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Figure 1.  Selection of Trials for Inclusion in the Review and Meta-analysis
Selection of Trials for Inclusion in the Review and Meta-analysis

NSAIDs indicates nonsteroidal anti-inflammatory drugs.

aOther sources include reference mining of the included studies, gray literature search, and the technical experts panel.

bThe purpose of using these systematic reviews and clinical trial registries was to identify relevant studies that may have been missed in the database search and in other sources. The studies found matched those that were already included, and no additional studies were identified through existing systematic reviews and clinical trial registries.

Figure 2.  Findings of Meta-analysis of Calcitonin Gene-Related Peptide Receptor Antagonists on Pain and Function Measured as Binary Outcomes for Episodic Migraine in Adults
Findings of Meta-analysis of Calcitonin Gene-Related Peptide Receptor Antagonists on Pain and Function Measured as Binary Outcomes for Episodic Migraine in Adults

eTable 3 in the Supplement lists definitions of outcomes. eTable 6 in the Supplement lists definitions of strength of evidence (SOE) and approaches used to grade SOE. RCT indicates randomized clinical trial; RR, relative risk.

Figure 3.  Findings of Meta-analysis of 5-HT1F Receptor Agonists on Pain and Function Measured as Binary Outcomes for Episodic Migraine in Adults
Findings of Meta-analysis of 5-HT1F Receptor Agonists on Pain and Function Measured as Binary Outcomes for Episodic Migraine in Adults

eTable 3 in the Supplement lists definitions of outcomes. eTable 6 in the Supplement lists definitions of strength of evidence (SOE) and approaches used to grade SOE. RCT indicates randomized clinical trial; RR, relative risk.

Figure 4.  Findings of Meta-analysis of Antiemetics on Pain and Function Measured as Binary Outcomes for Episodic Migraine in Adults
Findings of Meta-analysis of Antiemetics on Pain and Function Measured as Binary Outcomes for Episodic Migraine in Adults

eTable 3 in the Supplement lists definitions of outcomes. eTable 6 in the Supplement lists definitions of strength of evidence (SOE) and approaches used to grade SOE. RCT indicates randomized clinical trial; RR, relative risk.

Table.  Effectiveness of Triptans and Nonsteroidal Anti-inflammatory Drugs (NSAIDs) From Previous Systematic Reviewsa
Effectiveness of Triptans and Nonsteroidal Anti-inflammatory Drugs (NSAIDs) From Previous Systematic Reviewsa
Supplement.

eTable 1. Search strategy

eTable 2. List of the excluded interventions

eTable 3. Definition of pain and function outcomes

eTable 4. Pain and function scales included in the anaysis

eTable 5. Categories of adverse events

eTable 6. Definition and approaches to grade strength of evidence

eTable 7. Results of systematic reviews evaluating triptans and nonsteroidal anti-inflammatory drugs (NSAIDs)

eTable 8. Characteristics of included studies evaluating CGRP, 5-HT1F, antiemetics, ergot alkaloids, opioids, other pharmacological interventions, and nonpharmacological interventions

eTable 9. Adverse events

eTable10. Subgroup analysis

eTable 11. Risk of bias (Cochrane Risk of Bias tool for randomized trials [RoB 2.0]) for randomized clinical trials

eTable 12. Effectiveness of treatments other than triptans and nonsteroidal anti-inflammatory drugs

eFigure 1. Findings of Meta-analysis of 5-HT1F Receptor Agonists on Pain and Function Outcomes measured as Continuous Outcomes for Episodic Migraine in Adults

eFigure 2. Findings of Meta-analysis of Antiemetics on Pain Outcomes measured as Continuous Outcomes for Episodic Migraine in Adults

eFigure 3. Findings of Meta-analysis of Ergot Alkaloids on Pain and Function Outcomes measured as Binary Outcomes for Episodic Migraine in Adults

eFigure 4. Findings of Meta-analysis of Ergot Alkaloids on Pain Outcomes measured as Continuous Outcomes for Episodic Migraine in Adults

eFigure 5. Findings of Meta-analysis of Opioids on Pain and Function Outcomes measured as Binary Outcomes for Episodic Migraine in Adults

eFigure 6. Findings of Meta-analysis of Opioids on Pain Outcomes measured as Continuous Outcomes for Episodic Migraine in Adults

eFigure 7. Findings of Meta-analysis of Other Pharmacological Interventions on Pain and Function Outcomes measured as Binary Outcomes for Episodic Migraine in Adults

eFigure 8. Findings of Meta-analysis of Other Pharmacological Interventions on Pain and Function Outcomes measured as Continuous Outcomes for Episodic Migraine in Adults

eFigure 9. Findings of Meta-analysis of Nonpharmacological Interventions on Pain Outcomes measured as Binary Outcomes for Episodic Migraine in Adults

eFigure 10. Findings of Meta-analysis of Nonpharmacological Interventions on Pain Outcomes measured as Continuous Outcomes for Episodic Migraine in Adults

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Original Investigation
June 15, 2021

Acute Treatments for Episodic Migraine in Adults: A Systematic Review and Meta-analysis

Author Affiliations
  • 1Mayo Clinic Evidence-based Practice Center, Rochester, Minnesota
  • 2Department of Neurology, Mayo Clinic, Scottsdale, Arizona
  • 3Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota
  • 4Department of Library–Public Services, Mayo Clinic, Rochester, Minnesota
  • 5Division of Health Care Delivery Research, Mayo Clinic, Rochester, Minnesota
JAMA. 2021;325(23):2357-2369. doi:10.1001/jama.2021.7939
Key Points

Question  What are the benefits and adverse events associated with acute treatments for episodic migraine in adults?

Findings  In this systematic review and meta-analysis that included 15 systematic reviews and 115 randomized clinical trials of 28 803 participants with migraine headache, multiple acute interventions, including nonsteroidal anti-inflammatory drugs, triptans, calcitonin gene-related peptide receptor antagonists, 5-HT1F receptor agonist, dihydroergotamine, acetaminophen, and remote electrical neuromodulation, were associated with improvements in short-term pain outcomes, with moderate to high strength of evidence. The evidence for these end points regarding opioids and other interventions was low or insufficient.

Meaning  For the acute treatment of migraine, several established and newer therapies were associated with improvements in short-term pain outcomes, with varying strengths of evidence.

Abstract

Importance  Migraine is common and can be associated with significant morbidity, and several treatment options exist for acute therapy.

Objective  To evaluate the benefits and harms associated with acute treatments for episodic migraine in adults.

Data Sources  Multiple databases from database inception to February 24, 2021.

Study Selection  Randomized clinical trials and systematic reviews that assessed effectiveness or harms of acute therapy for migraine attacks.

Data Extraction and Synthesis  Independent reviewers selected studies and extracted data. Meta-analysis was performed with the DerSimonian-Laird random-effects model with Hartung-Knapp-Sidik-Jonkman variance correction or by using a fixed-effect model based on the Mantel-Haenszel method if the number of studies was small.

Main Outcomes and Measures  The main outcomes included pain freedom, pain relief, sustained pain freedom, sustained pain relief, and adverse events. The strength of evidence (SOE) was graded with the Agency for Healthcare Research and Quality Methods Guide for Effectiveness and Comparative Effectiveness Reviews.

Findings  Evidence on triptans and nonsteroidal anti-inflammatory drugs was summarized from 15 systematic reviews. For other interventions, 115 randomized clinical trials with 28 803 patients were included. Compared with placebo, triptans and nonsteroidal anti-inflammatory drugs used individually were significantly associated with reduced pain at 2 hours and 1 day (moderate to high SOE) and increased risk of mild and transient adverse events. Compared with placebo, calcitonin gene-related peptide receptor antagonists (low to high SOE), lasmiditan (5-HT1F receptor agonist; high SOE), dihydroergotamine (moderate to high SOE), ergotamine plus caffeine (moderate SOE), acetaminophen (moderate SOE), antiemetics (low SOE), butorphanol (low SOE), and tramadol in combination with acetaminophen (low SOE) were significantly associated with pain reduction and increase in mild adverse events. The findings for opioids were based on low or insufficient SOE. Several nonpharmacologic treatments were significantly associated with improved pain, including remote electrical neuromodulation (moderate SOE), transcranial magnetic stimulation (low SOE), external trigeminal nerve stimulation (low SOE), and noninvasive vagus nerve stimulation (moderate SOE). No significant difference in adverse events was found between nonpharmacologic treatments and sham.

Conclusions and Relevance  There are several acute treatments for migraine, with varying strength of supporting evidence. Use of triptans, nonsteroidal anti-inflammatory drugs, acetaminophen, dihydroergotamine, calcitonin gene-related peptide antagonists, lasmiditan, and some nonpharmacologic treatments was associated with improved pain and function. The evidence for many other interventions, including opioids, was limited.

Introduction

Quiz Ref IDThe 2016 Global Burden of Disease Study noted that migraine affected approximately 14.4% of the worldwide population1 and was ranked the second overall cause for years lived with disability and the leading cause of years lived with disability in young women.2 It is best conceptualized as a chronic neurologic disease punctuated by attacks of headache and accompanying symptoms such as photophobia, phonophobia, nausea/vomiting, and aura.3

In addition to modification of lifestyle and environmental factors, migraine management includes acute therapies (ie, interventions taken as needed for symptom relief during a migraine attack) and preventive therapies (ie, interventions taken to reduce the frequency and severity of migraine attacks). The need for preventive therapies depends on the frequency and severity of the migraine attacks and thus may not be required for every patient with migraine. However, all patients with migraine should be offered acute therapies with the goal of providing rapid, effective, and reliable pain and symptom relief with minimal adverse effects.

Patients with migraine encounter various barriers to receiving appropriate acute therapy. Prescribing data have demonstrated a mismatch between what patients receive for acute treatment of migraine and the evidence to support those treatments. In weighted results of National Ambulatory Medical Care Surveys conducted from 2006 to 2013 that included 2860 visits, use of any narcotic as an abortive medication was reported by 15.2% of responders compared with use of high-quality abortive medications reported by 18.9%.4

In this systematic review, the benefits and harms associated with acute treatments for episodic migraine were assessed, including pharmacologic and nonpharmacologic therapies. This review focused on pain-related outcomes, such as pain relief and pain freedom, as well as function and adverse events.

Methods

This review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statements and was part of a large systematic review of acute treatments for episodic migraine funded by the Agency for Healthcare Research and Quality. The study protocol was developed with input from clinical and research experts and registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42020163262). A 6-member technical expert panel was established at the beginning of the study to help protocol development. Given numerous systematic reviews that summarized evidence supporting the use of triptans and nonsteroidal anti-inflammatory drugs (NSAIDs) for acute treatment of migraine, an overview of previously published systematic reviews approach (also called umbrella systematic review) was used to synthesize the evidence for these 2 classes of drugs. For all other treatments, new systematic reviews were performed. This study was deemed exempt by the Mayo Clinic Institutional Review Board because only study-level published data were collected.

Data Sources and Searches

EMBASE, Epub Ahead of Print, In-Process & Other Non-Indexed Citations, MEDLINE Daily, MEDLINE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, PsycINFO, and Scopus from database inception to February 24, 2021, were searched. Clinical trial registries, government databases and websites, conference proceedings, patient advocate group websites, and medical society websites were also searched. Reference mining of existing systematic reviews/meta-analyses, clinical trial registries, and relevant primary studies was conducted to identify additional literature. The technical expert panel helped identify relevant literature. In addition, a Supplemental Evidence and Data for Systematic Reviews (SEADS) portal was posted on the Agency for Healthcare Research and Quality website to collect additional study-specific information. The literature search strategy was developed and executed by a medical reference librarian and peer reviewed by a second librarian. The detailed search strategy is provided in eTable 1 in the Supplement. A Federal Register notice was posted for this review (https://www.federalregister.gov/documents/2020/01/15/2020-00488/supplemental-evidence-and-data-request-on-treatments-for-acute-episodic-migraine).

Study Selection

Eligible studies (1) included adult patients (≥18 years) with episodic migraine; (2) evaluated abortive pharmacologic therapy or noninvasive nonpharmacologic abortive therapy; (3) involved comparisons of the intervention with placebo, usual care, another pharmacologic therapy, noninvasive nonpharmacologic therapy, wait list, no treatment, or attention control, (4) reported short-term outcomes of interest (≤4 weeks after the end of treatments); and (5) were published in English. Because the definition of migraine has changed, the definition used in the original studies was accepted as long as it also fit the current International Classification of Headache Disorders, Third Edition criteria for episodic migraine (defined as the presence of headache 14 or fewer days per month in someone who has migraine).3 Systematic reviews of triptans and NSAIDs, as well as randomized clinical trials (RCTs) of the other treatments, were included. Invasive treatments (defined as surgically implanted), preventive treatments, in vitro studies, studies without original data, and single-group studies were excluded. Therapies in development, with terminated development, or unavailable in the United States were also excluded (eTable 2 in the Supplement).

Pairs of independent reviewers screened the titles and abstracts of all citations. Studies included by either reviewer were retrieved for full-text screening. Independent pairs of reviewers screened the full-text version of eligible studies. Conflicts between the reviewers were resolved by a third senior investigator. For systematic reviews of triptans and NSAIDs, when more than 1 systematic review was available per drug, the most recent one with the largest number of included studies was chosen.

Data Extraction and Quality Assessment

A standardized data extraction form was developed to extract study characteristics. Reviewers worked independently to extract study details. An additional reviewer reviewed data extraction and resolved conflicts. Authors were contacted for missing or incomplete information.

The risk of bias of the included RCTs was evaluated with the Cochrane Collaboration’s Risk of Bias 2 tool.5 For systematic reviews of triptans and NSAIDs, credibility of the review process was assessed,6 which included the comprehensiveness of the search and rigor of study selection procedures, using items from the AMSTAR tool.7

Outcome Measures

The primary outcomes were pain freedom, pain relief, sustained pain freedom, sustained pain relief, and adverse events. Additional outcomes included improved function, restored function, pain as reported with a pain scale, function as reported with a function scale, opioid overdose, and medication overuse headache. In the Supplement, eTable 3 lists the definitions of the pain and function outcomes, eTable 4 summarizes pain scales and function scales included in the analyses, and eTable 5 describes categorization of adverse events. For serious adverse events, the definitions in the original studies were used.

Data Synthesis and Analysis

All statistical analyses for RCTs involved analyzing participants according to their original allocation group. For crossover RCTs, outcomes before crossover were used in meta-analysis.8 Studies that randomized migraine attacks instead of patients were not meta-analyzed because correlations between attacks could not be controlled for.

Relative risk (RR) and risk difference (RD) for binary outcomes were extracted or estimated. For ordinal outcomes (pain scale and function scale), standardized mean difference was calculated and the direction of all measures was converted so that a higher score represented better outcome. For adverse events, rate ratio (ie, ratio of the incidence rate of events within a given time between the intervention and the comparison) was calculated. Meta-analyses were conducted according to length of follow-up after treatment (2 hours, 1 day, and 1 week). The DerSimonian-Laird random-effects model with Hartung-Knapp-Sidik-Jonkman variance correction was used to combine direct comparisons between treatments if the number of studies included in the analysis was larger than 3.9 The fixed-effect method based on the Mantel-Haenszel method was adopted when the number of studies was 3 or fewer. Heterogeneity between studies was evaluated with the I2 indicator. To further explore heterogeneity, prespecified subgroup analyses were conducted according to age, sex, race, body mass index, route of administration, dose, study setting, and prior response to treatment. Race was defined according to the methods used by the original studies. Analyses were also stratified by risk of bias (low, moderate, and high). Publication bias could not be quantitatively evaluated due to the small number of studies included in meta-analyses (n < 10). Two-sided P < .05 was deemed to be statistically significant.

Grading the Strength of Evidence

The strength of evidence (SOE) was graded following the Agency for Healthcare Research and Quality Methods Guide for Effectiveness and Comparative Effectiveness Reviews and categorized as “high,” “moderate,” “low,” or “insufficient evidence.”10 eTable 6 in the Supplement provides a description of this approach.

Results

The literature search identified 16 319 citations. An additional 185 citations were identified through reference mining, through gray literature search, and by the technical experts panel. Evidence on triptans and NSAIDs was summarized from 15 systematic reviews. For other interventions, 115 RCTs from 121 articles with 28 803 patients were included in the analyses (Figure 1). Details of the interventions reported in each study can be found in eTables 7 and 8 in the Supplement.

Pharmacologic Therapy

Evidence on triptans and NSAIDs was summarized from 15 existing systematic reviews. For other pharmacologic interventions, 97 RCTs with 27 052 patients were included. Forty-nine studies were conducted in the emergency department, 46 in the outpatient setting, 1 in urgent care, and 1 in an inpatient setting. The results of the meta-analyses on effectiveness are summarized in the Table11-21; Figures 2, 3, and 4; and eFigures 1-8 in the Supplement. Adverse events and subgroup analyses are summarized in eTables 9 and 10 in the Supplement, respectively.

Triptans and NSAIDs

Numerous systematic reviews have been published evaluating triptans and NSAIDs (eTable 7 in the Supplement). Most of the systematic reviews were judged to have high credibility.6 The Table summarizes pain and function outcomes from 11 systematic reviews, when triptans and NSAIDs were compared with placebo.

According to 7 systematic reviews, triptans (various administration routes, including oral, subcutaneous, and intranasal) compared with placebo were significantly associated with increased pain freedom and pain relief at 2 hours and 1 day (high SOE), and increased risk of mild and transient adverse events (eg, malaise, nausea, chest pain, flushing sensation, palpitation, paresthesia).

According to 3 systematic reviews, NSAIDs (various administration routes, including oral, intravenous, and intramuscular) compared with placebo were significantly associated with increased pain freedom and pain relief at 2 hours and 1 day (moderate SOE), and increased risk of mild and transient adverse events (eg, dyspepsia, nausea, somnolence, dizziness).

According to 1 systematic review, the combination of sumatriptan (oral) and naproxen (oral) compared with placebo was significantly associated with improved pain freedom (high SOE) and pain relief (high SOE) at 2 hours, sustained pain freedom (high SOE) and sustained pain relief (high SOE) at 1 day, and improved function (high SOE) at 2 hours.

Calcitonin Gene-Related Peptide Receptor Antagonists (Gepants)

Six RCTs22-27 with 7620 patients evaluated calcitonin gene-related peptide receptor antagonists for the acute treatment of migraine. The overall risk of bias was low to moderate (2 RCTs with low risk; 2, moderate risk; and 2, high risk) (eTable 11 in the Supplement), without notable differences in findings based on risk of bias assessment (eTable 10.1 in the Supplement).

Compared with placebo, rimegepant (3 RCTs; oral and sublingual) and ubrogepant (3 RCTs; oral) were associated with significant improvement in pain freedom and pain relief at 2 hours (moderate to high SOE) and sustained pain freedom at 1 day and at 1 week (low to high SOE). Ubrogepant was associated with significantly more adverse events related to ear, nose, and throat symptoms. The results of the meta-analyses of the pain and function outcomes are summarized in Figure 2.

5-HT1F Receptor Agonists (Ditans)

Six RCTs from 7 articles with 8988 patients evaluated lasmiditan for the acute treatment of migraine.28-34 The overall risk of bias was low to moderate (3 RCTs with low risk; 1, moderate risk; and 2, high risk) (eTable 11 in the Supplement). Studies with different risk of bias demonstrated consistent findings (eTable 10.4 in the Supplement).

Compared with placebo, lasmiditan (oral and intravenous) was associated with significant improvement in pain freedom at 2 hours (5 RCTs; high SOE) and pain relief at 2 hours (5 RCTs; high SOE). It was also associated with significant improvement in sustained pain freedom at 1 day (3 RCTs; high SOE) and 1 week (2 RCTs; high SOE). Lasmiditan was associated with significantly increased risk of gastrointestinal adverse events, neurologic adverse events, serious adverse events, and total number of adverse events. The meta-analyses of pain and function outcomes, as well as adverse events, are summarized in Figure 3 and eFigure 1 and eTable 9.2 in the Supplement.

A subgroup analysis35 by prior response to triptans based on 2 RCTs31,32 demonstrated that, regardless of prior triptan response, lasmiditan was associated with significantly more pain freedom and pain relief at 2 hours compared with placebo (eTable 10.10 in the Supplement).

Antiemetics

Twenty-six RCTs36-61 with 2561 patients evaluated antiemetic medications. The overall risk of bias was moderate to high (4 RCTs with low risk; 8, moderate risk; and 14, high risk) (eTable 11 in the Supplement).

Compared with placebo, chlorpromazine (2 RCTs; intramuscular and intravenous) was associated with significantly more pain freedom and pain relief at 2 hours (low SOE) and 1 day (low SOE); prochlorperazine (2 RCTs; oral and rectal) and droperidol (1 RCT; intramuscular) individually were associated with significantly improved pain freedom (low SOE) and pain relief at 2 hours (low SOE); and metoclopramide (3 RCTs; intravenous) and haloperidol (1 RCT; intravenous) were each associated with improved pain relief at 2 hours (low SOE). Haloperidol, droperidol, and prochlorperazine significantly increased the risk of adverse events. Figure 4 and eFigure 2 and eTable 9.3 in the Supplement present the results of meta-analyses of pain and function outcomes and adverse events for the antiemetic drugs.

Ergot Alkaloids

Fifteen RCTs62-76 with 2535 patients were included in the analyses of ergot alkaloid medications. The overall risk of bias was high (2 RCTs with low risk; 2, moderate risk; and 11, high risk) (eTable 11 in the Supplement). No notable differences in findings between studies with low and moderate/high risk of bias (eTable 10.14 in the Supplement) were found.

Compared with placebo, dihydroergotamine (3 RCTs; intranasal) was associated with significantly more pain freedom and pain relief at 2 hours, 1 day, and 1 week (moderate to high SOE), sustained pain freedom and pain relief at 1 day and 1 week (high SOE), and gastrointestinal adverse events.

Compared with placebo, ergotamine plus caffeine (1 RCT; oral) was associated with significantly more pain relief at 2 hours (moderate SOE). The results of meta-analyses of pain and function outcomes and adverse events for the ergot alkaloid drugs are summarized in eFigures 3 and 4 and eTable 9.4, respectively, in the Supplement.

Opioids

Thirteen RCTs77-89 with 1847 patients were included in the analyses of opioid medications. The overall risk of bias was high (12 RCTs with high risk and 1 RCT with moderate risk) (eTable 11 in the Supplement).

Compared with placebo, tramadol in combination with acetaminophen (1 RCT; oral) was significantly associated with improved pain freedom at 2 hours (RR, 2.42 [95% CI, 1.34-4.35]; RD, 0.11 [95% CI, 0.04-0.17]; 1 RCT; 375 patients; low SOE) and 1 day (RR, 1.43 [95% CI, 1.09-1.88]; RD, 0.13 [95% CI, 0.03-0.23]; 1 RCT; 375 patients; low SOE), sustained pain freedom at 1 day (RR, 2.26 [95% CI, 1.15-4.46]; RD, 0.07 [95% CI, 0.02-0.13]; 1 RCT; 375 patients; low SOE), pain relief at 2 hours (RR, 1.68 [95% CI, 1.27-2.22]; RD, 0.18 [95% CI, 0.09-0.28]; 1 RCT; 375 patients; low SOE) and 1 day (RR, 1.75 [95% CI, 1.35-2.25]; RD, 0.23 [95% CI, 0.13-0.32]; 1 RCT; 375 patients; low SOE), and sustained pain relief at 1 day (RR, 1.56 [95% CI, 1.08-2.27]; RD, 0.11 [95% CI, 0.02-0.19]; 1 RCT; 375 patients; low SOE). Significantly more adverse events were reported in the group treated with tramadol and acetaminophen (rate ratio, 2.49; 95% CI, 1.48-4.18). Tramadol alone (1 RCT; intravenous) vs placebo failed to show a significant difference in pain freedom at 2 hours (RR, 2.50 [95% CI, 0.56-11.16]; RD, 0.18 [95% CI, −0.09 to 0.44]; 1 RCT; 34 patients; insufficient SOE) and pain relief at 2 hours (RR, 2.00 [95% CI, 0.98-4.08]; RD, 0.35 [95% CI, 0.04-0.67]; 1 RCT; 34 patients; insufficient SOE) or change in pain scale at 2 hours (standardized mean difference, 0.25; 95% CI, −0.43 to 0.92; 1 RCT; 34 patients; insufficient SOE).

Two RCTs compared butorphanol with placebo (intranasal). Butorphanol was associated with improvement over placebo regarding pain freedom at 2 hours (RR, 2.90 [95% CI, 1.20-7.01]; RD, 0.19 [95% CI, 0.07-0.31]; 1 RCT; 157 patients; low SOE) and 1 day (RR, 1.83 [95% CI, 1.10-3.05]; RD, 0.22 [95% CI, 0.06-0.37]; 1 RCT; 157 patients; low SOE), pain relief at 2 hours (RR, 3.37 [95% CI, 1.83-6.22]; RD, 0.43 [95% CI, 0.29-0.57]; 1 RCT; 157 patients; low SOE) and 1 day (RR, 2.07 [95% CI, 1.43-2.98]; RD, 0.41 [95% CI, 0.25-0.56]; 1 RCT; 157 patients; low SOE). Butorphanol was also associated with significantly increased total number of adverse events (rate ratio, 6.08; 95% CI, 4.19-8.82; I2 = 94.00%).

Meperidine (5 RCTs; intramuscular), morphine (1 RCT; intravenous), and hydromorphone (1 RCT; intravenous) failed to show superiority over various comparators regarding pain and function outcomes (eFigures 4 and 5 in the Supplement). There were increased numbers of adverse events associated with these medications (eTable 9.5 in the Supplement).

No study reported opioid overdose or opioid-specific adverse events, such as opioid misuse, opioid use disorder, or overdose.

Other Pharmacologic Interventions

eTable 9.6, eTables 10.16 to 10.19, and eFigures 7 and 8 in the Supplement list the findings for other pharmacologic therapies, including acetaminophen, dexamethasone, greater occipital nerve blocks, ketamine, lidocaine, magnesium sulfate, octreotide, propofol, secobarbital, and valproate.

Compared with placebo, acetaminophen was associated with significantly improved pain freedom at 2 hours (RR, 1.89 [95% CI, 1.24-2.86]; I2 = 0.00%; RD, 0.07 [95% CI, 0.03-0.12]; 2 RCTs; 729 patients; moderate SOE) and 1 day (RR, 1.78 [95% CI, 1.38-2.30]; I2 = 0.00%; RD, 0.15 [95% CI, 0.09-0.21]; 2 RCTs; 729 patients; moderate SOE) and pain relief at 2 hours (RR, 1.61 [95% CI, 1.33-1.95]; I2 = 0.00%; RD, 0.18 [95% CI, 0.11-0.25]; 2 RCTs; 729 patients; moderate SOE) and 1 day (RR, 1.71 [95% CI, 1.43-2.04]; I2 = 0.00%; RD, 0.22 [95% CI, 0.15-0.29]; 2 RCTs; 729 patients; moderate SOE). There was no significant difference on adverse events.

Nonpharmacologic Therapy

Eighteen RCTs in 19 articles with 1751 patients evaluated nonpharmacologic therapies.90-108 Five were conducted in the emergency department setting91,94,97,101,107 and 13 (in 14 articles) in the outpatient setting.90,92,93,95,96,98,100,102-106,108 The overall risk of bias was moderate (3 RCTs with low risk; 7, moderate risk; and 8, high risk) (eTable 11 in the Supplement). Nonpharmacologic studies with low risk of bias reported similar findings compared with studies with moderate or high risk of bias. The results of meta-analyses of pain and function outcomes, adverse events, and subgroup analyses are summarized in eTable 9.7 and eTable 10.20, and in eFigures 9 and 10 in the Supplement.

Compared with sham, remote electrical neuromodulation was significantly associated with improved pain freedom (RR, 1.95 [95% CI, 1.19-3.19]; RD, 0.14 [95% CI, 0.04-0.24]; 1 RCT; 252 patients; moderate SOE) and pain relief at 2 hours (RR, 1.65 [95% CI, 1.22-2.24]; RD, 0.21 [95% CI, 0.09-0.33]; 1 RCT; 252 patients; moderate SOE), and improved sustained pain freedom (RR, 2.57 [95% CI, 1.11-5.94]; RD, 0.09 [95% CI, 0.01-0.16]; 1 RCT; 252 patients; moderate SOE) and sustained pain relief at 1 week (RR, 2.27 [95% CI, 1.30-3.95]; RD, 0.15 [95% CI, 0.05-0.25]; 1 RCT; 252 patients; moderate SOE).

Compared with sham, external trigeminal nerve stimulation was significantly associated with improved ratings on the pain scale at 2 hours (standardized mean difference, 1.25; 95% CI, 0.90-1.60; I2 = 98.65%; 2 RCTs; 189 patients; low SOE) and 1 day (standardized mean difference, 0.53; 95% CI, 0.14-0.92; 1 RCT; 106 patients; moderate SOE). The RCT with low risk of bias reported notably smaller improvement on the pain scale at 2 hours than the RCT with high risk of bias.

Compared with sham, transcranial magnetic stimulation was significantly associated with more pain freedom at 2 hours (RR, 1.73 [95% CI, 1.04-2.86]; RD, 0.13 [95% CI, 0.01-0.25]; 1 RCT; 201 patients; low SOE). There was no significant difference in adverse events or other outcomes. No serious adverse events were reported in either group.

Noninvasive vagus nerve stimulation compared with sham was significantly associated with more pain relief at 2 hours (RR, 1.49 [95% CI, 1.04-2.13]; RD, 0.13 [95% CI, 0.02-0.25]; 1 RCT; 248 patients; moderate SOE). There was no significant difference in adverse events.

Discussion

Quiz Ref IDThe findings of this systematic review and meta-analysis demonstrated that several acute treatments for migraine were associated with improvements in pain and function and also with increased risk of adverse effects, with varying strengths of evidence to support their use. In particular, use of triptans, NSAIDs, acetaminophen, dihydroergotamine, calcitonin gene-related peptide antagonists, lasmiditan, and remote electrical neuromodulation was associated with improved pain and function with relatively robust SOE (eTable 12 in the Supplement). In contrast, the evidence for many other interventions, including opioids, was limited.

Choosing an acute treatment for migraine attacks requires an individualized approach for each patient; a number of factors must be considered such as patient characteristics (including age, comorbidities, and affordability/insurance coverage), migraine attack characteristics (such as severity, speed of onset, and presence of nausea/vomiting), and reported effectiveness and harms associated with available interventions. All these factors should be considered in a shared decision-making approach.

Quiz Ref IDIn 2015, the American Headache Society recommended either a triptan or an NSAID for migraine attacks, or acetaminophen for nonincapacitating attacks.109 This systematic review found high and moderate SOE in support of triptans and NSAIDs, respectively, and these drug classes should remain as the primary choice for the acute treatment of migraine in patients who do not have contraindications.109 The combination of triptans and NSAIDs was also effective and well tolerated, and can be used for patients with partial response to either agent. However, triptans and ergot alkaloids should be avoided in individuals who have a history of myocardial infarction, stroke, or multiple vascular risk factors because they are considered vasoactive.110-112 Additionally, NSAID use may be limited if patients have certain gastrointestinal, kidney, or cardiac comorbidities. A notable feature of the newest Food and Drug Administration–approved treatments, lasmiditan and calcitonin gene-related peptide receptor antagonists, is that, by their mechanisms of action, they are deemed to be nonvasoconstrictive.113 These drugs had moderate to high strength of supporting evidence, and can be considered for individuals who have not found triptans and NSAIDs to be effective or tolerated, or have contraindications to their use. Ubrogepant and rimegepant should not be used in patients who are receiving strong or moderate cytochrome P450 3A4 inducers or inhibitors.114 Given its central mechanism of action and risks of somnolence and dizziness, lasmiditan carries an 8-hour driving restriction postdose.115 Treatment guidelines will need to be updated to determine the place of lasmiditan and calcitonin gene-related peptide receptor antagonists among established therapies, given these unique features and adverse effect profiles, especially in people with vascular comorbidities.

The choice between pharmacologic and nonpharmacologic acute treatments of migraine depends on patient preference (ie, not wanting to receive a medication), tolerability, and contraindications in various patient populations. Compared with sham, several nonpharmacologic treatments may improve various measures of pain but had low to moderate SOE. Quiz Ref IDSeveral noninvasive neuromodulation devices have gained Food and Drug Administration clearance for the acute treatment of migraine, such as remote electrical neuromodulation, transcranial magnetic stimulation, external trigeminal nerve stimulation, and noninvasive vagus nerve stimulation. When using remote electrical neuromodulation, individuals wear a wireless, battery-operated device on the lateral aspect of the upper arm that stimulates small skin nerves to induce conditioned pain modulation, an innate mechanism to inhibit perception of pain in other remote body areas.116 With transcranial magnetic stimulation, a handheld magnetic device is held against the occiput; when the tool is discharged, a brief magnetic pulse interrupts the pattern of neuronal firing that is believed to be associated with migraine. External trigeminal nerve stimulation is another noninvasive neuromodulation option that is applied to the forehead to stimulate the supraorbital nerves.91 Vagus nerve stimulation is a noninvasive device applied over the vagus nerve on either side of the neck. Although there is a role for these nonpharmacologic treatments, given their potential better tolerability, cost and lack of insurance coverage are barriers for many individuals. Patients who have access to these devices can use them at any stage of migraine treatment, including as initial therapy, adjunctive therapy, or options to consider when other acute medications have not been helpful or tolerated, or are contraindicated.

Quiz Ref IDCurrent guidelines recommend against the use of opioids and butalbital-containing medications for acute treatment of migraine.116 Despite this, opioids are frequently prescribed for the acute treatment of migraine in varied clinical settings and patient populations.117-123 This review found the overall SOE to be low or insufficient for opioids, and opioids were associated with higher rates of adverse effects compared with other treatment options or placebo. As such, the current guideline recommendations against opioids stand.

The adverse events captured in this review are those experienced from the immediate exposure. Harms with frequent or long-term use of medications may relate to end-organ damage (eg, nephrotoxicity and cardiotoxicity with NSAIDs, hepatotoxicity with acetaminophen, ergotism or peritoneal fibrosis with ergot alkaloids), as well as secondary conditions that may develop in the setting of consuming medications (eg, medication overuse headache, opioid use disorder, overdose). Medication overuse headache is defined according to headache frequency (15 or more days per month for greater than 3 months) and days of use of specific medications per month.3 Opioids and butalbital-containing medications have a 2-fold higher risk of medication overuse headache development compared with simple analgesics and triptans.124 Concerns about risk of opioid gastrointestinal-related adverse events, as well as addiction and drug abuse secondary to treatment of migraine, have also been raised.121,125,126 No included studies in the systematic review evaluated risk mitigation strategies or instruments to predict the risk of abuse or dependency in patients treated with opioids for a migraine attack, which has implications for implementation of treatment algorithms that include opioids.

Limitations

This study has several limitations. First, many of the RCTs compared treatments against placebo, limiting comparative effectiveness inferences. Head-to-head trials of active therapies and trials of combinations of therapies are needed to support shared decision making among all of the available treatment options. Second, nonpain symptoms of migraine, such as nausea, photophobia, and phonophobia, can be as bothersome as or more bothersome than pain, and this can vary, depending on the patient. Recent migraine trials are therefore evaluating the most bothersome symptom as an end point. Third, many clinical trials excluded certain populations from enrollment, including older individuals; those with hemiplegic migraine, comorbid second headache conditions, or other primary headache disorders; and those with significant mental health or vascular diagnoses. Consequently, lack of efficacy and safety data in these populations was a limitation. Fourth, trials included various clinical settings (emergency department, outpatient, inpatient, and urgent care), which may indicate a differing degree of migraine attack severity or refractoriness, depending on presenting location. Fifth, although statistical heterogeneity was minor in most analyses (I2 < 30%), some heterogeneity that relates to patients’ characteristics and study settings did exist, and some important subgroup analyses (eg, based on migraine attack characteristics, comorbidities) to evaluate heterogeneity could not be conducted.

Conclusions

There are several acute treatments for migraine, with varying degrees of supporting evidence. Use of triptans, NSAIDs, acetaminophen, dihydroergotamine, calcitonin gene-related peptide antagonists, lasmiditan, and some nonpharmacologic treatments was associated with improved pain and function. The evidence for many other interventions, including opioids, was limited.

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Article Information

Corresponding Author: Zhen Wang, PhD, Health Care Delivery Research, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (wang.zhen@mayo.edu).

Accepted for Publication: May 3, 2021.

Author Contributions: Drs VanderPluym and Wang had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: VanderPluym, Halker Singh, Nayfeh, Farah, Saadi, Murad, Wang.

Acquisition, analysis, or interpretation of data: VanderPluym, Halker Singh, Urtecho, Morrow, Nayfeh, Torres Roldan, Hasan, Saadi, Shah, Abd-Rabu, Daraz, Prokop, Murad, Wang.

Drafting of the manuscript: VanderPluym, Halker Singh, Urtecho, Torres Roldan, Farah, Saadi, Abd-Rabu, Murad, Wang.

Critical revision of the manuscript for important intellectual content: VanderPluym, Halker Singh, Urtecho, Morrow, Nayfeh, Torres Roldan, Farah, Hasan, Saadi, Shah, Daraz, Prokop, Murad, Wang.

Statistical analysis: Halker Singh, Nayfeh, Saadi, Murad, Wang.

Obtained funding: Murad, Wang.

Administrative, technical, or material support: Halker Singh, Urtecho, Morrow, Nayfeh, Farah, Hasan, Saadi, Shah, Murad, Wang.

Supervision: VanderPluym, Halker Singh, Urtecho, Abd-Rabu, Wang.

Conflict of Interest Disclosures: Dr VanderPluym reports consulting for Teva and receiving a research grant from Amgen. Dr Halker Singh reports consulting for Teva and Impel. No other disclosures were reported.

Funding/Support: This project was funded under contract HHSA290201500013I task order 75Q80119F32007 from the Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services (HHS).

Role of the Funder/Sponsor: Mayo Clinic was awarded the contract by AHRQ to conduct this review through a competitive bidding process. A representative from AHRQ served as a Contracting Officer’s Technical Representative and provided technical assistance during the conduct of the full evidence report and provided comment on draft versions of the full evidence report. AHRQ did not directly participate in the literature search, design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The authors of this article are responsible for its content. Statement in the article does not necessarily represent the official views of or imply endorsement by AHRQ or HHS.

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