A Comparative Effectiveness Meta-Analysis of Drugs for the Prophylaxis of Migraine Headache

Jeffrey L Jackson; Elizabeth Cogbill; Rafael Santana-Davila; Christina Eldredge; William Collier; Andrew Gradall; Neha Sehgal; Jessica Kuester

doi:10.1371/journal.pone.0130733

. 2015 Jul 14;10(7):e0130733. doi: 10.1371/journal.pone.0130733

A Comparative Effectiveness Meta-Analysis of Drugs for the Prophylaxis of Migraine Headache

Jeffrey L Jackson ^1,^*,^#, Elizabeth Cogbill ^2,^#, Rafael Santana-Davila ^3,^#, Christina Eldredge ^4,^#, William Collier ^5,^#, Andrew Gradall ^6,^#, Neha Sehgal ^7,^¤,^#, Jessica Kuester ^1,^#

Editor: Oscar Arias-Carrion⁸

PMCID: PMC4501738 PMID: 26172390

Abstract

Objective

To compare the effectiveness and side effects of migraine prophylactic medications.

Design

We performed a network meta-analysis. Data were extracted independently in duplicate and quality was assessed using both the JADAD and Cochrane Risk of Bias instruments. Data were pooled and network meta-analysis performed using random effects models.

Data Sources

PUBMED, EMBASE, Cochrane Trial Registry, bibliography of retrieved articles through 18 May 2014.

Eligibility Criteria for Selecting Studies

We included randomized controlled trials of adults with migraine headaches of at least 4 weeks in duration.

Results

Placebo controlled trials included alpha blockers (n = 9), angiotensin converting enzyme inhibitors (n = 3), angiotensin receptor blockers (n = 3), anticonvulsants (n = 32), beta-blockers (n = 39), calcium channel blockers (n = 12), flunarizine (n = 7), serotonin reuptake inhibitors (n = 6), serotonin norepinephrine reuptake inhibitors (n = 1) serotonin agonists (n = 9) and tricyclic antidepressants (n = 11). In addition there were 53 trials comparing different drugs. Drugs with at least 3 trials that were more effective than placebo for episodic migraines included amitriptyline (SMD: -1.2, 95% CI: -1.7 to -0.82), -flunarizine (-1.1 headaches/month (ha/month), 95% CI: -1.6 to -0.67), fluoxetine (SMD: -0.57, 95% CI: -0.97 to -0.17), metoprolol (-0.94 ha/month, 95% CI: -1.4 to -0.46), pizotifen (-0.43 ha/month, 95% CI: -0.6 to -0.21), propranolol (-1.3 ha/month, 95% CI: -2.0 to -0.62), topiramate (-1.1 ha/month, 95% CI: -1.9 to -0.73) and valproate (-1.5 ha/month, 95% CI: -2.1 to -0.8). Several effective drugs with less than 3 trials included: 3 ace inhibitors (enalapril, lisinopril, captopril), two angiotensin receptor blockers (candesartan, telmisartan), two anticonvulsants (lamotrigine, levetiracetam), and several beta-blockers (atenolol, bisoprolol, timolol). Network meta-analysis found amitriptyline to be better than several other medications including candesartan, fluoxetine, propranolol, topiramate and valproate and no different than atenolol, flunarizine, clomipramine or metoprolol.

Conclusion

Several drugs good evidence supporting efficacy. There is weak evidence supporting amitriptyline’s superiority over some drugs. Selection of prophylactic medication should be tailored according to patient preferences, characteristics and side effect profiles.

Introduction

Migraine headaches are common, with a worldwide prevalence ranging between 8 and 18% [1–7]. Migraines cause significant disability [8–11], even during periods between attacks [12], and are responsible for $1 billion in medical costs and $16 billion in lost productivity per year [13,14] in the US alone. The diagnostic criteria for migraine headaches have evolved over time. Currently, the International Headache Society (IHS) diagnostic criteria for migraine includes having at least 5 attacks that last 4–72 hours, that are unilateral, pulsating, moderate or severe in intensity and aggravated by or cause avoidance of routine physical activity and are also accompanied by nausea and/or vomiting, photophobia or phonophobia [15]. IHS further classifies migraine as with or without an aura and as episodic or chronic. Chronic migraine is defined as more than 15 migraine headaches per month for more than 3 months. Chronic migraines result in significantly greater disability than episodic migraines[16].

Treatment of headaches can be either abortive or prophylactic. Abortive treatment provides symptom relief for the acute headache [17,18], while prophylactic treatment aims to reduce the frequency or severity of headaches over time. We focus on prophylactic migraine headache treatment in this manuscript. There are a large number of prophylactic treatment options available; common ones include alpha antagonists, anti-convulsants [19], beta-blockers [20], botulinum-A [21], calcium channel blockers [22], serotonin agonists[23], serotonin reuptake inhibitors (SSRIs) [24] and tricyclic antidepressants (TCAs) [25]. Two emerging prophylactic candidates are angiotensin converting enzymes (ACE) and angiotensin receptor antagonists (ARB). Unfortunately nearly half of males and a third of females who are candidates for prophylactic therapy do not receive it [26]. Selection of prophylactic treatment is tailored on individual patient characteristics, costs and side effects of the available options. However, for patients and their providers, the decision about which prophylactic regimen to use is hampered by the lack of head to head trials comparing the different classes of medications. In addition, previous systematic reviews have focused on single classes of drugs. Two recent systematic reviews that looked more broadly at different drug options have been published. One only included studies since 1999 and did not pool any results, providing qualitative statements about relative treatment effectiveness [27]. Another review analyzed focused only on dichotomous outcomes among patients with episodic migraines and found no difference in likelihood of experiencing at least 50% improvement in headaches between different classes of oral medications [28]. Previous systematic reviews have also had methodological problems. Some combine outcomes from the end of the study, regardless of study duration. This inappropriately combines study results at markedly different time points. This also tends to overstate the strength of the evidence by making it appear that there are more studies contributing data to the results and produces inappropriately narrow confidence intervals. We conducted a meta-analysis asking what is the comparative effectiveness and side effects of the prophylactic treatment of migraine headaches in adults using oral pharmacological medications.

Materials and Methods

This report closely adheres to the PRISMA guidelines for conducting a systematic review [29]. We searched MEDLINE, EMBASE, the bibliographies of all retrieved articles, published systematic reviews and the Cochrane Database of Clinical Trials for each of the classes of medications (Table 1) through 7 November 2014. The search was conducted independently in duplicate. We included published, randomized clinical trials that evaluated efficacy in reducing the frequency or severity of migraine headaches that were at least 4 weeks in duration among adults. These comparisons could be between active treatment with placebo controls or comparative trials comparing two or more active treatments. We did not include unpublished data as there is no systematic means of searching for it. Because the classification of headache has changed over time [30,31], two authors independently reviewed each included article's headache definition and, where possible, classified it according to the 3rd edition of the International Headache Society (IHS) criteria (ICDH-III) and included only those that could reasonably be defined based on these diagnostic criteria [15]. For headache trials before 2004, we classified trials as focusing on episodic or chronic migraine based on the number of headaches experienced by participants at baseline.

Table 1. Search Strategies.

Search Purpose	Search Strategy
Headaches	(headache OR headache disorders OR migrain^* OR headache^* OR cephalgi^* OR cephalalgi^* OR tension^*)
Randomized controlled trials	(randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh] OR random allocation [mh] OR double-blind method [mh] OR single-blind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR ("clinical trial" [tw]) OR ((singl^* [tw] OR doubl^* [tw] OR trebl^* [tw] OR tripl^* [tw]) AND (mask^* [tw] OR blind^* [tw])) OR (placebos [mh] OR placebo^* [tw] OR random^* [tw] OR research design [mh:noexp] OR comparative study [mh] OR evaluation studies [mh] OR follow-up studies [mh] OR prospective studies [mh] OR control^* [tw] OR prospectiv^* [tw] OR volunteer^* [tw]) NOT (animals [mh] NOT humans [mh])
Alpha blockers	(“Adrenergic alpha-Antagonists”[MeSH Terms]or clonidine OR tizanidine)
Angiotension converting enzyme inhibitor	“Angiotenin-Converting Enzyme Inhibitors” [mh] OR benzapril OR captopril OR enalapril OR lisinopril OR moexipril OR perindopril OR quinapril OR ramipril OR trandolapril
Angiotension receptor blockers	“Angiotensin Receptor Antagonists” [mh] OR losartan OR irbesartan OR olmesartan OR candesartan OR valsartan OR telmisartan
Anticonvulsants	((anticonvulsants [mh] OR (anticonvulsant^* OR antiepileptic^* OR acetazolamide OR carbamazepine OR chlormethiazole OR clobazam OR clorazepate OR divalproex OR ethosuximide OR felbamate OR fosphenytoin OR gabapentin OR lamotrigine OR levetiracetam OR mephobarbital OR methsuximide OR midazolam OR oxcarbazepine OR paraldehyde OR pentobarbital OR phenobarbital OR phenytoin OR primidone OR valproate OR tiagabine OR topiramate OR valproic^* OR vigabatrin OR zonisamide)
Beta-blocker	adrenergic beta receptor blockaders [mh] OR (alprenolol OR bucindolol OR carteolol OR carvedilol OR labetalol OR nadolol OR penbutolol OR pindolol OR propranolol OR Sotalol OR timolol OR acebutolol OR atenolol OR betaxolol OR bisoprolol OR celiprolol OR esmolol OR metoprolol OR nebivolol)
Calcium channel blocker	(calcium channel blockers/therapeutic use"[mh] OR (amlodipine OR aranidipine OR azelnidipine OR barnidipine OR benidipine OR bepridil OR cilnidipine OR clevidipine OR diltiazem OR efonidipine OR felodipine OR fendiline OR flunarizine OR fluspirilene OR gallopamil OR isradipine OR lacidipine OR lercanidipine OR manidipine OR mibefradil OR nicardipine OR nifedipine OR nilvadipine OR nimodipine OR nisoldipine OR nitrendipine OR pranidipine OR verapamil))
Selective serotonin reuptake inhibitor	serotonin Uptake Inhibitors/therapeutic use [MH] OR (citalopram OR dapoxetine OR escitalopram OR fluoxetine OR fluvoxamine OR indalpine OR paroxetine OR sertraline OR vilazodone OR zimelidine OR venlafaxine OR desvenlafaxine OR duloxetine OR milnacipran OR levomilnacipran OR sibutramine OR bicifadine)
Serotonin agonist (Pizotifen)	Pizotyline [mh] OR pizotifen OR sandomigran
Tricyclic antidepressant	antidepressive agents, tricyclic OR antidepressive$ OR tricyclic$ OR amitriptyline OR amoxapine OR clomipramine OR desipramine OR dibenzepin OR dothiepin OR doxepin OR imipramine OR lofepramine OR nortriptyline OR opipramol OR protriptyline OR trimipramine

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* (is the symbol for wild-card in MEDLINE)

Two authors independently abstracted data. Because measures of headache outcomes varied, a priori we followed International Headache Society outcome recommendations by prioritizing abstraction and analysis in this order: 1) headache frequency, 2) a headache index that included frequency, 3) severity or 4) duration [32]. Headache frequency was standardized to number of headaches per month. Whenever possible, we pooled frequency as the number of headaches/month. When not possible, we pooled standardized mean differences between studies, a measure also known as an effect size. By convention, effect sizes greater than 0.8 are considered to be large effect sizes, 0.5–0.8 moderate and 0.2–0.5 small [33]. When missing, variances were calculated from reported mean, sample size and p values [34]; for one non-placebo comparison trial [35] variance was imputed based on sample size and the reported effect size (r² = 0.76) When not explicitly reported, to verify we were using the proper variance, we tested the abstracted data for each article to ensure that the p value reported in the article matched our analysis. This helped insure that standard errors weren’t abstracted as standard deviations, a common error in systematic reviews [36]. In addition, because of reports on the potential for misleading data [37,38], we only accepted data that was unadjusted and that was either based on a true intention to treat analysis or based on the subjects remaining in the trial. We rejected any “modified intention to treat” analyses or analyses subject to other adjustments. We assessed article quality independently and in duplicate, using both component and scales approaches using the Cochrane Risk of Bias Tool [39] and the Jadad scale [40] with good inter-rater agreement (Cochrane ICC: 0.83; Jadad kappa: 0.85). Disagreements were resolved by consensus.

For studies with more than one arm or using a cross-over design, we followed the recommendations of the Cochrane collaboration by pooling the arms into a single arm (if the study reported no differences between arms) or by reducing the sample sizes for cross-over trials by 50% [41]. We abstracted data from each trial at the following time points: baseline, 4, 8, 12, 24, 30 and 36 weeks using the DerSimonian and Laird random effects model [42]. Because of controversy about the accuracy of reporting of off-label use of one of gabapentin [37,38], we relied on data in McCrory’s reanalysis of misleading data presented in one of the studies [43] based on drug company trial data.

The main focus of our analysis is between active treatment and placebo controls. We also included data from comparative effectiveness trials. In addition to direct comparisons between drugs, we also conducted a network meta-analysis [44–47]. In brief, network meta-analysis asks if one drug has a pooled efficacy compared to placebo of X and another drug has a pooled efficacy compared to placebo of Y, are X and Y statistically different? We only included drugs with at least 2 clinical trials and at least 8 weeks in duration, adjusting for duration and for correlation between outcomes reported from the same trial. Because these studies did not always report their outcomes in frequency of headaches, the network meta-analysis was done using standardized mean differences (SMD) rather than weighted mean differences.

Heterogeneity was assessed visually using Galbraith plots [48], and I-square [49].We assessed for small study effects (publication bias) using the methods of Peters [50] for dichotomous outcomes and Eggers [51] for continuous ones. We explored the potential source of heterogeneity using stratified analysis and random-effects meta-regression [52]. These analyses included assessment of the impact of quality, study duration, percentage women, losses to follow-up, and drug dose. All analyses were done using STATA (v 13.1, College Station TX). There was no external funding for this study.

Results

Individual searches yielded 4789 unique articles: 138 ACE, 195 alpha blockers, 109 ARB, 1391 anticonvulsants, 654 beta blockers, 711 calcium channel blockers, 279 serotonin agonists, 363 SSRI and 876 TCA publications. Application of inclusion criteria (Fig 1) resulted in selecting 179 randomized clinical trials. These included the following placebo controlled trials: 9 alpha blockers [53–61], 3 ACE trials [62–64] 3 ARB [65–67], 33 anticonvulsants [43,68–99], 39 beta-blockers [66,73,100–136], 12 calcium channel blocker [106,137–147], 7 flunarizine [148–154], 6 SSRI [155–160], 1 SNRI [161], 9 serotonin agonists [162–170] and 9 TCA [118,136,171–177] trials. Fifteen of these placebo-controlled trials included more than one active treatment [66,74,106,116,118,131,136,141,163,167,169,170,175,178,179]. In addition, we also include 53 non-placebo controlled comparative effectiveness trials [178–230].

Placebo Comparisons

Table 2 provides study characteristics of trials investigating prophylactic treatment of episodic migraines (< 15 headaches/month), Table 3 provides details about studies of chronic migraine (>15 headaches/month) and chronic daily headache. There were a total of 15,493 participants in the placebo controlled trials. Studies averaged 112 participants, ranging from 9 to 783. The average patient was 39.2 years old and 78% of subjects were women. Included studies averaged 12 weeks in duration (range 4–82) and had a mean dropout rate of 24%. Thirty nine trials used the 1962 Ad Hoc Committee criteria, seven used the 1969 World Federation of Neurology criteria, forty seven studies used the 1988 International Headache Society criteria, and sixteen the 2004 IHS criteria. Among included trials, most (n = 120) studied episodic migraine headaches with subjects averaging 5.6 headaches per month (range 1.2–11.7). Ten studies focused on subjects with chronic migraine with an average of 18.6 (range 12–24) headaches a month. Six studied chronic daily headaches; the majority of participants (73%) had chronic migraine. Ninety trials (57%) used a parallel-group design, while sixty-six used a crossover design. There were 23 countries contributing studies. Fifty-one trials (46%) were sponsored by industry. Most studies (82%) used frequency as their outcome measure, nineteen (13.7%) used a headache index, two used headache duration and three headache intensity.

Table 2. Study characteristics of included randomized trials of treatment of episodic (<15 headaches/month) migraine headaches.

Author, year, Country	Migraine Type	Baseline Headache Frequency	Drugs (mg)	Headache Measure	Study design (washout)	Duration, weeks	Sample size	Dropouts	Age	Female
ALPHA BLOCKER
Adam [53], 1978, UK	Episodic	ns	Clonidine (0.15)	Frequency	Crossover (0)	24	96	27%	37.5	84%
Boison [54], 1978, Denmark	Episodic	ns	Clonidine (0.1)	Frequency	Crossover (0)	8	71	31%	ns	ns
Bredfeldt[55], 1989, USA	Episodic	ns	Clonidine (0.2)	Frequency	Crossover	6	43	30%	ns	80%
Lynggaard [56], 1975, Denmark	Episodic	ns	Clonidine (0.1)	Frequency	Crossover (1)	12	37	26%	34.1	95%
Mondrup[57], 1977, Denmark	Episodic	ns	Clonidine (0.1)	Frequency	Crossover (4)	12	32	34%	35	76%
Ryan [58], 1975, USA	Episodic	ns	Clonidine (0.15)	Frequency	Crossover (2 days)	8	133	ns	41	78%
Shafar [60], 1972, UK	Episodic	8.4	Clonidine (0.1)	Frequency	Crossover	8	65	23%	47.4	84%
Stensrud, 1976, Norway	Episodic	5.8	Clonidine (0.15)	Frequency	Crossover (0)	7	29	7%	43.3	83%
ANGIOTENSIN ENZYME CONVERTING INHIBITORS
Paterna [62] 1992, Italy	Episodic		Captopril (75)	Headache Index	Crossover	16	20	23%	37	81%
Schrader [63] 2001,Norway	Episodic	2.3	Lisinopril (20)	Frequency	Parallel	12	30	5%	41	81%
Sonbolestan [64], 2013, Iran	Episodic	11.3	Enalapril (10)	Frequency	Parallel	8	34	0%	34.4	825
ANGIOTENSIN RECEPTOR BLOCKER
Diener[65] 2009, Germany	Episodic	6.9	Telmisartan (80)	Frequency	Parallel	12	95	5%	47	85%
Stovner[66], 2013, Norway	Episodic	4.8	Candesartan (16), Propranolol (160)	Frequency	Crossover	12	61	15%	37	82%
Tronvik [67](2003) Norway	Episodic	5.7	Candesartan (16)	Frequency	Parallel	12	57	5%	43.2	79%
ANTICONVULSANTS
Brandes [69], 2004, Canada/USA	Episodic	5.7	Topiramate, (50,100,200)	Frequency	Parallel	26	483	46%	38.9	87%
Cady [70], 2009, USA	Episodic	4.4	Carisbamate (100,300,600)	Frequency	Parallel	14	318	30%	41.3	85%
de Tommaso [71], 2007, Italy	Episodic	10.9	Topiramate (100), Levitracetam (1000)	Frequency	Parallel	8	45	16%	37.8	78%
Di’ Trapani [72], 2000, Italy	Episodic	5.2	Gabapentin (1200)	Frequency	Parallel	12	63	0%	ns	52%
Diener [73], 2004 Europe	Episodic	5.1	Topiramate (100, 200) Propranolol (160)	Frequency	Parallel	20	568	37%	40.8	80%
Edwards [75], 2003, USA	Episodic	4.5	Topiramate (200)	Frequency	Parallel	4	70	0%	41.4	97%
Freitag [76], 2002,USA	Episodic	4.2	Divalproex (1000)	Frequency	Parallel	12	237	15%	40.5	79%
Ghose[77], 2002, New Zealand	Episodic (74%) Chronic (26%)	7.6	Vigabatrin (2000)	Frequency	Crossover (4)	12	23	17%	43.6	74%
Gupta [78], 2007, India	Episodic	7.0	Topiramate (50), Lamotrigene (50)	Frequency	Crossover ()	4	60	7%	30	78%
Hering [79],1992. Israel	Episodic	7.7	Valproate (800)	Frequency	Crossover (0)	8	32	9%	34	79%
Jensen [80],1994, Denmark	Episodic	6.6	Valproate (1500)	Frequency	Crossover (4)	12	43	21%	46	86%
Klapper [81],1997, USA	Episodic	5.0	Divalproex (500,100,1500)	Frequency	Parallel	12	176	22%	40.8	89%
Lipton [82], 2011, USA	Episodic	11.7	Topiramate (100)	Frequency	Parallel	26	385	14%	40.3	89%
Mathew [83], 1995, USA	Episodic	6.2	Valproate (750)	Frequency	Parallel	12	107	16%	45.6	78%
Mathew [43], 2001,USA	Episodic	4.9	Gabapentin (2400)	Frequency	Parallel	12	143	39%	40	83%
Rompel [85], 1970, S Africa	Episodic	3.0	Carbamazepin (ns)	Frequency	Crossover ()	6	48	2%	60	69%
Silberstein [87],2004, USA	Episodic	5.5	Topiramate (50,100,200)	Frequency	Parallel	24	487	46%	40.4	89%
Silberstein [88], 2006, USA	Episodic	4.9	Topiramate (200)	Frequency	Parallel	20	211	27%	40.8	86%
Silberstein [90], 2008, USA	Episodic	3–9	Oxcarbazepine(1200)	Frequency	Parallel	15	170	26%	40.5	85%
Silberstein [91], 2013, USA	Episodic	9.2	Gabapentin (1200,1800,2400,3000)	Frequency	Parallel	20	263	29%	39.3–40.6	83%
Steiner [94],1997, UK	Episodic	4.1	Lamotrigine (200)	Frequency	Parallel	12	77	31%	37.2	82%
Stensrud [95],1979, Norway	Episodic	6.3	Clonazepam (1)	Frequency	Crossover ()	4	38	11%	ns	71%
Storey [96],2001, USA	Episodic	4.7	Topiramate (200)	Frequency	Parallel	16	40	13%	38.3	98%
Vahedi [97],2002, France	Episodic	5.0	Acetazolamide (500)	Frequency	Parallel	12	53	34%	39.2	75%
Verma[98], 2013, India	Episodic	5.7	Levetiracetam	Frequency	Parallel	12	65	20%	31.1	73%
Beta Blockers
Ahuja[100], 1985, India	Episodic	7.2	Propranolol (120)	Frequency	Crossover	8	26	ns	ns	46%
Al-Qassab [101], 1993, UK	Episodic	4	Propranolol (80, 160)	Frequency	Crossover	8	45	33%	36	80%
Andersson [102], 1983, Denmark	Episodic	4.9	Metoprolol (200)	Frequency	Parallel	8	71	13%	39.6	85%
Borgesen [103], 1974, Denmark	Episodic	1.8	Propranolol (120)	Frequency	Crossover	12	45	33%	37.6	83%
Briggs [104], 1979, UK	Episodic	6.9	Tomolol (20)	Frequency	Crossover	6	24	4%	ns	71%
Dahlof [105], 1987, Sweden	Episodic	4.3	Propranolol (120)	Frequency	Crossover	4	29	0%	ns	83%
Diener [106], 1996, Germany	Episodic	4	Propranolol (120) Clyclandelate (1200)	Duration	Parallel	20	214	19%	39	78%
Diener [73], 2004, Germany	Episodic	5.1	Propranolol (160)	Frequency	Parallel	20	568	37%	40.8	80%
Ekbom [107], 1972, Sweden	Episodic	11.7	Pindolol (7.5, 15)	Frequency	Parallel	4	30	13%	33.7	87%
Ekbom [108], 1975, Sweden	Episodic	2.2	Alprenolol (400)	Frequency	Parallel	6	33	15%	41.3	82%
Ekbom [109],1977, Sweden	Episodic	>3	Oxprenolol	Headache Index	Crossover (1)	12	34	46%	41.8	89%
Forssman [110], 1976, Sweden	Episodic	6.9	Propranolol (240)	Frequency	Crossover	12	40	20%	37.4	97%
Forssman [111], 1983, Sweden	Episodic	>3	Atenolol (100)	Frequency	Crossover	12	24	17%	40	80%
Freitag [112], 1984, USA	Unclear	ns	Nadolol (160, 240)	Frequency	Parallel	ns	32	ns	ns	81%
Holroyd [113], 2010, USA	Episodic	5.4	Propranolol (180)	Frequency	Parallel	64	232 (35%)	35%	38.2	78%
Johannsson [114], 1987, Sweden	Episodic	>2	Atenolol (100)	Frequency	Crossover	12	Ns	14%	43	70%
Johnson [115], 1986, New Zealand	Episodic	5	Propranolol (240)	Frequency	Crossover	12	29	41%	42	69%
Kangasniemi [116], 1987, Norway	Episodic	4.3	Metoprolol (200)	Frequency	Crossover (4)	8	74	1%	37.5	79%
Langohr [175],1985, Germany	Episodic		Propranolol () Clomipramine (	Frequency	Crossover (4)	12	36	43%	44	74%
Malvea [117], 1973, USA	Episodic	>4	Propranolol (?)	Headache Index	Crossover	6	31	6%	ns	87%
Mathew [118], 1981, USA	Unclear	ns	Propranolol (75)Amitriptyline (75)	Headache Index	Parallel	24	554	22%	38	95%
Mikkelsen [119], 1986, Denmark	Episodic	>3	Propranolol (120)	Frequency	Crossover (0)	12	39	21%	ns	84%
Nadelmann [120], 1986, USA	Unclear	ns	Propranolol (240)	Headache Index	Crossover (0)	6	64	36%	ns	86%
Nanda [121], 1977, Scotland	Episodic	4.8	Acebutolol (800)	Frequency	Crossover (4)	12	43	24%	ns	74%
Pita [123], 1977, Spain	Episodic	5.5	Propranolol (160)	Headache Index	Crossover (0)	8	9	11%	32	78%
Pradalier [124], 1989, France	Episodic	6.1	Propranolol (160)	Frequency	Parallel	12	74	25%	37.5	76%
Sargent [125], 1985, USA	Episodic	>2	Propranolol (120)	Frequency	Parallel	16	161	13%	30	79%
Sjaastad [126], 1972, Norway	Episodic	7.5	Pindolol (7.5)	Frequency	Crossover (3)	4	24	17%	35.3	75%
Standnes [127], 1982, Norway,	Episodic	6.7	Propranolol (160) Timolol (20)	Frequency	Crossover	0	25	28%	ns	80%
Steiner [128], 1988, UK	Episodic	4	Metoprolol (100)	Frequency	Parallel	8	59	19%	37.6	76%
Stellar [129], 1984, USA	Episodic	6.8	Timolol (30)	Frequency	Crossover	6	107	8%	43	72%
Stensrud [130], 1976, Norway	Episodic	6.1	Propranolol (160)Inderal (160)	Headache Index	Crossover (1)	4	20	5%	ns	70%
Stensrud [131], 1980, Norway	Episodic (n = 21)	<15>15	Atenolol (100)Propranolol (160)	Frequency	Crossover (1)	6	21	20%	ns	69%
Tfelt-Hansen [132], 1984, Scandinavia	Episodic	6.0	Timolol (20)Propranolol(160)	Frequency	Crossover (2)	10	96	10%	39.5	74.5%
Van de Ven [133], 1997, Denmark	Episodic	5.5	Bisoprolol (10)	Frequency	Parallel	8	226	14%	38.7	82%
Weber [134], 1972, USA	Unclear	ns	Propranolol (80)	Headache Index	Crossover (0)	12	25	24%	40.5	52%
Wideroe [135], 1974, Norway	Episodic	3	Propranolol (160)	Headache Index	Crossover (0)	12	30	13%	38	87%
Zeigler [136], 1987, USA	Episodic	2–12	Propranolol (240)	Headache Index	Crossover (4)	4	30	ns	38	73%
Calcium Channel Blockers
Nimodipine European Migraine (with aura) Trial [137], 1989, EU	Episodic	3.3	Nimodipine (120)	Frequency	Parallel	12	89	19%	33.8	79%
Nimodipine European Migraine (Without aura) trial (1989) [138], EU	Episodic	4.4	Nimodipine (120)	Frequency	Parallel	12	192	16%	38.1	78%
Ansell [139], 1988, UK	Episodic	>2	Nimodipine (120)	Headache Index	Parallel	12	68	16%	ns	71%
Gelmers [140], 1983, Netherlands	Episodic	9.1	Nimodipine (120)	Headache Index	Parallel	12	60	17%	30	62%
Havanka-Kanniainen [141], 1985, Finland	Episodic	7.9	Nimodipine (120)	Frequency	Crossover (0)	8	33	12%	33	85%
Leandri [142], 1990, Italy	Episodic	4.3	Nicardipine (40)	Frequency	Crossover (ns)	8	35	15%	ns	ns
Markley [143], 1984, USA	Episodic	3.4	Verapamil (240)	Frequency	Crossover (ns)	8	20	30%	33	86%
McArthur [144], 1989, USA	Episodic	2.3	Nifedipine (90)	Frequency	Crossover (1)	12	24	42%	ns	ns
Shukla [145], 1995, UK	Episodic	10.4	Nifedipine (15)	Frequency	Crossover (ns)	6	36	22%	22.8	50%
Solomon [146], 1983, USA	Episodic	6.7	Verapamil (320)	Frequency	Crossover (ns)	6	12	52%	38	78%
Stewart [147], 1988, Canada	Episodic	6.3	Nimodipine (120)	Frequency	Parallel	8	37	19%	ns	ns
Flunarizine
Diamond [148], 1992, USA	Episodic	4.3	Flunarizine (10)	Frequency	Parallel	20	143	8%	34.8	74%
Frenken [149], 1984, Netherlands	Episodic	3.6	Flunarizine (10)	Frequency	Parallel	12	35	0%	NS	83%
Louis [150], 1981, Belgium	Episodic	1.2	Flunarizine (10)	Frequency	Parallel	12	58	0%	29	50%
Mendenopoulos [151], 1985, Greece	Episodic	4	Flunarizine (10)	Headache Index	Parallel	12	20	0%	44	80%
Pini [152], 1986, Italy	Episodic	9.9	Flunarizine (20)	Headache Index	Parallel	4	18	0%	40.2	83%
Sorensen [153], 1986, Denmark	Episodic	3	Flunarizine (10)	Frequency	Crossover (4)	16	29	7%	40	79%
Thomas [154], 1991, India	Episodic	6.7	Flunarizine (10)	Headache Index	Crossover (2)	12	29	48%	30.5	87%
Selective Serotonin Reuptake Inhibitor
Adly [155], 1993, USA.	Episodic	>4	Fluoxetine (40)	Headache Index	Parallel	10	32	44%	37.5	83%
d'Amato [156], 1999, Italy.	Episodic	1–4	Fluoxetine (20)	Headache Index	Parallel	20	52	0%	37.6	63%
Landy [157], 1998, USA.	Episodic	>2	Sertraline (50)	Headache Index	Parallel	8	27	41%	36	93%
Steiner [159], 1998, UK.	Episodic	3.9	s-Fluoxetine (40)	Frequency	Parallel	12	53	32%	37	75%
Zeeberg [160], 1981, Sweden	Episodic	3.5	Femoxitine (300)	Headache Index	Parallel	12	59	ns	ns	ns
Serotonin Norepinephrine Reuptake Inhibitor
Ozyalcin [161], 2004, Turkey	Episodic	2.3	Venlafaxine (75, 150)	Frequency	Parallel	8	60	17%	36.5	83%
Serotonin Agonist
Arthur [162], 1971, New Zealand	Episodic	8.1	Pizotifen (3.0)	Frequency	Crossover (ns)	4	63	17%	ns	ns
Bellavance [163], 1990, Canada	Episodic	6.7	Pizotifen (1.5)	Frequency	Parallel	12	176	14%	32.5	79%
Carroll [164], 1975, UK	Episodic	>3	Pizotifen (3.0)	Headache Index	Crossover (2)	4	27	48%	ns	ns
Cleland [165], 1997, UK	Episodic	3.4	Pizotifen (2.0)	Frequency	Crossover (ns)	12	130	32%	40.5	63%
Hughes [166], 1971, UK	Episodic	9.1	Pizotifen (0.5)	Frequency	Crossover (ns)	12	26	0%	ns	81%
Kangasniemi [167], 1979, Finland	Episodic	4.3	Pizotifen (1.5)	Frequency	Crossover (0)	7	50	22%	36	80%
Lance, 1968			Pizotifen
Lawrence [168], 1977, UK	Episodic	>4	Pizotifen (1.5)	Headache Index	Parallel	12	36	14%	ns	79%
Osterman [169], 1977, Sweden	Episodic	5.1	Pizotifen (0.5)	Frequency	Crossover (2)	8	30	10%	37	70%
Ryan [170], 1968, USA	Episodic	8.9	Pizotifen (4)	Frequency	Crossover (ns)	4	62	ns	ns	ns
Tricyclic Antidepressants
Couch [241], 1976, USA	Episodic	6.9	Amitriptyline (100)	Headache Index	Parallel	4	73	36%	NS	64%
Couch [171], 1979	Episodic	6.9	Amitriptyline (100)	Frequency	Parallel	8	162	38%	NS	85%
Couch [172], 2011, USA	Episodic	7.6	Amitriptyline (100)	Frequency	Parallel	16	391	51%	34.9	81%
Gomersall [173], 1973, UK	Episodic	2.7	Amitriptyline (60)	Frequency	Crossover (0)	26	20	20%	42	75%
Jacobs [174], 1972, UK	Episodic	3.3	Opipramol (75)	Frequency	Parallel	12	27	43%	42	78%
Langohr [175], 1985, Germany	Episodic	>4	Clomipramine (100)	Frequency	Crossover (4)	4	36	43%	44	67%
Mathew [118], 1981, USA	Unclear	Unclear	Amitriptyline (75)	Headache Index	Parallel	24	554	22%	38	95%
Noone [177], 1980, UK	Episodic	6	Clomipramine (30)	Frequency	Crossover	4	10	50%	Ns	70%
Ziegler [136], 1987, USA	Episodic	2–12	Amitriptyline (100)	Headache Index	Crossover (1)	8	30	0%	38	73%

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Table 3. Study characteristics of included randomized trials of treatment of chronic (≥15 headaches/month) migraine headaches.

Alpha Blocker
Saper [59], 2002, USA	Chronic	ns	Tizanidine (24)	Headache Index	Parallel	12	136	32%	40	79%
Anticonvulsant
Diener [74], 2007, Italy	Chronic	15.9	Topiramate (100)	Frequency	Parallel	24	59	36%	46.1	75%
Mei [84], 2006, Italy	Chronic	24	Topiramate (100)	Frequency	Parallel	12	50	42%	45.8	69%
Silberstein [89], 2007, USA	Chronic	17.0	Topiramate (100)	Frequency	Parallel	16	306	46%	38.2	85%
Silvestrini [92], 2003, Italy	Chronic	20	Topiramate (50)	Frequency	Parallel	8	28	0%	43.5	64%
Yurekli, 2008, Turkey	Chronic	22	Valproate (1000)	Frequency	Parallel	12	29	9%	40.4	83%
Beta-Blockers
Palferman [122], 1983, UK	Chronic	12.1	Propranolol (120)	Frequency	Crossover(?)	8	22	39%	37.8	73%
Stensrud [131], 1980, Norway	Chronic	>15	Atenolol (100) Propranolol (160)	Frequency	Crossover (1)	6	7	20%	ns	69%
Chronic Daily Headache (>15 Headaches/Month)
Anticonvulsants
Beran[68], 2010, Australia	Chronic Daily Headache	19.6	Levetiracetam (3000)	Frequency	Crossover (1)	11	96	30%	48.8	53%
Sarchielli [86], 2014, Italy	Chronic Daily Headache (Medication overuse)	21.8	Valproate (800)	Frequency	Parallel	24	88	17%	ns	90%
Spira [93], 2003,Australia	Chronic Daily Headache	27.4	Gabapentin (2400)	Frequency	Crossover (1)	8	133	17%	43	69%
Yurekli [99], 2008, Turkey	Chronic Daily	22.7	Valproate (1000)	Frequency	Parallel	12	29	0%	40.4	83%
Selective Serotonin Reuptake Inhibitor
Saper [158], 1994, USA	Chronic Daily	>16	Fluoxetine (40)	Frequency	Parallel	12	111	5	36.5	87%
Stensrud [131], 1980, Norway	Episodic (n = 21)Chronic (n = 7)	<15>15	Atenolol (100) Propranolol (160)	Frequency	Crossover (1)	6	35	20%	ns	69%

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Overall, the studies varied in quality. Quality ratings for placebo controlled trials are given in Table 4. By Jadad criteria, 34% of studies had scores ≤ 3.0, suggesting low quality, 39% had scores between 3 and 5 consistent with modest quality and only 37% had scores ≥ 5 suggesting high quality. Only 36% used an intention to treat analysis, 27% assessed compliance, 26% had concealed allocation, and 51% had adequate blinding. There was no difference in the overall effect sizes for placebo controlled trials using Jadad criteria as a scale (p = 0.44) or when coded as high, modest or low quality (p = 0.37), or when assessed by most of the specific Jadad or Cochrane Risk of Bias quality characteristics (compliance p = 0.59; blinding p = 0.36; adequacy of blinding p = 0.50, industry sponsorship p = 0.52; incomplete outcome reporting p = 0.96, reporting of withdrawals p = 0.24). However, trials which had inadequate concealed allocation had significantly (p = 0.02) higher reported effects (SMD: -0.52, 95% CI: -0.63 to -0.41) than those who had concealed allocation (SMD: -0.26, 95% CI: -0.34 to 0.17).

Table 4. Quality Ratings of included placebo controlled trials.

			Cochrane Risk of Bias
Study	Jadad Score (0–8)	Intention to Treat	Adequate sequence generation	Adequate concealed allocation	Adequate Blinding	Incomplete outcome data addressed	Free of selective outcome reporting	Free of “other” bias	Industry sponsored
EPISODIC MIGRAINES
Alpha Blockers
Adam, 1978, UK	2	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	No
Boison, 1978, Sweden	2	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	No
Bredfeldt, 1989, USA	5	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Yes
Lynggaard, 1975, Denmark	4	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Mondrup, 1977, Denmark	6	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	No
Ryan, 1975, USA	1	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	No
Shafar, 1972, UK	4	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Yes
Stensrud, 1976, Norway	0	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	No
Antiogensin Enzyme Converting Inhibitors
Schrader (2001), Norway, Lisinopril	6	Yes	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Yes
Angiotensin Receptor Blocker
Diener (2009), Germany, Telmisartan	3	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Yes
Trovnik (2003) Norway, Candesartan	8	Yes	Yes	Yes	Yes	Unclear	Unclear	Unclear	Yes
Anticonvulsants
Brandes, 2004, Canada/USA, Topiramate	8	Yes	Yes	Yes	Yes	Yes	Yes	Unclear	Yes
Cady, 2009, USA, Carisbamate	8	Yes	Yes	Yes	Yes	Unclear	Unclear	Unclear	Yes
de Tommaso, 2007, Italy, Topiramate, Levitracetam	4	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Di’ Trapani, 2000, Italy, Gabapentin	4	Yes	Unclear	Unclear	Unclear	Yes	Unclear	Unclear	Unclear
Diener, 2004 Europe, Topiramate, Propropranolol	6	Yes	Unclear	Unclear	Unclear	Yes	Yes	Unclear	Yes
Diener, 2007, Italy, Topiramate	8	No	Yes	Yes	Yes	Yes	Unclear	Unclear	Unclear
Edwards, 2003, USA, Topiramate	4	Yes	Unclear	Unclear	Unclear	Yes	Unclear	Unclear	Yes
Freitag, 2002, USA, divalproex	8	Yes	Yes	Yes	Yes	Yes	Unclear	Unclear	Yes
Gupta, 2007, India, Topiramate	8	Yes	Yes	Yes	Yes	Yes	Unclear	No	Unclear
Hering 1992, Israel, Valproate	4	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Jensen,1994, Denmark, Valproate	6	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Yes
Klapper,1997, USA, Divalproex	4	Yes	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Yes
Lipton, 2011, USA, Topiramate	8	Yes	Yes	Yes	Yes	Yes	No	Unclear	Yes
Mathew, 1995, USA, Valproate	6	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Yes
Mathew, 2001, USA, Gabapentin	6	Yes	Yes	Unclear	Unclear	Unclear	Unclear	Unclear	Yes
Rompel, 1970, S Africa, Carbamazepine	5	No	Yes	Yes	Yes	Yes	Yes	Unclear	Yes
Silberstein,2004, USA, Topiramate	6	Yes	Yes	Yes	Unclear	Yes	Unclear	Unclear	Yes
Silberstein, 2006, USA, Topiramate	4	Yes	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Yes
Silberstein, 2008, USA, Oxcarbazepine	8	Yes	Yes	Yes	Yes	Yes	Unclear	Unclear	Yes
Steiner,1997, UK, Lamotrigine	6	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Unclear
Stensrud,1979, Norway, Clonazepam	2	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Storey,2001, USA, Topiramate	4	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Yes
Vahedi,2002, France, Acetazolamide	6	Yes	Yes	Yes	Yes	Yes	Yes	Unclear	Yes
Beta Blockers
Ahuja, 1985, India, Propanolol	2	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Yes
Al-Qassab, 1993, England, Propanolol	3	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Yes
Andersson, 1983, Denmark, Metoprolol	2	Yes	Unclear	Unclear	Yes	No	Unclear	Unclear	Unclear
Borgesen, 1974, Denmark, Propranolol	4	No	Unclear	Unclear	Yes	No	No	No	Unclear
Dahlof, 1987, Sweden, Propranolol	5	Yes	Unclear	Unclear	Yes	No	No	No	Unclear
Diener, 1996, Germany, Propranolol, Clyclandelate	4	Yes	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Diener, 2004, Germany, Propranolol	6	Yes	Unclear	Unclear	Unclear	Yes	Yes	Unclear	Yes
Ekbom, 1972, Sweden, Pindolol	2	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Ekbom, 1975, Sweden, Alprenolol	2	No	Unclear	Unclear	Unclear	Yes	Unclear	Unclear	Yes
Forssman, 1976, Sweden, Propranolol	6	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Yes
Forssman, 1983, Sweden, Atenolol	2	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Yes
Freitag, 1984, USA, Nadolol	3	Yes	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Unclear
Holroyd, 2010, USA, Propanolol	6	Yes	Yes	Yes	Yes	Yes	Yes	Unclear	Unclear
Johannsson, 1987, Sweden, Atenolol	2	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Johnson, 1986, New Zealand, Propanolol	3	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Unclear
Kangasniemi, 1987, Norway, Metoprolol	0	4	Yes	Unclear	Unclear	Unclear	Yes	Unclear	Unclear
Malvea, 1973, USA, Propanolol	4	Yes	Unclear	Unclear	Unclear	Yes	Unclear	Unclear	Unclear
Mathew, 1981, USA, Propanolol, Amitriptyline	2	No	Unclear	Unclear	No	No	No	Yes	Unclear
Mikkelsen, 1986, Denmark, Propanolol	6	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Yes
Nadelmann, 1986, USA, Propanolol	6	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Yes
Nanda, 1977, Scotland, Acebutolol	2	No	Unclear	Unclear	Unclear	No	Unclear	Unclear	Yes
Pita, 1977, Spain, Propranolol	6	No	No	Unclear	Yes	Yes	Unclear	Unclear	Yes
Pradalier, 1989, France, Propranolol	5	Yes	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Unclear
Sargent, 1985, USA, Propranolol	4	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Sjaastad, 1972, Norway, Pindolol	5	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Unclear
Standnes, 1982, Norway, Propranolol, Timolol	4	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Yes
Steiner, 1988, UK, Metoprolol	6	No	Unclear	Unclear	Yes	No	No	Unclear	Unclear
Stellar, 1984, USA, Timolol	7	No	Yes	Unclear	Yes	No	Unclear	Unclear	Unclear
Stensrud, 1976, Norway, Propranolol, Inderal	5	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Yes
Tfelt-Hansen, 1984, Scandinavia, Timolol, Propranolol	6	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Unclear
Van de Ven, 1997, Denmark, Bisoprolol	4	Yes	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Wideroe, 1974, Norway, Propranolol	4	No	Unclear	Unclear	Yes	No	Unclear	Unclear	Yes
Zeigler, 1987, USA, Propranolol	3	No	Unclear	Unclear	Yes	Yes	Unclear	Unclear	No
Calcium Channel Blockers
Ansell, 1988, UK, Nimodipine	3	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Gelmers, 1983, Netherlands, Nimodipine	4	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Havanka-Kanniainen, 1985, Finland, Nimodipine	4	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Yes
Leandri, 1990, Italy, Nicardipine	3	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Yes
Markley, 1984, USA, Verapamil	3	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
McArthur, 1989, USA, Nifedipine	3	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Yes
Nimodipine European Migraine (with aura) Trial, 1989, EU, Nimodipine	2	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Nimodipine European Migraine (Without aura) trial (1989), EU, Nimodipine	5	Yes	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Unclear
Shukla, 1995, UK, Nifedipine	5	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Unclear
Solomon, 1983, USA, Verapamil	5	No	Unclear	Unclear	Yes	No	No	Unclear	Yes
Stewart, 1988, Canada, Nimodipine	2	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Flunarazine
Diamond, 1993, USA,	2	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Frenken, 1984, Netherlands, Flunarizine	6	Yes	Unclear	Unclear	Yes	Yes	Unclear	Unclear	Yes
Louis, 1981, Belgium, Flunarizine	5	Yes	Unclear	Unclear	Yes	Yes	Yes	Unclear	No
Mendenopoulos, 1985, Greece, Flunarizine	7	Yes	Yes	Yes	Yes	Yes	Unclear	Unclear	Yes
Pini, 1986, Italy, Flunarizine	2	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Sorensen, 1986, Denmark, Flunarizine	4	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Thomas, 1991, India, Flunarizine	3	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Unclear
Selective Serotonin Reuptake Inhibitors
Adly, 1993, USA, Fluoxetine	2	No	Unclear	Yes	Unclear	No	No	Unclear	Unclear
d'Amato, 1999, Italy, Fluoxetine	5	No	Unclear	Unclear	Yes	No	No	Unclear	Unclear
Landy, 1998, USA, Sertaline	3	No	Unclear	Unclear	Unclear	No	No	Unclear	No
Steiner, 1998, UK, s-Fluoxetine	6	No	Unclear	Unclear	Yes	No	No	Unclear	Unclear
Zeeberg, 1981, Sweden, Femoxitine	2	No	No	No	No	Unclear	Unclear	Unclear	Unclear
Serotonin Norepinephrine Reuptake Inhibitor
Ozyalcin, 2004, Turkey, Venlafaxine	3	No	Unclear	Unclear	Unclear	No	No	Unclear	Yes
Serotonin Agonist (Pizotifen)
Arthur, 1971, New Zealand, Pizotifen	2	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Yes
Bellavance, 1990, Canada, Pizotifen	4	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Carroll, 1975, UK, Pizotifen	4	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Cleland, 1997, UK, Pizotifen	4	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Hughes, 1971, UK, Pizotifen	4	Yes	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Kangasniemi, 1979, Finland, Pizotifen	4	Yes	Unclear	Unclear	Unclear	Yes	Unclear	Unclear	Unclear
Lance, 1968, Pizotifen
Lawrence, 1977, UK, Pizotifen	4	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Unclear
Osterman, 1977, Sweden, Pizotifen	5	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Unclear
Ryan, 1968, USA, Pizotifen	5	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Tricyclic Antidepressants
Couch, 1976, USA, Amitriptyline	3	No	Unclear	Unclear	Yes	No	Unclear	Yes	Yes
Couch, 1979, Amitriptyline	6	No	Unclear	Unclear	Yes	No	Unclear	Unclear	Yes
Couch, 2011, USA, Amitriptyline	8	No	Yes	Yes	Yes	No	Unclear	Unclear	Yes
Gomersall, 1973, UK, Amitriptyline	3	No	Unclear	Unclear	Unclear	No	No	Yes	Yes
Jacobs, 1972, UK, Opipramol	4	No	Unclear	Yes	Yes	No	No	Yes	Yes
Langohr, 1985, Germany, Clomipramine	4	No	Unclear	Unclear	Unclear	No	No	Yes	Yes
Morland, 1979, Norway, Doxepin	3	No	Unclear	Unclear	Unclear	No	Unclear	Yes	Unclear
Noone, 1980, UK, Clomipramin	4	No	Yes	Yes	Unclear	No	Unclear	Yes	Yes
Ziegler, 1987, USA, Amitriptyline	3	No	Unclear	Unclear	Yes	Yes	Unclear	Unclear	No
CHRONIC MIGRAINES
Alpha-blockers
Saper, 2002, USA	6	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Yes
Anticonvulsants
Diener, 2007, Italy, Topiramate	8	No	Yes	Yes	Yes	Yes	Unclear	Unclear	Unclear
Mei, 2006, Italy, Topiramate	4	Yes	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Silberstein, 2007, USA, Topiramate	8	Yes	Yes	Yes	Yes	Yes	Unclear	Unclear	Yes
Silvestrini, 2003, Italy, Topiramate	4	Yes	Unclear	Unclear	Unclear	Yes	Unclear	Unclear	Unclear
Beta Blockers
Palferman, 1983, UK, Propranolol	3	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
CHRONIC DAILY HEADACHE
Anticonvulsants
Beran, 2010, Australia, Levetiracetam	5	No	Yes	Yes	Unclear	Unclear	Unclear	Unclear	Yes
Spira, 2003, Australia, Gabapentin	4	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Yurekli, 2008, Turkey, Valproate	4	No	Unclear	Unclear	Yes	Yes	Unclear	Unclear	Unclear
Selective Serotonin Reuptake Inhibitors
Saper, 1994, USA, Fluoxetine	8	No	Yes	Yes	Yes	Unclear	Unclear	Unclear	Yes
MIXED (CHRONIC + EPISODIC)
Anticonvulsants
Ghose, 2002, New Zealand, Vigabatrin	4	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Beta Blockers
Stensrud, 1980, Norway, Atenolol	5	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Yes
Unclear Migraine Headache Type
Beta Blockers
Freitag, 1984, USA, Nadolol	3	Yes	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Unclear
Mathew, 1981, USA, Propranolol, Amitriptyline	2	No	Unclear	Unclear	No	No	No	Yes	Unclear
Nadelmann, 1986, USA, Propranolol	6	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Yes
Weber, 1972, USA, Propranolol	3	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Yes
Selective Serotonin Reuptake Inhibitors
Saper, 1994, USA, Fluoxetine	8	No	Yes	Yes	Yes	Unclear	Unclear	Unclear	Yes
Tricyclic Antidepressants
Mathew, 1981, USA, Amitriptyline	2	No	Unclear	Unclear	No	No	No	Yes	Unclear

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Alpha-blockers

There were 9 trials comparing alpha blockers to placebo with a total of 4590 participants who averaged 39.3 (range 12–76) years in age with 84% women (Table 2). All of the studies measured headache frequency. Eight of these trials focused on episodic migraine headaches; all studied clonidine. One trial focused on chronic migraines using tizanidine. The average rate of withdrawals was 32%. Studies averaged 11 weeks (range 4–82) with a mean of 71.3 participants (range 11–67). At no time point was clonidine more effective than placebo for episodic migraines (Table 5, Fig 2) and tizanidine was no more effective than placebo for chronic migraine headaches (Table 6). None of these trials reported on the likelihood of a 50% reduction in headaches.

Table 5. Placebo Controlled Randomized Clinical Trials of Continuous Outcomes among patients with episodic migraines (<15 headaches/month).

Drug	Time Point (weeks)	Metric	Study (Year)	Pooled Mean Difference (95% CI)	Heterogeneity
Alpha Blockers
Clonidine	8	Headaches/month	Boisen (1978)	-0.09 (-0.99 to 0.80)
	8	Headaches/month	Bredfeldt (1989)	-0.96 (-2.6 to 0.64)
	8	Headaches/month	Ryan (1975)	-0.46 (-2.7 to 1.8)
	8	Headaches/month	Shafar (1972)	-0.72 (-1.6 to 0.14)
	8	Headaches/month	Stensrud (1976)	-1.0 (-3.1 to 1.1)
	8		Pooled (HA/Month):	-0.52 (-1.06 to 0.02)	Q = 1.57, df = 4, I² = 0.0%
	12	Headaches/month	Lynggaard (1975)	-0.37 (-3.4 to 2.)
	12	Headaches/month	Mondrup (1977)	1.1 (-2.5 to 4.8)
	12		Pooled (HA/Month):	0.24 (-2.1 to 2.6)	Q = 0.38, df = 1, I² = 0.0%
	24	Headaches/month	Adam (1978)	0.00 (-0.47 to 0.47)
Angiotensin Converting Enzyme Inhibitors
Enalapril	4	Headaches/month	Sonbolestan (2013)	-2.4 (-7.5 to 2.7)
Enalapril	8	Headaches/month	Sonbolestan (2013)	-0.83 (-6.2 to 4.5)
Lisinopril	12	Headaches/month	Schrader (2001)	-1.4 (-2.6 to -0.2)
Captopril	16	Headache Index	Paterna (1992)	-0.86 (-1.5 to -0.21)
Angiotensin Receptor Blockers
Candesaran	12	Headaches/month	Stovner (2013)	-0.58 (-1.4 to 0.23)
	12	Headaches/month	Trovnik (2003)	-1.6 (-3.0 to -0.16)
	12		Pooled (HA/Month)	-0.9 (-1.8 to 0.03)	Q = 1.46, df = 1, I² = 31.7%
Telmisartan	12	Headaches/month	Diener (2009)	-1.9 (-3.6 to -0.23)	—
Telmisartan	12		Pooled (HA/Month)	-1.1 (-1.9 to -0.27)	Q = 2.82, df = 3 I ² = 29.1%
Anticonvulsants
Acetazolamide	12	Headaches/month	Vahedi (2002)	0.5 (-1.7 to 2.7)
Carbamazipine	6	Headaches/month	Rompel (1970)	-3.2 (-6.6 to 0.20)
Carisbamate	14	Headaches/month	Cady (2009)	-0.09 (-0.34 to 0.17)
Clonazepam	4	Headaches/month	Stensrud (1979)	-3.6 (-7.2 to 0.03))
Gabapentin	4	Headaches/month	Di’Trapani	-0.2 (-1.6 to 1.2)
	8	Headaches/month	Di”Trapani	-1.1 (-2.5 to 0.34)
	12	Headaches/month	Di’ Trapani (2000)	-1.9 (-3.4 to -0.41)
	12	Headaches/month	Mathew (2001)	-0.2 (-0.89 to 0.49)
	12		Pooled (HA/Month)	—0.92 (-2.6 to 0.74)	Q = 4.1, df = 2, I2 = 75.6%
	20	Headaches/month	Silberstein (2013)	-0.33 (-0.71 to 0.04)
Lamotrigine	4	Headaches/month	Gupta (2006)	-1.2 (-2.2 to -0.18)
Lamotrigine	12	Headaches/month	Steiner (1997)	0.20 (-0.36 to 0.76)
Levetiracetam	8	Headaches/month	De Tommaso (2007)	-4.2 (-7.2 to -1.3)
	12	Headaches/month	Verma (2013)	-2.2 (-3.0 to -1.3)
			Pooled (HA/Month)	-2.7 (-4.4 to -0.97)	Q = 1.69, df = 1 I² = 40.9%
Oxcarbazepine	15	Headaches/month	Silberstein (2008)	0.17 (-0.13 to 0.47)
Topiramate	4 (50 mg/day)	Headaches/month	Brandes (2004)	-0.75 (-1.4 to -0.06)
	4 (50 mg/day)	Headaches/month	Gupta (2006)	-2.1 (-3.0 to -1.1)
	4 (50 mg/day)	Headaches/month	Silberstein (2004)	-1.0 (-1.9 to– 0.13)
	4 (50 mg/day)	Headaches/month	Silvestrini (2003)	-5.0 (-9.2 to -0.8)
	4 (50 mg/day)		Pooled (HA/Month)	-1.4 (-2.2 to -0.5)	Q = 7.81, df = 3, I² = 43.0%
Topiramate	4 (100 mg/day)	Headaches/month	Brandes (2004)	-0.80 (-1.4 to -0.18)
	4 (100 mg/day)	Headaches/month	Diener (2004)	-1.1 (-1.9 to -0.2)
	4 (100 mg/day)	Headaches/month	Silberstein (2004)	-0.9 (-1.7 to -0.14)
	4 (100 mg/day)		Pooled (HA/Month)	-0.89 (-1.3 to -0.48)	Q = 0.23, df = 2, I2 = 0.0%
	4 (200 mg/day)	Headaches/month	Brandes (2004)	-1.9 (-2.4 to -1.3)
	4 (200 mg/day)	Headaches/month	Edwards (2003)	-0.60 (-1.1 to -0.13)
	4 (200 mg/day)	Headaches/month	Silberstein (2004)	-1.4 (-2.2 to -0.62)
	4 (200 mg/day)	Headaches/month	Silberstein (2006)	-0.9 (-2.3 to 0.55)
	4 (200 mg/day)		Pooled (HA/Month)	-0.91 (-1.3 to -0.48)	Q = 12.07, df = 3 I2 = 75.1%
	4 (all doses)		Pooled (HA/Month)	-1.1 (-1.5 to-0.79)	Q = 21.3, df = 10, I² = 53%
	8 (50 mg/day)	Headaches/month	Brandes (2004)	-0.50 (01.2 to 0.19)
	8 (50 mg/day)	Headaches/month	Silberstein (2004)	-0.80 (-1.4 to -0.20)
	8 (50 mg/day)	Headaches/month	Silberstein (2006)	-12.5 (-17.1 to -7.9)
	8 (50 mg/day)	Headaches/month	Pooled (HA/Month)	-2.3 (-4.4 to -0.23)	Q = 25.56, df = 2, I² = 92.2%
	8 (100 mg/day)	Headaches/month	Brandes (2004)	-0.8 (-1.4 to -0.18)
	8 (100 mg/day)	Headaches/month	De Tammosa (2007)	-5.2 (-7.8 to -2.5)
	8 (100 mg/day)	Headaches/month	Diener (2004)	-0.85 (-2.1 to 0.39)
	8 (100 mg/day)	Headaches/month	Silberstein (2004)	-1.1 (-1.7 to -0.53)
	8 (100 mg/day)		Pooled (HA/Month)	-1.3 (-2.2 to -0.43)	Q = 10.18, df = 3, I²70.5%
	8 (200 mg/day)	Headaches/month	Brandes (2004)	-1.8 (-2.3 to -1.3)
	8 (200 mg/day)	Headaches/month	Silberstein (2004)	-1.5 (-2.1 to -0.9)
	8 (200 mg/day)	Headaches/month	Silberstein (2006)	-0.30 (-1.7 to 1.1)
	8 (200 mg/day)		Pooled (HA/Month)	-1.5 (-2.1 to -0.87)	Q = 3.68, df = 2, I² = 45.7%
	8 (All Doses)		Pooled (HA/Month)	-1.3 (-1.9 to -0.7)	Q = 46.42, df = 9, I² = 80.6%
	12 (50 mg/day)	Headaches/month	Brandes (2004)	-0.40 (-1.1 to 0.29)
	12 (50 mg/day)	Headaches/month	Silberstein (2004)	-0.70 (-1.4 to 0.02)
	12 (50 mg/day)		Pooled (HA/Month):	-0.54 (-1.0 to -0.05)	Q = 0.39, df = 2, I² = 0.0%
	12 (100 mg/day)	Headaches/month	Brandes (2004)	-0.75 (-1.4 to -0.13)
	12 (100 mg/day)	Headaches/month	Diener (2004)	-0.90 (-2.2 to 0.39)
	12 (100 mg/day)	Headaches/month	Silberstein (2004)	-1.1 (-2.0 to -0.19)
	12 (100 mg/day)		Pooled (HA/Month):	-0.87 (-1.3 to -0.39)	Q = 1.52, df = 2, I² = 0.0%
	12 (200 mg/day)	Headaches/month	Brandes (2004)	-1.7 (-2.2 to -1.1)
	12 (200 mg/day)	Headaches/month	Silberstein (2004)	-1.4 (-2.2 to -0.59)
	12 (200 mg/day)	Headaches/month	Silberstein (2006)	-0.70 (-2.1 to 0.75)
	12 (200 mg/day)		Pooled (HA/Month):	-1.5 (-1.9 to -1.1)	Q = 0.35, df = 1, I² = 0.0%
	12 (All doses)		Pooled (HA/Month):	-0.99 (-1.3 to -0.64)	Q = 0.04, df = 1, I² = 0.0%
	16 (50 mg/day)	Headaches/month	Brandes (2004)	-0.50 (-1.2 to 0.19)
	16 (50 mg/day)	Headaches/month	Silberstein (2004)	-0.40 (-1.1 to 0.33)
	16 (50 mg/day)		Pooled (HA/Month):	-0.45 (-0.95 to 0.05)	Q = 0.04, df = 1, I² = 0.0%
	16 (100 mg/day)	Headaches/month	Brandes (2004)	-0.70 (-1.3 to -0.08)
	16 (100 mg/day)	Headaches/month	Diener (2004)	-1.1 (-2.4 to 0.24)
	16 (100 mg/day)	Headaches/month	Silberstein (2004)	-1.2 (-2.0 to -0.38)
	16 (100 mg/day)	Headaches/month	Silberstein (2007)	-1.5 (-3.1 to 0.06)
	16 (100 mg/day)		Pooled (HA/Month):	-0.95 (-1.4 to -0.51)	Q = 1.51, df = 3, I² = 0.0%
	16 (200 mg/day)	Headaches/month	Brandes (2004)	-1.6 (-2.1 to -1.1)
	16 (200 mg/day)	Headaches/month	Silberstein (2004)	-1.3 (-2.2 to -0.45)
	16 (200 mg/day)	Headaches/month	Silberstein (2006)	-0.05 (-1.5 to 1.4)
	16 (200 mg/day)	Headaches/month	Storey (2001)	-0.52 (-1.67 to 0.63)
	16 (200 mg/day)		Pooled (HA/Month):	-1.0 (-1.7 to -0.44)	Q = 5.76, df = 3, I² = 47.9%
	16 (All doses)		Pooled (HA/Month):	-0.92 (-1.2 to -0.59)	Q = 13.41, df = 9, I² = 32.9%
	20 (50mg/day)	Headaches/month	Brandes (2004)	-0.50 (-1.2 to 0.19)
	20 (50mg/day)	Headaches/month	Silberstein (2004)	-0.55 (-1.5 to 0.40)
	20 (50mg/day)		Pooled (HA/Month):	-0.52 (-1.1 to 0.04)	Q = 0.01, df = 1, I² = 0.0%
	20 (100 mg/day)	Headaches/month	Brandes (2004)	-0.70 (-1.3 to -0.08)
	20 (100 mg/day)	Headaches/month	Diener (2004)	-1.2 (-2.6 to 0.17)
	20 (100 mg/day)	Headaches/month	Silberstein (2004)	-1.4 (-2.3 to -0.39)
	20 (100 mg/day)		Pooled (HA/Month):	-0.93 (-1.4 to -0.44)	Q = 1.42, df = 2, I² = 0.0%
	20 (200 mg/day)	Headaches/month	Brandes (2004)	-1.5 (-2.0 to -0.95)
	20 (200 mg/day)	Headaches/month	Silberstein (2004)	-1.4 (-2.3 to -0.36)
	20 (200 mg/day)	Headaches/month	Silberstein (2006)	-0.50 (-1.9 to 0.95)
	20 (200 mg/day)		Pooled (HA/Month):	-1.4 (-1.8 to 0.92)	Q = 1.61, df = 2, I² = 0.0%
	20 (all doses)		Pooled (HA/Month):	-0.98 (-1.3 to -0.66)	Q = 8.52, df = 7, I² = 17.8%
	24 (50 mgday)	Headaches/month	Brandes (2004)	-0.40 (-1.2 to 0.44)
	24 (50 mgday)	Headaches/month	Silberstein (2004)	-0.50 (-1.5 to 0.48)
	24 (50 mgday)		Pooled (HA/Month):	-0.44 (-1.1 to 0.20)	Q = 0.02, df = 1, I² = 0.0%
	24 (100 mg/day)	Headaches/month	Brandes (2004)	-1.0 (-1.8 to -0.18)
	24 (100 mg/day)	Headaches/month	Lipton (2011)	-1.4 (-2.2 to -0.60)
	24 (100 mg/day)	Headaches/month	Silberstein (2004)	-1.3 (-2.3 to -0.34)
	24 (100 mg/day)		Pooled (HA/Month):	-1.2 (-1.7 to -0.74)	Q = 0.49, df = 2, I² = 0.0%
	24 (200 mg/day)	Headaches/month	Brandes (2004)	-1.5 (-2.2 to -0.84)
	24 (200 mg/day)	Headaches/month	Silberstein (2004)	-1.3 (-2.3 to -0.31)
	24 (200 mg/day)		Pooled (HA/Month):	-1.4 (-2.0 to -0.89)	Q = 0.11, df = 1, I² = 0.0%
	24 (All doses)		Pooled (HA/Month):	-1.1 (-1.4 to -0.77)	Q = 6.4, df = 6, I² = 6.4%
Valproate	4	Headaches/month	Freitag (2002)	-0.20 (-0.61 to 0.21)
	4	Headaches/month	Klapper (1997)	-1.8 (-2.6 to -0.95)
	4	Headaches/month	Mathew (1995	-1.8 (-3.6 to -0.03)
	4		Pooled (HA/Month):	-1.4 (-2.2 to -0.56)	Q = 14.48, df = 2, I² = 51.6%
	8	Headaches/month	Freitag (2002)	-0.25 (-0.51 to 0.01)
	8	Headaches/month	Hering (1992)	-6.8 (-12.10 to -1.5)
	8	Headaches/month	Klapper (1997)	-1.6 (-2.3 to -0.95)
	8	Headaches/month	Mathew (1995)	-2.1 (-3.6 to -0.56)
	8		Pooled (HA/Month):	-1.5 (-2.2 to -0.76)	Q = 17.35, df = 3. I² = 42.6%
	12	Headaches/month	Freitag (2002)	-0.45 (-0.86 to -0.04)
	12	Headaches/month	Jensen (1994)	-2.6 (-5.5 to 0.26)
	12	Headaches/month	Klapper (1997)	-1.7 (-2.4 to -0.96)
	12	Headaches/month	Mathew (1995)	-2.8 (-4.8 to -0.74)
	12		Pooled (HA/Month):	-1.5 (-2.1 to -0.80)	Q = 24.7, I² = 63.6%
Vigabatrin	4	Headaches/month	Ghose (2002)	-0.54 (-1.9 to 0.77)
	8	Headaches/month	Ghose (2002)	-0.27 (-2.3 to 1.7)
	12	Headaches/month	Ghose (2002)	-0.42 (-2.3 to 1.6)
Beta-Blockers
Acebutolol	4	Headaches/month	Nanda (1977)	0.10 (-0.75 to 0.95)
	8	Headaches/month	Nanda (1977)	-0.50 (-1.35 to 0.35)
	12	Headaches/month	Nanda (1977)	-0.68 (-1.68 to 0.32)
Alprenolol	8	Headaches/month	Ekbom (1975)	0.20 (-0.91 to 1.3)
Atenolol	8	Headaches/month	Stensrud (1980)	-1.5 (-3.0 to -0.04)
	12	Headaches/month	Forssman (1983)	-5.4 (-12.6 to 1.8)
	12	Headaches/month	Johansson (1987)	-2.05 (-3.76to -0.48)
	12		Pooled SMD	-2.2 (-3.7 to -0.67)	Q = 0.80, df = 1, I² = 0.0%
Bisoprolol	4	Headaches/month	Van de Ven (1997)	-0.40 (-0.87 to 0.07)
Bisoprolol	8	Headaches/month	Van de Ven (1997)	-0.61 (-1.1 to -0.16)
Metoprolol	4	Headaches/month	Langor (1985)	-0.63 (-1.5 to 0.25)
	8	Headaches/month	Andersson (1983)	-1.5 (-2.4 to -0.60)
	8	Headaches/month	Kangasniemi (1987)	-0.70 (-1.4 to -0.03)
	8	Headaches/month	Steiner (1987)	-0.80 (-1.7 to 0.13)
	8		Pooled HA/Month	-0.94 (-1.4 to -0.46)	Q = 1.02, I² = 0.0%
Oxprenolol	8	Headaches/month	Ekbom (1977)	-080 (-3.9 to 2.3)
Pindolol	4	Headaches/month	Ekbom (1972)	2.9 (-1.0 to 6.8)
	4	Headaches/month	Sjaastad (1972)	1.5 (-5.5 to 2.6)
	4		Pooled HA/Month	1.2 (-2.5 to 4.9)	Q = 0.49, I² = 0.0%
Propranolol	4	Headaches/month	Dahlof (1987)	-1.1 (-2.2 to 0.05)
	4	Headaches/month	Diener (2004)	-1.1 (-1.9 to -0.28)
	4	Headaches/month	Pradalier (1989)	-1.5 (-2.1 to -0.87)
	4	Headaches/month	Stensrud (1976)	-1.1 (-3.5 to 1.3)
	4		Pooled HA/Month	-1.1 (-1.5 to -0.74)	Q = 3.44, df = 3, I² = 0.00%
	4	Headache Index	Zeigler (1987)	-0.68 (-1.4 to 0.06)
	8	Headaches/month	Ahuja (1985)	-5.9 (-11.4 to -0.37)
	8	Headaches/month	Al-Qassab (1993)	0.6 (-2.84 to 4.0)
	8	Headaches/month	Diener (2004)	-0.8 (-1.6 to -0.005)
	8	Headaches/month	Holroyd (2010)	-0.6 (-1.3 to 0.12)
	8	Headaches/month	Pita (1977)	-5.3 (-8.7 to -1.8)
	8		Pooled HA/Month	-1.0 (-2.1 to -0.39)	Q = 11.08, df = 4, I² = 54.9%
	8	Headache index	Nadelmann (1986)	-0.54 (-1.11 to 0.04)
	12	Headaches/month	Borgesen (1974)	-0.30 (-1.1 to -0.48)
	12	Headaches/month	Diener (2004)	-0.80 (-1.6 to -0.02)
	12	Headaches/month	Forssman (1976)	-1.8 (-3.9 to 0.4)
	12	Headaches/month	Holroyd (2010)	-0.8 (-1.5 to -0.08)
	12	Headaches/month	Johnson (1986)	-6.3 (-16.6 to 3.9)
	12	Headaches/month	Mikkelsen (1986)	-2.4 (-7.9 to 3.1)
	12	Headaches/month	Pradalier (1989)	-3.3 (-3.9 to -2.6)
	12	Headaches/month	Standnes (1982)	-1.4 (-2.7 to -0.12)
	12	Headaches/month	Stovner (2013)	-0.62 (-1.4 to 0.16)
	12	Headaches/month	Tfelt-Hansen (1983)	-1.2 (-2.8 to 0.45)
	12	Headaches/month	Wideroe (1974)	-1.3 (-1.8 to -0.78)
	12		Pooled HA/Month	-1.3 (-2.0 to -0.62)	Q = 46.35, df = 10, I² = 78.4%
	12	Headache hours/month	Diener (1996)	-12.9 (-31.8 to 5.9)
	16	Headaches/month	Diener (2004)	-1.1 (-2.2 to -0.01)
	16	Headaches/month	Holroyd (2010)	-0.90 (-2.6 to -0.19)
	16	Headaches/month	Sargent (1985)	0.5 (-0.22 to 1.2)
			Pooled HA/Month	-0.46 (-1.5 to 0.57)	Q = 9.40, df = 2, I² = 78.7%
	20	Headaches/month	Diener (2004)	-1.5(-2.9 to -0.03)
	20	Headaches/month	Holroyd (2010)	-0.9 (-1.6 to -0.18)
	20		Pooled HA/Month	-1.0 (-1.7 to -0.37)	Q = 0.52, df = 1, I² = 0.0%
Tomolol	8	Headaches/month	Briggs (1979	-2.3 (-5.2 to 0.63)
	8	Headaches/month	Stellar (1984)	-0.70 (-1.5 to 0.07)
	8		Pooled HA/Month	-0.85 (-1.8 to 0.07)	Q = 1.01, df = 1, I² = 6.8%
	12	Headaches/month	Standnes (1982)	-1.9 (-3.2 to -0.54)
	12	Headaches/month	Tfelt-Hansen (1984)	-1.5 (-3.0 to 0.05)
	12	Headaches/month	Pooled HA/Month	-1.7 (-2.7 to -0.70)	Q = 0.12, df = 1, I² = 0.0%
Calcium Channel Blockers
Cyclendelate	12	Headache duration/month (hours)	Diener (1996)	15.0 hours (-5.3 to 35.3)
Nicardipine	8	Headaches/month	Leandri (1990)	-1.6 (-3.3 to 0.15)
Nifedipine	4	Headaches/month	McArthur (1989)	-0.20 (-0.72 to 0.32)
	4	Headaches/month	Shukla (1995)	-3.8 (-4.8 to -2.8)
	4		Pooled HA/Month	-2.0 (-5.5 to 1.6)	Q = 2.92, df = 1, I² = 65.8%
	8	Headaches/month	McArthur (1989)	-0.20 (-0.72 to 0.32)
	12	Headaches/month	McArthur (1989)	-0.40 (-1.4 to 0.66)
Nimodipine	4	Headaches/month	Gelmers (1983)	-0.13 (-0.64 to 0.38)
	4	Headaches/month	MINES (1989)	0.48 (-0.47 to 0.46)
	4	Headaches/month	MINES (1989)	0.10 (-0.21 to 0.41)
	4	Headaches/month	Stewart (1988)	-0.31 (-3.3 to 2.7)
	4		Pooled HA/Month	-0.07 (-0.28 to 0.13)	Q = 1.51, df = 3, I² = 0.0%
	4	Headache Index	Ansell (1988)	-0.36 (-0.88 to 0.16)
	8	Headaches/month	Gelmers (1983)	-1.5 (-2.4 to -0.73)
	8	Headaches/month	Havanka (1985)	-2.2 (-4.2 to -0.24)
	8	Headaches/month	MINES (1989)	0.17 (-0.54 to 0.88)
	8	Headaches/month	MINES (1989)	0.94 (-0.45 to 2.32)
	8	Headaches/month	Stewart (1988)	-3.4 (-5.7 to -1.1)
	8		Pooled HA/Month	-0.98 (-2.3 to 0.30)	Q = 22.35, df = 4, I² = 82.1%
	8	Headache Index	Ansell (1988)	-0.48 (-1.01 to 0.05)
	12	Headaches/month	Gelmers (1983)	-1.3 (-1.9 to -0.69)
	12	Headaches/month	MINES (1989)	0.74 (0.03 to 1.5)
	12	Headaches/month	MINES (1989)	-0.01 (-1.4 to 1.4)
	12	Headaches/month	Stewart (1988)	-2.8 (-5.2 to -0.48)
	12		Pooled HA/Month	-0.65 (-2.0 to 0.74)	Q = 22.41,df-, I² = 86.6%
	12	Headache Index	Ansell (1988)	0.16 (-0.36 to 0.68)
Verapamil	4	Headaches/month	Solomon (1983)	-2.9 (-7.8 to 1.9)
Verapamil	8	Headaches/month	Markley (1984)	-0.60 (-1.4 to 0.19)
Flunarizine
Flunarizine	4	Headaches/month	Diamond (1993)	0.60 (-0.35 to 0.47)
	4	Headaches/month	Frenken (1984)	-1.3 (-2.4 to -0.24)
	4		Pooled Ha/Month	-0.53 (-1.8 to 0.79)	Q = 5.51, df = 1, I² = 81.9%
	4	Headache Index	Mendenopoulos (1985)	-0.63 (1.5 to 0.27)
	4	Headache Index	Pini (1986)	0.19 (-0.73 to 1.1)
	4	Headache Index	Pooled SMD	-0.23 (-1.0 to 0.58)	Q = 1.56, df = 1, I² = 35.8%
	4		Overall Pooled SMD	-0.27 (-0.76 to 0.23)	Q = 6.15, df = 3, I² = 51.2%
	8	Headaches/month	Diamond (1993)	-0.44 (-1.7 to 0.78)
	8	Headaches/month	Frenken (1984)	-1.9 (-3.5 to -0.31)
	8		Pooled Ha/Month	-1.1 (-2.5 to 0.34)	Q = 2.04, df = 1, I² = 51.1%
	8	Headache Index	Mendenopoulos (1985)	-1.2 (-2.1 to -0.2)
	8		Overall Pooled SMD	-0.60 (-1.2 to 0.005)	Q = 4.92, df = 2, I² = 59.3%
	12	Headaches/month	Diamond (1993)	-0.61 (-1.8 to 0.65)
	12	Headaches/month	Frenken (1984)	-1.8 (-3.3 to -0.38)
	12	Headaches/month	Louis (1981)	-1.1 (-1.7 to -0.6)
	12		Pooled Ha/Month	-1.1 (-1.6 to -0.67)	Q = 1.39, df = 2, I² = 0.0%
	12	Headache Index	Mendenopoulos (1985)	-1.6 (-2.6 to -0.6)
	12	Headache Index	Thomas (1989)	-0.87 (2.0 to 0.24)
	12	Headache Index	Pooled SMD	-1.3 (-2.0 to -0.52)	Q = 0.94, df = 1, I² = 0.0%
	12		Overall Pooled SMD	-0.84 (-1.3 to -0.34)	Q = 10.33, df = 4, I² = 61.3%
	16	Headaches/month	Diamond (1993)	-1.2 (-2.1 to -0.24)
	16	Headaches/month	Sorensen (1986)	-1.2 (-2.7 to 0.37)
	16		Pooled Ha/Month	-1.2 (-2.0 to -0.38)
	20	Headaches/month	Diamond (1993)	-0.36 (-2.4 to 1.69)
Selective Serotonin Reuptake Inhibitors
	4	Headaches/month	Orholm (1986)	-0.20 (-1.3 to 0.93)
	4	Headaches/month	Zeeberg (1981	0.00 (-1.8 to 1.8)
Femoxitine	4		Pooled Ha/Month	-0.14 (-1.1 to 0.81)	Q = 0.03, df = 1, I² = 0.0%
	8	Headaches/month	Orholm (1986)	-0.10 (-1.2 to 1.0)
	8	Headaches/month	Zeeberg (1981)	-1.8 (-3.6 to -0.04)
	8		Pooled Ha/Month	—0.81 (-2.5 to 0.83)	Q = 2.53, df-1, I² = 60.4%
	12	Headaches/month	Orholm (1986)	0.50 (-0.63 to 1.6)
	12	Headaches/month	Zeeberg (1981)	-1.4 (-3.2 to 0.36)
	12		Pooled Ha/Month	-0.33 (-2.2 to 1.5)	Q = 3.16, df = 1, I² = 68.3%
	16	Headaches/month	Orholm (1986)	0.30 (-0.83 to 1.4)
Fluoxetine	4	Headache index	Adly (1993)	-0.34 (-1.27 to 0.59)
	4	Headache index	d’Amato (1999)	-0.08 (-0.63 to 0.48)
	4	Headaches/month	Steiner (1998)	-0.71 (-1.36 to -0.06)
	4		Pooled SMD	-0.35 (-0.75 to 0.05)	Q = 2.11, df = 3, I² = 5.2%
	8	Headache index	Adly (1993)	-0.74 (-1.70 to 0.22)
	8	Headache index	d’Amato (1999)	-0.01 (-0.56 to 0.55)
	8	Headaches/month	Steiner (1998)	-0.32 (-0.98 to 0.35)
	8		Pooled SMD	-0.23 (-0.63 to 0.16)	Q = 1.76, I² = 0.0%
	12	Headache index	Adly (1993)	-1.02 (-2.01 to -0.03)
	12	Headache index	d’Amato (1999)	-0.32 (-0.88 to 0.24)
	12	Headaches/month	Steiner (1998)	-0.74 (-1.44 to -0.03)
	12		Pooled SMD	-0.57 (-0.97 to -0.17)	Q = 1.77, df = 2, I² = 0.0%
	16	Headache index	d’Amato (1999)	-0.64 (-1.22 to -0.07)
	20	Headache index	d’Amato (1999)	-0.32 (-0.88 to 0.24)
Sertraline	4	Headache index	Landy (1999)	0.44 (-0.59 to 1.5)
	8	Headache index	Landy (1988)	0.08 (-0.94 to 1.09)
Pooled SMD (12 weeks)				-0.35 (-0.75 to 0.05)	Q = 7.49, df = 4, I²² = 46.6%
Serotonin Norepinephrine Reuptake Inhibitors
Venlafaxine	8	Headaches/month	Ozyalcin (2004)	-2.0 (-4.0 to -0.06)
Serotonin Antagonist
Pizotifen	4	Headaches/month	Arthur (1971)	-0.51 (-1.07 to 0.05)
	4	Headaches/month	Ryan (1968)	-0.36 (-0.86 to 0.15)
	4		Pooled HA/month	-0.42 (-0.80 to -0.05)	Q = 0.16m df = 1, I² = 0.0%
	4	Headache index	Carroll (1975)	0.18 (-0.87 to 1.23)
	4	Headache index	Lawrence (1977)	-0.04 (-0.78 to 0.70)
	4		Pooled SMD	-0.15 (-0.47 to 0.17)	Q = 6.40, df = 1, I² = 0.0%
	4		Overall Pooled SMD	-0.30 (-0.62 to 0.02)	Q = 6.40, df = 7, I² = 0.0%
	8	Headaches/month	Kangasniemi (1979)	-0.57 (-1.26 to 0.12)
	8	Headaches/month	Osterman (1977)	-0.63 (-1.4 to 0.1)
	8		Pooled HA/month	-0.60 (-1.1 to -0.08)	Q = 0.01, df = 1, I² = 0.0%
	8	Headache index	Lawrence (1977)	-0.56 (-1.32 to 0.20)
	8		Overall Pooled SMD	-0.48 (-0.85 to -0.12)	Q = 1.37, df = 4, I² = 0.0%
	12	Headaches/month	Bellavance (1990)	-0.49 (-0.86 to -0.12)
	12	Headaches/month	Cleland (1997)	-0.41 (-0.83 to 0.14)
	12	Headaches/month	Hughes (1971)	-0.26 (-1.03 to 0.52)
	12		Pooled HA/month	-0.43 (-0.66 to -0.21)	Q = 0.30, df = 2, I² = 0.0%
	12	Headache index	Lawrence (1977)	-0.56 (-1.32 to 0.20)
			Overall Pooled SMD	-0.44 (-0.69 to -0.20)	Q = 0.48, df = 5, I² = 0.0%
Tricyclic Antidepressants
Amitriptyline	4	Headache index	Couch (2011)	-0.34 (-0.62 to -0.05)
	4	Headache index	Zeigler (1987)	-0.52 (-1.25 to 0.21)
	4		Pooled SMD	-0.57 (-0.92 to -0.23)	Q = 0.08, df = 1, I² = 0.0%
	24	Headaches/month	Gomersall (1973)	-1.29 (-1.79 to -0.46)
	24	Headache index	Mathew (1981)	-1.31 (-1.85 to -0.77)
	24		Pooled SMD	-1.2 (-1.7 to -0.82)	Q = 0.35, df = 2, I² = 0.0%
Clomipramine	4	Headaches/month	Langohr (1985)	0.10 (-1.2 to 1.01)
	4	Headaches/month	Loldrup (1989)	-0.51 (-0.81 to -0.20)
	4	Headaches/month	Noone (1980)	-0.3 (-1.19 to 0.58)
	4		Pooled SMD	-0.46 (-0.74 to -0.18)
Doxepin	4	Headache index	Morland (1979)	-0.77 (-1.54 to 0.00)	—
Opipramol	4	Headaches/month	Jacobs (1972)	-1.2 (-2.1 to -0.3)
Opipramol	12		Jacobs (1972)	-1.3 (-2.5 to -0.12)

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SMD: Standardized Mean Difference

Table 6. Placebo controlled comparisons of continuous outcomes among patients with chronic migraine headache (≥ 15 headaches/month).

Chronic Daily Headache
Fluoxetine	12	Headaches/month	Saper (1994)	-0.40 (-1.1 to 0.35)	—
Gabapentin	8	Headaches/month	Spira (2003)	-2.7 (-5.2 to 0.28)	—
Levetiracetam	82	Headaches/month	Beran (2010)	-3.6 (-7.7 to 0.56)	—
Chronic Migraines (15 or more headaches/month)
Atenolol	6	Headaches/month	Stensrud (1980)	0.32 (-0.73 to 1.38)	—
Propranolol	8	Headaches/month	Palferman (1988)	-0.70 (-1.3 to -0.09)
	6	Headaches/month	Stensrud (1980)	0.24 (-0.82 to 1.29)
			Pooled SMD	-0.34 (-1.23 to 0.56)	Q = 0.13, df = 2, I² = 56.1%
Tizanidine	4	Headaches/month	Saper (2002)	-1.1 (—2.4 to 0.16)	—
	8	Headaches/month	Saper (2002)	-1.0 (-2.3 to 0.30)	—
	12	Headaches/month	Saper (2002)	-0.50 (-1.6 to 0.62)	—
Topiramate	4	Headaches/month	Diener (2007)	-4.9 (-7.7 to -2.1)
	4	Headaches/month	Mei (2006)	-9.2 (-15.7 to -2.7)
	4	Headaches/month	Silvestrini (2003)	-5.0 (-9.2 to -0.81)
	4		Pooled (HA/Month)	-5.4 (-7.6 to -3.2)	Q = 0.34, df = 2, I² = 0.0%
	8	Headaches/month	Diener (2007)	-3.1 (-5.9 to -0.29)
	8	Headaches/month	Mei (2006)	-12.7 (-10.2 to -6.2)
	8	Headaches/month	Silvestrini (2003)	-12.5 (-17.1 to -7.9)
			Pooled (HA/Month):	-9.1 (-16.3 to -1.9)	Q = 9.33, df = 2, I² = 78.6%
	12	Headaches/month	Diener (2007)	-6.0 (-8.8 to -3.2)
	12	Headaches/month	Mei (2006)	-12.2 (-18.7 to -5.7)
			Pooled (HA/Month):	-8.4 (-14.3 to -2.5)	Q = 0.81, df = 1, I² = 0.0%
	16		Diener (2007)	-7.6 (-10.4 to -4.8)
Valproate	4	Headaches/month	Yurekli (2008)	-12.6 (-17.9 to -7.3)
	12	Headaches/month	Sarchelli (2014)	-4.3 (-7.1 to -1.5)
	12	Headaches/month	Yurekli (2008)	-14.3 (-19.5 to -9.1)
	12		Pooled (HA/Month):	-10.9 (-18.5 to -3.4)	Q = 26.2, df = 1, I² = 92.4%

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Angiotensin Converting Enzyme Inhibitors (ACE)/ Angiotensin Receptor Blockers (ARB)

There were three ACE (captopril, enalapril, lisinopril) and three ARB (candesartan x2, telmisartan) placebo-controlled trials, all focusing on episodic migraines (Table 2). The ACE studies were 8, 12 and 16 weeks in duration with 120 participants who averaged 7.3 headaches per month. All three ARB studies were 12 weeks in duration with a total of 231 participants, averaging 6.5 headaches/month. One of the ACE trials suggested no benefit at 4 or 8 weeks (enalapril), another found benefit at 12 weeks (lisinopril) and a third benefit at 16 weeks (captopril, Table 5, Fig 3); none of the trials reported outcomes at a common time-point. At twelve weeks, ARBs were better than placebo in reducing the frequency of headaches (Table 5, Fig 3). The likelihood of experiencing at least 50% improvement was not reported in all clinical trials. One of the ACE trials (captopril) was more likely than placebo to achieve at least a 50% reduction in headache frequency (Table 7). This was not found in the trial studying lisinopril or for two of the ARB trials.

Table 7. Placebo controlled comparisons of >50% improvement in episodic migraine headaches (<15 migraines/month).

Drug	Time Point (weeks)	Study (Year)	RR (95% CI)	Heterogeneity
Angiotensin Converting Enzyme Inhibitors
Captopril	8	Sonbolestan (2013)	5.6 (1.4–21.9)
Lisinopril	12	Schrader (2012)	0.82 (0.46–1.5)
Angiotensin Receptor Blockers
Candesartan	12	Tronvik (2003)	18.0 (2.5–130.4)
Telmisartan	12	Diemer (2009)	1.6 (0.85–3.0)
	12	Pooled RR	4.4 (0.43–46.2)	Q = 5.2, df = 1 I² = 80.8%
Anticonvulsants
Acetazolamide	12	Vahedi (2002)	0.92 (0.42–2.0)
Carisbamate	12	Cady (2009)	0.75 (0.58–0.98)
Lamotrigine	4	Gupta (2006)	1.4 (0.86–2.2)
Lamotrigine	12	Steiner (1997)	0.20 (-0.36 to 0.76)
Levetiracetam	12	Verma (2003)	1.4 (0.86–2.4)
Oxcarbazepine	15	Silberstein (2008)	0.90 (0.59–1.4)
Topiramate	4	Edwards (2003)	4.2 (1.3–13.7)
	4	Gupta (2006)	2.1 (1.3–3.2)
	4	Pooled RR:	2.4 (1.3–4.2)	Q = 11.27, df = 1, I² = 21.0%
	12	Silberstein (2006)	1.2 (0.8–1.7)
	16	Silberstein (2004)	2.1 (1.6–2.7)
	16	Silberstein (2009)	1.3 (0.9–2.0)
	16	Pooled RR:	1.9 (1.4–2.5)	Q = 6.4, df = 1, I² = 52.9%
	26	Brandes (2004)	1.7 (1.3–2.2)
	26	Diener (2004)	1.6 (1.1–2.4)
	26	Pooled RR:	1.8 (1.5–2.2)	Q = 1.72, df = 1, I² = 0.0%
	26	Freitag (2002)	1.2 (0.8–1.9)
Valproate	12	Jensen (1994)	2.8 (1.3–6.3)
	12	Klapper (1997)	2.3 (1.6–3.3)
	12	Mathew (1995)	3.6 (1.5–8.4)
	12	Pooled RR	2.1 (1.5–3.0)	Q = 9.1, df = 3, I² = 45.1%
Beta-blockers
Propranolol	4	Stensrud (1976)	1.25 (0.55–2.8)
	8	Pita (1977)	17.0 (1.0–281.9)
	8	Zeigler (1993)	2.5 (0.65–9.7)
	8	Pooled RR:	4.3 (0.79–23.6)	Q = 1.45, df = 1, I² = 31.1%
	12	Telt-Hansen (1984)	2.0 (1.2–2.8)
	12	Weber (1972)	7.5 (1.9–28.4)
	12	Wideroe (1974)	2.2 (1.4–3.4)
	12	Pooled RR:	2.1 (1.6–2.9)	Q = 4.2, df = 2, I² = 52.2%
	24	Diener (1996)	1.4 (0.9–2.2)
	26	Diener (2004)	2.0 (1.4–2.9)
Metoprolol	4	Langohr (1985)	1.2 (0.86–1.5)
Timolol	8	Stellar (1984)	1.6 (1.1–2.4)
Timolol	12	Tfelt-Hansen (1984)	1.9 (1.4–2.5)
Calcium Channel Blockers
Cinnarizine	4	Togha (2007)	0.98 (0.74–1.3)
Cyclendalate	24	Diener (1996)	1.3 (0.8–2.1)
Flunarizine	12	Thomas (1991)	2.5 (0.6–10.9)
	16	Bunoso (1998)	0.99 (0.72–1.4)
	16	Diener (2002)	1.0 (0.88–1.2)
	16	Pooled RR:	1.02 (00.91–1.1)	Q = 1.6, df = 1, I² = 82.4%
Nifedipine	24	Albers (1989)	0.45 (0.21–0.95)
Fluoxetine	4	Singh (2002)	4.5 (1.1–18.8)
Fluoxetine	12	Saper (1994)	1.0 (0.57–1.8)
Tricyclic Antidepressants
Amitriptyline	4	Couch (1976)	2.2 (1.0–4.8)
	4	Couch (1979)	1.60 (1.0–2.5)
	4	Pooled RR:	1.7 (1.2–2.6)	Q = 0.54,df = 1, I² = 0.0%
	8	Nelson (1998)	2.22 (1.3–3.9)
	8	Zeigler (1993)	0.83 (0.43–1.6)
	8	Pooled RR:	1.1 (0.6–2.0)	Q = 0.64,df = 1, I² = 3.0%
	12	Canepari (1985))	1.60 (0.31–3.1)
	26	Dodick (2009)	0.82 (0.61–1.1)
Clomipramine	4	Langohr (1985)	0.94 (0.53–1.7)
Tetracyclic
Maprotiline	12	Amelin (2000)	0.76 (0.32–1.8)

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Anticonvulsants

There were 32 trials comparing anticonvulsants to placebo with a total of 8529 participants who averaged 41 years (range 12–76) in age; 81% of participants were women (Table 2). Twenty-seven of these trials focused on episodic migraine headaches (Table 2), five evaluated chronic migraine and four chronic daily headaches (Table 3). The average rate of withdrawals was 23%. Studies averaged 15 weeks (range 4–82) with a mean of 153 participants (range 23–487). All of the studies reported headache frequency as their outcome. The two most commonly tested anticonvulsants were topiramate (n = 12) and valproate (n = 6). Other anticonvulsants tested included acetazolamide (n = 1), carbamazepine (n = 1), carisbamate (n = 1), clonazepam (n = 1), gabapentin (n = 4), lamotrigine (n = 1), levetiracetam (n = 3), oxcarbazepine (n = 1), and vigabatrin (n = 1).

In single trials, several anticonvulsants were no better than placebo for episodic migraines including acetazolamide, carbamazepine, carisbamate, clonazepam, oxcarbazepine and vigabatrin (Table 5). In single trials, lamotrigine was found effective at 4 weeks though ineffective at 12 weeks (Table 5). In several trials, gabapentin was not superior to placebo (Table 5). Several of these anticonvulsants were assessed for ability to reduce headaches by 50% (Table 7). Carisbamate was less effective than placebo and anticonvulsants no more likely than placebo to reduce headaches by at least 50% included acetazolamide, gabapentin, lamotrigine, levetiracetam and oxcarbazepine.

Anticonvulsants that were found to be more effective than placebo for episodic migraine included levetiracetam (Table 6), topiramate (Fig 4) and valproate (Fig 5). Both topiramate and valproate had numerous trials demonstrating benefit at multiple time points (Table 5).

Topiramate

Topiramate has been evaluated in twelve placebo-controlled trials that reported outcomes at numerous time points and different doses (50, 100 and 200mg). Pooled results suggest that topiramate was more effective than placebo at all time points (4–24 weeks, Table 5) and at all doses assessed. There was evidence that higher doses of topiramate was more effective than lower ones, with a stepwise increase as the dose increased from 50 to 100 to 200mg (Fig 6). For chronic migraine, 2 studies of topiramate suggested effectiveness for up to 16 weeks (Table 6). In several studies (n = 8) topiramate was also demonstrated to be more effective than placebo at reducing migraine by more than 50% (Table 7).

Valproate

Valproate also had been compared to placebo in six trials with multiple time points and varying doses (500-1500mg). Valproate was found to be more effective than placebo for episodic migraine at all time points assessed including 4, 8 and 12 weeks (Table 5, Fig 5). However, unlike topiramate there was no evidence of a difference in response to increased doses (dose-response p = 0.83). Valproate was also found in numerous trials (n = 5) to reduce headaches by more than 50% (Table 7).

Beta Blockers

There were 38 trials comparing beta-blockers to placebo with a total of 2019 participants, 37 focusing on episodic (Table 2) and 1 on chronic migraine headaches (Table 3). The average rate of withdrawals was 18%. Study duration averaged 11 weeks (range 4–64) with a mean of 64 participants (range 20–568). The majority (82%) reported headache frequency, four trials used headache index, and one duration. There were a variety of beta-blockers tested including acebutolol (n = 1), alprenolol (n = 1), atenolol (n = 3), bisoprolol (n = 1), metoprolol (n = 4), oxprenolol (n = 1), pindolol (n = 2), propranolol (n = 19) and timolol (n = 4).

Beta blockers no more effective than placebo included acebutolol, alprenolol, bisoprolol, oxprenolol and pindolol (Table 5). Beta-blockers superior to placebo for episodic migraine headaches (Table 5) included atenolol, metoprolol, propranolol (Fig 7) and timolol. Seven studies found that propranolol reduced headache by 50% (Table 7). Neither atenolol (1 study) nor propranolol (2 studies) were effective for chronic migraine (Table 6).

Calcium Channel Blockers

Calcium blockers headache trials tested cyclendelate (n = 1), nicardipine (n = 1), nifedipine (n = 2), nimodipine (n = 5) and verapamil (n = 2). All studies focused on episodic migraines (Table 2). Overall there were a total of 878 participants who averaged 35 years in age (range 15–65) with 78% women. The average rate of withdrawals was 18%. Study duration averaged 11 weeks (range 4–20) with a mean of 52 participants (range 12–192). No calcium channel blocker was more effective than placebo, including cyclendelate, nicardipine, nifedipine, nimodipine and verapamil (Table 5). When the dihydropyridines (nicardipine, nifedipine, nimodipine) were pooled, they were no better than placebo at reducing headaches.

Flunarizine

While classified as a calcium channel blocker, flunarizine has no influence on blood pressure and its side effect profile suggests that its site of action is on cellular receptors other than the calcium channel [231,232]. Flunarizine is not available in the United States. There were 7 studies of episodic migraines, totaling 332 participants (Table 2). Studies averaged 47 participants, 36.4 years in age, 77% women, 12.5 weeks in duration and 9% dropouts. Four studies reported headache frequency and three reported headache outcomes based on a headache index. Flunarizine was superior to placebo at 8 and 12 weeks (Table 5, Fig 8), though not at 4 weeks. Only a single trial reported the likelihood of a 50% reduction in headache with flunarizine with insignificant results (Table 7).

Selective Serotonin Reuptake Inhibitors (SSRI)/ Selective Norepinephrine Reuptake inhibitors (SNRI)

There were six SSRI and one SNRI placebo controlled trials, five focusing on migraines and 1 on chronic daily headaches. There were a total of 335 participants who averaged 36.9 years in age (range 18–65) with 81% women (Table 2). The average rate of withdrawals was 25% (range 0–41%). Study duration averaged 12 weeks (range 8–20) with a mean of 56 participants (range 27–111). Specific drugs tested include three SSRIs (femoxitine, n = 1, fluoxetine, n = 4 and sertraline, n = 1), and one SNRI (venlaxafine, n = 1). Four of the SSRI trials reported a headache index. One SSRI trial and the SNRI trial reported frequency of headaches per month.

For migraine headaches, two SSRI’s, femoxitine and sertraline, were no more effective than placebo while fluoxetine was effective at 12 weeks (Fig 9). A single trial of venlafaxine found benefit at 8 weeks (Table 5). For chronic daily headache a single trial of fluoxetine found no benefit (Table 6). Only a single trial (fluoxetine) investigated the likelihood of reducing headaches by at least 50% and found no benefit over placebo (Table 7).

Serotonin Antagonists

Pizotifen is a serotonin antagonist, commonly used for migraine treatment in the 1970’s and 80’s. There were 9 placebo controlled trials with a total of 600 participants and all focused on episodic migraine headaches (Table 2). The average rate of withdrawals was 20% (range 0–48). Study duration averaged 8 weeks (range 4–12) with a mean of 67 participants (range 26–176). Two studies reported a headache index, the other 7 headache frequency. Pizotifen was superior to placebo at all time points (Fig 10, Table 5). No trials reported on the likelihood of achieving at least 50% improvement in headaches.

Tricyclic Antidepressants (TCA)

There were 8 trials comparing a TCA to placebo, one focusing on chronic daily headaches, the remainder on episodic migraine headaches. There were a total of 1570 participants. The average rate of withdrawals was 37% (range 20–52%). Study duration averaged 10 weeks (range 4–24) with a mean of 143 participants (range 10–554). Tricyclic’s studied included amitriptyline (n = 5), clomipramine (n = 2) doxepin (n = 1) and opipramol (n = 1). Four trials reported headache frequency and 4 used a headache index as their outcome measure.

For episodic migraines, amitriptyline, clomipramine and doxepin were better than placebo (Table 5, Fig 11), while opipramol (Table 5) was ineffective. Amitriptyline was the best studied TCA (Fig 12), though two of the studies were only 4 weeks in duration. Amitriptyline was more likely than placebo to produce a 50% reduction in episodic migraine headaches (Table 7). A single trial found amitriptyline ineffective for chronic daily headaches (Table 6).

Comparative Effective Trials

There were a total of 60 trials with comparisons between different prophylactic drugs for headaches, 55 including subjects with episodic headaches, five with chronic migraine headaches. Not all prophylactic drugs were directly compared with each other (Table 8). Quality ratings for these trials are given in Table 9. Drugs that were frequently compared to other active drugs include amitriptyline, metoprolol, pizotifen, propranolol, topiramate and valproate. There were few differences in effectiveness between the different drugs. Amitriptyline was no more effective than SSRIs, venlafaxine, topiramate or propranolol. Among beta-blockers, metoprolol was superior to clonidine, flunarizine and nifedipine and propranolol was better than femoxitine. Propranolol was equivalent to metoprolol, atenolol, nadolol as well as to flunarizine and topiramate (Table 10). Among the anticonvulsants, topiramate was equivalent to flunarizine, lamotrigine and to valproate and valproate was equivalent to flunarizine. For chronic migraines, popranolol was better than nortriptyline.

Table 8. Characteristics of comparative effectiveness trials.

Author, year, Country	Migraine Type	Baseline Headache Frequency	Comparison Drugs	Headache Measure	Study design (washout, weeks)	Duration, weeks	Sample size	Drop-outs	Age	Female
Episodic (<15 headaches/month)
Afshari [180], 2012, Iran	Episodic	7.6	Topiramate (50) v. Valproate (400)	Frequency	Parallel	12	76	26%	30.7	79%
Albers [181], 1989, USA	Episodic	4.3	Propranolol (180) v. Nifedipine (90)	Frequency	Parallel	24	40	50%	35.2	85%
Amelin[182], 2000, Russia	Episodic	4.3	Amitriptyline (25) v. Fluoxetine (20)	Frequency	Parallel	12	46	23%	36	95%
Andersson [183], 1973, Denmark	Episodic	2.3	Pizotifen (2) v. Methysergide (4)	Frequency	Crossover (0)	12	73	33%	ns	84%
Andersson [242], 1981, Denmark	Episodic	5.7	Propranolol (160) vs. Femoxetine (400)	Frequency	Crossover (0)	8	49	24%	38	69%
Ashtari [185], 2008, Iran	Episodic	5.95	Propranolol (80) v. Topiramate (50)	Frequency	Parallel	8	62	3%	30.8	82%
Bank [186], 1994, Hungary	Episodic	ns	Amitriptyline (25) v. Fluvoxamine (50)	Frequency	Parallel	12	44	23%	34	80%
Bellavance [163], 1990, Canada	Episodic	6.7	Pizotifen (1.5) v. Naproxen (1100)	Frequency	Parallel	12	176	14%	32.5	79%
Bordini [190], 1997, Brazil	Episodic	3.9	Propranolol (60) v. Flunarizine (10)	Headache Index	Parallel	24	52	13%	ns	91%
Bostani [191], 2013, Iran	Episodic	6.1	Valproate (400) v. Cinnarizine (50)	Frequency	Parallel	12	132	21%	32.2	68%
Bulut [192], 2004, Turkey	Episodic	3.5	Amitriptyline (75) v Venlafaxine (150)	Frequency	Crossover (4)	12	52	32%	31.9	85%
Cady [193], 2011, USA	Episodic	5.9	Topiramate (100) v. frovatriptan (5- with aura)	Frequency	Parallel	8	55	20%	37.5	78%
Cerbo [194], 1986, Italy	Episodic	ns	Flunarizine (15) v. Pizotofen (1.5)	Frequency	Crossover (2)	8	27	33%	ns	ns
Diener [106], 1996, Germany	Episodic	4	Propranolol(120) v Cyclendalate (1200) v. Placebo	Duration (hours)	Parallel	12	214	17%	39	78%
Diener [195], 2002, EU	Episodic	3	Propranolol (160) v. Flunarizine (5) v. Flunarizine (10)	Frequency	Parallel	16	783	18%	37	81%
Diener [73], 2004, EU	Episodic	3.9	Propranolol (160) v. Topiramate (100) v. Placebo	Frequency	Parallel	26	568	37%	40.8	80%
Dodick [196], 2009, USA	Episodic	6.9	Amitriptyline (100) v. Topiramate (100)	Frequency	Parallel	26	331	43%	38.8	85%
Formisano [198], 1991, Italy	Episodic	4	Propranolol (120) v. Nimodipine (120)	Frequency	Parallel	12	22	14%	39.2	55%
Forssman [199], 1972, Sweden	Episodic	6.8	Pizotifen (3) v. methysergide (3)	Frequency	Crossover (0)	10	22	23%	40.3	53%
Gawel [200], 1992, Canada	Episodic	4.7	Propranolol (160) v. Flunarizine (10)	Frequency	Parallel	16	94	19%	35.7	90%
Gerber [201], 1991, Germany	Episodic	3.5	Propranolol (120) v. Metoprolol (200) v. Nifedipine (20)	Frequency	Parallel	12	58	28%	42.4	81%
Gupta [202], 2007, India	Episodic	6.9	Topiramate (50) v. Lamotrigine (50)	Frequency	Crossover (1)	4	57	7%	29.4	78%
Havanka-Kannianen [141], 1987, Finland	Episodic	5.2	Nimodipine (120mg) v. Pizotifen (1.5) v. Placebo	Frequency	Crossover (4)	12	43	14%	37.6	79%
Hübbe [35], 1973, Denmark	Episodic	ns	Pizotifen (1.5) v. Prochlorperazine (15) v. Placebo	Frequency	Crossover (0)	8	50	32%	35	71%
Kalita [204], 2013, India	Episodic	10.8	Amitriptyline (50) v. Valproate (1000)	Frequency	Parallel	24	300	0%	32	80
Kangasniemi [167], 1979, Finland	Episodic	6.2	Pizotifen (1.5) v. Divascan (5) v. Placebo	Frequency	Crossover (4)	7	50	13%	37	71%
Kangasniemi [205], 1983, Finland	Episodic	7.2	Propranolol (160) v. Femoxitine (400)	Frequency	Crossover (1)	16	29	17%	37	86%
Kangasniemi [116], 1984, Finland	Episodic	5.3	Propranolol (240) v. Metoprolol (200)	Frequency	Crossover (3)	8	36	8%	33.8	89%
Kaniecki [206], 1997, USA	Episodic	4.4	Dvalproex (1500) v. Propranolol (240) v. Placebo	Headache Index	Parallel	12	37	14%	ns	81%
Kass [178], 1980, Norway	Episodic	ns	Propranolol (40) v. Clonidine (0.05)	Frequency	Crossover (0)	16	23	9%	39.7	70%
Keskinbora [207], 2008, Turkey	Episodic	6.1	Amitriptyline (150) v Topiramate (200)	Frequency	Parallel	12	63	16%	37	67%
Krymchantowski [209], 2012, Brazil	Episodic	7	Topiramate (100) v. Nortriptyline (30) v. combination	Frequency	Parallel	10	38	13%	36	85%
Langohr [175], 1985, Germany	Episodic	ns	Clomipramine (100) v. Metoprolol (100) v. Placebo	Frequency	Crossover (4)	4	36	43%	44	67%
Louis [210], 1982, Belgium/Netherlands	Episodic	2.2	Flunarizine (10) v. Pizotifen (3)	Frequency	Crossover (0)	16	75	ns	37	57%
Louis [179], 1985, Belgium	Episodic	ns	Metoprolol (100) v. Clonidine (0.1)	Frequency	Crossover (2)	8	33	6%	33.5	81%
Lucking [211], 1988, Germany	Episodic	6	Propranolol (120) v Flunarizine (10)	Frequency	Parallel	16	434	23%	42	82%
Ludin [212], 1989. Switzerland	Episodic	6.3	Propranolol (120) v. Flunarizine (10)	Frequency	Parallel	16	87	17%	42	74%
Luo [213], 2012, China	Episodic	4.5	Topiramate () v. Flunarizine (5) v. combination	Frequency	Parallel	48	150	16%	43	71%
Mathew [118], 1981, USA	Unclear	ns	Amitriptyline (75) v Propranolol (160) v. Placebo	Frequency	Parallel	24	554	22%	38	95%
Mitsikostas [214], 1997, Greece	Episodic	4.6	Valproate (1000) v. Flunarizine (10)	Frequency	Parallel	8	44	ns	35.4	73%
Mohammadianinejad [215], 2011, Iran	Episodic	7.4	Topiramate (100) v. Zonisamide (200)	Frequency	Parallel	12	80	6%	34.3	69%
Olerud [216], 1986, Sweden	Episodic	4.6	Propranolol (80) v. Nadolol (80)	Frequency	Parallel	12	28	ns	ns	ns
Olsson [217], 1984, Sweden	Episodic	5.4	Propranolol (80) v. Metoprolol (100)	Frequency	Crossover (4)	8	56	5%	39	73%
Osterman [169], 1977, Sweden	Episodic		Pizotifen (0.5) v. Divascan v. Placebo	Frequency	Crossover (2)	8	30	10%	37	70%
Presthus [218], 1971, Norway	Episodic		Pizotifen (1.5) v. Methysergide (3)	Frequency	Crossover (1)	21	21	10%	42.7	67%
Rampello [219], 2004, Italy	Episodic		Amitriptyline (50) v. Citalopram (20)	Frequency	Parallel	16	88	0%	39	63%
Rascol [220], 1986, France	Episodic	4.3	Flunarizine (10) v. Pizotifen (2)	Frequency	Parallel	16	35	9%	38	71%
Ryan [170], 1968, USA	Episodic	8.5	Pizotifen (4) v. Methysergide (4) v. Placebo	Frequency	Crossover (0)	4	62	ns	ns	ns
Ryan [221], 1984, USA	Episodic	6.5	Propranolol (160) v. Nadolol (80) v. Nadolol (160)	Frequency	Parallel	12	48	6%	ns	73%
Scholz (188), 1987, Germany	Episodic		Propranolol (80) v. Metoprolol (100) v. Nifedipine (40) v. Flunarizine (10)	Frequency	Parallel	12	109	24%	40.4	83%
Shaygannejad [223], 2006, Iran	Episodic	5.4	Topiramate (50) v. Valproate (500)	Crossover (8)	Parallel	8	64	0%	34.1	60%
Shimell [224], 1990, S Africa	Episodic	4.7	Propranolol (240) v. Flunarizine (10)	Frequency	Parallel	16	57	2%	34	70%
Sorensen [225], 1991, Denmark	Episodic	4.3	Metoprolol (200) v. Flunarizine (10)	Frequency	Parallel	20	149	15%	42	79%
Stovner, 2013, Norway	Episodic		Candesartan (16), Propranolol (160)	Frequency	Crossover	12	61	15%	37	82%
Sudilovsky [226], 1987, USA	Episodic	5.3	Nadolol (80) v. Nadolol (160)	Frequency	Parallel	8	168	20%	ns	ns
Stensrud (107), 1980, Norway	Episodic	5.6	Propranolol (160) v. Atenolol (100) v. Placebo	Crossover(1)Crossover (1)	Parallel	6	7	20%	25	69%
Tarasova [227], 2008, Russia			Amitriptyline () v. Fluvoxamine ()	Frequency	Parallel
Togha [228], 2008, Iran	Episodic	7.2	Valproate (600) v. Cinnarizine (75)	Frequency	Parallel	12	125	37%	34.1	80%
Vilming [229], 1985, Sweden/Norway	Episodic	6	Metoprolol (100) v. Pizotifen (1.5)	Frequency	Crossover (0)	4	35	ns	37.6	83%
Zain [230], 2013, Pakistan	Episodic	11.32	Topiramate (200) v. Gabapentin (1200)	Frequency	Parallel	12	80	0%	32	80%
Ziegler [136], 1987, USA	Episodic	Ns	Amitriptyline (150) v. Propranolol (240) v. Placebo	Frequency	Crossover (4)	4	30	44%	38	73%
Chronic Migraine (≥15 headaches/month)
Bartolini [187], 2005, Italy	Chronic Migraine	26.6	Topiramate (75) v. Valproate (750)	Frequency	Parallel	8	49	14%	41.8	70%
Behan [188], 1986, UK	Chronic Migraine	15	Pizotifen (1.5) v. Naproxen (1100)	Frequency	Parallel	12	74	45%	ns	82%
Domingues [197], 2009, Brazil	Chronic Migraine	16.7	Nortriptyline (40) v. Propranolol (80)	Frequency	Parallel	6	76	42%	ns	ns
Krymchantowski [208], 2002, Brazil	Chronic (transformed) migraine	25.7	Amitriptyline (40) v. Amitriptyline (40)+Fluoxetine (40)	Frequency	Parallel	9	39	44%	36.4	67%
Stensrud (107), 1980, Norway	Chronic	22	Propranolol (160) v. Atenolol (100) v. Placebo	Crossover(1)Crossover (1)	Parallel	6	28	20%	25	69%

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Table 9. Quality Assessment among comparative effectiveness trials.

			Cochrane Risk of Bias
Study	Jadad Score (0–8)	Intention to Treat	Adequate sequence generation	Adequate concealed allocation	Adequate Blinding	Incomplete outcome data addressed	Free of selective outcome reporting	Free of “other” bias	Industry sponsored
EPISODIC MIGRAINES
Afshari [180], 2012, Topiramate/valoproate	4	No	Unclear	Unclear	Unclear	No	Unclear	Unclear	No
Albers [181], 1989, Propranolol/Nifedipine	5	No	Yes	Yes	No	No	No	No	Yes
Amelin[182], 2000, Amitriptyline/Fluoxetine	4	No	No	Unclear	No	No	Unclear	Yes	No
Andersson [183], 1973, Pizotifen/Methysergide	4	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Yes
Andersson [242], 1981, Propranolol/Femoxitine	4	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Ashtari [185], 2008, Propranolol/Topiramate	5	No	Yes	Yes	Unclear	No	Yes	Unclear	Unclear
Bank [186], 1994, Amitriptyiline/Fluvoxamine	4	No	Unclear	Unclear	Unclear	No	Unclear	Yes	Unclear
Bartolini [187], 2005, Topiramate/Valproate	3	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Behan [188], 1986, Pizotifen/Naproxen	2	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Bellavance [163], 1990, Pizotifen/Naproxen	3	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Bordini [190], 1997, Propranolol/Flunarizine	4	No	Unclear	Unclear	Yes	No	No	No	Unclear
Bulut [192], 2004, Amitriptyline/Venlafaxine	6	No	Unclear	Unclear	Yes	No	Unclear	Yes	Yes
Cady [193], 2011, Topiramate/Froyatriptan	3		Unclear	Unclear	No	Unclear	Unclear	Unclear	Yes
Cerbo [194], 1986, Flunarizine/Pizotifen	6	Yes	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Unclear
Diener [106], 1996, Propranolol/Cyclendalate/Placebo	4	Yes	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Diener [195], 2002, Propranolol/Flunarizine	8	No	Yes	Yes	Yes	No	Unclear	Unclear	Yes
Diener [73], 2004, Propranolol/Topiramate/Placebo	8	Yes	Unclear	Unclear	Unclear	Yes	Yes	Unclear	Yes
Dodick [196], 2009, Amitriptyline/Topiramate	8	No	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Domingues [197], 2009, Nortriptyline/Propranolol	4	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Formisano [198], 1991, Propranolol/Nimodipine	4	No	Unclear	Unclear	No	No	No	No	Unclear
Forssman [199], 1972, Pizotifen/Methyergide	5	No	Unclear	Unclear	t	Unclear	Unclear	Unclear	Unclear
Gawel [200], 1992, Propranolol/Flunarizine	4	No	Unclear	Unclear	Unclear	No	No	Unclear	Yes
Gerber [201], 1991, Propranolol/Metoprolol/Nifedipine	3	No	Unclear	Unclear	Unclear	No	Yes	Unclear	Unclear
Gupta, 2007, Lamotrigin/Topiramate/Placebo	8	Yes	Yes	Yes	Yes	Unclear	Unclear	Unclear	Yes
Havanka-Kannianen [141], 1987, Nimodipine/Pizotifen/Placebo	3	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Hübbe [35], 1973, Pizotifen/Prochlorperazine/Placebo	3	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Yes
Kangasniemi [167], 1979, Pizotifen/Divascan/Placebo	6	No	50 (32%)	37 (71%)	Unclear	Unclear	Unclear	Unclear	Unclear
Kangasniemi [205], 1983, Propranolol/Femoxitine	2	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Kangasniemi [116], 1984, Propranolol/Femoxitine/Placebo	2	No	29 (17%)	37 (86%)	Unclear	Unclear	Unclear	Unclear	Unclear
Kaniecki [206], 1997, Divalproex/Propranolol/Placebo	4	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Kaas, 1980, Norway, Propranolol/Clonidine	4	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	No
Keskinbora [207], 2008, Amitiprytilne/Topiramate	6	No	Unclear	Yes	Yes	No	Yes	Yes	Unclear
Krymchantowski [208], 2002, Amitriptyline/Amitriptyline+Fluoxetine	5	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	No
Krymchantowski [209], 2012, Topiramate/Nortiptyline/Combination	8	No	Yes	Yes	Yes	Unclear	Unclear	Unclear	Unclear
Langohr [175], 1985, Clomipramine/Metoprolol/Placebo	4	No	Unclear	Unclear	Unclear	No	No	Yes	Yes
Louis [210], 1982, Flunarizine/Pizotifen	4	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Louis, 1985, Metoprolol/Clonidine	4	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	No
Lucking [211], 1988, Propranolol/Flunarizine	4	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Yes
Ludin [212], 1989, Propranolol/Flunarizine	3	Yes	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Luo [213], 2012, Topiramate/Flunarizine/Combination	2		Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Mathew [118], 1981, Amitriptyline/Propranolol/Placebo	2	No	Unclear	Unclear	No	No	No	Yes	Unclear
Mitsikostas [214], 1997, Valproate/Flunarizine	4	No	Unclear	Unclear	No	Unclear	Unclear	Unclear	Unclear
Mohammadianinejad [215], 2011, Topiramate/Zonisamide	6	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Unclear
Olerud [216], 1986, Propranolol/Nadolol	4	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Unclear
Olsson [217], 1984, Propranolol/Metoprolol	6	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Unclear
Osterman [169], 1977, Pizotifen/Divascan/Placebo	5	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Unclear
Presthus [218], 1971, Pizotifen/Methysergide	1	No		Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Rampello [219], 2004, Amitriptyline/Citalopram	4	Yes	Unclear	Unclear	No	Yes	Unclear	Yes	Unclear
Rascol [220], 1986, Flunarizine/Pizotifen	4	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Ryan [170], 1968, Pizotifen/Methysergide/Placebo	5	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Ryan [221], 1984, Propranolol/Nadolol	2	Yes	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Scholz (188), 1987, Propranolol/Metoprolol/Nifedipine/Flunarizine	3	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Shaygannejad [223], 2006, Topiramate/Valproate	4	Yes	Unclear	Unclear	Unclear	Unclear	Yes	Unclear	Unclear
Shimell [224], 1990, Propranolol/Flunarizine	6	Yes	Unclear	Unclear	Yes	No	No	Unclear	Yes
Sorensen [225], 1991, Metoprolol/Flunarizine	6	No	Unclear	Unclear	Yes	Yes	Yes	Unclear	Unclear
Stensrud (107), 1980, Propranolol/Atenolol	7	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Yes
Sudilovsky [226], 1987, Nadolol (two doses)	5	No	Unclear	Unclear	Yes	Unclear	Unclear	Unclear	Unclear
Togha [228], 2008, Valproate/Cinnarizine	8	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Unclear
Vilming [229], 1985, Metoprolol/Pizotifen	4	No	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Ziegler [136], 1987, Amitriptyline/Propranolol/Placebo	3	No	Unclear	Unclear	Unclear	No	Unclear	Yes	No

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Table 10. Comparative Effectiveness Trial Outcomes.

Drug 1	Drug 2	Study (year)	Standardized Mean Difference (95% CI)^δ	Heterogeneity
Episodic Migraines (<14 headaches/month)
Amitriptyline	Fluoxetine	Amelin (2000)	-0.14 (-0.85 to 0.58)
Amitriptyline	Fluvoxamine	Bank (1994)	0.37 (-0.20 to 0.93)
Amitriptyline	SSRI	Pooled SMD	0.17 (-0.32 to 0.65)	Q = 1.15, df = 1. I² = 12.9%
Amitriptyline	Maprotiline	Amelin (2000)	-0.15 (-0.87 to 0.57)
Amitriptyline	Topiramate	Dodick (2009)	-0.08 (-0.30 to 0.13)
Amitriptyline	Topiramate	Keskinbora (2008)	0.31 (-0.30 to 0.92)
Amitriptyline	Topiramate	Pooled SMD	0.01 (-0.32 to 0.33)	Q = 1.41, df = 1, I² = 29.2%
Amitriptyline	Venlafaxine	Bulut (2004)	-0.12 (-0.51 to 0.26)
Amitriptyline	Propranolol	Ziegler (1987)	0.17 (-0.55 to 0.88)
Flunarizine	Flunarizine + Topiramate	Luo (2012)	0.21 (-0.23 to 0.64)
Metoprolol	Flunarizine	Scholz (1981)	-0.83 (-1.65 to -0.01)
Metoprolol	Flunarizine	Sorensen (1991)	-0.35 (-0.69 to -0.02)
Metoprolol	Flunarizine	Pooled SMD	-0.43 (-0.77 to -0.10)	Q = 1.06, df = 1. I² = 5.8%
Metoprolol	Nifedipine	Gerber (1991)	-0.66 (-1.31 to -0.01)
Metoprolol	Nifedipine	Scholz (1987)	-0.92 (-1.78 to -0.06)
Metoprolol	Nifedipine	Pooled SMD	-0.75 (-1.27 to -0.24)	Q = 0.24, df = 1, I² = 0.0%).
Metoprolol	Clomipramine	Langohr (1985)	-1.4 (-2.8 to 0.03)
Metoprolol	Clonidine	Louis (1985)	-0.54 (-1.07 to -0.01)
Metoprolol	Pizotifen	Vliming (1985)	-0.43 (-1.15 to 0.30)
Pizotifen	Flunarizine	Cerbo (1986)	0.19 (-0.74 to 1.12)
Pizotifen	Flunarizine	Louis (1982)	0.14 (-0.34 to 0.63)
Pizotifen	Flunarizine	Rascol (1986)	0.40 (-0.29 to 1.08)
Pizotifen	Flunarizine	Pooled SMD	0.22 (-0.14 to 0.59)	Q = 0.36, df = 2, I² = 0.0%
Pizotifen	Divascan	Osterman (1977)	-0.38 (-1.14 to 0.39)	—
Pizotifen	Methysergide	Andersson (1973)	-0.17 (-0.74 to 0.40)
Pizotifen	Methysergide	Forsmann (1972)	0.10 (-0.66 to 0.85)
Pizotifen	Methysergide	Presthus (1971)	0.24 (-0.64 to 1.12)
Pizotifen	Methysergide	Ryan (1968)	-0.13 (-0.63 to 0.37)
Pizotifen	Methysergide	Pooled SMD	-0.06 (-0.37 to 0.26)	Q = 0.83, df = 3, I² = 0.0%
Pizotifen	Nimodipine	Havanka (1987)	0.11 (-0.59 to 0.71)	—
Pizotifen	Naproxen	Bellavance (1990)	0.10 (-0.27 to 0.46)	—
Pizotifen	Prochloperazine	Hübbe (1973)	-0.33 (-0.96 to 0.29)	—
Propranolol	Atenolol	Stensrud (1980)	0.02 (-0.84 to 0.88)	—
Propranolol	Clonidine	Kaas (1980)	0.03 (-0.58 to 0.63)	—
Propranolol	Cyclandelate	Diemer (1996)	-0.07 (-0.38 to 0.24)	—
Propranolol	Femoxetine	Andersson (1981)	-0.40 (-1.05 to 0.25)
Propranolol	Femoxetine	Kangasniemi (1983)	-2.03 (-2.66 to -1.39)
Propranolol	Femoxetine	Pooled SMD	-1.21 (-2.8 to -0.37)	Q = 17.35, df = 1, I² = 88.5%
Propranolol	Flunarizine	Bordini (1997)	-0.32 (-0.40 to 1.05)
Propranolol	Flunarizine	Diener (2002)	-0.38 (-0.52 to -0.24)
Propranolol	Flunarizine	Gawel (1992)	0.58 (0.12 to 1.04)
Propranolol	Flunarizine	Lucking (1988)	-0.20 (-0.67 to 0.27)
Propranolol	Flunarizine	Ludin (1989)	-0.21 (-0.73 to 0.30)
Propranolol	Flunarizine	Scholz (1987)	-0.37 (-1.16 to 0.43)
Propranolol	Flunarizine	Shimell (1990)	-0.02 (-0.55 to 0.50)
Propranolol	Flunarizine	Pooled SMD	-0.04 (-0.34 to 0.26)	Q = 20.62, df = 6, I² = 70.9%
Propranolol	Metoprolol	Olsson (1984)	0.00 (-0.46 to 0.46)
Propranolol	Metoprolol	Scholz (1987)	0.03 (-0.58 to 0.65)
Propranolol	Metoprolol	Pooled SMD	0.15 (-0.27 to 0.57)	Q = 1.14, df = 1, I² = 12.6
Propranolol	Nadolol	Olerud (1986)	0.37 (-0.39 to 1.13)
Propranolol	Nadolol	Ryan (1984)	-0.42 (-1.15 to 0.27)
Propranolol	Nadolol	Sudilovsky (1987)	0.28 (-0.08 to 0.64)
Propranolol	Nadolol	Pooled SMD	0.19 (-0.18 to 0.56)	Q = 2.81, df = 2, I² = 28.9%
Propranolol	Nifedipine	Albers (1989)	0.84 (-0.12 to 1.79)
Propranolol	Nifedipine	Gerber (1991)	-0.63 (-1.30 to 0.05)
Propranolol	Nifedipine	Scholz (1987)	-0.46 (-1.29 to 0.37)
Propranolol	Nifedipine	Pooled SMD	-0.14 (-0.98 to 0.71)	Q = 10.41, df = 2, I² = 61.6%
Propranolol	Nimodipine	Formisano (1991)	-0.19 (-1.10 to 0.73)	—
Propranolol	Topiramate	Ashtari (2008)	-0.24 (-0.27 to 0.75)
Propranolol	Topiramate	Diener (2004)	0.12 (-0.08 to 0.32)
Propranolol	Topiramate	Pooled SMD	-0.02 (-0.30 to 0.33)	Q = 1.65, df = 2, I² = 39.5%
Topiramate	Flunarizine	Luo (2012)	0.23 (-0.07 to 0.53)
Topiramate	Frovatriptan (abortive)	Cady (2011)	-0.49 (-1.09 to 0.11)
Topiramate	Topiramate+Flunarizine	Luo (2012)	0.35 (-0.07 to 0.78)
Topiramate	Lamotrigine	Gupta (2007)	-0.30 (-0.83 to 0.22)
Topiramate	Topiramate + Nortriptyline	Krymchantowski (2012)	0.53 (0.04 to 1.02)
		Afshari (2012)	-0.32 (-0.85 to 0.20)
		Shaygannejad (2006)	-0.19 (-0.68 to 0.30)
Topiramate	Valproate	Pooled SMD	-0.28 (-0.70 to 0.15)	Q = 0.09, df = 1, I² = 0.0%
Topiramate	Zonisamide	Mohammadianinejad (2011)	-0.26 (-0.72 to 0.19)
Valproate	Cinnarizine	Togha (2008)	-0.07 (-0.42 to 0.28)
Valproate	Flunarizine	Mitsikostas (1997)	-0.06 (-0.67 to 0.56)
Chronic Migraine (>15 headaches/month)
Amitriptyline	Amitriptyline+Fluoxetine	Krymchantowski (2002)	-0.44 (-1.20 to 0.33)
Pizotifen	Naproxen	Behan (1986)	0.08 (-0.56 to 0.73)
Propranolol	Atenolol	Stensrud (1980)	0.08 (-1.40 to 1.56)
Propranolol	Nortriptyline	Domingues (2009)	-0.83 (-0.06 to -1.61)
Topiramate	Valproate	Bartolini (2005)	-0.13 (-0.72 to 0.46)

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δ negative number favors drug 1, positive number favors drug 2 in these comparisons.

Network Meta-analysis

Candidate drugs for the network meta-analysis were those drugs found effective for treatment of episodic migraine headaches with at least 3 randomized clinical trials. These included eleven different drugs used in prophylaxis of episodic migraine headaches (Fig 13). Indirect comparisons of these eleven individual drugs using meta-regression suggested that amitriptyline was more effective than several of the other drugs including candesartan (p = 0.04), fluoxetine (p = 0.03), propranolol (p = 0.009), topiramate (p = 0.005) and valproate (p = 0.009, Fig 12), and no different than atenolol (p = 0.20), flunarizine (p = 0.06), clomipramine (p = 0.15) or metoprolol (p = 0.15). The network meta-analysis found no differences between the other drugs in the relative effectiveness in the prophylaxis against migraine headaches. (p = 0.21).

Placebo effect

There were 78 studies that provided baseline headache frequency that included 4579 episodic migraine sufferers who were randomized to placebo. On average, patients randomized to the placebo group experienced 5.3 (95% CI: 4.9–5.8) headaches/month at baseline. Patients receiving placebos experienced a significant decline in headache frequency by 4 weeks, an effect that persisted through 12 weeks. By weeks 16, 20 and 24, the number of headaches experienced by patients given placebo increased back to values that were not different than baseline (Fig 14).

Side Effects

Patients receiving prophylactic treatment were more likely than those receiving placebo to experience side effects (RR: 1.27, 95% CI: 1.19 to 1.37) and to withdraw from treatment (RR: 1.18, 95% CI: 1.08–1.29). The specific side effects varied by study medication (Table 11). Drowsiness was the most common side effect, increased among patients taking gabapentin, pizotifen, topiramate, TCA and valproate. Tricyclic antidepressants also caused dry mouth and weight gain. Beta-blockers were associated with feeling depressed, dizzy and insomnia. Topiramate increased rates of nausea and paresthesia. Pizotifen had marked increased rates of weight gain with participants averaging 4.3 kg (95% CI: 3.0–5.6).

Table 11. Side Effects Compared with Placebo.

	Alpha Blockers	Anti-convulsants	Beta Blockers	Calcium Channel Blockers	Flunarizine	SSRI	TCA
“Any” side effect	1.25 (0.91–1.71)	1.20 (1.14–1.27)	1.65 (1.41–1.93)	1.25 (1.03–1.53)	1.26 (0.67–2.37)	1.0 (0.51–1.97)	1.54 (1.37–1.74)
Withdrawal	1.07 (0.65–1.78)	1.23 (1.13–1.34)	1.29 (1.03–1.61)	1.14 (0.84–1.57)	1.0 (0.3–3.2)	1.13 (0.79–1.61)	1.53 (1.27–1.85)
Depression	3.0 (0.13–70.6)	ns	4.1 (1.1–15.2)	0.2 (0.01–4.0)	0.7 (0.1–3.4)	ns	ns
Dizziness	1.80 (0.36–9.08)	1.61 (1.16–2.21)	1.75 (1.04–2.95)	1.19 (0.45–3.18)	ns	1.28 (0.23–7.14)	1.20 (0.77–1.86)
Fatigue	2.65 (0.94–7.51)	2.22 (1.67–2.96)	1.19 (0.90–1.56)	3.07 (1.26–7.48)	1.3 (0.7–2.1)	ns	1.84 (1.25–2.71)
Dry Mouth	7.09 (2.31–21.7)	2.33 (0.43–12.8)	ns	0.21 (0.01–4.27)	0.26 (0.03–2.3)	ns	2.32 (1.63–3.28)
Nausea/vomiting	1.50 (0.27–8.3)	1.44 (1.01–2.03)	1.8 (1.05–3.02)	0.68 (0.37–1.24)	0.12 (0.01–2.0) (1 study)	2.15 (0.80–5.8)	1.18 (0.42–3.3)
Parasthesias	6.2 (1.5–26.3)	4.2 (2.7–6.6)	1.4 (0.49–4.2)	5.0 (0.25–101.9)	ns	ns	1.5 (0.26–9.0) (1 study)
Sleep disturbance	Ns	0.84 (0.53–1.33)	1.64 (1.08–2.5)	Ns	ns	1.27 (0.66–2.5)	0.63 (0.36–1.1)
Weight gain	Ns	1.02 (0.12–8.5)	6.1 (0.73–51.3)	3.08 (0.60–15.9)	0.79 (0.36–1.71) (4 studies)	ns	1.65 (1.02–3.04)

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Network meta-analysis and direct comparisons found no difference in likelihood of experiencing “any” side effect or in the rate of withdrawing from studies.

Sensitivity Analysis

There was evidence of publication bias for beta-blockers (Egger p = 0.02), and for each of topiramate (p = 0.001) and valproate (p = 0.04). There was no evidence of publication bias for the remaining drugs or classes. The metatrim test reduced the effect estimate four these four drugs, though only for valproate did the adjusted effect become insignificant (beta-blocker SMD: -0.24, 95% CI: -0.45 to -0.04; topiramate: SMD: -0.35, 95% CI: -0.57 to -0.12; valproate: SMD: -0.40, 95% CI: -0.90 to 0.10).

There were a number of quality problems (Tables 4 and 9). However, total Jadad score (p = 0.51), intention to treat (p = 0.84), sequence generation (p = 0.47), concealed allocation (p = 0.18), blinding (p = 0.84) or industry sponsorship (p = 0.17) had no relationship or impact on pooled outcomes.

The amount of heterogeneity varied considerably among the various drugs and drug classes. Longer duration of treatment was associated with greater effects for tricyclic antidepressants (β = -0.06, 95% CI: -0.09 to -0.03) as well as for valproate (β = -0.02, 95% CI -0.04 to -0.01) and flunarizine (β = -0.03, 95% CI -0.07 to -0.001). The other treatment options did not appear to be time-sensitive. There was no relationship between type of measurement (frequency vs. headache index) and outcomes (p = 0.72). Age, percent women, sample size, dropout rate, percent of maximum dose attained, study design and whether or not depressed patients were allowed to participate had no relationship with outcomes.

Discussion

There has long been consensus that some drugs are useful in prophylaxis against migraine headaches. Our review confirms that there is good evidence for amitriptyline, atenolol, flunarizine, fluoxetine, metoprolol, pizotifen, propranolol, timolol, topiramate and valproate in reducing episodic migraine headache. At baseline, episodic migtaine sufferers averaged slightly over six headaches per month and most drugs reduced the number of headaches by 1 or 2 per month. Amitriptyline had the greatest benefit and while the network meta-analysis suggested that it was the most effective drug for preventing migraine headaches, this was not confirmed in clinical trials in which amitriptyline was directly compared with other drugs (including SSRIs, topiramate and propranolol), though all candidate drugs have not been included. Beta-blockers (atenolol, propranolol, timolol), anticonvulsants (topiramate, valproate), flunarizine and pizotifen had moderate benefit in reducing headache burden while the serotonin reuptake inhibitors had a small effect.

On average, across the effective prophylactic medications, migraine sufferers had about twice the chance of experiencing at least a 50% reduction in headaches as those receiving placebo. Our pooled risk reduction (ARR: 0.15, 95% CI: 0.09–0.21) suggests that 7 people would need to be treated to produce 50% reduction in headache burden in one subject. Side effects were common, but were predictable based on the drug mechanisms of action and are well-known.

There was a significant placebo effect that was seen within 4 weeks of placebo initiation with a gradual increase in the benefit of placebo on headaches through 12 weeks. By week 16, patients randomized to placebo had a gradual increase in the number of headaches experienced with no difference from baseline through 24 weeks of treatment. This is similar to the placebo effect we saw in our meta-analysis of pediatric migraine trials [233]. Uncontrolled trials of drugs for treatment of migraine headaches are still published, our data reinforces the importance of placebo controls.

Our study is the first to pool all the data from the numerous randomized controlled clinical trials to explore potential differences for both continuous and dichotomous outcomes and for both episodic and chronic migraine headaches. We also avoid a common error found in previous meta-analyses in which researchers pooled the outcome at the end of the study, regardless of the time point. This inappropriately pooled studies of different treatment durations.

There have been no previous systematic reviews of ACE/ARB, flunarizine or beta-blockers other than propranolol for migraine headaches. A recent Neurology Academy review was limited by several factors: 1) it included only studies since 2009, 2) it provided only qualitative statements about the level of evidence with no formal pooling of data and 3) it had no comparative effectiveness data [27]. While our findings are similar to previous reviews of anticonvulsants [234], the beta-blocker propranolol [235], anticonvulsants [236] and tricyclic antidepressants [237], we found some important differences. Anticonvulsants were less effective than a 2004 Cochrane review[234], though our review includes nearly twice as many studies. A 2004 Cochrane beta-blocker review included exclusively propranolol, while we include all beta-blockers. Our 2010 TCA review[237] inappropriately pooled both migraine and tension headaches together. Our 1996 review [238] also combined migraine and tension headaches, likely inappropriate given potentially important pathophysiologic differences. A 2005 Cochrane review of SSRIs found no benefit[239], but that trial was largely based on tension headaches and it also combined both migraine and tension headaches in their pooled analysis. In contrast, our larger review focuses on migraine headaches and suggests a modest effect from fluoxetine. To date, there have been no quantitative systematic reviews comparing the different classes of treatment, though one recent qualitative systematic review concluded that the choice should be tailored to patients based on side effects and comorbidities [240].

A recent systematic review examined the efficacy of prophylactic treatment for episodic migraine headaches[28] in reducing headaches by 50%, a dichotomous outcome. Our study includes both continuous and dichotomous outcomes and examines the effects for both episodic and migraine headaches. That study was limited to English language only and includes a smaller number of studies than this analysis. Our results are similar and in agreement with their conclusion that there is no difference in efficacy between the different drugs; however we found that the benefit for most drugs was less than they reported.

Our study has a number of important limitations. First the pooled differences between the various drugs and classes suggested important clinical differences. Some drugs had a large effect in headache reduction, others only small or modest ones. Our network meta-analysis suggested superiority for amitriptyline, a finding not confirmed in head-head trials. While there have been 51 trials directly comparing different drugs, these comparisons have been somewhat haphazard and many important potential comparisons have not been made.

Conclusions

Our data suggests that the current practice of tailoring prophylactic medication according to patient characteristics and expected side effects is a good approach. Patients with migraine headaches and hypertension should consider trials with a beta blocker. Patients with depression may benefit from either SSRI or TCA. Patients with restless leg syndrome or another indication for an anticonvulsant may benefit from topiramate or valproate. Our analysis suggests that amitryptyline is more effective than the other medications, this has not been confirmed in the limited number of direct comparative effectiveness trials that have been conducted. The placebo effect, that lasts through at least 12 weeks in our study, suggests that non-placebo controlled trials should not be performed. Nearly all studies of headache treatment were 24 weeks or less in duration, this is an important limitation since migraine is a chronic condition. Whether treatment benefit persists, increases or wanes is unknown and deserving of further studies. The paucity of head-to-head comparative effectiveness trials between some classes of medication also indicates a direction for future headache research.

Supporting Information

S1 File. PRISMA Checklist.

(DOC)

Click here for additional data file.^{(63.5KB, doc)}

Data Availability

Relevant data are available on figshare.com: (http://dx.doi.org/10.6084/m9.figshare.1431538).

Funding Statement

The authors have no support or funding to report.

References

1. Rasmussen BK (2001) Epidemiology of headache. Cephalalgia 21: 774–777. [DOI] [PubMed] [Google Scholar]
2. Wang SJ (2003) Epidemiology of migraine and other types of headache in Asia. Current Neurology & Neuroscience Reports 3: 104–108. [DOI] [PubMed] [Google Scholar]
3. Radtke A, Neuhauser H (2009) Prevalence and burden of headache and migraine in Germany. Headache 49: 79–89. HED1263 [pii]; 10.1111/j.1526-4610.2008.01263.x [DOI] [PubMed] [Google Scholar]
4. Karli N, Zarifoglu M, Ertafs M, Saip S, Ozturk V, Bicakci S, et al. (2006) Economic impact of primary headaches in Turkey: a university hospital based study: part II. J Headache Pain 7: 75–82. 10.1007/s10194-006-0273-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
5. Falavigna A, Teles AR, Velho MC, Vedana VM, Silva RC, Mazzocchin T, et al. (2010) Prevalence and impact of headache in undergraduate students in Southern Brazil. Arq Neuropsiquiatr 68: 873–877. S0004-282X2010000600008 [pii]. [DOI] [PubMed] [Google Scholar]
6. Lipton RB, Bigal ME, Kolodner K, Stewart WF, Liberman JN, Steiner TJ (2003) The family impact of migraine: population-based studies in the USA and UK. Cephalalgia 23: 429–440. [DOI] [PubMed] [Google Scholar]
7. Lipton RB, Liberman JN, Kolodner KB, Bigal ME, Dowson A, Stewart WF (2003) Migraine headache disability and health-related quality-of-life: a population-based case-control study from England. Cephalalgia 23: 441–450. 546 [pii]. [DOI] [PubMed] [Google Scholar]
8. Blumenfeld AM, Varon SF, Wilcox TK, Buse DC, Kawata AK, Manack A, et al. (2011) Disability, HRQoL and resource use among chronic and episodic migraineurs: results from the International Burden of Migraine Study (IBMS). Cephalalgia 31: 301–315. 0333102410381145 [pii]; 10.1177/0333102410381145 [DOI] [PubMed] [Google Scholar]
9. Leonardi M, Raggi A, Bussone G, D'Amico D (2010) Health-related quality of life, disability and severity of disease in patients with migraine attending to a specialty headache center. Headache 50: 1576–1586. 10.1111/j.1526-4610.2010.01770.x [DOI] [PubMed] [Google Scholar]
10.Raggi A, Leonardi M, Bussone G, D'Amico D (2010) Value and utility of disease-specific and generic instruments for assessing disability in patients with migraine, and their relationships with health-related quality of life. Neurol Sci. 10.1007/s10072-010-0466-3 [DOI] [PubMed]
11. Tepper SJ (2008) A pivotal moment in 50 years of headache history: the first American Migraine Study. Headache 48: 730–731. HED1117_1 [pii]; 10.1111/j.1526-4610.2008.01117_1.x [DOI] [PubMed] [Google Scholar]
12. Freitag FG (2007) The cycle of migraine: patients' quality of life during and between migraine attacks. Clin Ther 29: 939–949. S0149-2918(07)00137-3 [pii]; 10.1016/j.clinthera.2007.05.008 [DOI] [PubMed] [Google Scholar]
13. Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML (1999) Burden of migraine in the United States: disability and economic costs. Archives of Internal Medicine 159: 813–818. [DOI] [PubMed] [Google Scholar]
14. Goldberg LD (2005) The cost of migraine and its treatment. Am J Manag Care 11: S62–S67. 2883 [pii]. [PubMed] [Google Scholar]
15.(2013) The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 33: 629–808. 10.1177/0333102413485658 [DOI] [PubMed] [Google Scholar]
16.Adams AM, Serrano D, Buse DC, Reed ML, Marske V, Fanning KM, et al. (2014) The impact of chronic migraine: The Chronic Migraine Epidemiology and Outcomes (CaMEO) Study methods and baseline results. Cephalalgia. 0333102414552532 [pii]; 10.1177/0333102414552532 [DOI] [PMC free article] [PubMed]
17.Law S, Derry S, Moore RA (2010) Triptans for acute cluster headache. Cochrane Database Syst Rev CD008042. 10.1002/14651858.CD008042.pub2 [DOI] [PMC free article] [PubMed]
18.McCrory DC, Gray RN (2003) Oral sumatriptan for acute migraine. Cochrane Database Syst Rev CD002915. 10.1002/14651858.CD002915 [DOI] [PubMed]
19. Chronicle E, Mulleners W (2004) Anticonvulsant drugs for migraine prophylaxis. Cochrane Library. [DOI] [PubMed] [Google Scholar]
20.Linde K, Rossnagel K (2004) Propranolol for migraine prophylaxis. Cochrane Database Syst Rev CD003225. 10.1002/14651858.CD003225.pub2. [DOI] [PubMed]
21. Jackson JL, Kuriyama A, Hayashino Y (2012) Botulinum toxin A for prophylactic treatment of migraine and tension headaches in adults: a meta-analysis. JAMA 307: 1736–1745. 307/16/1736 [pii]; 10.1001/jama.2012.505 [DOI] [PubMed] [Google Scholar]
22. Pringsheim T, Davenport WJ, Becker WJ (2010) Prophylaxis of migraine headache. CMAJ 182: E269–E276. cmaj.081657 [pii]; 10.1503/cmaj.081657 [DOI] [PMC free article] [PubMed] [Google Scholar]
23. Lance JW, Anthony M (1968) Clinical trial of a new serotonin antagonist, BC105, in the prevention of migraine. Med J Aust 1: 54–55. [DOI] [PubMed] [Google Scholar]
24.Moja PL, Cusi C, Sterzi RR, Canepari C (2005) Selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type headaches. Cochrane Database Syst Rev CD002919. 10.1002/14651858.CD002919.pub2 [DOI] [PubMed]
25. Jackson JL, Shimeall W, Sessums L, Dezee KJ, Becher D, Diemer M, et al. (2010) Tricyclic antidepressants and headaches: systematic review and meta-analysis. BMJ 341: c5222 10.1136/bmj.c5222 [DOI] [PMC free article] [PubMed] [Google Scholar]
26. Rapaport AM (1994) Recurrent migraine: cost-effective care. Neurology 44: S25–S28. [PubMed] [Google Scholar]
27. Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E (2012) 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 78: 1337–1345. 78/17/1337 [pii]; 10.1212/WNL.0b013e3182535d20 [DOI] [PMC free article] [PubMed] [Google Scholar]
28. Shamliyan TA, Choi JY, Ramakrishnan R, Miller JB, Wang SY, Taylor FR, et al. (2013) Preventive pharmacologic treatments for episodic migraine in adults. J Gen Intern Med 28: 1225–1237. 10.1007/s11606-013-2433-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
29. Moher D, Liverati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLos Med 6: e1000097 10.1371/journal.pmed.1000097 [DOI] [PMC free article] [PubMed] [Google Scholar]
30. Ad Hoc Committee on the Classification of Headache of the National Institute of Neurological Diseases and Blindness (1962) Classification of headache. JAMA 179: 717–718. [Google Scholar]
31. Headache Classification Committee of the International Headache Society (1988) Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 8: 1–96. [PubMed] [Google Scholar]
32. Silberstein S, Tfelt-Hansen P, Dodick DW, Limmroth V, Lipton RB, Pascual J, et al. (2008) Guidelines for controlled trials of prophylactic treatment of chronic migraine in adults. Cephalalgia 28: 484–495. CHA1555 [pii]; 10.1111/j.1468-2982.2008.01555.x [DOI] [PubMed] [Google Scholar]
33. Kazis LE, Anderson JJ, Meenan RF (1989) Effect sizes for interpreting changes in health status. Med Care 27: S178–S189. [DOI] [PubMed] [Google Scholar]
34. Follmann D, Elliott P, Suh I, Cutler J (1992) Variance imputation for overviews of clinical trials with continuous response. J Clin Epidemiol 45: 769–773. 0895-4356(92)90054-Q [pii]. [DOI] [PubMed] [Google Scholar]
35. Hubbe P (1973) The prophylactic treatment of migraine with an antiserotonin pizotifen. Acta Neurol Scand 49: 108–114. [DOI] [PubMed] [Google Scholar]
36. Gotzsche PC, Hrobjartsson A, Maric K, Tendal B (2007) Data extraction errors in meta-analyses that use standardized mean differences. JAMA 298: 430–437. 298/4/430 [pii];10.1001/jama.298.4.430. [DOI] [PubMed] [Google Scholar]
37.McCrory D (2012) Report on gabapentin (Neurontin) for migraine prophylaxis: Evaluation of efficacy, effectiveness and marking. Expert Consultant's report.
38. Vedula SS, Bero L, Scherer RW, Dickersin K (2009) Outcome reporting in industry-sponsored trials of gabapentin for off-label use. N Engl J Med 361: 1963–1971. 361/20/1963 [pii]; 10.1056/NEJMsa0906126 [DOI] [PubMed] [Google Scholar]
39. Alderson P, Green S, Higgins JPT (2004) Assessment of Study Quality In: Alderson P, Green S, Higgins JPT, editors. Cochrane Reviewers' Handbook 4.2.2. John Wiley & Sons, Ltd. [Google Scholar]
40. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials 17: 1–12. [DOI] [PubMed] [Google Scholar]
41.Higgins JPT, Green S (2009) Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated September 2009]. www.cochrane-handbook.org.
42. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7: 177–188. 0197-2456(86)90046-2 [pii]. [DOI] [PubMed] [Google Scholar]
43. Mathew NT (2001) Antiepileptic drugs in migraine prevention. Headache 41 Suppl 1: S18–S24. 01154–4 [pii]. [DOI] [PubMed] [Google Scholar]
44. Ades AE, Mavranezouli I, Dias S, Welton NJ, Whittington C, Kendall T (2010) Network meta-analysis with competing risk outcomes. Value Health 13: 976–983. 10.1111/j.1524-4733.2010.00784.x [DOI] [PubMed] [Google Scholar]
45. Lumley T (2002) Network meta-analysis for indirect treatment comparisons. Stat Med 21: 2313–2324. [DOI] [PubMed] [Google Scholar]
46. Salanti G, Ades AE, Ioannidis JP (2011) Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol 64: 163–171. 10.1016/j.jclinepi.2010.03.016 [DOI] [PubMed] [Google Scholar]
47. Woods BS, Hawkins N, Scott DA (2010) Network meta-analysis on the log-hazard scale, combining count and hazard ratio statistics accounting for multi-arm trials: a tutorial. BMC Med Res Methodol 10:54: 54. 10.1186/1471-2288-10-54 [DOI] [PMC free article] [PubMed] [Google Scholar]
48. Galbraith RF (1988) A note on graphical presentation of estimated odds ratios from several clinical trials. Statistics in Medicine 7: 889–894. [DOI] [PubMed] [Google Scholar]
49. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327: 557–560. 10.1136/bmj.327.7414.557 327/7414/557 [pii]. [DOI] [PMC free article] [PubMed] [Google Scholar]
50. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L (2006) Comparison of two methods to detect publication bias in meta-analysis. JAMA 295: 676–680. 295/6/676 [pii]; 10.1001/jama.295.6.676 [DOI] [PubMed] [Google Scholar]
51. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315: 629–634. [DOI] [PMC free article] [PubMed] [Google Scholar]
52. Sharp S (1998) Meta-analysis regression. Stata Technical Bulletin 42: 16–22. [Google Scholar]
53. Adam EI, Gore SM, Price WH (1978) Double blind trial of clonidine in the treatment of migraine in a general practice. J R Coll Gen Pract 28: 587–590. [PMC free article] [PubMed] [Google Scholar]
54. Boisen E, Deth S, Hubbe P, Jansen J, Klee A, Leunbach G (1978) Clonidine in the prophylaxis of migraine. Acta Neurol Scand 58: 288–295. [DOI] [PubMed] [Google Scholar]
55. Bredfeldt RC, Sutherland JE, Kruse JE (1989) Efficacy of transdermal clonidine for headache prophylaxis and reduction of narcotic use in migraine patients. A randomized crossover trial. J Fam Pract 29: 153–156. [PubMed] [Google Scholar]
56. Lynggaard F, Ostergaard F (1975) [Clonidine in prevention of migraine. Report of a double-blind study of 38 patients referred for neurological assessment]. Ugeskr Laeger 137: 149–151. [PubMed] [Google Scholar]
57. Mondrup K, Moller CE (1977) Prophylactic treatment of migraine with clonidine. A controlled clinical trial. Acta Neurol Scand 56: 405–412. [DOI] [PubMed] [Google Scholar]
58. Ryan RE Sr, Diamond S, Ryan RE Jr (1975) Double blind study of clonidine and placebo for the prophylactic treatment of migraine. Headache 15: 202–210. [DOI] [PubMed] [Google Scholar]
59. Saper JR, Lake AE III, Cantrell DT, Winner PK, White JR (2002) Chronic daily headache prophylaxis with tizanidine: a double-blind, placebo-controlled, multicenter outcome study. Headache 42: 470–482. hed02122 [pii]. [DOI] [PubMed] [Google Scholar]
60. Shafar J, Tallett ER, Knowlson PA (1972) Evaluation of clonidine in prophylaxis of migraine. Double-blind trial and follow-up. Lancet 1: 403–407. [DOI] [PubMed] [Google Scholar]
61. Stensrud P, Sjaastad O (1976) Clonidine (Catapresan)-double-blind study after long-term treatment with the drug in migraine. Acta Neurol Scand 53: 233–236. [DOI] [PubMed] [Google Scholar]
62. Paterna S, di Pasquale P, Martino S, Arrostuto A, Ingurgio NC, Parrinello G, et al. (1992) [Captopril versus placebo in the prevention of hemicrania without aura. A randomized double-blind study]. Clin Ter 141: 475–481. [PubMed] [Google Scholar]
63. Schrader H, Stovner LJ, Helde G, Sand T, Bovim G (2001) Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): randomised, placebo controlled, crossover study. BMJ 322: 19–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
64. Sonbolestan SA, Heshmat K, Javanmard SH, Saadatnia M (2013) Efficacy of Enalapril in Migraine Prophylaxis: A Randomized, Double-blind, Placebo-controlled Trial. Int J Prev Med 4: 72–77. [PMC free article] [PubMed] [Google Scholar]
65. Diener HC, Gendolla A, Feuersenger A, Evers S, Straube A, Schumacher H, et al. (2009) Telmisartan in migraine prophylaxis: a randomized, placebo-controlled trial. Cephalalgia 29: 921–927. CHA1825 [pii]; 10.1111/j.1468-2982.2008.01825.x [DOI] [PubMed] [Google Scholar]
66.Stovner LJ, Linde M, Gravdahl GB, Tronvik E, Aamodt AH, Sand T, et al.(2013) A comparative study of candesartan versus propranolol for migraine prophylaxis: A randomised, triple-blind, placebo-controlled, double cross-over study. Cephalalgia. 0333102413515348 [pii]; 10.1177/0333102413515348 [DOI] [PubMed]
67. Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G (2003) Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. JAMA 289: 65–69. joc21661 [pii]. [DOI] [PubMed] [Google Scholar]
68. Beran RG, Spira PJ (2011) Levetiracetam in chronic daily headache: A double-blind, randomised placebo-controlled study: (The Australian KEPPRA Headache Trial [AUS-KHT]). Cephalalgia 31: 530–536. 0333102410384886 [pii]; 10.1177/0333102410384886 [DOI] [PubMed] [Google Scholar]
69. Brandes JL, Saper JR, Diamond M, Couch JR, Lewis DW, Schmitt J, et al. (2004) Topiramate for migraine prevention: a randomized controlled trial. JAMA 291: 965–973. 10.1001/jama.291.8.965 291/8/965 [pii]. [DOI] [PubMed] [Google Scholar]
70. Cady RK, Mathew N, Diener HC, Hu P, Haas M, Novak GP (2009) Evaluation of carisbamate for the treatment of migraine in a randomized, double-blind trial. Headache 49: 216–226. HED1326 [pii]; 10.1111/j.1526-4610.2008.01326.x [DOI] [PubMed] [Google Scholar]
71. deTommaso M., Marinazzo D, Nitti L, Pellicoro M, Guido M, Serpino C, et al. (2007) Effects of levetiracetam vs topiramate and placebo on visually evoked phase synchronization changes of alpha rhythm in migraine. Clin Neurophysiol 118: 2297–2304. S1388-2457(07)00323-9 [pii]; 10.1016/j.clinph.2007.06.060 [DOI] [PubMed] [Google Scholar]
72. Di Trapani G, Mei D, Marra C, Mazza S, Capuano A (2000) Gabapentin in the prophylaxis of migraine: a double-blind randomized placebo-controlled study. Clin Ter 151: 145–148. [PubMed] [Google Scholar]
73. Diener HC, Tfelt-Hansen P, Dahlof C, Lainez MJ, Sandrini G, Wang SJ, et al. (2004) Topiramate in migraine prophylaxis—results from a placebo-controlled trial with propranolol as an active control. J Neurol 251: 943–950. 10.1007/s00415-004-0464-6 [DOI] [PubMed] [Google Scholar]
74. Diener HC, Bussone G, Van Oene JC, Lahaye M, Schwalen S, Goadsby PJ (2007) Topiramate reduces headache days in chronic migraine: a randomized, double-blind, placebo-controlled study. Cephalalgia 27: 814–823. CHA1326 [pii]; 10.1111/j.1468-2982.2007.01326.x [DOI] [PubMed] [Google Scholar]
75. Edwards KR, Potter DL, Wu SC, Kamin M, Hulihan J (2003) Topiramate in the preventive treatment of episodic migraine: a combined analysis from pilot, double-blind, placebo-controlled trials. CNS Spectr 8: 428–432. [DOI] [PubMed] [Google Scholar]
76. Freitag FG, Collins SD, Carlson HA, Goldstein J, Saper J, Silberstein S, et al. (2002) A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis. Neurology 58: 1652–1659. [DOI] [PubMed] [Google Scholar]
77. Ghose K, Niven B (1998) Prophylactic sodium valproate therapy in patients with drug-resistant migraine. Methods Find Exp Clin Pharmacol 20: 353–359. 485692 [pii]. [DOI] [PubMed] [Google Scholar]
78. Gupta VK (2006) Topiramate for migraine prophylaxis: addressing the blood-brain barrier-related pharmacokinetic-pathophysiological disconnect. Int J Clin Pract 60: 367–368. IJCP796a [pii]; 10.1111/j.1368-5031.2006.0796a.x [DOI] [PubMed] [Google Scholar]
79. Hering R, Kuritzky A (1992) Sodium valproate in the prophylactic treatment of migraine: a double-blind study versus placebo. Cephalalgia 12: 81–84. [DOI] [PubMed] [Google Scholar]
80. Jensen R, Brinck T, Olesen J (1994) Sodium valproate has a prophylactic effect in migraine without aura: a triple-blind, placebo-controlled crossover study. Neurology 44: 647–651. [DOI] [PubMed] [Google Scholar]
81. Klapper J (1997) Divalproex sodium in migraine prophylaxis: a dose-controlled study. Cephalalgia 17: 103–108. [DOI] [PubMed] [Google Scholar]
82. Lipton RB, Silberstein S, Dodick D, Cady R, Freitag F, Mathew N, et al. (2011) Topiramate intervention to prevent transformation of episodic migraine: the topiramate INTREPID study. Cephalalgia 31: 18–30. 0333102410372427 [pii]; 10.1177/0333102410372427 [DOI] [PubMed] [Google Scholar]
83. Mathew NT, Saper JR, Silberstein SD, Rankin L, Markley HG, Solomon S, et al. (1995) Migraine prophylaxis with divalproex. Arch Neurol 52: 281–286. [DOI] [PubMed] [Google Scholar]
84. Mei D, Ferraro D, Zelano G, Capuano A, Vollono C, Gabriele C, et al. (2006) Topiramate and triptans revert chronic migraine with medication overuse to episodic migraine. Clin Neuropharmacol 29: 269–275. 10.1097/01.WNF.000022888.49044.99 00002826-200609000-00005 [pii]. [DOI] [PubMed] [Google Scholar]
85. Rompel H, Bauermeister PW (1970) Aetiology of migraine and prevention with carbamazepine (Tegretol): results of a double-blind, cross-over study. S Afr Med J 44: 75–80. [PubMed] [Google Scholar]
86. Sarchielli P, Messina P, Cupini LM, Tedeschi G, Di Pero V, Livrea P, et al. (2014) Sodium valproate in migraine without aura and medication overuse headache: a randomized controlled trial. Eur Neuropsychopharmacol 24: 1289–1297. S0924-977X(14)00095-9 [pii]; 10.1016/j.euroneuro.2014.03.010 [DOI] [PubMed] [Google Scholar]
87. Silberstein SD, Neto W, Schmitt J, Jacobs D (2004) Topiramate in migraine prevention: results of a large controlled trial. Arch Neurol 61: 490–495. 10.1001/archneur.61.4.490 61/4/490 [pii]. [DOI] [PubMed] [Google Scholar]
88. Silberstein SD, Hulihan J, Karim MR, Wu SC, Jordan D, Karvois D, et al. (2006) 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 28: 1002–1011. S0149-2918(06)00165-2 [pii]; 10.1016/j.clinthera.2006.07.003 [DOI] [PubMed] [Google Scholar]
89. Silberstein SD, Lipton RB, Dodick DW, Freitag FG, Ramadan N, Mathew N, et al. (2007) Efficacy and safety of topiramate for the treatment of chronic migraine: a randomized, double-blind, placebo-controlled trial. Headache 47: 170–180. HED684 [pii]; 10.1111/j.1526-4610.2006.00684.x [DOI] [PubMed] [Google Scholar]
90. Silberstein S, Saper J, Berenson F, Somogyi M, McCague K, D'Souza J (2008) Oxcarbazepine in migraine headache: a double-blind, randomized, placebo-controlled study. Neurology 70: 548–555. 70/7/548 [pii]; 10.1212/01.wnl.0000297551.27191.70 [DOI] [PubMed] [Google Scholar]
91. Silberstein S, Goode-Sellers S, Twomey C, Saiers J, Ascher J (2013) Randomized, double-blind, placebo-controlled, phase II trial of gabapentin enacarbil for migraine prophylaxis. Cephalalgia 33: 101–111. 0333102412466968 [pii]; 10.1177/0333102412466968 [DOI] [PubMed] [Google Scholar]
92. Silvestrini M, Bartolini M, Coccia M, Baruffaldi R, Taffi R, Provinciali L (2003) Topiramate in the treatment of chronic migraine. Cephalalgia 23: 820–824. 592 [pii]. [DOI] [PubMed] [Google Scholar]
93. Spira PJ, Beran RG (2003) Gabapentin in the prophylaxis of chronic daily headache: a randomized, placebo-controlled study. Neurology 61: 1753–1759. [DOI] [PubMed] [Google Scholar]
94. Steiner TJ, Findley LJ, Yuen AW (1997) Lamotrigine versus placebo in the prophylaxis of migraine with and without aura. Cephalalgia 17: 109–112. [DOI] [PubMed] [Google Scholar]
95. Stensrud P, Sjaastad O (1979) Clonazepam (rivotril) in migraine prophylaxis. Headache 19: 333–334. [DOI] [PubMed] [Google Scholar]
96. Storey JR, Calder CS, Hart DE, Potter DL (2001) Topiramate in migraine prevention: a double-blind, placebo-controlled study. Headache 41: 968–975. 01190 [pii]. [DOI] [PubMed] [Google Scholar]
97. Vahedi K, Taupin P, Djomby R, El-Amrani M, Lutz G, Filipetti V, et al. (2002) Efficacy and tolerability of acetazolamide in migraine prophylaxis: a randomised placebo-controlled trial. J Neurol 249: 206–211. [DOI] [PubMed] [Google Scholar]
98. Verma A, Srivastava D, Kumar A, Singh V (2013) Levetiracetam in migraine prophylaxis: a randomized placebo-controlled study in a rural medical institute in Northern India. Clin Neuropharmacol 36: 193–197. 10.1097/WNF.0000000000000005 [DOI] [PubMed] [Google Scholar]
99. Yurekli VA, Akhan G, Kutluhan S, Uzar E, Koyuncuoglu HR, Gultekin F (2008) The effect of sodium valproate on chronic daily headache and its subgroups. J Headache Pain 9: 37–41. 10.1007/s10194-008-0002-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
100. Ahuja GK, Verma AK (1985) Propranolol in prophylaxis of migraine. Indian J Med Res 82: 263–265. [PubMed] [Google Scholar]
101. al-Qassab HK, Findley LJ (1993) Comparison of propranolol LA 80 mg and propranolol LA 160 mg in migraine prophylaxis: a placebo controlled study. Cephalalgia 13: 128–131. [DOI] [PubMed] [Google Scholar]
102. Andersson PG, Dahl S, Hansen JH, Hansen PE, Hedman C, Kristensen TN, et al. (1983) Prophylactic treatment of classical and non-classical migraine with metoprolol—a comparison with placebo. Cephalalgia 3: 207–212. [DOI] [PubMed] [Google Scholar]
103. Borgesen SE, Nielsen JL, Moller CE (1974) Prophylactic treatment of migraine with propranolol. A clinical trial. Acta Neurol Scand 50: 651–656. [DOI] [PubMed] [Google Scholar]
104. Briggs RS, Millac PA (1979) Timolol in migraine prophylaxis. Headache 19: 379–381. [DOI] [PubMed] [Google Scholar]
105. Dahlof C (1987) No clearcut longterm prophylactic effect of one month of treatment with propranolol in migraineurs. Cephalalgia 7: 459–460. [Google Scholar]
106. Diener HC, Foh M, Iaccarino C, Wessely P, Isler H, Strenge H, et al. (1996) Cyclandelate in the prophylaxis of migraine: a randomized, parallel, double-blind study in comparison with placebo and propranolol. The Study group. Cephalalgia 16: 441–447. [DOI] [PubMed] [Google Scholar]
107. Ekbom K, Lundberg PO (1972) Clinical trial of LB-46 (d, 1-4-(2-hydroxy-3-isopropylaminopropoxy)indol. An adrenergic beta-receptor blocking agent in migraine prophylaxis. Headache 12: 15–17. [DOI] [PubMed] [Google Scholar]
108. Ekbom K (1975) Alprenolol for migraine prophylaxis. Headache 15: 129–132. [DOI] [PubMed] [Google Scholar]
109. Ekbom K, Zetterman M (1977) Oxprenolol in the treatment of migraine. Acta Neurol Scand 56: 181–184. [DOI] [PubMed] [Google Scholar]
110. Forssman B, Henriksson KG, Johannsson V, Lindvall L, Lundin H (1976) Propranolol for migraine prophylaxis. Headache 16: 238–245. [DOI] [PubMed] [Google Scholar]
111. Forssman B, Lindblad CJ, Zbornikova V (1983) Atenolol for migraine prophylaxis. Headache 23: 188–190. [DOI] [PubMed] [Google Scholar]
112. Freitag FG, Diamond S (1984) Nadolol and placebo comparison study in the prophylactic treatment of migraine. J Am Osteopath Assoc 84: 343–347. [PubMed] [Google Scholar]
113. Holroyd KA, Cottrell CK, O'Donnell FJ, Cordingley GE, Drew JB, Carlson BW, et al. (2010) Effect of preventive (beta blocker) treatment, behavioural migraine management, or their combination on outcomes of optimised acute treatment in frequent migraine: randomised controlled trial. BMJ 341: c4871 10.1136/bmj.c4871 [DOI] [PMC free article] [PubMed] [Google Scholar]
114. Johannsson V, Nilsson LR, Widelius T, Javerfalk T, Hellman P, Akesson JA, et al. (1987) Atenolol in migraine prophylaxis a double-blind cross-over multicentre study. Headache 27: 372–374. [DOI] [PubMed] [Google Scholar]
115. Johnson RH, Hornabrook RW, Lambie DG (1986) Comparison of mefenamic acid and propranolol with placebo in migraine prophylaxis. Acta Neurol Scand 73: 490–492. [DOI] [PubMed] [Google Scholar]
116. Kangasniemi P, Hedman C (1984) Metoprolol and propranolol in the prophylactic treatment of classical and common migraine. A double-blind study. Cephalalgia 4: 91–96. [DOI] [PubMed] [Google Scholar]
117. Malvea BP, Gwon N, Graham JR (1973) Propranolol prophylaxis of migraine. Headache 12: 163–167. [DOI] [PubMed] [Google Scholar]
118. Mathew NT (1981) Prophylaxis of migraine and mixed headache. A randomized controlled study. Headache 21: 105–109. [DOI] [PubMed] [Google Scholar]
119. Mikkelsen B, Pedersen KK, Christiansen LV (1986) Prophylactic treatment of migraine with tolfenamic acid, propranolol and placebo. Acta Neurol Scand 73: 423–427. [DOI] [PubMed] [Google Scholar]
120. Nadelmann JW, Phil M, Stevens J, Saper JR (1986) Propranolol in the prophylaxis of migraine. Headache 26: 175–182. [DOI] [PubMed] [Google Scholar]
121. Nanda RN, Johnson RH, Gray J, Keogh HJ, Melville ID (1978) A double blind trial of acebutolol for migraine prophylaxis. Headache 18: 20–22. [DOI] [PubMed] [Google Scholar]
122. Palferman TG, Gibberd FB, Simmonds JP (1983) Prophylactic propranolol in the treatment of headache. Br J Clin Pract 37: 28–29. [PubMed] [Google Scholar]
123. Pita E, Higueras A, Bolanos J, Perez N, Mundo A (1977) Propranolol and migraine. A clinical trial. Arch Farmacol Toxicol 3: 273–278. [PubMed] [Google Scholar]
124. Pradalier A, Serratrice G, Collard M, Hirsch E, Feve J, Masson M, et al. (1989) Long-acting propranolol in migraine prophylaxis: results of a double-blind, placebo-controlled study. Cephalalgia 9: 247–253. [DOI] [PubMed] [Google Scholar]
125. Sargent J, Solbach P, Damasio H, Baumel B, Corbett J, Eisner L, et al. (1985) A comparison of naproxen sodium to propranolol hydrochloride and a placebo control for the prophylaxis of migraine headache. Headache 25: 320–324. [DOI] [PubMed] [Google Scholar]
126. Sjaastad O, Stensrud P (1972) Clinical trial of a beta-receptor blocking agent (LB 46) in migraine prophylaxis. Acta Neurol Scand 48: 124–128. [DOI] [PubMed] [Google Scholar]
127. Standnes B (1982) The prophylactic effect of timolol versus propranolol and placebo in common migraine: beta-blockers in migraine. Cephalalgia 2: 165–170. [DOI] [PubMed] [Google Scholar]
128. Steiner TJ, Joseph R, Hedman C, Rose FC (1988) Metoprolol in the prophylaxis of migraine: parallel-groups comparison with placebo and dose-ranging follow-up. Headache 28: 15–23. [DOI] [PubMed] [Google Scholar]
129. Stellar S, Ahrens SP, Meibohm AR, Reines SA (1984) Migraine prevention with timolol. A double-blind crossover study. JAMA 252: 2576–2580. [PubMed] [Google Scholar]
130. Stensrud P, Sjaastad O (1976) Short-term clinical trial of phopranolol in racemic form (Inderal), D-propranolol and placebo in migraine. Acta Neurol Scand 53: 229–232. [DOI] [PubMed] [Google Scholar]
131. Stensrud P, Sjaastad O (1980) Comparative trial of Tenormin (atenolol) and Inderal (propranolol) in migraine. Headache 20: 204–207. [DOI] [PubMed] [Google Scholar]
132. Tfelt-Hansen P, Standnes B, Kangasneimi P, Hakkarainen H, Olesen J (1984) Timolol vs propranolol vs placebo in common migraine prophylaxis: a double-blind multicenter trial. Acta Neurol Scand 69: 1–8. [DOI] [PubMed] [Google Scholar]
133. van de Ven LL, Franke CL, Koehler PJ (1997) Prophylactic treatment of migraine with bisoprolol: a placebo-controlled study. Cephalalgia 17: 596–599. [DOI] [PubMed] [Google Scholar]
134. Weber RB, Reinmuth OM (1972) The treatment of migraine with propranolol. Neurology 22: 366–369. [DOI] [PubMed] [Google Scholar]
135. Wideroe TE, Vigander T (1974) Propranolol in the treatment of migraine. Br Med J 2: 699–701. [DOI] [PMC free article] [PubMed] [Google Scholar]
136. Ziegler DK, Hurwitz A, Hassanein RS, Kodanaz HA, Preskorn SH, Mason J (1987) Migraine prophylaxis. A comparison of propranolol and amitriptyline. Arch Neurol 44: 486–489. [DOI] [PubMed] [Google Scholar]
137.(1989) European multicenter trial of nimodipine in the prophylaxis of classic migraine (migraine with aura). Migraine-Nimodipine European Study Group (MINES). Headache 29: 639–642. [PubMed] [Google Scholar]
138.(1989) European multicenter trial of nimodipine in the prophylaxis of common migraine (migraine without aura). Migraine-Nimodipine European Study Group (MINES). Headache 29: 633–638. [PubMed] [Google Scholar]
139. Ansell E, Fazzone T, Festenstein R, Johnson ES, Thavapalan M, Wilkinson M, et al. (1988) Nimodipine in migraine prophylaxis. Cephalalgia 8: 269–272. [DOI] [PubMed] [Google Scholar]
140. Gelmers HJ (1983) Nimodipine, a new calcium antagonist, in the prophylactic treatment of migraine. Headache 23: 106–109. [DOI] [PubMed] [Google Scholar]
141. Havanka-Kanniainen H, Hokkanen E, Myllyla VV (1985) Efficacy of nimodipine in the prophylaxis of migraine. Cephalalgia 5: 39–43. [DOI] [PubMed] [Google Scholar]
142. Leandri M, Rigardo S, Schizzi R, Parodi CI (1990) Migraine treatment with nicardipine. Cephalalgia 10: 111–116. [DOI] [PubMed] [Google Scholar]
143. Markley HG, Cheronis JC, Piepho RW (1984) Verapamil in prophylactic therapy of migraine. Neurology 34: 973–976. [DOI] [PubMed] [Google Scholar]
144. McArthur JC, Marek K, Pestronk A, McArthur J, Peroutka SJ (1989) Nifedipine in the prophylaxis of classic migraine: a crossover, double-masked, placebo-controlled study of headache frequency and side effects. Neurology 39: 284–286. [DOI] [PubMed] [Google Scholar]
145. Shukla R, Garg RK, Nag D, Ahuja RC (1995) Nifedipine in migraine and tension headache: a randomised double blind crossover study. J Assoc Physicians India 43: 770–772. [PubMed] [Google Scholar]
146. Solomon GD, Steel JG, Spaccavento LJ (1983) Verapamil prophylaxis of migraine. A double-blind, placebo-controlled study. JAMA 250: 2500–2502. [PubMed] [Google Scholar]
147. Stewart DJ, Gelston A, Hakim A (1988) Effect of prophylactic administration of nimodipine in patients with migraine. Headache 28: 260–262. [DOI] [PubMed] [Google Scholar]
148. Diamond S, Freitag FG (1992) A double-blind trial of flunarizine in migraine prophylaxis. Headache Quarterly 4: 169–172. [Google Scholar]
149. Frenken CW, Nuijten ST (1984) Flunarizine, a new preventive approach to migraine. A double-blind comparison with placebo. Clin Neurol Neurosurg 86: 17–20. 0303-8467(84)90273-7 [pii]. [DOI] [PubMed] [Google Scholar]
150. Louis P (1981) A double-blind placebo-controlled prophylactic study of flunarizine (Sibelium) in migraine. Headache 21: 235–239. [DOI] [PubMed] [Google Scholar]
151. Mendenopoulos G, Manafi T, Logothetis I, Bostantjopoulou S (1985) Flunarizine in the prevention of classical migraine: a placebo-controlled evaluation. Cephalalgia 5: 31–37. [DOI] [PubMed] [Google Scholar]
152. Pini LA, Ferrari A, Guidetti G, Galetti G, Barbieri L, Sternieri E (1986) Effectiveness of flunarizine in altering electronystagmographic patterns in migraine patients: a preliminary report. Int J Clin Pharmacol Res 6: 27–32. [PubMed] [Google Scholar]
153. Sorensen PS, Hansen K, Olesen J (1986) A placebo-controlled, double-blind, cross-over trial of flunarizine in common migraine. Cephalalgia 6: 7–14. [DOI] [PubMed] [Google Scholar]
154. Thomas M, Behari M, Ahuja GK (1991) Flunarizine in migraine prophylaxis: an Indian trial. Headache 31: 613–615. [DOI] [PubMed] [Google Scholar]
155. Adly C, Straumanis J, Chesson A (1992) Fluoxetine prophylaxis of migraine. Headache 32: 101–104. [DOI] [PubMed] [Google Scholar]
156. d'Amato CC, Pizza V, Marmolo T, Giordano E, Alfano V, Nasta A (1999) Fluoxetine for migraine prophylaxis: a double-blind trial. Headache 39: 716–719. [DOI] [PubMed] [Google Scholar]
157. Landy S, McGinnis J, Curlin D, Laizure SC (1999) Selective serotonin reuptake inhibitors for migraine prophylaxis. Headache 39: 28–32. HEDhed3901028 [pii]; 10.1046/j.1526-4610.1999.3901028.x [DOI] [PubMed] [Google Scholar]
158. Saper JR, Silberstein SD, Lake AE III, Winters ME (1994) Double-blind trial of fluoxetine: chronic daily headache and migraine. Headache 34: 497–502. [DOI] [PubMed] [Google Scholar]
159. Steiner TJ, Ahmed F, Findley LJ, MacGregor EA, Wilkinson M (1998) S-fluoxetine in the prophylaxis of migraine: a phase II double-blind randomized placebo-controlled study. Cephalalgia 18: 283–286. [DOI] [PubMed] [Google Scholar]
160. Zeeberg I, Orholm M, Nielsen JD, Honore PL, Larsen JJ (1981) Femoxetine in the prophylaxis of migraine—a randomised comparison with placebo. Acta Neurol Scand 64: 452–459. [DOI] [PubMed] [Google Scholar]
161. Ozyalcin SN, Talu GK, Kiziltan E, Yucel B, Ertas M, Disci R (2005) The efficacy and safety of venlafaxine in the prophylaxis of migraine. Headache 45: 144–152. HED05029 [pii]; 10.1111/j.1526-4610.2005.05029.x [DOI] [PubMed] [Google Scholar]
162. Arthur GP, Hornabrook RW (1971) The treatment of migraine with BC 105 (pizotifen): a double blind trial. N Z Med J 73: 5–9. [PubMed] [Google Scholar]
163. Bellavance AJ, Meloche JP (1990) A comparative study of naproxen sodium, pizotyline and placebo in migraine prophylaxis. Headache 30: 710–715. [DOI] [PubMed] [Google Scholar]
164. Carroll JD, Maclay WP (1975) Pizotifen (BC 105) in migraine prophylaxis. Curr Med Res Opin 3: 68–71. 10.1185/03007997509113649 [DOI] [PubMed] [Google Scholar]
165. Cleland PG, Barnes D, Elrington GM, Loizou LA, Rawes GD (1997) Studies to assess if pizotifen prophylaxis improves migraine beyond the benefit offered by acute sumatriptan therapy alone. Eur Neurol 38: 31–38. [DOI] [PubMed] [Google Scholar]
166. Hughes RC, Foster JB (1971) BC 105 in the prophylaxis of migraine. Curr Ther Res Clin Exp 13: 63–68. [PubMed] [Google Scholar]
167. Kangasniemi P (1979) Placebo, 1-isopropylnoradrenochrome-5-monosemicarbazono and pizotifen in migraine prophylaxis. Headache 19: 219–222. [DOI] [PubMed] [Google Scholar]
168. Lawrence ER, Hossain M, Littlestone W (1977) Sanomigran for migraine prophylaxis, controlled multicenter trial in general practice. Headache 17: 109–112. [DOI] [PubMed] [Google Scholar]
169. Osterman PO (1977) A comparison between placebo, pizotifen and 1-isopropyl-3-hydroxy-5-semicarbazono-6-oxo-2.3.5.6-tetrahydroindol (Divascan) in migraine prophylaxis. Acta Neurol Scand 56: 17–28. [DOI] [PubMed] [Google Scholar]
170. Ryan RE (1968) Double-blind crossover comparison of bc-105, methysergide and placebo in the prophylaxis of migraine headache. Headache 8: 118–126. [DOI] [PubMed] [Google Scholar]
171. Couch JR, Hassanein RS (1979) Amitriptyline in migraine prophylaxis. Arch Neurol 36: 695–699. [DOI] [PubMed] [Google Scholar]
172. Couch JR (2011) Amitriptyline in the prophylactic treatment of migraine and chronic daily headache. Headache 51: 33–51. 10.1111/j.1526-4610.2010.01800.x [DOI] [PubMed] [Google Scholar]
173. Gomersall JD, Stuart A (1973) Amitriptyline in migraine prophylaxis. Changes in pattern of attacks during a controlled clinical trial. J Neurol Neurosurg Psychiatry 36: 684–690. [DOI] [PMC free article] [PubMed] [Google Scholar]
174. Jacobs H (1972) A trial of opipramol in the treatment of migraine. J Neurol Neurosurg Psychiatry 35: 500–504. [DOI] [PMC free article] [PubMed] [Google Scholar]
175. Langohr HD, Gerber WD, Koletzki E, Mayer K, Schroth G (1985) Clomipramine and metoprolol in migraine prophylaxis—a double-blind crossover study. Headache 25: 107–113. [DOI] [PubMed] [Google Scholar]
176. Morland TJ, Storli OV, Mogstad TE (1979) Doxepin in the prophylactic treatment of mixed 'vascular' and tension headache. Headache 19: 382–383. [DOI] [PubMed] [Google Scholar]
177. Noone JF (1980) Clomipramine in the prevention of migraine. J Int Med Res 8 Suppl 3: 49–52. [PubMed] [Google Scholar]
178. Kass B, Nestvold K (1980) Propranolol (Inderal) and clonidine (Catapressan) in the prophylactic treatment of migraine. A comparative trial. Acta Neurol Scand 61: 351–356. [DOI] [PubMed] [Google Scholar]
179. Louis P, Schoenen J, Hedman C (1985) Metoprolol v. clonidine in the prophylactic treatment of migraine. Cephalalgia 5: 159–165. [DOI] [PubMed] [Google Scholar]
180. Afshari D, Rafizadeh S, Rezaei M (2012) A comparative study of the effects of low-dose topiramate versus sodium valproate in migraine prophylaxis. Int J Neurosci 122: 60–68. 10.3109/00207454.2011.626908 [DOI] [PubMed] [Google Scholar]
181. Albers GW, Simon LT, Hamik A, Peroutka SJ (1989) Nifedipine versus propranolol for the initial prophylaxis of migraine. Headache 29: 215–218. [DOI] [PubMed] [Google Scholar]
182. Amelin AV, Skoromets AA, Korenko LA, Tumelevich BC, Gonchar MA (2000) [A comparative efficiency of amitriptyline, fluoxetine and maprotiline in prevention of migraine in attack-free period]. Zh Nevrol Psikhiatr Im S S Korsakova 100: 20–23. [PubMed] [Google Scholar]
183. Andersson PG (1973) BC-105 and deseril in migraine prophylaxis. (A double-blind study). Headache 13: 71–73. [DOI] [PubMed] [Google Scholar]
184. Andersson PG, Petersen EN (1981) Propranolol and femoxetine, a HT-uptake inhibitor, in migraine prophylaxis. A double-blind crossover study. Acta Neurol Scand 64: 280–288. [DOI] [PubMed] [Google Scholar]
185. Ashtari F, Shaygannejad V, Akbari M (2008) A double-blind, randomized trial of low-dose topiramate vs propranolol in migraine prophylaxis. Acta Neurol Scand 118: 301–305. ANE1087 [pii]; 10.1111/j.1600-0404.2008.01087.x [DOI] [PubMed] [Google Scholar]
186. Bank J (1994) A comparative study of amitriptyline and fluvoxamine in migraine prophylaxis. Headache 34: 476–478. [DOI] [PubMed] [Google Scholar]
187. Bartolini M, Silvestrini M, Taffi R, Lanciotti C, Luconi R, Capecci M, et al. (2005) Efficacy of topiramate and valproate in chronic migraine. Clin Neuropharmacol 28: 277–279. 00002826-200511000-00006 [pii]. [DOI] [PubMed] [Google Scholar]
188. Behan PO, Connelly K (1986) Prophylaxis of migraine: a comparison between naproxen sodium and pizotifen. Headache 26: 237–239. [DOI] [PubMed] [Google Scholar]
189. Bonuso S, Di Stasio E, Marano E, de Angelis S, Amato D, Scellini T, et al. (1998) Long-term outcome of migraine therapy: predictive value of the frontotemporal nitroglycerin test. Neurology 51: 1475–1478. [DOI] [PubMed] [Google Scholar]
190. Bordini CA, Arruda MA, Ciciarelli MC, Speciali JG (1997) Propranolol vs flunarizine vs flunarizine plus propranolol in migraine without aura prophylaxis. A double-blind trial. Arq Neuropsiquiatr 55: 536–541. [DOI] [PubMed] [Google Scholar]
191. Bostani A, Rajabi A, Moradian N, Razazian N, Rezaei M (2013) The effects of cinnarizine versus sodium valproate in migraine prophylaxis. Int J Neurosci 123: 487–493. 10.3109/00207454.2013.765419 [DOI] [PubMed] [Google Scholar]
192. Bulut S, Berilgen MS, Baran A, Tekatas A, Atmaca M, Mungen B (2004) Venlafaxine versus amitriptyline in the prophylactic treatment of migraine: randomized, double-blind, crossover study. Clin Neurol Neurosurg 107: 44–48. S0303846704000599 [pii]; 10.1016/j.clineuro.2004.03.004 [DOI] [PubMed] [Google Scholar]
193. Cady RK, Voirin J, Farmer K, Browning R, Beach ME, Tarrasch J (2012) Two Center, Randomized Pilot Study of Migraine Prophylaxis Comparing Paradigms Using Pre-Emptive Frovatriptan or Daily Topiramate: Research and Clinical Implications. Headache 52: 749–764. 10.1111/j.1526-4610.2011.02054.x [DOI] [PubMed] [Google Scholar]
194. Cerbo R, Casacchia M, Formisano R, Feliciani M, Cusimano G, Buzzi MG, et al. (1986) Flunarizine-pizotifen single-dose double-blind cross-over trial in migraine prophylaxis. Cephalalgia 6: 15–18. [DOI] [PubMed] [Google Scholar]
195. Diener HC, Matias-Guiu J, Hartung E, Pfaffenrath V, Ludin HP, Nappi G, et al. (2002) Efficacy and tolerability in migraine prophylaxis of flunarizine in reduced doses: a comparison with propranolol 160 mg daily. Cephalalgia 22: 209–221. 309 [pii]. [DOI] [PubMed] [Google Scholar]
196. Dodick DW, Freitag F, Banks J, Saper J, Xiang J, Rupnow M, et al. (2009) Topiramate versus amitriptyline in migraine prevention: a 26-week, multicenter, randomized, double-blind, double-dummy, parallel-group noninferiority trial in adult migraineurs. Clin Ther 31: 542–559. S0149-2918(09)00095-2 [pii]; 10.1016/j.clinthera.2009.03.020 [DOI] [PubMed] [Google Scholar]
197. Domingues RB, Silva AL, Domingues SA, Aquino CC, Kuster GW (2009) 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 67: 973–977. S0004-282X2009000600002 [pii]. [DOI] [PubMed] [Google Scholar]
198. Formisano R, Falaschi P, Cerbo R, Proietti A, Catarci T, D'Urso R, et al. (1991) Nimodipine in migraine: clinical efficacy and endocrinological effects. Eur J Clin Pharmacol 41: 69–71. [DOI] [PubMed] [Google Scholar]
199. Forssman B, Henriksson KG, Kihlstrand S (1972) A comparison between BC 105 and methysergide in the prophylaxis of migraine. Acta Neurol Scand 48: 204–212. [DOI] [PubMed] [Google Scholar]
200. Gawel MJ, Kreeft J, Nelson RF, Simard D, Arnott WS (1992) Comparison of the efficacy and safety of flunarizine to propranolol in the prophylaxis of migraine. Can J Neurol Sci 19: 340–345. [PubMed] [Google Scholar]
201. Gerber WD, Diener HC, Scholz E, Niederberger U (1991) Responders and non-responders to metoprolol, propranolol and nifedipine treatment in migraine prophylaxis: a dose-range study based on time-series analysis. Cephalalgia 11: 37–45. [DOI] [PubMed] [Google Scholar]
202. Gupta P, Singh S, Goyal V, Shukla G, Behari M (2007) Low-dose topiramate versus lamotrigine in migraine prophylaxis (the Lotolamp study). Headache 47: 402–412. HED599 [pii]; 10.1111/j.1526-4610.2006.00599.x [DOI] [PubMed] [Google Scholar]
203. Hubbe P (1973) The prophylactic treatment of migraine with an antiserotonin pizotifen. Acta Neurol Scand 49: 108–114. [DOI] [PubMed] [Google Scholar]
204. Kalita J, Bhoi SK, Misra UK (2013) Amitriptyline vs divalproate in migraine prophylaxis: a randomized controlled trial. Acta Neurol Scand 128: 65–72. 10.1111/ane.12081 [DOI] [PubMed] [Google Scholar]
205. Kangasniemi PJ, Nyrke T, Lang AH, Petersen E (1983) Femoxetine—a new 5-HT uptake inhibitor—and propranolol in the prophylactic treatment of migraine. Acta Neurol Scand 68: 262–267. [DOI] [PubMed] [Google Scholar]
206. Kaniecki RG (1997) A comparison of divalproex with propranolol and placebo for the prophylaxis of migraine without aura. Arch Neurol 54: 1141–1145. [DOI] [PubMed] [Google Scholar]
207. Keskinbora K, Aydinli I (2008) A double-blind randomized controlled trial of topiramate and amitriptyline either alone or in combination for the prevention of migraine. Clin Neurol Neurosurg 110: 979–984. S0303-8467(08)00202-3 [pii]; 10.1016/j.clineuro.2008.05.025 [DOI] [PubMed] [Google Scholar]
208. Krymchantowski AV, Silva MT, Barbosa JS, Alves LA (2002) Amitriptyline versus amitriptyline combined with fluoxetine in the preventative treatment of transformed migraine: a double-blind study. Headache 42: 510–514. hed02125 [pii]. [DOI] [PubMed] [Google Scholar]
209. Krymchantowski AV, da Cunha JC, Bigal ME (2012) Topiramate plus nortriptyline in the preventive treatment of migraine: a controlled study for nonresponders. J Headache Pain 13: 53–59. 10.1007/s10194-011-0395-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
210. Louis P, Spierings EL (1982) Comparison of flunarizine (Sibelium) and pizotifen (Sandomigran) in migraine treatment: a double-blind study. Cephalalgia 2: 197–203. [DOI] [PubMed] [Google Scholar]
211. Lucking CH, Oestreich W, Schmidt R, Soyka D (1988) Flunarizine vs. propranolol in the prophylaxis of migraine: two double-blind comparative studies in more than 400 patients. Cephalalgia 8 Suppl 8: 21–26. [DOI] [PubMed] [Google Scholar]
212. Ludin HP (1989) Flunarizine and propranolol in the treatment of migraine. Headache 29: 219–224. [DOI] [PubMed] [Google Scholar]
213. Luo N, Di W, Zhang A, Wang Y, Ding M, et al. (2012) A randomized, one-year clinical trial comparing the efficacy of topiramate, flunarizine, and a combination of flunarizine and topiramate in migraine prophylaxis. Pain Med 13: 80–86. 10.1111/j.1526-4637.2011.01295.x [DOI] [PubMed] [Google Scholar]
214. Mitsikostas DD, Polychronidis I (1997) Valproate versus flunarizine in migraine prophylaxis: a randomized, double-open, clinical trial. Funct Neurol 12: 267–276. [PubMed] [Google Scholar]
215. Mohammadianinejad SE, Abbasi V, Sajedi SA, Majdinasab N, Abdollahi F, Hajmanouchehri R, et al. (2011) Zonisamide versus topiramate in migraine prophylaxis: a double-blind randomized clinical trial. Clin Neuropharmacol 34: 174–177. 10.1097/WNF.0b013e318225140c [DOI] [PubMed] [Google Scholar]
216. Olerud B, Gustavsson CL, Furberg B (1986) Nadolol and propranolol in migraine management. Headache 26: 490–493. [DOI] [PubMed] [Google Scholar]
217. Olsson JE, Behring HC, Forssman B, Hedman C, Hedman G, Johansson F, et al. (1984) Metoprolol and propranolol in migraine prophylaxis: a double-blind multicentre study. Acta Neurol Scand 70: 160–168. [DOI] [PubMed] [Google Scholar]
218. Presthus J (1971) BC 105 and methysergide (Deseril) in migraine prophylaxis. Acta Neurol Scand 47: 514–518. [DOI] [PubMed] [Google Scholar]
219. Rampello L, Alvano A, Chiechio S, Malaguarnera M, Raffaele R, Vecchio I, et al. (2004) 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 50: 322–328. NPS2004050004322 [pii]; 10.1159/000080960 [DOI] [PubMed] [Google Scholar]
220. Rascol A, Montastruc JL, Rascol O (1986) Flunarizine versus pizotifen: a double-blind study in the prophylaxis of migraine. Headache 26: 83–85. [DOI] [PubMed] [Google Scholar]
221. Ryan RE Sr (1984) Comparative study of nadolol and propranolol in prophylactic treatment of migraine. Am Heart J 108: 1156–1159. [DOI] [PubMed] [Google Scholar]
222. Scholz E, Gerber WD, Diener HC, Langohr HD, Reinecke M (1987) Dihydroergotamine vs Flunarizine vs Nifedipine vs Metoprolol vs Propranolol in migraine prophylaxis: a comparitive study based on time series analysis. In: Clifford-Rose F, editors. London: John Libley & Co Ltd; pp. 139–145. [Google Scholar]
223. Shaygannejad V, Janghorbani M, Ghorbani A, Ashtary F, Zakizade N, Nasr V (2006) Comparison of the effect of topiramate and sodium valporate in migraine prevention: a randomized blinded crossover study. Headache 46: 642–648. HED413 [pii]; 10.1111/j.1526-4610.2006.00413.x [DOI] [PubMed] [Google Scholar]
224. Shimell CJ, Fritz VU, Levien SL (1990) A comparative trial of flunarizine and propranolol in the prevention of migraine. S Afr Med J 77: 75–77. [PubMed] [Google Scholar]
225. Sorensen PS, Larsen BH, Rasmussen MJ, Kinge E, Iversen H, Alslev T, et al. (1991) Flunarizine versus metoprolol in migraine prophylaxis: a double-blind, randomized parallel group study of efficacy and tolerability. Headache 31: 650–657. [DOI] [PubMed] [Google Scholar]
226. Sudilovsky A, Elkind AH, Ryan RE Sr, Saper JR, Stern MA, Meyer JH (1987) Comparative efficacy of nadolol and propranolol in the management of migraine. Headache 27: 421–426. [DOI] [PubMed] [Google Scholar]
227. Tarasova SV, Amelin AV, Skoromets AA (2008) [Fluvoxamine, amitriptyline and transcranial electrostimulation of the brain in the treatment of chronic daily headache]. Zh Nevrol Psikhiatr Im S S Korsakova 108: 43–46. [PubMed] [Google Scholar]
228. Togha M, Rahmat JM, Nilavari K, Ashrafian H, Razeghi S, Kohan L (2008) Cinnarizine in refractory migraine prophylaxis: efficacy and tolerability. A comparison with sodium valproate. J Headache Pain 9: 77–82. 10.1007/s10194-008-0013-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
229. Vilming S, Standnes B, Hedman C (1985) Metoprolol and pizotifen in the prophylactic treatment of classical and common migraine. A double-blind investigation. Cephalalgia 5: 17–23. [DOI] [PubMed] [Google Scholar]
230. Zain S, Khan M, Alam R, Zafar I, Ahmed S (2013) Comparison of efficacy and safety of topiramate with gabapentin in migraine prophylaxis: randomized open label control trial. J Pak Med Assoc 63: 3–7. [PubMed] [Google Scholar]
231. Brucke T, Wober C, Podreka I, Wober-Bingol C, Asenbaum S, Aull S, et al. (1995) D2 receptor blockade by flunarizine and cinnarizine explains extrapyramidal side effects. A SPECT study. J Cereb Blood Flow Metab 15: 513–518. 10.1038/jcbfm.1995.63 [DOI] [PubMed] [Google Scholar]
232. Holmes D, Moullet C (1992) Clinical equivalence of once-daily administration of a modified-release formulation of isradipine and twice-daily administration of the standard formulation. Multicentre Study Group. J Cardiovasc Pharmacol 19 Suppl 3: S61–S65. [PubMed] [Google Scholar]
233. El-Chammas K, Keyes K, Thompson N, Vijayakumar J, Jackson JL (2013) Pharmacological Treatment of Pediatric Headaches: A Meta-analysis. JAMA Pediatr 167: 250–258. 10.1001/jamapediatrics.2013.508 [DOI] [PMC free article] [PubMed] [Google Scholar]
234.Chronicle E, Mulleners W (2004) Anticonvulsant drugs for migraine prophylaxis. Cochrane Database Syst Rev CD003226. [DOI] [PubMed]
235.Linde K, Rossnagel K (2004) Propranolol for migraine prophylaxis. Cochrane Database Syst Rev CD003225. [DOI] [PubMed]
236.Mulleners WM, McCrory DC, Linde M (2014) Antiepileptics in migraine prophylaxis: An updated Cochrane review. Cephalalgia. 0333102414534325 [pii]; 10.1177/0333102414534325 [DOI] [PubMed]
237. Jackson JL, Shimeall W, Sessums L, Dezee KJ, Becher D, Diemer M, et al. (2010) Tricyclic antidepressants and headaches: systematic review and meta-analysis. BMJ 341:c5222 doi: 10.1136/bmj.c5222.: c5222 [DOI] [PMC free article] [PubMed] [Google Scholar]
238. Tomkins GE, Jackson JL, O'Malley PG, Balden E, Santoro JE (2001) Treatment of chronic headache with antidepressants: a meta-analysis. Am J Med 111: 54–63. S0002-9343(01)00762-8 [pii]. [DOI] [PubMed] [Google Scholar]
239.Moja PL, Cusi C, Sterzi RR, Canepari C (2005) Selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type headaches. Cochrane Database Syst Rev CD002919. [DOI] [PubMed]
240. Pringsheim T, Davenport WJ, Becker WJ (2010) Prophylaxis of migraine headache. CMAJ 182: E269–E276. cmaj.081657 [pii]; 10.1503/cmaj.081657 [DOI] [PMC free article] [PubMed] [Google Scholar]
241. Couch JR, Ziegler DK, Hassanein R (1976) Amitriptyline in the prophylaxis of migraine. Effectiveness and relationship of antimigraine and antidepressant effects. Neurology 26: 121–127. [DOI] [PubMed] [Google Scholar]
242. Ryan RE (1971) BC-105 a new preparation for the interval treatment of migraine—a double blind evaluation compared with a placebo. Headache 11: 6–18. [DOI] [PubMed] [Google Scholar]

Associated Data

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Supplementary Materials

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Data Availability Statement

Relevant data are available on figshare.com: (http://dx.doi.org/10.6084/m9.figshare.1431538).

[pone.0130733.ref001] 1. Rasmussen BK (2001) Epidemiology of headache. Cephalalgia 21: 774–777. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref002] 2. Wang SJ (2003) Epidemiology of migraine and other types of headache in Asia. Current Neurology & Neuroscience Reports 3: 104–108. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref003] 3. Radtke A, Neuhauser H (2009) Prevalence and burden of headache and migraine in Germany. Headache 49: 79–89. HED1263 [pii]; 10.1111/j.1526-4610.2008.01263.x [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref004] 4. Karli N, Zarifoglu M, Ertafs M, Saip S, Ozturk V, Bicakci S, et al. (2006) Economic impact of primary headaches in Turkey: a university hospital based study: part II. J Headache Pain 7: 75–82. 10.1007/s10194-006-0273-7 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0130733.ref005] 5. Falavigna A, Teles AR, Velho MC, Vedana VM, Silva RC, Mazzocchin T, et al. (2010) Prevalence and impact of headache in undergraduate students in Southern Brazil. Arq Neuropsiquiatr 68: 873–877. S0004-282X2010000600008 [pii]. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref006] 6. Lipton RB, Bigal ME, Kolodner K, Stewart WF, Liberman JN, Steiner TJ (2003) The family impact of migraine: population-based studies in the USA and UK. Cephalalgia 23: 429–440. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref007] 7. Lipton RB, Liberman JN, Kolodner KB, Bigal ME, Dowson A, Stewart WF (2003) Migraine headache disability and health-related quality-of-life: a population-based case-control study from England. Cephalalgia 23: 441–450. 546 [pii]. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref008] 8. Blumenfeld AM, Varon SF, Wilcox TK, Buse DC, Kawata AK, Manack A, et al. (2011) Disability, HRQoL and resource use among chronic and episodic migraineurs: results from the International Burden of Migraine Study (IBMS). Cephalalgia 31: 301–315. 0333102410381145 [pii]; 10.1177/0333102410381145 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref009] 9. Leonardi M, Raggi A, Bussone G, D'Amico D (2010) Health-related quality of life, disability and severity of disease in patients with migraine attending to a specialty headache center. Headache 50: 1576–1586. 10.1111/j.1526-4610.2010.01770.x [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref010] 10.Raggi A, Leonardi M, Bussone G, D'Amico D (2010) Value and utility of disease-specific and generic instruments for assessing disability in patients with migraine, and their relationships with health-related quality of life. Neurol Sci. 10.1007/s10072-010-0466-3 [DOI] [PubMed]

[pone.0130733.ref011] 11. Tepper SJ (2008) A pivotal moment in 50 years of headache history: the first American Migraine Study. Headache 48: 730–731. HED1117_1 [pii]; 10.1111/j.1526-4610.2008.01117_1.x [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref012] 12. Freitag FG (2007) The cycle of migraine: patients' quality of life during and between migraine attacks. Clin Ther 29: 939–949. S0149-2918(07)00137-3 [pii]; 10.1016/j.clinthera.2007.05.008 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref013] 13. Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML (1999) Burden of migraine in the United States: disability and economic costs. Archives of Internal Medicine 159: 813–818. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref014] 14. Goldberg LD (2005) The cost of migraine and its treatment. Am J Manag Care 11: S62–S67. 2883 [pii]. [PubMed] [Google Scholar]

[pone.0130733.ref015] 15.(2013) The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 33: 629–808. 10.1177/0333102413485658 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref016] 16.Adams AM, Serrano D, Buse DC, Reed ML, Marske V, Fanning KM, et al. (2014) The impact of chronic migraine: The Chronic Migraine Epidemiology and Outcomes (CaMEO) Study methods and baseline results. Cephalalgia. 0333102414552532 [pii]; 10.1177/0333102414552532 [DOI] [PMC free article] [PubMed]

[pone.0130733.ref017] 17.Law S, Derry S, Moore RA (2010) Triptans for acute cluster headache. Cochrane Database Syst Rev CD008042. 10.1002/14651858.CD008042.pub2 [DOI] [PMC free article] [PubMed]

[pone.0130733.ref018] 18.McCrory DC, Gray RN (2003) Oral sumatriptan for acute migraine. Cochrane Database Syst Rev CD002915. 10.1002/14651858.CD002915 [DOI] [PubMed]

[pone.0130733.ref019] 19. Chronicle E, Mulleners W (2004) Anticonvulsant drugs for migraine prophylaxis. Cochrane Library. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref020] 20.Linde K, Rossnagel K (2004) Propranolol for migraine prophylaxis. Cochrane Database Syst Rev CD003225. 10.1002/14651858.CD003225.pub2. [DOI] [PubMed]

[pone.0130733.ref021] 21. Jackson JL, Kuriyama A, Hayashino Y (2012) Botulinum toxin A for prophylactic treatment of migraine and tension headaches in adults: a meta-analysis. JAMA 307: 1736–1745. 307/16/1736 [pii]; 10.1001/jama.2012.505 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref022] 22. Pringsheim T, Davenport WJ, Becker WJ (2010) Prophylaxis of migraine headache. CMAJ 182: E269–E276. cmaj.081657 [pii]; 10.1503/cmaj.081657 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0130733.ref023] 23. Lance JW, Anthony M (1968) Clinical trial of a new serotonin antagonist, BC105, in the prevention of migraine. Med J Aust 1: 54–55. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref024] 24.Moja PL, Cusi C, Sterzi RR, Canepari C (2005) Selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type headaches. Cochrane Database Syst Rev CD002919. 10.1002/14651858.CD002919.pub2 [DOI] [PubMed]

[pone.0130733.ref025] 25. Jackson JL, Shimeall W, Sessums L, Dezee KJ, Becher D, Diemer M, et al. (2010) Tricyclic antidepressants and headaches: systematic review and meta-analysis. BMJ 341: c5222 10.1136/bmj.c5222 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0130733.ref026] 26. Rapaport AM (1994) Recurrent migraine: cost-effective care. Neurology 44: S25–S28. [PubMed] [Google Scholar]

[pone.0130733.ref027] 27. Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E (2012) 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 78: 1337–1345. 78/17/1337 [pii]; 10.1212/WNL.0b013e3182535d20 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0130733.ref028] 28. Shamliyan TA, Choi JY, Ramakrishnan R, Miller JB, Wang SY, Taylor FR, et al. (2013) Preventive pharmacologic treatments for episodic migraine in adults. J Gen Intern Med 28: 1225–1237. 10.1007/s11606-013-2433-1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0130733.ref029] 29. Moher D, Liverati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLos Med 6: e1000097 10.1371/journal.pmed.1000097 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0130733.ref030] 30. Ad Hoc Committee on the Classification of Headache of the National Institute of Neurological Diseases and Blindness (1962) Classification of headache. JAMA 179: 717–718. [Google Scholar]

[pone.0130733.ref031] 31. Headache Classification Committee of the International Headache Society (1988) Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 8: 1–96. [PubMed] [Google Scholar]

[pone.0130733.ref032] 32. Silberstein S, Tfelt-Hansen P, Dodick DW, Limmroth V, Lipton RB, Pascual J, et al. (2008) Guidelines for controlled trials of prophylactic treatment of chronic migraine in adults. Cephalalgia 28: 484–495. CHA1555 [pii]; 10.1111/j.1468-2982.2008.01555.x [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref033] 33. Kazis LE, Anderson JJ, Meenan RF (1989) Effect sizes for interpreting changes in health status. Med Care 27: S178–S189. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref034] 34. Follmann D, Elliott P, Suh I, Cutler J (1992) Variance imputation for overviews of clinical trials with continuous response. J Clin Epidemiol 45: 769–773. 0895-4356(92)90054-Q [pii]. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref035] 35. Hubbe P (1973) The prophylactic treatment of migraine with an antiserotonin pizotifen. Acta Neurol Scand 49: 108–114. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref036] 36. Gotzsche PC, Hrobjartsson A, Maric K, Tendal B (2007) Data extraction errors in meta-analyses that use standardized mean differences. JAMA 298: 430–437. 298/4/430 [pii];10.1001/jama.298.4.430. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref037] 37.McCrory D (2012) Report on gabapentin (Neurontin) for migraine prophylaxis: Evaluation of efficacy, effectiveness and marking. Expert Consultant's report.

[pone.0130733.ref038] 38. Vedula SS, Bero L, Scherer RW, Dickersin K (2009) Outcome reporting in industry-sponsored trials of gabapentin for off-label use. N Engl J Med 361: 1963–1971. 361/20/1963 [pii]; 10.1056/NEJMsa0906126 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref039] 39. Alderson P, Green S, Higgins JPT (2004) Assessment of Study Quality In: Alderson P, Green S, Higgins JPT, editors. Cochrane Reviewers' Handbook 4.2.2. John Wiley & Sons, Ltd. [Google Scholar]

[pone.0130733.ref040] 40. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials 17: 1–12. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref041] 41.Higgins JPT, Green S (2009) Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated September 2009]. www.cochrane-handbook.org.

[pone.0130733.ref042] 42. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7: 177–188. 0197-2456(86)90046-2 [pii]. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref043] 43. Mathew NT (2001) Antiepileptic drugs in migraine prevention. Headache 41 Suppl 1: S18–S24. 01154–4 [pii]. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref044] 44. Ades AE, Mavranezouli I, Dias S, Welton NJ, Whittington C, Kendall T (2010) Network meta-analysis with competing risk outcomes. Value Health 13: 976–983. 10.1111/j.1524-4733.2010.00784.x [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref045] 45. Lumley T (2002) Network meta-analysis for indirect treatment comparisons. Stat Med 21: 2313–2324. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref046] 46. Salanti G, Ades AE, Ioannidis JP (2011) Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol 64: 163–171. 10.1016/j.jclinepi.2010.03.016 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref047] 47. Woods BS, Hawkins N, Scott DA (2010) Network meta-analysis on the log-hazard scale, combining count and hazard ratio statistics accounting for multi-arm trials: a tutorial. BMC Med Res Methodol 10:54: 54. 10.1186/1471-2288-10-54 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0130733.ref048] 48. Galbraith RF (1988) A note on graphical presentation of estimated odds ratios from several clinical trials. Statistics in Medicine 7: 889–894. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref049] 49. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327: 557–560. 10.1136/bmj.327.7414.557 327/7414/557 [pii]. [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0130733.ref050] 50. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L (2006) Comparison of two methods to detect publication bias in meta-analysis. JAMA 295: 676–680. 295/6/676 [pii]; 10.1001/jama.295.6.676 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref051] 51. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315: 629–634. [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0130733.ref052] 52. Sharp S (1998) Meta-analysis regression. Stata Technical Bulletin 42: 16–22. [Google Scholar]

[pone.0130733.ref053] 53. Adam EI, Gore SM, Price WH (1978) Double blind trial of clonidine in the treatment of migraine in a general practice. J R Coll Gen Pract 28: 587–590. [PMC free article] [PubMed] [Google Scholar]

[pone.0130733.ref054] 54. Boisen E, Deth S, Hubbe P, Jansen J, Klee A, Leunbach G (1978) Clonidine in the prophylaxis of migraine. Acta Neurol Scand 58: 288–295. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref055] 55. Bredfeldt RC, Sutherland JE, Kruse JE (1989) Efficacy of transdermal clonidine for headache prophylaxis and reduction of narcotic use in migraine patients. A randomized crossover trial. J Fam Pract 29: 153–156. [PubMed] [Google Scholar]

[pone.0130733.ref056] 56. Lynggaard F, Ostergaard F (1975) [Clonidine in prevention of migraine. Report of a double-blind study of 38 patients referred for neurological assessment]. Ugeskr Laeger 137: 149–151. [PubMed] [Google Scholar]

[pone.0130733.ref057] 57. Mondrup K, Moller CE (1977) Prophylactic treatment of migraine with clonidine. A controlled clinical trial. Acta Neurol Scand 56: 405–412. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref058] 58. Ryan RE Sr, Diamond S, Ryan RE Jr (1975) Double blind study of clonidine and placebo for the prophylactic treatment of migraine. Headache 15: 202–210. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref059] 59. Saper JR, Lake AE III, Cantrell DT, Winner PK, White JR (2002) Chronic daily headache prophylaxis with tizanidine: a double-blind, placebo-controlled, multicenter outcome study. Headache 42: 470–482. hed02122 [pii]. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref060] 60. Shafar J, Tallett ER, Knowlson PA (1972) Evaluation of clonidine in prophylaxis of migraine. Double-blind trial and follow-up. Lancet 1: 403–407. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref061] 61. Stensrud P, Sjaastad O (1976) Clonidine (Catapresan)-double-blind study after long-term treatment with the drug in migraine. Acta Neurol Scand 53: 233–236. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref062] 62. Paterna S, di Pasquale P, Martino S, Arrostuto A, Ingurgio NC, Parrinello G, et al. (1992) [Captopril versus placebo in the prevention of hemicrania without aura. A randomized double-blind study]. Clin Ter 141: 475–481. [PubMed] [Google Scholar]

[pone.0130733.ref063] 63. Schrader H, Stovner LJ, Helde G, Sand T, Bovim G (2001) Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): randomised, placebo controlled, crossover study. BMJ 322: 19–22. [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0130733.ref064] 64. Sonbolestan SA, Heshmat K, Javanmard SH, Saadatnia M (2013) Efficacy of Enalapril in Migraine Prophylaxis: A Randomized, Double-blind, Placebo-controlled Trial. Int J Prev Med 4: 72–77. [PMC free article] [PubMed] [Google Scholar]

[pone.0130733.ref065] 65. Diener HC, Gendolla A, Feuersenger A, Evers S, Straube A, Schumacher H, et al. (2009) Telmisartan in migraine prophylaxis: a randomized, placebo-controlled trial. Cephalalgia 29: 921–927. CHA1825 [pii]; 10.1111/j.1468-2982.2008.01825.x [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref066] 66.Stovner LJ, Linde M, Gravdahl GB, Tronvik E, Aamodt AH, Sand T, et al.(2013) A comparative study of candesartan versus propranolol for migraine prophylaxis: A randomised, triple-blind, placebo-controlled, double cross-over study. Cephalalgia. 0333102413515348 [pii]; 10.1177/0333102413515348 [DOI] [PubMed]

[pone.0130733.ref067] 67. Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G (2003) Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. JAMA 289: 65–69. joc21661 [pii]. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref068] 68. Beran RG, Spira PJ (2011) Levetiracetam in chronic daily headache: A double-blind, randomised placebo-controlled study: (The Australian KEPPRA Headache Trial [AUS-KHT]). Cephalalgia 31: 530–536. 0333102410384886 [pii]; 10.1177/0333102410384886 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref069] 69. Brandes JL, Saper JR, Diamond M, Couch JR, Lewis DW, Schmitt J, et al. (2004) Topiramate for migraine prevention: a randomized controlled trial. JAMA 291: 965–973. 10.1001/jama.291.8.965 291/8/965 [pii]. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref070] 70. Cady RK, Mathew N, Diener HC, Hu P, Haas M, Novak GP (2009) Evaluation of carisbamate for the treatment of migraine in a randomized, double-blind trial. Headache 49: 216–226. HED1326 [pii]; 10.1111/j.1526-4610.2008.01326.x [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref071] 71. deTommaso M., Marinazzo D, Nitti L, Pellicoro M, Guido M, Serpino C, et al. (2007) Effects of levetiracetam vs topiramate and placebo on visually evoked phase synchronization changes of alpha rhythm in migraine. Clin Neurophysiol 118: 2297–2304. S1388-2457(07)00323-9 [pii]; 10.1016/j.clinph.2007.06.060 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref072] 72. Di Trapani G, Mei D, Marra C, Mazza S, Capuano A (2000) Gabapentin in the prophylaxis of migraine: a double-blind randomized placebo-controlled study. Clin Ter 151: 145–148. [PubMed] [Google Scholar]

[pone.0130733.ref073] 73. Diener HC, Tfelt-Hansen P, Dahlof C, Lainez MJ, Sandrini G, Wang SJ, et al. (2004) Topiramate in migraine prophylaxis—results from a placebo-controlled trial with propranolol as an active control. J Neurol 251: 943–950. 10.1007/s00415-004-0464-6 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref074] 74. Diener HC, Bussone G, Van Oene JC, Lahaye M, Schwalen S, Goadsby PJ (2007) Topiramate reduces headache days in chronic migraine: a randomized, double-blind, placebo-controlled study. Cephalalgia 27: 814–823. CHA1326 [pii]; 10.1111/j.1468-2982.2007.01326.x [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref075] 75. Edwards KR, Potter DL, Wu SC, Kamin M, Hulihan J (2003) Topiramate in the preventive treatment of episodic migraine: a combined analysis from pilot, double-blind, placebo-controlled trials. CNS Spectr 8: 428–432. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref076] 76. Freitag FG, Collins SD, Carlson HA, Goldstein J, Saper J, Silberstein S, et al. (2002) A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis. Neurology 58: 1652–1659. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref077] 77. Ghose K, Niven B (1998) Prophylactic sodium valproate therapy in patients with drug-resistant migraine. Methods Find Exp Clin Pharmacol 20: 353–359. 485692 [pii]. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref078] 78. Gupta VK (2006) Topiramate for migraine prophylaxis: addressing the blood-brain barrier-related pharmacokinetic-pathophysiological disconnect. Int J Clin Pract 60: 367–368. IJCP796a [pii]; 10.1111/j.1368-5031.2006.0796a.x [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref079] 79. Hering R, Kuritzky A (1992) Sodium valproate in the prophylactic treatment of migraine: a double-blind study versus placebo. Cephalalgia 12: 81–84. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref080] 80. Jensen R, Brinck T, Olesen J (1994) Sodium valproate has a prophylactic effect in migraine without aura: a triple-blind, placebo-controlled crossover study. Neurology 44: 647–651. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref081] 81. Klapper J (1997) Divalproex sodium in migraine prophylaxis: a dose-controlled study. Cephalalgia 17: 103–108. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref082] 82. Lipton RB, Silberstein S, Dodick D, Cady R, Freitag F, Mathew N, et al. (2011) Topiramate intervention to prevent transformation of episodic migraine: the topiramate INTREPID study. Cephalalgia 31: 18–30. 0333102410372427 [pii]; 10.1177/0333102410372427 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref083] 83. Mathew NT, Saper JR, Silberstein SD, Rankin L, Markley HG, Solomon S, et al. (1995) Migraine prophylaxis with divalproex. Arch Neurol 52: 281–286. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref084] 84. Mei D, Ferraro D, Zelano G, Capuano A, Vollono C, Gabriele C, et al. (2006) Topiramate and triptans revert chronic migraine with medication overuse to episodic migraine. Clin Neuropharmacol 29: 269–275. 10.1097/01.WNF.000022888.49044.99 00002826-200609000-00005 [pii]. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref085] 85. Rompel H, Bauermeister PW (1970) Aetiology of migraine and prevention with carbamazepine (Tegretol): results of a double-blind, cross-over study. S Afr Med J 44: 75–80. [PubMed] [Google Scholar]

[pone.0130733.ref086] 86. Sarchielli P, Messina P, Cupini LM, Tedeschi G, Di Pero V, Livrea P, et al. (2014) Sodium valproate in migraine without aura and medication overuse headache: a randomized controlled trial. Eur Neuropsychopharmacol 24: 1289–1297. S0924-977X(14)00095-9 [pii]; 10.1016/j.euroneuro.2014.03.010 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref087] 87. Silberstein SD, Neto W, Schmitt J, Jacobs D (2004) Topiramate in migraine prevention: results of a large controlled trial. Arch Neurol 61: 490–495. 10.1001/archneur.61.4.490 61/4/490 [pii]. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref088] 88. Silberstein SD, Hulihan J, Karim MR, Wu SC, Jordan D, Karvois D, et al. (2006) 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 28: 1002–1011. S0149-2918(06)00165-2 [pii]; 10.1016/j.clinthera.2006.07.003 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref089] 89. Silberstein SD, Lipton RB, Dodick DW, Freitag FG, Ramadan N, Mathew N, et al. (2007) Efficacy and safety of topiramate for the treatment of chronic migraine: a randomized, double-blind, placebo-controlled trial. Headache 47: 170–180. HED684 [pii]; 10.1111/j.1526-4610.2006.00684.x [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref090] 90. Silberstein S, Saper J, Berenson F, Somogyi M, McCague K, D'Souza J (2008) Oxcarbazepine in migraine headache: a double-blind, randomized, placebo-controlled study. Neurology 70: 548–555. 70/7/548 [pii]; 10.1212/01.wnl.0000297551.27191.70 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref091] 91. Silberstein S, Goode-Sellers S, Twomey C, Saiers J, Ascher J (2013) Randomized, double-blind, placebo-controlled, phase II trial of gabapentin enacarbil for migraine prophylaxis. Cephalalgia 33: 101–111. 0333102412466968 [pii]; 10.1177/0333102412466968 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref092] 92. Silvestrini M, Bartolini M, Coccia M, Baruffaldi R, Taffi R, Provinciali L (2003) Topiramate in the treatment of chronic migraine. Cephalalgia 23: 820–824. 592 [pii]. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref093] 93. Spira PJ, Beran RG (2003) Gabapentin in the prophylaxis of chronic daily headache: a randomized, placebo-controlled study. Neurology 61: 1753–1759. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref094] 94. Steiner TJ, Findley LJ, Yuen AW (1997) Lamotrigine versus placebo in the prophylaxis of migraine with and without aura. Cephalalgia 17: 109–112. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref095] 95. Stensrud P, Sjaastad O (1979) Clonazepam (rivotril) in migraine prophylaxis. Headache 19: 333–334. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref096] 96. Storey JR, Calder CS, Hart DE, Potter DL (2001) Topiramate in migraine prevention: a double-blind, placebo-controlled study. Headache 41: 968–975. 01190 [pii]. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref097] 97. Vahedi K, Taupin P, Djomby R, El-Amrani M, Lutz G, Filipetti V, et al. (2002) Efficacy and tolerability of acetazolamide in migraine prophylaxis: a randomised placebo-controlled trial. J Neurol 249: 206–211. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref098] 98. Verma A, Srivastava D, Kumar A, Singh V (2013) Levetiracetam in migraine prophylaxis: a randomized placebo-controlled study in a rural medical institute in Northern India. Clin Neuropharmacol 36: 193–197. 10.1097/WNF.0000000000000005 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref099] 99. Yurekli VA, Akhan G, Kutluhan S, Uzar E, Koyuncuoglu HR, Gultekin F (2008) The effect of sodium valproate on chronic daily headache and its subgroups. J Headache Pain 9: 37–41. 10.1007/s10194-008-0002-5 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0130733.ref100] 100. Ahuja GK, Verma AK (1985) Propranolol in prophylaxis of migraine. Indian J Med Res 82: 263–265. [PubMed] [Google Scholar]

[pone.0130733.ref101] 101. al-Qassab HK, Findley LJ (1993) Comparison of propranolol LA 80 mg and propranolol LA 160 mg in migraine prophylaxis: a placebo controlled study. Cephalalgia 13: 128–131. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref102] 102. Andersson PG, Dahl S, Hansen JH, Hansen PE, Hedman C, Kristensen TN, et al. (1983) Prophylactic treatment of classical and non-classical migraine with metoprolol—a comparison with placebo. Cephalalgia 3: 207–212. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref103] 103. Borgesen SE, Nielsen JL, Moller CE (1974) Prophylactic treatment of migraine with propranolol. A clinical trial. Acta Neurol Scand 50: 651–656. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref104] 104. Briggs RS, Millac PA (1979) Timolol in migraine prophylaxis. Headache 19: 379–381. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref105] 105. Dahlof C (1987) No clearcut longterm prophylactic effect of one month of treatment with propranolol in migraineurs. Cephalalgia 7: 459–460. [Google Scholar]

[pone.0130733.ref106] 106. Diener HC, Foh M, Iaccarino C, Wessely P, Isler H, Strenge H, et al. (1996) Cyclandelate in the prophylaxis of migraine: a randomized, parallel, double-blind study in comparison with placebo and propranolol. The Study group. Cephalalgia 16: 441–447. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref107] 107. Ekbom K, Lundberg PO (1972) Clinical trial of LB-46 (d, 1-4-(2-hydroxy-3-isopropylaminopropoxy)indol. An adrenergic beta-receptor blocking agent in migraine prophylaxis. Headache 12: 15–17. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref108] 108. Ekbom K (1975) Alprenolol for migraine prophylaxis. Headache 15: 129–132. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref109] 109. Ekbom K, Zetterman M (1977) Oxprenolol in the treatment of migraine. Acta Neurol Scand 56: 181–184. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref110] 110. Forssman B, Henriksson KG, Johannsson V, Lindvall L, Lundin H (1976) Propranolol for migraine prophylaxis. Headache 16: 238–245. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref111] 111. Forssman B, Lindblad CJ, Zbornikova V (1983) Atenolol for migraine prophylaxis. Headache 23: 188–190. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref112] 112. Freitag FG, Diamond S (1984) Nadolol and placebo comparison study in the prophylactic treatment of migraine. J Am Osteopath Assoc 84: 343–347. [PubMed] [Google Scholar]

[pone.0130733.ref113] 113. Holroyd KA, Cottrell CK, O'Donnell FJ, Cordingley GE, Drew JB, Carlson BW, et al. (2010) Effect of preventive (beta blocker) treatment, behavioural migraine management, or their combination on outcomes of optimised acute treatment in frequent migraine: randomised controlled trial. BMJ 341: c4871 10.1136/bmj.c4871 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0130733.ref114] 114. Johannsson V, Nilsson LR, Widelius T, Javerfalk T, Hellman P, Akesson JA, et al. (1987) Atenolol in migraine prophylaxis a double-blind cross-over multicentre study. Headache 27: 372–374. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref115] 115. Johnson RH, Hornabrook RW, Lambie DG (1986) Comparison of mefenamic acid and propranolol with placebo in migraine prophylaxis. Acta Neurol Scand 73: 490–492. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref116] 116. Kangasniemi P, Hedman C (1984) Metoprolol and propranolol in the prophylactic treatment of classical and common migraine. A double-blind study. Cephalalgia 4: 91–96. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref117] 117. Malvea BP, Gwon N, Graham JR (1973) Propranolol prophylaxis of migraine. Headache 12: 163–167. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref118] 118. Mathew NT (1981) Prophylaxis of migraine and mixed headache. A randomized controlled study. Headache 21: 105–109. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref119] 119. Mikkelsen B, Pedersen KK, Christiansen LV (1986) Prophylactic treatment of migraine with tolfenamic acid, propranolol and placebo. Acta Neurol Scand 73: 423–427. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref120] 120. Nadelmann JW, Phil M, Stevens J, Saper JR (1986) Propranolol in the prophylaxis of migraine. Headache 26: 175–182. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref121] 121. Nanda RN, Johnson RH, Gray J, Keogh HJ, Melville ID (1978) A double blind trial of acebutolol for migraine prophylaxis. Headache 18: 20–22. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref122] 122. Palferman TG, Gibberd FB, Simmonds JP (1983) Prophylactic propranolol in the treatment of headache. Br J Clin Pract 37: 28–29. [PubMed] [Google Scholar]

[pone.0130733.ref123] 123. Pita E, Higueras A, Bolanos J, Perez N, Mundo A (1977) Propranolol and migraine. A clinical trial. Arch Farmacol Toxicol 3: 273–278. [PubMed] [Google Scholar]

[pone.0130733.ref124] 124. Pradalier A, Serratrice G, Collard M, Hirsch E, Feve J, Masson M, et al. (1989) Long-acting propranolol in migraine prophylaxis: results of a double-blind, placebo-controlled study. Cephalalgia 9: 247–253. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref125] 125. Sargent J, Solbach P, Damasio H, Baumel B, Corbett J, Eisner L, et al. (1985) A comparison of naproxen sodium to propranolol hydrochloride and a placebo control for the prophylaxis of migraine headache. Headache 25: 320–324. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref126] 126. Sjaastad O, Stensrud P (1972) Clinical trial of a beta-receptor blocking agent (LB 46) in migraine prophylaxis. Acta Neurol Scand 48: 124–128. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref127] 127. Standnes B (1982) The prophylactic effect of timolol versus propranolol and placebo in common migraine: beta-blockers in migraine. Cephalalgia 2: 165–170. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref128] 128. Steiner TJ, Joseph R, Hedman C, Rose FC (1988) Metoprolol in the prophylaxis of migraine: parallel-groups comparison with placebo and dose-ranging follow-up. Headache 28: 15–23. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref129] 129. Stellar S, Ahrens SP, Meibohm AR, Reines SA (1984) Migraine prevention with timolol. A double-blind crossover study. JAMA 252: 2576–2580. [PubMed] [Google Scholar]

[pone.0130733.ref130] 130. Stensrud P, Sjaastad O (1976) Short-term clinical trial of phopranolol in racemic form (Inderal), D-propranolol and placebo in migraine. Acta Neurol Scand 53: 229–232. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref131] 131. Stensrud P, Sjaastad O (1980) Comparative trial of Tenormin (atenolol) and Inderal (propranolol) in migraine. Headache 20: 204–207. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref132] 132. Tfelt-Hansen P, Standnes B, Kangasneimi P, Hakkarainen H, Olesen J (1984) Timolol vs propranolol vs placebo in common migraine prophylaxis: a double-blind multicenter trial. Acta Neurol Scand 69: 1–8. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref133] 133. van de Ven LL, Franke CL, Koehler PJ (1997) Prophylactic treatment of migraine with bisoprolol: a placebo-controlled study. Cephalalgia 17: 596–599. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref134] 134. Weber RB, Reinmuth OM (1972) The treatment of migraine with propranolol. Neurology 22: 366–369. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref135] 135. Wideroe TE, Vigander T (1974) Propranolol in the treatment of migraine. Br Med J 2: 699–701. [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0130733.ref136] 136. Ziegler DK, Hurwitz A, Hassanein RS, Kodanaz HA, Preskorn SH, Mason J (1987) Migraine prophylaxis. A comparison of propranolol and amitriptyline. Arch Neurol 44: 486–489. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref137] 137.(1989) European multicenter trial of nimodipine in the prophylaxis of classic migraine (migraine with aura). Migraine-Nimodipine European Study Group (MINES). Headache 29: 639–642. [PubMed] [Google Scholar]

[pone.0130733.ref138] 138.(1989) European multicenter trial of nimodipine in the prophylaxis of common migraine (migraine without aura). Migraine-Nimodipine European Study Group (MINES). Headache 29: 633–638. [PubMed] [Google Scholar]

[pone.0130733.ref139] 139. Ansell E, Fazzone T, Festenstein R, Johnson ES, Thavapalan M, Wilkinson M, et al. (1988) Nimodipine in migraine prophylaxis. Cephalalgia 8: 269–272. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref140] 140. Gelmers HJ (1983) Nimodipine, a new calcium antagonist, in the prophylactic treatment of migraine. Headache 23: 106–109. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref141] 141. Havanka-Kanniainen H, Hokkanen E, Myllyla VV (1985) Efficacy of nimodipine in the prophylaxis of migraine. Cephalalgia 5: 39–43. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref142] 142. Leandri M, Rigardo S, Schizzi R, Parodi CI (1990) Migraine treatment with nicardipine. Cephalalgia 10: 111–116. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref143] 143. Markley HG, Cheronis JC, Piepho RW (1984) Verapamil in prophylactic therapy of migraine. Neurology 34: 973–976. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref144] 144. McArthur JC, Marek K, Pestronk A, McArthur J, Peroutka SJ (1989) Nifedipine in the prophylaxis of classic migraine: a crossover, double-masked, placebo-controlled study of headache frequency and side effects. Neurology 39: 284–286. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref145] 145. Shukla R, Garg RK, Nag D, Ahuja RC (1995) Nifedipine in migraine and tension headache: a randomised double blind crossover study. J Assoc Physicians India 43: 770–772. [PubMed] [Google Scholar]

[pone.0130733.ref146] 146. Solomon GD, Steel JG, Spaccavento LJ (1983) Verapamil prophylaxis of migraine. A double-blind, placebo-controlled study. JAMA 250: 2500–2502. [PubMed] [Google Scholar]

[pone.0130733.ref147] 147. Stewart DJ, Gelston A, Hakim A (1988) Effect of prophylactic administration of nimodipine in patients with migraine. Headache 28: 260–262. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref148] 148. Diamond S, Freitag FG (1992) A double-blind trial of flunarizine in migraine prophylaxis. Headache Quarterly 4: 169–172. [Google Scholar]

[pone.0130733.ref149] 149. Frenken CW, Nuijten ST (1984) Flunarizine, a new preventive approach to migraine. A double-blind comparison with placebo. Clin Neurol Neurosurg 86: 17–20. 0303-8467(84)90273-7 [pii]. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref150] 150. Louis P (1981) A double-blind placebo-controlled prophylactic study of flunarizine (Sibelium) in migraine. Headache 21: 235–239. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref151] 151. Mendenopoulos G, Manafi T, Logothetis I, Bostantjopoulou S (1985) Flunarizine in the prevention of classical migraine: a placebo-controlled evaluation. Cephalalgia 5: 31–37. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref152] 152. Pini LA, Ferrari A, Guidetti G, Galetti G, Barbieri L, Sternieri E (1986) Effectiveness of flunarizine in altering electronystagmographic patterns in migraine patients: a preliminary report. Int J Clin Pharmacol Res 6: 27–32. [PubMed] [Google Scholar]

[pone.0130733.ref153] 153. Sorensen PS, Hansen K, Olesen J (1986) A placebo-controlled, double-blind, cross-over trial of flunarizine in common migraine. Cephalalgia 6: 7–14. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref154] 154. Thomas M, Behari M, Ahuja GK (1991) Flunarizine in migraine prophylaxis: an Indian trial. Headache 31: 613–615. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref155] 155. Adly C, Straumanis J, Chesson A (1992) Fluoxetine prophylaxis of migraine. Headache 32: 101–104. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref156] 156. d'Amato CC, Pizza V, Marmolo T, Giordano E, Alfano V, Nasta A (1999) Fluoxetine for migraine prophylaxis: a double-blind trial. Headache 39: 716–719. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref157] 157. Landy S, McGinnis J, Curlin D, Laizure SC (1999) Selective serotonin reuptake inhibitors for migraine prophylaxis. Headache 39: 28–32. HEDhed3901028 [pii]; 10.1046/j.1526-4610.1999.3901028.x [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref158] 158. Saper JR, Silberstein SD, Lake AE III, Winters ME (1994) Double-blind trial of fluoxetine: chronic daily headache and migraine. Headache 34: 497–502. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref159] 159. Steiner TJ, Ahmed F, Findley LJ, MacGregor EA, Wilkinson M (1998) S-fluoxetine in the prophylaxis of migraine: a phase II double-blind randomized placebo-controlled study. Cephalalgia 18: 283–286. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref160] 160. Zeeberg I, Orholm M, Nielsen JD, Honore PL, Larsen JJ (1981) Femoxetine in the prophylaxis of migraine—a randomised comparison with placebo. Acta Neurol Scand 64: 452–459. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref161] 161. Ozyalcin SN, Talu GK, Kiziltan E, Yucel B, Ertas M, Disci R (2005) The efficacy and safety of venlafaxine in the prophylaxis of migraine. Headache 45: 144–152. HED05029 [pii]; 10.1111/j.1526-4610.2005.05029.x [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref162] 162. Arthur GP, Hornabrook RW (1971) The treatment of migraine with BC 105 (pizotifen): a double blind trial. N Z Med J 73: 5–9. [PubMed] [Google Scholar]

[pone.0130733.ref163] 163. Bellavance AJ, Meloche JP (1990) A comparative study of naproxen sodium, pizotyline and placebo in migraine prophylaxis. Headache 30: 710–715. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref164] 164. Carroll JD, Maclay WP (1975) Pizotifen (BC 105) in migraine prophylaxis. Curr Med Res Opin 3: 68–71. 10.1185/03007997509113649 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref165] 165. Cleland PG, Barnes D, Elrington GM, Loizou LA, Rawes GD (1997) Studies to assess if pizotifen prophylaxis improves migraine beyond the benefit offered by acute sumatriptan therapy alone. Eur Neurol 38: 31–38. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref166] 166. Hughes RC, Foster JB (1971) BC 105 in the prophylaxis of migraine. Curr Ther Res Clin Exp 13: 63–68. [PubMed] [Google Scholar]

[pone.0130733.ref167] 167. Kangasniemi P (1979) Placebo, 1-isopropylnoradrenochrome-5-monosemicarbazono and pizotifen in migraine prophylaxis. Headache 19: 219–222. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref168] 168. Lawrence ER, Hossain M, Littlestone W (1977) Sanomigran for migraine prophylaxis, controlled multicenter trial in general practice. Headache 17: 109–112. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref169] 169. Osterman PO (1977) A comparison between placebo, pizotifen and 1-isopropyl-3-hydroxy-5-semicarbazono-6-oxo-2.3.5.6-tetrahydroindol (Divascan) in migraine prophylaxis. Acta Neurol Scand 56: 17–28. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref170] 170. Ryan RE (1968) Double-blind crossover comparison of bc-105, methysergide and placebo in the prophylaxis of migraine headache. Headache 8: 118–126. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref171] 171. Couch JR, Hassanein RS (1979) Amitriptyline in migraine prophylaxis. Arch Neurol 36: 695–699. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref172] 172. Couch JR (2011) Amitriptyline in the prophylactic treatment of migraine and chronic daily headache. Headache 51: 33–51. 10.1111/j.1526-4610.2010.01800.x [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref173] 173. Gomersall JD, Stuart A (1973) Amitriptyline in migraine prophylaxis. Changes in pattern of attacks during a controlled clinical trial. J Neurol Neurosurg Psychiatry 36: 684–690. [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0130733.ref174] 174. Jacobs H (1972) A trial of opipramol in the treatment of migraine. J Neurol Neurosurg Psychiatry 35: 500–504. [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0130733.ref175] 175. Langohr HD, Gerber WD, Koletzki E, Mayer K, Schroth G (1985) Clomipramine and metoprolol in migraine prophylaxis—a double-blind crossover study. Headache 25: 107–113. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref176] 176. Morland TJ, Storli OV, Mogstad TE (1979) Doxepin in the prophylactic treatment of mixed 'vascular' and tension headache. Headache 19: 382–383. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref177] 177. Noone JF (1980) Clomipramine in the prevention of migraine. J Int Med Res 8 Suppl 3: 49–52. [PubMed] [Google Scholar]

[pone.0130733.ref178] 178. Kass B, Nestvold K (1980) Propranolol (Inderal) and clonidine (Catapressan) in the prophylactic treatment of migraine. A comparative trial. Acta Neurol Scand 61: 351–356. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref179] 179. Louis P, Schoenen J, Hedman C (1985) Metoprolol v. clonidine in the prophylactic treatment of migraine. Cephalalgia 5: 159–165. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref180] 180. Afshari D, Rafizadeh S, Rezaei M (2012) A comparative study of the effects of low-dose topiramate versus sodium valproate in migraine prophylaxis. Int J Neurosci 122: 60–68. 10.3109/00207454.2011.626908 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref181] 181. Albers GW, Simon LT, Hamik A, Peroutka SJ (1989) Nifedipine versus propranolol for the initial prophylaxis of migraine. Headache 29: 215–218. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref182] 182. Amelin AV, Skoromets AA, Korenko LA, Tumelevich BC, Gonchar MA (2000) [A comparative efficiency of amitriptyline, fluoxetine and maprotiline in prevention of migraine in attack-free period]. Zh Nevrol Psikhiatr Im S S Korsakova 100: 20–23. [PubMed] [Google Scholar]

[pone.0130733.ref183] 183. Andersson PG (1973) BC-105 and deseril in migraine prophylaxis. (A double-blind study). Headache 13: 71–73. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref184] 184. Andersson PG, Petersen EN (1981) Propranolol and femoxetine, a HT-uptake inhibitor, in migraine prophylaxis. A double-blind crossover study. Acta Neurol Scand 64: 280–288. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref185] 185. Ashtari F, Shaygannejad V, Akbari M (2008) A double-blind, randomized trial of low-dose topiramate vs propranolol in migraine prophylaxis. Acta Neurol Scand 118: 301–305. ANE1087 [pii]; 10.1111/j.1600-0404.2008.01087.x [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref186] 186. Bank J (1994) A comparative study of amitriptyline and fluvoxamine in migraine prophylaxis. Headache 34: 476–478. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref187] 187. Bartolini M, Silvestrini M, Taffi R, Lanciotti C, Luconi R, Capecci M, et al. (2005) Efficacy of topiramate and valproate in chronic migraine. Clin Neuropharmacol 28: 277–279. 00002826-200511000-00006 [pii]. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref188] 188. Behan PO, Connelly K (1986) Prophylaxis of migraine: a comparison between naproxen sodium and pizotifen. Headache 26: 237–239. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref189] 189. Bonuso S, Di Stasio E, Marano E, de Angelis S, Amato D, Scellini T, et al. (1998) Long-term outcome of migraine therapy: predictive value of the frontotemporal nitroglycerin test. Neurology 51: 1475–1478. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref190] 190. Bordini CA, Arruda MA, Ciciarelli MC, Speciali JG (1997) Propranolol vs flunarizine vs flunarizine plus propranolol in migraine without aura prophylaxis. A double-blind trial. Arq Neuropsiquiatr 55: 536–541. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref191] 191. Bostani A, Rajabi A, Moradian N, Razazian N, Rezaei M (2013) The effects of cinnarizine versus sodium valproate in migraine prophylaxis. Int J Neurosci 123: 487–493. 10.3109/00207454.2013.765419 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref192] 192. Bulut S, Berilgen MS, Baran A, Tekatas A, Atmaca M, Mungen B (2004) Venlafaxine versus amitriptyline in the prophylactic treatment of migraine: randomized, double-blind, crossover study. Clin Neurol Neurosurg 107: 44–48. S0303846704000599 [pii]; 10.1016/j.clineuro.2004.03.004 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref193] 193. Cady RK, Voirin J, Farmer K, Browning R, Beach ME, Tarrasch J (2012) Two Center, Randomized Pilot Study of Migraine Prophylaxis Comparing Paradigms Using Pre-Emptive Frovatriptan or Daily Topiramate: Research and Clinical Implications. Headache 52: 749–764. 10.1111/j.1526-4610.2011.02054.x [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref194] 194. Cerbo R, Casacchia M, Formisano R, Feliciani M, Cusimano G, Buzzi MG, et al. (1986) Flunarizine-pizotifen single-dose double-blind cross-over trial in migraine prophylaxis. Cephalalgia 6: 15–18. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref195] 195. Diener HC, Matias-Guiu J, Hartung E, Pfaffenrath V, Ludin HP, Nappi G, et al. (2002) Efficacy and tolerability in migraine prophylaxis of flunarizine in reduced doses: a comparison with propranolol 160 mg daily. Cephalalgia 22: 209–221. 309 [pii]. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref196] 196. Dodick DW, Freitag F, Banks J, Saper J, Xiang J, Rupnow M, et al. (2009) Topiramate versus amitriptyline in migraine prevention: a 26-week, multicenter, randomized, double-blind, double-dummy, parallel-group noninferiority trial in adult migraineurs. Clin Ther 31: 542–559. S0149-2918(09)00095-2 [pii]; 10.1016/j.clinthera.2009.03.020 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref197] 197. Domingues RB, Silva AL, Domingues SA, Aquino CC, Kuster GW (2009) 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 67: 973–977. S0004-282X2009000600002 [pii]. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref198] 198. Formisano R, Falaschi P, Cerbo R, Proietti A, Catarci T, D'Urso R, et al. (1991) Nimodipine in migraine: clinical efficacy and endocrinological effects. Eur J Clin Pharmacol 41: 69–71. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref199] 199. Forssman B, Henriksson KG, Kihlstrand S (1972) A comparison between BC 105 and methysergide in the prophylaxis of migraine. Acta Neurol Scand 48: 204–212. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref200] 200. Gawel MJ, Kreeft J, Nelson RF, Simard D, Arnott WS (1992) Comparison of the efficacy and safety of flunarizine to propranolol in the prophylaxis of migraine. Can J Neurol Sci 19: 340–345. [PubMed] [Google Scholar]

[pone.0130733.ref201] 201. Gerber WD, Diener HC, Scholz E, Niederberger U (1991) Responders and non-responders to metoprolol, propranolol and nifedipine treatment in migraine prophylaxis: a dose-range study based on time-series analysis. Cephalalgia 11: 37–45. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref202] 202. Gupta P, Singh S, Goyal V, Shukla G, Behari M (2007) Low-dose topiramate versus lamotrigine in migraine prophylaxis (the Lotolamp study). Headache 47: 402–412. HED599 [pii]; 10.1111/j.1526-4610.2006.00599.x [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref203] 203. Hubbe P (1973) The prophylactic treatment of migraine with an antiserotonin pizotifen. Acta Neurol Scand 49: 108–114. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref204] 204. Kalita J, Bhoi SK, Misra UK (2013) Amitriptyline vs divalproate in migraine prophylaxis: a randomized controlled trial. Acta Neurol Scand 128: 65–72. 10.1111/ane.12081 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref205] 205. Kangasniemi PJ, Nyrke T, Lang AH, Petersen E (1983) Femoxetine—a new 5-HT uptake inhibitor—and propranolol in the prophylactic treatment of migraine. Acta Neurol Scand 68: 262–267. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref206] 206. Kaniecki RG (1997) A comparison of divalproex with propranolol and placebo for the prophylaxis of migraine without aura. Arch Neurol 54: 1141–1145. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref207] 207. Keskinbora K, Aydinli I (2008) A double-blind randomized controlled trial of topiramate and amitriptyline either alone or in combination for the prevention of migraine. Clin Neurol Neurosurg 110: 979–984. S0303-8467(08)00202-3 [pii]; 10.1016/j.clineuro.2008.05.025 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref208] 208. Krymchantowski AV, Silva MT, Barbosa JS, Alves LA (2002) Amitriptyline versus amitriptyline combined with fluoxetine in the preventative treatment of transformed migraine: a double-blind study. Headache 42: 510–514. hed02125 [pii]. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref209] 209. Krymchantowski AV, da Cunha JC, Bigal ME (2012) Topiramate plus nortriptyline in the preventive treatment of migraine: a controlled study for nonresponders. J Headache Pain 13: 53–59. 10.1007/s10194-011-0395-4 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0130733.ref210] 210. Louis P, Spierings EL (1982) Comparison of flunarizine (Sibelium) and pizotifen (Sandomigran) in migraine treatment: a double-blind study. Cephalalgia 2: 197–203. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref211] 211. Lucking CH, Oestreich W, Schmidt R, Soyka D (1988) Flunarizine vs. propranolol in the prophylaxis of migraine: two double-blind comparative studies in more than 400 patients. Cephalalgia 8 Suppl 8: 21–26. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref212] 212. Ludin HP (1989) Flunarizine and propranolol in the treatment of migraine. Headache 29: 219–224. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref213] 213. Luo N, Di W, Zhang A, Wang Y, Ding M, et al. (2012) A randomized, one-year clinical trial comparing the efficacy of topiramate, flunarizine, and a combination of flunarizine and topiramate in migraine prophylaxis. Pain Med 13: 80–86. 10.1111/j.1526-4637.2011.01295.x [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref214] 214. Mitsikostas DD, Polychronidis I (1997) Valproate versus flunarizine in migraine prophylaxis: a randomized, double-open, clinical trial. Funct Neurol 12: 267–276. [PubMed] [Google Scholar]

[pone.0130733.ref215] 215. Mohammadianinejad SE, Abbasi V, Sajedi SA, Majdinasab N, Abdollahi F, Hajmanouchehri R, et al. (2011) Zonisamide versus topiramate in migraine prophylaxis: a double-blind randomized clinical trial. Clin Neuropharmacol 34: 174–177. 10.1097/WNF.0b013e318225140c [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref216] 216. Olerud B, Gustavsson CL, Furberg B (1986) Nadolol and propranolol in migraine management. Headache 26: 490–493. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref217] 217. Olsson JE, Behring HC, Forssman B, Hedman C, Hedman G, Johansson F, et al. (1984) Metoprolol and propranolol in migraine prophylaxis: a double-blind multicentre study. Acta Neurol Scand 70: 160–168. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref218] 218. Presthus J (1971) BC 105 and methysergide (Deseril) in migraine prophylaxis. Acta Neurol Scand 47: 514–518. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref219] 219. Rampello L, Alvano A, Chiechio S, Malaguarnera M, Raffaele R, Vecchio I, et al. (2004) 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 50: 322–328. NPS2004050004322 [pii]; 10.1159/000080960 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref220] 220. Rascol A, Montastruc JL, Rascol O (1986) Flunarizine versus pizotifen: a double-blind study in the prophylaxis of migraine. Headache 26: 83–85. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref221] 221. Ryan RE Sr (1984) Comparative study of nadolol and propranolol in prophylactic treatment of migraine. Am Heart J 108: 1156–1159. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref222] 222. Scholz E, Gerber WD, Diener HC, Langohr HD, Reinecke M (1987) Dihydroergotamine vs Flunarizine vs Nifedipine vs Metoprolol vs Propranolol in migraine prophylaxis: a comparitive study based on time series analysis. In: Clifford-Rose F, editors. London: John Libley & Co Ltd; pp. 139–145. [Google Scholar]

[pone.0130733.ref223] 223. Shaygannejad V, Janghorbani M, Ghorbani A, Ashtary F, Zakizade N, Nasr V (2006) Comparison of the effect of topiramate and sodium valporate in migraine prevention: a randomized blinded crossover study. Headache 46: 642–648. HED413 [pii]; 10.1111/j.1526-4610.2006.00413.x [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref224] 224. Shimell CJ, Fritz VU, Levien SL (1990) A comparative trial of flunarizine and propranolol in the prevention of migraine. S Afr Med J 77: 75–77. [PubMed] [Google Scholar]

[pone.0130733.ref225] 225. Sorensen PS, Larsen BH, Rasmussen MJ, Kinge E, Iversen H, Alslev T, et al. (1991) Flunarizine versus metoprolol in migraine prophylaxis: a double-blind, randomized parallel group study of efficacy and tolerability. Headache 31: 650–657. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref226] 226. Sudilovsky A, Elkind AH, Ryan RE Sr, Saper JR, Stern MA, Meyer JH (1987) Comparative efficacy of nadolol and propranolol in the management of migraine. Headache 27: 421–426. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref227] 227. Tarasova SV, Amelin AV, Skoromets AA (2008) [Fluvoxamine, amitriptyline and transcranial electrostimulation of the brain in the treatment of chronic daily headache]. Zh Nevrol Psikhiatr Im S S Korsakova 108: 43–46. [PubMed] [Google Scholar]

[pone.0130733.ref228] 228. Togha M, Rahmat JM, Nilavari K, Ashrafian H, Razeghi S, Kohan L (2008) Cinnarizine in refractory migraine prophylaxis: efficacy and tolerability. A comparison with sodium valproate. J Headache Pain 9: 77–82. 10.1007/s10194-008-0013-2 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0130733.ref229] 229. Vilming S, Standnes B, Hedman C (1985) Metoprolol and pizotifen in the prophylactic treatment of classical and common migraine. A double-blind investigation. Cephalalgia 5: 17–23. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref230] 230. Zain S, Khan M, Alam R, Zafar I, Ahmed S (2013) Comparison of efficacy and safety of topiramate with gabapentin in migraine prophylaxis: randomized open label control trial. J Pak Med Assoc 63: 3–7. [PubMed] [Google Scholar]

[pone.0130733.ref231] 231. Brucke T, Wober C, Podreka I, Wober-Bingol C, Asenbaum S, Aull S, et al. (1995) D2 receptor blockade by flunarizine and cinnarizine explains extrapyramidal side effects. A SPECT study. J Cereb Blood Flow Metab 15: 513–518. 10.1038/jcbfm.1995.63 [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref232] 232. Holmes D, Moullet C (1992) Clinical equivalence of once-daily administration of a modified-release formulation of isradipine and twice-daily administration of the standard formulation. Multicentre Study Group. J Cardiovasc Pharmacol 19 Suppl 3: S61–S65. [PubMed] [Google Scholar]

[pone.0130733.ref233] 233. El-Chammas K, Keyes K, Thompson N, Vijayakumar J, Jackson JL (2013) Pharmacological Treatment of Pediatric Headaches: A Meta-analysis. JAMA Pediatr 167: 250–258. 10.1001/jamapediatrics.2013.508 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0130733.ref234] 234.Chronicle E, Mulleners W (2004) Anticonvulsant drugs for migraine prophylaxis. Cochrane Database Syst Rev CD003226. [DOI] [PubMed]

[pone.0130733.ref235] 235.Linde K, Rossnagel K (2004) Propranolol for migraine prophylaxis. Cochrane Database Syst Rev CD003225. [DOI] [PubMed]

[pone.0130733.ref236] 236.Mulleners WM, McCrory DC, Linde M (2014) Antiepileptics in migraine prophylaxis: An updated Cochrane review. Cephalalgia. 0333102414534325 [pii]; 10.1177/0333102414534325 [DOI] [PubMed]

[pone.0130733.ref237] 237. Jackson JL, Shimeall W, Sessums L, Dezee KJ, Becher D, Diemer M, et al. (2010) Tricyclic antidepressants and headaches: systematic review and meta-analysis. BMJ 341:c5222 doi: 10.1136/bmj.c5222.: c5222 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0130733.ref238] 238. Tomkins GE, Jackson JL, O'Malley PG, Balden E, Santoro JE (2001) Treatment of chronic headache with antidepressants: a meta-analysis. Am J Med 111: 54–63. S0002-9343(01)00762-8 [pii]. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref239] 239.Moja PL, Cusi C, Sterzi RR, Canepari C (2005) Selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type headaches. Cochrane Database Syst Rev CD002919. [DOI] [PubMed]

[pone.0130733.ref240] 240. Pringsheim T, Davenport WJ, Becker WJ (2010) Prophylaxis of migraine headache. CMAJ 182: E269–E276. cmaj.081657 [pii]; 10.1503/cmaj.081657 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0130733.ref241] 241. Couch JR, Ziegler DK, Hassanein R (1976) Amitriptyline in the prophylaxis of migraine. Effectiveness and relationship of antimigraine and antidepressant effects. Neurology 26: 121–127. [DOI] [PubMed] [Google Scholar]

[pone.0130733.ref242] 242. Ryan RE (1971) BC-105 a new preparation for the interval treatment of migraine—a double blind evaluation compared with a placebo. Headache 11: 6–18. [DOI] [PubMed] [Google Scholar]

PERMALINK

A Comparative Effectiveness Meta-Analysis of Drugs for the Prophylaxis of Migraine Headache

Jeffrey L Jackson

Elizabeth Cogbill

Rafael Santana-Davila

Christina Eldredge

William Collier

Andrew Gradall

Neha Sehgal

Jessica Kuester

Roles

Abstract

Objective

Design

Data Sources

Eligibility Criteria for Selecting Studies

Results

Conclusion

Introduction

Materials and Methods

Table 1. Search Strategies.

Results

Fig 1. PRISMA Flowchart of study selection.

Placebo Comparisons

Table 2. Study characteristics of included randomized trials of treatment of episodic (<15 headaches/month) migraine headaches.

Table 3. Study characteristics of included randomized trials of treatment of chronic (≥15 headaches/month) migraine headaches.

Table 4. Quality Ratings of included placebo controlled trials.

Alpha-blockers

Table 5. Placebo Controlled Randomized Clinical Trials of Continuous Outcomes among patients with episodic migraines (<15 headaches/month).

Fig 2. Alpha blockers compared to placebo for episodic migraine headaches.

Table 6. Placebo controlled comparisons of continuous outcomes among patients with chronic migraine headache (≥ 15 headaches/month).

Angiotensin Converting Enzyme Inhibitors (ACE)/ Angiotensin Receptor Blockers (ARB)

Fig 3. ACE and ARBs compared to placebo for episodic migraine headaches.

Table 7. Placebo controlled comparisons of >50% improvement in episodic migraine headaches (<15 migraines/month).

Anticonvulsants

Fig 4. Topiramate compared to placebo for episodic migraine headaches.

Fig 5. Valproate compared to placebo for episodic migraine headaches.

Topiramate

Fig 6. Dose response relationship of headache to topiramate dose.

Valproate

Beta Blockers

Fig 7. Propranolol compared to placebo for episodic migraine headaches.

Calcium Channel Blockers

Flunarizine

Fig 8. Flunarizine compared to placebo for episodic migraine headaches.

Selective Serotonin Reuptake Inhibitors (SSRI)/ Selective Norepinephrine Reuptake inhibitors (SNRI)

Fig 9. SSRI/SNRIs compared to placebo for episodic migraine headaches.

Serotonin Antagonists

Fig 10. Pizotifen compared to placebo for episodic migraine headaches.

Tricyclic Antidepressants (TCA)

Fig 11. TCAs compared to placebo for episodic migraine headaches.

Fig 12. Amitriptyline compared to placebo for migraine headaches.

Comparative Effective Trials

Table 8. Characteristics of comparative effectiveness trials.

Table 9. Quality Assessment among comparative effectiveness trials.

Table 10. Comparative Effectiveness Trial Outcomes.

Network Meta-analysis

Fig 13. Network meta-analysis.

Placebo effect

Fig 14. Placebo effect of treatment of episodic migraine headaches.

Side Effects

Table 11. Side Effects Compared with Placebo.

Sensitivity Analysis

Discussion

Conclusions

Supporting Information

Data Availability

Funding Statement

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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