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The Triptans: A Summary

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The Triptans
A Summary
Stewart J. Tepper1 and Alan M. Rapoport2,3
1 Department of Neurology, The Polyclinic, University of Washington Medical School, Seattle,
Washington, USA
2 The New England Center for Headache, Stamford, Connecticut, USA
3 Yale University School of Medicine, New Haven, Connecticut, USA

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
1. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404
2. Clinical End-Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404
3. Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
4. Sumatriptan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
4.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
4.2 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
4.3 Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
5. The New Triptans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
5.1 Zolmitriptan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
5.2 Naratriptan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409
5.3 Rizatriptan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410
6. Future Triptans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
6.1 Eletriptan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
6.2 Frovatriptan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
6.3 Almotriptan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413

Abstract New migraine-specific medications, the triptans, are changing the clinician’s
approach to the treatment of migraine. These drugs are pharmacologically based
on agonism of serotonin (5-hydroxytryptamine; 5-HT) receptors.
The triptans are selective 5-HT1B/1D receptor agonists and are believed to
reverse the mechanisms of migraine, which may include changes in dural vessel
calibre, neurogenic inflammation and central trigeminal neuronal activation.
The first marketed triptan was sumatriptan. Sumatriptan is available in a highly
effective and rapidly active subcutaneous injectable formulation (optimal dose
6mg), as well as nasal (optimal dose 20mg), oral (optimal dose 50mg) and sup-
pository (optimal dose 25mg) forms. The multiple forms allow for maximal flex-
ibility in crafting an acute care regimen for patients.
New triptans are being released in rapid sequence; each new drug has some
distinct clinical advantages. All of the triptans released after sumatriptan are more
lipophilic and have higher oral bioavailability than sumatriptan. Zolmitriptan was
the second marketed triptan, and is available in oral tablet form (optimal dose
404 Tepper & Rapoport

2.5mg). A fast melt preparation is to be released in Europe in 1999 and a nasal

spray form is under development. Zolmitriptan is a well absorbed oral triptan
with very high consistency of effect in nonblind studies of over 1 year in duration.
Naratriptan (optimal dose 2.5mg) has a relatively slow onset of action but is
associated with the lowest headache recurrence rate of the currently available
triptans. It has a very good adverse event profile with excellent tolerability.
Rizatriptan is available as an oral tablet and a rapidly dissolving oral wafer
(melt formulation). The optimal dose is 10mg. It is similar to sumatriptan in being
an effective oral triptan with a relatively high recurrence rate.
Future triptans include eletriptan, which has a very high efficacy in oral form
at a dose of 80mg, but a high rate of adverse events at this dose. Lower doses (20
and 40mg) are similar in profile to sumatriptan. Frovatriptan (optimal dose 2.5mg)
has an onset of effect and overall efficacy similar to those of naratriptan, but a
very low recurrence rate. Almotriptan has the highest oral bioavailability of the
triptans.
Selection of an acute care migraine medication should be based on need for
specific delivery form, headache- and pain-free response at 2 and 4 hours after
administration, adverse event profile, consistency of response and recurrence
rate.
Adverse events for triptans include tightening, flushing and paraesthesias of
unknown cause. All triptans cause narrowing of arteries, including coronary ar-
teries, and although serious adverse vascular events are very rare, triptan use is
contraindicated in patients with vascular disease.

New migraine-specific medications, the triptans,
are changing the clinician’s approach to the treat-
ment of migraine. These drugs are being released
all over the world in rapid sequence. The purpose
of this article is to review how improvements in the
diagnosis of migraine and understanding its patho-
physiology can help to distinguish among the ac-
tions of some of these drugs. In addition, we will
summarise the characteristics of the acute care mi-
graine-specific drugs and review their clinical ac-
tivity to provide a brief guide for clinicians who
treat migraine.
1. Diagnosis
Developing a verified system for diagnosis of
both benign recurring headaches and secondary head-
aches has been crucial in standardising clinical re-
search. Once headaches could be diagnosed reli-
ably and consistently, international clinical studies
on headache medications became more meaningful
because they adhered to a common set of inclusion
standards. The International Headache Society (IHS)
1988 classification system[1] accomplished just that,
and its set of diagnostic criteria has been adopted
throughout the world.
Use of the IHS criteria for diagnosis not only
helps clarify and standardise clinical research, it
also makes clinical diagnosis significantly easier
and more accurate. The IHS system permits clinici-
ans to rule in moderate migraine and unusual head-
ache syndromes. At the same time, the failure of a
headache to meet IHS criteria for a recognisable
benign recurring headache disorder raises suspicion
for a secondary cause of headache, which should
trigger a workup or referral.
2. Clinical End-Points
The IHS has published guidelines for clinical
headache research; these are standards by which
medications can be evaluated.[2]
The clinical intensity scale is a rating scale for
intensity of headache. This is a 4-point scale, 0 to
3, where 1 is mild, 2 moderate and 3 represents
severe intensity.

 Adis International Limited. All rights reserved. CNS Drugs 1999 Nov; 12 (5)
The Triptans in Migraine
A modified criterion for headache response to a
medication is that of migraine intensity being re-
duced from moderate or severe to none or mild at
a point in time. The IHS has recommended mea-
suring pain relief at 2 hours post-administration for
comparison purposes, based on the clinical judg-
ment that this time to headache response is best for
patients. Some studies, however, have used head-
ache response at 4 hours as the primary end-point
to assess oral triptans that may have a slower onset
of clinical effect.
Therapeutic gain (TG) is defined as the response
to active drug minus the placebo response. The use
of TG allows for some measure of comparison of
medications across clinical trials when head-to-head
comparator trials are not available, by subtracting
the variable placebo response. A TG of 30% sug-
gests a good drug response, 40% excellent, and 50%
superb.
Some other clinical responses to medication are
now being used as primary or secondary end-points.
One is the IHS-recommended pain-free state, which
is defined as a migraine decreasing from moderate
or severe to no pain after treatment with a medica-
tion at a given time, preferably 2 hours post-admin-
istration. Obviously, this is a superior end-point
from the patient’s standpoint, and reduces placebo
response. Disability measurements and relief of
associated symptoms such as nausea and photo-
phonophobia are also measured at 2 hours.
A complex parameter is time to pain relief. This
statistical measure uses a sliding scale or survivor
curve to calculate statistical significance over a pe-
riod of time, measuring the chance of obtaining
relief over time. For example, it evaluates the pa-
tient’s chance of achieving a headache response at
any time point measured up to 2 hours. Thus, even
if individual fixed end-points do not show statisti-
cal significance, evaluating all the end-points in an
integral (at 30, 60, 90 and 120 minutes) may show
significance when the entire survivor curve for all
end-points is calculated.
Time to headache relief measures the survival
of the headache. Unfortunately, if the patient has a
headache response at 30 minutes, but the headache
 Adis International Limited. All rights reserved.
405
returns at 90 minutes, the patient is still counted as
a success in this analysis. Recently, pre-planned
sensitivity analysis have removed these ‘quick re-
currence’ patients, increasing the usefulness of this
measure.[3]
Recurrence is usually defined as the return of
moderate or severe headache within 24 hours of
treatment, following a headache response at 2 hours.
This definition is occasionally altered in studies.[4]
Finally, there is the concept of complete or sus-
tained pain-free response. This is defined as a pa-
tient being pain-free at 2 hours and having no re-
currence or use of rescue medications within 24
hours.
3. Pathophysiology
Multiple threads of research over the last 15 years
have led to the concept that migraine is generated
from a hyperexcitable brain. The basis of this low-
ered threshold to neuronal firing is probably gen-
etic and may involve a dysfunctional calcium channel
on nerve membranes or abnormal nitric oxide me-
tabolism or sensitivity. Mitochondrial dysfunction
and abnormalities of magnesium metabolism are
also likely contenders.
It is not clear whether migraine is generated
in the cortex or brainstem. One possible scenario
would include a cascade of events beginning with
cortical activation, followed by brainstem activa-
tion, leading to activation of ascending and descen-
ding pathways, with initiation of a perimeningeal
vasodilation and neurogenic inflammation. Affer-
ent pathways would then carry this peripheral noci-
ceptive signal centrally to trigeminal nucleus cau-
dalis, and then rostrally to thalamus and cortex.
Where migraine begins is controversial, but cer-
tainly aura is a central event. A current causation
theory for aura suggests a cortical depolarisation
with hyperaemia followed immediately by a spread-
ing cortical electrical depression associated with
decreased cerebral blood flow travelling forwards
from the occipital cortex at a rate of 3 mm/min in
the wake of the activation.
Patients with minimal reversible neurological
events prior to migraine headache (e.g. paraesthe-
CNS Drugs 1999 Nov; 12 (5)
406
sia or hemisensory deficits) may also show cortical
spreading depression. This may have been seren-
dipitously captured when a woman had brief visual
blurring followed by a migraine during a positron
emission tomography (PET) scan done for other
reasons.[5]
Cortical spreading depression is probably then
linked to brainstem activation. Weiler et al.[6] found
activation of the contralateral dorsal raphe nucleus
in PET scans of patients with unilateral migraine
without aura, with activation continuing after suc-
cessful treatment with subcutaneous sumatriptan.
The authors speculated that the dorsal raphe might
be a central generator for migraine since it remained
activated even after pain had disappeared.
The next step would be activation of the efferent
limb of the trigeminovascular system, connecting
the central activation to meningeal blood vessels.
Trigeminovascular activation would result in re-
lease of inflammatory peptides around the vessels,
causing neurogenic inflammation and sensitising
nociceptive afferents, and associated with perimen-
ingeal vasodilation.[7,8]
Agonists at certain serotonin (5-hydroxytrypt-
amine; 5-HT) receptors inhibit or reverse trigem-
inovascular neurogenic inflammation and vasodi-
lation. 5-HT1B receptors, which are located on the
meningeal vessels, vasoconstrict these vessels when
activated by 5-HT1 agonists. 5-HT1D receptors are
presynaptic inhibitory autoreceptors on trigeminal
sensory neurons. Activation of these receptors by
agonists turns off the neurogenic inflammation by
inhibiting the release of neuropeptides such as cal-
citonin gene-related peptide.
5-HT1D receptors are also located centrally in
the lower brainstem, in the trigeminal nucleus cau-
dalis.[9] After vasodilation and neurogenic inflam-
mation are activated and primary nociceptive affer-
ents are sensitised, pain signals are transduced by
the afferent limb of the trigeminal nerve to the tri-
geminal nucleus caudalis. Activation of the central
5-HT1D receptors appears to interfere with trans-
mission of the pain signals centrally.
The newer triptans are more lipophilic and thus
cross the blood-brain barrier better than the most
 Adis International Limited. All rights reserved.
Tepper & Rapoport
hydrophilic triptan, sumatriptan. However, the blood-
brain barrier may break down during a migraine,
which would allow central access even to suma-
triptan.[10]
4. Sumatriptan
Sumatriptan was the first designer 5-HT1B/1D ag-
onist and was synthesised by Humphrey and his
team at Glaxo in the early 1980s. It was first re-
leased in Europe in 1991, and it is estimated to have
been used in over 200 million attacks by close to
10 million patients. Sumatriptan is available in mul-
tiple formulations, including 6mg subcutaneous in-
jection, 25, 50 and 100mg oral tablets, 5 and 20mg
nasal spray and a 25mg suppository, depending on
the country.
4.1 Pharmacokinetics
The 2-hour half-life of sumatriptan is the short-
est of all the migraine-specific acute care agents
(table I). The primary hepatic enzyme responsible
for sumatriptan metabolism is monoamine oxidase-A
(MAO-A), which contraindicates concomitant use
with MAO-A inhibitors, such as phenelzine and
moclobemide. A combination of sumatriptan and
the MAO-B inhibitor antidepressants pargyline and
selegiline (deprenyl) is not contraindicated.[33-37]
4.2 Efficacy
The 6mg subcutaneous injection of sumatriptan
is both the fastest acting form of a 5-HT1B/1D ago-
nist and the most effective at 1 and 2 hours. After
the first exposure to the drug, 50% of patients ach-
ieve a headache response at 30 minutes, 77% at 1
hour (placebo rate 26%) and well over 80% at 2
hours. 93% of patients respond in at least 1 of 3
attacks at 60 minutes. Headache response at 90 min-
utes was 86 to 90%.[38] Recurrence of migraine,
defined as the percentage of patients showing a
return of moderate-to-severe headache within 24
hours of a headache response by 2 hours, was re-
ported as 34 to 38% in the first 2 large studies on
the subcutaneous form.[39,40] The injection is pack-
CNS Drugs 1999 Nov; 12 (5)
The Triptans in Migraine 407

Table I. Pharmacokinetics of the triptans. Studies were performed in healthy volunteers and involved oral formulations except where indicated
Drug tmax (h) Lipophilicity t1⁄2 (h) Bioavailability Doses studied Elimination route/metabolism References
(%) (mg/single
dose)
Sumatriptan Low 2 25, 50, 100 Hepatic; MAO-A; 60% renal 10-13
50mg tablet 2-2.5 (2 in 14
nonmigraine,
2.5 in
migraine)
20mg nasal spray 1 (range 17
0.08-4)
6mg subcutaneous 0.2 97
Zolmitriptan 2 Moderate 2.5-3 40-48 2.5, 5 Hepatic (1 active and 2 inactive 14-16
metabolites); CYP/MAO-A
Rizatriptan 1.3 (tablet); Moderate 2-3 45 5, 10
Hepatic MAO-A; 15% active 17-20
1.6-25 (melt) N-demethyl metabolite; 30%
excreted renally unchanged
Naratriptan 2-3 High 5-6.3 63 (men); 1, 2.5 70% excreted renally 21-24
74 (women) unchanged; CYP; not MAO-A
Eletriptan 1-2 High 3.6-5.5 50 20, 40, 80 Hepatic CYP3A4; 15% active 25-28
(probable) N-demethyl metabolite; not
MAO-A
Frovatriptan 2-4 Low 25 24-30 2.5 (probable) 50% renal; not MAO-A 29,30
Almotriptan 1.4-3.8 Unknown 3.2-3.7 80 12.5, 25 Hepatic; CYP/MAO-A; 26-35% 31,32
(probable) excreted renally unchanged
CYP = cytochrome P450; MAO-A = monoamine oxidase-A; tmax = time to peak plasma concentration; t1⁄2 = half-life.

aged as an easy to use self-administration unit,
which improves patient acceptance.[41]
The sumatriptan oral tablet has a bioavailability
of 14%.[11] An international study[42] has clarified
the dose-response curve of oral sumatriptan and
has established 50mg as the optimal starting dose.
This study showed statistically significant effects
for the 50mg dose as early as 30 minutes when
measured against placebo, with a 61% headache
response at 2 hours (placebo rate 28%, TG 33%).
77% of patients had a headache response at 4 hours
(placebo rate 39%). There was no significant differ-
ence in headache response between 50 and 100mg
doses, but there was an increase in adverse events
with the higher dose. On the other hand, there was
a statistically significant increase in headache re-
sponse when the dose was increased from 25 to
50mg, but no major increase in adverse events. Mean
recurrence rate for the 50mg dose was 32%.[42]
Sumatriptan nasal spray, which became avail-
able in the US in September 1997, provides faster
onset of effect than the tablets but produces a sim-
ilar headache response at 2 hours. The 20mg spray
demonstrated difference from placebo at 15 min-
utes in 3 of 5 placebo-controlled studies.[12,43-47]
Nearly 40% of recipients have a headache response
at 30 minutes, with about 64% headache response
at 2 hours (placebo rate 30%, TG 34%).[47] The spray
comes in a single-use device. The patient sprays
once into a single nostril without sniffing and dis-
cards the device.
The 25mg sumatriptan suppository is available
in 9 countries in Europe and Asia. The headache re-
sponse is 68% at 2 hours, (placebo 25%, TG 43%).[48]
All forms of sumatriptan relieve nausea and
photo/phonophobia at about the same rates at 2 hours.
Thus, sumatriptan, and all the new triptans, relieve
the entire migraine symptom complex. Headache
recurrence is in the 30 to 40% range, and occasion-
ally higher.
Each dose formulation of sumatriptan has a dif-
ferent efficacy. In long term nonblind studies, 70%
of attacks were aborted at 1 hour with the injec-
tion,[13] 84% at 2 hours with the 100mg tablet[49]

 Adis International Limited. All rights reserved. CNS Drugs 1999 Nov; 12 (5)
408
and 77% at 2 hours with the nasal spray[50] over 1
year.
4.3 Adverse Events
The common adverse events with sumatriptan
are now referred to as ‘triptan sensations’. These
include paraesthesias, tightness of jaw, neck and
chest, chest discomfort, flushing and heat sensa-
tions, dizziness, somnolence and nausea. The tight-
ening chest symptoms are of unknown aetiology,
may be oesophageal in origin and are very rarely
associated with cardiac ischaemia.
The nasal spray has an additional adverse effect
of an unpleasant bitter taste. The taste can be min-
imised and absorption, efficacy and consistency of
response maximised by having the patient spray
upward and forward with the head in a neutral po-
sition without sniffing or swallowing.[51,52]
A major concern with the triptans has been their
potential to cause vasoconstrictive effects. MacIn-
tyre et al.[53] measured coronary artery narrowing
to be 14% following subcutaneous administration
of sumatriptan during coronary angiography. Maa-
senVanDenBrink et al.[54] applied triptans to iso-
lated human coronary artery segments to obtain the
maximal contractile response. All of the clinically
available triptans caused similar mild coronary
artery contraction, and the authors concluded that
‘these drugs are unlikely to cause myocardial isch-
emia at therapeutic plasma concentrations in heal-
thy patients’.
O’Quinn et al.[55] published an open label study
on the tolerability of subcutaneous sumatriptan con-
sisting of a database of 12 339 typical migraineurs
using the injection for up to 12 months each. Of the
25 fatalities during the study, none was attributable
to sumatriptan injection. Two strokes occurred within
24 hours of sumatriptan injection, but the back-
ground frequency of stroke in migraineurs and in
the age group of the patients made the attribution
of causality uncertain. The authors felt that none of
the 3 myocardial infarctions was due to sumatrip-
tan injection use. They concluded that ‘patients with
cardiovascular risk factors, but properly screened
not to have established cardiovascular disease, had
 Adis International Limited. All rights reserved.
Tepper & Rapoport
no increase in the probablility of a sumatriptan-re-
lated adverse event’.
The vascular risks are very low, although trip-
tans are not recommended for use in people with
known cardiovascular or cerebrovascular disease.
It is recommended that patients with multiple car-
diovascular disease risk factors should be appropri-
ately studied before administration of triptans. The
US Food and Drug Administration has used an id-
entical template warning in the package insert for
all the triptans.
In summary, one disadvantage of sumatriptan is
its potential risk in patients with vascular disease,
a risk shared by all medications in this class. An-
other is the relatively high recurrence rate after use.
Sumatriptan has been the standard for all acute care
migraine medications since 1991. It has flexibility
of form, which permits the patient and physician to
match the form of administration to the intensity
and speed of onset of the pain as well as to the
degree of disability produced. Sumatriptan injec-
tion provides the fastest relief and highest 1- and
2-hour efficacy of any antimigraine medicine avail-
able. Sumatriptan is clearly the most carefully stud-
ied migraine drug in history. The next few years
will tell whether any of the newer triptans will have
any clinical advantages over sumatriptan.
5. The New Triptans
5.1 Zolmitriptan
Zolmitriptan was developed with the goal of cre-
ating a more lipophilic, centrally active and rapidly
absorbed oral tablet than sumatriptan. Its oral bio-
availability is 40 to 48% and its half-life is 2.5 to 3
hours (table I).
Zolmitriptan undergoes hepatic metabolism to 1
active and 2 inactive metabolites via the cytochrome
P450 (CYP) pathway, and then the active metabo-
lite is broken down by the MAO-A pathway.[14] No
significant drug interactions in healthy volunteers
have been described with propranolol at the usual
clinical doses, paracetamol (acetaminophen), me-
toclopramide, oral dihydroergotamine or fluoxet-
ine.[15] It is recommended, because of the MAO-A
CNS Drugs 1999 Nov; 12 (5)
The Triptans in Migraine
metabolism of zolmitriptan, to restrict patients tak-
ing moclobemide to a maximum of 7.5mg of zol-
mitriptan in 24 hours.[37]
The 2-hour headache response rate for zolmi-
triptan 2.5mg orally is 62 to 65% (placebo rate 34
to 36%, TG 28 to 29%). The 4-hour headache re-
sponse with the 2.5mg oral dose was 70 to 75%.
The 5mg dose fails to add significant additional
benefit, but does increase the incidence of adverse
events. Pain-free response at 2 hours after 2.5mg
was 22 to 27% (placebo 7 to 10%), and at 4 hours
was 38 to 45% (placebo 11 to 13%). Interestingly,
the 2-hour pain-free response with the 5mg dose
was considerably better, at 33 to 38% (placebo 7 to
13%).[56,57]
Recurrence rate was variable, ranging from 22
to 37%, averaging 30%. The most commonly re-
ported adverse events were the typical triptan sen-
sations.[56,57]
Studies have been completed on both fast melt
dissolvable oral and nasal spray forms of zolmi-
triptan, but these results are not yet available. It is
anticipated that the fast melt formulation will be
marketed in Europe in late 1999.
A large comparative trial of oral zolmitriptan
2.5mg versus oral sumatriptan 25 and 50mg found
that headache response at 2 hours was statistically
higher for zolmitriptan 2.5mg (67.1%) than for su-
matriptan 25mg (59.6%) or 50mg (63.8%). Pain-
free response at 2 hours was also significantly higher
for zolmitriptan compared with both of the suma-
triptan doses.[58]
Two major 1-year nonblind studies on the con-
sistency of effect of oral zolmitriptan have yielded
good results. In 1 study,[59] 81% of attacks treated
showed a headache response at 2 hours for the 5mg
dose. In the other study,[59-61] there was a 95% re-
sponse with 1 to 2 doses of zomitriptan. The latter
is the highest reported consistency for any triptan
with long term use, but consistency was measured
by allowing patients to take 2.5 to 5mg and repeat
at 2 hours, if desired, a greater flexibility than in
other nonblind studies.[59-61]
 Adis International Limited. All rights reserved.
409
5.2 Naratriptan
Naratriptan has a bioavailability of 63% for men
and 74% for women. The mean half-life is 6 hours
(table I). The 2.5mg oral tablet has a slow onset of
effect, however, with about 48% of patients obtain-
ing a headache response at 2 hours (placebo 30%,
TG 18%) and 60 to 68% at 4 hours (placebo 34%).
A 1mg tablet is also available in some countries,
but 2.5mg is the recommended adult dose.[62,63]
In several studies,[62,63] the incidence of triptan
sensations with naratriptan was very low. In fact,
the incidence of all adverse events was low, some-
times even lower than placebo, and naratriptan has
been referred to as ‘the gentle triptan’. Because
naratriptan is metabolised by a variety of CYP en-
zymes and not by the MAO system, it has not been
found to have significant drug interactions.[21,22,64]
Recurrence of headache with naratriptan after
4-hour headache response is also low, ranging from
17 to 28%.[65] The probability of taking a second
dose or other rescue medication within 24 hours of
the initial dose is about the same with naratriptan
as with dihydroergotamine, although no head-to-
head comparison has been done. Both drugs have
a long half-life and duration of action.
There has been speculation that the problem of
recurrence may be related to an intrinsic property
of triptans. Recurrence is not an independent vari-
able, since a patient must have a headache response
in order to have a recurrence. Goadsby et al.[66]
have compared naratriptan 5mg subcutaneous in-
jection with sumatriptan 6mg subcutaneous injec-
tion. (Note that these parenteral data are only in the
distributed copy of their poster presentation, not in
the published abstract.[65]) Using data published by
Dahlof et al.,[67] Goadsby et al.[66] noted 2-hour
headache response rates of 94% for naratriptan, 89%
for sumatriptan and 41% for placebo. However,
recurrence remained significantly lower for nar-
atriptan than for sumatriptan (21% for naratriptan,
40% for sumatriptan and 14% for placebo), sug-
gesting that some intrinsic quality of naratriptan
accounts for the low recurrence rate. However, it
is not clear what the correct dose of injectable nar-
atriptan for comparison with sumatriptan should
CNS Drugs 1999 Nov; 12 (5)
410
be. Injectable naratriptan 2.5mg has a 2-hour head-
ache response of 83%, but recurrence was 41%,
which is virtually the same as the recurrence rate
of 40% for sumatriptan 6mg, making the recurr-
ence argument less clear.
Also, recurrence must be calculated as the per-
centage of patients with headache response at a par-
ticular time-point who have a return to moderate-
to-severe headache within 24 hours. If recurrence
is calculated as return of headache in all patients,
not just those who showed headache response, then
the number for recurrence will be artificially low-
er.[68]
Further evaluation of naratriptan recurrence rate
was conducted by Sheftell et al.;[69] the results have
been published in abstract form. Patients who ad-
ministered naratriptan after a median headache
duration of 97 minutes did not have recurrence,
whereas those who administered naratriptan after a
median headache duration of 146 minutes did have
recurrence. These investigators stated that the ‘low
incidence of recurrence for naratriptan may be en-
hanced in those patients who obtain complete pain
relief postdose, treat less severe attacks, and treat
earlier in a migraine attack’.[69]
Consistency data for naratriptan have been re-
ported for 12 months of use; headache relief 4 hours
postdose was reported in a mean of 70% of attacks.[70]
Thus, naratriptan has a more gentle adverse ef-
fect profile, a slower onset of significant relief and
a lower recurrence rate than the other available trip-
tans.
5.3 Rizatriptan
Rizatriptan, like zolmitriptan, was synthesised
in the hope of creating a faster acting, more lipo-
philic, tablet. It has a similarly high oral bioavail-
ability of 45%. The half-life is 2 to 3 hours, and
time to peak plasma concentration (tmax) is 1.3 hours
for the conventional tablet and slightly longer for
the ‘melt’ formulation (table I).
Rizatriptan is available in 5 and 10mg doses as
both a tablet and an orally dissolving mint flav-
oured melt, which is placed on the tongue and dis-
solves rapidly. The melt is used for convenience
 Adis International Limited. All rights reserved.
Tepper & Rapoport
where liquid is not available or when the patient
wants to use the medication discretely.
Placebo-controlled studies found 2-hour head-
ache responses ranging from 67% (placebo rate 40%)
to 77% (placebo response 37%), with TG ranging
from 27 to 40%. Pain-free response at 2 hours ran-
ged from 40 to 44% (placebo response 2 to 10%)
for the 10mg traditional tablet. Efficacy for the 5mg
dose is lower. The recurrence rate for the 10mg
tablet was 30 to 47%.[71-73]
The melt is not absorbed from the tongue or mu-
cous membranes but rather dissolves in, and is sub-
sequently swallowed with, saliva for gastrointesti-
nal absorption. The 2-hour headache response for
the rapidly dissolving tablet ranges from 66% (pla-
cebo response 47%) to 74% (placebo response 28%).
The TG thus varies from 19 to 46%.[17,74]
The optimal dose for rizatriptan is 10mg. The
US package insert[17] states that propranolol increa-
ses the area under the curve for rizatriptan. There-
fore, patients taking concomitant propranolol should
take rizatriptan 5mg.[17] According to the recent
article by van Haarst et al.,[37] there is also an in-
teraction between rizatriptan and moclobemide via
MAO-A inhibition. This suggests that it would be
clinically prudent to avoid concomitant use of the
two medications.
The mean consistency of response for rizatrip-
tan over 1 year was 80% for the 10mg tablet and
70% for the 5mg tablet.[75,76] The recurrence rate
was similar to that of sumatriptan.[71,77,78]
In comparative studies, rizatriptan was evalu-
ated with sumatriptan at various doses, including
10 versus 100mg, 10 versus 50mg and 5 versus
25mg. Rizatriptan 10mg was statistically superior
to sumatriptan 100mg at 1 hour for headache re-
sponse. However, at no time was rizatriptan 10mg
superior to sumatriptan 50mg. Rizatriptan 5mg was
statistically superior to sumatriptan 25mg for head-
ache response at both 1 and 2 hours. Using the in-
tegral of time to headache relief between 0 and 2
hours, however, rizatriptan 10mg was superior to
sumatriptan 50 and 100mg, and rizatriptan 5mg was
superior to sumatriptan 25mg.[77,78] Rizatriptan 10mg
CNS Drugs 1999 Nov; 12 (5)
The Triptans in Migraine
was also superior to sumatriptan 100mg in im-
provement in functional disability and relief of nau-
sea.[79]
Recently, data have been presented on 2 other
comparative studies. The first was a comparison
of rizatriptan 10mg versus naratriptan 2.5mg. Not
surprisingly, given the speed of onset of effect of
the 2 medications, rizatriptan was significantly
superior to naratriptan in time to headache relief,
headache response at all end-points up to 2 hours,
pain-free response at 2 hours, relief of migraine-
associated symptoms and return to normal function
at 2 hours. Interestingly, the recurrence rate was
lower with naratriptan than rizatriptan, but the time
to headache recurrrence was the same, which ap-
pears to separate the low recurrence rate of nar-
atriptan from its duration of action.[80]
Rizatriptan 10mg was also compared with zol-
mitriptan 2.5mg.[81] Rizatriptan was significantly
superior to zolmitriptan at 2 hours for pain free
reponse, relief of photophobia and nausea, and re-
turn to normal function. The primary end-point of
the study was ‘time to pain free’. Since the optimal
dose for achieving a pain free response at 2 hours
for zolmitriptan is 5mg, comparable doses may not
have been used.
As noted, time to pain free was the primary end-
point in this study. One of the criticisms of the time
to relief analysis was that patients who had relief
early, but quick recurrence of headache in under 2
hours, were counted as successes. So, in this study,
a pre-planned sensitivity analysis allowed for ex-
clusion of patients with quick recurrence in under
2 hours. Excluding these patients, rizatriptan was
superior to zolmitriptan in time to pain free.[81]
In summary, rizatriptan is a very fast-acting oral
triptan, with a recurrence rate comparable with that
of oral sumatriptan, that is available in melt and
conventional tablet forms.
6. Future Triptans
6.1 Eletriptan
Eletriptan has a short tmax of 1 to 2 hours with a
half-life of 3.6 to 5.5 hours. It has a 50% oral bio-
 Adis International Limited. All rights reserved.
411
availability (table I).[25,26,82] Oral doses of 20 to
80mg have been studied in humans.[83]
Eletriptan undergoes hepatic metabolism via the
CYP system, and in particular CYP3A4 and prob-
ably CYP1A2. This enzymatic system is also res-
ponsible for the metabolism of quinolone antibiotics
(erythromycin, clarithromycin and azithromycin),
fluvoxamine and antifungal agents (fluconazole).
These drug interaction concerns, which were sig-
nificant in the past with terfenadine, may necessi-
tate contraindications to use and are being evalu-
ated currently.[25,82,84]
Phase III data on the efficacy of eletriptan were
presented in abstract form at multiple meetings.
Headache response at 2 hours was 55% for 20mg,
65% for 40mg and 77% for 80mg of eletriptan (pla-
cebo 24%, TG = 31% for 20mg, 41% for 40mg,
53% for 80mg). Pain-free response at 2 hours was
18% for 20mg, 29% for 40mg and 37% for 80mg
(compared with 6% for placebo).[85]
Three studies have now been partially reported
in different venues comparing eletriptan and su-
matriptan. Eletriptan 80mg has consistently been
significantly superior to sumatriptan 100, 50 and
25mg for headache response at 2 hours. Eletriptan
40mg was significantly superior to sumatriptan 100
and 50mg for headache response at 2 hours in 1 of
2 trials, but not in the other trial.[86-88]
Pain-free response at 2 hours was statistically
superior for eletriptan over sumatriptan only when
the 80mg dose of eletriptan (37% pain-free) was
compared with the 100mg dose of sumatriptan (23%
pain-free), but was not different at the lower doses
in 2 trials.[83,85]
In one other trial, both 40 and 80mg eletriptan
were significantly superior to 50 and 100mg of su-
matriptan for pain-free at 2 hours.[86] In this trial,
eletriptan at the 2 doses was more effective than
sumatriptan at providing relief of functional dis-
ability, nausea, photophobia and phonophobia.[86]
All of the eletriptan comparative trials used forms
of encapsulated sumatriptan for blinding. Although
these forms were bioequivalent to marketed suma-
triptan in healthy volunteers, they have not been
CNS Drugs 1999 Nov; 12 (5)
412
studied for bioequivalence in the setting of acute
migraine.
Adverse events with eletriptan were classic trip-
tan sensations, and occurred with a higher frequ-
ency at 80mg than lower doses. Recurrence rates
from phase III data were very low, 28% for 20mg,
19 to 23% for 40mg and 16 to 21% for 80mg, com-
pared with placebo 36%.[86-88] The doses of ele-
triptan which will be approved by regulatory agen-
cies are not known.
6.2 Frovatriptan
Frovatriptan (VML-251) is an unusual triptan
with a very long half-life of approximately 25 hours.
The oral bioavailability is approximately 24 to 30%,
and the tmax is approximately 2 to 4 hours (table
I).[29]
Frovatriptan is metabolised by CYP1A2. This
raises the possibility of an interaction with the oral
contraceptive pill, quinolone antibiotics, fluvoxa-
mine and antifungals. There appears to be no me-
tabolism via the MAO system, and therefore no
contraindications with the use of inhibitors of ei-
ther MAO-A or -B.[89,90]
Frovatriptan has been studied in 3 phase III tri-
als, reported in abstract form. Headache response
at 2 hours ranged from 36% (placebo 23%) to 46%
(placebo 27%), with TG from 13 to 19%. The 4-
hour headache responses were better, ranging from
56% (placebo 31%) to 65% (placebo 38%).[91]
Adverse events for frovatriptan were recently
summarised in abstract form, for phase III short
term, placebo-controlled and long term open label
studies. In the short term studies, 1% of patients
withdrew due to adverse events, and in the long
term studies, 5% of patients withdrew due to ad-
verse events. Adverse events were typical triptan
sensations and were higher for frovatriptan (at 47%)
than placebo (at 34%). However, no serious treat-
ment-related adverse events occurred.[92]
Recurrence, as measured by return to moderate-
to-severe headache within 24 hours in patients hav-
ing headache response at 4 hours, was summarised
in an abstract by Goldstein, et al.[93] The range of
recurrence was from 7 to 25% for the patients re-
 Adis International Limited. All rights reserved.
Tepper & Rapoport
ceiving 2.5mg frovatriptan, compared with 20 to
31% for the patients treated with placebo.[93]
6.3 Almotriptan
Almotriptan, both the subcutaneous (2 to 10mg)
and oral (5 to 150mg) routes has been studied in
phase II trials. The mean tmax for the expected oral
dose of 12.5mg is 2.2 hours. The half-life is 3.2 to
3.7 hours.
The drug has 80% oral bioavailability, and fol-
lowing 5 and 10mg oral treatment, 27% of the dose
was recovered in urine as unchanged compound
over 12 hours after administration (table I).[31,32]
Almotriptan is metabolised both by MAO and
CYP3A. Its drug interactions are unknown at this
time, but there may be concern about interactions
with MAOIs and medications metabolised by CYP
enzymes such as quinolones, certain selective sero-
tonin reuptake inhibitors and antifungals.[31,32,94]
In phase II trials, reported in abstract form,[95]
headache response was 96.5% at 2 hours with sub-
cutaneous almotriptan 6mg and 61.2% for 2mg. Ad-
verse events listed included headache, injection site
reactions, nausea and flushing. By the oral route,
headache response at 2 hours was 66% for 5mg,
80% for 25mg and up to 86% at higher doses (pla-
cebo 42%). There are no data for 4-hour headache
response. ‘No serious adverse events occurred’ with
oral administration.[95]
A comparative study was presented at the Amer-
ican Association for the Study of Headache meet-
ing in June 1998. In this larger study, 668 patients
were randomised to receive either almotriptan 12.5
or 25mg, sumatriptan 100mg or placebo. Here, how-
ever, an encapsulated tablet formulation of each
drug was used rather than the commercially avail-
able sumatriptan or the planned formulation for al-
motriptan, complicating the interpretation of the
results. Headache response at 2 hours for both 12.5
and 25mg of almotriptan was 57% versus 64% for
sumatriptan 100mg (placebo 42%, TG 15% for
almotriptan) [nonsignificant difference]. The 24-
hour recurrence rate was 18% for almotriptan 12.5mg
and 15% for almotriptan 25mg versus 25% for su-
matriptan 100mg (20% for placebo).[96]
CNS Drugs 1999 Nov; 12 (5)
The Triptans in Migraine
7. Conclusions
The triptans work on serotonergic mechanisms
to stop migraine pain and associated symptoms.
The hydrophilic agent sumatriptan works periph-
erally, reducing vasodilation and neurogenic infla-
mmation. The newer triptans zolmitriptan, naratrip-
tan and rizatriptan may in addition interfere with
central transmission.
The acute-care migraine drugs can be distingui-
shed by formulation (table II). Sumatriptan is the
most versatile, with oral, nasal, injectable and sup-
pository formulations available around the world.
Rizatriptan is available in both tablet and melt forms,
although both work via gastrointestinal absorption.
Zolmitriptan nasal and melt preparations are being
studied to complement the tablet.
Table III summarises the clinical end-point data
for the existing and emerging triptans. Headache
response at 2 hours seems somewhat higher for
sumatriptan, zolmitriptan, eletriptan, almotriptan
and rizatriptan, and lower for naratriptan and fro-
vatriptan. Using the concept of TG, oral sumatrip-
tan, zolmitriptan, eletriptan and rizatriptan reach
levels of 27 to 41%, indicating good to excellent
therapeutic responses. Injectable sumatriptan has
the highest TG at 48%.
Consistency data from nonblind trials, in terms
of mean response over 12 months for oral tablets,
were 70% for naratriptan, 80% for rizatriptan, 84%
for sumatriptan (all with 1 dose) and 95% for zol-
mitriptan (with 1 to 2 doses). Adverse events, or
Table II. Availability and prescribing information for the marketed triptans
Drug Formulation
Sumatriptan Tablet
Subcutaneous injection
Nasal spray
Suppository (not US or
Canada)
Zolmitriptan Tablet
Naratriptan Tablet
Rizatriptan Regular tablet and melt
a Variable by country.
EU = European Union.
 Adis International Limited. All rights reserved.
413
triptan sensations, are comparable for oral suma-
triptan, zolmitriptan and rizatriptan. There are sig-
nificantly fewer adverse events for naratriptan, and
more for injectable sumatriptan.
The recurrence rate is approximately 35% for
sumatriptan and rizatriptan, 30% for zolmitriptan,
24% for naratriptan, 21% for eletriptan, 18% for
almotriptan and 13% for frovatriptan.
The clinician is being presented with an ever
expanding variety of rapidly acting, effective head-
ache medications, available in multiple formula-
tions, with good safety and tolerability profiles.
The selection of an acute antimigraine drug for
a patient depends upon the stratification of the pa-
tient’s migraine by peak intensity, time to peak in-
tensity, disability and time to disability. The fol-
lowing are 5 examples of how triptans can be used
according to selection criteria: Patient 1 wakes up
with migraine at peak intensity, has severe peak
intensity and minimal time to severe pain and dis-
ability, and vomiting. Selecting the most appropri-
ate abortive drug would involve considerations of
the forms available for the drug, speed of onset of
effect, i.e. headache response and pain free rates up
to 2 hours, and adverse events. Sumatriptan, with
its fastest onset in injectable and nasal forms, would
be the only reasonable choice.
Patient 2 has a long menstrual migraine, with
pain and nausea that build slowly over 4 to 6 hours
on the first day of flow. Selecting the most appro-
priate drug might take into account the need for
Dose (mg) Directions
25, 50 (US), 100 Can repeat in 2h. Maximum 200 mg/24h (US); 300 mg/24h (EU)
6 Can repeat in 1h; maximum 12 mg/24h
5, 20 Can repeat in 2h; 1 spray in 1 nostril only; maximum 40 mg/24h
25 Maximum 2/24h
2.5, 5 Can repeat in 2h; maximum 10 mg/24h (US); 15 mg/24h (UK);
10-15 mg/24h (EU and international)a
1, 2.5 Can repeat in 4h; maximum 5 mg/24h
5, 10 Can repeat in 2h; maximum 30 mg/24h (US); 20 mg/24h (EU);
use 5mg when patient is on concomitant propranolol
CNS Drugs 1999 Nov; 12 (5)
414 Tepper & Rapoport

Table III. Clinical end-points for the triptans from selected clinical trials (see text for specific references)
Drug Dose (mg) and route Headache response Therapeutic Recurrence Consistency (mean % of attacks
at 2h (%) gain (%)a rate (%) aborted over 1 year)
Sumatriptan 6 subcutaneous 77b 48 34-38 70 at 1h
50 oral 61 33 32 84 at 2h for 100mg dose
20 nasal spray 64 34 32-34 77 at 2h
25 suppository 68 43 44 NA
Zolmitriptan 2.5 oral 62-65 28-29 30 95 with 1-2 doses of 2.5-5mg
Naratriptan 2.5 oral 48 18 17-28 70 at 4h
Rizatriptan 10 oral 67-77 27-40 30-47 80 at 2h
Eletriptan 40 oral 65 41 19-23 NA
Frovatriptan 2.5 oral 36-46 13-19 7-25 NA
Almotriptan 12.5 oral 57 15 18 NA
a Response to active drug minus response to placebo.
b At 1h.
NA = not available.

duration of action and convenience of administra-
tion. Thus naratriptan tablets, with a low recurr-
ence rate, would be the first choice. The second
choice would be frovatriptan which has a slower
onset but a very low absolute recurrence rate.
Patient 3 experiences many triptan sensations
from oral sumatriptan, zolmitriptan and/or rizatrip-
tan such as tightening of the throat, nausea and as-
thenia. Naratriptan, with its good adverse event pro-
file, would be the obvious choice for this patient.
Patient 4 would like high efficacy, quick onset,
but lower recurrence. In one study,[58] zolmitriptan
had a higher 2-hour efficacy than sumatriptan, and
a longer duration of effect. Eletriptan 80mg is su-
perior to sumatriptan at 2 hours, and has a low ab-
solute recurrence rate,[83,85-87] although compara-
tive recurrence rates with sumatriptan have not yet
been presented.
Patient 5 wants the fastest acting triptan tablet.
Rizatriptan has a superior time to headache relief
over oral sumatriptan, naratriptan and zolmitriptan
by survivor curve analysis.[77,78,80,81] Eletriptan is
superior to oral sumatriptan 100mg in headache re-
sponse at 1 hour.[83,86] These oral triptans are all
very fast acting, and it may require a ‘taste test’ for
a patient to find the fastest. Of course, sumatriptan
by nasal spray or injection is faster acting than any
oral tablet.
Clinical use will yield familiarity with the various
triptans, and it should be possible to match individ-
ual patient needs with the specific characteristics
of the individual triptans to optimise therapeutic
benefit.
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clinic, 1145 Broadway, Seattle, WA 98122, USA.
CNS Drugs 1999 Nov; 12 (5)