Reviews
treating migraines Reviews
Loosening the grip of migraine
attacks
American Pharmacists Association
Understanding the prevalence and impact of migraine
Migraine is a common and disabling condition. Annually, approximately 30 million
people in the United States experience migraine,1 three-quarters of whom are women.2 Up to 4% of people are affected by chronic daily headache (headache >15 days/
month)—a leading risk factor for which is overuse of analgesics.3
Migraine accounts for more than $11 billion in national health care costs, and
migraineurs spend $2,571 more per year on health care than nonmigraineurs.4
Migraine has even greater indirect costs: industry loses $50 billion per year to absenteeism and headache-related medical expenses, and people with migraine miss
more than 157 million workdays annually.1
Pharmacists are in a prime position to help minimize migraine-related suffering
and disability by ensuring appropriate use of OTC and prescription therapies. In a
survey of pharmacists attending a migraine-related continuing education (CE) symposium, 68% of community pharmacists surveyed indicated that headache patients
are an important part of their practice, and 85% said that they make one to five recommendations for OTC headache medications daily.5 Yet, pharmacists typically receive little education about migraine. Of a median of about 500 hours of core course
contact hours, pharmacists receive a median of 1 hour of training on headache.6 This
CE article provides an overview of current standards of care for migraine assessment and management.
Advisory board: Richard Wenzel, PharmD,
Diamond Headache Clinic Inpatient Unit, St.
Joseph Hospital, Resurrection Health Care,
Chicago. Sheena K. Aurora, MD, Swedish
Headache Center, Swedish Pain Center,
Seattle.
Acknowledgement: Any potential faculty
conflicts of interest were resolved via peer
review by Dr. Richard Wenzel.
Funding: This activity is supported by an independent educational grant from Allergan,
Inc.
This publication was prepared by Lauren
Cerruto of MedPen, Inc., on behalf of the
American Pharmacists Association.
This article is based on the education session, Loosening the Grip of Migraine Attacks,
presented by Richard Wenzel, PharmD, and
Sheena K. Aurora, MD, at APhA2011, the
American Pharmacists Association Annual
Meeting & Exposition.
Migraine pathophysiology
Contrary to popular belief and previous hypotheses, migraine is not a result of vasodilation or ischemia. Recent imaging studies show spreading cortical depression
during aura, which suggests that migraine is a neurologic electrophysiologic event
rather than a vascular event.7,8
Migraine pain starts with activation of trigeminal nerve fibers surrounding blood
vessels. These neurons release vasoactive and proinflammatory neuropeptides,
which contribute to increased blood flow and inflammation.9 Perivascular inflammation sensitizes trigeminal nerve cells to nonspecific stimuli, such that sensory
inputs that normally are not painful—such as light, sound, or movement—become
Accreditation Information
Provider: American Pharmacists Association
Target audience: Pharmacists
Release date: January 15, 2011
Expiration date: January 15, 2015
Learning objectives
Learning level: 2
ACPE number: 202-000-12-106-H01-P
CPE credit: 2.0 hours (0.2 CEUs)
Fee: There is no fee associated with this activity.
The American Pharmacists Association is accredited by the Accreditation Council
for Pharmacy Education as a provider of continuing pharmacy education (CPE). The
ACPE Universal Activity Number assigned to this activity by the accredited provider is
202-000-12-106-H01-P.
Disclosure: Dr. Wenzel serves on a speaker’s bureau for GlaxoSmithKline. Dr. Aurora has received
grants and research support from Advanced Bionics, Alexza, Allergan, Boston Scientific, Capnia,
GlaxoSmithKline, MAP Pharmaceuticals, Merck and Co., Ortho-McNeil Pharmaceutical, Inc.,
Neuraleve, NuPathe, and Takeda; has served as a consultant for Ortho-McNeil Pharmaceutical, Inc.,
Medtronic, Merck and Co., GlaxoSmithKline, Allergan, Neuraleve, and NuPathe; and has received
honoraria from Merck and Co., GlaxoSmithKline, Nautilius, NuPathe, and Zogenix. APhA’s editorial
staff declare no conflicts of interests in any product or service mentioned in this activity, including
grants, employment, gifts, stock holdings, and honoraria. For complete staff disclosures, please see
the Education and Accreditation Information section at www.pharmacist.com/education.
www.pharmacist.com
At the conclusion of this knowledge-based
activity, the pharmacist will be able to:
n Identify self-treating patients with migraine
who are appropriate for physician referral.
n Educate patients about the appropriate
use of abortive and prophylactic treatment
options.
n Describe novel classes of selected investigational migraine therapies.
n Assist patients in the selection and use of
nonpharmacologic treatment strategies
for preventing migraines, including the use
of a headache diary to identify and avoid
triggers.
n Identify opportunities for pharmacists to
contribute to improved quality of life and
work productivity for patients with migraines.
january 2012 • Pharmacy Today 61
Reviews
treating migraines
perceived as painful.9 This trigeminal hyperexcitability is
known as “central sensitization.”9,10 After the pain receptors
are activated, central sensitization is maintained, even when
the incoming sensory input that activated them is no longer
present.10
Migraine attacks can have several phases. About 70% of
migraineurs experience harbinger symptoms suggesting that
a headache is about to start (e.g., mood or cognitive changes,
muscle pain, food cravings, fluid retention, yawning).11 This
phase is called the prodrome or premonitory phase. The next
phase, the aura, consists of slowly evolving, reversible, visual,
sensory, or speech disturbances12 and is experienced by about
15% of migraine patients.11 Next is the actual headache, consisting of worsening head pain and, in the later phases, nausea/vomiting, photophobia, phonophobia, and other symptoms.11 Resolution of headache is often followed by a prodrome
consisting of other persistent migraine-related symptoms.11
Migraine is a progressive disease that worsens over time
and becomes more difficult to treat. Annually, about 3% of
migraine patients progress to chronic migraine.13 Chronic migraine is characterized by frequent though less severe headaches that can lead to prolonged, pervasive disability.13,14
Overuse of migraine medications contributes to persistent
changes in neurotransmitters, promoting sustained central
sensitization.15
Assessing patients with symptoms of
migraine
Recognizing migraine
The International Headache Society has established diagnostic criteria for migraine (available at http://ihs-classification.
org/en/02_klassifikation/02_teil1/01.00.00_migraine.html).
In brief, the criteria for migraine consist of at least five attacks
lasting 4 to 72 hours if untreated or unsuccessfully treated,
with at least two of the following: unilateral location, pulsating
quality, moderate/severe pain, and symptoms that either cause
or are exacerbated by routine physical activity. The headache
also must be accompanied by either nausea/vomiting and/or
photophobia/phonophobia. Migraine with aura consists of
at least two attacks with aura (reversible visual, sensory, or
speech disturbances that develop gradually or in succession
over at least 5 minutes) and headache fulfilling migraine criteria.12 Only about one-half of patients who report symptoms
of headache that fulfill International Headache Society criteria
for migraine12 have been given a migraine diagnosis by a physician.2 This means that as many as 15 million migraine sufferers remain undiagnosed.
The most important step in diagnosing a primary headache
disorder is a thorough patient history. Clinicians should ask
patients about symptoms, triggers, family history, and medication response.
Whether concurrent medications (e.g., dipyridamole, dihydropyridine calcium channel blockers, nitroglycerin) might be
exacerbating headache is also important to consider. Imaging
with computed tomography or magnetic resonance imaging
is typically not warranted in patients with recurrent migraine
62 Pharmacy Today • January 2012
Preactivity questions
Before participating in the activity, test your knowledge by
answering the following questions.
1. The U.S. Headache Consortium guidelines recommend that abortive
medications not be used more than:
a. Once a day.
b. Once a week.
c. 2 days per week.
d. Once a month.
2. A.K. asks about OTC treatments for migraine. She describes symptoms consisting of moderate to severe pain, nausea and vomiting,
and photophobia, occurring once or twice a month. She has tried
acetaminophen/aspirin/caffeine without much success. Based on
the U.S. Headache Consortium guidelines, you should recommend:
a.Ibuprofen.
b.Aspirin.
c.Acetaminophen.
d. A prescription medication.
3. Preventive therapy is recommended for patients who have headaches that interfere with daily activities at least this many times per
month.
a.2
b.4
c.10
d.15
and normal neurologic examination.16
Lipton and colleagues17,18 developed a set of three “yes/no”
migraine screening questions referred to as the ID Migraine
Screener. The questionnaire asks patients whether, in the previous 3 months, their headaches were accompanied by nausea,
sensitivity to light, or difficulty working, studying, or performing daily tasks for at least 1 day.18 “Yes” answers to at least two
of these questions have a sensitivity rate of 81% and a specificity rate of 75% for migraine relative to diagnosis by a headache
specialist.17
Further assessment for patients with migraine
A number of validated, standardized tools can help to assess
migraine-related disability (see tools for assessment of migrainerelated disability). Such tools aid in illuminating the real-world
impact of migraine and, when used serially, can indicate
whether symptoms are improving or worsening.
Tools for assessment of migraine-related disability
■■ Migraine Disability Assessment Scale (MIDAS):
www.achenet.org/midas
■■ Headache Impact Test (HIT): www.headachetest.com
■■ Henry Ford Headache Disability Inventory (HDI): www.cebp.nl/
vault_public/filesystem/?ID=1354
Typical pharmacy patients present with a question such as,
“What should I take for my headaches?” Wenzel et al.19 developed a four-question algorithm to help pharmacists field such
questions: (1) What percentage of your headaches prohibit you
from performing your daily tasks and/or are accompanied by
www.pharmacytoday.org
acetaminophen
combination
aspirin
Step 1
vomiting? (2) How many days per month are you completely
headache free? (3) What are the symptoms of your attacks? (4)
What OTC products have you tried in the past, and how have
they worked?
Wenzel et al. refer patients to physicians for prescription
medications if responses show that more than one-half of their
headaches have been disabling or that more than 20% have
involved vomiting.19 Such patients are poor candidates for OTC
therapies. A referral to a physician also is warranted for patients who spend fewer than 15 days per month free of headache because these patients have a high probability of chronic
daily headache and overuse of abortive drugs and may need detoxification. Otherwise, if the answers to questions 1 and 2 do
not warrant a referral and the response to question 3 reveals
symptoms typical of migraine, the pharmacist can recommend
an OTC product. The response to question 4 reveals what the
patient has already tried. The pharmacist can then recommend an OTC product the patient has not used in the past. If the
product provides inadequate relief in at least two of three attacks, the patient should try a distinctly different OTC therapy.
Patients who have failed two or more OTC products should see
a physician for evaluation and prescription therapy.19
Pharmacists should regularly assess the effectiveness of
the patient’s current migraine therapy because many patients
are undermedicated. The Migraine Assessment of Current
Therapy is a tool to facilitate assessment of current treatment
efficacy. It consists of four questions20: (1) Does your migraine
medication work consistently, in the majority of your attacks?
(2) Does the headache pain disappear within 2 hours? (3) Are
you able to function normally within 2 hours? (4) Are you comfortable enough with your medication to be able to plan your
daily activities? More than two “no” answers to these questions
may warrant a change in management strategy.20
Abortive treatment options
Abortive therapies are intended to halt or substantially reduce
an attack that is occurring or about to occur. Effective abortive
therapy should treat attacks rapidly and consistently without
recurrence and restore patients’ ability to function.21 Ideally,
abortive therapy should necessitate minimal use of rescue
medications, optimize self-care, be cost-effective, and have
minimal adverse effects.21
The more rapidly migraine is treated, the more effective
therapy tends to be. Rapid treatment may mean administering
abortive therapy at the first recognition of migraine symptoms
or aura. For some patients, it may require a fast-acting nonoral formulation such as an injectable therapy, a nasal spray,
or a rectal suppository. Nonoral therapies also should be considered if nausea/vomiting is an early feature of the patient’s
migraine.21 Having abortive therapies on hand in multiple formulations increases patient satisfaction with care, and combinations have been found to be effective and well tolerated.22
Stratified versus step care
The U.S. Headache Consortium endorses “stratified care,”
which involves tailoring treatment based on severity (Figure
1). The first step is to assess the impact of migraine on the
www.pharmacist.com
Step 2
Step 3
Step 4
treating migraines Reviews
Migraine patients may end up trying 4 to 6
therapies and having multiple office visits before
finding one that provides adequate relief.
StratifiedCare StratifiedCare
Low Need
OTCs
Migraine
Diagnosis
Disability
Assessment
(MIDAS/HIT)
Moderate Need
OTCs, Rx
High Need
Abortive Rx, Preventive Rx
Figure 1. Stratified care: the currently recommended approach
StepCare StepCare StepCare
acetaminophen
combination
aspirin
Step 1
Step 2
isometheptene
combination
Step 3
butalbital
combination
Step 4
triptan
Step 5
Migraine patients may end up trying 4 to 6
therapies and having multiple office visits before
finding one that provides adequate relief.
Figure 2. Step care: Avoid this approach
StratifiedCare StratifiedCare
patient’s life. Patients with highly debilitating symptoms are
prescribed migraine-specific drugs from the onset rather than
OTC products. Use of MIDAS or HIT may help
identify
Low
Needthese patients.
OTCs
Many clinicians continue to use a “step care” approach
in which all patients start
with OTC therapies, and treatment
Disability
Moderate Need
Migraine
is escalated
if
OTC
products
are inadequate
(Figure 2). With
Assessment
Diagnosis
OTCs, Rx
(MIDAS/HIT)
this approach, patients
may have to “step through” multiple
therapies before finding one that is effective. Despite a lack of
High
Need
supportive evidence, this approach is taught
in many
pharmacy
Abortive Rx, Preventive Rx
textbooks/CE programs and is sanctioned by managed care organizations. Although step care is widely purported to ensure
lower costs by starting with OTC therapies, this argument fails
to take into account the high costs associated with greater disability, repeat office visits, and wasted medications.
The stratified care approach was found more effective
than step care in the prospective, randomized Disability in
Strategies of Care (DISC) study.23 Patients were randomly assigned to receive one of three management approaches:
■■ Stratified care (n = 354)
■■ Baseline MIDAS II: aspirin and metoclopramide
■■ Baseline MIDAS III or intravenous: zolmitriptan 2.5 mg
■■ Step care across attacks (n = 352)
january 2012 • Pharmacy Today 63
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treating migraines
■■ Aspirin and metoclopramide, irrespective of MIDAS
score for first three attacks
■■ Failure in two of first three attacks: step up to zolmitriptan 2.5 mg for next three attacks; otherwise remain
on aspirin/metoclopramide
■■ Step care within attack (n = 356)
■■ Aspirin and metoclopramide, irrespective of MIDAS
score, for all attacks
■■ If headache not resolved at 2 hours, step up to zolmitriptan 2.5 mg
For six attacks, rate of response at 2 hours was 53% in the
stratified care group, 41% with step care across attacks, and
36% for step care within attacks (P < 0.001 for comparison of
stratified care vs. either step care approach).23
Efficacy and safety of abortive therapies
According to the stratified care approach in the U.S. Headache
Consortium guidelines, mild to moderate migraines can be
treated initially with OTC analgesics.21 (However, the definition
of “mild” migraine remains controversial.) Patients with moderate to severe migraines, and those who have failed NSAIDs
or other nonopiate analgesics should receive migraine-specific
agents such as triptans, dihydroergotamine, or ergotamine.21
Oral or parenteral antiemetics may be useful adjuncts in patients who have nausea or vomiting.21
Butorphanol nasal spray and acetaminophen with codeine
were given “grade A” ratings in the U.S. Headache Consortium
guidelines, but their use should be limited because of increased
risk of dependency, overuse headache, and withdrawal.21 Use
of barbiturates or opioids also is associated with an increased
risk of transformation from episodic to chronic migraine.24
The U.S. Headache Consortium guidelines recommend
limiting and carefully monitoring use of butalbital-containing
products.21 No randomized studies of these products in migraine have been performed, and the products can cause dependency and withdrawal symptoms. However, they are frequently prescribed as first-line treatments.25
Other migraine therapies have less supportive evidence
and should be reserved for patients for whom the recommended therapies are contraindicated or inadequate.
OTC products. Of the OTC analgesics, the U.S. Headache
Consortium found evidence to support use of aspirin, ibuprofen, naproxen sodium, tolfenamic acid, and combination acetaminophen/aspirin/caffeine but not acetaminophen alone.21
In a systematic review of the literature on OTC products and
migraine, Wenzel et al.19 concluded that these therapies are
more effective than placebo, lack serious safety issues, eliminate pain within 120 minutes in a significant minority of patients, and allow return to normal functioning within 2 hours in
about 21% to 76% of patients. No one OTC product has been
proven to be more effective than the others.19 A recent study of
11,453 patients found that use of NSAIDs helps protect against
chronic migraine, but frequent use (≥15 days/month) increases
risk.26 According to the U.S. Headache Consortium guidelines,
patients should limit use of OTC analgesics to no more than 2
days per week.21 Patients who feel compelled to use abortive
64 Pharmacy Today • January 2012
agents more frequently should contact their physician.
Ergotamine and dihydroergotamine. Ergotamine and
dihydroergotamine (DHE) act as vasoconstrictors and as alpha adrenergic antagonists and serotonin agonists.27 The U.S.
Headache Consortium strongly endorsed intranasal DHE for
patients with moderate to severe migraine. Clinical trials indicate that intravenous, intramuscular, or subcutaneous DHE
is safe and effective.28­–31 Intramuscular DHE has been shown
to provide efficacy comparable with that of meperidine (without the opioid-related adverse effects)29 or intravenous valproate,30 and subcutaneous DHE has been shown to be at least
as effective as subcutaneous sumatriptan.31 The U.S. Headache
Consortium guidelines have assigned a grade C rating to nonnasal DHE and notes that clinical opinion supports use of these
products, especially for patients with nausea/vomiting who
cannot tolerate oral therapies. The subcutaneous product is favored for its safety and efficacy.21 Evidence supporting ergotamine was considered inconsistent, and ergotamine has a higher incidence of adverse events compared with sumatriptan,
NSAIDs, and some other therapies.21 Similarly, the American
Academy of Neurology endorses use of either ergotamine or
DHE but recommends that ergotamine use be limited to a maximum of 2 days per week (except at the time of menstruation)
and to no more than 10 mg per week.27
Triptans. Triptans are serotonin 5-HT1B/1D agonists21 that
act at peripheral and central neurons and at blood vessels.32
Seven triptans are present in oral, intranasal, and subcutaneous formulations (Table 1).33–44 Some triptans (e.g.,
sumatriptan) are available as generics, but rapidly dissolving
formulations are available as brand-name products only. A sumatriptan/naproxen combination tablet is more effective than
either sumatriptan or naproxen alone.41 A 2001 meta-analysis
of 53 trials found all oral triptans to be effective and well tolerated, but the highest likelihood of consistent success was with
10 mg rizatriptan, 80 mg eletriptan, or 12.5 mg almotriptan.45
Individual responses to triptans vary, so trial and error often
is required to find the “best” triptan for any given patient.45
Patients who do not respond to one triptan may respond to another.45,46 Triptan efficacy also has been demonstrated in menstrual migraine.47,48
Brainstorming solutions to common treatment challenges
Case 1. G.R. approaches the pharmacy counter and asks you to
recommend an OTC headache product for menstrual migraine. She says
she has tried acetaminophen, ibuprofen, and several of the migrainelabeled products, but they have not been helping. She is desperate for
relief because she has been missing several days of work each month
and has missed two of her son’s recent baseball games.
Question 1. What would you recommend for G.R.?
Please turn to page 67 for answer.
Triptans produce “cardiac-like” chest, neck, or throat complications in about 3% of patients.49 These effects, which may
be esophageal in origin,49 are generally not serious and not
caused by ischemia.50 The incidence of serious cardiovascular
events with triptans in clinical trials and clinical practice apwww.pharmacytoday.org
treating migraines Reviews
Table 1. Triptans in migraine products
Formulation
Drug
Almotriptan
Eletriptan
Frovatriptan
Naratriptan
Rizatriptan
Sumatriptan
Sumatriptan/naproxen
combination tablet
Zolmitriptan
Typically effective dose
mg/daya
Oral
Oral
Oral
Oral
Oral
Oral
Nasal
Subcutaneousb
Oral
Oral
Nasal
Maximum dose
mg/day
6.25–12.5
40
2.5
2.5
10
50–100
20
6
25
40
7.5
5
30
200
40
12
85/500 (1 tablet)
2.5–5
5
170/1,000 (2 tablets)
10
10
Individual responses vary; patients may require higher or lower doses.
Available in needle-free delivery system.
Source: References 33–44.
a
b
pears to be extremely low, but most of the data were derived
from patients without coronary artery disease.50 One clinical
management option is to advise patients that if these effects
occur, they should seek medical assistance if symptoms do not
resolve within 30 to 45 minutes. The risk-to-benefit ratio favors
use of triptans in otherwise healthy patients without major cardiovascular risk factors.50
Whether triptans interact with selective serotonin reuptake inhibitors (SSRIs) has been met with some controversy.
In 2006, based on 27 case reports, FDA issued an alert that
the risk of serotonin syndrome increases when triptans are
combined with SSRIs or serotonin/norepinephrine reuptake
inhibitors (SNRIs).51 Closer analysis of these cases shows that
none met criteria for serotonin syndrome.52 The combination
of triptans plus SSRIs is not contraindicated, and an estimated
700,000 patients per year in the United States, totaling millions
during the previous decade, take triptans with either SSRIs or
SNRIs.52 Patients taking this combination should be educated
about the symptoms of serotonin syndrome but advised that it
is extremely rare.
Brainstorming solutions to common treatment challenges
Case 2. C.J. hands you a prescription for refills on the triptan he has been
using for the previous 2 years. You ask him whether it has been working
well for him, and he replies that it does a good job of eliminating the
headache, except that it takes a long time to work. He says his migraines
come on quickly and rapidly.
Question 2. What would you recommend for C.J.?
Please turn to page 67 for answer.
Preventive treatment options
Preventive therapy is intended to decrease the frequency, severity, or duration of attacks, improve response to abortive
therapy, and improve function.53 Not all migraineurs require
preventive medication. Such therapy is indicated for patients
who have frequent (e.g., four or more per month) recurrences
www.pharmacist.com
that interfere with daily activities considerably.53 Other candidates for preventive therapy include patients for whom abortive therapies are overused, contraindicated, poorly tolerated,
or inconsistently effective and those with uncommon migraine
conditions.53 Preventive medications must be taken daily and
may take 2 to 3 months to show benefit.53
Efficacy and safety
The U.S. Headache Consortium guidelines on migraine prevention indicated that the following preventive therapies have
proven highly efficacious with mild to moderate adverse events:
divalproex sodium (500–1,500 mg/day), (off-label) sodium valproate (800–1,500 mg/day), long-acting propranolol (80–240
mg/day), timolol (20–30 mg/day), or (off-label) amitriptyline
(30–150 mg/day).53 Other preventive therapies either have less
evidence of efficacy (e.g., other anticonvulsants, antidepressants, or beta blockers; calcium channel blockers; NSAIDs) or
greater adverse effects (e.g., flunarizine, several of the serotonin antagonists) but also may be considered.53
Choice of preventive therapy should be individualized
based on the patient’s comorbidities and lifestyle, taking into
account potential adverse effects. For example, amitriptyline
might be preferred for a patient with insomnia, whereas a beta
blocker might not be the best choice for an athlete who is training to run a marathon and sodium valproate may not be a good
option for a patient who is trying to conceive.
Valproate products. Small randomized clinical trials suggest that valproate reduces migraine frequency by at least onehalf in 45% to 65% of patients; some but not all trials showed
reductions in severity and duration of attacks.54–57 There are
multiple brands and formulations of sodium valproate or divalproex sodium. The delayed-release and extended-release formulations are not interchangeable. Valproate products are teratogenic,58 which is noteworthy given that most migraine sufferers
are women of childbearing age. In three of four trials, rates of
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treating migraines
adverse events were comparable for valproate and placebo, but
a fourth trial showed increased risk of nausea, asthenia, somnolence, vomiting, tremor, and alopecia with valproate.53
Topiramate. When the U.S. Headache Consortium guidelines were published, topiramate’s efficacy had not been established in placebo-controlled trials.53 Topiramate 100 mg/day
received FDA approval for migraine prophylaxis based on two
randomized placebo-controlled trials, both of which reduced
headaches by about two per month from a baseline frequency
of 5.5 per month.59 Most recently, in the randomized placebocontrolled INTREPID trial, topiramate significantly reduced the
mean number of migraine headache days in patients with highfrequency migraine but did not prevent transformation from
episodic to chronic daily headache.60
Topiramate should be initiated at 25 mg/day, given nightly
for the first week, then increased weekly by increments of 25
mg/day up to the recommended dose of 100 mg/day in two divided doses.59 Adverse events may include paresthesias, taste
alterations, nearsightedness with secondary angle closure
glaucoma, decreased sweating/increased body temperature,
metabolic acidosis, cognitive and neuropsychiatric effects, and
teratogenicity.59
Propranol and timolol. The beta blockers propranolol
and timolol reduced migraine headache frequency in about
65% of patients in randomized clinical trials.22,61 About 27% to
34% of patients had at least a 50% reduction in headache.61,62
Efficacy of propranolol was comparable with that of timolol,
divalproex sodium, or amitriptyline in comparative trials.22,63,64
Beta blockers may cause fatigue, depression, nausea, dizziness, and insomnia.53
Amitriptyline. Amitriptyline reduced headache frequency
by at least one-half in 45% to 55% of patients in randomized
clinical trials of patients with chronic daily headache.65–67 Like
other tricyclic antidepressants, amitriptyline may produce anticholinergic adverse effects.53 Most common adverse effects
include dry mucous membranes, constipation, urinary retention, dizziness, and somnolence.66
Treatment of chronic headache
Onabotulinumtoxin A
In late 2010, FDA approved onabotulinumtoxin A for treatment of chronic migraine (headache >15 days/month and
lasting ≥4 days).68 Administration of onabotulinumtoxin A requires trained personnel, and technique may affect the results.
Onabotulinumtoxin A is supplied as single-use vials in 100 or
200 units.68 For use in migraine, the product should be diluted
with sterile, nonpreserved 0.9% Sodium Chloride Injection
USP to 200 units/4 mL, to a final concentration of 5 units/0.1
mL.68 The recommended dose for treating chronic migraine is
155 units given intramuscularly via 30-gauge, 0.5-inch needle
(0.1-mL injections per each of seven specific head or neck muscle areas).68 Potency units are not interchangeable with other
preparations of botulinum products.68 Reconstituted product
can be stored in a refrigerator for up to 24 hours.68
Pooled analyses from two 24-week pivotal trials showed
a significantly greater mean reduction in number of days with
66 Pharmacy Today • January 2012
headache from baseline with onabotulinumtoxin A compared
with placebo (–8.4 vs. –6.6, respectively; P < 0.001) and significant improvement in function and overall health-related
quality of life.69 Prophylactic effects last about 3 months.68 In
a small (n = 59) multicenter pilot study, onabotulinumtoxin A
showed efficacy similar to topiramate in patients with chronic
migraine.70
Reported adverse effects include neck pain, headache/
worsening migraine, muscular weakness, and eyelid ptosis.68
In rare cases, the toxin spreads beyond the injection site causing more severe symptoms of muscle weakness, dysphagia,
breathing difficulties, and urinary incontinence.68
Other treatments for chronic headache
A limited group (~10–20%) of patients with chronic refractory headache respond to continuous opioid therapy.71 Such
patients require formal monitoring to ensure appropriate use,
safety, and efficacy and should be treated only by experienced
prescribers.71 In addition to dependency, continuous opioid
therapy is associated with nausea, constipation, insomnia,
sleep apnea, respiratory depression, sudden cardiac death,
reduced sex hormone levels, and altered neurocognitive function.71 Paradoxically, opioids may result in heightened pain
sensitivity, medication overuse headache, and reduced efficacy
of triptans and NSAIDs.71
Intravenous sodium valproate (loading dose 15 mg/kg, then
5 mg/kg every 8 hours) added to preventive therapies reduced
headache in 80% of patients with chronic daily migraine and
was well tolerated.72
Brainstorming solutions to common treatment challenges
Case 3. D.W. refills her prescription for hydrocodone/acetaminophen
early. Discussion with her reveals that she is taking it virtually daily and
is still having migraine headaches on 20 or more days per month, with
headache often lasting 4 or more days at a time.
Question 3. What recommendations would you make for D.W.?
Please turn to page 67 for answer.
Investigational therapies
As understanding of migraine pathophysiology improves, more
targets are being identified for development of new therapeutics.
Calcitonin gene–related peptide (CGRP) antagonists, once
a promising class, seem to have fallen by the wayside. CGRP is
elevated during migraine attacks and contributes to vasodilation and nociceptive pain.73 Telcagepant (MK-0974) and MK320774 have now been dropped from development after Phase
II and III studies, at least in part because of liver enzyme elevations.75 Another CGRP antagonist, BI 44370 has not progressed
from Phase II76 to Phase III. A number of other new classes are
still being investigated for treatment of acute migraine, chronic
migraine, and migraine prophylaxis (Table 2).77–79
Alternative delivery systems also are needed. Inhaled DHE
and transdermal sumatriptan have completed Phase III trials
with promising results.79
www.pharmacytoday.org
treating migraines Reviews
Table 2. Investigational migraine therapies
Abortive therapies
Preventive therapies
Treatment of chronic
migraine
Class
Serotonin 5-HT1F
agonist
5-HT1 receptor agonist and neuronal
nitric oxide synthase inhibitor
ACE inhibitors
Sartans
Benzopyran
derivative
Hormone
Drug
Lasmiditan
NXN-188
Lisinopril
Telmisartan,
candesartan
Tonabersat
Intranasal oxytocin
Abbreviation used: ACE, angiotensin-converting enzyme.
Source: References 77-79.
Alternative therapies and nonpharmacologic
strategies
Alternative therapies for which some evidence of efficacy exists in preventing migraine include acupuncture,80 coenzyme
Q10,81 riboflavin,82 butterbur,83 and feverfew.84 Some of these
therapies also are available in combination products.
Nonpharmacologic strategies are a key component of a
comprehensive migraine plan. Providing patients with a long
list of potential triggers to avoid is of little practical benefit
and has scant scientific support. Instead, patients should be
asked to keep a headache diary, such as the one available from
the National Headache Foundation (www.headaches.org/For_
Professionals/Headache_Diary). Other headache diaries are
available online or as apps for mobile devices. Headache diaries can help identify a patient’s actual migraine triggers that
then can be avoided or modified (Table 3).11,13,85 Patients also
should record attack frequency, severity, duration, disability,
response to abortive therapy, and any medication adverse effects.53 As with most chronic illnesses, lifestyle changes are an
important component of treatment.
The U.S. Headache Consortium guidelines endorse cognitive-behavioral therapy, biofeedback, and relaxation as additions to preventive drug therapy to enhance migraine relief.86
Sufficient data do not exist to recommend hypnosis, acupuncture, transcutaneous electrical nerve stimulation, cervical manipulation, occlusal adjustment, or hyperbaric oxygen.86 A recent systematic review suggested that some evidence supports
massage, physiotherapy, relaxation, and chiropractic spinal
manipulation as prophylaxis for migraine.87
Results of a recent randomized study showed that surgery
to deactivate trigger sites eliminated migraine in 29% of patients and otherwise significantly reduced headache in 59%.88
Other procedures, such as occipital nerve stimulation89 and
transcranial magnetic stimulation,77 also are showing promise, particularly in chronic headache patients, but additional
research is needed.
www.pharmacist.com
Table 3. Modifiable risk factors for migraine or chronic
headache
Risk factor
Analgesic overuse
Obesity
Caffeine overuse
Stress, or letdown from stress
Alterations in sleep patterns
Skipped meals
Alcohol consumption
Menses/hormonal changes
Certain foods (e.g., aged cheese, chocolate, aspartame, MSG)
Certain odors (e.g., perfume, paint thinner, smoke)
Bright lights/sun glare
Physical exertion, sex
Changes in weather or barometric pressure
Medications (e.g., vasodilators, oral contraceptives)
Abbreviation used: MSG, monosodium glutamate.
Source: References 11, 13, 85.
Patient education: from diaries to dosing
regimens
Pharmacists have an opportunity to improve outcomes for
patients with migraine by providing much-needed education.
Establishing realistic patient expectations about migraine
therapy is necessary. Important issues to discuss with patients
include:
■■ The use of a headache diary to identify avoidable or modifiable triggers.
■■ The need to treat headache at onset rather than waiting until pain has worsened.
■■ How best to use abortive therapies including proper route,
formulation, and dose.
■■ Maximum drug dose and frequency.
■■ “Rescue” medication.
Improving quality of life and work productivity
One of the key goals of migraine management is helping patients regain normal function. “Some relief” is too low a standard, and providing a therapy that relieves pain but impairs
function in other ways (e.g., by causing sedation or grogginess)
is not acceptable. Pharmacists can help improve outcomes
by asking patients at time of refills how well they have been
responding to and tolerating migraine medication. Some “red
flags” pharmacists should be aware of include high frequency
of abortive medication refills or dose escalations (especially if
patient initiated) and prescriptions from multiple physicians.
Pharmacists should convey to patients that migraine medications work best when taken at the onset of headache, when
pain is mild.90–93 More than three-quarters of migraine sufferers delay taking medications until pain is moderate to severe.94
Patients report delaying because they want to see if the headache is truly a migraine, want to take medication only if the
pain is severe, and have concerns about adverse effects, dejanuary 2012 • Pharmacy Today 67
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treating migraines
pendency, or costs of the products.94
Pharmacists also should ask patients what they plan to do
if their first-line medication fails. If the patient does not have
a plan, suggest that they ask their physician about “rescue
therapies.” Every migraine patient should be given at least two
pharmacologically distinct abortive drugs and, ideally, more
than one formulation. Patients also should be told that narcotic
agents are not the treatment of choice for any primary headache disorder and should be used only when the goal of rescue
therapy is pain relief rather than reversal of the attack and return to normal function.
Case study answers
■■ Question 1. Because she has failed several OTC medications already, G.R. is a poor candidate for additional OTC medications and
should be referred to a physician for evaluation and a prescription
medication. Triptans, in particular, recently have shown efficacy in
treating menstrual migraine.
■■ Question 2. You could tell C.J. that triptans are available in intranasal and subcutaneous formulations that have a more rapid onset of
action.
■■ Question 3. Medication overuse is probably contributing to chronic
daily headache in her case. D.W. needs to taper off the hydrocodone/acetaminophen, which may require referral to a headache
clinic for detoxification. She also should seek a prescription for a
preventive therapy such as sodium valproate, propranolol, timolol,
or amitriptyline.
Conclusion
Migraine is a chronic condition that can cause intense suffering and disability. Although it has no cure, effective therapies
include abortive treatments, preventive medications, and nonpharmacologic strategies. In consultation with the treating
physician, pharmacists can help guide patients to optimal and
appropriate use of these therapies to maximize function and
productivity.
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70 Pharmacy Today • January 2012
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treating migraines Reviews
CPE assessment
Instructions: This exam must be taken online; please see “CPE information” for further instructions. There is only one correct
answer to each question. This CPE activity will be available online at www.pharmacist.com no later than January 31, 2012.
1. The U.S. Headache Consortium guidelines recommend
that abortive medications not be used more than:
a. Once a day.
b. Once a week.
c. 2 days per week.
d. Once a month.
2. A.K. asks about OTC treatments for migraine. She describes symptoms consisting of moderate to severe
pain, nausea and vomiting, and photophobia, occurring once or twice a month. She has tried acetaminophen/aspirin/caffeine without much success. Based on
the U.S. Headache Consortium guidelines, you should
recommend:
a.Ibuprofen.
b.Aspirin.
c.Acetaminophen.
d. A prescription medication.
3. Assessing the degree of a patient’s headache-related
morbidity via tools such as the Migraine Disability
Assessment Scale or Headache Impact Test and then
selecting medications on the basis of this morbidity is
called:
a. Step care within attacks.
b. Stratified care.
c. Step care between attacks.
d. Pharmaceutical care.
4. C.M. has severe migraines that have not responded
well to eletriptan. He would like to try a different medication. Of the options below, which is the least appropriate?
a. A different triptan
b.Dihydroergotamine
c. Butorphanol nasal spray
d.Ergotamine
5. The combination of triptans and selective serotonin
reuptake inhibitors triggers a computer alert regarding serotonin syndrome. You should:
a. Not dispense this combination; it is contraindicated.
b. Advise patients the risk is high and educate them about
symptoms.
c. Advise patients the risk is extremely low and educate
them about symptoms.
d. Ignore the computer alert.
6. Preventive therapy is recommended for patients who
have headaches that interfere with daily activities at
least this many times per month.
www.pharmacist.com
a.2
b.4
c.10
d.15
7. The U.S. Headache Consortium identified five preventive therapies for migraine that have been proven highly efficacious with mild to moderate adverse
events. They are:
a. Divalproex sodium, sodium valproate, propranolol,
timolol, and amitriptyline.
b. Gabapentin, sodium valproate, flunarizine, fluoxetine,
and amitriptyline.
c. Carbamazepine, topiramate, propranolol, timolol, and
fluoxetine.
d. Divalproex sodium, flunarizine, amlodipine, venlafaxine, and ibuprofen.
8. Using the four-question algorithm to assess pharmacy
patients with headache, you should nearly always refer
patients to a physician if:
a. More than 20% of headaches are associated with disability.
b. At least one headache has involved vomiting.
c. The patient spends fewer than 15 days a month headache free.
d. The patient meets International Headache Society
Diagnostic Criteria for migraine.
9. Which of the following triptans are available in nonoral
formulations as well as oral?
a. Almotriptan and eletriptan
b. Frovatriptan and sumatriptan
c. Naratriptan and rizatriptan
d. Sumatriptan and zolmitriptan
10.Of the three case vignettes presented in this article,
which patient is a candidate for onabotulinumtoxin A?
a. Case 1 (G.R.)
b. Case 2 (C.J.)
c. Case 3. (D.W.)
d. None of the three patients is an appropriate candidate
for onabotulinumtoxin A.
11.Which of the following novel classes is being studied
as an abortive therapy for migraine?
a.Sartans
b.5-HT1F agonist
c. Angiotensin-converting enzyme inhibitors
d. Benzopyran derivative
january 2012 • Pharmacy Today 71
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treating migraines
12.Telcagepant and related agents from the same novel
class were once thought to be promising investigational therapies for migraine, but have now been
dropped from development. What did they target?
a. Calcitonin gene–related peptide
b. Epidermal growth factor receptors
c. Vascular endothelial growth factor
d. Serotonin 5-HT1 receptors
13.With regard to lifestyle modifications to prevent migraine, pharmacists should:
a. Provide patients with an extensive list of common migraine triggers to avoid.
b. Provide patients with a list of the three most common
migraine triggers that should be avoided.
c. Encourage patients to keep a headache diary to identify their specific migraine triggers.
d. Advise patients that lifestyle modifications are ineffective.
14.Which of the following nonpharmacologic management strategies for migraine prevention is endorsed
in the U.S. Headache Consortium guidelines?
a.Hypnosis
b.Acupuncture
c. Hyperbaric oxygen
d.Biofeedback
15.To help patients derive the greatest benefit from their
migraine medication, pharmacists should advise:
a. Taking the medication at the first sign of headache,
when pain is mild.
b. Waiting to see if the headache is truly a migraine before taking medication.
c. Trying to use OTC products as much as possible, reserving stronger prescription medications for severe
headaches only.
d. Considering routinely adding a narcotic agent to current nonopioid therapy to boost efficacy.
CPE information
To obtain 2.0 contact hours of CPE credit (0.2 CEUs) for this activity, complete and submit the CPE exam online at www.pharmacist.com/education. A
Statement of Credit will be awarded for a passing grade of 70% or better. You will have two opportunities to successfully complete the CPE exam. Pharmacists
who successfully complete this activity before January 15, 2015, can receive credit.
Your Statement of Credit will be available online immediately upon successful completion of the CPE exam.
CPE instructions: Get your documentation of credit now! Posttests can be completed at www.pharmacist.com/education using these steps:
1. Go to Online CPE Quick List and click on the title of this activity.
2. Log in. APhA members enter your user name and password. Not an APhA member? Just click “Create one now” to open an account.
No fee is required to register.
3. Go to www.pharmacist.com/CPEMonitor to provide APhA with your required NABP e-Profile ID.
4. Successfully complete the CPE exam and evaluation form to gain immediate access to your documentation of credit.
Live step-by-step assistance is available Monday through Friday 8:30 am to 5:00 pm ET at APhA Member Services at 800-237-APhA (2742) or by e-mailing
InfoCenter@pharmacist.com.
72 Pharmacy Today • January 2012
www.pharmacytoday.org