Drugs 2003; 63 (21): 2285-2305

REVIEW ARTICLE 0012-6667/03/0021-2285/$33.00/0

© Adis Data Information BV 2003. All rights reserved.

Newer Formulations of the Triptans

Advances in Migraine Management
Jonathan Paul Gladstone and Marek Gawel
Sunnybrook & Women’s College Health Sciences Centre, University of Toronto, Toronto,
Ontario, Canada

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2285
1. Migraine Treatments Throughout History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2287
2. Current Status of Acute Migraine Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2288
2.1 Parenteral Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2288
2.2 Oral Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2289
2.3 Intranasal Spray . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2289
2.4 Orally Disintegrating Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2289
2.5 Rectal Suppositories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2290
2.6 Sublingual Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2290
2.7 Emerging Treatment Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2290
3. Evaluating Abortive Migraine Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2291
4. Importance of Associated Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2292
5. Orally Disintegrating Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2293
5.1 Rizatriptan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2293
5.1.1 Pharmacokinetic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2293
5.1.2 Efficacy Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2293
5.1.3 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2296
5.2 Zolmitriptan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2297
5.2.1 Pharmacokinetic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2297
5.2.2 Efficacy Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2297
5.2.3 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2298
6. Intranasal Spray . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2298
6.1 Sumatriptan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2299
6.2 Zolmitriptan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2299
7. Rectal Suppository . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2300
7.1 Sumatriptan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2300
8. Topical/Transdermal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2301
9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2302

Abstract Migraine is a common, frequently incapacitating, headache disorder that

imposes a substantial burden on both the individual patient and society. The last
two decades have witnessed an explosion in our understanding of the patho-
physiology of migraine, and in our development of an efficacious and diverse
therapeutic armamentarium.
There are several routes of drug administration available to patients with
migraine. All the serotonin 5-HT1B/1D receptor agonists (triptans) are available as
2286 Gladstone & Gawel

oral tablets (sumatriptan, rizatriptan, zolmitriptan, naratriptan, almotriptan, frova-

triptan and eletriptan). Only sumatriptan is available as a subcutaneous injection.
Some triptans are also available via newer routes of administration, including
orally disintegrating tablets (rizatriptan and zolmitriptan), rectal suppositories
(sumatriptan) and intranasal sprays (sumatriptan and zolmitriptan).
Oral disintegrating tablets and other non-oral triptan routes (subcutaneous,
intranasal, rectal) are a useful alternative to conventional oral tablets for patients
who have difficulty swallowing pills or prefer not to do so, and for patients whose
nausea and/vomiting precludes swallowing tablets and/or makes the likelihood of
complete absorption unpredictable. This is important because epidemiological
studies in migraine reveal that the vast majority of patients (>90%) have experi-
enced nausea during a migraine attack and more than 50% have nausea with the
majority of attacks. Similarly, most (almost 70%) have vomited at some time
during an attack and of these patients, almost one-third vomit in the majority of
attacks.
The newer formulations, rapidly dissolving tablets and intranasal sprays,
afford patients the opportunity to use abortive therapy without the need for
liquids, at anytime and anywhere, at the onset of a migraine attack. Furthermore,
the intranasal sprays are absorbed rapidly and have a prompt onset of action
allowing for significant pain free rates versus placebo as early as 15 minutes post
administration. The ability to administer treatment early in a migraine attack and
have a rapid onset of action is particularly important in acute migraine treatment
in order to prevent the development of central sensitisation.
While many patients and physicians choose conventional oral tablets because
of familiarity and ease of administration, the newer formulations, oral disintegrat-
ing tablets and intranasal sprays, should be given consideration as first-line agents
in selected patients.

Migraine is a common, frequently incapacitating, pact on psychological well-being, family dynamics

headache disorder characterised by episodic attacks
of moderate-to-severe headaches, and various com-
binations of neurological, gastrointestinal and/or au-
tonomic nervous system dysfunction.[1] The 1-year
overall prevalence of migraines is 11% in the US
and Western Europe; 15–18% for females and 6%
for males. One percent of individuals have at least 1
day of migraine per week.[1-6]
Typically, migraines are intense (with >80% of
patients describing their pain as severe or very se-
vere), frequent (median attack frequency 1–2
migraines/month), and long-lasting (71% and 48%
of attacks last >24 hours in women and men, respec-
tively).[6] The aggregate impact of migraine reflects
not only its attack characteristics (pain severity,
duration and associated symptoms) but also its im-
and occupational performance. Migraine imposes a
substantial burden on the individual patient, as well
as his/her family, employer and society as a
whole.[7-12] The effect of migraine on quality of life
is similar to that of other chronic medical conditions
such as depression, osteoarthritis and diabetes mel-
litus.[7] A recent report by the WHO classifies severe
migraine, along with psychosis, quadriplegia and
dementia, as one of the most disabling chronic con-
ditions.[13] Notably, migraine prevalence peaks from
age 25–55 years, corresponding to the most produc-
tive employment years as well as the time period
when family demands are greatest.
Almost all migraine patients report some func-
tional impairments associated with their headaches.
Hu et al.[14] estimated that US patients with migraine

© Adis Data Information BV 2003. All rights reserved. Drugs 2003; 63 (21)
Newer Formulations of the Triptans
spend 112 million days per year bedridden. The
economic impact of migraine is enormous. In 1998,
Hu et al.[14] estimated the direct costs of migraine in
the US to be in excess of $US1 billion annually
while the indirect costs to society from the com-
bined impact of work absenteeism and decreased
productivity was estimated to be in excess of $US13
billion annually.[14]
This article focuses on the newer routes of ad-
ministration and delivery systems available for the
serotonin 5-HT1B/1D receptor agonist (triptan) class
of acute migraine medications. A brief overview of
migraine treatments throughout history is provided
to put into context the rapid advancements in mi-
graine therapeutics the preceding decade has wit-
nessed. The following section outlines the response
variables that are utilised in clinical trials to evaluate
the efficacy and tolerability of abortive therapies.
This section is complemented by a review of the
treatment attributes that patients desire and expect
from an ideal migraine abortive agent as well as the
factors that influence patient preference for various
medications or drug-delivery systems. The final sec-
tion provides an evidence-based summary of the
recent clinical trials supporting the introduction of
newer formulations of triptans (orally disintegrating
tablets, intranasal sprays, rectal suppositories) to our
therapeutic armamentarium. To generate this infor-
mation a Medline (1990 to present) search was
performed, and all published studies and abstracts
discussing rizatriptan and zolmitriptan orally disin-
tegrating tablets, sumatriptan rectal suppositories
and zolmitriptan intranasal sprays were reviewed.
1. Migraine Treatments
Throughout History
Attempts have been made to ameliorate the
symptoms of migraine throughout history.[15-17] In
ancient Greece, headaches were ascribed to malevo-
lent beings that either occupied the cranium or im-
planted the headache within the skull.[16] According-
ly, treatments were directed at appeasing the spirits
by offering prayers or by applying valued items to
the head.[16] In early Greece (150–600BC), an im-
balance of the elements with a rise of humours to the
© Adis Data Information BV 2003. All rights reserved.
2287
head was the postulated mechanism, and remedies
included blood-letting and purging to rid the body of
noxious substances.[16] European manuscripts from
as recently as the 17th century advocated trephina-
tion.[16] In the late 1700s, Erasmus Darwin, grandfa-
ther of Charles Darwin, suggested that headaches
could be treated by centrifugation to force the excess
blood from the head to the feet.[16] The late 19th
century brought reports of benefit derived from ex-
tracts of ergot.[15-17] The first pure ergot alkaloid,
ergotamine (a nonselective serotonin 5-HT1 recep-
tor agonist), was subcutaneously administered suc-
cessfully for intractable migraine in 1925.[18,19] Di-
hydroergotamine was synthesised by Stoll and Hoff-
man in 1943 and was utilised by Horton et al. to treat
migraine at the Mayo Clinic, Rochester, Minnesota,
USA, in 1945 (see reviews by Bove,[18] and Silber-
stein and Hargreaves[19]).
In the 1980s, the pioneering work of Patrick
Humphrey,[20] led to the creation of a new class of
acute migraine specific medications, the ‘triptans’.
With the development of sumatriptan, a novel, po-
tent, highly selective 5-HT receptor agonist,
Humphrey and his team at Glaxo (now called
GlaxoSmithKline) revolutionised the acute abortive
treatment of migraine.[21] Sumatriptan is thought to
act predominantly as an agonist at the 5HT1B/1D
receptor, although binding at other subtypes, includ-
ing the 5HT1A and 5-HT1F receptors has also been
observed. During a migraine attack, through stimu-
lation of the 5HT1B receptor on cranial blood ves-
sels, sumatriptan causes vasoconstriction that is rel-
atively selective for cerebral blood vessels (since
peripheral vasoconstriction is mediated predomi-
nately by 5-HT2 receptors). Additionally, suma-
triptan activates 5-HT1D receptors located on first
and second order neurons of the trigeminal nerve,
effectively decreasing the release of neuropeptides
(such as calcitonin gene-related peptide) responsible
for vasodilatation and the activity of pain signalling
neurons within the trigeminal nucleus.[22]
Since its worldwide introduction in the early
1990s, sumatriptan has been used in the treatment of
hundreds of millions of migraine attacks. The intro-
duction of sumatriptan was followed closely by the
Drugs 2003; 63 (21)
2288
Table I. Different routes of administration available for the acute treatment of migraine
Route of administration Specificity of the
mechanism of action
Intravenous, intramuscular, Nonspecific
subcutaneous
Specific
Oral tablets Nonspecific
Specific
Intranasal spray Nonspecific
Specific
Orally disintegrating tablets Nonspecific
Specific
Rectal suppositories Nonspecific
Specific
a Use of tradenames is for product purposes only and does not imply endorsement.
development of six other second generation triptans,
including rizatriptan, zolmitriptan, naratriptan, al-
motriptan, eletriptan and frovatriptan. All are
5-HT1B/1D receptor agonists and are believed to
have the same mechanism of action.
2. Current Status of Acute
Migraine Treatment
The preceding 2 decades have witnessed an ex-
plosion both in our understanding of migraine and in
the number of therapies available to treat migraine.
Currently physicians and patients have an array of
therapeutics options for abortive migraine therapy
ranging from nonspecific to specific therapy. Non-
specific therapy includes acetylsalicylic acid, para-
cetamol, NSAIDs, products containing one or more
of caffeine, isometheptene, butalbital, codeine and/
or opiates. Migraine-specific medications include
ergotamine, dihydroergotamine mesylate and the
triptans. Furthermore, there is a range of routes of
administration available to migraine patients includ-
ing intravenous, subcutaneous and intramuscular in-
jections, intranasal sprays, oral and orally disinte-
grating tablets, sublingual tablets and rectal supposi-
tories (see table I). The major factors influencing the
medication and formulation choice made by physi-
cians and patients include efficacy (speed of onset,
efficacy in decreasing or eliminating headache, con-
© Adis Data Information BV 2003. All rights reserved.
Gladstone & Gawel
Various medications
Opioids (e.g. pethidine), NSAIDs (e.g. ketorolac), antiemetics (e.g.
prochlorperazine)
Dihydroergotamine mesylate, sumatriptan
Paracetamol, aspirin, NSAIDs, antiemetics and prokinetic-agents, products
containing one or more of the following isometheptene, butalbital, caffeine,
codeine and/or opiates
Triptans (sumatriptan, rizatriptan, zolmitriptan, naratriptan, almotriptan,
frovatriptan, eletriptan)
Butorphanol
Dihydroergotamine mesylate, sumatriptan, zolmitriptan
Paracetamol and caffeine (Excedrin brand QuickTabs™)a
Rizatriptan, zolmitriptan
Paracetamol, aspirin, NSAIDs, antiemetics, combination products
Ergotamine, sumatriptan
sistency of response, and prevention of recurrence),
tolerability (convenience and ease of administration,
personal ability to swallow tablets during an acute
migraine attack, and idiosyncratic and dose-related
side effects) and economic (cost, insurance cover-
age) factors.
2.1 Parenteral Administration
Parenteral formulations (intravenous, intramus-
cular or subcutaneous) offer the fastest and most
effective relief for patients with migraine. As early
as 10 minutes after subcutaneous injection, suma-
triptan provided superior headache relief compared
with placebo.[21,23,24] After 2 hours, headache res-
ponse rates (decrease in headache severity from
moderate-to-severe intensity to mild or none) were
approximately 80% with between 60% and 65% of
patients achieving pain-free status.[21,23,24]
In the emergency department or physician’s of-
fice setting, parenteral pethidine, ketorolac, pro-
chlorperazine, and dihydroergotamine mesylate are
all used successfully.[25] Importantly, parenteral for-
mulations can be administered in the setting of nau-
sea with or without vomiting; however, they are
associated with disadvantages such as inconve-
nience of administration, expense, patient discom-
fort and increased adverse effect rates compared
with oral formulations.
Drugs 2003; 63 (21)
Newer Formulations of the Triptans
Patients can be successfully taught how to self-
inject subcutaneous sumatriptan and subcutaneous/
intramuscular dihydroergotamine mesylate; the ad-
ministration of sumatriptan via autoinjector is some-
what easier than the administration of dihydroergo-
tamine mesylate via injection. Sumatriptan is the
only triptan currently available with a parenteral
formulation, which became available in 1991.[23,24]
Parenteral formulations should be considered for
patients who have significant nausea with or without
vomiting that precludes (or makes difficult) oral
administration of medication, who have rapid onset
and progression of pain, whose pain reaches severe
intensity and who fail to respond to any oral triptan.
As there have been no recently introduced parenteral
formulations of triptans, this route of administration
is not be reviewed in detail.
2.2 Oral Tablets
Migraine patients have a wide range of oral thera-
pies to select from. There is a wide-variety of over-
the-counter analgesics, anti-inflammatories and
anti-emetics as well as a numerous prescription
analgesics, opiates and combination products. There
are currently seven oral triptans available that have
been approved or are in the process of regulatory
approvable worldwide; these include sumatriptan,
rizatriptan, zolmitriptan, naratriptan, almotriptan,
frovatriptan and eletriptan. Oral formulations have
the advantage of greater convenience, patient famili-
arity, tolerability and lower cost. Potential disadvan-
tages of oral therapies include a slower onset of
action, and difficulty of administration in the setting
of nausea with or without vomiting. Prokinetic
agents can be coadministered with oral analgesics to
enhance gastric motility and drug absorption in ad-
dition to minimising nausea and vomiting.[26]
While there are more similarities than differences
amongst the oral triptan medications, differences do
exist in terms of pharmacokinetic parameters, effi-
cacy, tolerability and drug interactions.[27-33] Ac-
cording to the recent meta-analysis by Ferrari et
al.[32] rizatriptan and eletriptan offer the greatest
likelihood of 2-hour headache response, rizatriptan,
almotriptan and eletriptan provide the greatest like-
© Adis Data Information BV 2003. All rights reserved.
2289
lihood for sustained pain-free status at 2 hours,
rizatriptan and almotriptan provide the most consis-
tent response across attacks, and naratriptan and
almotriptan are the best tolerated.
The focus of this article is on the non-oral mi-
graine abortive formulations and interested readers
are directed to the many excellent reviews evaluat-
ing the orally administered triptans individually,
collectively and via meta-analysis.[27-33]
2.3 Intranasal Spray
Intranasal formulations provide another fast and
effective alternative for patients who find parenteral
drugs too invasive and oral medications too difficult
to tolerate secondary to nausea and vomiting.[34-37]
The advantages of nasal administration include con-
venience of administration (relative to subcutaneous
administration), and speed of onset of headache
relief. The disadvantages of intranasal formulations
include nasal irritation, bitter after-taste, less dis-
creet administration, inconsistent absorption, and
variable efficacy secondary to incorrect self-admin-
istration technique. Currently available intranasal
treatment options include dihydroergotamine mesy-
late, butorphanol, sumatriptan and the newly intro-
duced nasal formulation of zolmitriptan. This article
reviews the emerging literature for zolmitriptan na-
sal spray and highlights the evidence for the older,
more established intranasal treatment options.
2.4 Orally Disintegrating Tablets
Orally disintegrating tablets or wafers have rap-
idly gained acceptance as an important new drug
delivery system.[38] It is a novel dosage formulation
consisting of a solid dosage form that rapidly dis-
solves or disintegrates on the tongue (within secon-
ds) without the need for liquids or chewing; it is
swallowed with saliva and is absorbed from the
gastrointestinal tract. The disintegrating tablets were
developed as oral alternatives to conventional tab-
lets, with the objective of offering greater patient
tolerability and convenience. For an overview of
orally disintegrating tablet delivery systems, inter-
ested readers are directed to the recent review by
Habib et al.[38]
Drugs 2003; 63 (21)
2290
This formulation is an important alternative to
conventional oral tablets for patients who have diffi-
culty swallowing pills or prefer not to do so (as
many as 20% of the general population are reluctant
to swallow tablets).[39,40] Rapid dissolving formula-
tions are particularly useful for migraine patients
whose nausea and/or vomiting precludes swallow-
ing tablets, and patients whose nausea and/or vomit-
ing makes the likelihood of complete absorption
unpredictable.[2,41-44] Furthermore, rapidly dissolv-
ing tablets allow for the consumption of abortive
therapy without the need for liquids at anytime,
anywhere (i.e. while driving or at a business meet-
ing) at the onset of a migraine attack (i.e. before the
headache increases in severity).
Bristol-Myers-Squibb recently introduced to the
market the first over-the-counter, nonspecific orally
disintegrating tablet (Excedrin brand Quicktab™1; a
combination of paracetamol and caffeine) for the
treatment of headaches. Currently, there are two
triptans, rizatriptan and zolmitriptan, that are avail-
able as orally disintegrating tablet formulations.
Since their introduction, rizatriptan in 1998 and
zolmitriptan in 2001, they have captured a substan-
tial and rapidly growing percentage of the market.
This article reviews the salient reasons for the addi-
tion of this drug delivery system to currently avail-
able conventional orally administered triptans, and
the evidence supporting the use of rizatriptan and
zolmitriptan orally disintegrating tablet from place-
bo-controlled, comparison and patient preference
studies.
2.5 Rectal Suppositories
Absorption via the rectal mucosa is another alter-
native route of administration for patients with mi-
graine with significant nausea and/or vomiting. The
rectal route of administration is widely used for a
range of drug classes including antiemetics, an-
tiepileptic drugs, anti-inflammatories and opi-
oids.[45-47] The mechanism of drug absorption from
the rectum is similar to that in the upper part of the
gastrointestinal tract. Rectal administration has the
1 Use of tradenames is for product identification purposes only and does not imply endorsement.
© Adis Data Information BV 2003. All rights reserved.
Gladstone & Gawel
advantage of partial avoidance of first pass metabol-
ism of the liver, thereby leading to high and consis-
tent drug levels. The major disadvantages of rectal
administration are inconvenience of administration,
patient discomfort, lack of patient acceptability in
some parts of the world, possible irritation of the
rectal mucosa, interruption of absorption by defeca-
tion, and erratic absorption.[45-47] Ergotamine sup-
positories have rarely been reported (typically with
chronic abuse) to cause anorectal lesions, strictures
and fistulae.[48]
Rectal formulations are available for antiemetics,
analgesics, ergotamine and triptans (sumatrip-
tan).[49-54] Currently, rectal sumatriptan supposito-
ries are mainly available in Europe (Austria, Belgi-
um, Denmark, Finland, France, Germany, Greece,
Italy, Luxembourg, Netherlands, Norway, Sweden
and Switzerland) and are unavailable in North
America (personal communication, GlaxoSmith-
Kline, September 2002). This article reviews the
current literature on sumatriptan suppositories and
briefly highlights the utility of ergotamine supposi-
tories.
2.6 Sublingual Administration
Sublingual formulations are beneficial in popula-
tions of patients who cannot tolerate swallowing.
Absorption via the oral mucosa typically occurs
faster than similar conventional tablets absorbed via
the gastric mucosa. Currently, the only migraine-
specific agent available in a sublingual preparation
is ergotamine tartate and there are no randomised,
placebo-controlled trials demonstrating its efficacy.
The triptan orally disintegrating tablets are not de-
signed or intended for sublingual administra-
tion.[55,56]
2.7 Emerging Treatment Strategies
An emerging treatment paradigm is to treat
migraines early in the attack before pain esca-
lates.[57] Experimentally, it has been shown that
triptans can prevent but not reverse central sensitisa-
tion, a phenomena which occurs in many patients
Drugs 2003; 63 (21)
Newer Formulations of the Triptans
with migraine during acute attacks.[58] Central sen-
sitisation, the clinical consequence of which is cuta-
neous allodynia, appears to be resistant to therapy in
migraine patients once fully developed.[59] Random-
ised, controlled studies have demonstrated that acute
therapy with triptans is significantly more effective
when given while pain is mild and, recently, early
administration of triptans has been shown to im-
prove a wide range of headache response out-
comes.[60,61] Patients with episodic migraines are
now being encouraged to administer their acute
medication as soon as possible after the recognition
of their characteristic migraine headache, preferably
within 20 minutes, and before pain becomes moder-
ate or severe.[22,57]
3. Evaluating Abortive
Migraine Treatments
The proliferation of new abortive medications in
the past decade has led to numerous trials evaluating
the safety and efficacy of these new agents. There
are numerous clinical endpoints used in these
trials.[62,63] Headache relief/response is quantified by
a decrease in headache intensity from moderate-to-
severe to mild-to-moderate evaluated at prespecified
time points (i.e. 1, 2 or 4 hours) or by time to onset
(i.e. 15, 30, 60 minutes, etc.). Freedom from head-
ache (pain-free status) refers to the complete ab-
sence of any ongoing headache pain and is also
measured at prespecified time intervals (2, 4 or 24
hours). Recurrence of headache reflects the re-emer-
gence of a moderate-to-severe headache after pre-
viously being eliminated or diminished to mild in-
tensity. Consistency of response relates to the ability
of the medication to reproducibly provide pain relief
from attack to attack. Other commonly described
secondary endpoints are the ability to diminish the
migraine-associated symptoms of nausea, vomiting,
photophobia and phonophobia. Reduction in clinical
disability quantifies the ability of the abortive agent
to reduce functional impairment due to headache
pain and associated symptoms. Overall, these end-
points may be measured within a single attack or
across multiple attacks.
© Adis Data Information BV 2003. All rights reserved.
2291
The majority of these endpoints were predefined
for use in clinical trials as mandatory components to
satisfy licensing requirements. Interestingly, recent
consideration has been given as to whether these
endpoints are the most clinically relevant. This is
critical because failure to appropriately understand
patient preferences may reduce adherence and dis-
courage patients from continuing treatment. As the
number of therapeutic options for migraine contin-
ues to escalate, it is important to consider whether
the newer acute treatment options meet the needs of
migraine patients. Determining how well these new-
er agents meet the needs of patients requires an
understanding of what treatment attributes patients’
value most in their therapeutic decision mak-
ing.[64-75]
Lipton and Stewart,[64] using random-digit tele-
phone surveying, identified and polled 688 US pa-
tients with migraine. More than 70% of patients
indicated that they were less than completely satis-
fied with their current treatment. Of the patients who
were less than completely satisfied with their current
treatment, 87% indicated that pain relief takes too
long (71% thought it should work within 30 minutes
and an additional 21% thought it should work within
60 minutes), 84% stated that they had incomplete
pain relief, 84% noted that the medications were
inconsistently effective, 71% were displeased with
headache recurrence and only 35% mentioned that
there were too many adverse effects. The treatment
attributes that were ranked as important or very
important were complete pain relief (by 87% of
patients), no headache recurrence (86%), rapid onset
of action (83%), no adverse effects (79%), relief of
associated symptoms (76%) and the route of admin-
istration (56%).
In another survey by Lipton et al.[65] evaluating
patient preferences, 300 patients with migraine were
divided into those who were experienced triptan
users and those who were triptan-naïve. Both groups
indicated that combined efficacy attributes were
more important to them than a composite of tolera-
bility and/or consistency of effect attributes. This is
consistent with the prioritisation of treatment attrib-
Drugs 2003; 63 (21)
2292
utes seen with primary care physicians and neurolo-
gists.[66,67]
Davies et al.[68] analysed two trials where both
conventional clinical trial endpoints and measures
of satisfaction with treatment were recorded in pa-
tient diaries. They found that in excess of 90% of
patients who were pain-free at 2 hours were at least
somewhat satisfied with their treatment. Notably,
only 60–80% of those with absent-to-mild pain at 2
hours were at least somewhat satisfied with treat-
ment; this supported the notion that the measure of
headache relief/response is not the most sensitive
indicator of patient acceptance.
4. Importance of Associated Symptoms
Often the most unpleasant associated symptoms
with migraine are gastrointestinal disturbances, no-
tably nausea and vomiting, and they can be signif-
icant and incapacitating. These gastrointestinal
symptoms play an intimate role with drug efficacy
and preference. Gastric emptying may be delayed
and oral drug absorption impaired during a migraine
attack (even without the presence of nausea), nausea
can interfere with the ability to take oral medications
and vomiting may result in drug loss.[42,43] Corre-
spondingly, non-oral routes (intravenous, intramus-
cular, subcutaneous, intranasal, rectal) and oral
routes that do not require liquids or exacerbate nau-
sea/vomiting (orally disintegrating tablets) have
been designed to bypass the influence of these gas-
trointestinal disturbances.
The majority of studies report that in patients
with migraine, up to 90% also had nausea and
approximately 50% had vomiting.[2,41,44] These per-
centages are probably modestly higher than in the
general population as a result of the selection bias of
clinic-based studies. In a study of 500 self-reported
migraine patients,[41] 91.8% indicated that they had
ever experienced nausea during an attack and 56.4%
indicated that they had experienced nausea in >50%
of attacks. Fifty-seven percent noted that they had
nausea during their most recent attack and nearly
one-third reported experiencing nausea during every
attack. Similarly, vomiting occurred at some point in
© Adis Data Information BV 2003. All rights reserved.
Gladstone & Gawel
almost 70% of patients with migraine; nearly one-
third of these patients had vomiting in the majority
of attacks. In those with vomiting, 42% indicated
that it interfered with their ability to take oral medi-
cations.
In the 1990s, evidence from surveys and from the
distribution of market share for the various abortive
agents suggested that that the majority of patients
preferred oral tablets for their route of migraine drug
administration. When Lipton and Stewart[64] asked
study participants to select their preferred route of
administration, 73% selected oral tablets requiring
water as their first choice followed by oral rapidly
dissolving tablets (15%), nasal sprays (8.3%) and
subcutaneous administration (2.6%). When asked to
provide their second choice route of administration,
51% indicated rapidly dissolving tablets, 26% nasal
spray, 17% oral tablet and 3.5% subcutaneous ad-
ministration. When nausea makes it difficult to take
a tablet, 73% believed it was important or very
important to have access to an orally disintegrating
tablet (which doesn’t require water for administra-
tion). Notably, this study preceded the release onto
the market of the two currently available rapidly
dissolving triptan tablets; therefore, the study par-
ticipants would not have had any previous exposure
to orally disintegrating tablets.
Silberstein[2] notes that a substantial proportion
of patients with migraine suffer needlessly because
they do not report their symptoms of nausea or
vomiting to physicians, or physicians fail to
recognise that patients have such symptoms. Nausea
and vomiting is an under-recognised cause of disa-
bility in migraine patients not only directly as a
result of the morbidity associated with these symp-
toms, but also indirectly owing to the negative effect
on oral administration of medications. While many
patients choose conventional oral tablets because of
their familiarity with this modality and the ease of
administration, non-oral (or non–liquid requiring)
routes of administration should be given serious
consideration as first-line agents or as back-up or
rescue medication for patients with prominent gas-
trointestinal symptoms.
Drugs 2003; 63 (21)
Newer Formulations of the Triptans
5. Orally Disintegrating Tablets
As stated in section 2.4, there are currently two
orally disintegrating tablets available for acute mi-
graine therapy: rizatriptan[76] and zolmitriptan.[77]
Rizatriptan uses the Zydis® technology and masks
the active ingredient with a peppermint flavour.
Zolmitriptan uses the OraSolv® technology devel-
oped by CIMA Labs, Eden Prairie, Minnesota,
USA, and consists of tablets containing an orange-
flavoured masking agent.
5.1 Rizatriptan
5.1.1 Pharmacokinetic Studies
Rizatriptan is a highly efficacious, well tolerated
triptan that is available both as a conventional and as
an orally disintegrating tablet in 5 and 10mg dosage
formulations.[78] Preclinical studies demonstrated
that the pharmacokinetic profile of the rizatriptan
orally disintegrating tablet is similar to that of the
conventional oral tablet. The mean oral absolute
bioavailability of the rizatriptan conventional tablet
is approximately 45% following oral administration
and mean peak plasma concentrations (tmax) are
reached in approximately 1–1.5 hours. The bioavail-
ability and Cmax of rizatriptan were similar follow-
ing administration of rizatriptan conventional tablets
and rizatriptan orally disintegrating tablets, but the
rate of absorption is somewhat slower with riza-
triptan orally disintegrating tablet, with tmax averag-
ing 1.6–2.5 hours.[76]
5.1.2 Efficacy Studies
Rizatriptan Orally Disintegrating Tablets
versus Placebo
There is one large, multicentre, randomised,
double-blind, placebo-controlled, parallel-group
study examining the efficacy and safety of riza-
triptan orally disintegrating tablets.[79] The study
was conducted at 19 sites in five countries; 634
patients were randomised and 546 completed the
study as per protocol. Patients were randomised to
treatment with either rizatriptan orally disintegrating
tablet 5 mg, 10mg or placebo wafer (in a ratio of
1 : 1 : 1), and were required to treat a single moder-
ately severe migraine attack. After 2 hours, non-
© Adis Data Information BV 2003. All rights reserved.
2293
responders whose headache failed to improve to
mild or no pain were allowed to take additional
analgesia/antiemetic medications. Patients were in-
structed to treat a headache recurrence to moderate
or severe intensity with a second dose of the blinded
study medication. Patients were required to record
response on a diary card at 0.5, 1.0, 1.5, 2 and 24
hours after the initial dose. At the post-treatment
visit, patients completed a preference questionnaire.
Both doses of rizatriptan orally disintegrating
tablet (5 and 10mg) were superior to placebo in
achieving a headache response (pain from moder-
ate-severe to mild-none).[79] Headache response
rates were significantly greater than placebo from 30
minutes onward with the 10mg wafer (21.6% vs
11.2%, p = 0.008) and from 60 minutes onward with
the 5mg wafer (39.8% vs 21.2%, p < 0.001). Res-
ponse rates at 2 hours were significantly greater with
rizatriptan 10mg (74.1%) and 5mg (58.6%) than
with placebo (27.9%) [both doses p < 0.05]. Pain-
free rates were statistically superior to placebo from
30 minutes onwards with rizatriptan 10mg (4.3% vs
0.0%, respectively, p < 0.001) and from 90 minutes
onward with rizatriptan 5mg (18.2% vs 6.1%, re-
spectively, p < 0.001). Pain-free rates at 2 hours
were significantly greater with the 10mg dose
(42.2%) and the 5mg dose (34.8%) compared with
placebo (9.5%) [p < 0.01 for both doses].
With respect to associated symptoms, rizatriptan
orally disintegrating tablet 10mg was highly effec-
tive in relieving nausea compared with rizatriptan
5mg and placebo (45.5% vs 27.1% and 26.1%,
respectively, p < 0.01).[79] In a post hoc analysis
looking only at patients with nausea at baseline,[80]
the percentage of patients with nausea at 30 minutes
was 80%, 82% and 83% with rizatriptan 10mg wa-
fer, rizatriptan 5mg wafer and placebo, respectively.
By 1 hour the rate of nausea had reduced to 55%,
63% and 72% with rizatriptan 10mg wafer, riza-
triptan 5mg wafer and placebo, respectively (p <
0.05 for the 10mg wafer vs placebo), and at 2 hours
nausea was present in only 34%, 38% and 61% with
10mg, 5mg and placebo, respectively (p < 0.01 for
both doses of rizatriptan vs placebo). There was no
statistically significant difference in recurrence rates
Drugs 2003; 63 (21)
2294
between rizatriptan 10mg wafer, rizatriptan 5mg
wafer and placebo groups (42%, 34% and 36%,
respectively). Fewer rizatriptan-treated patients (re-
ceiving either 5 or 10mg) required additional
analgesics/antiemetics or a second dose of study
medication (64% and 60%, respectively) compared
with placebo (76%), p < 0.01 for both). The adverse
event profile was similar to that seen with the con-
ventional tablet (i.e. somnolence, dizziness, asthe-
nia/fatigue and nausea).[79]
With respect to the evaluation of patient prefer-
ence, 76% of patients taking either rizatriptan orally
disintegrating tablet dose (5 or 10mg) and 91% of
the placebo patients reported the wafer taste to be
acceptable.[79] The majority of patients who indicat-
ed a preference stated that they would prefer using a
wafer than a conventional tablet to treat their
migraines (75% of those receiving rizatriptan 10mg
wafer, 78% of those receiving rizatriptan 5mg wafer
and 83% of placebo recipients).
In an abstract, Cady et al.[81] reported the results
from a 6-month open-label, extension trial following
the randomised controlled study. Patients with mi-
graine were initially randomly assigned to one of
three groups: rizatriptan orally disintegrating tablet
5mg (n = 181), rizatriptan orally disintegrating tab-
let 10mg (n = 191), or their standard care (n = 86)
[i.e. their typical abortive therapy – analgesics, an-
tiemetics or triptans]. The mean number of treated
attacks was 19, 17 and 18, for the 5mg, 10mg and
standard care groups, respectively. The median
number of attacks during which patients experi-
enced pain relief at 2 hours was significantly greater
with the 10mg orally disintegrating tablet (82%),
compared with both the 5mg orally disintegrating
tablet (72%, p < 0.001) and standard care (73%, p =
0.004). The median number of attacks during which
patients experienced pain-free status at 2 hours was
also significantly greater with the 10mg orally disin-
tegrating tablet (46%) compared with both the 5mg
dose (25%, p < 0.001) and standard care group
(30%, p = 0.011).
The results of the placebo-controlled trial and the
6-month open-label extension trial demonstrate that
rizatriptan wafers (in particular the 10mg dose) are
© Adis Data Information BV 2003. All rights reserved.
Gladstone & Gawel
well tolerated and highly efficacious. Results for
headache response, pain-free status and other prima-
ry and secondary efficacy and tolerability measures
are similar to those achieved with the conventional
tablets.[78] Given its increased efficacy and similar
tolerability, the 10mg dose is typically the dosage of
choice.
Rizatriptan Orally Disintegrating Tablets versus
Sumatriptan Oral Tablets
Two large-scale comparison trials have been
published that have compared rizatriptan 10mg oral-
ly disintegrating tablet versus sumatriptan 50mg
oral tablets.[82,83] For the purposes of this study, the
authors indicated that the 10mg dose of rizatriptan
was selected because of its higher efficacy and the
50mg dose of sumatriptan was chosen because it is
the defined dose by the WHO and it is the most
commonly prescribed dose of oral sumatriptan.[82]
The two treatments were evaluated in terms of pref-
erence as well as efficacy measures such as head-
ache relief, freedom from headache, relief of asso-
ciated symptoms, functional disability, recurrence
and safety. The reasons for patient preference were
elicited based on directed questionnaires.
One of these studies, by Loder et al.[82] was a
recently completed US, multicentre, randomised,
open-label, two-period crossover study comparing
patient preferences for rizatriptan 10mg orally disin-
tegrating tablet versus sumatriptan 50mg oral tablet.
The study involved 524 patients with migraine; no-
tably, previous exposure to either rizatriptan or su-
matriptan was an exclusion criterion. Patients were
instructed to treat two moderate-to-severe mi-
graines, one during each treatment period according
to the randomisation schedule (either rizatriptan
then sumatriptan or vice versa). 386 patients treated
two migraines, one with each study medication and
374 indicated their treatment preference. Patients
could take one additional dose of study medication
to treat recurrences. Both treatment sequences were
balanced in terms of baseline headache severity.
In this study, a greater proportion of rizatriptan-
treated patients reported headache relief at every
time interval compared with sumatriptan recipients;
however, this reached statistical significance only at
Drugs 2003; 63 (21)
Newer Formulations of the Triptans
45 minutes (38% vs 29%, p = 0.008) and 60 minutes
(58% vs 49%, p = 0.004).[82] Similarly, more riza-
triptan-treated patients reported pain-free status at
every time point compared with sumatriptan recipi-
ents; however, this reached statistical significance
only at 60 minutes (23% vs 17%, p = 0.019) and 120
minutes (60% vs 52%, p = 0.007). Return to normal
function was more likely for rizatriptan-treated pa-
tients at all time intervals compared with patients
receiving sumatriptan with statistical significance
demonstrated only at 60 minutes (36% vs 27%, p =
0.004) and 120 minutes (70% vs 64%, p = 0.029).
Recurrence rates and adverse events were similar
between the two groups.
In this study, significantly more patients pre-
ferred rizatriptan (57% vs 43%, p = 0.009).[82] When
queried on the most important reason for their pref-
erence, 51% indicated that their choice provided
faster pain relief; this exceeded all other answers by
a substantial margin. Interestingly, perceived “faster
pain relief” was the “most important reason for their
preference” whether participants chose rizatriptan or
sumatriptan.
In a post hoc analysis presented in abstract form
at the International Headache Society (IHS) meeting
held in New York City, New York, USA in 2001,
Bohidar et al.[84] evaluated the relationship between
preference choice and the speed of onset of pain
relief with rizatriptan orally disintegrating tablets
and oral sumatriptan. The analysis revealed that a
vast majority of patients (78%) who experienced
faster pain relief with rizatriptan expressed a prefer-
ence for rizatriptan; similarly, a substantial majority
of patients (66%) who experienced faster relief with
sumatriptan preferred sumatriptan. Most notably,
for those who did not detect a difference in speed of
onset of pain relief, there was absolutely no differ-
ence in their preferred drug of choice (rizatriptan
50% vs sumatriptan 50%).
Pascual et al.[83] conducted a similar trial at 44
sites in 12 European countries, comparing riza-
triptan orally disintegrating tablets with suma-
triptan. In this study, 548 patients with migraine
were randomised, of whom 427 completed the trial.
Headache response rates with rizatriptan orally dis-
© Adis Data Information BV 2003. All rights reserved.
2295
integrating tablet was significantly greater within 30
minutes of dose administration (29.6% vs 21.6%
with sumatriptan, p < 0.001) and continued for up to
2 hours (75.9% vs 66.6% with sumatriptan, p <
0.001). Similarly, a significant improvement in free-
dom from pain was observed with rizatriptan orally
disintegrating tablet beginning at 1 hour (18.4% vs
12.9% with sumatriptan, p < 0.01) and maintained
for up to 2 hours (55.0% vs 42.1% with sumatriptan,
p < 0.001).
Rizatriptan was effective in eliminating or
preventing nausea and in producing a return to nor-
mal functioning.[83] At 2 hours, 85.2% of rizatriptan-
treated patients were nausea-free compared with
75.7% with sumatriptan (p = 0.004). At 2 hours,
59% of rizatriptan recipients had returned to normal
function compared with 48.6% of sumatriptan-treat-
ed patients (p < 0.001). At 2 hours, more rizatriptan-
treated patients had complete resolution of migraine
symptoms such as pain, associated symptoms, disa-
bility (46.1%) compared with patients receiving su-
matriptan (33.6%, p < 0.001). Recurrence rates of
headache were similar between the two groups.
Rizatriptan patients required less additional med-
ication from 2 to 24 hours post-treatment than suma-
triptan patients (32.4% vs 21.0%, p < 0.001). Both
treatments were generally well tolerated with simi-
lar overall clinical adverse event rates (31.5% and
34.1% of patients experienced adverse events with
rizatriptan and sumatriptan, respectively).
Two hours after treatment, more patients were
satisfied (completely, very or somewhat) with riza-
triptan than sumatriptan (73.3% vs 59%, p <
0.001).[83] Similarly, on the stricter criteria of very or
completely satisfied, patients also favoured riza-
triptan over sumatriptan (48.3% vs 34.1%, p <
0.001). At 2 hours, more patients found rizatriptan
convenient to take (87.2%) compared with suma-
triptan (76.3%, p < 0.001). Out of the 425 patients
who completed the preference questionnaire, 44
(10.4%) indicated no preference. Of those who did
express a preference, 64.3% preferred rizatriptan
and 35.7% preferred sumatriptan (p < 0.001). Faster
headache relief was the most important reason cited
by patients preferring either medication
Drugs 2003; 63 (21)
2296
Von Seggern et al.[85] presented a poster at the
2002 American Headache Society Scientific Meet-
ing in Seattle, Washington, USA that evaluated the
main determinants of patient preference in the trials
comparing rizatriptan oral disintegrating tablet ver-
sus oral sumatriptan. Interestingly, the primary
treatment attribute that influenced preference (for
either rizatriptan or sumatriptan) was perceived su-
periority in speed of pain relief (chosen by approxi-
mately 50% in each group in both studies). Surpris-
ingly, other variables such as convenience of admin-
istration, patient comfort with the route of
administration, ability to take without water, not
exacerbating nausea and flexibility to take in any
setting were not ranked highly as the main contribu-
tor to patient preference. All other components on
the 15-item list of potential preference questions
were selected by <15% of respondents. The ability
to take “the preferred treatment no matter where I
am” was the only item selected exclusively by those
preferring rizatriptan (14% in the US study and 4%
in the European study).
Rizatriptan Orally Disintegrating Tablet versus
Rizatriptan Conventional Tablet
Adelman et al.[86] published a unique naturalistic
preference study comparing rizatriptan conventional
tablets with rizatriptan orally disintegrating tablets.
At his US headache clinic, whenever rizatriptan was
the recommended drug of choice, patients were giv-
en sample packs of two 10mg tablets and two 10mg
orally disintegrating tablets. 367 patients requested a
prescription for rizatriptan during a 6-month interval
in 1999. For the last refill during that period, prefer-
ences appeared to be equally divided with 179 re-
quests for the conventional tablet and 188 requests
for the orally disintegrating tablet.
Cutrer et al.[87] performed a prospective, cross-
over trial evaluating the clinical efficacy and safety
of the rizatriptan conventional or orally disintegrat-
ing tablets. Patients chose which formulation they
wanted to receive first. Patients recorded their thera-
peutic results into an interactive voice response sys-
tem within 24 hours of drug administration. 2367
patients entered the study but only 1385 took both
formulations. Headache relief was faster with the
© Adis Data Information BV 2003. All rights reserved.
Gladstone & Gawel
orally disintegrating tablet (23% of patients) com-
pared with conventional tablets (17% of patients, p <
0.001). There was no differences in any other out-
come measures (headache relief at 2 hours, 67% for
both formulations), largely free of symptoms (52%
for both formulations), return to usual activities
(51% vs 50% for orally disintegrating and conven-
tional tablets, respectively), very or somewhat satis-
fied (74% vs 73% for orally disintegrating and con-
ventional tablets, respectively).
5.1.3 Summary
Rizatriptan orally disintegrating tablets are well
tolerated and highly effective with a clinical and
pharmacokinetic profile similar to that of the con-
ventional tablet formulation of rizatriptan. The only
head-to-head comparison trials that have compared
rizatriptan orally disintegrating tablets with another
triptan investigated rizatriptan 10mg orally disinte-
grating tablet with oral sumatriptan 50mg, and dem-
onstrated its superiority in obtaining headache res-
ponse, pain-free status, decreased functional disabil-
ity and nausea.[82,83] Correspondingly, rizatriptan
10mg orally disintegrating tablets were preferred
overall by study participants. Intriguingly, the over-
whelming factor influencing preference for riza-
triptan was its perceived speed of onset of headache
relief rather than attributes relating to ease of admin-
istration or tolerability. Rizatriptan conventional
tablets and orally disintegrating tablet have been
compared only in open-label studies and the formu-
lations were shown to be similar on all measured
efficacy parameters except speed of onset of head-
ache relief that was faster with rizatriptan orally
disintegrating tablet.
Rizatriptan orally disintegrating tablet is current-
ly available in more than 65 countries worldwide.
Because of a variable combination of efficacy attrib-
utes, patient preference for rapidly dissolving for-
mulations, and aggressive industry promotion, glob-
ally, the ratio of sales for the rizatriptan orally
disintegrating tablet versus the conventional tablet is
60 : 40 (personal communication, Merck & Co.,
August 2002). In Canada, the difference is even
more pronounced with approximately 80% of riza-
triptan prescriptions being filled for the rizatriptan
Drugs 2003; 63 (21)
Newer Formulations of the Triptans
orally disintegrating tablet formulation (personal
communication, Merck & Co., August 2002).
5.2 Zolmitriptan
5.2.1 Pharmacokinetic Studies
Preclinical studies demonstrate that the pharma-
cokinetic profile of the zolmitriptan orally disinte-
grating tablet is similar to that of the conventional
tablet.[77,88,89] Area under the curve (AUC) and Cmax
are similar following either conventional tablets or
orally disintegrating tablet. Similar to the tmax delay
observed with other orally disintegrating tablets (i.e.
rizatriptan), the tmax of the parent compound was
longer with zolmitriptan orally disintegrating tablets
(3 hours) versus conventional tablets (1.5 hours).
More importantly, the AUC, Cmax and tmax for the
active N-desmethyl metabolite of zolmitriptan are
comparable with either formulation indicating that
they are likely to demonstrate similar efficacy
profiles.
5.2.2 Efficacy Studies
There is one large, multicentre, randomised,
double-blind, placebo-controlled, published study
evaluating the efficacy and tolerability of zolmi-
triptan orally disintegrating tablet.[88] This study was
conducted at centres in Canada, South Africa and
the UK. 573 patients aged 18–65 with established
migraine (as defined by the IHS) were randomised
to receive either zolmitriptan 2.5mg orally disinte-
grating tablet or placebo tablet (matched for taste,
size and shape) for the acute treatment of a single
migraine. Patients were instructed to treat only mod-
erate or severe migraines and to take the medication
within 4 hours of migraine onset or within 4 hours of
waking with a migraine. If required, a second dose
of trial medication or rescue medication could be
taken from 2 hours after the initial dose. The res-
ponse to study medications was reported on diary
cards.
The intention-to-treat analysis consisted of 470
patients (231 orally disintegrating tablet and 239
placebo).[88] Significantly more patients experienced
greater headache relief at 2 hours with zolmitriptan
orally disintegrating tablets compared with placebo
© Adis Data Information BV 2003. All rights reserved.
2297
(63% vs 22%, p < 0.0001). The percentage of pa-
tients experiencing headache relief were similar to
results that were reported in other trials with zolmi-
triptan 2.5mg conventional tablet (2 hour headache
relief seen in 59–67% of patients).[89] At 30 minutes,
a greater proportion of patients treated with zolmi-
triptan orally disintegrating tablet demonstrated
headache relief (16%) compared with placebo
(10%), however, this did not reach statistical signifi-
cance (p = 0.0538).[88] At all other time points mea-
sured, zolmitriptan orally disintegrating tablet pro-
vided significantly greater headache relief compared
with placebo: at 1 hour (45% vs 19% of patients, p <
0.0001), at 4 hours (51% vs 14% of patients, p <
0.0001), and at 24 hours (40% vs 12% of patients
had headache relief at 2 hours with no recurrence by
24 hours postdose). Significantly more patients ex-
perienced pain-free status with zolmitriptan orally
disintegrating tablet, compared with placebo, at 1
hour (8% vs 3%, p = 0.0207), at 2 hours (27% vs
7%, p < 0.0001), and at 4 hours (37% vs 11%, p <
0.0001).
The proportion of patients who experienced relief
of their baseline nausea was higher in the zolmi-
triptan orally disintegrating tablet group that in the
placebo group (at 1 hour: 34% vs 24%; at 2 hours:
52% vs 32%).[88] The median time to rescue med-
ication was 2 hours and 10 minutes in the placebo
group and 5 hours and 45 minutes in the zolmitriptan
group. The percentage of patients requiring a second
dose of study medication or another rescue med-
ication was 84.9% in the placebo group and 56.7%
in the zolmitriptan group. Adverse events rates with
zolmitriptan orally disintegrating tablets were simi-
lar to those reported with zolmitriptan conventional
tablets.
This study also included several additional pref-
erence questions to evaluate the tolerability of the
orally disintegrating tablet;[88] 70% preferred to tak-
er the wafer when compared historically with con-
ventional oral tablets, 78% stated that the wafer was
convenient, 70% felt that the wafer can be taken
earlier in the migraine attack than with a conven-
tional tablet, 92% believed that the wafer was easy
to handle and 80% enjoyed the orange taste. Surpris-
Drugs 2003; 63 (21)
2298
ingly, the presence of nausea at baseline had no
effect on patients preferring a wafer to a convention-
al tablet.
One large, US, multicentre, randomised, double-
blind, placebo-controlled, two-attack study was re-
cently presented in abstract form at the 2002 Ameri-
can Headache Society (AHS) Scientific Meeting,
Seattle, Washington, USA.[90] The intention-to-treat
analysis consisted of 565 patients with migraine
who treated at least one mild, moderate or severe
migraine attack. Patients receiving zolmitriptan
2.5mg orally disintegrating tablet were significantly
more likely to achieve pain-free status, compared
with placebo, at 1 hour (13% vs 8%, p < 0.01), 1.5
hours (25% vs 14%, p < 0.001), and 2 hours (40% vs
20%, p < 0.001). Sustained pain-free response (de-
fined as pain free at 2 hours with no recurrence,
persistence or need for rescue medication up to 24
hours) was significantly greater in the zolmitriptan
group than in the placebo group (31% vs 14%, p <
0.001).
Charlesworth et al.[91] also presented an abstract
at the 2002 AHS Scientific Meeting, which com-
pared zolmitriptan 2.5mg orally disintegrating tab-
lets with rizatriptan 10mg orally disintegrating tab-
let in terms of patient preferences for taste and ease-
of-use. 171 patients with migraine were given
zolmitriptan and rizatriptan on alternate days during
a migraine-free period. The order was rotated to
reduce bias. Overall, patients strongly preferred
zolmitriptan to rizatriptan (70% vs 27%, p < 0.001).
More patients preferred zolmitriptan to rizatriptan in
terms of the following attributes: overall taste (73%
vs 24%), packaging (86% vs 12%), more convenient
to use (85% vs 11%), easier to understand how to
open (87% vs 9%), and easier to take out of the
package (91% vs 8%) [all p < 0.001]. The abstract
concluded that zolmitriptan was rated significantly
higher for strength of taste, sweetness, less bitter-
ness, less after-taste, less medicine taste (all p <
0.05) but no raw data was presented. Overall, 81%
liked the zolmitriptan orally disintegrating tablet
while 68% liked the rizatriptan orally disintegrating
tablet overall (p < 0.05). Finally, 84% indicated they
would be likely to use the zolmitriptan wafer in the
© Adis Data Information BV 2003. All rights reserved.
Gladstone & Gawel
future, whereas 71% thought they would try the
rizatriptan wafer in the future. While several inter-
esting tolerability differences are highlighted in this
study, the study was not performed in a clinical
context (i.e. the patients were instructed to take the
medications during a migraine-free period) and
therefore all efficacy considerations were eliminated
from this study.
5.2.3 Summary
Zolmitriptan orally disintegrating tablets are well
tolerated and efficacious for the acute abortive treat-
ment of migraine attacks. Currently, there are two
randomised controlled trials (one fully published
and one presented in abstract form), which have
compared zolmitriptan orally disintegrating tablets
with placebo. Efficacy parameters from these two
studies are similar to those obtained with the con-
ventional tablet formulation of zolmitriptan.[89]
There are no comparative studies evaluating the
efficacy of zolmitriptan head-to-head against other
oral triptans or against the rizatriptan orally disinte-
grating tablets.
Currently, zolmitriptan orally disintegrating tab-
lets are available in more than 25 countries world-
wide including the US, Canada, Mexico, Japan and
throughout Europe (personal communication, Astra-
Zeneca, August 2003). The proportion of overall
sales attributable to the orally disintegrating tablet
formulation varies widely between countries and is
influenced by the attitudes of physicians, patients
and healthcare institutions to the formulation, as
well as by the relative promotional efforts of the
different pharmaceutical suppliers. In Canada,
zolmitriptan orally disintegrating tablets were
launched in March 2001 and now represents approx-
imately 30% of overall sales. Elsewhere, in Sweden
and the UK the corresponding figure is around 10%,
in the US 20%, in France and Spain 60% and in
Japan 70% (personal communication, AstraZeneca,
August 2003).
6. Intranasal Spray
Intranasal administration of medication has be-
come a convenient and reliable route of systemic
administration for a range of drugs.[34-37] Intranasal
Drugs 2003; 63 (21)
Newer Formulations of the Triptans
butorphanol[92-97] and dihydroergotamine mesy-
late[98-102] have been on the market since the mid
1990s. Intranasal sumatriptan gained approval
worldwide at the end of the 1990s and intranasal
zolmitriptan gained approval in Europe in 2002.
The evaluation of the intranasal formulation of
the triptans is based on placebo-controlled trials and
clinical experience as there is a paucity of head-to-
head trials or comparison trials with other non-nasal
formulations.
6.1 Sumatriptan
Sumatriptan was the first triptan available as a
nasal spray formulation.[103-108] Initially, sumatriptan
nasal spray has a higher plasma concentration than
sumatriptan oral tablets, but by 2 hours, the plasma
concentration of both formulations are similar.
Five randomised, double-blind, placebo-control-
led trials have demonstrated that intranasal suma-
triptan 20mg has significantly higher 2-hour head-
ache response rates (ranging from 55% to 64%)
compared with placebo.[103-108] Headache relief with
intranasal sumatriptan reached significance at 15
minutes in three out of five studies. Two out of three
studies (that were prospectively designed and pow-
ered to compare the incidences of pain elimination)
reported that 2-hour headache pain-free status was
significantly higher with intranasal sumatriptan
(26% and 42% in the two studies) compared with
placebo (4% and 20% in the two studies).
A multinational, randomised, double-blind,
crossover study compared the efficacy and tolerabil-
ity of sumatriptan 20mg nasal spray with dihydroer-
gotamine mesylate (1mg plus an optional second
1mg dose).[108] 368 patients treated two attacks. Sig-
nificantly more patients experienced headache res-
ponse with sumatriptan than with dihydroergota-
mine mesylate, beginning at 45 minutes and contin-
uing to 2 hours. Complete elimination of headache
pain, return to normal functioning (or only mild
clinical disability) and freedom from associated
symptoms did not differ between the two groups at 2
hours. Both treatments were well tolerated with bad
taste being more common with sumatriptan and
© Adis Data Information BV 2003. All rights reserved.
2299
nasal symptoms being more likely with dihydroer-
gotamine mesylate.
Sumatriptan 20mg nasal spray has been reported
to have a faster onset of headache response com-
pared with 100mg oral sumatriptan tablet.[104] In this
study, headache response rates were higher with
sumatriptan nasal spray than with oral sumatriptan
at both 15 minutes (18% vs 6%, p < 0.001) and 1
hour (60% vs 47%, p < 0.05). By 2 hours, however,
headache response rates were similar for both treat-
ment groups (67% vs 70%).
6.2 Zolmitriptan
Zolmitriptan nasal spray is the most recent in-
tranasal migraine abortive agent to gain regulatory
approval. Zolmitriptan nasal spray is currently only
available in Sweden, the UK, Austria and Germany
and will be launched in many other European coun-
tries in 2003. Zolmitriptan nasal spray’s clinical
program consisted of five pharmacokinetic trials, an
efficacy and dose-comparison trial (intranasal doses
of 0.5–5mg vs placebo and vs oral zolmitriptan
across three migraine attacks), and a 1-year long-
term efficacy and safety trial.[109-113]
Initial pharmacokinetic studies demonstrated
rapid absorption of zolmitriptan after nasal spray
administration. After the administration of in-
tranasal zolmitriptan 2.5mg, all 12 volunteers had
detectable plasma levels after 5 minutes, whereas
after the administration of a zolmitriptan tablet
2.5mg only 10 out of 12 volunteers had detectable
plasma levels after 20 minutes.[109] AUC and Cmax
values were comparable following zolmitriptan
2.5mg nasal spray (at pH 5.0, the currently available
formulation) and zolmitriptan 2.5mg tablet (AUC =
22.4 ng • h/mL and 22.0 ng • h/mL, respectively;
Cmax = 3.93 μg/L and 4.48 μg/L, respectively).
Zolmitriptan nasal spray is rapidly absorbed with at
least 50% of Cmax achieved within 15 minutes of
dose administration.[109,110]
The pharmacokinetic parameters of absorption
have been assessed using positron emission tomog-
raphy (PET) scanning of the nasopharynx, lungs and
abdomen following nasal spray and/or tablet admin-
istration in healthy volunteers.[111] The PET data
Drugs 2003; 63 (21)
2300
suggests that up to 30% of intranasal zolmitriptan is
absorbed directly via the nasal mucosal, the remain-
der via the gastrointestinal mucosa. Absorption via
the richly vascularized nasal mucosa is faster than
via the gastrointestinal mucosa thereby leading to
early plasma levels.
In a dose-finding study, Becker et al.[112,113] ran-
domised a total of 1547 patients to zolmitriptan
nasal spray 0.5, 1.0, 2.5 or 5.0mg, oral zolmitriptan
2.5mg tablets or placebo in a double-blind, double-
dummy manner for the treatment of three moderate-
to-severe migraine attacks. The primary endpoint
was headache response and 1371 patients were in-
cluded in the intention-to-treat population. All doses
of zolmitriptan nasal spray (0.5, 1.0, 2.5 and 5.0mg)
resulted in significantly greater 2-hour headache
response rates (41%, 55%, 59% and 70%, respec-
tively) compared with placebo (31%, p < 0.001).
The headache response rates at 2 hours obtained
with the higher doses were similar to that observed
with oral zolmitriptan (61%). The speed of onset
with the nasal spray was rapid; within 15 minutes
significantly greater headache response rates were
seen with intranasal zolmitriptan 5.0mg and 2.5mg
(11% and 8%, respectively) compared with placebo
(5%).
Zolmitriptan nasal spray, at doses of 1.0, 2.5 and
5.0mg was superior to placebo in achieving a pain-
free response at 30, 45, 60, 120 and 240 minutes (p <
0.05 for all).[112,113] The 2-hour pain free response
rates were (25%, 26% and 36% for the nasal spray
1.0, 2.5 and 5.0mg, respectively, 36% for the oral
tablet and 8% for placebo). Complete headache res-
ponse rates (defined as a 2-hour headache response,
with no recurrence and no need for rescue medica-
tions) were significantly higher with nasal spray 1.0,
2.5 and 5.0mg (26%, 34% and 41%, respectively)
compared with placebo (14%). The complete head-
ache response rate with oral zolmitriptan was 43%.
The nasal spray also provided consistent efficacy in
responses across attacks; 74% of patients receiving
the 5mg nasal spray had a 2-hour headache response
in >2 out of 3 treated attacks, compared with 25% of
the placebo-treated patients. The nasal spray was
well tolerated with the most common adverse events
© Adis Data Information BV 2003. All rights reserved.
Gladstone & Gawel
in the 5mg group being taste disturbance (15%) and
intranasal parathesias (4%).[112,113] Purdy et al.[114]
noted that a higher proportion of patients treated
with the nasal spray had a satisfaction rating of
good/excellent compared with placebo; satisfaction
was highest in the 5mg group (57% vs 13% satisfac-
tion rating for placebo).
Once the optimal dose of 5mg was defined, a
year-long extension study evaluated its efficacy
with 783 patients treating 10 505 attacks.[114] This
dose and formulation was consistently effective
over time with 2-hour headache response rates of
73%, 75%, 75% and 75% over the periods 0–3, 4–6,
7–9 and 10–12 months, respectively. Pain-free re-
sponses with intranasal zolmitriptan 5mg were also
consistent over each 3-month interval with pain-free
status observed in 29–31% of patients at 1-hour
postdose and in 52–57% of patients at 2 hours. The
long-term use of intranasal zolmitriptan was well
tolerated, with a low incidence of adverse events
that remained stable (20–24%) over the 12-month
period.
Zolmitriptan nasal spray is an effective, conve-
nient treatment option with a rapid onset of action
and good tolerability. The rapidity of onset may be
particularly beneficial in preventing the develop-
ment of central sensitisation in certain patients.
Pending regulatory approvals, zolmitriptan nasal
spray is likely to be a useful addition for patients
with migraine worldwide.
7. Rectal Suppository
Rectal suppositories available for abortive ther-
apy for migraine include ergotamine, prochlorpera-
zine, metoclopramide and sumatriptan (not avail-
able in North America).[49-54]
7.1 Sumatriptan
The suppository formulation of sumatriptan is
available in Austria, Belgium, Denmark, Finland,
France, Germany, Greece, Italy, Luxembourg, The
Netherlands, Norway, Sweden, and Switzerland
(personal communication, GlaxoSmithKline, Sep-
tember 2002). This formulation of sumatriptan is
efficacious, well tolerated locally and systemically,
Drugs 2003; 63 (21)
Newer Formulations of the Triptans
and is rapidly absorbed. The pharmacokinetic pro-
file of sumatriptan 25mg suppositories is as follows:
tmax = 1.5, Cmax = 27 μg/L, bioavailability = 19.2%,
half-life = 1.8, AUC = 78 ng • h/mL.[49-52]
Two placebo-controlled trials have evaluated the
efficacy and tolerability of rectal suppositories of
sumatriptan in the abortive treatment of mi-
graines.[49,51] Bertin et al.[49] conducted a dose-rang-
ing, randomised, double-blind, placebo-controlled
parallel group study. 431 patients from 59 centres in
11 countries treated a single migraine attack with
sumatriptan suppositories (6, 12.5, 25, 50 or 100mg)
or placebo. All doses of sumatriptan, with the excep-
tion of the 6mg dose, were significantly better than
placebo and achieved similar rates of 2-hour head-
ache relief (all p < 0.004). The highest response rate
occurred in the 25mg group (72% vs 37% with
placebo, p < 0.001). Two-hour pain-free status was
achieved in 34% of patients treated with the 25mg
sumatriptan suppository compared with 23% of
those treated with placebo. The reduction in nausea
was significant with sumatriptan 50mg (37% vs
14% with placebo, p = 0.009) but did not reach
significance with sumatriptan 25mg (23% vs 14%).
Headache recurrence rates were similar between the
groups. The suppositories were relatively well toler-
ated with adverse event rates ranging from 17% with
sumatriptan 6mg to 29% with the 100mg dose,
compared with 14% in the placebo group. Only 3 of
317 patients reported rectal irritation. Overall, the
higher doses, 50 and 100mg, did not increase effi-
cacy but did increase adverse events, 12.5mg was
the minimum effective dose and 25mg was consid-
ered the ideal dose.
A second, randomised, double-blind, parallel-
group, placebo-controlled trial by Tepper et al.[51]
assessed the efficacy and tolerability of sumatriptan
12.5 and 25mg suppositories. 184 patients were
recruited from 25 US sites. Two-hour response rates
were significantly higher for both doses (68% for
the 25mg dose, 47% for the 12.5mg dose) compared
with placebo (25%). Beginning at 30 minutes and
continuing through to 2 hours, a significantly greater
percentage of patients receiving sumatriptan 25mg
experienced headache relief compared with place-
© Adis Data Information BV 2003. All rights reserved.
2301
bo-treated patients (p < 0.05 for all times points).
Two-hour pain-free rates reached significance for
both 25mg and 12.5mg doses (50% and 33%, re-
spectively) compared with placebo (14%, p < 0.05
for both doses). At 2 hours, the percentage of indi-
viduals with no associated symptoms (nausea,
vomiting, phonophobia or photophobia) was signifi-
cantly reduced in the 25mg group (p < 0.05). The
percentage of patients who had no clinical disability
was significantly higher with the 25mg dose at 30
minutes compared with placebo. At 2 hours, both
25mg and 12.5mg doses were extremely effective in
eliminating disability (50% vs 33%, respectively)
compared with placebo (15%, p < 0.05 for both
doses). The pattern and incidence of adverse effects
did not differ from placebo.
8. Topical/Transdermal
There are no currently available transdermal drug
delivery systems for migraine. However, there are
two recent abstracts evaluating the efficacy of pri-
vately compounded topical/transdermal formula-
tions of sumatriptan.[115,116] Aung-Din and col-
leagues[115] crushed and compounded commercially
available sumatriptan tablets in a proprietary formu-
la to give a concentration of 100 mg/mL in pluronic
lecithin organogel. In a small, open-label study, they
evaluated the efficacy of topical sumatriptan in a
small cohort of patients with migraine who were
being treated with subcutaneous, intranasal or oral
sumatriptan.[113] Patients were instructed to apply
50mg of sumatriptan cream to a clean area of the
forehead on the side of the headache at the time they
would usually resort to a sumatriptan formulation
for migraine relief. Fifty-five percent (5 of 11) re-
ported that the formulation provided relief for their
headache.
In a second open-label study, Aung-Din[116] com-
pounded 100mg of sumatriptan in a water-soluble
vehicle (Lipoderm) to create a transdermal formula-
tion. In a cohort of 30 patients, the transdermal
sumatriptan was administered to the posterior cervi-
cal area at the time when patients would normally
take their abortive medications. Pain relief and re-
duction of associated symptoms was observed by 30
Drugs 2003; 63 (21)
2302
minutes. Seventy percent of patients experienced
complete headache relief within 2 hours. Initial re-
lief of headache was noted by 15 minutes in all
patients and 50% had complete headache relief by
45 minutes. Adverse effects were minimal. It is
likely that continued research will be pursued to
investigate the potential for the role of this novel
drug delivery system in the management of acute
migraine attacks.
9. Conclusions
Migraine is a common, frequently incapacitating,
headache disorder that imposes a substantial burden
on the individual patient and on society. The last two
decades have witnessed an explosion in our under-
standing of the pathophysiology of migraine, our
appreciation for the expectations of patients with
migraine regarding treatment attributes, and in the
development of an efficacious and diverse therapeu-
tic armamentarium.
Oral disintegrating tablets and other non-oral
routes of administration (subcutaneous, intranasal,
rectal) are useful alternatives to conventional oral
tablets for patients who have difficulty swallowing
pills or prefer not to do so, and for patients whose
nausea/vomiting precludes swallowing tablets and/
or makes the likelihood of complete absorption un-
predictable. The newer formulations, oral disinte-
grating tablets and intranasal sprays, afford patients
the opportunity to use abortive therapy without the
need for liquids, at anytime and anywhere, at the
onset of a migraine attack. The ability to administer
treatment early in a migraine attack, especially with
medications and formulations with a fast onset of
action, is particularly important in acute migraine
treatment in order to prevent the development of
central sensitisation. Correspondingly, while many
patients and physicians select conventional oral tab-
lets because of their familiarity with this modality,
the newer formulations, oral disintegrating tablets
and intranasal sprays, should be given consideration
as first-line agents in selected migraine patients.
© Adis Data Information BV 2003. All rights reserved.
Gladstone & Gawel
Acknowledgements
Dr Gawel has served as an advisor for GlaxoSmithKline,
Merck and AstraZeneca. No sources of funding were used to
assist in the preparation of this manuscript directly relevant to
the content of this review.
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Correspondence and offprints: Dr Marek Gawel, Sun-
nybrook & Women’s College Health Sciences Centre, 60
Grosvenor Street, Toronto, M5S 1B6, Canada.
E-mail: jon.gladstone@utoronto.ca
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