Drugs and Devices for Migraine Prevention: Interactive Evidence Maps

Amy Y. Tsou; Benjamin Rouse; Aaron Bloschichak; Johnathan R. Treadwell

doi:10.25302/EMV1.2021.2

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Drugs and Devices for Migraine Prevention: Interactive Evidence Maps

Amy Y. Tsou, Benjamin Rouse, Aaron Bloschichak, and Johnathan R. Treadwell.

Author Information and Affiliations

Washington (DC): Patient-Centered Outcomes Research Institute (PCORI); 2021 Feb.

Structured Abstract

Background:

Migraine headache is a common, disabling condition that impacts 1 in 6 Americans. Although many interventions for migraine prevention have been shown to be effective, decision making for patients and physicians can be complex. Although many newer interventions have received United States (US) Food and Drug Administration (FDA) clearance, no systematic reviews have synthesized evidence for efficacy or harms across old and newer interventions.

Purpose:

To summarize evidence from randomized controlled trials (RCTs) for pharmacologic drugs and devices for migraine prevention in visual web-based evidence maps. Specifically, these evidence maps were intended to do the following:

Visualize all existing evidence from randomized clinical trials on drugs and non-invasive devices for migraine prevention.
Assess effectiveness of guideline recommended drugs and noninvasive devices for migraine reduction, tolerability, and reported harms.
Present findings in an easy-to-use interactive visual format.

Methods:

The ECRI Evidence-based Practice Center performed a rapid review of the literature to identify existing RCTs for 44 drugs and 2 devices for migraine prevention. We searched PubMed and EMBASE from inception to June 24, 2020. We included English-language RCTs enrolling adults with episodic or chronic migraine, a study duration ≥ 8 weeks, and >10 patients per arm.

For a subset of interventions (15 drugs, 2 devices) we performed meta-analyses of inactive controlled RCTs to assess efficacy and harms. We used the Cochrane risk of bias tool to assess individual studies and Grading and Recommendations Assessment, Development and Evaluation (GRADE) rating system to assess the quality of evidence.

We summarized findings using 3 web-based evidence maps, accessible here: https://www.pcori.org/research-results/evidence-synthesis/evidence-maps-and-evidence-visualizations/drugs-devices-migraine.

Results:

Overall, 203 RCTs were included: 78 trials in Map 1, 123 trials in Map 2, and 133 trials in Map 3. Two visualizations (Maps 1 and 2) presented findings from placebo-/sham-controlled RCTs, while Map 3 displayed comparisons from head-to-head RCTs.

Key Findings: Placebo-/Sham-Controlled RCTs:

Episodic migraine: Aside from onabotulinumtoxinA (no effect), interventions improved headaches by 0.5 to 2.4 migraine days per month. Efficacy for common first-line interventions (amitriptyline, propranolol, topiramate) was underwhelming (0.73 to 0.95 fewer migraine days per month) and based on low/very-low quality evidence. Calcitonin gene–related peptide (CGRP) antagonists generally provided larger efficacy with fewer side effects and higher quality evidence. Further research is needed to confirm efficacy of devices.
Chronic migraine: Aside from valproate, interventions reduced migraines by 0.9 to 4.2 migraine days per month. Based on 2 small trials, valproate offered a large reduction of 13.2 migraine days per month, although this evidence was rated very low quality.
Sparse evidence for tricyclic antidepressants: Although commonly used as first-line therapy, placebo-controlled RCTs supporting efficacy are sparse (amitriptyline) or nonexistent (nortriptyline).

Key Findings: Head-to-Head RCTs:

Key evidence gaps: No direct comparisons of CGRP antagonists or devices to standard migraine prevention therapies exist.

Conclusions:

Many interventions are effective for reducing migraine, although to what extent these reductions are clinical significant remains unclear. While the largest migraine reduction was seen for valproate (an older drug), most newer therapies appeared to have comparable efficacy and favorable tolerability. Head-to-head comparisons are needed to assess comparative effectiveness to support policy and treatment decisions.

Background

Migraine headache is a common, disabling condition that affected 16% of American adults in 2018; in 2016, migraine accounted for 4 million emergency department visits.¹ Interventions for migraine prevention aim to reduce the number and severity of migraine headaches. Because numerous therapies for migraine prevention therapy exist, selecting a therapy can be challenging. Most pharmacologic therapies commonly used for migraine prevention were originally developed for treatment of other medical conditions, such as hypertension, epilepsy, or depression. Many of these drugs have potential side effects (eg, sedation, hypertension, kidney stones, teratogenicity) that could preclude use in groups of patients, depending on a variety of clinical factors. Thus, choosing a therapy for migraine prevention typically requires careful consideration of patient comorbidities and preferences. Decision making also requires consideration of access: patients are typically required to use older pharmacologic therapies (such as tricyclic antidepressants or beta-blockers) before they are eligible for newer, more costly therapies.

Although many drugs for migraine prevention have been in use for several decades, recently, multiple newer interventions have received FDA clearance, including calcitonin gene–related peptide (CGRP) antagonists and devices (eg, the transcutaneous supraorbital nerve stimulator, noninvasive vagus nerve stimulator). Assessment of the efficacy, tolerability, and side effects of traditional therapies for migraine prevention alongside newer therapies could help inform decisions and identify important evidence gaps.

Scope and Purpose

Migraine prevention therapies encompass a wide range of interventions, including traditional pharmacologic drugs and devices, as well as behavioral therapies, nutritional supplements, and complementary and alternative medicine (CAM) therapies. After considering multiple factors such as existing evidence-based clinical practice guidelines (see Appendix A), anticipated size of evidence base, visual design considerations, and desired timeline, we decided this project would focus on evidence for pharmacologic drugs and devices for migraine prevention.

At the request of the Patient-Centered Outcomes Research Institute (PCORI), ECRI performed a rapid review and conducted meta-analyses to inform creation of 3 web-based interactive evidence maps to present findings using an accessible visual format for clinicians, researchers, and policymakers. In addition, patients may find the maps informative for exploring treatment options. We completed this review on a compressed timeline (in a little more than 6 months) to meet the needs of PCORI stakeholders.

Methods

We performed a rapid review/meta-analysis to address the following 2 key questions for adult patients with episodic or chronic migraine:

Key Question 1: What are the benefits and harms of selected newer drugs and devices (CGRP antagonists and devices) and established pharmacologic therapies (ie, recommended by evidence-based guidelines) for migraine prevention?

Key Question 2: What pharmacologic and noninvasive device interventions for migraine prevention have been assessed using randomized controlled trials (RCTs)?

We designed 3 web-based visual evidence maps to summarize evidence addressing these key questions. Key characteristics of these maps are presented in Table 1.

Table 1

Overview of Map Characteristics.

Table 2 shows included drugs and devices. For Map 1 (assessing effectiveness), we selected 17 interventions of interest. For Maps 2 and 3 (which summarize existing RCTs but do not assess efficacy), we included all interventions included in Map 1, plus 29 additional interventions.

Table 2

Included Interventions by Map.

Stakeholder Input

To inform map content and design, we interviewed key stakeholders including clinicians, patients, policymakers, and primary care physicians (see Acknowledgments). Early input from clinicians and patients informed scope (selection of interventions and outcomes) and map design. Input from policymakers including payers and funders as well as primary care physicians informed data visualization and usability considerations. Our clinician stakeholders were neurologists with expertise in treating migraine headaches and headache research. Our patient stakeholders were women with a personal history of treatment for migraine headaches and experience advocating for and communicating with the migraine community. Finally, the report and evidence maps underwent peer review by our clinician stakeholders and a reviewer with expertise in systematic review and meta-analysis methodology.

Literature Search

A medical information specialist searched PubMed and EMBASE/Medline to identify RCTs for migraine prevention interventions from inception to June 24, 2020. In addition, the specialist searched EMBASE/Medline for relevant systematic reviews through December 16, 2019. Bibliographies from relevant systematic reviews (SRs) were used to identify additional trials. The full search strategy is available in Appendix B.

Inclusion/Exclusion Criteria

We included studies that met the following criteria:

RCT comparing intervention of interest to placebo/sham (for Map 1/Map 2) or active intervention (Map 3)
Full-length, English-language published study
At least one intervention of interest assessed
Study included >80% patients with migraine (or reported data separately for patients with migraine). We included episodic and/or chronic migraine patients; studies were not required to report outcome separately for episodic/chronic.
Age ≥ 16
N ≥ 10 in each study arm at follow-up and reported outcome data for ≥50% of patients enrolled
Trial duration ≥ 8 weeks

Study reported at least 1 of the following 5 outcomes for migraine efficacy: migraine days or migraines per month, number of headache days or headaches per month, or 50% reduction in migraine frequency. Studies that did not report any of these outcomes, but reporting related efficacy outcomes (eg, index based on migraine frequency and severity) were excluded from Map 1 but included in Maps 2 or 3.

In addition, for Map 1, if crossover RCTs reported a washout period, we included data for both study periods. To avoid carryover effects, if studies failed to report a washout period (or its length), we included only period 1 data. If period 1 data were not reported separately, we excluded the study from Map 1 (but included it in Map 2 or 3, as appropriate).

Screening

We performed dual independent screening for abstracts and full-text articles using DistillerSR (Evidence Partners, Ottawa, Ontario, Canada) with disagreements resolved by a third reviewer. See Appendix C for the flow diagram.

Rapid-Review Methodology

To complete this work in a compressed timeline, we used 2 streamlined rapid-review methods: risk of bias and quality-of-evidence assessments performed by a single analyst with a 10% random check by a second analyst for risk of bias only. In addition, this work differs from typical systematic reviews in that results are primarily presented in the data visualizations, along with this report. However, in other respects, our methods were aligned with standard guidance for systematic reviews.²^,³

Data Extraction and Meta-analysis

A single experienced analyst extracted data from full-text articles, with a 10% random validation by another analyst.

We extracted study characteristics including country, year, migraine type, years since onset of migraine, and type of RCT (parallel vs crossover), interventions, comparisons, and number of patients randomized per arm from all included studies. We categorized migraine type as episodic (<15 migraines or headaches per month), chronic (≥15 migraines or headaches per month), episodic plus chronic, and other/not reported. See Appendix D for more details.

Map 1 Outcomes

For studies included in Map 1, we also extracted outcomes for migraine reduction, trial dropout from adverse effects (as a measure of tolerability), and adverse effects. For each outcome, we extracted the data point closest to 8 weeks, 12 weeks, and 6 months, as well as the longest reported timepoint, with data for multiple timepoints extracted if reported.

Specifically, we categorized data from various timepoints as follows:

8 weeks: 8 to <12 weeks
12 weeks: 12 weeks to <6 months
6 months: ≥6 months

Migraine Reduction and Trial Dropout

For migraine reduction, we extracted the following specific outcomes, in descending order of preference:

Migraine days per month
Migraines per month
Headache days per month
Headaches per month

We also extracted 50% reduction in migraine frequency (migraines or migraine days) if reported.

For trial dropout, we extracted the proportion of patients from each arm who dropped out of trials due to adverse effects.

Efficacy Measures and Minimally Important Difference

One accepted threshold for efficacy for migraine prevention is a 50% reduction in number of migraines per month.⁴ However, only roughly half (41 of 78) of studies included in Map 1 reported this outcome, instead reporting results using 1 of the 4 other continuous outcomes of interest (eg, migraine days per month). Ideally, we would have generated a pooled analysis of 50% reduction in migraine/headache frequency by converting these data from continuous outcomes into the dichotomous 50% reduction outcome. However, nearly no studies reported individual before-and-after patient-level data necessary to support meta-analysis of these data across migraine subtypes and multiple end points planned for this map. Thus, we chose to use migraine days per month as the primary outcome measure to display migraine reduction efficacy.

No consensus regarding a minimally important difference (MID) for migraine days per month exists. However, 2 older studies specified a reduction of 1.5 migraines per month as a “clinically important” difference between groups for migraine reduction.⁵^,⁶ Using the median baselines (for migraines per month and migraine days per month), this corresponds to 2.5 migraine days per month reduction, which we used as the MID for quality-of-evidence assessment.

Meta-analysis

To prepare efficacy data for meta-analysis, we calculated or imputed means and standard deviations (SDs) when not reported. We used Hedges’ g as the measure of treatment effect for efficacy and relative risk (RR) for withdrawal due to adverse events. For crossover trials that did not report results accounting for the paired nature of the data, we estimated the standardized mean difference and its standard error using a correlation coefficient of 0.5. If only 50% reduction in migraine frequency was reported, we estimated the Hedges’ g by dividing the log odds ratio by 1.65.7 These statistical approaches supported inclusion of as much data as possible in our meta-analyses. Studies that reported results of interest, but were not suitable for inclusion in the meta-analyses (despite these approaches), are included in the appropriate hover text in the map.

Before combining different doses of the same treatment within or across trials, we considered whether doses assessed in trials were used in current clinical practice. Based on input from our technical expert panel, we excluded data for eptinezumab 1000 mg from the analysis.

We used random-effects meta-analytic models based on the DerSimonian and Laird method to incorporate between-study heterogeneity.⁸ We performed all analyses in Stata 13.⁹ We synthesized evidence for efficacy and trial dropout in 230 analyses, of which 129 were meta-analyses.

Adverse Events

To prioritize adverse events for extraction, our 3 technical expert panel (TEP) members independently listed 5 to 7 key adverse effects for each intervention. These key adverse effects were combined to create a list of adverse events for extraction (see Appendix D). If studies did not report individual side effects (eg, dizziness) by study arm, we extracted information regarding serious adverse events or general adverse events.

For each intervention, we calculated pooled RR and absolute risk difference for each adverse effect. We characterized frequency of adverse effects for each intervention by selecting the adverse effect with the largest absolute risk difference (between intervention and placebo/sham groups). Based on this difference, we categorized frequency of adverse effects for each intervention as the following:

0 to 5%: Rare
≥ 5 to 15%: Infrequent
≥ 15%: More common

This approach flagged an intervention as having “more common” adverse effects if any adverse effect had an absolute risk difference of ≥15% for the intervention arm (compared with placebo/sham). For adverse effects (unlike outcomes for efficacy and dropout), we pooled all available data across all migraine types and study durations for each intervention.

For 2 interventions, we noted substantial differences in risk at higher doses. For these 2 interventions (topiramate ≤200 mg vs topiramate >200 mg) and (onabotulinumtoxinA <225 units vs onabotulinumtoxinA ≥225 units), we calculated pooled RR for all combined doses as well as for each dose separately. However, the overall rating (rare, infrequent, or more common) was determined using the absolute risk difference from combined doses. For example, onabotulinumtoxinA ≥225 units had an absolute risk difference of 19% and onabotulinumtoxinA <225 units had an absolute risk difference of 14%. However, as their combined absolute risk difference was 14.6%, we categorized frequency of adverse effects as infrequent.

Risk of Bias Assessment

We used the Cochrane risk of bias tool³ to assess risk of bias for 5 domains: selection bias (randomization and allocation concealment), performance bias (blinding of participants and personnel), detection bias (blinding of outcome assessors), attrition bias, and reporting bias. All except performance bias and selective outcome reporting bias were considered key domains for rating the overall risk of bias. We piloted assessment of 2 studies and resolved discrepancies. Remaining studies were rated by a single analyst with a 10% check by a second analyst for agreement.

Quality-of-Evidence Assessment

We used GRADE to rate the quality of evidence for migraine efficacy and trial dropout outcomes as high, moderate, low, or very low for each permutation of filters.¹⁰ We piloted assessment of 5 evidence bases across all analysts and resolved discrepancies. Remaining evidence for each outcome was assessed by a single analyst.

To assess study limitations, we used the Cochrane risk of bias tool.³ To assess indirectness, in addition to typical considerations, we downgraded studies selectively enrolling “enriched” populations (randomizing only patients who had already responded to treatment during a baseline phase). For inconsistency, we examined the forest plot as well as the value of I² to judge whether inconsistency was serious. We did not formally assess publication bias because it was not feasible.

To assess imprecision, given the absence of a clear MID for our primary outcome measure (migraine days per month), we used a between-group difference of 1.5 migraines per month cited by 2 studies (as noted above).⁵^,⁶ Using the typical SD for migraine frequency, this difference was equivalent to Hedges’ g of 0.69. We used this value as an MID to assess the evidence base (summary g’s for each meta-analyses), downgrading for imprecision if the confidence interval crossed +0.69 or –0.69. For trial dropout due to adverse effects, we downgraded for imprecision for RR < 0.8 or > 1.25 based on FDA guidance that 0.8 to 1.25 is an appropriate range for therapeutic equivalence of the ratio of plasma drug levels.¹¹

Data Visualization

Map data from Microsoft Excel was incorporated into Tableau for data visualization by Lovelytics, a data visualization firm. For Map 1, to enhance clinically interpretability in the visualization, we converted results from g to migraine days per month using typical migraine type-specific SDs derived from the data. Similarly, for trial dropout due to adverse effects, we converted RR to risk differences by assuming a 1% rate in the placebo or sham groups. Users can customize the display of data for efficacy and trial dropout using the following filters:

Migraine type (any, episodic, chronic, other/not reported)
Study duration (any, 8-11 weeks only, 12-25 weeks, ≥6 months)
Quality of evidence (high, moderate, low, very low)

We sought and iteratively incorporated feedback on visualization and usability from potential end-users including primary care providers (physicians and nurse practitioner), migraine experts, a payer, guideline developers, and funders (see Acknowledgments).

In addition to efficacy, dropout, and adverse effects, we extracted disease impact outcomes as a measure of quality of life. However, as relatively few RCTs reported this outcome, we chose not to include it in the visualizations.

To ensure accuracy of data translation, we performed a 5% validity check of data points for each outcome (efficacy, dropout, adverse effects) to ensure consistency between visualization and Excel data.

Results

We identified 203 RCTs (published in 254 articles) that met inclusion criteria: 78 trials for Map 1, 123 trials for Map 2, and 133 trials with head-to-head comparisons for Map 3. See Appendix C for a flow diagram. Appendix D provides characteristics of included studies.

Map 1. Benefits and Harms of Selected Interventions for Migraine Prevention: Evidence From Placebo-/Sham-Controlled RCTs

This map summarized 78 placebo or sham-controlled RCTs assessing benefits and harms for 15 drugs and 2 devices. Results and links to individual studies can be viewed using the map, here. Below, we summarize key findings.

Of interventions included in Map 1, we identified the largest number of trials for CGRP antagonists (22 RCTs), followed by antiepileptics (20 trials), and botulinum toxin type A (17 trials). Only 2 trials assessed devices (noninvasive vagal nerve stimulation [1 RCT] and transcutaneous supraorbital nerve stimulation [1 RCT]). Similarly, only a single RCT respectively assessed lisinopril and atogepant. No trials assessed nortriptyline. Most trials (83%) were published after 2000. Older trials (published before 2000) assessed valproate (n = 3), propranolol (n = 9), and metoprolol (n = 2).

Overall, the median baseline number of migraine days per month for study participants across included trials was 9 (any migraine type), 8 (episodic migraine), and 18 (chronic migraine).

Efficacy for All Migraine Types

The efficacy of interventions considering data for all migraine types and follow-up durations ranged from 0.56 to 3.4 fewer migraine days per month (forest plots for each intervention are included in Appendix E). Overall, valproate offered the largest reduction: pooled analysis of 7 trials^12-18 found valproate provided 3.4 fewer migraine days per month, although the quality of evidence was low. Patients receiving valproate were more likely to drop out of trials due to adverse effects (RR 1.7; 95% CI, 0.7-4.2). However, the absolute risk of dropping out remained relatively low (1.9% vs 1% for valproate vs placebo), and adverse effects were rare. Compared with placebo, valproate was slightly more likely to cause weight gain (5% risk difference [RD]), dizziness (4% RD), and fatigue (4% RD).

Only 6 (of 17) interventions represented in Map 1 had high-quality evidence for efficacy: the 5 CGRP antagonists (atogepant, eptinezumab, erenumab, fremanezumab, galcanezumab), and noninvasive vagal nerve stimulation. Efficacy for CGRP antagonists ranged from 1.4 to 1.9 fewer migraine days per month compared with placebo, while noninvasive vagal nerve stimulation had the smallest effect size (only 0.56 fewer migraine days per month compared with sham stimulation). An additional 5 interventions had moderate-quality evidence for efficacy: amitriptyline, candesartan, metoprolol, propranolol, and onabotulinumtoxinA.

Episodic Migraine

Fifty trials specifically assessed efficacy for episodic migraine (select “episodic migraine” filter on the left-hand side of the visual). Topiramate and propranolol each had 8 trials, followed by onabotulinumtoxinA and galcanezumab (6 trials each), erenumab (5 trials), valproate (4 trials), metoprolol, fremanezumab, and amitriptyline (2 trials each), and lisinopril, atogepant, eptinezumab, and venlafaxine, and the 2 devices (1 trial each).

Venlafaxine, transcutaneous supraorbital nerve stimulation (Cefaly), and valproate offered the highest efficacy (2 to 2.4 fewer migraine days per month compared with placebo). While effect sizes were slightly larger for venlafaxine and Cefaly, each was supported by only a single RCT¹⁹^,²⁰ enrolling fewer than 70 patients (compared with 4 trials for valproate). Notably, venlafaxine was not well tolerated: patients randomized to venlafaxine were more likely to drop out due to adverse events (5.6% RD) and reported higher rates of nausea (16% RD), insomnia (9% RD), and fatigue (3% RD) compared with placebo. Cefaly and valproate were better tolerated with rare adverse effects and low trial dropout.

Efficacy for topiramate, propranolol, and amitriptyline (drugs widely used for migraine prevention) ranged from 0.7 to 0.9 fewer migraine days per month (compared with placebo). However, adverse effects were more common in patients using these drugs. For example, compared with placebo, the proportion of patients who reported dry mouth and somnolence was >20% higher for those taking amitriptyline.

High-quality evidence supported 2 treatments (galcanezumab, erenumab) for episodic migraine at all timepoints, including 6 months, although the magnitude of improvement could be considered relatively modest (1.85 fewer migraine days per month or less; see Table 3).

Table 3

Episodic Migraine—High Quality Evidence for Efficacy by Trial Duration.

Chronic Migraine

Fourteen trials specifically assessed efficacy for chronic migraine (select “chronic migraine” filter on the left-hand side of the visual). OnabotulinumtoxinA had the most trials (n = 4), followed by valproate, topiramate, fremanezumab, and galcanezumab (2 trials each). The remaining interventions (amitriptyline, eptinezumab, erenumab) had been assessed with only a single trial.

Valproate offered by far the largest reduction, with 13.2 fewer migraine days per month (pooled data from 2 small trials, very-low-quality evidence),¹²^,¹⁸ followed by onabotulinumtoxinA, with 3 fewer migraine days per month, and 3 CGRP antagonists (eptinezumab, erenumab, galcanezumab), which offered reductions of about 2.6 migraine days per month. Of note, evidence for valproate was based on 2 small, non-US trials performed in Turkey¹⁸ and Iran¹² that randomized only a combined 52 patients to valproate.

Only a single intervention reported outcomes for chronic migraine patients at 6 months: onabotulinumtoxinA improved migraines by 2.3 migraine days per month, although quality of evidence was low.²¹ Only 4 interventions (galcanezumab, fremanezumab, erenumab, eptinezumab) had high-quality evidence supporting efficacy that ranged from 1.7 to 3 fewer migraine days per month (see Table 4).

Table 4

Chronic Migraine—High Quality Evidence for Efficacy by Trial Duration.

Tolerability (Trial Dropout and Adverse Effects)

Interventions with the highest relative risk of trial dropout due to adverse events were venlafaxine and onabotulinumtoxinA. (Of note, data for venlafaxine were drawn from only a single, relatively small study of 60 patients.) Conversely, the 2 devices and atogepant had the lowest relative risks of dropout (RR 0.2 to 1). For noninvasive vagal nerve stimulation (gammaCore), patients receiving sham were more likely to drop out than those receiving gammaCore.

The frequency of adverse effects was categorized as more common for 5 interventions (candesartan, topiramate, propranolol, venlafaxine, amitriptyline), infrequent for 4 interventions (lisinopril, metoprolol, onabotulinumtoxinA, galcanezumab), and rare for 7 interventions (valproate, atogepant, eptinezumab, erenumab, fremanezumab, noninvasive vagal nerve stimulation, transcutaneous supraorbital nerve stimulation).

Map 2. What Types of Drugs and Devices Have Been Studied With RCTs for Migraine Prevention?

This map summarized 123 placebo or sham controlled RCTs assessing 46 interventions (17 of these interventions are also summarized in Map 1; 29 additional interventions are included in Map 2). Interventions with the largest volume of evidence were the following:

Antiepileptics: 26 trials, 2859 patients
Beta-blockers: 25 trials, 1543 patients
CGRP antagonists: 23 trials, 9317 patients
Botulinum toxin type A: 19 trials, 2878 patients

Remaining intervention categories had been studied with only <10 RCTs. Notably, although antiepileptics and beta-blockers had more RCTs, CGRP antagonist trials had more than 3 times as many patients randomized compared with antiepileptics.

Map 3. Head-to-Head Comparisons of Drugs and Devices for Migraine Prevention

This map displays existing head-to-head comparisons from 133 RCTs and highlights potential evidence gaps. Overall, included studies captured 207 head-to-head comparisons, of which 42% (n = 86) compared different doses of the same drug. (Users can hide dose comparison trials by selecting the “Hide Dose Comparison Trials” filter on the bottom left-hand side of the visual.)

Not surprisingly, older interventions widely considered effective for migraine prevention (topiramate, valproate, propranolol, botulinum toxin type A, amitriptyline) were the most frequently assessed in head-to-head comparisons, often compared against each other. Notably, the map demonstrates that several of these interventions have also been compared against nutraceuticals (melatonin, riboflavin) and CAM such as acupressure, acupuncture, exercise, and relaxation. (Users can view these by hovering over dots in the “Other” column.)

Map 3 reveals 2 important evidence gaps. Both CGRP antagonists and transcutaneous supraorbital stimulation performed well for migraine reduction in placebo- or sham-controlled trials (as demonstrated in Map 1) with relatively few side effects. No head-to-head trials comparing these interventions against older, commonly used pharmacologic interventions for migraine prevention exist. In fact, CGRP antagonists have not been compared against any other interventions, and only a single trial²² compared transcutaneous supraorbital stimulation to another type of electrical stimulation (a nonstandard treatment). Direct comparisons of these newer interventions against older therapies to confirm relative efficacy is needed to support decisions by payers, policymakers, and shared decision-making between doctors and patients. Also, comparative effectiveness trials have primarily focused on episodic migraine; only 19 head-to-head comparisons (including 8 dose comparison trials) for chronic migraine exist. However, we note that most of these trials were performed in the past 10 years, which could suggest increased interest in addressing this evidence gap.

Discussion

To our knowledge, this work represents the first rapid review/meta-analysis to assess efficacy for many traditional pharmacologic interventions along with newer drugs and devices. Our analyses confirm that multiple interventions are effective for migraine reduction compared with placebo/sham. As evident in Map 1, older interventions in common use and recommended by guidelines²³^,²⁴ (eg, propranolol, topiramate, valproate, amitriptyline, candesartan) were effective. However, aside from valproate, the size of migraine reduction offered by several newer therapies (CGRP antagonists, transcutaneous supraorbital stimulation) was roughly comparable or slightly larger, but with fewer side effects and dropouts from adverse effects. Of all therapies used for migraine prevention, valproate demonstrated the largest migraine reduction: pooled analysis of 7 trials¹²^-¹⁸ found a reduction of 3.4 migraine days per month, although this evidence was rated low quality. Specifically, valproate provided a large reduction for chronic migraine (13.2 migraine days per month) and smaller effect for episodic migraine (2 migraine days per month).

Important evidence gaps are clear from Map 1. First, few trials reported outcomes beyond 12 weeks, and only 7 interventions had 6-month outcomes. Second, all drugs and devices captured in Map 1 (except for nortriptyline) demonstrated some degree of efficacy for reducing migraines (as anticipated since drugs or devices in common use or recommended in guidelines were intentionally prioritized for inclusion). However, only 6 interventions (of which 5 were CGRP antagonists) were supported by high-quality evidence. For included interventions recommended as first line by an evidence-based practice guideline,²³^,²⁴ overall quality of evidence was only moderate (propranolol, metoprolol), low (valproate), or very low (topiramate). In general, many of these studies were older and had higher risk of bias for many reasons, including poor randomization, unclear blinding procedures, or high attrition. The evidence base for other recommended drugs was quite small: amitriptyline and candesartan were each supported by only 2 trials, and venlafaxine and lisinopril were each supported by only 1.

For most interventions (including CGRP antagonists), the magnitude of improvement was underwhelming. For instance, for included trials of episodic migraine, the baseline median number of migraine days per month was 8. Efficacy for 8 of 9 interventions supported by more than a single RCT ranged from 0.73 to 1.95 fewer migraine days per month (the ninth intervention, onabotulinumtoxinA, is not recommended for episodic migraine). Furthermore, adverse effects were more common for 3 of these interventions (topiramate, amitriptyline, propranolol).

Patients are typically required to start with older drugs (such as propranolol, amitriptyline, or nortriptyline) with failure of several classes of traditional drugs (eg, antihypertensives, antidepressants, antiepileptics) before they are eligible to receive newer, more costly drugs such as CGRP antagonists. Our work highlights the sparse evidence for drugs commonly used first line (particularly amitriptyline and nortriptyline) and suggests patients could experience fewer side effects if CGRP antagonists were considered for initial therapy, although policymakers would also need to consider the uncertainty regarding long-term side effects and substantively higher cost.

Selecting a migraine prevention therapy requires shared decision making that considers multiple factors, including benefits and harms, patient comorbidities, cost/coverage, and (for women) childbearing potential. Patients often inquire at length about potential side effects; investment in visual evidence maps such as these, which display data on adverse effects alongside efficacy, may support realistic expectations for physicians and patients as they weigh potential tradeoffs.

Limitations

We note several important limitations. First, we used migraine days per month, an accepted measure, as the primary efficacy outcome for meta-analyses. We found that most interventions reduced migraine days per month by fewer than 3. However, because this measure averages effects across all patients, some patients may have experienced greater reductions while others had no change. An alternative measure of efficacy, such as 50% reduction in migraine frequency, may reveal which treatments are likely to provide greater reductions for some patients, even if overall average effects are modest.

As previously noted, inconsistencies in reporting did not allow us to calculate 50% reduction in migraine frequency across all studies. However, we extracted these data whenever reported (see Appendix F), also available by selecting a blue bar in Map 1, and the hyperlink “Data on 50% reduction in migraines or migraine days per month” which appears in the hover). We note that these studies generally defined 50% reduction as a truly successful response, not necessarily an MID (the smallest between-group difference needed to be considered important). Furthermore, it is unclear if patients would consider improving from 20 to 10 migraines a month as equally beneficial as improving from 8 to 4 migraines a month. Although quality-of-life measures (eg, disease impact scores) could help address this question, we found that few studies reported disease impact scores. Thus, while potentially informative, we did not incorporate disease impact scores into the evidence map.

For adverse effect frequency (in Map 1), we extracted only selected adverse effects our clinical experts identified as important for clinical decision making (see Appendix G) and compared reported frequency for intervention and placebo arms. However, in some cases, these estimates could fail to capture side effects important to patients (such as teratogenicity). Many migraine prevention therapies are drugs primarily used for other medical conditions, such as hypertension, depression, or epilepsy. For example, valproate and topiramate have known potential teratogenic side effects from the epilepsy literature; however, no migraine trials reported teratogenicity, since studies of valproate or topiramate excluded women of child-bearing age due to this already known side effect. These concerns would also be relevant to other interventions with known teratogenicity, such as candesartan and lisinopril. We also note that, although CGRP antagonists appear to have generally favorable side effect profiles, as new drugs, their long-term safety remains unknown.²⁵

Given variability in study inclusion criteria across studies, it was not feasible to consider all factors that could have impacted efficacy (such as enrolling only patients who had failed a certain number of prior medications). However, this could have led to underestimation of true efficacy in some cases. Similarly, we did not perform subanalyses based on patient clinical characteristics (eg, number of drugs failed, concurrent headache therapies) and demographics (age or gender) to identify particular patient groups more likely to respond.

In some cases, there may appear to be incongruities between reported findings for efficacy from individual studies and those presented in the visualization (eg, a study reporting no statistically significant difference between intervention and control, but the visualization indicating there is). These differences may be due to differences between the analytic approach taken by trial investigators compared with our approach. To facilitate pooling of data across studies, we focused on group-level means and SDs reported by trials; investigators may have used other approaches to derive P values. For example, Schoenen 201319 used the Mann-Whitney U test to assess the distributions of migraine days per month for supraorbital transcutaneous nerve stimulation compared with sham and found no statistically significant difference. On the other hand, when directly comparing the means of each group, there is a significant difference.

We included all RCTs regardless of publication date, recognizing that many migraine prevention trials were published as early as the 1980s. However, as expected for an evidence base spanning nearly 4 decades, findings from older trials could be less generalizable today. Older studies were often assessed as high risk of bias due to failure to report methods for randomization or allocation concealment. In fact, randomization method was unclear for 100% of studies published prior to 2000 (n = 13). However, we acknowledge that reporting standards in the past were different, and, in some cases, authors may simply have failed to report the method due to different expectations for reporting at the time.

Finally, some users may primarily be interested in evaluating how interventions perform relative to each other (instead of efficacy compared with placebo/sham). However, Map 1 provides limited utility to evaluate comparative effectiveness. While users could attempt to extrapolate the relative effects by, for example, subtracting the effect of one intervention from another, this could lead to erroneous conclusions. Strong assumptions regarding the similarity of trials are necessary to ensure these indirect comparisons are valid, and we did not formally assess these assumptions, as would be done in a network meta-analysis.²⁶

Future Directions

Our work suggests CGRP antagonists offer similar efficacy to many commonly used drugs for migraine prevention with higher tolerability, although long-term safety remains unknown. Future studies reporting on long-term side effects will be important to better inform discussions of risk and benefits and support clinical decision making. Although only assessed with a single smaller RCT, transcutaneous supraorbital nerve stimulation also showed promise for episodic migraine, with significant reduction in migraine days per month and high tolerability. Further trials to confirm efficacy are needed.

As noted, patients often begin therapy with older drug therapies. Head-to-head comparisons of both CGRP antagonists and transcutaneous supraorbital nerve stimulation against other traditional migraine prevention drugs could inform policymakers, particularly given the current higher cost of CRGP antagonists.

More research is needed to confirm efficacy for interventions specific for chronic migraine. Also, although not addressed by this project, many patients express preferences for nonpharmacologic drugs (ie, vitamins or supplements), CAM therapies, devices, or behavioral therapies given perceived lower risk of side effects. Although this work did not assess efficacy of these interventions, head-to-head trials with comparisons against standard pharmacologic drugs exist. Future studies assessing effectiveness and comparative effectiveness of these interventions compared with traditional pharmacologic therapies and devices could inform treatment decisions for patients interested in nonpharmacologic treatments.

Conclusion

Multiple drugs and devices successfully reduced migraines, although the magnitude of migraine reduction for many interventions was not large. Valproate offered the largest reduction in migraine days per month, particularly for chronic migraine sufferers, although this evidence was low or very low quality. Compared with older, traditional drug interventions (except valproate), newer therapies (including CGRP antagonists and transcutaneous supraorbital nerve stimulation) had generally comparable or slightly larger effects with fewer side effects. However, only CGRP antagonists and one device were supported by high-quality evidence for efficacy and few studies assessed outcomes beyond 12 weeks.

References

1.: Burch R, Rizzoli P, Loder E. The prevalence and impact of migraine and severe headache in the United States: updated age, sex, and socioeconomic-specific estimates from government health surveys. Headache. 2021;61(1):60-68. doi: 10.1111/head.14024. [PubMed: 33349955] [CrossRef]
2.: Methods guide for effectiveness and comparative effectiveness reviews. AHRQ publication no. 10(14)-EHC063-EF. Agency for Healthcare Research and Quality (AHRQ); 2014:384. Accessed May 21, 2019. https://www.effectivehealthcare.ahrq.gov. [PubMed: 21433403]
3.: Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0. The Cochrane Collaboration. Accessed May 21, 2019. http://www.handbook.cochrane.org.
4.: Peres MF, Silberstein S, Moreira F, et al. Patients' preference for migraine preventive therapy. Headache. 2007;47(4):540-545. doi: 10.1111/j.1526-4610.2007.00757.x11/head.14024. [PubMed: 17445103] [CrossRef]
5.: Relja M, Poole AC, Schoenen J, Pascual J, Lei X, Thompson C. A multicentre, double- blind, randomized, placebo-controlled, parallel group study of multiple treatments of botulinum toxin type A (BoNTA) for the prophylaxis of episodic migraine headaches. Cephalalgia. 2007;27(6):492-503. doi: 10.1111/j.1468-2982.2007.01315.x. [PubMed: 17428299] [CrossRef]
6.: Elkind AH, O'Carroll P, Blumenfeld A, DeGryse R, Dimitrova R. A series of three sequential, randomized, controlled studies of repeated treatments with botulinum toxin type A for migraine prophylaxis. J Pain. 2006;7(10):688-696. doi: 10.1016/j.jpain.2006.03.002. [PubMed: 17018329] [CrossRef]
7.: Sanchez-Meca J, Marin-Martinez F, Chacon-Moscoso S. Effect-size indices for dichotomized outcomes in meta-analysis. Psychol Methods. 2003;8(4):448-467. [PubMed: 14664682]
8.: DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177-188. [PubMed: 3802833]
9.: Stata Statistical Software: Release 13. StataCorp LP;
10.: What is GRADE? Clinical Evidence [database online]. BMJ Publishing Group Limited; Accessed January 13, 2020. http://clinicalevidence.bmj.com/
11.: Guidance for Industry: Statistical Approaches to Establishing Bioequivalence. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research; January 2001:48.
12.: Ebrahimi-Monfared M, Sharafkhah M, Abdolrazaghnejad A, Mohammadbeigi A, Faraji F. Use of melatonin versus valproic acid in prophylaxis of migraine patients: a double-blind randomized clinical trial. Restor Neurol Neurosci. 2017;35(4):385-393. doi: 10.3233/RNN-160704. [PubMed: 28800342] [CrossRef]
13.: Freitag FG, Collins SD, Carlson HA, et al. A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis. Neurology. 2002;58(11):1652-1659. doi: 10.1212/WNL.58.11.1652. [PubMed: 12058094] [CrossRef]
14.: Jensen R, Brinck T, Olesen J. Sodium valproate has a prophylactic effect in migraine without aura: a triple-blind, placebo-controlled crossover study. Neurology. 1994;44(4):647-651. [PubMed: 8164818]
15.: Klapper J. Divalproex sodium in migraine prophylaxis: a dose-controlled study. Cephalalgia. 1997;17(2):103-108. doi: 10.1046/j.1468-2982.1997.1702103.x. [PubMed: 9137847] [CrossRef]
16.: Mathew NT, Saper JR, Silberstein SD, et al. Migraine prophylaxis with divalproex. Arch Neurol. 1995;52(3):281-286. [PubMed: 7872882]
17.: Sadeghian H, Motiei-Langroudi R. Comparison of levetiracetam and sodium valproate in migraine prophylaxis: a randomized placebo-controlled study. Ann Indian Acad Neurol. 2015;18(1):45-48. doi: 10.4103/0972-2327.144290. [PMC free article: PMC4350213] [PubMed: 25745310] [CrossRef]
18.: Yurekli VA, Akhan G, Kutluhan S, Uzar E, Koyuncuoglu HR, Gultekin F. The effect of sodium valproate on chronic daily headache and its subgroups. J Headache Pain. 2008;9(1):37- 41. doi: 10.1007/s10194-008-0002-5. [PMC free article: PMC3476175] [PubMed: 18231713] [CrossRef]
19.: Schoenen J, Vandersmissen B, Jeangette S, et al. Migraine prevention with a supraorbital transcutaneous stimulator: a randomized controlled trial. Neurology. 2013;80(8):697-704. doi: 10.1212/WNL.0b013e3182825055. [PubMed: 23390177] [CrossRef]
20.: Ozyalcin SN, Talu GK, Kiziltan E, Yucel B, Ertas M, Disci R. The efficacy and safety of venlafaxine in the prophylaxis of migraine. Headache. 2005;45(2):144-152. doi: 10.1111/j.1526-4610.2005.05029.x. [PubMed: 15705120] [CrossRef]
21.: Silberstein SD, Stark SR, Lucas SM, Christie SN, DeGryse RE, Turkel CC. Botulinum toxin type A for the prophylactic treatment of chronic daily headache: a randomized, double- blind, placebo-controlled trial. Mayo Clin Proc. 2005;80(9):1126-1137. doi: 10.4065/80.9.1126. [PubMed: 16178492] [CrossRef]
22.: Deng Y, Zheng M, He L, Yang J, Yu G, Wang J. A head-to-head comparison of percutaneous mastoid electrical stimulator and supraorbital transcutaneous stimulator in the prevention of migraine: a prospective, randomized controlled study. Neuromodulation. 2020;23:770–777. doi: 10.1111/ner.13127. [PubMed: 32096902] [CrossRef]
23.: Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults. Report of the quality standards subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337-1345. doi: 10.1212/WNL.0b013e3182535d20. [PMC free article: PMC3335452] [PubMed: 22529202] [CrossRef]
24.: Network SIG. Pharmacological Management of Migraine. A National Clinical Guideline. Scottish Intercollegiate Guidelines Network (SIGN). Accessed December 15, 2020. http://www.sign.ac.uk/
25.: Loder EW, Burch RC. Who should try new antibody treatments for migraine? JAMA Neurol. 2018;75(9):1039-1040. doi: 10.1001/jamaneurol.2018.1268. [PubMed: 29799961] [CrossRef]
26.: Rouse B, Chaimani A, Li T. Network meta-analysis: an introduction for clinicians. Intern Emerg Med. 2017;12(1):103-111. doi: 10.1007/s11739-016-1583-7. [PMC free article: PMC5247317] [PubMed: 27913917] [CrossRef]
27.: Jackson JL, Cogbill E, Santana-Davila R, et al. A comparative effectiveness meta- analysis of drugs for the prophylaxis of migraine headache. PLoS ONE. 2015;10(7):e0130733. doi: 10.1371/journal.pone.0130733. [PMC free article: PMC4501738] [PubMed: 26172390] [CrossRef]
28.: Jackson JL, Kuriyama A, Kuwatsuka Y, et al. Beta-blockers for the prevention of headache in adults, a systematic review and meta-analysis. PLoS ONE. 2019;14(3):e0212785. doi: 10.1371/journal.pone.0212785. [PMC free article: PMC6426199] [PubMed: 30893319] [CrossRef]
29.: Couch JR. Amitriptyline in the prophylactic treatment of migraine and chronic daily headache. Headache. 2011;51(1):33-51. doi: 10.1111/j.1526-4610.2010.01800.x. [PubMed: 21070231] [CrossRef]
30.: Goncalves AL, Ferreira AM, Ribeiro RT, Zukerman E, Cipolla-Neto J, Peres MFP. Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention. J Neurol Neurosurg Psychiatry. 2016;87(10):1127-1132. Epub 2016 May 1110. doi: 10.1136/jnnp-2016-313458. [PMC free article: PMC5036209] [PubMed: 27165014] [CrossRef]
31.: Goadsby PJ, Dodick DW, Ailani J, et al. Safety, tolerability, and efficacy of orally administered atogepant for the prevention of episodic migraine in adults: a double-blind, randomised phase 2b/3 trial. Lancet Neurol. 2020;19(9):727-737. doi: 10.1016/S1474-4422(20)30234-9. [PubMed: 32822633] [CrossRef]
32.: Stovner LJ, Linde M, Gravdahl GB, et al. A comparative study of candesartan versus propranolol for migraine prophylaxis: a randomised, triple-blind, placebo-controlled, double cross-over study. Cephalalgia. 2014;34(7):523-532. doi: 10.1177/0333102413515348. [PubMed: 24335848] [CrossRef]
33.: Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G. Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. JAMA. 2003;289(1):65-69. doi: 10.1001/jama.289.1.65. [PubMed: 12503978] [CrossRef]
34.: Ashina M, Saper J, Cady R, et al. Eptinezumab in episodic migraine: a randomized, double-blind, placebo-controlled study (PROMISE-1). Cephalalgia. 2020;40(3):241-254. doi: 10.1177/0333102420905132. [PMC free article: PMC7066477] [PubMed: 32075406] [CrossRef]
35.: Dodick DW, Lipton RB, Silberstein S, et al. Eptinezumab for prevention of chronic migraine: a randomized phase 2b clinical trial. Cephalalgia. 2019;39(9):1075-1085. doi: 10.1177/0333102419858355. [PubMed: 31234642] [CrossRef]
36.: Lipton RB, Goadsby PJ, Smith J, et al. Efficacy and safety of eptinezumab in patients with chronic migraine: PROMISE-2. Neurology. 2020;94:e1365-e1377. doi: 10.1212/WNL.0000000000009169. [PMC free article: PMC7274916] [PubMed: 32209650] [CrossRef]
37.: Dodick DW, Ashina M, Brandes JL, et al. ARISE: a Phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia. 2018;38(6):1026-1037. doi: 10.1177/0333102418759786. [PubMed: 29471679] [CrossRef]
38.: Goadsby PJ, Reuter U, Hallström Y, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med. 2017;377(22):2123-2132. doi: 10.1056/NEJMoa17058486. [PubMed: 29171821] [CrossRef]
39.: Reuter U, Goadsby PJ, Lanteri-Minet M, et al. Efficacy and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous preventive treatments were unsuccessful: a randomised, double-blind, placebo-controlled, phase 3b study. Lancet. 2018;392(10161):2280-2287. Epub 2018 Oct 2222. doi: 10.1016/S0140-6736(18)32534-0. [PubMed: 30360965] [CrossRef]
40.: Sakai F, Takeshima T, Tatsuoka Y, et al. A randomized phase 2 study of erenumab for the prevention of episodic migraine in Japanese adults. Headache. 2019;59(10):1731-1742. Epub 2019 Oct 1714. doi: 10.1111/head.13652. [PMC free article: PMC6900095] [PubMed: 31612482] [CrossRef]
41.: Sun H, Dodick DW, Silberstein S, et al. Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(4):382-390. doi: 10.1016/S1474-4422(16)00019-3. [PubMed: 26879279] [CrossRef]
42.: Tepper S, Ashina M, Reuter U, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2017;16(6):425-434. doi: 10.1016/S1474-4422(17)30083-2. [PubMed: 28460892] [CrossRef]
43.: Bigal ME, Dodick DW, Rapoport AM, et al. Safety, tolerability, and efficacy of TEV- 48125 for preventive treatment of high-frequency episodic migraine: A multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol. 2015;14(11):1081-1090. doi: 10.1016/S1474-4422(15)00249-5. [PubMed: 26432182] [CrossRef]
44.: Bigal ME, Edvinsson L, Rapoport AM, et al. Safety, tolerability, and efficacy of TEV- 48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol. 2015;14(11):1091-1100. doi: 10.1016/S1474-4422(15)00245-8. [PubMed: 26432181] [CrossRef]
45.: Dodick DW, Silberstein SD, Bigal ME, et al. Effect of fremanezumab compared with placebo for prevention of episodic migraine a randomized clinical trial. JAMA. 2018;319(19):1999-2008. doi: 10.1001/jama.2018.4853. [PMC free article: PMC6583237] [PubMed: 29800211] [CrossRef]
46.: Ferrari MD, Diener HC, Ning X, et al. Fremanezumab versus placebo for migraine prevention in patients with documented failure to up to four migraine preventive medication classes (FOCUS): a randomised, double-blind, placebo-controlled, phase 3b trial. Lancet. 2019;394(10203):1030-1040. doi: 10.1016/S0140-6736(19)31946-4. [PubMed: 31427046] [CrossRef]
47.: Silberstein SD, Dodick DW, Bigal ME, et al. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med. 2017;377(22):2113-2122. doi: 10.1056/NEJMoa1709038. [PubMed: 29171818] [CrossRef]
48.: Detke HC, Goadsby PJ, Wang S, Friedman DI, Selzler KJ, Aurora SK. Galcanezumab in chronic migraine: the randomized, double-blind, placebo-controlled REGAIN study. Neurology. 2018;91(24):e2211-e2221. doi: 10.1212/WNL.0000000000006640. [PMC free article: PMC6329331] [PubMed: 30446596] [CrossRef]
49.: Dodick DW, Goadsby PJ, Spierings ELH, Scherer JC, Sweeney SP, Grayzel DS. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2014;13(9):885-892. doi: 10.1016/S1474-4422(14)70128-0. [PubMed: 25127173] [CrossRef]
50.: Mulleners WM, Kim BK, Láinez MJA, et al. Safety and efficacy of galcanezumab in patients for whom previous migraine preventive medication from two to four categories had failed (CONQUER): a multicentre, randomised, double-blind, placebo-controlled, phase 3b trial. Lancet Neurol. 2020;19(10):814-825. doi: 10.1016/S1474-4422(20)30279-9. [PubMed: 32949542] [CrossRef]
51.: Sakai F, Ozeki A, Skljarevski V. Efficacy and safety of galcanezumab for prevention of migraine headache in Japanese patients with episodic migraine: a phase 2 randomized controlled clinical trial. Cephalalgia Reports. 2020;3:1-10. doi: 10.1177/2515816320932573. [CrossRef]
52.: Skljarevski V, Oakes TM, Zhang Q, et al. Effect of different doses of galcanezumab vs placebo for episodic migraine prevention a randomized clinical trial. JAMA Neurol. 2018;75(2):187-193. doi: 10.1001/jamaneurol.2017.3859. [PMC free article: PMC5838630] [PubMed: 29255900] [CrossRef]
53.: Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim BK, Yang JY. Efficacy and safety of galcanezumab for the prevention of episodic migraine: results of the EVOLVE-2 Phase 3 randomized controlled clinical trial. Cephalalgia. 2018;38(8):1442-1454. Epub 2018 May 1431. doi: 10.1177/0333102418779543. [PubMed: 29848108] [CrossRef]
54.: Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. Evaluation of galcanezumab for the prevention of episodic migraine: the EVOLVE-1 randomized clinical trial. JAMA Neurol. 2018;75(9):1080-1088. doi: 10.1001/jamaneurol.2018.1212. [PMC free article: PMC6143119] [PubMed: 29813147] [CrossRef]
55.: Schrader H, Stovner LJ, Helde G, Sand T, Bovim G. Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): randomised, placebo controlled, crossover study. BMJ. 2001;322(7277):19-22. [PMC free article: PMC26600] [PubMed: 11141144]
56.: Andersson PG, Dahl S, Hansen JH. Prophylactic treatment of classical and non-classical migraine with metoprolol - a comparison with placebo. Cephalalgia. 1983;3(4):207-212. [PubMed: 6640652]
57.: Bayer O, Adrion C, Al Tawil A, et al. Results and lessons learnt from a randomized controlled trial: prophylactic treatment of vestibular migraine with metoprolol (PROVEMIG). Trials. 2019;20:813. doi: 10.1186/s13063-019-3903-5. [PMC free article: PMC6937687] [PubMed: 31888723] [CrossRef]
58.: Steiner TJ, Joseph R, Hedman C, Rose FC. Metoprolol in the prophylaxis of migraine: parallel-groups comparison with placebo and dose-ranging follow-up. Headache. 1988;28(1):15- 23. [PubMed: 3277926]
59.: Diener HC, Goadsby PJ, Ashina M, et al. Non-invasive vagus nerve stimulation (nVNS) for the preventive treatment of episodic migraine: the multicentre, double-blind, randomised, sham-controlled PREMIUM trial. Cephalalgia. 2019;39(12):1475-1487. doi: 10.1177/0333102419876920. [PMC free article: PMC6791025] [PubMed: 31522546] [CrossRef]
60.: Anand KS, Prasad A, Singh MM, Sharma S, Bala K. Botulinum toxin type A in prophylactic treatment of migraine. Am J Ther. 2006;13(3):183-187. doi: 10.1097/01.mjt.0000212705.79248.74. [PubMed: 16772757] [CrossRef]
61.: Aurora SK, Gawel M, Brandes JL, Pokta S, VanDenburgh AM. Botulinum toxin type A prophylactic treatment of episodic migraine: a randomized, double-blind, placebo-controlled exploratory study. Headache. 2007;47(4):486-499. doi: 10.1111/j.1526-4610.2006.00624.x . [PubMed: 17445098] [CrossRef]
62.: Aurora SK, Dodick DW, Turkel CC, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia. 2010;30(7):793-803. doi: 10.1177/0333102410364676. [PubMed: 20647170] [CrossRef]
63.: Barrientos N, Chana P. Botulinum toxin type A in prophylactic treatment of migraine headaches: a preliminary study. J Headache Pain. 2003;4(3):146-151. doi: 10.1007/s10194-003-0049-2. [CrossRef]
64.: Cady R, Schreiber C. Botulinum toxin type A as migraine preventive treatment in patients previously failing oral prophylactic treatment due to compliance issues. Headache. 2008;48(6):900-913. doi: 10.1111/j.1526-4610.2007.00953.x . [PubMed: 18047501] [CrossRef]
65.: Diener HC, Dodick DW, Aurora SK, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia. 2010;30(7):804-814. doi: 10.1177/0333102410364677. [PubMed: 20647171] [CrossRef]
66.: Evers S, Vollmer-Haase J, Schwaag S, al. e. Botulinum toxin A in the prophylactic treatment of migraine - a randomized, double-blind, placebo-controlled study. Cephalalgia. 2004;24(10):838-843. doi: 10.1111/j.1468-2982.2004.00754.x. [PubMed: 15377314] [CrossRef]
67.: Freitag FG, Diamond S, Diamond M, Urban G. Botulinum toxin type A in the treatment of chronic migraine without medication overuse. Headache. 2008;48(2):201-209. doi: 10.1111/j.1526-4610.2007.00963.x. [PubMed: 18042229] [CrossRef]
68.: Hou M, Xie JF, Kong XP, et al. Acupoint injection of onabotulinumtoxin a for migraines. Toxins (Basel). 2015;7(11):4442-4454. doi: 10.3390/toxins7114442. [PMC free article: PMC4663513] [PubMed: 26529014] [CrossRef]
69.: Pijpers JA, Kies DA, Louter MA, Van Zwet EW, Ferrari MD, Terwindt GM. Acute withdrawal and botulinum toxin A in chronic migraine with medication overuse: a double-blind randomized controlled trial. Brain. 2019;142(5):1203-1214. doi: 10.1093/brain/awz052. [PMC free article: PMC6511115] [PubMed: 30982843] [CrossRef]
70.: Sandrini G, Perrotta A, Tassorelli C, et al. Botulinum toxin type-A in the prophylactic treatment of medication-overuse headache: a multicenter, double-blind, randomized, placebo- controlled, parallel group study. J Headache Pain. 2011;12(4):427-433. Epub 2011 Apr 2016. doi: 10.1007/s10194-011-0339-z. [PMC free article: PMC3139089] [PubMed: 21499747] [CrossRef]
71.: Saper JR, Mathew NT, Loder EW, Degryse R, Vandenburgh AM. A double-blind, randomized, placebo-controlled comparison of botulinum toxin type a injection sites and doses in the prevention of episodic migraine. Pain Med. 2007;8(6):478-485.doi: 10.1111/j.1526-4637.2006.00168.x. [PubMed: 17716321] [CrossRef]
72.: Silberstein S, Mathew N, Saper J, Jenkins S, Group BMCR. Botulinum toxin type A as a migraine preventive treatment. Headache. 2000;40(6):445-450. [PubMed: 10849039]
73.: Vo AA, Satori R, Jabbari B, et al. Botulinum toxin type-A in the prevention of migraine: a double-blind controlled trial. Aviat Space Environ Med. 2007;78(5 Suppl):B113-118. [PubMed: 17547312]
74.: al-Qassab HK, Findley LJ. Comparison of propranolol LA 80 mg and propranolol LA 160 mg in migraine prophylaxis: a placebo controlled study. Cephalalgia. 1993;13(2):128-131. [PubMed: 8495455]
75.: Dahlof C. No clearcut longterm prophylactic effect of one month of treatment with propranolol in migraineurs. Cephalalgia. 1987;7(Suppl 6):459-460.
76.: Diener HC, Föh M, Iaccarino C, et al. Cyclandelate in the prophylaxis of migraine: A randomized, parallel, double-blind study in comparison with placebo and propranolol. Cephalalgia. 1996;16(6):441-447. doi: 10.1046/j.1468-2982.1996.1606441.x. [PubMed: 8902255] [CrossRef]
77.: Diener HC, Tfelt-Hansen P, Dahlöf C, et al. Topiramate in migraine prophylaxis: results from a placebo-controlled trial with propranolol as an active control. J Neurol. 2004;251(8):943- 950. [PubMed: 15316798]
78.: Forssman B, Henriksson KG, Johannsson V. Propranolol for migraine prophylaxis. Headache. 1976;16(5):238-245. [PubMed: 977330]
79.: Pradalier A, Serratrice G, Collard M, et al. Long-acting propranolol in migraine prophylaxis: results of a double-blind, placebo-controlled study. Cephalalgia. 1989;9(4):247- 253. [PubMed: 2692838]
80.: Sargent J, Solbach P, Damasio H. A comparison of naproxen sodium to propranolol hydrochloride and a placebo control for the prophylaxis of migraine headache. Headache. 1985;25(6):320-324. [PubMed: 3902723]
81.: Tfelt Hansen P, Standnes B, Kangasneimi P. Timolol vs propranolol vs placebo in common migraine prophylaxis: a double-blind multicenter trial. Acta Neurol Scand. 1984;69(1):1-8. [PubMed: 6367336]
82.: Wideroe TE, Vigander T. Propranolol in the treatment of migraine. BMJ. 1974;2(5921):699-701. [PMC free article: PMC1611139] [PubMed: 4604977]
83.: Brandes JL, Saper JR, Diamond M, et al. Topiramate for migraine prevention: a randomized controlled trial. JAMA. 2004;291(8):965-973. doi: 10.1001/jama.291.8.965. [PubMed: 14982912] [CrossRef]
84.: de Tommaso M, Marinazzo D, Nitti L, et al. Effects of levetiracetam vs topiramate and placebo on visually evoked phase synchronization changes of alpha rhythm in migraine. Clin Neurophysiol. 2007;118(10):2297-2304. doi: 10.1016/j.clinph.2007.06.060. [PubMed: 17709295] [CrossRef]
85.: Diener HC, Agosti R, Allais G, et al. Cessation versus continuation of 6-month migraine preventive therapy with topiramate (PROMPT): a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2007;6(12):1054-1062. doi: 10.1016/S1474-4422(07)70272-7. [PubMed: 17988947] [CrossRef]
86.: Diener HC, Bussone G, Van Oene JC, Lahaye M, Schwalen S, Goadsby PJ. Topiramate reduces headache days in chronic migraine: a randomized, double-blind, placebo-controlled study. Cephalalgia. 2007;27(7):814-823. doi: 10.1111/j.1468-2982.2007.01326.x . [PubMed: 17441971] [CrossRef]
87.: Lipton RB, Silberstein S, Dodick D, et al. Topiramate intervention to prevent transformation of episodic migraine: the topiramate INTREPID study. Cephalalgia. 2011;31(1):18-30. doi: 10.1177/0333102410372427. [PubMed: 20974598] [CrossRef]
88.: Mei D, Capuano A, Vollono C, et al. Topiramate in migraine prophylaxis: a randomised double-blind versus placebo study. Neurol Sci. 2004;25(5):245-250.doi: 10.1007/s10072-004-0350-0. [PubMed: 15624081] [CrossRef]
89.: Mei D, Ferraro D, Zelano G, et al. Topiramate and triptans revert chronic migraine with medication overuse to episodic migraine. Clin Neuropharmacol. 2006;29(5):269-275. doi: 10.1097/01.WNF.000022888.49044.99. [PubMed: 16960472] [CrossRef]
90.: Silberstein SD, Neto W, Schmitt J, Jacobs D. Topiramate in migraine prevention: results of a large controlled trial. Arch Neurol. 2004;61(4):490-495. doi: 10.1001/archneur.61.4.490. [PubMed: 15096395] [CrossRef]
91.: Silberstein SD, Hulihan J, Rezaul Karim M, et al. Efficacy and tolerability of topiramate 200 mg/d in the prevention of migraine with/without aura in adults: a randomized, placebo- controlled, double-blind, 12-week pilot study. Clin Ther. 2006;28(7):1002-1011. doi: 10.1016/j.clinthera.2006.07.003. [PubMed: 16990078] [CrossRef]
92.: Silberstein SD, Lipton RB, Dodick DW, et al. Efficacy and safety of topiramate for the treatment of chronic migraine: a randomized, double-blind, placebo-controlled trial. Headache. 2007;47(2):170-180.doi: 10.1111/j.1526-4610.2006.00684.x. [PubMed: 17300356] [CrossRef]
93.: Silvestrini M, Bartolini M, Coccia M, Baruffaldi R, Taffi R, Provinciali L. Topiramate in the treatment of chronic migraine. Cephalalgia. 2003;23(8):820-824. doi: 10.1046/j.1468-2982.2003.00592.x. [PubMed: 14510929] [CrossRef]
94.: Storey JR, Calder CS, Hart DE, Potter DL. Topiramate in migraine prevention: a double- blind, placebo-controlled study. Headache. 2001;41(10):968-975.doi: 10.1046/j.1526-4610.2001.01190.x. [PubMed: 11903524] [CrossRef]
95.: Diener HC, Gendolla A, Feuersenger A, et al. Telmisartan in migraine prophylaxis: a randomized, placebo-controlled trial. Cephalalgia. 2009;29(9):921-927. doi: 10.1111/j.1468-2982.2008.01825.x. [PubMed: 19250283] [CrossRef]
96.: Sonbolestan SA, Heshmat K, Javanmard SH, Saadatnia M. Efficacy of enalapril in migraine prophylaxis: a randomized, double-blind, placebo-controlled trial. Int J Prev Med. 2013;4(1):72-77. [PMC free article: PMC3570915] [PubMed: 23413003]
97.: Adam EI, Gore SM, Price WH. Double blind trial of clonidine in the treatment of migraine in a general practice. J R Coll Gen Pract. 1978;28(195):587-590. [PMC free article: PMC2158890] [PubMed: 368333]
98.: Boisen E, Deth S, Hübbe P, Jansen J, Klee A, Leunbach G. Clonidine in the prophylaxis of migraine. Acta Neurol Scand. 1978;58(5):288-295.doi: 10.1111/j.1600-0404.1978.tb02889.x. [PubMed: 367043] [CrossRef]
99.: Martucci N, Manna V, Porto C, Agnoli A. Migraine and the noradrenergic control of vasomotricity: a study with alpha-2 stimulant and alpha-2 blocker drugs. Headache. 1985;25(2):95-100. doi: 10.1111/j.1526-4610.1985.hed2502095.x. [PubMed: 3886600] [CrossRef]
100.: Mondrup K, Moller CE. Prophylactic treatment of migraine with clonidine. A controlled clinical trial. Acta Neurol Scand. 1977;56(5):405-412. doi: 10.1111/j.1600-0404.1977.tb01448.x. [PubMed: 339659] [CrossRef]
101.: Ryan Sr RE. Double blind study of clonidine and placebo for the prophylactic treatment of migraine. Headache. 1975;15(3):202-210. doi: 10.1111/j.1526-4610.1975.hed1503202.x. [PubMed: 1100565] [CrossRef]
102.: Shafar J, Tallett ER, Knowlson PA. Evaluation of clonidine in prophylaxis of migraine. Double-blind trial and follow-up. Lancet. 1972;1(7747):403-407. [PubMed: 4110641]
103.: Afshari D, Rafizadeh S, Rezaei M. A comparative study of the effects of low-dose topiramate versus sodium valproate in migraine prophylaxis. Int J Neurosci. 2012;122(2):60-68. doi: 10.3109/00207454.2011.626908. [PubMed: 21950578] [CrossRef]
104.: Ali AM, Awad TG, Al-Adl NM. Efficacy of combined topiramate/thioctic acid therapy in migraine prophylaxis. Saudi Pharm J. 2010;18(4):239-243. doi: 10.1016/j.jsps.2010.07.006. [PMC free article: PMC3731023] [PubMed: 23960733] [CrossRef]
105.: Ashtari F, Shaygannejad V, Akbari M. A double-blind, randomized trial of low-dose topiramate vs propranolol in migraine prophylaxis. Acta Neurol Scand. 2008;118(5):301-305. doi: 10.1111/j.1600-0404.2008.01087.x. [PubMed: 18713156] [CrossRef]
106.: Bavrasad R, Nejad SEM, Yarahmadi AR, Sajedi SI, Rahim F. Assessment of the middle dose of topiramate in comparison with sodium valproate for migraine prophylaxis: a randomized-double-blind study. Int J Pharmacol. 2010;6(5):670-675. doi: 10.3923/ijp.2010.670.675. [CrossRef]
107.: Blumenfeld AM, Schim JD, Chippendale TJ. Botulinum toxin type A and divalproex sodium for prophylactic treatment of episodic or chronic migraine. Headache. 2008;48(2):210- 220. doi: 10.1111/j.1526-4610.2007.00949.x. [PubMed: 18047502] [CrossRef]
108.: Bostani A, Rajabi A, Moradian N, Razazian N, Rezaei M. The effects of cinnarizine versus sodium valproate in migraine prophylaxis. Int J Neurosci. 2013;123(7):487-493. doi: 10.3109/00207454.2013.765419. [PubMed: 23311688] [CrossRef]
109.: Cady RK, Schreiber CP, Porter JAH, Blumenfeld AM, Farmer KU. A multi-center double-blind pilot comparison of onabotulinumtoxina and topiramate for the prophylactic treatment of chronic migraine. Headache. 2011;51(1):21-32. doi: 10.1111/j.1526-4610.2010.01796.x. [PubMed: 21070228] [CrossRef]
110.: Cady RK, Voirin J, Farmer K, Browning R, Beach ME, Tarrasch J. Two center, randomized pilot study of migraine prophylaxis comparing paradigms using pre-emptive frovatriptan or daily topiramate: research and clinical implications. Headache. 2012;52(5):749- 764. doi: 10.1111/j.1526-4610.2011.02054.x. [PubMed: 22188311] [CrossRef]
111.: Chitsaz A, Ghorbani A, Hoseinzadeh H, Nazari F, Norouzi R, Tajic S. Comparison of botulinum toxin type-A and divalproex sodium for prevention of chronic and episodic migraine. Neurol Asia. 2012;17(2):127-132.
112.: Chitsaz A, Najafi MR, Zangeneh FA, Norouzi R, Salari M. Pizotifen in migraine prevention: a comparison with sodium valproate. Neurol Asia. 2012;17(4):319-324.
113.: Choudhary MU, Nawaz J, Saddique M, Zameer A. Comparison between topiramate and sodium valproate efficacy in the treatment of migraine. Pak J Med Health Sci. 2017;11(3):1005- 1007.
114.: Cosentino G, Paladino P, Maccora S, Indovino S, Fierro B, Brighina F. Efficacy and safety of topiramate in migraine prophylaxis: an open controlled randomized study comparing sincronil and topamax formulations. Panminerva Med. 2013;55(3):303-307. [PubMed: 24088805]
115.: Dakhale G, Sharma V, Thakre M, Kalikar M. Low-dose sodium valproate versus low- dose propranolol in prophylaxis of common migraine headache: a randomized, prospective, parallel, open-label study. Indian J Pharmacol. 2019;51(4):255-262. doi: 10.4103/ijp.IJP_457_18. [PMC free article: PMC6759533] [PubMed: 31571712] [CrossRef]
116.: Di Trapani G, Mei D, Marra C, Mazza S, Capuano A. Gabapentin in the prophylaxis of migraine: a double-blind randomized placebo-controlled study. Clin Ter. 2000;151(3):145-148. [PubMed: 10958046]
117.: Dodick DW, Freitag F, Banks J, et al. Topiramate versus amitriptyline in migraine prevention: a 26-week, multicenter, randomized, double-blind, double-dummy, parallel-group noninferiority trial in adult migraineurs. Clin Ther. 2009;31(3):542-559. doi: 10.1016/j.clinthera.2009.03.020. [PubMed: 19393844] [CrossRef]
118.: Facco E, Liguori A, Petti F, Fauci AJ, Cavallin F, Zanette G. Acupuncture versus valproic acid in the prophylaxis of migraine without aura: a prospective controlled study. Minerva Anestesiol. 2013;79(6):634-642. [PubMed: 23511357]
119.: Hering R, Kuritzky A. Sodium valproate in the prophylactic treatment of migraine: a double-blind study versus placebo. Cephalalgia. 1992;12(2):81-84. doi: 10.1046/j.1468-2982.1992.1202081.x. [PubMed: 1576648] [CrossRef]
120.: Hesami O, Shams MR, Ayazkhoo L, et al. Comparison of pregabalin and sodium valproate in migraine prophylaxis: a randomized double-blinded study. Iran J Pharm Res. 2018;17(2):783-789. [PMC free article: PMC5985194] [PubMed: 29881434]
121.: Hesami O, Sistanizad M, Asadollahzade E, Johari MS, Beladi-Moghadam N, Mazhabdar- Ghashghai H. Comparing the effects of atorvastatin with sodium valproate (divalproex) on frequency and intensity of frequent migraine headaches: a double-blind randomized controlled study. Clin Neuropharmacol. 2018;41(3):94-97. doi: 10.1097/WNF.0000000000000280. [PubMed: 29746282] [CrossRef]
122.: Kalita J, Bhoi SK, Misra UK. Amitriptyline vs divalproate in migraine prophylaxis: a randomized controlled trial. Acta Neurol Scand. 2013;128(1):65-72. doi: 10.1111/ane.12081. [PubMed: 23406477] [CrossRef]
123.: Kaniecki RG. A comparison of divalproex with propranolol and placebo for the prophylaxis of migraine without aura. Arch Neurol. 1997;54(9):1141-1145. [PubMed: 9311358]
124.: Karimi N, Razian A, Heidari M. The efficacy of magnesium oxide and sodium valproate in prevention of migraine headache: a randomized, controlled, double-blind, crossover study. Acta Neurol Belg. 2019:Epub ahead of print. doi: 10.1007/s13760-019-01101-x. [PubMed: 30798472] [CrossRef]
125.: Kashipazha D, Ghadikolaei HS, Siavashi M. Levetiracetam in compare to sodium valproate for prophylaxis in chronic migraine headache: a randomized double-blind clinical trial. Curr Clin Pharmacol. 2017;12(1):55-59. doi: 10.2174/1574884712666170329094419. [PubMed: 28356053] [CrossRef]
126.: Keskinbora K, Aydinli I. A double-blind randomized controlled trial of topiramate and amitriptyline either alone or in combination for the prevention of migraine. Clin Neurol Neurosurg. 2008;110(10):979-984. [PubMed: 18620801]
127.: Krymchantowski AV, da Cunha Jevoux C, Bigal ME. Topiramate plus nortriptyline in the preventive treatment of migraine: a controlled study for nonresponders. J Headache Pain. 2012;13(1):53-59. doi: 10.1007/s10194-011-0395-4. [PMC free article: PMC3253150] [PubMed: 22008899] [CrossRef]
128.: Lai KL, Niddam DM, Fuh JL, et al. Flunarizine versus topiramate for chronic migraine prophylaxis: a randomized trial. Acta Neurol Scand. 2017;135(4):476-483. doi: 10.1111/ane.12626. [PubMed: 27306581] [CrossRef]
129.: Liu F, Ma T, Che X, Wang Q, Yu S. The efficacy of venlafaxine, flunarizine, and valproic acid in the prophylaxis of vestibular migraine. Front Neurol. 2017;8:524. doi: 10.3389/fneur.2017.00524. [PMC free article: PMC5641552] [PubMed: 29075232] [CrossRef]
130.: Lo YL, Lum SY, Fook-Chong S, Siow HC. A pilot study of topiramate dosages for migraine prophylaxis in an Asian population. J Headache Pain. 2010;11(2):175-178. doi: 10.1007/s10194-010-0193-4. [PMC free article: PMC3452284] [PubMed: 20143246] [CrossRef]
131.: Luo N, Di W, Zhang A, et al. A randomized, one-year clinical trial comparing the efficacy of topiramate, flunarizine, and a combination of flunarizine and topiramate in migraine prophylaxis. Pain Med. 2012;13(1):80-86. doi: 10.1111/j.1526-4637.2011.01295.x. [PubMed: 22233396] [CrossRef]
132.: Mansoureh T, Rahmat Jirde M, Nilavari K, Ashrafian H, Razeghi S, Kohan L. Cinnarizine in refractory migraine prophylaxis: efficacy and tolerability. A comparison with sodium valproate. J Headache Pain. 2008;9(2):77-82. doi: 10.1007/s10194-008-0013-2. [PMC free article: PMC3476188] [PubMed: 18286231] [CrossRef]
133.: Mathew NT, Rapoport A, Saper J, et al. Efficacy of gabapentin in migraine prophylaxis. Headache. 2001;41(2):119-128. doi: 10.1046/j.1526-4610.2001.111006119.x. [PubMed: 11251695] [CrossRef]
134.: Mathew NT, Jaffri SFA. A double-blind comparison of onabotulinumtoxina (BOTOX) and topiramate (TOPAMAX) for the prophylactic treatment of chronic migraine: a pilot study. Headache. 2009;49(10):1466-1478. doi: 10.1111/j.1526-4610.2009.01566.x. [PubMed: 19912346] [CrossRef]
135.: Millán-Guerrero RO, Isais-Millán R, Barreto-Vizcaíno S, et al. Subcutaneous histamine versus topiramate in migraine prophylaxis: a double-blind study. Eur Neurol. 2008;59(5):237- 242.doi: 10.1111/j.1526-4637.2011.01295.x. [PubMed: 18264012] [CrossRef]
136.: Millán-Guerrero RO, Isais-Millán R, Barreto-Vizcaíno S, et al. Subcutaneous histamine versus sodium valproate in migraine prophylaxis: a randomized, controlled, double-blind study. Eur J Neurol. 2007;14(10):1079-1084. doi: 10.1111/j.1468-1331.2007.01744.x. [PubMed: 17880560] [CrossRef]
137.: Mitsikostas DD, Polychronidis I. Valproate versus flunarizine in migraine prophylaxis: a randomized, double-open, clinical trial. Funct Neurol. 1997;12(5):267-276. [PubMed: 9439944]
138.: Mohammadianinejad SE, Abbasi V, Sajedi SA, et al. Zonisamide versus topiramate in migraine prophylaxis: a double-blind randomized clinical trial. Clin Neuropharmacol. 2011;34(4):174-177. doi: 10.1097/WNF.0b013e318225140c. [PubMed: 21738025] [CrossRef]
139.: Naderinabi B, Saberi A, Hashemi M, et al. Acupuncture and botulinum toxin A injection in the treatment of chronic migraine: a randomized controlled study. Caspian J Int Med. 2017;8(3):196-204. doi: 10.22088/cjim.8.3.196. [PMC free article: PMC5596191] [PubMed: 28932372] [CrossRef]
140.: Rahimdel A, Zeinali A, Yazdian-Anari P, Hajizadeh R, Arefnia E. Effectiveness of vitamin B2 versus sodium valproate in migraine prophylaxis: a randomized clinical trial. Electron Physician. 2015;7(6):1344-1348. doi: 10.14661/1344. [PMC free article: PMC4623793] [PubMed: 26516440] [CrossRef]
141.: Rodríguez-Leyva I, Sánchez-Aguilar M, Hernández-Sierra JF, et al. Topiramate vs. amitriptyline in prophylactic treatment of migraine: a controlled clinical trial. Revista Mexicana de Neurociencia. 2010;11(5):338-342.
142.: Shaygannejad V, Janghorbani M, Ghorbani A, Ashtary F, Zakizade N, Nasr V. Comparison of the effect of topiramate and sodium valporate in migraine prevention: randomized blinded crossover study. Headache. 2006;46(4):642-648. doi: 10.1111/j.1526-4610.2006.00413.x. [PubMed: 16643559] [CrossRef]
143.: Silberstein S, Saper J, Berenson F, Somogyi M, McCague K, D'Souza J. Oxcarbazepine in migraine headache: a double-blind, randomized, placebo-controlled study. Neurology. 2008;70(7):548-555. doi: 10.1212/01.wnl.0000297551.27191.70. [PubMed: 18268247] [CrossRef]
144.: Spira PJ, Beran RG, Australian Gabapentin Chronic Daily Headache G. Gabapentin in the prophylaxis of chronic daily headache: a randomized, placebo-controlled study. Neurology. 2003;61(12):1753-1759. [PubMed: 14694042]
145.: Steiner TJ, Findley LJ, Yuen AW. Lamotrigine versus placebo in the prophylaxis of migraine with and without aura. Cephalalgia. 1997;17(2):109-112. [PubMed: 9137848]
146.: Varkey E, Cider A, Carlsson J, Linde M. Exercise as migraine prophylaxis: a randomized study using relaxation and topiramate as controls. Cephalalgia. 2011;31(14):1428-1438. Epub 2011 Sep 1422. doi: 10.1177/0333102411419681. [PMC free article: PMC3236524] [PubMed: 21890526] [CrossRef]
147.: Xu JH, Mi HY. A randomized controlled trial of acupressure as an adjunctive therapy to sodium valproate on the prevention of chronic migraine with aura. Medicine (Baltimore). 2017;96(27):e7477. doi: 10.1097/MD.0000000000007477. [PMC free article: PMC5502191] [PubMed: 28682918] [CrossRef]
148.: Yang CP, Chang MH, Liu PE, et al. Acupuncture versus topiramate in chronic migraine prophylaxis: a randomized clinical trial. Cephalalgia. 2011;31(15):1510-1521. doi: 10.1177/0333102411420585. [PubMed: 22019576] [CrossRef]
149.: Zain S, Khan M, Alam R, Zafar I, Ahmed S. Comparison of efficacy and safety of topiramate with gabapentin in migraine prophylaxis: randomized open label control trial. J Pak Med Assoc. 2013;63(1):3-7. [PubMed: 23865122]
150.: Albers GW, Simon LT, Hamik A, Peroutka SJ. Nifedipine versus propranolol for the initial prophylaxis of migraine. Headache. 1989;29(4):215-218. doi: 10.1111/j.1526-4610.1989.hed22904215.x. [PubMed: 2654067] [CrossRef]
151.: Bordini CA, Arruda MA, Ciciarelli MC, Speciali JG. Propranolol vs flunarizine vs flunarizine plus propranolol in migraine without aura prophylaxis: a double-blind trial. Arq Neuropsiquiatr. 1997;55(3):536-541. doi: 10.1590/S0004-282X1997000400003. [PubMed: 9629401] [CrossRef]
152.: Borgesen SE. Treatment of migraine with propranolol. Postgrad Med J. 1976;52 Suppl 4:163-165. [PubMed: 787958]
153.: Carroll JD, Reidy M, Savundra PA, Cleave N, McAinsh J. Long-acting propranolol in the prophylaxis of migraine: a comparative study of two doses. Cephalalgia. 1990;10(2):101-105. [PubMed: 2193712]
154.: Diener HC, Hartung E, Chrubasik J, et al. A comparative study of oral acetylsalicyclic acid and metoprolol for the prophylactic treatment of migraine. A randomized, controlled, double-blind, parallel group phase III study. Cephalalgia. 2001;21(2):120-128. doi: 10.1046/j.1468-2982.2001.00168.x. [PubMed: 11422094] [CrossRef]
155.: Diener HC, Matias-Guiu J, Hartung E, et al. Efficacy and tolerability in migraine prophylaxis of flunarizine in reduced doses: a comparison with propranolol 160 mg daily. Cephalalgia. 2002;22(3):209-221. doi: 10.1046/j.1468-2982.2002.t01-1-00309.x. [PubMed: 12047461] [CrossRef]
156.: Domingues RB, Pirajá da Silva AL, Domingues SA, Aquino CC, Kuster GW. A double- blind randomized controlled trial of low doses of propranolol, nortriptyline, and the combination of propranolol and nortriptyline for the preventive treatment of migraine. Arq Neuropsiquiatr. 2009;67(4):973-977. doi: 10.1590/S0004-282X2009000600002. [PubMed: 20069203] [CrossRef]
157.: Forssman B, Lindblad CJ, Zbornikova V. Atenolol for migraine prophylaxis. Headache. 1983;23(4):188-190. [PubMed: 6350226]
158.: Gawel MJ, Kreeft J, Nelson RF, Simard D, Arnott WS. Comparison of the efficacy and safety of flunarizine to propranolol in the prophylaxis of migraine. Can J Neurol Sci. 1992;19(3):340-345. [PubMed: 1393843]
159.: Gerber WD, Schellenberg R, Thom M, et al. Cyclandelate versus propranolol in the prophylaxis of migraine--a double-blind placebo-controlled study. Funct Neurol. 1995;10(1):27- 35. [PubMed: 7649498]
160.: Ghobadi SH, Jivad N. The prophylactic activity of propranol and nimodipineon migraine headache. World J Med Sci. 2013;8(2):144-146.
161.: Hesse J, Mogelvang B, Simonsen H. Acupuncture versus metoprolol in migraine prophylaxis: a randomized trial of trigger point inactivation. J Intern Med. 1994;235(5):451-456. doi: 10.1111/j.1365-2796.1994.tb01102.x. [PubMed: 8182401] [CrossRef]
162.: Johannsson V, Nilsson LR, Widelius T, et al. Atenolol in migraine prophylaxis; a double- blind cross-over multicentre study. Headache. 1987;27(7):372-374. [PubMed: 3308768]
163.: Johnson RH, Hornabrook RW, Lambie DG. Comparison of mefenamic acid and propranolol with placebo in migraine prophylaxis. Acta Neurol Scand. 1986;73(5):490-492. [PubMed: 3524092]
164.: Kangasniemi P, Hedman C. Metoprolol and propranolol in the prophylactic treatment of classical and common migraine. A double-blind study. Cephalalgia. 1984;4(2):91-98. [PubMed: 6428749]
165.: Kaushik R, Kaushik RM, Mahajan SK, Rajesh V. Biofeedback assisted diaphragmatic breathing and systematic relaxation versus propranolol in long term prophylaxis of migraine. Complement Ther Med. 2005;13(3):165-174. doi: 10.1016/j.ctim.2005.04.004. [PubMed: 16150370] [CrossRef]
166.: Kjaersgard Rasmussen MJ, Larsen BH, Borg L, Soelberg Sorensen P, Hansen PE. Tolfenamic acid versus propranolol in the prophylactic treatment of migraine. Acta Neurol Scand. 1994;89(6):446-450. [PubMed: 7976233]
167.: Mathew NT. Prophylaxis of migraine and mixed headache. A randomized controlled study. Headache. 1981;21(3):105-109. doi:. 10.1111/j.1526-4610.1981.hed2103105.x4. [PubMed: 7021472] [CrossRef]
168.: Mikkelsen B, Pedersen KK, Christiansen LV. Prophylactic treatment of migraine with tolfenamic acid, propranolol and placebo. Acta Neurol Scand. 1986;73(4):423-427. [PubMed: 3727918]
169.: Millán-Guerrero RO, Isais-Millán R, Guzmán-Chávez B, Castillo-Varela G. N alpha methyl histamine versus propranolol in migraine prophylaxis. Can J Neurol Sci. 2014;41(2):233- 238. doi: 10.1017/s0317167100016632. [PubMed: 24534036] [CrossRef]
170.: Nadelmann JW, Stevens J, Saper JR. Propranolol in the prophylaxis of migraine. Headache. 1986;26(4):175-182. doi: 10.1111/j.1526-4610.1986.hed2604175.x. [PubMed: 3519529] [CrossRef]
171.: Nambiar NJ, Aiyappa C, Srinivasa R. Oral riboflavin versus oral propranolol in migraine prophylaxis: an open label randomized controlled trial. Neurol Asia. 2011;16(3):223-229.
172.: RE RS. Comparative study of nadolol and propranolol in prophylactic treatment of migraine. Am Heart J. 1984;108(4):1156-1159. [PubMed: 6148878]
173.: Salviz M, Yuce T, Acar H, Karatas A, Acikalin RM. Propranolol and venlafaxine for vestibular migraine prophylaxis: a randomized controlled trial. Laryngoscope. 2016;126(1):169- 174. doi: 10.1002/lary.25445. [PubMed: 26228645] [CrossRef]
174.: Schellenberg R, Lichtenthal A, Wöhling H, Graf C, Brixius K. Nebivolol and metoprolol for treating migraine: an advance on beta-blocker treatment? Headache. 2008;48(1):118-125. doi: 10.1111/j.1526-4610.2007.00785.x. [PubMed: 18184294] [CrossRef]
175.: Shimell CJ, Fritz VU, Levien SL. A comparative trial of flunarizine and propranolol in the prevention of migraine. S Afr Med J. 1990;77(2):75-78. [PubMed: 2404346]
176.: Sorensen PS, Larsen BH, Rasmussen MJK, et al. Flunarizine versus metoprolol in migraine prophylaxis: a double-blind, randomized parallel group study of efficacy and tolerability. Headache. 1991;31(10):650-657. [PubMed: 1769820]
177.: Stellar S, Ahrens SP, Meibohm AR, Reines SA. Migraine prevention with timolol. A double-blind crossover study. JAMA. 1984;252(18):2576-2580. [PubMed: 6387197]
178.: Streng A, Linde K, Hoppe A, et al. Effectiveness and tolerability of acupuncture compared with metoprolol in migraine prophylaxis. Headache. 2006;46(10):1492-1502. doi: 10.1111/j.1526-4610.2006.00598.x. [PubMed: 17115982] [CrossRef]
179.: Sudilovsky A, Elkind AH, Ryan Sr RE. Comparative efficacy of nadolol and propranolol in the management of migraine. Headache. 1987;27(8):421-426. [PubMed: 3312113]
180.: Van De Ven LLM, Franke CL, Koehler PJ. Prophylactic treatment of migraine with bisoprolol: a placebo- controlled study. Cephalalgia. 1997;17(5):596-599. doi: 10.1046/j.1468-2982.1997.1705596.x. [PubMed: 9251876] [CrossRef]
181.: Weber RB, Reinmuth OM. The treatment of migraine with propranolol. Neurology. 1972;22(4):366-369. [PubMed: 4552716]
182.: Ziegler DK, Hurwitz A, Hassanein RS, Kodanaz HA, Preskorn SH, Mason J. Migraine prophylaxis. A comparison of propranolol and amitriptyline. Arch Neurol. 1987;44(5):486-489. [PubMed: 3579659]
183.: Ziegler DK, Hurwitz A, Preskorn S, Hassanein R, Seim J. Propranolol and amitriptyline in prophylaxis of migraine. Pharmacokinetic and therapeutic effects. Arch Neurol. 1993;50(8):825-830. [PubMed: 8352668]
184.: Chankrachang S, Arayawichanont A, Poungvarin N, et al. Prophylactic botulinum type A toxin complex (Dysport®) for migraine without aura. Headache. 2011;51(1):52-63. doi: 10.1111/j.1526-4610.2010.01807.x. [PubMed: 21083558] [CrossRef]
185.: Magalhaes E, Menezes C, Cardeal M, Melo A. Botulinum toxin type A versus amitriptyline for the treatment of chronic daily migraine. Clin Neurol Neurosurg. 2010;112(6):463-466. doi: 10.1016/j.clineuro.2010.02.004. [PubMed: 20399553] [CrossRef]
186.: Millán-Guerrero RO, Isais-Millán S, Barreto-Vizcaíno S, Rivera-Castano L, Rios- Madariaga C. Subcutaneous histamine versus botulinum toxin type A in migraine prophylaxis: a randomized, double-blind study. Eur J Neurol. 2009;16(1):88-94. doi: 10.1111/j.1468-1331.2008.02352.x. [PubMed: 19087155] [CrossRef]
187.: Petri S, Toelle T, Straube A, Pfaffenrath V, Stefenelli U, Ceballos-Baumann A. Botulinum toxin as preventive treatment for migraine: a randomized double-blind study. Eur Neurol. 2009;62(4):204-211. doi: 10.1159/000228987. [PubMed: 19622887] [CrossRef]
188.: Shehata HS, Esmail EH, Abdelalim A, et al. Repetitive transcranial magnetic stimulation versus botulinum toxin injection in chronic migraine prophylaxis: a pilot randomized trial. J Pain Res. 2016;9:771-777. doi: 10.2147/JPR.S116671. [PMC free article: PMC5063492] [PubMed: 27785091] [CrossRef]
189.: Ahuja GK, Verma AK. Propranolol in prophylaxis of migraine. Indian J Med Res. 1985;82:263-265. [PubMed: 3908306]
190.: Ansell E, Fazzone T, Festenstein R, et al. Nimodipine in migraine prophylaxis. Cephalalgia. 1988;8(4):269-272. doi: 10.1046/j.1468-2982.1988.0804269.x. [PubMed: 3064919] [CrossRef]
191.: Gelmers HJ, Henry P, Lucas J, et al. European multicenter trial of nimodipine in the prophylaxis of classic migraine (migraine with aura). Headache. 1989;29(10):639-642. [PubMed: 2693406]
192.: Gelmers HJ, Henry P, Lucas J, et al. European multicenter trial of nimodipine in the prophylaxis of common migraine (migraine without aura). Headache. 1989;29(10):633-638. [PubMed: 2693405]
193.: Havanka-Kanniainen H, Hokkanen E, Myllyla VV. Efficacy of nimodipine in the prophylaxis of migraine. Cephalalgia. 1985;5(1):39-43. [PubMed: 3886153]
194.: Lamsudin R, Sadjimin T. Comparison of the efficacy between flunarizine and nifedipine in the prophylaxis of migraine. Headache. 1993;33(6):335-338. [PubMed: 8349477]
195.: Leandri M, Rigardo S, Schizzi R, Parodi CI. Migraine treatment with nicardipine. Cephalalgia. 1990;10(3):111-116. [PubMed: 2245455]
196.: Markley HG, Cheronis JCD, Piepho RW. Verapamil in prophylactic therapy of migraine. Neurology. 1984;34(7):973-976. [PubMed: 6539877]
197.: McArthur JC, Marek K, Pestronk A, McArthur J, Peroutka SJ. Nifedipine in the prophylaxis of classic migraine: a crossover, double-masked, placebo-controlled study of headache frequency and side effects. Neurology. 1989;39(2):284-286. [PubMed: 2644581]
198.: Nuti A, Lucetti C, Pavese N, Dell'Agnello G, Rossi G, Bonuccelli U. Long-term follow- up after flunarizine or nimodipine discontinuation in migraine patients. Cephalalgia. 1996;16(5):337-340. [PubMed: 8869769]
199.: Stewart DJ, Gelston A, Hakim A. Effect of prophylactic administration of nimodipine in patients with migraine. Headache. 1988;28(4):260-262. [PubMed: 3170182]
200.: Dodick DW, Goadsby PJ, Silberstein SD, et al. Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol. 2014;13(11):1100-1107. doi: 10.1016/S1474-4422(14)70209-1. [PubMed: 25297013] [CrossRef]
201.: Adly C, Straumanis J, Chesson A. Fluoxetine prophylaxis of migraine. Headache. 1992;32(2):101-104. [PubMed: 1551787]
202.: Bank J. A comparative study of amitriptyline and fluvoxamine in migraine prophylaxis. Headache. 1994;34(8):476-478. [PubMed: 7960733]
203.: Bulut S, Berilgen MS, Baran A, Tekatas A, Atmaca M, Mungen B. Venlafaxine versus amitriptyline in the prophylactic treatment of migraine: randomized, double-blind, crossover study. Clin Neurol Neurosurg. 2004;107(1):44-48. doi: 10.1016/j.clineuro.2004.03.004. [PubMed: 15567552] [CrossRef]
204.: Colucci d'Amato C, Pizza V, Marmolo T, Giordano E, Alfano V, Nasta A. Fluoxetine for migraine prophylaxis: a double-blind trial. Headache. 1999;39(10):716-719. [PubMed: 11279947]
205.: Rampello L, Alvano A, Chiechio S, et al. Evaluation of the prophylactic efficacy of amitriptyline and citalopram, alone or in combination, in patients with comorbidity of depression, migraine, and tension-type headache. Neuropsychobiology. 2004;50(4):322-328. doi: 10.1159/000080960. [PubMed: 15539864] [CrossRef]
206.: Saper JR, Silberstein SD, Lake AEd, Winters ME. Double-blind trial of fluoxetine: chronic daily headache and migraine. Headache. 1994;34(9):497-502. [PubMed: 8002320]
207.: Steiner TJ, Ahmed F, Findley LJ, MacGregor EA, Wilkinson M. S-fluoxetine in the prophylaxis of migraine: A phase II double-blind randomized placebo-controlled study. Cephalalgia. 1998;18(5):283-286. doi: 10.1046/j.1468-2982.1998.1805283.x. [PubMed: 9673809] [CrossRef]
208.: Tarlaci S. Escitalopram and venlafaxine for the prophylaxis of migraine headache without mood disorders. Clin Neuropharmacol. 2009;32(5):254-258. doi: 10.1097/WNF.0b013e3181a8c84f. [PubMed: 19667978] [CrossRef]
209.: Bruno MAD, Krymchantowski AV. Amitriptyline and intraoral devices for migraine prevention: a randomized comparative trial. Arq Neuropsiquiatr. 2018;76(4):213-218. doi: 10.1590/0004-282x20180023. [PubMed: 29742243] [CrossRef]
210.: Couch JR, Hassanein RS. Amitriptyline in migraine prophylaxis. Arch Neurol. 1979;36(11):695-699. [PubMed: 508127]
211.: Gomersall JD, Stuart A. Amitriptyline in migraine prophylaxis. Changes in pattern of attacks during a controlled clinical trial. J Neurol Neurosurg Psychiatry. 1973;36(4):684-690. doi: 10.1136/jnnp.36.4.684. [PMC free article: PMC494428] [PubMed: 4731336] [CrossRef]
212.: Krymchantowski AV, Silva MT, Barbosa JS, Alves LA. Amitriptyline versus amitriptyline combined with fluoxetine in the preventative treatment of transformed migraine: a double-blind study. Headache. 2002;42(6):510-514. doi: 10.1046/j.1526-4610.2002.02125.x. [PubMed: 12167139] [CrossRef]
213.: Lampl C, Huber G, Adl J, et al. Two different doses of amitriptyline ER in the prophylaxis of migraine: long-term results and predictive factors. Eur J Neurol. 2009;16(8):943-948. doi: 10.1111/j.1468-1331.2009.02631.x. [PubMed: 19456855] [CrossRef]
214.: Nelson CF, Bronfort G, Evans R, Boline P, Goldsmith C, Anderson AV. The efficacy of spinal manipulation, amitriptyline and the combination of both therapies for the prophylaxis of migraine headache. J Manipulative Physiol Ther. 1998;21(8):511-519. [PubMed: 9798179]
215.: Santiago MDS, Carvalho DS, Gabbai AA, et al. Amitriptyline and aerobic exercise or amitriptyline alone in the treatment of chronic migraine: a randomized comparative study. Arq Neuropsiquiatr. 2014;72(11):851-855. doi: 10.1007/s10072-017-2888-7. [PubMed: 25410451] [CrossRef]
216.: Villani V, Prosperini L, Palombini F, Orzi F, Sette G. Single-blind, randomized, pilot study combining shiatsu and amitriptyline in refractory primary headaches. Neurol Sci. 2017;38(6):999-1007. doi: 10.1007/s10072-017-2888-7. [PubMed: 28283760] [CrossRef]

Disclaimer

All statements, findings, and conclusions in this publication are solely those of the authors and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute (PCORI) or its Board of Governors. This publication was developed through a contract to support PCORI’s work. Questions or comments may be sent to PCORI at info@pcori.org or by mail to 1828 L Street NW, Suite 900, Washington, DC 20036.

Acknowledgments

We gratefully acknowledge contributions from the following individuals:

Our TEP members: Christopher H. Gottschalk, MD, FAHS; Katherine Hamilton, MD; and Mia Tova Minen, MD, MPH. In addition, Larry Charleston IV, MD, provided valuable feedback during the scoping and protocol design.

We also interviewed key representatives of potential intended end-users to refine content and usability; their input was invaluable to informing map design. Specifically, the following individuals provided feedback: David T. O’Gurek, MD, FAAFP, Robert Rich, MD, and Christina Worst, CRNP (primary care providers); Desiree Otenti, MSN, MPH (payer); William Lawrence, MD, MS; and Layla Lavasani, PhD, MHS (research funders).

We also thank Nancy Bonk and Angie Glaser, migraine patients and advocates who provided valuable input during protocol development.

We also thank Lovelytics for supporting data visualization.

Finally, we acknowledge contributions from many ECRI colleagues: Helen Dunn and Kitty Donahue (references); Joann Fontanorosa, PhD (data validation checks); Jacquelyn Hostetter (administrative support); Laura Koepfler, MLS (performing literature searches); Jennifer Maslin (formatting); and Michael Phillips (copyediting).

Suggested citation:

Tsou AY, Rouse B, Bloschichak A, et al. Drugs and Devices for Migraine Prevention: Interactive Evidence Maps. Patient-Centered Outcomes Research Institute; February 2021. Prepared by ECRI under Contract No. IDIQ-TO#12-ECRI-SCI-EVIDENCEMAP-2019-07-15. https://doi.org/10.25302/EMV1.2021.2

This document is in the public domain and may be used and reprinted without special permission. Citation of the source is appreciated.

Bookshelf ID: NBK576984PMID: 35099854DOI: 10.25302/EMV1.2021.2

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Tsou AY, Rouse B, Bloschichak A, et al. Drugs and Devices for Migraine Prevention: Interactive Evidence Maps [Internet]. Washington (DC): Patient-Centered Outcomes Research Institute (PCORI); 2021 Feb. doi: 10.25302/EMV1.2021.2
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Drugs and Devices for Migraine Prevention: Interactive Evidence Maps

Authors

Affiliations

Structured Abstract

Background:

Purpose:

Methods:

Results:

Conclusions:

Background

Scope and Purpose

Methods

Table 1

Table 2

Stakeholder Input

Literature Search

Inclusion/Exclusion Criteria

Screening

Rapid-Review Methodology

Data Extraction and Meta-analysis

Map 1 Outcomes

Migraine Reduction and Trial Dropout

Efficacy Measures and Minimally Important Difference

Meta-analysis

Adverse Events

Risk of Bias Assessment

Quality-of-Evidence Assessment

Data Visualization

Results

Map 1. Benefits and Harms of Selected Interventions for Migraine Prevention: Evidence From Placebo-/Sham-Controlled RCTs

Efficacy for All Migraine Types

Episodic Migraine

Table 3

Chronic Migraine

Table 4

Tolerability (Trial Dropout and Adverse Effects)

Map 2. What Types of Drugs and Devices Have Been Studied With RCTs for Migraine Prevention?

Map 3. Head-to-Head Comparisons of Drugs and Devices for Migraine Prevention

Discussion

Limitations

Future Directions

Conclusion

References

Disclaimer

Acknowledgments

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