74 Parenteral administration is
associated with bruising, redness, and discomfort at the injection site.
risk of vasoconstriction associated with triptan use, special attention is required for
patients with cardiovascular disease or risk factors. Although the rate of adverse
cardiovascular events has been low,
76 sumatriptan should not be used in patients with
pathway disorders, coronary artery disease, previous myocardial infarction,
Prinzmetal angina, or coronary vasospasm. The provocation of coronary artery spasm
secondary to sumatriptan administration has been demonstrated in those with variant
angina, an effect likely mediated via the 1B receptor subtype.
electrocardiogram is recommended for patients with potential cardiac risk prior to
triptan administration, and such an intervention may be considered for those patients
without cardiovascular risk factors experiencing chest tightness following triptan
Initial dosing should occur under medical supervision for patients
that possess cardiac risk factors but are deemed appropriate treatment candidates.
Drug interaction potential associated with sumatriptan centers on the modulation of
serotonergic activity, the risk of serotonin syndrome, and the potential for additive
vasoconstrictive properties. Serotonin syndrome potential exists with the
concomitant use of sumatriptan and ergot derivatives, selective serotonin reuptake
inhibitors (SSRIs), lithium, and/or monoamine oxidase inhibitors (MAOIs).
Food and Drug Administration advisory further underscored the need for caution and
consideration of risk versus benefit with combination use of triptans used in
combination with SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs).
The medication profile for L.P. includes venlafaxine, an SNRI, for the management
of GAD; however, this does not exclude the possibility of using triptans to manage
her migraines. The clinician should evaluate the entire regimen to ensure optimal
management of all indications, and if the addition of a triptan is deemed appropriate,
L.P. should be educated on the potential for interaction and the clinical implications
of the combination. Because L.P. has attempted treatment with conventional
analgesics, she would be a candidate for initiating sumatriptan.
Dosing and Comparative Pharmacokinetic Parameters of Triptans
Pharmacokinetic Parameters of Triptans in Healthy Volunteers and in Patients With Migraine
Frovatriptan ↓ 2.5 mg orally 3 4.2/7
Naratriptan ↓ 2.5 mg orally 2 12.6 74 5.5 98 ≈28
Rizatriptan ↓ 5–10 mg orally 1–1.5,
↓ 100 mg orally 1.5 54 14 2 158 —
Zolmitriptan ↓ 2.5 mg orally 1.5, 3
aAUC, area under the curve; Cmax
, maximal drug concentration; Tmax
, time to maximal drug concentration; t1/2
bValue for men and women, respectively.
cOrally disintegrating tablets.
Source: Facts & Comparisons. eAnswers. http://online.factsandcomparisons.com/MonoDisp.aspx?
monoID=fandc-hcp10008#fandc-hcp10008.b11. Accessed June 16, 2015.
CASE 58-1, QUESTION 8: During her annual physical examination, L.P. reports success in managing her
sumatriptan? Is an alternative triptan appropriate for L.P.?
Second-generation triptans include almotriptan, eletriptan, frovatriptan, rizatriptan,
naratriptan, and zolmitriptan. All triptans have demonstrated superiority to placebo in
81 These agents differ based on the pharmacokinetic profile and
the capacity for headache recurrence.
82 Among the class, zolmitriptan, rizatriptan,
eletriptan, and almotriptan are associated with a faster onset and higher likelihood of
recurrence compared with naratriptan and frovatriptan, both of which have a slower
onset of action with a lower risk of recurrence.
82 Naratriptan, in particular, is
metabolized by multiple isozymes, without strong enzymatic inhibition or induction
potential, creating less potential for CYP-induced interactions
is subject to a dual metabolic path via CYP1A2 and renal excretion.
sumatriptan, oral bioavailability of second-generation agents is increased.
Meta-analyses have offered insight into triptan comparisons. For headache
response at 2 hours, eletriptan 80 mg and rizatriptan 10 mg elicited higher response
rates with sumatriptan 100 mg as the reference whereas eletriptan 20 mg, frovatriptan
2.5 mg, and naratriptan 2.5 mg were inferior to sumatriptan.
freedom from pain, greater efficacy has been observed with rizatriptan 10 mg,
eletriptan 80 mg, and almotriptan 12.5 mg.
83 The opposite effect in this efficacy
endpoint for almotriptan 12.5 mg has been observed in a parallel-group investigation
with sumatriptan 50 mg as a reference.
84 Further comparisons of 74 randomized trials
found that among the triptans, eletriptan was associated with the greatest potential of
producing a pain-free state at 2 hours and at 24 hours.
further observed for rizatriptan (2 hours) and zolmitriptan (24 hours).
between rizatriptan and frovatriptan have yielded similar pain-free outcomes at 2
hours and have favored frovatriptan for pain-free status at 4 hours.
therapeutic endpoint of the combination of freedom from pain with no incidence of
adverse outcomes has been used in studies involving migraines.
endpoint as a primary measure of comparison between zolmitriptan (2.5 mg) and
almotriptan (12.5 mg) in a multicenter European trial, both treatments were deemed
Striking the balance between theoretic drug interaction risk for triptans and what is
observed in clinical practice presents a challenge, especially because it relates to the
92 For L.P., potential drug interactions exist between
triptans and venlafaxine (SNRI) and levonorgestrel/ethinyl estradiol (oral
contraceptive). Attributed to metabolism via CYP1A2, a slight increase in
frovatriptan AUC has been observed with oral contraceptive administration.
Prospective investigations assessing the combination of paroxetine and rizatriptan
and fluoxetine and zolmitriptan
found no instances of serotonin syndrome. These
studies lie in contrast to reports of symptoms of serotonin syndrome with the
combination of triptans and SSRIs or SNRIs.
41 The administration of a triptan should
not be excluded based on L.P.’s medication profile; however, educating her on the
potential for the interaction is warranted.
Increases in rizatriptan and zolmitriptan exposure have been observed secondary
Inhibition of CYP3A4 has facilitated increases in eletriptan
L.P. can be considered an appropriate candidate for triptan prescribing. Although
associated migraine symptoms are reported, the rapidity of onset for such symptoms
(e.g., nausea, vomiting) is less clear and should be a point of discussion with the
patient. Such information is important for the optimal formulation selection. A
nonoral formulation may be recommended in the context of early-onset vomiting.
Although a loss of efficacy is associated with triptan discontinuation,
for triptan use prior to discontinuation has spanned years.
one triptan with another is mixed. If treatment with one triptan results in suboptimal
efficacy, an alternative triptan may be prescribed.
evaluating the impact of such change does not suggest substantial benefit.
CASE 58-1, QUESTION 9: L.P. has noted that for some migraine episodes, nausea and vomiting has been
Relative to triptans, ergot alkaloids function as receptor agonists with strong affinity
at 5-HT1A, 5-HT1B, and 5-HT1D.
In addition, these agents express activity at 5-
, as well as alpha and dopaminergic receptors.
differs from that of the triptans because the latter exhibit no affinity for dopaminergic
98 Actions of ergot alkaloids are multifaceted, blocking neuropeptide
release, stimulating the ventroposteromedial thalamus, and blocking transmission of
afferent signals in trigeminal circuit.
98 Although ergot alkaloids have demonstrated
the more targeted pharmacologic profile of the
triptans has gained preference.
Intranasal administration of dihydroergotamine has yielded significant
improvements in both pain reduction and functional status in comparison with
102 A 2-mg DHE dose achieved headache resolution at 4 hours post
administration for 70% of subjects, compared with 28% in the placebo group.
level of efficacy at the 4-hour time point for DHE has been further substantiated in
103 Subcutaneous administration of 1 mg DHE or 6 mg
sumatriptan resulted in comparable headache resolution.
hour as well as the proportion of patients achieving pain relief at 2 hours
postadministration favored sumatriptan.
103 Adverse outcomes of nausea, vomiting,
and injection-site pain were more prominent for those administering DHE, whereas
incidence of chest pain was more common in the sumatriptan-treated group.
inhaled DHE represents a newer, noninvasive delivery (TEMPO inhaler, MAP
105 Superiority to placebo has been demonstrated in the
FREEDOM-301 Study across endpoints of pain relief and freedom from auditory
sensitivity, light sensitivity, and nausea.
104 Associated adverse effects included
product taste and nausea, 6% and 4%, respectively.
104 This delivery system is not yet
Peripheral and cerebrovascular disease, renal and hepatic disease, sepsis, and
cardiac disease qualify as contraindications to the use of ergot alkaloids.
Further, with the potential to induce uterine contraction and distribute into breast
milk, use is contraindicated during pregnancy and lactation.
history of hypertension, it is important to determine whether blood pressure is
appropriately controlled before considering the use of these agents in migraine due to
the potential for arterial constriction peripherally.
DHE exerts a more variable effect on blood pressure.
Nausea is the most prominent adverse outcome with ergot alkaloids.
dose-related and is linked with 5-HT2 and
Intranasal DHE and orally inhaled DHE have been
associated with prolonged nasal congestion
administration has been associated with lightheadedness and leg cramping.
In most patients, triptan agents provide effective relief of migraine-associated
nausea. Therefore, specific antiemetic therapy usually is not required. However, as
mentioned previously, persistent nausea is more common in patients who use
ergotamine for acute migraine therapy. In these patients, and in triptan-treated
patients who experience incomplete nausea relief, adjunctive antiemetic therapy
should be considered. Results from a more recent comparative trial
(prochlorperazine IV 10 mg vs. metoclopramide IV 20 mg) found similar efficacy in
108 Efficacy of metoclopramide has been demonstrated at the lower
end of the dosing scale (10 mg), but higher doses (20–40 mg) were not associated
available for outpatient treatment of acute migraine?
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND COMBINATION
Many NSAIDs and combination analgesics containing caffeine have been shown to
be effective for the acute treatment of migraine headache.
benefit in double-blind, placebo-controlled trials has been shown for aspirin,
ibuprofen, naproxen sodium, and combination analgesics containing acetaminophen,
112 Ketoprofen doses of 75 or 150 mg have demonstrated
efficacy relative to placebo in reducing migraine severity.
CASE 58-1, QUESTION 11: L.P. reports that her migraines have been successfully managed with
managing status migrainosus in L.P.?
Status migrainosus, or intractable migraine, is characterized by an extended duration
of headache, exceeding 72 hours.
5 The typical management strategy usually requires
hydration and parenteral therapy with ergot derivatives, sumatriptan, or opioid
Dihydroergotamine has demonstrated efficacy in treating intractable migraine by
either intermittent or continuous administration.
114 The successful resolution of
symptoms by DHE avoids the need for administration of corticosteroids and opioids
for the same purpose. Adjunctive antiemetics should be administered for
Sumatriptan 6 mg subcutaneously is also effective for the treatment of established
If the first injection does not provide relief at 1 hour, a second injection
may be administered. Sumatriptan should not be administered within 24 hours of
ergot alkaloids because of the potential for prolonged vasospastic reactions.
Prochlorperazine has established efficacy in managing migraine-related nausea, with
intravenous administration being effective during intractable migraine.
randomized, controlled trials, prochlorperazine 10 mg IV was more effective than
placebo, IV metoclopramide, IV ketorolac, and IV valproate for the treatment of
Parenteral dexamethasone may be administered in cases of intractable migraine.
Among a subset of patients experiencing migraine symptoms beyond 72 hours, a
greater percentage of patients achieved pain-free status following parenteral
dexamethasone administration, relative to placebo.
recurrence has been observed in patients receiving dexamethasone after standard
L.P. may be treated with DHE, sumatriptan, prochlorperazine, or metoclopramide
due to demonstrated efficacy and tolerability in comparison with other treatment
The relevance for initiating prophylactic therapy for migraine is not simply defined
by one common feature among patients. Rather, the impact of migraine for an
individual patient needs to be assessed. Estimates pertaining to prevalence suggest
that only a small percentage (around 5%) receive prophylactic management.
Targeted outcomes for prophylactic therapy includes a reduction in both migraine
frequency and severity, enhancing response to acute management strategies, and a
general improvement in daily function.
120 As previous criteria have addressed the
frequency of migraine episodes (two or more episodes monthly) as a principle
further guidance on suitability for such treatment should also
address disability associated with the episodes, track record of failure with acute
treatments or the overuse of acute treatments, adverse effects precipitated by acute
treatments, or a more pathologically complex migraine (e.g., basilar or hemiplegic
121 Optimizing prophylactic treatment may likely
require a 2- to 3-month window. This becomes an important consideration to convey
to patients with a focus on maintaining adherence. Medications utilized in
prophylactic migraine management generally fall into the categories of
antihypertensives, antidepressants, or anticonvulsants. A fourth category comprised
of nonprescription treatments is considered as well. The evaluation of evidence
associated with prophylactic treatments is often challenging due to the lack of studies
with comparisons between agents or with crossover design.
An evidence-based guideline for prophylactic treatment of migraine has been
created by the US Headache Consortium, published through the American Academy
120 Further evidence has been provided via a combined panel of the
American Academy of Neurology and the American Headache Society.
prophylaxis is an area for which the off-label use of medications is a particularly
common practical consideration. Only a select number of agents have been approved
by the Food and Drug Administration (FDA) for migraine prophylaxis in the
US, including propranolol, timolol, topiramate, valproic acid or divalproex
sodium, and botulinum toxin A (onabotulinumtoxinA). The approval of botulinum
toxin is within the context of treating chronic migraine. Although triptans are not
FDA-approved for migraine prophylaxis, select agents (frovatriptan, naratriptan, and
zolmitriptan) are considered off-label for migraine prophylaxis during menstruation.
Evidence supports propranolol safety and efficacy in migraine prophylaxis.
Various mechanisms for efficacy may be considered, including the modulation of
124 and interaction with serotonin receptors.
has also demonstrated a suppressive effect on cortical spreading depression in
In a small study of migraine patients, propranolol has decreased
cerebrovascular reactivity, mediated by action on vascular tone.
prescribing of propranolol for migraine prophylaxis could be considered, as there
are no contraindications within her profile that would prevent use. A limiting
variable to continued use may be the adverse effect profile, including lethargy,
fatigue, and sleep disruption.
128 As an alternative to propranolol, metoprolol could
be considered similarly appropriate for L.P. Comparisons with aspirin
120 suggest that metoprolol would be appropriately effective. Metoprolol
has been further compared with nebivolol.
130 While similarly effective in
prophylactic migraine management, better tolerability and ease of titration were
Initial dosing for propranolol for prophylaxis of migraine headaches is 20 mg by
mouth 2 or 3 times a day with gradual titration (weekly intervals) according to
patient tolerability to 80 to 160 mg/day in two to four divided doses.
daily dosage of propranolol required to control headaches is established, patient
adherence may be improved by changing to a long-acting oral dosage form (e.g.,
substances. Which information is consistent with the diagnosis of migraine with aura in V.M.?
Although both the “throbbing” character of the headache and associated
gastrointestinal (GI) symptoms are consistent with migraine, it is the presence of both
the visual (light flashes) and sensory (numbness) disturbances correlate with the
diagnosis of migraine with aura. Relevant information for confirming this diagnosis
would be a minimum of two episodes, the accompaniment of an aura symptom, the
duration and unilateral nature of the aura, and the evolution of the headache following
Propagating glial and neuronal depolarization, characterized as cortical spreading
depression, has been implicated in aura.
It is suggested that the pathologic basis
for aura involves gap junction modulation at the neuronal level of the
20 Aura has been associated with migraine in
approximately one-third of patients
131 and visual phenomena are typically the most
It is important to note that visual effects are substantially
varied and can include flashing lights, waving lines, or areas of localized blindness
132 Further, a “visual snow” effect has been described in the literature,
bearing resemblance to television static.
133 Although visual phenomena are most
prevalent, sensory disturbances (e.g., numbness, pins, and needles sensation) may
In the case of V.M., the aura includes both visual and sensory
disturbance, and coupled with the report of additional symptoms (e.g., throbbing
headache, n/v), a diagnosis of migraine with aura is appropriate. The temporal
relationship between the aura and evolution of the migraine is one of further
consideration. Although V.M. reports the evolution of the migraine following the
aura, there is evidence to support classical migraine symptoms occurring during the
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