to slightlylower the percentage of patients whoexperience recurrent migraine.43 However,clinical trials indicate that 2.5 mg of nara-triptan is less effective than 100 mg ofsumatriptan but also produces feweradverse events. According to 1 study,adverse events produced by naratriptanincluded vomiting (7% of patients), nau-sea (7%), and tingling (3%).41 Adverse



events reported in other clinical trialsincluded dizziness, drowsiness, andmalaise or fatigue (4% to 7%); paresthesia(2% to 4%); and pain and pressure sensa-tion (2% to 4%). The side effect of chesttightness is not mentioned on the productlabel, which indicates that a low inci-dence of chest pain or pressure and throator neck symptoms are associated withnaratriptan. It is important to note thatthe decreased frequency of chest symp-toms associated with that drug does notdiminish the importance of alertingpatients with active or potential coronaryartery disease or cardiac ischemia to theirpotential occurrence.

Zolmitriptan. Zolmitriptan, the nextsecond-generation triptan to enter themarket, has an oral bioavailability ofapproximately 50%, which exceeds that ofsumatriptan (14%).42 In addition, the half-life of zolmitriptan (3 hours) provided amore prolonged therapeutic plasma con-centration than did sumatriptan. In arecent study, zolmitriptan was effective inrelieving acute migraine 2 hours afteradministration at an oral dose of 2.5 mg(in 67% of the patients) or 5 mg (in 65%).44

Patients using zolmitriptan 2.5 mg or 5 mghad a statistically significant 2-hourresponse rate compared with that ofpatients using sumatriptan 25 mg (P <.001). When compared with sumatriptan50 mg, zolmitriptan 2.5 mg also pro-duced a statistically significant 2-hourresponse (P = .017). The rate of headacherecurrence consistently associated withzolmitriptan is about 30%.45 Adverseevents of zolmitriptan, including thoseaffecting the CNS, are similar to those oforal sumatriptan, although zolmitriptancan cross the blood-brain barrier.42 Themost common adverse events caused byzolmitriptan 2.5 mg were nausea (in 8% to11% of the patients), dizziness (8% to 9%),paresthesia (6%), somnolence (5% to 7%),chest tightness (5%), and vomiting(2%).46,47 In clinical practice, zolmitriptan2.5 mg is equivalent to sumatriptan 50 mg.

Rizatriptan. Rizatriptan, another sec-ond-generation triptan, has an improved

pharmacologic profile and an oral bio-availability of about 40%.40 Its half-life (2.5to 3 hours) is only slightly longer than thatof sumatriptan. Rizatriptan has a morerapid onset (tmax < 1 hour) than other trip-tans currently on the market.40 In clinicaltrials, rizatriptan produced pain relief 2hours after administration at doses rang-ing from 2.5 to 40 mg; a dose of 10 mgproduced the most benefit (52% ofpatients experienced relief from headacheand few adverse events).40 Common adverseevents included dizziness (in 4% of thepatients), nausea (3%), somnolence (3%),chest symptoms (2%), and fatigue (1%). Aswith other triptans, the number of adverseevents caused by rizatriptan was dosedependent.

Newer Triptans. Eletriptan has an oralbioavailability of almost 50%; it is rapidlyabsorbed (tmax < 1 hour) but has a half-lifeof 5 hours.42 In 2 recent multicenter stud-ies, the efficacy and tolerability of eletrip-tan in acute migraine were examined. Inthe first study, doses of oral eletriptan 5,20, or 30 mg were studied in the treatmentof acute migraine in 365 patients.48 Twohours after administration of the drug,relief from headache was reported by 41%,47%, and 49% of patients who had receivedeletriptan 5, 20, or 30 mg, respectively.Thirty-five percent of the patients hadreceived placebo. In the second trial, theeffect of oral eletriptan 20, 40, or 80 mgwas compared with that of sumatriptan100 mg or placebo in 270 patients.48

Relief from headache 2 hours after drugadministration was reported by 44%, 67%,80%, and 57% of the patients who hadreceived eletriptan 20, 40, or 80 mg orsumatriptan 100 mg, respectively. In thatstudy, 25% of the patients had receivedplacebo. The adverse events produced byeletriptan were similar to those of suma-triptan. In another study, adverse eventsfrom doses of eletriptan 20 or 40 mg wereless than those produced by sumatriptan100 mg.49

Frovatriptan, another second-genera-tion triptan, has a higher affinity for 5-HT1B/1D receptors than does sumatriptan.In higher doses, frovatriptan is an agonist


REPORTS

of the 5-HT receptors that might causevasodilation on, for example, coronaryvessels.42 It is absorbed relatively slowlyand reaches its tmax 2 hours after adminis-tration; its pharmacokinetic properties aresimilar to those of naratriptan. Thus, 2hours after receiving frovatriptan 2.5 or 5mg, 38% and 37% of the patients, respec-tively, reported headache relief. Fourhours after they received the drug, 68%and 67% of patients, respectively, reportedheadache relief.50 Frovatriptan has a longhalf-life (> 10 hours); this may result in alower incidence of headache recurrence,which was reported by 7% to 25% ofpatients.51

Prophylaxis Against Migraine

The objective of prophylactic treatmentof migraine is to reduce the frequency,severity, and/or duration of attacks whilekeeping adverse events to a minimum.No single prophylactic drug is superiorwhen potential adverse events are alsoconsidered.25

Prophylactic therapy is indicated whenpatients report that their acute migrainesare not adequately controlled or thatthey often use medication to treat anacute attack (Table 3). Prophylaxis shouldbe considered when nonpharmacologicattempts have failed.25 Low doses of pro-phylactic medication should be used atfirst and slowly titrated upward.25 Treat-ment can be administered for 3 months,reassessed before being continued for anadditional 6 months or more, and thengradually withdrawn after the frequency ofmigraine attacks has been decreased.

Prophylaxis is also indicated after thediagnosis of comorbid conditions (such asdepression) that can be treated with med-ications effective in the treatment ofmigraine.52 Patients with sleep distur-bances or depression may benefit mostfrom treatment with a tricyclic antide-pressant (eg, amitriptyline, doxepin, nor-triptyline, imipramine, protriptyline,desipramine). Those with agitation orbipolar disorder or patients who have ter-minated their drug therapy may benefitfrom divalproate sodium. A beta-blockersuch as atenolol, nadolol, metoprolol, pro-

pranolol, or timolol may be the most effec-tive initial therapy in patients who experi-ence situational anxiety or “letdown”migraine or in those with hypertension. Acalcium channel blocker may be appropri-ate for patients with peripheral vasculardisease or hypertension. Doses of thosemedications to prevent migraine often aremuch lower than those used to treat acomorbid disorder.

The amine ergot alkaloid methysergideis an effective prophylactic agent inmigraine therapy.53 Although the drug isdevoid of α-adrenergic activity, long-termuse may result in pleural, pericardial, orretroperitoneal fibrosis. However, thoseproblems can usually be avoided by closemedical monitoring and by advising thepatient to take a 1-month “drug holiday”every 6 months.

Beta-blocking adrenergic drugs withoutintrinsic sympathomimetic activity arethe only class of beta-blockers effective forthe prophylaxis of migraine.25 Their effectis observed within 4 weeks and seems toincrease with time. That group of drugs isparticularly useful for treating patientswhose attacks are triggered by stress.Propranolol and timolol have been studiedin numerous clinical trials and have alsobeen found to be effective.54 However, theadverse events caused by beta-blockingdrugs must be considered before they areprescribed. Propranolol is likely to pro-duce adverse events on the CNS, whichmay cause physicians to avoid prescribingit. Metoprolol, which has been shown todecrease the number of migraine attacksby 22% to 49%, is a useful alternative topropranolol. A lack of adequate, controlledclinical trials prevents conclusions withrespect to the use of atenolol or nadolol asalternatives to propranolol.25

Valproate, a gamma-aminobutyric acidtransaminase inhibitor and activator ofglutamic acid decarboxylase, was found tobe effective in double-blind, placebo-con-trolled trials in reducing migraine fre-quency in at least 48% to 65% of patients;the placebo-treated patients experienceda reduction of 14% to 18%. Unlike otherprophylactic agents, valproate reducedthe severity and duration of migraine



attacks.55,56 Adverse events of valproateinclude nausea, tremor, transient hair loss,increase in appetite, and weight gain.Hepatotoxicity was observed in patientstreated with valproate who were youngerthan 2 years of age. Women of childbearingage who consider treatment with valproatemust be cautioned about the potentialincreased risk of spina bifida in the newborn.

The tricyclic antidepressant amitripty-line may be effective because of its 5-HT2-receptor-blocking and/or calcium-channel-blocking effect on cerebral blood vesselsand its inhibitory effect on the dorsal raphenuclei.57 Amitriptyline, which reduces thefrequency and duration of migraine attacks,is superior to placebo and more effectivethan propranolol in decreasing the severityof migraine attacks.58,59 However, amitripty-line produces anticholinergic adverseevents and causes increased appetite andweight gain. Other tricyclic antidepressantswith varying adverse-event profiles canalso be tried.

The use of calcium antagonists inmigraine prophylaxis has been disappoint-ing.60 The dihydropyridine derivativesnifedipine and nimodipine can actuallycause headache. Either verapamil or dil-tiazem is usually used to prevent migraineonly after trials of the more effective beta-blockers or amitriptyline have failed.According to 1 review, verapamil was 19%to 49% more effective than placebo indecreasing the frequency of migraineattacks.61 The most common adverseevents produced by verapamil are hyper-tension and constipation. Despite wide-spread use for treatment of migraine, theresults of clinical studies of diltiazem are“underwhelming.”

Tolerability and Safety of Migraine Treatment

Some adverse events (particularly nau-sea) of drugs used to treat migraine canmimic the signs or symptoms of the disor-der. It is therefore critical to distinguishdrug-induced symptoms from thosecaused by headache. Nausea, a commonsymptom of migraine, occurs in 78% ofmigraine sufferers. Because it is oftenmoderate to severe, nausea contributes to

the disability of the patient.62 It can alsointerfere with the administration of oralmedication. Exacerbation of nausea afterthe administration of oral medication canindicate either the development of newnausea or a disease-related worsening ofnausea, and alternative medications forthe treatment of migraine should beexplored.

Clinical Safety of Dihydroergota-mine and Ergotamine. The clinical safe-ty experience with DHE is based on 21clinical studies; unfortunately, few ofthose studies had clinical controls, manywere open label and unblinded, and mostdid not compare DHE with placebo.63

Adverse events were often not document-ed systematically because the focus of thestudies was the efficacy of the medication.No clinical studies evaluated the effects orefficacy of long-term intramuscularadministration of DHE, and only a fewevaluated the results of repetitive intra-venous administration in hospital patients.

Although nausea was reported in anumber of trials after treatment of migrainewith DHE, critical quantitative observa-tions demonstrated that the drug-inducedsymptom was difficult to differentiatefrom nausea caused by migraine. Opentrials reported few adverse events ofDHE. In summary, closed clinical trialsand open-label studies suggested thatserious adverse events occur very rarelyafter a recommended dose of DHE hasbeen taken, regardless of the route ofadministration.64

The clinical safety experience with ETindicates that it is much more likely thanDHE to produce nausea and vomiting,uterine effects, and rebound headache.63

Most of the adverse events produced byET were associated with excessive dosageand/or long-term administration. Theperipheral vasoconstrictor effect of ET isconsiderably stronger than that of DHE.When primary care physicians prescribeeither DHE or ET, they must be aware thatboth are safe in the treatment of migrainewith or without aura when used in recom-mended doses and frequencies in adultswho have no contraindications to the


REPORTS

medications. When compared with ET,DHE causes less arterial constriction and(according to indirect comparisons) lessfrequent nausea and vomiting.63

The Quality Standards Subcommitteeof the American Academy of Neurologyappointed an advisory committee fromexperts in its headache and facial painsection to review the clinical literature onthe appropriate use of DHE and ET in thetreatment of migraine.65 On the basis ofthat thorough literature review, practiceguidelines were formulated to define thelimits of ergot use. ET and DHE werefound to be safe and effective for the treat-ment of migraine as long as recommendeddosages were not exceeded and high-riskpatients (those with uncontrolled hyper-tension, coronary or peripheral artery dis-ease, thyrotoxicosis, or sepsis) did notreceive those drugs. The committee alsorecommended restricting the use of ETin some instances, because its overusehas been associated with physical andpsychological dependence. Drug-dependentpatients often experience predictablerecurrent and/or rebound headaches, andsubsequent medications are required toalleviate the symptoms of withdrawal,such as nausea. None of those symptomshas been associated with DHE.

Clinical Safety of Triptans. First- andsecond-generation triptans represent abreakthrough treatment for patients withacute migraine. However, those drugs causesome degree of coronary vasoconstriction insusceptible patients.66,67 At therapeutic doses,triptans are unlikely to cause myocardialischemia in individuals with normal coronarycirculation.66 Although that effect is notclinically significant for patients who donot have coronary artery disease, triptansare contraindicated in those who have orare at risk for that disorder.66

Adverse-event databases compiled forthe triptans show that the risk of life-threatening cardiovascular events pro-duced by those medications is probablyless than 1 in 1 million.67 The level of riskassociated with triptans is actually similarto (or perhaps even better than) that ofprescription NSAIDs.67 The patient’s level

of risk (rather than the number of risk fac-tors) is the most important factor.67

“Therapeutic gain” refers to the propor-tion of patients who respond to treatmentwith a drug tested minus the proportion ofpatients who respond to placebo. A reviewof 30 clinical trials demonstrated that, 1hour after administration, subcutaneoussumatriptan 6 mg administered for theacute treatment of migraine resulted in agreater therapeutic gain than did 100 mgof orally administered sumatriptan or 20mg of intranasal sumatriptan 2 hours afteradministration.68 Although 6 mg of subcu-taneous sumatriptan is more effectivethan the other doses and dosage formsmentioned above, it causes more adverseevents than does 100 mg of oral sumatrip-tan, which appears to have the better ben-efit-to-risk ratio. However, most adverseevents produced by the subcutaneousform of the drug were mild and short-last-ing, and patients may find that the greaterefficacy and quicker onset of action ofsubcutaneous sumatriptan outweigh thehigher incidence of adverse events.69

Placebo-controlled studies have report-ed an incidence of chest-related adverseevents in up to 4% of patients treated withsecond-generation triptans, comparedwith an incidence ranging from less than1% to 3% in placebo-treated patients.20 Ananalysis of safety data indicates thatmigraine patients seem to have a higherlevel of risk for cardiovascular eventsthan does the general population; thisimplies that such events may be associat-ed with the underlying condition ratherthan the treatment.70,71 However, thoseagents should be used with caution in anypatient with vascular risk factors.

Clinical judgment is key when the deci-sion to use triptans is made. If a patienthas ischemic heart disease and uncon-trolled high blood pressure, the primarycare physician or specialist should not pre-scribe a triptan.70 A patient with a familyhistory of heart disease and a high choles-terol level should first receive other med-ications for migraine treatment beforetreatment with a triptan is initiated.

Safety is indeed a viable concern in theselection of appropriate migraine treat-



ment for a patient; however, it is importantto recognize that whether the patient cantolerate the drug is also an important (yetseparate) issue. It is crucial to approachthose 2 distinct characteristics as separatefactors in treatment choice. The safety ofa drug is of primary importance to ensurethat a patient is least likely to experienceany serious life-threatening outcomesfrom treatment. After the safety of treat-ment has been established, the tolerabil-ity of the treatment (ie, the point atwhich adverse events are sufficientlyreduced so that a patient is most likely tocontinue treatment) becomes an addedconsideration.

Almotriptan—Pharmacology, Efficacy,and Tolerability

Almotriptan, the most recent 5-HT1B/1D

agonist agent, demonstrates selective andequipotent nanomolar affinity for 5-HT1B

and 5-HT1D receptors; this mechanism ofaction is similar to that of sumatriptan.72

Functional affinity assays indicate thatalmotriptan has a lower potency thandoes sumatriptan at the 5-HT1D receptorand that its potency at the 5-HT1B recep-tor is similar to that of rizatriptan andsumatriptan.72 Almotriptan exhibits 25times the vasoconstrictor activity ofsumatriptan in the human meningealartery.72 The oral formulation of almotrip-tan has the highest bioavailability (70%)among the second-generation triptans; itshalf-life, however, is 3.0 to 3.7 hours.Almotriptan is rapidly absorbed after anoral dose and reaches a peak plasma con-centration of 66.2 ng/mL at 1.38 hoursafter administration.73 The plasma elimi-nation half-life of almotriptan is 3.9 hoursin healthy volunteers. This may have clin-ical relevance, especially when comparedwith sumatriptan’s half-life of about 2hours (regardless of the route of adminis-tration).71 Sumatriptan’s shorter half-lifemay explain its association with recurringheadache, which has affected 21% to57% of patients in trials of both oral andsubcutaneous formulations of the drug.71

Oral almotriptan has a bioavailability of70%. In contrast, zolmitriptan has anabsolute bioavailability of 49%, and

sumatriptan has an absolute bioavailabili-ty of only 14%.73-75

Of the approximately 45% of almotrip-tan that is metabolized, about 27% ismetabolized by monoamine oxidase A and12% by the cytochrome P-450 isozymesCYP 3A4 and 2D6. As a result, almotriptanhas no substantial effect on the pharmaco-kinetics of fluoxetine, which is metabo-lized by CYP 2D6, or other commonly useddrugs such as verapamil or propranolol.76-78

Moclobemide, a reversible monoamineoxidase-A (MAO-A) inhibitor, modestlydecreased the clearance of almotriptan.Thus the lowest available dose of almotrip-tan should be used in patients treated withMAO-A inhibitors.79 MAO-A inhibitors dra-matically reduce the metabolism of suma-triptan and zolmitriptan; thus concurrentadministration of MAO-A inhibitors or theuse of sumatriptan or zolmitriptan within 2weeks of the discontinuation of MAO-Ainhibitor therapy is contraindicated.

The efficacy of almotriptan was estab-lished in 3 multicenter, randomized, dou-ble-blind, placebo-controlled trials.80-82 Inthose studies, a significantly higher per-centage of patients who received eitheralmotriptan 6.25 or 12.5 mg as opposed toplacebo experienced pain relief (mild or nopain) 2 hours after treatment. A higherpercentage of patients in all 3 studiesreported pain relief after treatment withthe 12.5-mg dose as opposed to the 6.25-mg dose. In 2 of those studies, oralalmotriptan (as opposed to placebo) pro-duced statistically significant 2-hour painrelief rates (59% versus 34% and 65% ver-sus 33%, respectively), and 1 hour afteradministration, significant pain relief wasalso experienced by patients given oralalmotriptan as opposed to placebo (36%versus 19%, P = .007; and 34% versus 21%,P = .001).80,81 In Table 4, the 2-hour pain-relief rates after oral almotriptan adminis-tration during an initial migraine aresummarized.

When compared with the results ofplacebo, oral almotriptan 12.5 mg provid-ed consistent pain relief over the course of3 consecutive migraine attacks in anotherdouble-blind, placebo-controlled study.82

Although oral almotriptan 12.5 mg also


REPORTS

produced pain relief rates similar to thoseof oral sumatriptan 100 mg in a random-ized, double-blind, placebo-controlledclinical study, almotriptan 12.5 mg wasassociated with a significantly lower inci-dence of treatment-related adverse events(P < .05).81 In addition, almotriptan 12.5mg and sumatriptan 50 mg were com-pared in a randomized, double-blindtrial.83 Pain relief occurred 2 hours afteradministration in 58% of patients treatedwith almotriptan and in 57% of thosetreated with sumatriptan. However, signif-icantly fewer patients in the almotriptangroup (P < .05) experienced treatment-related adverse events (9.1% versus 15.5%)and chest symptoms in particular (0.3%versus 2.2%).

The tolerability of almotriptan was inmost instances similar to that of placebo.In controlled clinical trials, nausea in 2%of the patients was the only adverse eventrecorded in 2% or more of those treatedwith almotriptan.84 Headache was fre-quently noted when oral almotriptan 6.25to 25 mg was administered. Infrequentadverse events, all of which were mild andtransient in nature, included abdominalcramps, vasodilation, palpitations, tachy-cardia, dry mouth, diarrhea, vomiting, anddyspepsia. In those trials, the adverseevents were similar to those attributed toplacebo.84 Patients who experienced migraine-associated photophobia, phonophobia, nau-sea, or vomiting at baseline had a decreasedincidence of those symptoms after theadministration of almotriptan as opposed toplacebo.

In controlled clinical studies, a total of2809 patients were treated with almotrip-tan (527 with 6.25 mg, 1313 with 12.5 mg,and 387 with 25 mg) or sumatriptan (582with 50 mg).84 The overall adverse eventrates in those studies were 12.4% (thosewho received placebo), 14% (almotriptan6.25 mg), 15.4% (almotriptan 12.5 mg),20.4% (almotriptan 25 mg), and 19.4%(sumatriptan 50 mg). The most commonadverse events associated with almotrip-tan use (at a rate of at least 1%—a rategreater than that of placebo) in the con-trolled studies at the recommended dosesof 6.25 or 12.5 mg were headache, dry

mouth, nausea, paresthesia, and somno-lence. No adverse events in the groupswho received the 6.25 or 12.5-mg doseoccurred at a rate of 1 or more percentagepoints higher than that of the placebogroup. Dry mouth, paresthesia, and som-nolence are adverse events produced bytriptans, and nausea and headache areoften observed in migraine patients. Otheradverse events associated with triptan use,such as asthenia, chest pain, localizedpain, palpitation, vasodilation, and dizzi-ness, were not associated with almotriptanadministered at recommended doses. Forboth doses, the only adverse event thatoccurred in 2% or more of the patients wasnausea (2% in those who receivedalmotriptan 12.5 mg).

The adverse-event profile for sumatrip-tan in the studies cited above is consis-tent with data from other studies of thatdrug.85,86 Although the types of adverseevents in the almotriptan-treated groupswere similar to those observed in thegroups treated with sumatriptan, almotrip-tan 6.25 and 12.5 mg produced lower ratesof chest pain and nausea than did suma-triptan 50 mg. Vomiting occurred at ahigher rate in the placebo-treated group(1.6%) than in any of the other main treat-ment groups (all > 1%). Adverse-eventrates (particularly for chest pain, nausea,



Table 4. Clinical Studies of Oral Almotriptan DemonstratingPain Relief* in the Treatment of Acute Migraine

Placebo Almotriptan AlmotriptanStudy Author(s) (%) 6.25 mg (%) 12.5 mg (%)

Dahlöf et al80 33.8 56.3† 58.5‡

(n = 80) (n = 166) (n = 164)

Dowson81 42.4 — 56.8§

(n = 99) (n = 183)

Pascual et al82 33.0 55.6‡ 64.9‡

(n =176) (n = 374) (n = 370)

*Pain relief was noted at 2 hours after administration of the drug for initialheadache.†P = .002 in comparison with placebo.‡P ≤ .001 in comparison with placebo.§P = .025 in comparison with placebo.

dizziness, or somnolence) in the groupstreated with higher doses of almotriptan(25, 100, or 150 mg) were usually higherthan those in the patients who receivedlower doses of the drug.

Conclusions

Migraine is an underdiagnosed andundertreated disorder that is experiencedmost often during peak productive years(25 to 55 years of age). The recently devel-oped IHS criteria for headache classifica-tion have provided a uniform casedefinition that has facilitated epidemiolog-ic research on headaches. The disabilitycaused by headaches has a great effect onindividuals and on society, and healthinterventions are critical to the manage-ment of those disorders. Physicians mustbe aware of the diagnostic criteria forheadaches and must be able to prescribeeffective therapy in accordance with thepatient’s possible intolerance of variousmedications.

Primary care physicians are concernedwith 2 critical aspects in treating migrainepatients. The first is the efficacy of anagent in rapidly relieving headache andpreventing recurrence. The second is theknowledge that the agent does not produceharmful adverse events. Therefore, at thisstage in the development of triptans usedto treat acute migraine, the tolerability andsafety of the drug are very important con-siderations, especially when several agentsare now available to relieve headache. Inmost patients, triptans alleviate migrainepain in 2 hours, regardless of the time ofonset. However, the adverse events pro-duced by triptans must be considered bythe primary care physician before he orshe prescribes a particular drug.

Although similar adverse events areproduced by triptans as a class, a benefit-to-risk ratio must always be considered foreach drug in that class. This implies that aparticular oral dose of a triptan can pro-duce an excellent therapeutic effect aswell as minimal adverse events. As newer,more effective oral triptans are developed,it is hoped that an improved benefit-to-risk ratio will also be achieved. Naratriptanappears to produce fewer adverse events

than do the other marketed triptans.However, when compared with othertriptans, its delayed onset of action is adisadvantage.

Almotriptan is characterized by a rapidonset of action, effectiveness over 24hours with a low recurrence rate ofmigraine, and few adverse events. It is notcontraindicated in patients with severerenal or hepatic impairment. However,because of the potential of 5-HT1B/1D recep-tor agonists to cause coronary vasospasm,almotriptan should not be given topatients with documented ischemic orvasospastic coronary artery disease,ischemic heart disease, or uncontrolledhypertension. Low tolerability is not syn-onymous with improved safety.

Almotriptan is well tolerated. Controlledclinical trials of that drug indicate that attherapeutic doses, it causes a lower inci-dence of chest pain than does sumatrip-tan, that it produces no dose-relatedclinically relevant effects on electrocardio-graphic results, and that (when comparedwith placebo) it produces a low incidenceof somnolence and other CNS effects andhas a similar tolerability profile. In clinicaltrials in which 20,000 migraine attacksoccurred in nearly 4000 patients, thedropout rate of almotriptan-treated indi-viduals was very low, and those patientsexperienced no unanticipated adverseevents. Almotriptan should expand thearmamentarium of antimigraine drugsavailable to physicians and patients.

. . .REFERENCES . . .

1. Bartelson JD. Treatment of migraine headaches.Mayo Clin Proc 1999;74:702-708.2. Lipton RB, Stewart WF, von Korff M. Migraineimpact and functional disability. Cephalalgia1995;15(suppl 15):4-9.3. Hu XH, Markson LE, Lipton RB, Stewart WF,Berger ML. Burden of migraine in the United States:Disability and economic costs. Arch Intern Med1999;159:813-818.4. Lipton RB, Stewart WF, Simon D. Medical consul-tation for migraine: Results from the AmericanMigraine Study. Headache 1998;38:87-96.5. Gallagher RM, Kunkel R. Migraine patient con-cerns affecting compliance: Results from the NHF sur-vey. Headache. 2002. In press.6. Goadsby PJ. Current concepts of the pathophysiol-ogy of migraine. Neurol Clin 1997;15:27-42.


REPORTS

7. Stewart WF, Shechter A, Rasmussen BK. Migraineprevalence. A review of population-based studies.Neurology 1994;44(suppl 4):S17-S23.8. Prevalence of chronic migraine headaches—UnitedStates, 1980-1989. MMWR Morb Mortal Wkly Rep1991;40:331-338.9. Sillanpaa M. Headache in children. In: Olesen J,ed. Headache Classification and Epidemiology. NewYork, NY: Raven Press; 1994:273-281.10. Rasmussen BK. Epidemiology of headache.Cephalalgia 1995;15:45-68.11. Lipton RB. Disability assessment as a basis forstratified care. Cephalalgia 1998;18(suppl 22):40-46.12. Marcus DA. Serotonin and its role in headachepathogenesis and treatment. Clin J Pain 1993;9:159-167.13. Hargreaves RJ, Shepheard SL. Pathophysiology of migraine—new insights. Can J Neurol Sci 1999;26(suppl 3):S12-S19.14. Headache Classification Committee of theInternational Headache Society. Classification anddiagnostic criteria for headache disorders, cranialneuralgias and facial pain. Cephalalgia 1988;8(suppl7):1-96.15. Olesen J, Lipton RB. Migraine classification anddiagnosis. International Headache Society criteria.Neurology 1994;44(suppl 4):S6-S10.16. Capobianco DJ, Cheshire WP, Campbell JK. Anoverview of the diagnosis and pharmacologic treatmentof migraine. Mayo Clin Proc 1996;71:1055-1066.17. Pryse-Phillips WE, Dodick DW, Edmeads JG.Guidelines for the diagnosis and management ofmigraine in clinical practice. CMAJ 1997;156:1273-1287.18. Diamond S. Diagnosing and Managing Headache.2nd ed. Caddo, OK: Professional Communications,Inc; 1998.19. Cady RK, Sheftell F, Lipton RB, et al. Effect ofearly intervention with sumatriptan on migraine pain:Retrospective analyses of data from three clinical tri-als. Clin Ther 2000;22:1035-1048.20. Deleu D, Hanssens Y. Current and emerging sec-ond-generation triptans in acute migraine therapy: Acomparative review. J Clin Pharmacol 2000;40:687-700.21. Silberstein SD. Practice parameter: Evidence-based guidelines for migraine headache (an evidence-based review): Report of the Quality StandardsSubcommittee of the American Academy ofNeurology. Neurology 2000;55:754-762.22. Lobo BL, Cooke SC, Landy SH. Symptomaticpharmacotherapy of migraine. Clin Ther1999;21:1118-1130.23. Buzzi MG, Sakas DE, Moskowitz MA.Indomethacin and acetylsalicylic acid block neuro-genic plasma protein extravasation in rat dura matter.Eur J Pharmacol 1989;165:251-258.24. Peatfield RC, Petty RG, Rose FC. Double blindcomparisons of mefenamic acid and acetaminophen(paracetamol) in migraine. Cephalalgia 1983;3:129-134.25. Deleu D, Hanssens Y, Worthing EA. Symptomaticand prophylactic treatment of migraine: A criticalreappraisal. Clin Neuropharmacol 1998;21:267-279.26. Massiou H, Serrurier D, Lasserre O, BousserMG. Effectiveness of oral diclofenac in the acute

treatment of common migraine attacks: A double-blind study versus placebo. Cephalalgia 1991;11:59-63.27. Silberstein DS, Lipton RB, Dalessio DJ, eds.Wolff's Headache and Other Head Pain. 7th ed. NewYork, NY: Oxford University Press; 2001.28. Carleton SC, Shesser RF, Pietzrak MP, et al.Double-blind, multicenter trial to compare the efficacy of intramuscular dihydroergotamine plushydroxyzine versus intramuscular meperidine plushydroxyzine for the emergency department treatmentof acute migraine headache. Ann Emerg Med1998;32:129-138.29. Ellis GL, Delaney J, DeHart DA, Owens A. Theefficacy of metoclopramide in the treatment ofmigraine headache. Ann Emerg Med 1993;22:191-195.30. Ferrari MD. Migraine. Lancet 1998;351:1043-1051.31. Silberstein SD. The pharmacology of ergotamineand dihydroergotamine. Headache 1997;37(suppl1):S15-S25.32. Goadsby PJ, Gundlach AL. Localization of 3H-dihydroxyergotamine-binding sites in the cat centralnervous system: Relevance to migraine. Ann Neurol1991;29:91-94.33. Saadah HA. Abortive headache therapy in theoffice with intravenous dihydroergotamine plusprochlorperazine. Headache 1992;32:143-146.34. Dihydroergotamine Nasal Spray MulticenterInvestigators. Efficacy, safety, and tolerability of dihy-droergotamine nasal spray as monotherapy in thetreatment of acute migraine. Headache 1995;35:177-184.35. Gallagher RM, the Dihydroergotamine WorkingGroup. Acute treatment of migraine with dihydroer-gotamine nasal spray. Arch Neurol 1996;53:1285-1291.36. Raskin NH. Repetitive intravenous dihydroergota-mine as therapy for intractable migraine. Neurology1986;36:995-997.37. Goadsby PJ. Serotonin 5-HT1B/1D receptor ago-nists in migraine. Comparative pharmacology and itstherapeutic implications. CNS Drugs 1998;10:271-286.38. Peroutka SJ. 5-Hydroxytryptamine receptor sub-types. Pharmacol Toxicol 1990;67:373-383.39. Weiss J. Assessment and management of theclient with headaches. Nurse Pract 1993;18:44-54.40. Diener HC, Limmroth V. Acute management ofmigraine: Triptans and beyond. Curr Opin Neurol1999;12:261-267.41. Diener HC, Kaube H, Limmroth V. Antimigrainedrugs. J Neurol 1999;246:515-519.42. Limmroth V, Diener HC. New anti-migrainedrugs: Present and beyond the millennium. Int J ClinPract 1998;52:566-570.43. Klassen A, Elkind A, Asgharnejad M, Webster C,Laurenza A. Naratriptan is effective and well toleratedin the acute treatment of migraine. Results of a dou-ble-blind, placebo-controlled, parallel-group study.Naratriptan S2WA3001 Study Group. Headache1997;37:640-645.44. Gallagher RM, Dennish G, Spierings EL, ChitraR. A comparative trial of zolmitriptan and sumatriptanfor the acute oral treatment of migraine. Headache2000;40:119-128.



45. Ferrari MD. 311C90: Increasing the options fortherapy with effective acute antimigraine 5HT1B/1Dreceptor agonists. Neurology 1997;48(suppl 3):S21-S24.46. Rapoport AM, Ramadan NM, Adelman JU, et al.Optimizing the dose of zolmitriptan (Zomig, 311C90)for the acute treatment of migraine. A multicenter,double-blind, placebo-controlled, dose range-findingstudy. The 017 Clinical Trial Study Group. Neurology1997;49:1210-1218.47. Solomon GD, Cady RK, Klapper JA, Earl NL,Saper JR, Ramadan NM. Clinical efficacy and tolera-bility of 2.5 mg zolmitriptan for the acute treatment of migraine. The 042 Clinical Trial Study Group.Neurology 1997;49:1219-1225.48. Farkkhila M, Diener HC, Dahlöf C, Steiner TJ,on behalf of the Eletriptan Steering Committee. Adose-finding study of eletriptan (5-30 mg) for theacute treatment of migraine [abstract]. Cephalalgia1996;16:387.49. Jackson NC, for the Eletriptan SteeringCommittee. A comparison of oral eletriptan (20-80mg) and oral sumatriptan (100 mg) in the acute treat-ment of migraine [abstract]. Cephalalgia 1996;16:368.50. Goldstein J, Keywood C. A low-dose range find-ing study of frovatriptan, a potent selective 5-HT1B/1Dagonist for the treatment of migraine. Funct Neurol1998;13:178.51. Migraine, frovatriptan. Available at http://www.vernalis.com/r_d_portfolio/content1/content.htmAccessed April 30, 2001.52. Tomkins GE, Jackson JE, O’Malley PG, Balden E,Santero JE. Treatment of chronic headache with anti-depressants: A meta-analysis. Am J Med 2001;111:54-63.53. Steardo L, Marano E, Barone P, Denman DW,Monteleone P, Cardone G. Prophylaxis of migraineattacks with a calcium-channel blocker: Flunarizineversus methysergide. J Clin Pharmacol 1986;26:524-528.54. Massiou H, Bousser MG. Beta-blocqants etmigraine. Pathol Biol (Paris). 1992;40:373-380.55. Jensen R, Brink T, Olesen J. Sodium valproatehas a prophylactic effect in migraine without aura: Atriple-blind, placebo-controlled crossover study.Neurology 1994;44:647-651.56. Mathew NT, Saper JR, Silberstein SD, et al.Migraine prophylaxis with divalproex. Arch Neurol1995;52:281-286.57. Peroutka SJ. 5-Hydroxytryptamine receptor sub-types and the pharmacology of migraine. Neurology1993;43:S34-S38.58. Couch JR, Hassanein RS. Amitriptyline inmigraine prophylaxis. Arch Neurol 1979;36:695-699.59. Ziegler DK, Hurwitz A, Preskorn S, HassaneinRS, Siem J. Propranolol and amitriptyline in prophy-laxis of migraine. Pharmacokinetic and therapeuticeffects. Arch Neurol 1993;50:825-830.60. Andersson KE, Vinge E. Beta-adrenoceptor block-ers and calcium antagonists in the prophylaxis andtreatment of migraine. Drugs 1990;39:355-373.61. Ramadan NM, Schultz LL, Gilkey SJ. Migraineprophylactic drugs: Proof of efficacy, utilization andcost. Cephalalgia 1997;17:73-80.62. Lipton RB, Solomon S, Newman LC, Sheftell FD.Gastrointestinal symptoms in migraine: Results fromthe AASH-Gallup survey [abstract]. Headache1995;45:563.

63. Lipton RB. Ergotamine tartrate and dihydroergota-mine mesylate: Safety profiles. Headache 1997;37(suppl 1):S33-S41.64. Silberstein SD. Migraine symptoms: Results of asurvey of self-reported migraineurs. Headache1995;35:387-396.65. Young WB. Appropriate use of ergotamine tartrateand dihydroergotamine in the treatment of migraine:Current perspectives. Headache 1997;37(suppl 1):S42-S45.66. MaassenVanDenBrink A, Reekers M, Bax WA,Ferrari MD, Saxena PR. Coronary side-effect potentialof current and prospective antimigraine drugs.Circulation 1998;98:25-30.67. MacIntyre PD, Bhargava B, Hogg KJ, GemmillJD, Hillis WS. Effect of subcutaneous sumatriptan, aselective 5HT1 agonist, on the systemic, pulmonary,and coronary circulation. Circulation 1993;87:401-405.68. Tfelt-Hansen P. Efficacy and adverse events ofsubcutaneous, oral, and intranasal sumatriptan usedfor migraine treatment: A systematic review based onnumber needed to treat. Cephalalgia 1998;18:532-538.69. Simmons VE, Blakebourough P. The safety profileof sumatriptan. Rev Contemp Pharmacother1994;5:319-328.70. O'Quinn S, Davis RL, Gutterman DL, Part GD,Fox AW. Prospective large-scale study of the tolera-bility of subcutaneous sumatriptan injection for acutetreatment of migraine. Cephalalgia 1999;19:223-231.71. Perry CM, Markham A. Sumatriptan. An updatedreview of its use in migraine. Drugs 1998;55:889-922.72. Bou J, Domenech T, Puig J, et al. Pharmacologicalcharacterization of almotriptan: An indolic 5-HTreceptor agonist for the treatment of migraine. Eur JPharmacol 2000;410:33-41.73. Cabarrocas X, Salva M. Pharmacokinetic andmetabolic data on almotriptan, a new antimigrainedrug. Cephalalgia 1997;17:421.74. Fowler PA, Lacey LF, Thomas M, Keene ON,Tanner RJ, Baber NS. The clinical pharmacology,pharmacokinetics and metabolism of sumatriptan. Eur Neurol 1991;31:291-294.75. Seaber E, On N, Dixon RM, et al. The absolutebioavailability and metabolic disposition of the novelantimigraine compound zolmitriptan (311C90). Br JClin Pharmacol 1997;43:579-587.76. Fleishaker JC, Ryan KK, Carel BJ, Azie NE.Evaluation of the potential pharmacokinetic interac-tion between almotriptan and fluoxetine in healthyvolunteers. J Clin Pharmacol 2001;41:217-223.77. Fleishaker JC, Sisson TA, Carel BJ, Azie NE. Lackof pharmacokinetic interaction between the antimi-graine compound, almotriptan, and propranolol inhealthy volunteers. Cephalalgia 2001;21:61-65.78. Fleishaker JC, Sisson TA, Carel BJ, Azie NE.Pharmacokinetic interaction between verapamil andalmotriptan in healthy volunteers. Clin PharmacolTher 2000;67:498-503.79. Fleishaker JC, Ryan KK, Carel BJ, Azie NE. Effectof MAO-A inhibition on the pharmacokinetics of anovel antimigraine agent, almotriptan, in humans. Paperpresented at: Annual Meeting of the American Academyof Neurology; April 17-24, 1999; Toronto, Ontario. 80. Dahlöf C, Tfelt-Hansen P, Massiou H, Fazekas A,for the Almotriptan Study Group. Dose finding,placebo-controlled study of oral almotriptan in the


REPORTS

acute treatment of migraine. Neurology 2001;57:1811-1817.81. Dowson A. Almotriptan is an effective and well-tolerated treatment for migraine pain: Results of a ran-domised, double-blind, placebo-controlled clinicaltrial. Cephalalgia 2002. In press.82. Pascual J, Falk RM, Piessens F, et al. Consistentefficacy and tolerability of almotriptan in the acutetreatment of multiple migraine attacks: Results of alarge, randomized, double-blind, placebo-controlledstudy. Cephalalgia 2000;20:588-596.83. Spierings EL, Gomez-Mancilla B, Grosz DE,Rowland CR, Whaley FS, Jirgens KJ. Oral almotriptanvs. oral sumatriptan in the abortive treatment ofmigraine: A double-blind, randomized, parallel-

group, optimum-dose comparison. Arch Neurol2001;58:944-950.84. Dodick DW. Oral almotriptan in the treatment ofmigraine: Safety and tolerability. Headache 2001;41:449-455.85. Pfaffenrath V, Cunin G, Sjonell G, Prendergast S.Efficacy and safety of sumatriptan tablets (25 mg, 50mg, and 100 mg) in the acute treatment of migraine:Defining the optimum doses of oral sumatriptan.Headache 1998;38:184-190.86. Multinational Oral Sumatriptan and CafergotComparative Study Group. A randomized, double-blind comparison of sumatriptan and cafergot in theacute treatment of migraine. Eur Neurol 1991;31:314-322.



PROJAP A14 Gallagher S58-S73€¦ · often delay taking medication, which ... The prevalence of a...

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