Articles

Naratriptan is effective and well tolerated

in the acute treatment of migraine
Results of a double-blind, placebo-controlled,
crossover study
Ninan T. Mathew, MD; Mahnaz Asgharnejad, PharmD; Margaret Peykamian, MD, DM, FRCP(c.1; and
Antonio Laurenza, MD; on behalf of the Naratriptan S2WA3003 Study Group*’

Article abstract-The efficacy and tolerability of naratriptan tablets (2.5 mg, 1 mg, and 0.25 nig) compared with placebo
in the acute treatment of migraine were evaluated in a randomized, double-blind, four-period crossover sixdy. Five
hundred eighty-six assessable patients received naratriptan 2.5 mg, 595 received 1 mg, 591 received 0.25 mg, 602 received
placebo. Headache relief (moderate or severe pain reduced to mild or none) 4 hours postdose was reported in 68% of
patients after treatment with naratriptan 2.5 mg compared with 57%after 1 mg, 39%’after 0.25 mg, and 33% after placebo
( p ‘< 0.001 naratriptan 2.5 mg and 1 mg versus placebo and 1 mg and 2.5 mg versus 0.25 mg). Headache relief was
maintained 8, 12, and 24 hours postdose with no use of rescue medication or a second dose of study medicat.ion by
significantly ( p < 0.001) greater percentages of patients after treatment with naratriptan 2.5 mg or 1 mg compared with
naratriptan 0.25 mg or placebo. Naratriptan was also more effective than placebo in reducing clinical disabilit,y and t h r
incidences of nausea, photophobia, and phonophobia. The overall incidence of adverse events and the incidences of specific
adverse events did not differ in the naratriptan groups compared with placebo. No clinically relevant changes in ECG,
blood pressure, or laboratory findings were reported. These data demonstrate that naratriptan is effective and well
tolerat,ed for the acute treatment of migraine. The 2.5-mg dose was associated with superior efficacy, whereas its adverse
event profile was similar t o that of placebo.
NISIJKOI,OGY 1997;49:148.5-1490

The 5HT, agonist sumatriptan is effective and well
tolerated in the majority of patients in clinical trials
and medical practice. I-(’ Research initiatives since the
introduction of sumatriptan have focused on identi-
fying and developing compounds for patients who do
not respond adequately to sumatriptan or other ther-
apies. For example, approximately one-third of pa-
tients experience recurrence of headache after it is
initially relieved with a variety of migraine thera-
pies, including sumatriptan,”I the 5HT, agonists
rizatriptanH and zolmitriptan (311C90),9 and older
medications such as ergotamine.’OIn addition to re-
currence, poor tolerability may limit the use of some
currently available migraine therapies.
Chemically related to sumatriptan, the novel 5HT,
agonist naratriptan has the biological and pharmaco-
logic properties of an effective migraine medication
that may fulfill unmet therapeutic needs. Naratriptan
interacts with cranial 5HT, receptors more potently in
vitro and in vivo than does sumatriptan,” and it has a
longer half-life and higher oral bioavailability (Glaxo
Wellcome data on file). This report of a double-blind,
placebo-controlled, four-way, crossover trial tests the
efficacy and tolerability of naratriptan in the acute
treatment of migraine.
M e t h o d s . Patients. Men and women aged 18 t o 65
years with at least a 1-year history of niigrainle with or
without a u r a diagnosed according to International Head-
ache Society criterial2 were eligible for the study Patients
had to have experienced between 1 and 6 molderate or
severe migraine attacks per month in each of the 2 months
before screening. Patients were excluded from i,he study
for any of the following reasons: basilar or hemiplegic mi-
graine; pregnancy or lactation; history suggestive of car-
diovascular disease or cerebrovascular p,2thology;
Raynaud’s syndrome; epilepsy; impaired hepatic or renal
function; 2 1 0 episodes or 15 days per month of‘ tension-
type headache in the 2 months before screening; blood

’ Mcwibers 11f tht. Naratriptan S2WA:i003 Study Group arc listed in the Appendix on page 1489.
I+om thc Houston Htwdiiche Clinic (Dr. Mathew) and the Dc.partment of Clinical Research (Drs. Asgharnejad, I’cykamian, and Laurcnza), Glaxw W e l l c t ~ i w .
I Z L ~ S ~ ~ H ~Triaiiglc~
CII Park. N C
S u p p o r t d h y Glaxo Wellconic Research Institute.
I’i.twntet1 i n part ;it the 49th annual nicetiiig of the American Academy of Neurology, Boston, MA, April 1997; the Anicrican Association for t h c Study i f
Iicntlarhc~.Ncw York. NY. June 1997; and the International Headache Congress, Amsterdam, the Netherlands, June 1997.
12caLivctl M a i d i 31, 1997. Accepted i n final forni July 9, 1997.
pondence and reprint requests ti, Dr. Ninan 7’. Mathew, The Houston Headache Clinic, 1213 Herinann Drive, Suite 350, Houston, TX 77004
Copyright 0 1997 by the American Acadeniy of Ncurclogy 1485
 pressure 295 mm Hg diastolic or 160 mm Hg systolic at
screening; history of ergotamine abuse within the past 3
months; or lithium use within 2 weeks of screening. All
patients provided written informed consent to participate
in the study.
Procedures. The protocol for this randomized, double-
blind, four-period, crossover study was approved by an in-
stitutional review board for each of the 50 study sites in
the United States. Screening procedures included physical
examinations, reviews of medical and migraine histories,
12-lead ECGs, and standard chemistry and hematology
tests. Patients were given instructions in the use of diary
cards for recording efficacy assessments.
Patients judged capable of correctly completing the di-
ary cards were randomized to 1 of 24 sequences in which
each patient received all four doses of study medication
(naratriptan tablets 2.5 mg, 1 mg, 0.25 mg, and matching
placebo) to treat four moderate or severe migraine attacks
at home.
Patients were asked not to take ergotamine-containing
medications or sumatriptan (any formulation) within 24
hours before o r after they administered study medication;
or analgesics, antienietics, or other acute migraine medica-
tions within 6 hours before they administered study medi-
cation. In case of inadequate relief, patients could take
rescue medication (with the exception of ergotamine-
containing medications or sumatriptan) beginning 4 hours
after dosing with study medication. Patients not using res-
cue medication and experiencing headache recurrence (de-
fined as return of moderate or severe pain 4 to 24 hours
postdose in patients who had mild or no pain 4 hours after
initial dosing) could use a second, identical dose of study
medication to treat recurrence. No more than two tablets
of study medication were permitted in any 24-hour period.
A pain-free interval of 24 hours had to elapse before a new
attack was treated with study medication.
Patients were to return to the clinic within 7 days of
treating their second and fourth migraines with study
medication to review and return completed diary cards and
review any adverse events. During the visit after the
fourth treated migraine, physical examinations, standard
blood chemistry and hematology tests, blood pressure
checks, and ECGs were performed.
Efficac,y assessments. For each migraine attack
treated with study medication, patients recorded on diary
cards headache severity ( 0 = no pain; 1 = mild pain; 2 =
moderate pain; 3 = severe pain) and presence or absence of
nausea, vomiting, photophobia, and phonophobia before
dosing and 0.5, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours after the
initial dose of study medication. Clinical disability ( 0 =
able to function normally; 1 = ability mildly impaired; 2 =
ability severely impaired; 3 = requires bed rest) was mea-
sured 0.5, l , 1.5, 2, 3, and 4 hours postdose. In addition,
patients recorded the time (through 4 hours postdose) to
meaningful relief of migraine, measured with a stopwatch
started at dosing and stopped when relief of any combina-
tion of headache, nausea, vomiting, photophobia, and pho-
nophobia became meaningful to the patient. Patients also
recorded any use of rescue medication and time of head-
ache recurrence.
Safety assessments. Safety assessments included the
incidence of adverse events and the results of clinical labo-
ratory tests, vital signs, and ECGs. Study personnel que-
1486 NEUROLOGY 49 December 1997
ried patients about the occurrence of adverse events
(defined as any untoward medical occurrence regardless of
its suspected relationship to administration of study medi-
cation) during clinic visits and periodic telephone calls.
Data analysis. The primary measure of efficacy was
the percentage of patients who experienced headache relief
(moderate or severe pain reduced to mild or no pain) 4
hours after the first dose of study medication. Other effi-
cacy measures, examined a t each measured time point
through 4 hours postdose, included the proportions of pa-
tients with headache relief, headache resolution (moderate
or severe pain reduced to no pain), clinical disability score
of 0 or 1, no nausea, no vomiting, no photophobia, and no
phonophobia. The proportion of patients with meaningful
relief within 4 hours postdose; the proportion of patients
with maintenance of headache relief (relief from 4 hours
postdose onward with no worsening and no use of rescue
medication) for 8, 12, and 24 hours; the proportion taking
rescue medication within 24 hours of initial dosing; and
the proportion experiencing headache recurrence within 24
hours of initial dosing were examined.
Logistic-regression crossover models including factors
for patients, period, and treatment were used to compare
dosing groups with respect to the proportions of patients
with headache relief, headache resolution, maintenance of
relief, no nausea, no photophobia, no phonophobia, clinical
disability score of 0 or 1, and rescue medication use at each
measured time point. The contrasts representing the lin-
ear effects of treatment were estimated using a method
accounting for the unequal spacing of the dose levels.'(
Descriptive statistics only were calculated for the propor-
tion of patients experiencing headache recurrence.
The primary measure of safety was the percentage of
patients experiencing specific adverse events. Other safety
measures included the number of patients with clinically
significant abnormalities in clinical laboratory tests, vital
signs, or ECGs. Descriptive statistics only were calculated
for the safety data.
It was estimated that a t least 125 patients per study
medication dose were required to detect statistically signif-
icant differences between naratriptan 2.5 mg and 1 mg
compared with placebo or naratriptan 0.25 mg in the pro-
portions of patients experiencing headache relief 4 hours
after the initial dose of study medication. This calculation
was performed under the assumptions that the proportions
of patients experiencing headache relief 4 hours postdose
would be 65%)after naratriptan 2.5 mg, 6 0 6 after 1 mg,
45% after 0.25 mg, and 30% after placebo, and t h a t
between-attack efficacy responses would have a correlation
of 50.5. The study was not powered to detect differences
between naratriptan 0.25 mg and placebo.
Results. Patients. Seven hundred forty patients were
randomized to receive study medication. The number of
patients treating attack 1 was 682, treating attack 2 was
632, treating attack 3 was 561, and treating attack 4 was
514. The number of patients treating an attack with
naratriptan 2.5 mg was 590, with 1 mg was 600, with 0.25
mg was 593, and with placebo was 606.
Demographic and safety analyses were performed on
data from all patients treating a t least one attack with
study medication (n = 682). Efficacy analyses were per-
formed on data from all patients who treated a n attack
and returned a diary card for that attack ( n = 586 for

100
L
0 bination of headache, nausea, vomiting, photophobia, and
s 40
20
0 patients with 0.25 mg, and 34%' of patients with placebo
4 8 12 24
hours h o u r$'B'c h o u r$'B'C ho u r k l B
Figure 1. Headache relief (moderate or severe p a i n re-
duced to mild or no p a i d and maintenance of headache
rclief'8, 12, and 24 hours postdose (among patients not
taking rcsi.ue medication or a sec0n.d dose of study medi-
cation after reporting headache relief4 hours postdose).
.\p < 0.05 naratriptan 2.5 tng verses placebo; Rp < 0.05
naratriptan 2.5 rng versus 0.25 nig; ''p < 0.05 naratriptan
1.0 Trig versus placebo.
naratriptan 2.5 mg, 595 for 1 mg, 591 for 0.25 mg, and 602
for placebo.
Patients" mean age was 41.2 years (SD = 9.6). The
majority of patients were Caucasian (93%) women (90%).
Seventy-one percent of patients had a history of migraine
without aura only; 9% had a history of migraine with aura
only; 20% had a history of both migraine with and with-
out aura.
Efficac,y data. Headache relief. Baseline headache
severity was moderate or severe for->99?k of patients for
each attack. Headache relief (moderate or severe pain re-
duced to mild or no pain) 4 hours postdose occurred in 68%'
of patients after treatment with naratriptan 2.5 mg com-
pared with 57% of patients during treatment with
naratriptan 1.0 mg, 3% of patients with 0.25 mg, and 33%
of patients with placebo (figure 1; p < 0.001 naratriptan
2.5 mg and 1 ing versus placebo or 0.25 mg). Significantly
( p i 0.001) greater percentages of patients experienced
relief during treatment with naratriptan 2.5 mg or 1 mg
compared with placebo beginning 60 minutes postdose.
Maintenance of .-headache relief. Among patients not
using rescue medication or a second dose of study medica-
tion, headache relief was maintained (headache relief from
4 hours postdose with no worsening) for 8, 12, and 24
hours postdose in significantly ( p < 0.05) greater percent-
ages of patients after treatment with naratriptan 2.5 mg
compared with placebo and naratriptan 0.25 mg. Headache
relief was maintained for 8 and 12 hours postdose in sig-
nificantly ( p i0.05) greater percentages of patients after
treatment with naratriptan 1 rng compared with placebo
(see figure 1).
Elimination of headache. Headache was eliminated
- ~ ~~~
(moderate or severe pain reduced to no pain) 4 hours post-
dose in 45% of patients after treatment with naratriptan
2.5 mg compared with 33% of patients after treatment
with naratriptan 1 nig, 20% of patients with 0 2 5 mg and
15% of patients with placebo ( p < 0.001 naratriptan 2.5
mg and 1 mg versus placebo or 0.25 mg). Significantly
( p < 0.001) greater percentages of patients experienced
elimination of headache after treatment with naratriptan
2.5 mg compared with placebo beginning 60 minutes post-
dose, and after 1 ing compared with placebo beginning 90
minutes postdose.
Meaningful relief. Meaningful relief (relief of any coni-
~~~
phonophobia became meaningful to t h e patient) w a s
achieved by 4 hours postdose in 67% of patients after treat-
ment with naratriptan 2.5 mg compared with 57% of pa-
tients after treatment with naratriptan l nig, 41% of'
( p < 0.001 naratriptan 2.5 mg and 1 mg versus placebo o r
0.25 mg).
Associated symptoms: nausea, vomiting, phonophobia,
~.~ ~ ~ ~
photophobia, and clinical disability. Freedom from n a u -
~-~~ -- ~ ~~
sea, phonophobia, and photophobia 2 and 4 hou.rs postdosr
was reported by significantly ( p < 0.005) greai,er percent-
ages of patients after treatment with naratripta.n 2.5 mg o r
1 mg compared with placebo or 0.25 nig (figure 2). A simi-
lar pattern of results was observed for a clinicd disabilitv
score of 0 or 1 (see figure 2). Naratriptan 41.5 mg w a s
associated with significantly ( p < 0.05) greater efficacv
than placebo beginning 30 minutes postdose for absence or'
phonophobia and clinical disability score of 0 o r 1, (50min-
utes postdose for absence of photophobia, and 120 minutcs
postdose for absence of nausea. The infrequent occurrence
of vomiting before or after dosing in any treatment contli-
tion precluded meaningful comparison betweeri groups.
Use of rescue medication within 24 hours of dosing.
~ ~~ ...
~~~~~~~~~~~~~
Rescue medication was used within 24 hours of initial
dosing in 26% of patients after treatment with naratriptan
2.5 mg and in 34% of patients after treatment with
naratriptan 1 mg, in 48% of patients with 0.25 mg, and i n
52% of patients with placebo ( p 0.001 naratriptan 2.5
mg and 1 mg versus placebo or 0.25 nig).
Headache recurrence. The percentage of patients ex-
periencing headache recurrence (after initial relief was
achieved 4 hours postdose) with naratriptan 2.5 mg was
27%, with 1 mg was 33%, with 0.25 mg was 34"%,and with
placebo was 36%'(differences not statistically !tested1. The
mean (SD) time to headache recurrence after treatment
with naratriptan 2 . 5 mg was 11.2 hours (0.6). with 1 mg
was 11.0 hours (0.6),with 0.25 mg was 10.0 hours ( O . O 6 i ,
and with placebo was 8.5 hours (0.5) (differences not sta-
tistically tested).
Safety and tolerability data. Adverse events. 'I'hr
overall incidence of adverse events after treatment wit li
any dose of naratriptan was not different from the inci-
dence after treatment with placebo (table). The percentagv
of patients reporting one or more adverse events did not
vary as a function of naratriptan dose or with the numbc~r
of naratriptan doses taken (see table).
Specific adverse events experienced by niorts than 3% of'
patients after treatment with any dose of study medication
are depicted in the table. These adverse events includcd
symptoms of migraine. Nausea and vomiting were t,hc
most frequently reported adverse events. (Adverse tlvents
December 1997 NEUROLOGY 49 1487
 -
VI

-
.-c
QJ

a
0
Figure 2. Percentage of patients
with no photophobia, no phonopho-
bia, no nausea, and clinical disabil-
ity score of 0 or 1 at dosing and 2
and 4 hours after dosing. "p < 0.005
naratriptan 1.0 mg or 2.5 mg uersus
placebo; Hp < 0.005 naratriptan 2.5
mg or 1 mg versus 0.25 mg.

were reported regardless of their suspected degree of rela-
tionship with administration of study medication and
could include symptoms of migraine.) The incidence of spe-
cific adverse events did not increase with the use of a
second dose of study medication to treat headache recur-
rence.
Cardiovascular adverse events (including blood pres-
sure changes, hemorrhage, bradycardia, tachyarrhyth-
niias, extrasystoles, palpitations, heart murmurs) after the
first dose of study medication were reported by 1%of pa-
tients after treatment with naratriptan 2.5 mg, by <1%
with 1 mg, by <1%1with 0.25 mg, and by 1%with placebo.
Similarly, chest discomfort after the first or second dose of
study medication was reported by 51% of patients after
treatment with any dose of naratriptan or placebo.
Thirteen patients withdrew from the study because of
adverse events, only one of which (an exacerbation of mi-
graine) was considered to be probably related to adminis-
tration of study medication. Five of the 13 events were
considered to be possibly related to administration of study
medication. The remaining seven events were assessed as
being unrelated to administration of study medication.

Table Overall incidence of adverse events and number (percent) ofputients reporting specific adverse events"
~~ ~ ~ ~~ ~~ ~~ ~~~~~ ~~~~~~~~~ ~~ ~ ~~ ~ ~~~ ~~~~ ~~ ~

Placebo +- Placebo 0.25 mg + 0.25 mg 1.0 mg + 1.0 mg 2.5 mg + 2.5 mg

( n = 458) (n = 148) ( n = 453) (11 = 140) ( n = 443) ( n = 157) ( n = 440) (n = 150)
~~
~~~ ~

Overall (a) 32 23 35 21 25 31 31 25
Vomiting 51 (11) 11 (7) 55 (12) 4 (3) 32 ( 7 ) 13 (8) 34 (8) 11 ( 7 )
Nausea ( % ) 38 (8) 9 (6) 49 (11) 4 (3) 25 (6) 18 (11) 30 (7) 9 (6)
Migraine ('5 ) 20 (4) l(1) 14 (3) 4 (3) 15 ( 3 ) 4 (3) 15 (3) 0 (0)
Photophobia ((5,) 17 (4) 0 (0) 9 (2) 2 (1) 3 (1) l(1) 8 (2) l(1)
Tingling (% ) 1(<1) 0 (0) 2 (<1) l(1) 5 (1) 3 (2) 5 (1) 7 (5)

Note: Adverse events reported by >3% of patients after either one or two administrations of any dose of study medication are re-
ported. The first column for each dosing condition displays adverse-event incidences for patients using only one dose to treat a n at-
tack; the second column includes all events reported by patients taking two doses, regardless of whether the adverse event occurred
after the first or second dose.
1488 NEUROLOGY 49 December 1997
 Other safety evaluations. No patient in the study ex-
~ ~~~
perTenced a clinically significant abnormality in clinical
laboratory parameters or ECGs. Similarly, no clinically
relevant changes in vital signs were reported.
Discussion. The results of this double-blind, four-
period, crossover study demonstrate that naratriptan
is effective and well tolerated in the treatment of mi-
graine. Four hours postdose, headache relief and
patient-defined meaningful relief were each experi-
cnced by more than two-thirds of patients after treat-
ment with naratriptan 2.5 mg compared with one-third
of patients after treatment with placebo. Similar effi-
cacy was reported for alleviation of clinical disability,
nausea, photophobia, and phonophobia. The 2.5-mg
dose of naratriptan was uniformly associated with
greater efficacy than placebo or the lower naratriptan
doses, although the 1.0-mg dose was also consistently
significantly more effective than placebo (and often
more effective than the 0.25-mg naratriptan dose).
Although conclusions regarding the relative effi-
cacy of the 5HT1 agonists in migraine cannot be
drawn in the absence of data from studies in which
they are directly compared, it is helpful to examine
data across studies in the absence of such data. The
2- and 4-hour efficacy data with naratriptan in this
study and the magnitude of treatment differences
compared with placebo are consistent with those re-
ported with the oral form of sumatriptan, the bench-
mark 5HT, agonist.’ 7 1 ’ 1 5 For example, Cutler et al.I4
reported that sumatriptan tablets 25 nig, 50 mg, or
100 mg relieved headache 4 hours postdose in 68 to
71% of patients compared with 38% of placebo-
treated patients in a double-blind, parallel-group
study ( n = 259). Similarly, Nappi et al.15 demon-
strated that sumatriptan tablets 100 mg relieved
headache by 4 hours postdose in 71% of patients
given one or two doses compared with 35% of
placebo-treated patients.
The 2-hour efficacy data with naratriptan in this
study and the magnitude of treatment differences
compared with placebo are also consistent with those
reported with clinically useful doses of the 5HT1 ago-
nists zolmitriptan” I h and rizatriptan.” The current
lack of published data regarding headache relief
rates beyond 2 hours postdose for zolmitriptan and
rizatriptan precludes comparisons among the newer
5HT, agonists of headache relief beyond 4 hours
postdose.
Because success a t maintenance of headache relief
beyond 2 hours postdose has not been reported for
either rizatriptan or zolmitriptan, it is also not possi-
ble to speculate about the relative efficacy of the
newer 5HT, agonists with regard t o maintenance of
headache relief. In the present study, headache relief
was maintained beyond the 4-hour postdose interval
in significantly greater proportions of patients after
treatment with naratriptan compared with placebo.
Headache relief 4 hours postdose was maintained
(with no significant worsening and no use of rescue
medication) for 8 and 12 hours postdose in the major-
ity of patients treated with naratriptan 2.5 mg and
for a t least 24 hours postdose in nearly 50% of pa-
tients after treatment with naratriptan 2.5 mg. In
contrast, headache relief was maintained for 24
hours in only one-fifth of placebo-treated patients.
These data demonstrate that naratriptan is effective
in maintaining headache relief beyond the immedi-
ate postdose interval.
Consistent with these data regarding mainte-
nance of headache relief was the finding that head-
ache recurred in a smaller proportion of patients
after treatment with naratriptan 2.5 nig (87%) com-
pared with lower doses of naratriptan (33 to 34%1 or
placebo (36%; difference not statistically tested 1.
This finding, in addition to the data showing that
naratriptan 2.5 mg was associated with a longer
mean time to headache recurrence than were the
lower doses of naratriptan or placebo, suggests that
naratriptan 2.5 nig may be associated vvith lower
recurrence rates and longer times to recurrence than
lower naratriptan doses.
Consistent with its efficacy profile, the tolerability
profile of naratriptan was favorable in this study.
The overall incidence of adverse events a t the 2.5-mg
dose was indistinguishable from that of placebo.
Likewise, the incidences of specific adverse events-
including those characteristic of the 5HT1 agonist
class of compounds-after treatment with any dose
of naratriptan were not different from the incidences
after placebo. In particular, naratriptan a t doses u p
to 2.5 mg was no more likely than placebo to be
associated with adverse events commonly associated
with 5HT1 agonists (e.g., sensations of Firessure or
tightness in the throat or chest). Naratriptan a t
doses up to 2.5 mg was also not strongly associated
with CNS events such as drowsiness or dizziness,
which may occur with compounds that more potently
affect the CNS.
The similarity between the naratriptan and pla-
cebo adverse-event profiles, considered in the context
of the efficacy data, suggests that naratriptan at a
dose of 2.5 mg may offer the optimum efficacy-to-
tolerability ratio in the dose range 0.25 mg to 2.5 mg.
The efficacy and tolerability profiles of the 1-mg dose
are also favorable, although the 1-mg dose was not
as effective as the 2.5-mg dose.
Appendix
Investigators of the Naratriptan S2WA3003 Stutly Group
include Frank H. Anderson, MD; C. Camak Baker, MD,
David Bartels, PharmD; Joan Ryder-Benz, AID; Thoinas
Bock, DO; Roger Cady, MD; Alice Chenault, MD; Thomas
Chippendale, MD; James Couch, MD, PhD; Seymour Dia
mond, MD; Kathleen Digre, MD; Michael Etlmond, MI),
Victor Elinoff, MD; Carol Foster, MD; Walter Gainan, MD,
Thomas Garland, MD; Scott Gold, MD; Jerome Goldstelti,
MD; Malcolm Gottesman, MD; Michael J. Maugh, MD,
Scott Hines, MD; Noel Holtz, MD; Terry R. Jackson, MI).
Robert G. Kaniecki, MD; Jack Klapper, MD; David Kud-
row, MD; Steven Landy, MD; Thomas Littlejohn, MD,
Frank Maggiacomo, DO; Nian T. Mathew, MD; Williani
December 1997 NElJROl.O(;Y 49 14H!)
M u l l i c a n , M D ; J a n e M u r r a y , M D ; D e n i s C. N a t h a n ,
MD; Donald O’Hair, M D ; A n t h o n y Puopolo, MD; S i d n e y
Rosenblatt, MD; John Rubino, MD; Reginald R u t h e r f o r d ,
MD; Robert R y a n , MD; Carl Sadowsky, MD; H a r r y S e r f e r ,
MD; S t e p h e n M. S e r g a y , DO; Stuart S t a r k , MD; S t e w a r t
Tepper, MD; Stephen T h e i n , J r , P h D ; H a r v e y T i l k e r , P h D ;
Michael Tuchman, MD; Thomas N. W a r d , MD; Donna K.
Whitney, MD; a n d Paul Willis, M D .
References
1. The Subcutaneous Sumatriptan International Study Group.
Treatment of migraine attacks with sumatriptan. N Engl
J Med 1991;325:316-321.
2. Cady RK, Wendt JK, Kirchner J R , et al. Treatment of acute
migraine with subcutaneous sumatriptan. JAMA 1991;265:
2831-2835.
3. The Oral Sumatriptan Dose-Defining Group. Sumatriptan: a n
oral, dose-defining study. Eur Neurol 1991;31:300-305.
4. The Oral Sumatriptan International Multiple-Dose Study
Group. Evaluation of a multiple-dose regimen of oral
sumatriptan for the acute treatment of migraine. Eur Neurol
1991;31:306-313.
5 . Goadsby PJ, Zagami AS, Donnan GA, et al. Oral sumatriptan
in acute migraine. Lancet 1991;338:782-783.
6. Dahlof CGH. How dose sumatriptan perform in clinical prac-
tice? Cephalalgia 1995;(suppl 15):21-28.
7. Ferrari MD, James MH, Bates D, et al. Oral sumatriptan:
effect of a second dose, and incidence and treatment of head-
ache recurrences. Cephalalgia 1994;14:330-338.
1490 NEUROLOGY 49 December 1997
8. Visser WH, Terwindt GM, Reines AS, Jiang K, Lines CR,
Ferrari MD. Rizatriptan vs sumatriptan in the acute treat-
nient of migraine: a placebo-controlled, dose-ranging study.
Arch Neurol 1996;53:1132-1137.
9. Geraud GEA. Evaluation of the long-term safety and efficacy
of 311C90 in the treatment of migraine. Eur Neurol 1996;
36(suppl 2):24-27.
10. The Multinational Oral Sumatriptan and Cafergot Compara-
tive Study Group. A randomized, double-blind comparison of
sumatriptan and cafergot in the acute treatment of migraine.
Eur Neurol 1991;31:314-322.
11. Connor HE, Feniuk W, Beattie DT, et al. Naratriptan: biolog-
ical profile in animal models relevant to migraine. Cephalal-
gia 1997;17:145-152.
12. Headache Classification Committee of t h e International
Headache Society. Classification and diagnostic criteria for
headache disorders, cranial neuralgias and facial pain. Ceph-
alalgia 1988;8(suppl 7):l-96.
13. Robson DS. A simple method for constructing orthogonal poly-
nomials when the independent variable is unequally spaced.
Biometrics 1959;15:187-191.
14. Cutler N, Mushet GR, Davis R, Clements B, Whitcher L. Oral
sumatriptan for the acute treatment of migraine: evaiua-
tion of three dosage strengths. Neurology 1995;45(suppl 7):
5-9.
15. Nappi G, Sicuteri F, Byrne M, et al. Oral sumatriptan com-
pared with placebo in the acute treatment of migraine. J Neu-
rol 1994;241:138-144.
16. Ferrari MD. The clinical effectiveness of 311C90 in the acute
treatment of migraine. E u r Neurol 1996;36(suppl 2):4-7.