Neuropsychiatr Dis Treat. 2006 Sep; 2(3): 247–259.

PMCID: PMC2671815

Rizatriptan in the treatment of migraine

Miguel JA Láinez
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Abstract
Migraine is a common, disabling disorder associated with considerable personal and
societal burden. Current guidelines recommend triptans for the acute treatment of
migraine unlikely to respond to less effective therapies. Rizatriptan is a second-
generation triptan available in tablet or orally disintegrating tablet (wafer)
formulations that offers several advantages over other members of its class.
Rizatriptan is rapidly absorbed from the gastrointestinal tract and achieves maximum
plasma concentrations more quickly than other triptans, providing rapid pain relief.
Clinical trials have shown that rizatriptan is at least as effective or superior to other
oral migraine-specific agents in the acute treatment of migraine, and has more
consistent long-term efficacy across multiple migraine attacks. Rizatriptan has a
favorable tolerability profile, and patients have reported greater satisfaction and a
preference for rizatriptan over other migraine-specific agents. Improvements in
quality of life reported with rizatriptan are consistent with its favorable efficacy and
tolerability profiles. Notably, multi-attribute decision models that combine clinical
data with patient- and physician-reported treatment preferences have identified
rizatriptan as one of three triptans closest to a hypothetical “ideal”. The efficacy and
tolerability of rizatriptan for the acute treatment of migraine have thus been well
established.

Keywords: rizatriptan, serotonin receptor agonists, triptans, acute migraine

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Introduction

Background and epidemiology

Migraine is a common, disabling disorder that affects approximately 3%–22% of

females and 1%–16% of males worldwide (Lipton and Bigal 2005). Results of a large
population-based study performed in the US suggest that migraine affects
approximately 18.2% of women and 6.5% of men, of whom most (62%) experience at
least 1 severe headache per month (Lipton, Stewart, et al 2001). Migraine without aura
is the commonest clinical subtype of migraine, and has a higher attack frequency and
is generally more disabling than migraine with aura (HCS 2004). Migraine without
aura is defined as a recurrent disorder that involves headache attacks lasting 4 hours
to 3 days, with at least 2 of the following characteristics: unilateral pain, pulsating
quality, aggravation on movement, and pain of moderate or severe intensity (HCS
2004). Patients with this migraine subtype also experience nausea and/or vomiting,
and/or photophobia and phonophobia (HCS 2004).

Migraine places a considerable burden on the sufferer, their friends and family, and
society, in terms of economic costs and quality of life. Direct costs of migraine include
visits to physicians, utilization of emergency care facilities, and prescription and over-
the-counter medications (Lipton and Bigal 2005). The majority of the not
inconsiderable indirect costs are borne by patients and their employers,
predominantly as a result of bedridden days and impaired work function (Hu et al
1999). A recent analysis, based principally on studies performed prior to 1995,
estimated that the annual cost of migraine in some Western European countries was
approximately €590 per patient, primarily due to lost productivity (Berg and Stovner
2005). Lost productivity due to headache (including but not limited to migraine) is
estimated to cost more than US$19 billion per year in the US, with migraine accounting
for at least US$13 billion per year (Hu et al 1999).

The results of several studies indicate that migraine affects quality of life during and
immediately after a migraine attack, as well as reducing quality of life between
episodes (Lipton and Bigal 2005). Population-based studies in the UK and US
demonstrate that migraine attacks also have a significant impact on family members
of afflicted individuals (Lipton et al 2003). Moreover, a survey of migraine sufferers
found that less than one-third of patients were “very satisfied” with their acute
migraine treatment (Lipton and Stewart 1999). Thus, migraine remains a major
healthcare problem, and there is significant opportunity to improve the treatment and
management of this condition.

Current treatments
There are a number of abortive therapy options for acute migraine. Nonsteroidal anti-
inflammatory agents, nonopiate analgesics, and combination analgesics may be
appropriate for some patients with mild-to-moderate migraine. Patients with
moderate-to-severe symptoms or those who respond poorly to adequate doses of
analgesics generally require migraine-specific agents or more potent nonspecific
agents such as opiate analgesics, although the latter should be used sparingly
(Silberstein and for the US Headache Consortium 2000; Goadsby et al 2002). Anti-
emetics may be used to treat migraine-associated nausea, and may also facilitate
absorption of oral migraine treatments by improving gastric motility.

The two principal classes of migraine-specific agents (ie, those targeting the
neurovasculature) are the ergot derivatives and the triptans. The ergot derivatives
ergotamine and dihydroergotamine have been used for the acute treatment of
migraine for many years. However, they have a number of limitations including
nonspecific vasoconstrictor effects and other side-effects (eg, nausea and vomiting)
owing to a low degree of receptor selectivity, and there is a lack of consistent efficacy
data for these agents (Tfelt-Hansen, Saxena, et al 2000). Improved understanding of the
pathology of migraine led to the development of selective serotonin (5-
hydroxytryptamine [5-HT]) receptor agonists (triptans) that activate 5-HT1B and 5-
HT1D receptors. Triptans are now generally preferred over ergot derivatives in
treating most patients with migraine, because of advantages including selective
pharmacology and well-established efficacy and safety (Goadsby et al 2002).

Sumatriptan was the first triptan to be introduced for the treatment of migraine
attacks, and is commonly used as the reference against which later triptans are
compared (Ferrari et al 2002). Although clinical trial results show only relatively small
differences between sumatriptan and newer, second-generation triptans for efficacy
and tolerability, these differences are considered clinically relevant for individual
patients (Ferrari et al 2002). This article reviews the evidence relating to rizatriptan, a
second-generation triptan available in 5- and 10-mg tablets and orally disintegrating
tablets (wafers) for the acute treatment of migraine.
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Pharmacology

Animal and preclinical results

Several pharmacologic effects of the 5-HT1B/1D receptor agonist rizatriptan are thought
to contribute to its antimigraine activity, including vasoconstriction of intracranial
extracerebral blood vessels (Longmore et al 1998), inhibition of nociceptive
neurotransmission in trigeminal pain pathways (Cumberbatch et al 1997), and
inhibition of neurogenic dural vasodilation and plasma protein extravasation
(Williamson et al 1997; Williamson et al 2001).

Preclinical studies showed that rizatriptan caused vasoconstriction in isolated human

cranial (middle meningeal) arteries (Longmore et al 1998) with an EC50 (concentration
required to produce 50% of maximum vasoconstriction) of 90 nM, which is similar to
the maximum plasma concentrations achieved following oral administration of a
single 5- or 10-mg rizatriptan dose in healthy individuals (30–70 nM) (Sciberras et al
1997). The vasoconstrictor action of rizatriptan is thought to occur primarily via 5-
HT1B receptors (Longmore et al 1998; Goadsby and Hargreaves 2000). A study in
healthy volunteers showed that rizatriptan significantly reduced cerebral blood flow
and arterial-to-capillary blood volume consistent with its vasoconstrictor activity in
large cerebral arteries, with a recovery pattern indicating no alteration of the
autoregulatory response of small arteries (Okazawa et al 2005). Another study in
healthy volunteers found no effect of rizatriptan 40 mg on regional cerebral blood
flow (Sperling and Tfelt-Hansen 1995). Furthermore, rizatriptan did not significantly
alter cerebral blood flow velocity during attacks in patients with migraine without
aura as compared with pretreatment or pain-free values, a finding that may support
the cerebrovascular safety of the drug (Gori et al 2005). Although, like other triptans,
rizatriptan has also been shown to contract isolated human coronary arteries in vitro
(Longmore et al 1997; MaassenVanDenBrink et al 1998), the EC50 for this effect (700–
1000 nM) (Longmore et al 1997) is so high that rizatriptan is considered unlikely to
cause myocardial ischemia at therapeutic plasma concentrations in patients with
normal coronary circulation (MaassenVanDenBrink et al 1998). Rizatriptan 10 mg
demonstrated only minimal and transient vasoconstrictor effects on peripheral
arteries in normal human subjects (Tfelt-Hansen et al 2002).
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Pharmacokinetics
Rizatriptan is rapidly and completely (~90%) absorbed from the gastrointestinal tract
following administration of the oral tablet, with an absolute bioavailability of 47%
owing to moderate first-pass metabolism (Vyas et al 2000). The mean time to
maximum plasma concentration (tmax) following a single rizatriptan 10-mg tablet in
healthy volunteers is approximately 1–1.5 hours (Sciberras et al 1997; Goldberg et al
2000; Vyas et al 2000), which is shorter than that of other available triptans (Ferrari et
al 2002). Rizatriptan has a relatively short plasma half-life (t1/2) of approximately 2–2.5
hours (Sciberras et al 1997; Lee et al 1999; Goldberg et al 2000; Vyas et al 2000). A
pharmacokinetic study in healthy males showed no unexpected accumulation of
rizatriptan 10 mg following administration of multiple doses (every 2 hours for 3 doses
on 4 consecutive days) (Goldberg et al 2000). Rizatriptan wafers have a similar
pharmacokinetic profile to tablets, although they have a slower rate of absorption
(mean tmax1.6–2.5 hours) (Merck & Co Inc. 2003).

Metabolism is the primary route of elimination of rizatriptan, with renal elimination

accounting for only 25% of total plasma clearance (Vyas et al 2000). Rizatriptan is
metabolized predominantly by monoamine oxidase A, accounting for 51% of urinary
rizatriptan metabolites (Vyas et al 2000). The clearance of rizatriptan is approximately
25% higher in males than in females (plasma clearance 1042 vs 821 mL/min,
respectively); however, this is not thought to be clinically relevant (Lee et al 1999).

Importantly, rizatriptan mean plasma concentrations and tmax are not affected by the
occurrence of a migraine attack (and associated gastric stasis) (Cutler et al 1999).
Administration of food prior to rizatriptan dosing in healthy volunteers was found to
increase the area under the curve (AUC) by approximately 20% and delay absorption,
but there were no significant effects on maximum concentration (Cmax) or tmax values
(Cheng et al 1996). The pharmacokinetics of rizatriptan in elderly patients (aged ≥ 65
years) are similar to those in younger patients (Musson et al 2001). Since the major
route of elimination of rizatriptan, oxidative deamination, is catalyzed by monoamine
oxidase A, inhibitors of cytochrome P-450 are expected to have minimal effects on the
pharmacokinetics of rizatriptan (Vyas et al 2000). Patients receiving propranolol
exhibit an increase in plasma rizatriptan concentration (Goldberg et al 2001), possibly
reflecting competitive inhibition of monoamine oxidase A rizatriptan metabolism.
Rizatriptan dose-reduction is therefore recommended in patients receiving
propranolol (see patient support–disease management programs section).
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Clinical studies

Efficacy
Recommended efficacy measures in clinical trials of migraine treatments include the
percentage of patients who are pain-free at 2 hours following treatment, headache
response–pain relief at 2 hours (reduction in intensity of the headache from severe or
moderate at baseline to mild or none), sustained pain-free response rate (pain-free
status within 2 hours with no rescue medication use or migraine recurrence within 48
hours), time to headache response or pain-free status (ie, speed of onset of action), and
the need for rescue medications within 2 hours of treatment (Tfelt-Hansen, Block, et al
2000).

The efficacy of rizatriptan 5 and 10 mg in acute migraine has been clearly established
in randomized, double-blind, placebo-controlled trials (Visser et al 1996; Gijsman et al
1997; Goldstein et al 1998; Teall et al 1998; Tfelt-Hansen et al 1998; Ahrens et al
1999; Bomhof et al 1999; Pascual et al 2000; Kolodny et al 2004). A meta-analysis of 7
phase III, randomized, double-blind, placebo-controlled trials in which a total of 4814
patients received treatment for at least 1 migraine attack demonstrated that
rizatriptan 10 mg was significantly more effective than placebo at 2 hours on
measures of pain relief, pain-free status, nausea, photophobia, phonophobia, and
functional disability (p < 0.001 for all comparisons) (Ferrari et al 2001). Furthermore,
compared with placebo recipients, significantly more patients taking rizatriptan 10 mg
had sustained pain relief (18% vs 37%, respectively, p < 0.001) and pain-free status (7%
vs 25%, p < 0.001) over 24 hours. The results of these trials have been further
confirmed in a large open-label, uncontrolled study (Göbel et al 2001).

In randomized comparative studies, rizatriptan 10 mg was at least as effective as, or

superior to, oral sumatriptan 50 or 100 mg (Visser et al 1996; Goldstein et al 1998; Tfelt-
Hansen et al 1998; Kolodny et al 2004), zolmitriptan 2.5 mg (Pascual et al 2000),
naratriptan 2.5 mg (Bomhof et al 1999), and ergotamine–caffeine 2 mg/200 mg (Christie
et al 2003) for a number of efficacy parameters, including headache relief and pain-
free status at 2 hours, functional improvement at 2 hours, and time to headache–pain
relief (Table 1, Figure 1). The proportion of patients experiencing headache recurrence
was generally similar between patients taking rizatriptan and those taking comparator
treatments. However, statistical analyses of this endpoint are usually not performed
because recurrence is conditional on initial headache relief and confounded by the use
of additional headache–pain medication, thus making interpretation of recurrence
rates difficult.
Figure11
Figure
Patients reporting pain relief at time points up to 2 hours following dosing with
rizatriptan or sumatriptan in a randomized, double-blind, placebo-controlled, cross-
over study (Goldstein et al 1998). Adults with at least a 6-month history of migraine ...

Table 11
Table
Comparative efficacy of rizatriptan in the acute treatment of migraine in randomized,
double-blind, comparative studies

Analyses of data from several of the above-mentioned comparator studies (Tfelt-

Hansen et al 1998; Goldstein et al 1998; Bomhof et al 1999; Pascual et al 2000; Kolodny
et al 2004) have confirmed the significantly greater efficacy of rizatriptan 10 mg
compared with oral sumatriptan 25, 50, or 100 mg, naratriptan 2.5 mg, and
zolmitriptan 2.5 mg for stringent efficacy measures (pain-free response at 2 hours,
symptom-free response at 2 hours, and 24-hour sustained pain-free response)
(Adelman et al 2001), ability to functional normally at 2 hours (Bussone et al 2002), and
freedom from nausea at 2 hours (sumatriptan and naratriptan) (Lipton, Pascual, et al
2001) (Table 2).

Table 22
Table
Efficacy of rizatriptan in the acute treatment of migraine in retrospective analyses of
comparative studies

Open-label trials have also shown benefits with rizatriptan 10 mg wafer vs oral
sumatriptan 50 mg (Pascual et al 2001; Loder et al 2001), almotriptan 12.5 mg (Leira et
al 2003), and zolmitriptan 5 mg (Mathew et al 2000), on efficacy measures such as
greater headache relief and/or freedom from pain at 2 hours (vs sumatriptan and
zolmitriptan), faster time to headache relief and pain-free status (vs sumatriptan) and
reductions in number of triptan doses needed for migraine (vs almotriptan). A small
single-blind, single-center, multiple-attack study comparing rizatriptan 10 mg,
sumatriptan 100 mg, almotriptan 12.5 mg, zolmitriptan 2.5 mg, and eletriptan 40 mg,
reported relatively homogeneous results overall, but superior efficacy with rizatriptan
with respect to pain-free response at 2 hours (vs sumatriptan and almotriptan) and
sustained pain-free response (vs sumatriptan) (Vollono et al 2005). The authors
considered rizatriptan to have the best performance of the triptans evaluated but
concluded that, owing to the unpredictability of responsiveness to individual triptans,
selection of an “ideal triptan” may require a process of trial and error in each patient
(Vollono et al 2005).

Patients treated with rizatriptan 10-mg tablet or wafer in a typical patient care setting
reported better treatment outcomes compared with their prior migraine treatment
experiences (primarily triptans, opiates and barbiturates, or nonsteroidal anti-
inflammatory drugs), in terms of speed of pain relief (18% and 23% of patients taking
rizatriptan tablet or wafer, respectively, reported onset of pain relief within 30
minutes vs 16% for comparator), and 2-hour efficacy endpoints including headache
response (66% and 67% vs 37%), pain-free status (31% for both rizatriptan
formulations vs 12%), freedom from migraine-associated symptoms (52% and 54% vs
35% largely symptom-free), and ability to resume normal activities (50% and 51% vs
31%) (Jamieson et al 2003). Similarly, an open-label, 2-attack study showed that among
patients with functional disability at the start of a migraine attack, more patients
reported a return to normal function 2 hours after treatment with rizatriptan 10-mg
wafer than after treatment of the preceding attack with their usual nontriptan therapy
(nonsteroidal anti-inflammatory drugs, analgesics, or ergot derivatives, used alone or
in combination) (48% vs 19%, respectively; p < 0.001) (Pascual et al 2005). After
adjusting for confounding factors, rizatriptan was twice as likely to return patients to
normal function compared with their usual nontriptan therapy (hazard ratio 2.08; 95%
confidence interval, 1.92–2.25; p < 0.001), and the speed of return to normal function
was significantly greater with rizatriptan therapy (p < 0.001) (Pascual et al 2005).

Long-term studies (up to 6 months or 1 year) of acute treatment with rizatriptan

tablets (Block et al 1998) or wafers (Cady et al 2001) for multiple attacks showed that
rizatriptan 10 mg was superior to rizatriptan 5 mg or “standard care” in terms of pain
relief and pain-free status at 2 hours after dosing (Figure 2). Headache relief rates
were consistently maintained over the duration of the studies, with no apparent
change in response over time. Importantly, there was no evidence of tolerance to the
therapeutic effects of rizatriptan after up to 1 year of treatment (Block et al 1998).
Rizatriptan also demonstrated consistent within-patient efficacy over multiple
migraine attacks (Kramer et al 1998; Dahlof et al 2000).

Figure 22
Figure
Median percent of migraine attacks in which patients achieved pain relief or pain-free
status 2 hours after dosing. (a) Results in patients enrolled in an open-label,
randomized, 6-month extension study who treated at least 1 moderate or severe
migraine ...

Quality of life benefits, as measured by the 24-hour Migraine Quality of Life

Questionnaire (Santanello et al 1995), have also been reported with rizatriptan
treatment. In randomized controlled trials, rizatriptan 10 mg was associated with
significantly better migraine-specific quality of life than placebo (p = 0.005) (Santanello
et al 1997), and provided improvements in 24-hour quality of life relative to baseline
similar to those achieved with oral sumatriptan 25, 50, or 100 mg (Goldstein et al 1998),
zolmitriptan 2.5 mg (Pascual et al 2000), and naratriptan 2.5 mg (Bomhof et al 1999).
One study found that rizatriptan 10 mg was superior to rizatriptan 5 mg in this regard
(p ≤ 0.001) (Santanello et al 1997).

Rizatriptan has demonstrated efficacy in special patient groups. In a retrospective

analyses of data from a subgroup of women with menstrual migraine from 2
randomized placebo-controlled trials, rizatriptan (5 or 10 mg) was significantly more
effective than placebo in achieving pain relief and pain-free status at 2 hours (p < 0.05
for both endpoints) (Silberstein et al 2000). Results from this and another retrospective
analysis of data from a long-term (up to 6 months) extension study suggest that
rizatriptan has similar efficacy in patients with menstrual migraine to that observed in
patients with nonmenstrual migraine (Silberstein et al 2002). Rizatriptan 5 mg tablets
or wafers were more effective in achieving 2-hour pain relief and pain-free status than
standard care (primarily ibuprofen, sumatriptan, zolmitriptan, and aspirin–
acetaminophen–caffeine) in adolescents aged 12–17 years, based on pooled data from
2 long-term, open-label studies (Visser et al 2004). In 2 randomized, double-blind,
single-attack studies in adolescent patients, rizatriptan 5 mg tablets were not
significantly different from placebo for pain relief or freedom from pain at 2 hours
(Winner et al 2002; Visser et al 2004); however, there were high placebo response rates
in both trials (eg, 2-hour pain relief rates with rizatriptan vs placebo were 66% vs 56%
(Winner et al 2002) and 68% vs 69% (Visser et al 2004), respectively).

In most clinical trials rizatriptan was generally administered to patients with

moderate-to-severe headaches; however, rizatriptan has also shown efficacy when
given for mild pain in the early stages of a migraine attack (Mathew et al 2004).

A meta-analysis of results from 53 studies of oral triptans in the treatment of migraine

showed that rizatriptan 10 mg appeared to have greater intra-patient consistency for
2-hour headache response and pain-free status over 3 migraine attacks than other
triptan dosages evaluated (sumatriptan 25–100 mg, naratriptan 2.5 mg, eletriptan 20–
80 mg, and almotriptan 12.5 mg) (Ferrari et al 2002). The analysis indicated that
rizatriptan 10 mg (along with eletriptan 80 mg and almotriptan 12.5 mg) was one of
three triptans most likely to be associated with consistent treatment success,
particularly when rapid and consistent relief of pain was required (Ferrari et al 2002).
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Tolerability and patient acceptability

Rizatriptan was generally well tolerated in the aforementioned randomized, placebo-
controlled studies. The frequency of adverse events with rizatriptan appears to be
dose-related (Visser et al 1996; Ferrari et al 2001). In a summary of adverse event data
from 7 randomized, placebo-controlled studies of rizatriptan for the acute treatment of
migraine attack, specific adverse events with an incidence of 5% or more in patients
receiving placebo (n = 1260), rizatriptan 5 mg (n = 1486), or rizatriptan 10 mg (n =
2068) were dizziness (4%, 6%, and 9%, respectively), somnolence (4%, 5%, and 8%),
nausea (4%, 5%, and 6%), and asthenia–fatigue (2%, 3%, and 5%) (Ferrari et al 2001).
Similarly, the most common adverse events in patients taking rizatriptan 5- or 10-mg
tablet or wafer in comparative clinical trials included dizziness (5%–11% of patients
across clinical trials), somnolence (4%–10%), asthenia–fatigue (2%–8%), dry mouth
(2%–7%), nausea (2%–6%), and chest pain (1%–4%); these events were predominantly
transient and mild or moderate in intensity (Visser et al 1996; Goldstein et al
1998; Tfelt-Hansen et al 1998; Bomhof et al 1999; Pascual et al 2000; Christie et al
2003; Kolodny et al 2004). In comparator studies, the overall incidence of drug-related
adverse events in patients receiving rizatriptan 5- or 10-mg tablet or wafer ranged
from 23% to 37%, compared with sumatriptan 25, 50, or 100 mg (28%–41%),
zolmitriptan 2.5 mg (28%), naratriptan 2.5 mg (19%), and ergotamine 2 mg–caffeine
200 mg (23%) (Bianchi et al 1989; Goldstein et al 1998; Tfelt-Hansen et al 1998; Bomhof
et al 1999; Christie et al 2003; Kolodny et al 2004). One study reported a significantly
lower adverse event rate in patients receiving rizatriptan 5 and 10 mg vs sumatriptan
100 mg (27% and 33%, respectively, vs 41%; p < 0.05) (Tfelt-Hansen et al 1998).
Rizatriptan 5-mg tablets and wafers were also well tolerated in adolescents (Winner et
al 2002; Visser et al 2004). Most studies reported no serious drug-related adverse
events, and very few patients discontinued due to adverse events.

In a large, open, noncomparative study involving 33147 patients receiving treatment

with rizatriptan 10 mg in a clinical setting for up to 3 migraine attacks, repeated
administration of rizatriptan was well tolerated, with very few adverse events
reported (Göbel et al 2001). In this study, 0.9% of patients experienced 1 or more
adverse events, the most frequent of which were dizziness (0.2%) and weakness–
fatigue (0.2%). A total of 157 patients discontinued rizatriptan owing to an unwanted
drug effect, representing 6.3% of all patients who discontinued rizatriptan for any
reason and 0.5% of patients enrolled on the study. Fewer than 4.5% of patients taking
rizatriptan 5 or 10 mg withdrew because of adverse events in long-term studies of
rizatriptan treatment for multiple migraine attacks (Block et al 1998; Cady et al 2001).

In the randomized, double-blind, comparative trials, rizatriptan 10 mg was associated

with a higher degree of patient satisfaction with medication compared with
sumatriptan 50 mg (mean satisfaction on a scale from 1 “completely satisfied; couldn’t
be better” to 7 “completely dissatisfied; couldn’t be worse”: 3.28 vs 3.56 at 2 hours and
3.06 vs 3.39 at 4 hours; p < 0.05 both comparisons) (Goldstein et al 1998), zolmitriptan
2.5 mg (mean 3.38 vs 3.67 at 2 hours; p = 0.038) (Pascual et al 2000), naratriptan 2.5 mg
(mean 3.55 vs 4.21 at 2 hours; p < 0.001) (Bomhof et al 1999), and ergotamine 2 mg–
caffeine 200 mg (43.8% vs 21.6% of patients completely satisfied or very satisfied at 2
hours; p ≤ 0.001) (Christie et al 2003).

In a randomized, open-label, crossover trial designed to compare preference for

rizatriptan 10-mg wafers vs sumatriptan 50-mg tablets, significantly more patients
preferred rizatriptan than preferred sumatriptan (64.3% vs 35.7%; p ≤ 0.001) (Pascual
et al 2001). The most common reasons for rizatriptan treatment preference were faster
relief of headache pain (46.9% of patients), ease of use (8.2%), and fewer side-effects
(6.1%). Similar results were seen in a second trial of similar design, with 57% of
patients expressing a preference for rizatriptan 10-mg wafers compared with 43% of
patients who preferred sumatriptan 50-mg tablets (p = 0.009) (Loder et al 2001). Among
those patients with a stated preference, the most important reasons were faster pain
relief (51% of patients), the ability to take the medication regardless of patient location
(8%; only reported for rizatriptan wafer), and the ability to return to normal activities
quicker (7%). It is possible that treatment choice could have been influenced by the
ease of use of the rizatriptan wafer formulation in these 2 studies. However, a
relatively small percentage of patients reported this as the reason for treatment
preference, and results of a separate retrospective nonblinded study in 367 patients
showed that a similar number of patients preferred the 10-mg wafer (n = 188) and 10-
mg tablet (n = 179) rizatriptan formulations (Adelman et al 2000), suggesting that
formulation was probably not the key factor.

A greater proportion of patients preferred rizatriptan 10-mg tablets than preferred

ergotamine 1-mg–caffeine 100-mg tablets in a randomized, double-blind, crossover
trial (69.9% vs 30.1% of 319 patients expressing a preference, respectively; p ≤ 0.001),
with faster relief of headache cited by the majority of these patients (67.3% vs 54.2%,
respectively) as the most important reason for preference (Christie et al 2003).

Similarly, among patients who reported a treatment preference in a prospective, open-

label, 2-attack study, more patients preferred rizatriptan 10-mg wafers than preferred
their usual nontriptan therapy (nonsteroidal anti-inflammatory drugs, analgesics, or
ergot derivatives, used alone or in combination) (78.8% vs 21.2%, respectively; p <
0.001). Overall, the most common reasons cited for preference of either treatment
were faster relief of headache pain and faster return to normal function (Pascual et al
2005).

The quality of life benefits afforded by rizatriptan, as mentioned above (Santanello et

al 1997; Goldstein et al 1998; Bomhof et al 1999; Pascual et al 2000), are consistent with
the favorable efficacy and tolerability profile of the agent.
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Patient support and disease management programs

The goals of migraine management are to treat attacks rapidly and consistently
without recurrence, restore the patient’s ability to function, minimize the use of rescue
medications, optimize self-care and subsequent resource use, be cost effective, and
have minimal or no adverse events (Silberstein and for the US Headache Consortium
2000).

British Association for the Study of Headache 2004 guidelines recommend a stepwise

treatment approach as a means of achieving individualized therapy, starting patients
on the safest and cheapest agents with known efficacy (BASH 2004). Treatment steps in
ascending order are (i) a simple oral analgesic (eg, aspirin) with or without an
antiemetic, (ii) a parenteral analgesic (eg, diclofenac) with or without an antiemetic,
and (iii) a migraine-specific agent (eg, triptan). Patients should start on the first step,
with treatment failure on 3 occasions being the suggested criterion for progression
from one step to the next. The guidelines note that different treatment steps may be
used in individual patients who experience attacks of different types or severities. The
American Academy of Family Physicians and American College of Physicians–
American Society of Internal Medicine (AAFP/ACP–ASIM) also recommend a stepwise
treatment approach (Snow et al 2002).

In contrast, United States Headache Consortium 2000 guidelines advocate stratified

treatment according to the severity of an individual migraine attack (Silberstein and
for the US Headache Consortium 2000). Migraine-specific agents (eg, triptans) are
recommended for the initial acute treatment of moderate-to-severe migraine where
there are no contraindications for their use. Triptans are also considered appropriate
for patients with mild-to-moderate headaches that respond poorly to nonsteroidal
anti-inflammatory drugs or combinations such as aspirin plus caffeine (Silberstein and
for the US Headache Consortium 2000). The relative benefits of stepwise and stratified
treatment, and the place of triptans in initial migraine therapy, remain a matter for
debate. However, there is evidence that stratified treatment provides more effective
headache relief for patients with moderate-to-severe migraine-related disability than
stepwise strategies used within or between migraine attacks (Lipton et al 2000).

While triptans are unlikely to cause substantial coronary vasoconstriction in patients

with relatively healthy coronary arteries, their effects may be less predictable in
patients with coronary artery disease; therefore, triptans are contraindicated in
patients with ischemic heart disease, uncontrolled hypertension, a history of coronary
vasospasm, and patients at high risk of asymptomatic coronary artery disease (Martin
and Goldstein 2005). Concerns about the cardiovascular safety of the triptans led to an
evaluation of triptan-associated cardiovascular risk by the Triptan Cardiovascular
Safety Expert Panel of the American Headache Society, and a consensus statement
arising from this evaluation concluded that triptans can be prescribed with confidence
in patients with low risk of coronary artery disease (Dodick et al 2004).

Patients report greater satisfaction with migraine-specific triptan therapy than with
analgesics, nonsteroidal anti-inflammatory drugs, or ergot derivatives (Ceballos
Hernansanz et al 2003). British Association for the Study of Headache guidelines state
that among the triptans, rizatriptan 10-mg tablet or wafer formulations are an
appropriate choice for patients who require stronger oral treatment than sumatriptan
(although, due to the pharmacological interaction described above [see
pharmacokinetics section], patients receiving prophylactic propranolol should take
rizatriptan 5 mg) (BASH 2004). United States Headache Consortium guidelines
(Silberstein and for the US Headache Consortium 2000) make no recommendations as
to which triptan should be selected. However, consideration should be given to those
features considered by patients and physicians as being important in a migraine
treatment. Research has shown that although a variety of attributes are desirable,
rapid onset of complete pain relief is considered particularly important both by
clinicians and patients (Lipton et al 2002). In a survey of US primary care physicians,
rapid achievement of pain-free and sustained pain-free status were considered the
most important efficacy attributes of triptan treatment (Cutrer et al 2004).

The TRIPSTAR project was developed to help physicians select oral triptans to best
match patient needs by combining data on patient- and physician-reported treatment
preferences with results from the aforementioned meta-analysis of triptan clinical
trial data (see efficacy section) (Lipton et al 2005). When the data from the meta-
analysis were evaluated using a Technique for Order Preference by Similarity to the
Ideal Solution (TOPSIS) multi-attribute decision model, which considers attributes of
the triptans weighted according to patient- and physician-reported treatment
preferences, rizatriptan, along with almotriptan and eletriptan, was one of the closest
available treatments to the hypothetical “ideal” triptan (defined as the best achievable
with current technology) (Lipton et al 2005). It is interesting to note that the
superiority of rizatriptan, almotriptan, and eletriptan relative to sumatriptan,
naratriptan, and zolmitriptan in the above analysis was supported by a separate
analysis using a TOPSIS model that considered all possible treatment attribute
weightings, rather than importance weights determined in a particular study (Ferrari
et al 2005).

The potential economic benefits of rizatriptan therapy may also be taken into account
when selecting from among the oral triptans. An open-label workplace study in 259
Spanish migraineurs showed that treatment with rizatriptan for 3 months led to
significant reductions in the use of medical services, absenteeism, and loss of
productivity, as well as improved quality of life compared with the 3 months before
starting rizatriptan (Láinez et al 2005). Similarly, a recent analysis determined that
substantial productivity costs of migraine to the US employer could be significantly
reduced if rizatriptan were used instead of patients’ existing therapies (Gerth et al
2004). Moreover, a US cost-effectiveness analysis performed from a societal
perspective showed that rizatriptan was more cost-effective in the treatment of acute
migraine than sumatriptan or ergotamine–caffeine, reflecting both reduced costs and
greater effectiveness (as measured by quality-adjusted life-years gained) (Zhang and
Hay 2005). In a meta-analysis of randomized, placebo-controlled trials of single-dose
oral triptans, rizatriptan 10 mg had the most advantageous cost-effectiveness ratio vs
other triptans (almotriptan, eletriptan, frovatriptan, naratriptan, zolmitriptan, and
sumatriptan) when results were compared using drug cost data from the US, the UK,
Canada, Germany, Italy, and The Netherlands, although the levels of statistical
significance vs comparators varied between countries (Belsey 2004).
Go to:
Conclusion
According to current guidelines advocating stepwise or stratified treatment
approaches, triptans are recommended for the acute treatment of migraine unlikely to
respond to less effective therapy. A number of triptans are available; however,
rizatriptan has several advantages over other members of its class (Table 3).
Rizatriptan reaches maximum plasma concentrations quickly, with
a shorter tmax than other available triptans, and produces rapid
onset of pain relief. This may prove advantageous in the early treatment of
migraine, allowing rapid relief of mild pain before an attack becomes moderate to
severe. Comparative clinical trials have shown that for the acute
treatment of migraine rizatriptan is at least as effective as, or
superior to, other oral migraine-specific agents.
Rizatriptan has demonstrated efficacy over the long term (up to 12
months) in the treatment of multiple migraine attacks, and appears
to have more consistent efficacy across multiple attacks than other
triptans. Rizatriptan is generally well tolerated, with an overall incidence of adverse
events and quality of life benefits similar to other triptans. It is associated with a
higher degree of patient satisfaction than other migraine-specific agents, with rapid
pain relief, ease of use (wafer formulation), and tolerability being important reasons
for patient preference. Multi-attribute decision models incorporating efficacy data and
weighted clinical attributes identify rizatriptan as one of three triptans closest to a
hypothetical ideal. In conclusion, rizatriptan is a well-established, effective,
and well-tolerated agent for the acute treatment of migraine.

Table 33
Table
Clinical summary of rizatriptan in the treatment of migraine
Go to:

Footnotes
Disclosures

Professor Miguel Láinez has received grant/research support from, has been a consultant/scientific advisor for, or
has received honoraria for oral presentations from Allergan, Almirall Prodesfarma, Böhringer Ingelheim, Bristol-
Myers Squibb, Elan Pharmaceuticals, GlaxoSmithKline, Janssen Cilag, Johnson & Johnson, Menarini, MSD,
Novartis, Pierre Fabre, and Sanofi-Synthelabo.

Go to:
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