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Abstract
Description:

The American College of Physicians (ACP) developed this guideline based on

the best available evidence on the comparative benefits and harms of

pharmacologic treatments of acute episodic migraine headache, patients’

values and preferences, and economic evidence about these pharmacologic

treatments.

Methods:

This guideline is based on a systematic review and network meta-analysis of

the comparative benefits and harms of pharmacologic treatments of acute

episodic migraine headaches, as well as systematic reviews of patients’ values

and preferences and comparative cost-effectiveness analyses. The Clinical
Guidelines Committee evaluated the following clinical outcomes using the

GRADE (Grading of Recommendations, Assessment, Development and

Evaluation) approach: pain freedom and pain relief at 2 hours; sustained pain

freedom and sustained pain relief up to 48 hours; need for rescue medication

within 24 hours; nausea, vomiting, and restored physical function at 2 hours;

and overall and serious adverse events (AEs). Additional data on AEs were

captured through U.S. Food and Drug Administration medication labels.

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 Audience and Population:

The audience for this clinical guideline is physicians and other clinicians. The
population is adults with acute episodic migraine headache (defined as 1 to 14

headache days per month) managed in outpatient settings.

Recommendation 1:

ACP recommends that clinicians add a triptan to a nonsteroidal anti-

inflammatory drug to treat moderate to severe acute episodic migraine

headache in outpatient settings for nonpregnant adults who do not respond

adequately to a nonsteroidal anti-inflammatory drug (strong

recommendation; moderate-certainty evidence).

Recommendation 2:

ACP suggests that clinicians add a triptan to acetaminophen to treat

moderate to severe acute episodic migraine headache in outpatient settings

for nonpregnant adults who do not respond adequately to acetaminophen

(conditional recommendation; low-certainty evidence).

Migraine is a prevalent and disabling condition, ranking as the second leading

cause of global disability (expressed as years lived with disability) in all adults
and the top cause in females aged 15 to 49 years (1, 2). In the United States,

migraine affects approximately 16% of people, and females are more affected

than males (21% of females and 11% of males) (3). Migraine is disproportionately

prevalent in adults aged 18 to 44 years (18%), people who are unemployed

(21%), and those with a household income less than $35 000 per year (20%) (4).
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 Migraine-related disability has increased in the United States despite the

prevalence of migraine remaining relatively consistent for the past 30 years

(5). Migraine accounts for about 4 million emergency department visits and

more than 4.3 million office visits per year (3), representing an important
health problem and a substantial economic burden of more than $78 billion

annually in medical expenses and lost productivity in the United States (6).

Migraine is characterized by recurrent episodes of headache of usually

moderate to severe intensity lasting 4 to 72 hours with or without aura

(sensory disturbances); generally pulsating; and often accompanied by

nausea, vomiting, photophobia, or phonophobia. Disabling episodes can

interfere with daily living and affect quality of life.

Migraine remains underdiagnosed and undertreated (7). Many pharmacologic

options are available to adults with migraine headache, including nonspecific

over-the-counter pain pharmacotherapies (such as nonsteroidal anti-

inflammatory drugs [NSAIDs]) and migraine-specific drugs (such as triptans

and dihydroergotamine). Newer, more costly therapeutic classes (that is,

calcitonin gene–related peptide antagonists [CGRP antagonists-gepants] and

selective 5-hydroxytryptamine 1F [5-HT1F] agonists [ditans]) have emerged as

potential alternative treatments.

Purpose and Scope

The purpose of this clinical guideline from the American College of Physicians

(ACP) is to present clinical recommendations to prioritize among effective

pharmacologic treatments of acute episodic migraine headaches, based on

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 the best available evidence on the comparative benefits and harms of these

treatments (8), consideration of patients’ values and preferences (9), and

economic evidence (8).

Pharmacologic treatments considered in this guideline for the treatment of

acute episodic migraine headache were initially identified through scoping of

the scientific literature for drugs previously shown to be effective compared

with placebo and through clinical input from the topic expert panel and the

Clinical Guidelines Committee (CGC). The pharmacologic treatments included

in the final list were selected through a stepwise approach based on the

following criteria: availability in the United States, evidence supporting

efficacy of pharmacologic treatments (compared with placebo) in published

systematic reviews, and alignment with eligibility criteria defined in the

comparative effectiveness systematic review used to inform this ACP clinical

guideline (8). Additional details on the selection of treatments are available in

Figure 1.
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 

Figure 1. Selection of interventions for the comparative effectiveness review and

clinical guideline recommendations.

5-HT1F = 5-hydroxytryptamine 1F; CGRP = calcitonin gene–related peptide; NSAID =

nonsteroidal anti-inflammatory drug; SR = systematic review.

* Monotherapy with a triptan, an NSAID, or acetaminophen either was inferior to

combination therapy or had already been attempted by patients seeking additional
care.

The comparative effectiveness review included the following pharmacologic

treatments:

• Analgesic: acetaminophen
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 • CGRP antagonists-gepants: rimegepant, ubrogepant, and zavegepant

• Ditan: lasmiditan

• Ergot alkaloid: dihydroergotamine (mesylate)

• NSAIDs: aspirin, celecoxib, diclofenac potassium, ibuprofen, and naproxen

• Serotonin-1B and serotonin-1D receptor agonists (triptans): almotriptan,

eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and

zolmitriptan

• Combination of any of the listed treatments, or any listed treatment

combined with an antiemetic

Population
The population is adults with acute episodic migraine headache (defined as 1
to 14 headache days per month) managed in outpatient settings. This

guideline does not address adults who have chronic migraine (defined as ≥15

headache days per month), status migrainosus (a migraine that lasts >3 days),

or other primary or secondary headache disorders or adults with probable

migraine (those with migraine-like headaches missing one of the features

required to fulfill all diagnostic criteria for a type or subtype of migraine).

Intended Audience
The intended audience is physicians and other clinicians caring for adults with
acute episodic migraine headache in outpatient settings.
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 Clinical Guideline Development Process
The CGC developed this guideline according to ACP’s guideline development

process (10) and policy on disclosure of interests and management of conflicts

of interest (11). ACP is a GRADE (Grading of Recommendations, Assessment,

Development and Evaluation) Center, and the CGC used GRADE methods to

develop this guideline, including Evidence-to-Decision tables when reporting

the evidence (Figure 2; Supplement) (12). The Appendix lists the key questions

(Appendix Table 1) for the supporting systematic review (8) and details the
methods for the guideline and systematic review. ACP completes the

Guidelines International Network (GIN) Standards for Reporting form (13) for

each guideline it publishes; the form can be found in GIN’s International

Guidelines Library or on ACP’s website (www.acponline.org/clinical-

information/guidelines/guideline-process).

Figure 2. Grading the certainty of evidence and strength of recommendations in

ACP clinical guidelines using GRADE.
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 ACP = American College of Physicians; GRADE = Grading of Recommendations,
Assessment, Development and Evaluation.

Appendix Table 1. Key Questions for the Systematic and Rapid Reviews 

Key Question 1a: What are the comparative benefits and harms of initial
pharmacologic treatments in adult patients with acute attacks of episodic
migraine?

Do treatment benefits and harms vary by:

Demographic characteristics (age, sex, gender, race/ethnicity)?

The presence of menstrual migraine?

Key Question 1b: What are the comparative benefits and harms of second-
step pharmacologic treatments in adult patients who did not achieve
adequate relief with an initial pharmacologic treatment attempt for an acute
migraine attack?

Do treatment benefits and harms vary by:

Demographic characteristics (age, sex, gender, race/ethnicity)?

The presence of menstrual (cyclical) migraine?

Key Question 2a: What are patients’ values and preferences regarding initial
pharmacologic treatments of acute attacks of episodic migraine?

Key Question 2b: What are patients’ values and preferences regarding
second-step pharmacologic treatments of acute attacks of episodic
migraine?

Key Question 3a: What is the cost-effectiveness of initial pharmacologic

treatments in adult patients with acute attacks of episodic migraine?

Do treatment outcomes vary by:

Demographic characteristics (age, sex, gender, race/ethnicity)?

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 The presence of menstrual (cyclical) migraine?

Key Question 3b: What is the cost-effectiveness of second-step

pharmacologic treatments in adult patients who did not achieve adequate
relief with an initial pharmacologic treatment attempt for an acute attack of
episodic migraine?

Do treatment outcomes vary by:

Demographic characteristics (age, sex, gender, race/ethnicity)?

The presence of menstrual (cyclical) migraine?

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Systematic Review of Benefits and Harms and

Summary of the Evidence
This guideline is based on an accompanying systematic review and network

meta-analysis (8) completed by the ACP Center for Evidence Reviews (CER) at
Cochrane Austria. The accompanying systematic review (8) and Evidence-to-

Decision tables (Supplement) provide a detailed summary of findings.

Outcomes of Interest
Benefits and Harms

The CGC and CGC Public Panel independently rated the importance of clinical
outcomes as critical, important, or less important for decision making

(Appendix Table 2). The prioritized outcomes used in the Summary of Findings

tables and appraised for certainty of evidence were pain freedom and pain

relief at 2 hours; sustained pain freedom and sustained pain relief up to 48

hours; need for rescue medication within 24 hours; nausea, vomiting, and
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 restored physical function at 2 hours; and overall and serious adverse events

(AEs). In addition, information on AEs was captured through U.S. Food and

Drug Administration medication labels. The CGC considered the directionality,

magnitude of effects, confidence intervals, and GRADE ratings to interpret the

effects of individual prioritized outcomes and made judgments across all

outcomes for each comparison to develop the recommendations.

Appendix Table 2. Outcome Ratings 

Outcomes rated as critical

AEs*

Migraine-related disability

Nausea*

Need for rescue medication*

Overall discontinuations

Pain freedom*

Pain relapse

Pain relief*

Pain relief satisfaction

Physical functioning*

Quality of life

Serious AEs*

Social functioning
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 Sustained pain freedom*

Sustained pain relief*

Vomiting*

Work productivity

Outcomes rated as important

Emotional functioning

Phonophobia

Photophobia

Visual problems

AE = adverse event.

* These outcomes were prioritized for decision making by the Clinical Guidelines
Committee (CGC) after considering ratings from the CGC, the topic expert panel,
and CGC Public Panel.

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Public and Patient Values and Preferences

The CGC incorporated public and patient values and preferences for eligible

interventions when developing this clinical guideline. The CGC considered

evidence about the values and preferences of the public and patients from 2

sources, the accompanying rapid review regarding patients’ values and

preferences (9) and consultation with the CGC Public Panel. The CGC Public
Panel participated in the outcome rating exercise, provided preferences for
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 interventions based on the systematic review’s findings on benefits and

harms (8), and provided feedback on the draft guideline recommendations.

Economic Evidence

The CGC considered economic evidence from cost-effectiveness analyses

(CEAs) and resource utilization (intervention cost) data when developing this

clinical guideline. The accompanying rapid review (8) summarizes the

evidence on the economic value of pharmacologic interventions for acute

episodic migraine headache based on willingness-to-pay thresholds reported

in high-quality CEAs that are applicable to the United States (Appendix Table

3). The CGC also considered resource utilization (intervention cost) data from
annualized wholesale acquisition cost (WAC) (Supplement) for each

pharmacologic treatment of interest (14).

 OPEN IN VIEWER
Appendix Table 3. CGC Value Thresholds for Economic Evidence in CEAs*

Level of Value ICER per QALY Gained

High value Cost-saving or <$100 000

Intermediate value $100 000 to $200 000

Low value >$200 000

No value Dominated†

CEA = cost-effectiveness analysis; CGC = Clinical Guidelines Committee; ICER =

incremental cost-effectiveness ratio; QALY = quality-adjusted life-year. * These
thresholds were used by the Center for Evidence Reviews in its rapid review of CEAs
to categorize interventions as having high, intermediate, low, or no value. The CGC
may adjust thresholds on a topic-by-topic basis based on the clinical aspects of
disease severity, the uniqueness of life-saving interventions, and ethical
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 considerations.

† The intervention is dominated by strict dominance (the intervention is less

effective and more costly than an alternative) or extended dominance (there is an
alternative that is more effective and more cost-effective).

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Recommendations
A visual clinical guideline for this topic displaying a visual summary of the
recommendations, rationales, and clinical considerations, alongside an
interactive data visualization (15).

Recommendation 1: ACP recommends that clinicians add a triptan to a

nonsteroidal anti-inflammatory drug to treat moderate to severe acute
episodic migraine headache in outpatient settings for nonpregnant adults
who do not respond adequately to a nonsteroidal anti-inflammatory drug
(strong recommendation; moderate-certainty evidence).

Recommendation 2: ACP suggests that clinicians add a triptan to

acetaminophen to treat moderate to severe acute episodic migraine
headache in outpatient settings for nonpregnant adults who do not respond
adequately to acetaminophen (conditional recommendation; low-certainty
evidence).

Rationale

The CGC determined that triptans, NSAIDs (aspirin, celecoxib, diclofenac,

ibuprofen, and naproxen), acetaminophen, and the combination of a triptan
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 with an NSAID or acetaminophen were efficacious compared with placebo for

the acute treatment of moderate to severe episodic migraine (Figure 1) (8).

Comparative effectiveness evidence showed that the combination of a triptan

(sumatriptan) and an NSAID (naproxen) had the greatest net benefit, with a

larger net benefit than monotherapy with a triptan (moderate-certainty

evidence), an NSAID (aspirin, celecoxib, diclofenac, ibuprofen, or naproxen;

high-certainty evidence), acetaminophen (low-certainty evidence), or a CGRP

antagonist-gepant (low-certainty evidence). The combination of a triptan

(rizatriptan) and acetaminophen had a similar net benefit to triptan

monotherapy (low-certainty evidence), but all prioritized benefit outcomes

with data showed a directionally favorable relationship for the combination of

a triptan and acetaminophen. This combination also showed a greater net

benefit than acetaminophen (low-certainty evidence) (Supplement). On the

basis of these data, the CGC determined that the combination therapy of a

triptan and an NSAID had the largest net benefit, followed by the
combination of a triptan and acetaminophen.

The CGC considered that some participants in the included studies had tried

over-the-counter medications, such as NSAIDs, acetaminophen, or both,

before enrolling in trials, and that the use of these medications is common in

nonpregnant adults with moderate to severe episodic migraine before

additional care is sought. The CGC determined that triptans are associated

with more AEs than NSAIDs and acetaminophen. Although these AEs are

generally mild (for example, fatigue, dizziness, and nausea) (Supplement), it is

important to consider that they could still affect daily activities and quality of
life in some people. When formulating the recommendations, the CGC also
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 considered the evidence of patients’ values and preferences showing that

they probably prioritize effectiveness for pain relief over accompanying

symptoms and harms (moderate-certainty evidence) and that “some pain

relief” may be more important than “absence of pain” (low-certainty evidence)

(Supplement) (9).

Combination therapy of a triptan (sumatriptan) and an NSAID (naproxen),

compared with triptan monotherapy, resulted in a higher likelihood of

sustained pain relief up to 48 hours after initial treatment (130 more events

per 1000 treated people) and lower likelihood of using rescue medication at 24

hours (130 fewer events per 1000 treated people) (high-certainty evidence). In
addition, combination therapy of a triptan and an NSAID probably results in a

higher likelihood of achieving pain relief at 2 hours (90 more events per 1000
treated people) and sustained pain freedom at 48 hours (40 more events per

1000 treated people) (moderate-certainty evidence). The CGC also

acknowledged a consistent directional trend of other benefit outcomes

probably favoring the combination of a triptan and an NSAID (moderate-

certainty evidence) (Supplement) over triptan monotherapy. Further, high-

certainty evidence showed a net benefit favoring combination therapy of a

triptan and an NSAID compared with NSAID monotherapy (Supplement).

Despite showing a higher risk for overall AEs (90 more events per 1000 treated

people; high-certainty evidence), the combination therapy of a triptan and an

NSAID resulted in a higher likelihood of pain freedom and relief at 2 hours (110

and 180 more events, respectively, per 1000 treated people), sustained pain

relief up to 48 hours (180 more events per 1000 treated people; high-certainty

evidence), and sustained pain freedom up to 48 hours (70 more events per
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 1000 treated people; moderate-certainty evidence) and a lower likelihood of

using rescue medication (160 fewer events per 1000 treated people; high-

certainty evidence) (Supplement). Finally, low-certainty evidence showed that

the combination of a triptan and an NSAID may have a favorable net benefit
compared with monotherapy using acetaminophen or a CGRP antagonist-

gepant (Supplement).

Low-certainty evidence showed that the combination therapy of a triptan

(rizatriptan) and acetaminophen, compared with triptan monotherapy, may

result in no important differences in pain freedom and relief at 2 hours,

sustained pain freedom up to 48 hours, freedom from nausea at 2 hours, and

restored physical function at 2 hours after initiating treatment, but all data

showed directionally favorable effects for this combination. Combination

therapy may also result in no important differences in overall AEs, and

evidence was uncertain about the effect on serious AEs (insufficient-certainty

evidence) (Supplement). Combination therapy of a triptan and

acetaminophen, compared with acetaminophen monotherapy, also resulted

in a probably higher likelihood of pain freedom at 2 hours (300 more events

per 1000 treated people) and sustained pain freedom up to 48 hours (250

more events per 1000 treated people; moderate-certainty evidence). However,

combination therapy of a triptan and acetaminophen may result in a higher

risk for overall AEs (200 more events per 1000 treated people; low-certainty
evidence) (Supplement). Low-certainty evidence showed that this

combination therapy, compared with an NSAID, may result in a higher

likelihood of pain freedom at 2 hours. However, comparative evidence was

uncertain for all other prioritized outcomes (insufficient-certainty evidence)

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 (Supplement).

The CGC recommends combination therapy of a triptan and an NSAID or

acetaminophen in nonpregnant adults seeking acute treatment of an

episodic migraine who have an inadequate response to NSAIDs and

acetaminophen monotherapies. Further, the CGC recognizes that triptan

monotherapy is an effective treatment with evidence supporting its

comparative benefits for treating episodic migraine (Supplement). However,

the CGC determined that combination therapy of a triptan (sumatriptan or

rizatriptan) and an NSAID (naproxen) or acetaminophen had a greater net

benefit than triptan monotherapy (Supplement). The evidence was uncertain

for combination therapy of an NSAID (aspirin) and acetaminophen

(Supplement).

No eligible CEAs compared the combination of a triptan and an NSAID versus

the combination of a triptan and acetaminophen (Supplement). The CGC

considered that differences in intervention costs between the combinations of

a triptan with an NSAID or acetaminophen and triptan monotherapy were

negligible (all had annualized wholesale acquisition costs of about $500);

however, combinations of a triptan with an NSAID or acetaminophen were

largely less costly than other treatments, particularly the CGRP antagonists-

gepants ($5994) and lasmiditan ($6668) (Supplement).

The evidence on patients’ values and preferences (9) showed that they

probably prioritize the effectiveness on pain outcomes over accompanying

symptoms, potential harms, or other treatment attributes (such as

convenience or route of administration, consistency of effect, ability to

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 function normally, numbers of doses required, and cost) (moderate-certainty

evidence). In addition, they may consider some pain relief more important

than absence of pain and prefer oral medication over other routes of

administration (suppository, nasal spray, subcutaneous injection,

intramuscular injection, or intravenous injection) (low-certainty evidence)

(Supplement). When asked to prioritize treatment options considered in this

guideline, the CGC Public Panel showed a preference for using

acetaminophen, an NSAID, triptan monotherapy, or combination therapies of

a triptan and an NSAID or acetaminophen (Supplement). None of the panel

reported a preference for using dihydroergotamine or CGRP antagonists-
gepants. The CGC Public Panel noted that factors supporting their

preferences were benefits, harms, and costs, with costs and benefits being

the most frequently identified important factors for decision making. The
Public Panel also reported a general preference for oral treatments, which is

consistent with the accompanying systematic review on values and

preferences (low-certainty evidence) (9).

Applicability

These recommendations apply to nonpregnant and nonlactating adults with

acute, episodic, moderate to severe migraine headache in outpatient settings.

Most participants in the included studies were females of reproductive age

with a history of 1 to 8 acute, episodic, moderate to severe migraine

headaches per month, with or without aura, and with or without concomitant

use of medication to prevent migraine. No eligible studies included

participants with mild migraine headaches, and studies in nonoutpatient

settings were excluded.
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 Clinical Considerations
• This guideline assessed the comparative effectiveness of medications that

are beneficial to treat acute, episodic, moderate to severe migraine to help

clinicians select which medication treatment or treatments to initiate

(Figure 1).

• Ask patients if they used an NSAID, acetaminophen, or the combination of

an NSAID and acetaminophen to treat episodic migraine headache and

ensure that they are using the appropriate dosage. Consider increasing the
dosage of an NSAID or acetaminophen without exceeding the
recommended maximum daily dose in patients who do not achieve

sufficient pain relief but may not be receiving an adequate or acceptable

dose.

• If patients use an adequate dose of an NSAID or acetaminophen and still do

not have sufficient pain relief, then add a triptan to an NSAID, or to

acetaminophen when NSAIDs are contraindicated or not tolerated.

• Be aware that patients who do not tolerate or have inadequate response to a

recommended migraine treatment may respond to another within the

same drug class. Choice of a specific NSAID (aspirin, celecoxib, diclofenac,

ibuprofen, or naproxen) or triptan (almotriptan, eletriptan, frovatriptan,

naratriptan, rizatriptan, sumatriptan, or zolmitriptan) should be based on

individualized decision making, taking into consideration patient

preferences on such factors as route of administration and cost.

• Consider treating mild episodic migraine headache with an NSAID,

acetaminophen, or the combination of an NSAID and acetaminophen.
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 • Although available comparative effectiveness data were uncertain, there is

evidence supporting efficacy for CGRP antagonists-gepants (rimegepant,

ubrogepant, or zavegepant) or ergot alkaloid (dihydroergotamine). Consider

using these options to treat moderate to severe acute episodic migraine

headache in nonpregnant outpatient adults who do not tolerate or have

inadequate response to combination therapy of a triptan and an NSAID or

acetaminophen.

• Consider using the ditan lasmiditan to treat moderate to severe acute

episodic migraine headache in nonpregnant outpatient adults who do not

tolerate or have inadequate response to all other pharmacologic treatments

included in this guideline.

• Do not use opioids or butalbital for the treatment of acute episodic

migraine.

• Consider using a nonoral triptan and an antiemetic in people having severe

nausea or vomiting.

• In people of childbearing potential and in those who are pregnant or

breastfeeding, discuss the AEs of pharmacologic treatments during

pregnancy and lactation.

• Counsel patients to begin treatment of migraine headache as soon as

possible after its onset, using combination therapy (such as a triptan with an

NSAID or acetaminophen) to improve efficacy.

• If the episodic migraine occurs frequently or treatment does not provide an

adequate response, the addition of preventive medications may be
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 warranted (16).

• Patients should be aware of medication overuse headache, which is a

potential complication of migraine treatment. Medication overuse headache

is defined as headache occurring on 15 or more days per month for at least 3

months in people with a preexisting headache disorder that develops

because of overuse of acute medication. Also, be aware that the threshold

for medication overuse headache varies by treatment (for example, ≥15 days

per month with NSAIDs; ≥10 days per month with triptans).

• Highlight the importance of lifestyle modifications with patients, including

staying well hydrated, maintaining regular meals, securing sufficient and

consistent sleep, engaging in regular physical activity (preferably moderate

to intense aerobic exercise), managing stress with relaxation techniques or

mindfulness practices, and, where applicable, pursuing weight loss for those

who are overweight or obese. Also, explore modifiable migraine triggers or

contributing factors during a detailed history.

• Prescribe less costly recommended medications (17).

Treatments With No Recommendations

The CGC determined that comparative evidence was inconclusive to inform

recommendations for monotherapy with a CGRP antagonist-gepant, the

ergot alkaloid dihydroergotamine, or the ditan lasmiditan but addressed

these pharmacologic treatments in the Clinical Considerations section. The

CGC determined that these 3 treatment options compared with placebo were
efficacious for the acute treatment of episodic migraine. However, CGRP
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 antagonists-gepants and dihydroergotamine had very little comparative

evidence for prioritized outcomes. For lasmiditan, there was either

insufficient-certainty evidence for any comparative effectiveness findings or

no data on prioritized health outcomes.

Monotherapy with a CGRP antagonist-gepant may have a lower likelihood of

pain freedom and relief at 2 hours, as well as sustained pain freedom up to 48

hours after initiating medication treatment, than the combination of a triptan

and an NSAID (low-certainty evidence) (Supplement). Compared with triptan

monotherapy, the ergot alkaloid dihydroergotamine may not differ in pain

relief at 2 hours (low-certainty evidence), but triptan monotherapy probably

had a higher likelihood of freedom from nausea and vomiting at 2 hours (200

and 40 more events per 1000 people, respectively; moderate-certainty

evidence) and may result in a lower likelihood of rescue medication use within

24 hours of treating an acute migraine (140 fewer events per 1000 treated

people; low-certainty evidence) (Supplement). Overall, the net benefit of these

treatments was worse, and costs were meaningfully higher than those of

recommended treatments. Annualized WAC of CGRP antagonists-gepants

ranged from $4959 to $5994 for the oral formulations and was $8800 for the

intranasal spray formulation. Annualized WAC for intranasal spray and

injectable formulations of dihydroergotamine was $1320 and $4042,

respectively (Supplement).

Evidence Gaps and Research Needs

There is a critical need for funding agencies, such as the Patient-Centered
Outcomes Research Institute or National Institute of Neurological Disorders
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 and Stroke, to support well-designed, comparative effectiveness trials of

newer medications to treat moderate to severe episodic migraine compared

with the combination of a triptan and an NSAID or acetaminophen. These

trials should focus on the combination therapies as initial treatment options

and in patients who did not achieve adequate relief with an initial

pharmacologic treatment attempt for a moderate to severe acute episodic

migraine. The trials should also be long enough to provide efficacy data across

multiple migraine headaches rather than focusing on the effects of a single

migraine headache. Further, longer trial periods will increase the likelihood
that enrolled participants will have a migraine during the trial and be
analyzed, as opposed to being excluded from analyses as was the case for

several included studies in the systematic review used to inform this clinical

guideline (8).

Areas of Insufficient Evidence

Most of the studies analyzed in this report compared an intervention of

interest versus a placebo (the common comparator in the network meta-

analysis); only some were direct head-to-head comparison studies. The

comparative evidence among acetaminophen, combination therapy of an

NSAID (aspirin) and acetaminophen, lasmiditan, dihydroergotamine, and

CGRP antagonists-gepants (rimegepant, ubrogepant, and zavegepant) was

very limited. Evidence is insufficient to draw firm conclusions about the

comparative benefits and harms of triptans compared with lasmiditan and

CGRP antagonists-gepants. These head-to-head comparisons are listed in

bullet points in the Supplement. The systematic review identified only 1 CEA
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 comparing 3 drug classes (triptans, CGRP antagonists-gepants, and the ditan

lasmiditan). No CEAs were identified assessing other pharmacologic

treatments of interest included in this guideline.

Areas of No Evidence
Included studies focused on a single migraine headache, with an absence of
efficacy data across multiple migraine headaches. The accompanying

systematic review (8) did not identify head-to-head comparative studies for

lasmiditan, celecoxib, eletriptan, frovatriptan, or naratriptan. In addition, it did

not find comparative effectiveness evidence eligible for this clinical guideline
to evaluate the efficacy of switching pharmacologic treatments in patients

who did not achieve adequate relief with an initial pharmacologic treatment
attempt for an acute migraine headache.

Appendix. Detailed Methods

Detailed Methods of the Systematic Review and Guideline

Details of the ACP guideline development process can be found in ACP's

methods articles (10, 11).

Committee Composition and Stakeholder Involvement

The CGC is a multidisciplinary group of 14 to 15 members: 12 to 13 are internal

medicine physicians representing various clinical areas of expertise across
hospital and ambulatory medicine, including internal medicine subspecialties,
and 2 are nonphysician public members. The CGC Public Panel, involving 6
members from the public, provided input at various points in the guideline
development process (see Public and Patient Values and Preferences). The
CGC convened a topic expert panel made up of clinical topic experts,
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 clinicians, and epidemiologists to inform the systematic review and assist in
refining the scope and key questions (see acknowledgments of individual
members in the accompanying systematic review [8]).

Disclosures of Interests and Management of Conflicts of

Interest

All financial and intellectual disclosures of interest were declared, and

potential conflicts were discussed and managed in accordance with CGC
policy (11). Disclosure of interests and management of any conflicts can be
found on ACP’s website (www.acponline.org/about-acp/who-we-
are/leadership/boards-committees-councils/clinical-guidelines-
committee/disclosure-of-interests-and-conflict-of-interest-management-
summary-for-clinical-guidelines).

Key Questions and Clinical Outcomes of Interest

The CGC identified the key questions (Appendix Table 1). The ACP CER at
Cochrane Austria assessed the efficacy of potentially eligible interventions
when compared with placebo and included only efficacious interventions.
Members of the CGC (clinicians and nonclinician public members), CGC
Public Panel, and topic expert panel independently rate the importance of
evaluated outcomes a priori (Appendix Table 2). The CGC prioritized outcomes
for decision making on the basis of the ratings.

Systematic Review on Benefits and Harms

The CER conducted the supporting systematic review and network meta-
analysis on benefits and harms (8), which was funded by ACP. The systematic
reviewers followed a 2-step approach for the literature searches. First, they
conducted literature searches in MEDLINE (Ovid) in February 2023 to detect
relevant systematic reviews of placebo-controlled and head-to-head trials of
migraine medications. Then, in a second step they performed a coherent
search strategy in databases (Ovid Medline ALL, Embase [Elsevier], and
CENTRAL [Cochrane Library/Wiley]) in May 2023 to identify randomized
controlled trials published in English applying date limits based on the search
:
 dates of the original systematic reviews. Those searches were updated in
October 2024. The CER and the CGC used the GRADE approach to summarize
the review findings and to rate the certainty of evidence for clinical outcomes.

Public and Patient Values and Preferences

Authors of the accompanying systematic review (9) searched databases (Ovid

Medline ALL and EBSCO CINAHL), used relevant studies as seed references for
backward citation searching in Scopus (Elsevier) and citationchaser
(https://estech.shinyapps.io/citationchaser), and manually searched the
reference lists of pertinent systematic reviews for any quantitative study that
reported patients’ values and preferences about pharmacologic treatment of
acute episodic migraine published in English from inception to October 2024.
The CER and the CGC used the GRADE approach to summarize review
findings and rate the certainty of evidence about values and preferences (18,
19). The CGC Public Panel participated in the outcome rating exercise,
provided its views on the findings from the systematic review about the
benefits and harms of interventions, shared preferences about treatment
options, and provided feedback on the draft recommendations.

Economic Evidence

The accompanying rapid review included studies addressing CEAs of eligible

interventions (8). The CER searched databases (Ovid Medline ALL and Embase
[Elsevier]; the International HTA database; and the repositories of the Center
for Health Decision Science [Harvard], the Institute for Clinical and Economic
Review, the National Health Service Economic Evaluation Database, and the
Cost-Effectiveness Analysis [CEA] Registry) for any peer-reviewed and non–
industry-conducted CEA or trial-based or model-based economic evaluation
that reported outcomes with units of health (such as quality-adjusted life-
years) in U.S. settings, included up-to-date reference cases, and was published
in English from January 2013 to October 2024. The CER used the Drummond
checklist (20) to assess the methodological quality of eligible CEAs and used a
scale developed by Doran (21) to assess the overall risk of bias. The CER graded
the certainty of evidence in accordance with GRADE guidance (22, 23). The
CGC applied a predefined set of value thresholds, derived through informal
:
 consensus, to categorize interventions as high, intermediate, low, or no value
(Appendix Table 3).

The CGC estimated annualized WAC (14) for each eligible pharmacologic
treatment; it was calculated by estimating 4 migraine headache days per
month, which was the median frequency reported in studies included in the
systematic review used to inform this clinical guideline. The CGC judged if
there were meaningful differences based on the distribution of costs
associated with resource utilization (cost of interventions) (Supplement).

Peer Review

The supporting systematic review and clinical guideline each had a peer-
review process through the journal. The guideline was posted online for
comments from ACP Regents and Governors, who represent internal
medicine and its subspecialty physician members at the national and
international level. The CGC considered any feedback before finalizing the
guideline.

Guideline Expiration or Living Guideline Process

All ACP clinical guidelines are considered automatically withdrawn or invalid 5

years after publication or once an update has been issued.

Supplemental Material
Supplementary Material

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References
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