Beta-blockers for the prevention of headache in adults, a systematic review and meta-analysis

Abstract

Background

Headaches are a common source of pain and suffering. The study’s purpose was to assess beta-blockers efficacy in preventing migraine and tension-type headache.

Methods

Cochrane Register of Controlled Trials; MEDLINE; EMBASE; ISI Web of Science, clinical trial registries, CNKI, Wanfang and CQVIP were searched through 21 August 2018, for randomized trials in which at least one comparison was a beta-blocker for the prevention of migraine or tension-type headache in adults. The primary outcome, headache frequency per month, was extracted in duplicate and pooled using random effects models.

Data synthesis

This study included 108 randomized controlled trials, 50 placebo-controlled and 58 comparative effectiveness trials. Compared to placebo, propranolol reduced episodic migraine headaches by 1.5 headaches/month at 8 weeks (95% CI: -2.3 to -0.65) and was more likely to reduce headaches by 50% (RR: 1.4, 95% CI: 1.1–1.7). Trial Sequential Analysis (TSA) found that these outcomes were unlikely to be due to a Type I error. A network analysis suggested that beta-blocker’s benefit for episodic migraines may be a class effect. Trials comparing beta-blockers to other interventions were largely single, underpowered trials. Propranolol was comparable to other medications known to be effective including flunarizine, topiramate and valproate. For chronic migraine, propranolol was more likely to reduce headaches by at least 50% (RR: 2.0, 95% CI: 1.0–4.3). There was only one trial of beta-blockers for tension-type headache.

Conclusions

There is high quality evidence that propranolol is better than placebo for episodic migraine headache. Other comparisons were underpowered, rated as low-quality based on only including single trials, making definitive conclusions about comparative effectiveness impossible. There were few trials examining beta-blocker effectiveness for chronic migraine or tension-type headache though there was limited evidence of benefit.

Registration

Prospero (ID: CRD42017050335).

About the Authors:

Jeffrey L. Jackson

Contributed equally to this work with: Jeffrey L. Jackson, Akira Kuriyama, Yachiyo Kuwatsuka, Sarah Nickoloff, Derek Storch, Wilkins Jackson, Zhi-Jiang Zhang, Yasuaki Hayashino

Roles Conceptualization, Data curation, Formal analysis, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliation: Department of Medicine, Zablocki VA Medical Center, Milwaukee, WI, United States of America

ORCID logo http://orcid.org/0000-0002-9820-5834

Akira Kuriyama

Contributed equally to this work with: Jeffrey L. Jackson, Akira Kuriyama, Yachiyo Kuwatsuka, Sarah Nickoloff, Derek Storch, Wilkins Jackson, Zhi-Jiang Zhang, Yasuaki Hayashino

Roles Data curation, Formal analysis, Validation, Writing – review & editing

Affiliation: Department of General Medicine, Kurashiki Central Hospital, Okayama, Japan

Yachiyo Kuwatsuka

Contributed equally to this work with: Jeffrey L. Jackson, Akira Kuriyama, Yachiyo Kuwatsuka, Sarah Nickoloff, Derek Storch, Wilkins Jackson, Zhi-Jiang Zhang, Yasuaki Hayashino

Roles Data curation, Investigation, Methodology, Writing – review & editing

Affiliation: Department of Medicine, Nagoya University Hospital, Nagoya, Japan

Sarah Nickoloff

Contributed equally to this work with: Jeffrey L. Jackson, Akira Kuriyama, Yachiyo Kuwatsuka, Sarah Nickoloff, Derek Storch, Wilkins Jackson, Zhi-Jiang Zhang, Yasuaki Hayashino

Roles Data curation, Writing – review & editing

Affiliation: Department of Medicine, Zablocki VA Medical Center, Milwaukee, WI, United States of America

Derek Storch

Contributed equally to this work with: Jeffrey L. Jackson, Akira Kuriyama, Yachiyo Kuwatsuka, Sarah Nickoloff, Derek Storch, Wilkins Jackson, Zhi-Jiang Zhang, Yasuaki Hayashino

Roles Data curation, Writing – review & editing

Affiliation: Department of Medicine, Zablocki VA Medical Center, Milwaukee, WI, United States of America

Wilkins Jackson

Contributed equally to this work with: Jeffrey L. Jackson, Akira Kuriyama, Yachiyo Kuwatsuka, Sarah Nickoloff, Derek Storch, Wilkins Jackson, Zhi-Jiang Zhang, Yasuaki Hayashino

Roles Data curation, Writing – review & editing

Affiliation: Department of Biology, University of Wisconsin-Milwaukee, Milwaukee, WI, United States of America

Zhi-Jiang Zhang

Contributed equally to this work with: Jeffrey L. Jackson, Akira Kuriyama, Yachiyo Kuwatsuka, Sarah Nickoloff, Derek Storch, Wilkins Jackson, Zhi-Jiang Zhang, Yasuaki Hayashino

Roles Data curation, Writing – review & editing

Affiliation: Department of Epidemiology and Biostatistics, School of Health Sciences, Wuhan University, Wuhan, China

Yasuaki Hayashino

Contributed equally to this work with: Jeffrey L. Jackson, Akira Kuriyama, Yachiyo Kuwatsuka, Sarah Nickoloff, Derek Storch, Wilkins Jackson, Zhi-Jiang Zhang, Yasuaki Hayashino

Roles Data curation, Writing – review & editing

Affiliation: Department of Endocrinology, Tenri Hospital, Nara, Japan

Introduction

Headaches are a common problem, world-wide. The two most common types of headaches are migraine and tension-type. Migraines have a prevalence of 6–8% [1–9], and cause significant disability [10–13], even during periods between attacks [14]. Migraines are responsible for $1 billion in medical costs and $16 billion in lost productivity per year [15;16] in the US alone. While episodic migraine is more common than chronic migraine, chronic migraine has greater disability as well as financial and occupational consequences [8;9] and has received much greater research attention [17].

Tension-type headache is more common than migraine; up to 90% of adults experience one at some time in their life [18–22]. In any given month, a tension-type headache occurs in 46% of adults [22]. Most tension-type headaches are managed with over the counter medications, consequently most do not seek medical attention. However, tension-type headache reduces the quality of life [23], results in up to a fifth of all missed work days [24], and costs EUR 21 billion annually in Europe [25].

There are several options available for preventing migraines including alpha antagonists, antiepileptics [26], beta-blockers [27], botulinum toxin-A [28], calcium channel blockers [29], flunarizine [17], pizotifen [17], serotonin agonists [30], serotonin reuptake inhibitors (SSRIs) [31] and tricyclic antidepressants (TCAs) [32]. Nearly half of males and a third of females who are candidates for prophylactic therapy do not receive it [33]. Selection of prophylactic treatment is tailored on individual patient characteristics, costs, perceived efficacy of the intervention and side effects of the available options.

The 2012 American Academy of Neurology guideline recommends beta-blockers, specifically propranolol and metoprolol, as first line therapy for preventing migraines [34]. Specific medications commonly used in prophylaxis has not been well described. In Europe, commonly prescribed prophylactic agents include antiepileptics, beta-blockers, flunarizine, pizotifen and TCAs [35]. Other studies found that specialists are twice as likely to prescribe antiepileptics than primary care providers [36], that treatment persistence is low [37] and that use of prophylactic medications has increased [38], though none of these three characterized the specific medications used.

The purpose of this study is to assess the efficacy of beta-blockers in the prophylaxis of migraine and tension-type headache. Two previous systematic reviews focused on the use of beta-blockers in migraine headaches, both are more than 15 years old [39;40], and included limited outcomes, though both suggest benefit of beta-blockers compared to placebo. There are two more recent comparative effectiveness analyses of headache management that included beta-blockers. Shamliyan reviewed pharmacologic treatment for episodic migraine and reported that beta-blockers were effective; their outcome was 50% reduction in headaches, an outcome recommended by the International Headache Society (IHS) as a secondary outcome. They also excluded beta-blockers not approved for headaches in the U.S [41]. In the other meta-analysis, we found that beta-blockers were beneficial for migraine headaches, but did not differentiate between episodic and chronic migraine headaches, did not include all possible outcomes and did not examine beta-blockers for management of tension-type headache [17].

Methods

This study was conducted in accordance with PRISMA guidelines (S1 Table. Prisma Checklist) [42] and was registered in PROSPERO (ID: CRD42017050335). Databases searched (without language restriction) included the Cochrane Central Register of Controlled Clinical Trials, MEDLINE, EMBASE, ISI Web of Science (SCI, SSCI, CPCI-S & CPCI-SSH), and three Chinese databases (CNKI, Wanfang and CQVIP) trough 21 August 2018 using the search strategies in supporting information (S2 Table. Search Strategy). Randomized controlled studies of adults that were at least four weeks in duration and used a beta-blocker in at least one study arm were included. Articles were assessed for inclusion in duplicate (JLJ, AK). Because the definition of headache has changed over time, articles were reviewed by at least two authors to determine if the headache could be reasonably classified as migraine or tension-type headache and as either frequent episodic or chronic according to the most recent IHS criteria [43]. IHS recommendations were followed by including only patient-reported outcomes [44] and including the monthly headache frequency as the primary outcome. Additional outcomes included headache index, headache days, severity, duration, quality of life, the use of acute analgesic medications, the proportion with at least 50% improvement in headaches, study withdrawal and the occurrence of adverse events. Data were abstracted in duplicate. Because of the large volume of articles, after training on a separate set of pediatric headache articles, the articles were divided among the authors with all authors serving as the primary abstractor for some articles and as the secondary reviewer, assessing for data accuracy in other articles. Disagreements resolved through consensus between the two and if consensus could not be reached, the entire group discussed and made consensual decisions.

Bias was assessed using the Cochrane risk of bias instrument [45] as well as the JADAD scale [46]. Study size was also included as a risk of bias based on sample size calculations. It was estimated that 60 subjects were required for continuous outcomes and 200 for dichotomous ones (S3 Table. Quality Ratings of Included Trials) based on results from our previous review of treatment of migraine headaches [17]. Studies with more than one arm were pooled into a single arm (if the study reported no differences between arms). For crossover trials, several approaches were used, depending on how the data was reported. For trials that provided only pooled data from both time-periods, the sample size was reduced by 50%, to avoid over-weighting the study [45]. For trials that provided data from both time periods separately, if there was no difference between the two-time periods, the average point estimates and variance was used, with reduction of the sample size by 50%.

The preference was to pool study outcomes in their original unit of analysis. Headache frequency was pooled as headache days per month, headache duration as hours per month, and analgesic use as number of doses per month. Since headache severity and headache index metrics varied, these outcomes were pooled using standardized mean differences [47]. Missing outcome variances were imputed from the reported mean, sample size, and P values [48]. Heterogeneity was assessed using Chi2 (Cochrane Q), Galbraith plots [49] and the I2 statistic [50]. Data were pooled at each reported time point using a random-effects model [51] using Stata (V15.1 College Station TX). A priori, the analytic plan was to pool data at 4, 8, 12, 16, 20 and 24 weeks. Studies that reported outcomes at different time points were combined at the closest time point available (for example, 9-week outcomes were pooled with the 8-week group). For comparative effectiveness trials with 2 or fewer studies, outcomes were reported at the last point reported. Small study effects (publication bias) was assessed using the methods of Peters [52] for dichotomous outcomes and Egger [53] for continuous outcomes if there were a sufficient number of studies. Trial sequential analysis was performed for the comparisons of propranolol to placebo for headache frequency (at 8 weeks), using the O’Brien-Fleming method of alpha-spending function to robustness of the pooled estimates against type 1 and type 2 error [54], using TSA software (Copenhagen, Denmark).

A network meta-analysis was performed for beta-blockers that were compared with placebo at 8 and 12 weeks using the residual maximum likelihood with a modification to the coefficients’ estimated variance using the Kapp and Hartung approach [55] that had a minimum of 2 studies. Both 8- and 12-week results were pooled including all beta-blockers using multivariate random-effects meta-analysis using the network package in STATA [56].

Finally, the quality of evidence was assessed using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) system to rate the quality of the evidence (GRADEPro GDT 2015) following Cochrane guidelines [45]. Grade assesses quality in four levels: High (further research is unlikely to change estimate of effect); Moderate (further research may impact effect estimate); Low (further research is likely to have important impact on estimate); Very low (any estimate of effect is very uncertain).

Results

The literature search yielded 3513 unique studies after excluding duplicates. Application of inclusion and exclusion criteria (Fig 1) resulted in 108 randomized controlled trials [57–164], of which 50 had a placebo arm [57–59;62;68;69;71;72;75;77–79;81–83;88;94–97;99;107;108;113;115;116;118;121–124;126;130;133–138;141;142;144;145;147;149;151;152;152;154;156;157;162]. Because some placebo-controlled trials included non-placebo comparisons, there were a total of 86 comparative effectiveness arms. Nearly all trials (n = 106) focused on migraine headaches, most (n = 83) could be classified as episodic. Only 4 trials studied chronic migraines [76;105;129;151] and there was only 1 trial of beta-blockers for chronic tension-type headache [57].

[Figure omitted. See PDF.]

Fig 1. PRISMA flow chart.

https://doi.org/10.1371/journal.pone.0212785.g001

The 108 included studies ranged from 4 to 64 weeks in duration (average: 12.9). Fifty-one were parallel in design and 57 had a crossover design. Among crossover trials, 43 were randomized, with washout periods ranging from zero to four weeks. Twenty-five different countries (Table 1) and four languages (Chinese (n = 15), English (n = 86), German (n = 6), Polish (n = 1) were represented. The average age was 38.6 years and 77% of participants were women. Ten different beta-blockers were studied. Propranolol (n = 74) and metoprolol (n = 21) were the most commonly evaluated beta-blockers. Atenolol, nadolol, pindolol and timolol had two studies each. Several beta-blockers were evaluated in only a single trial (acebutolol, alprenolol, bisoprolol and oxprenolol). Study characteristics for included trials are provided in Table 1 and quality ratings are given in S2 Table.

[Figure omitted. See PDF.]

Table 1. Included trial characteristics.

https://doi.org/10.1371/journal.pone.0212785.t001

Studies had a number of common quality problems (S3 Table) including high drop-out rates (16.1%, range 0–51%), lack of intention to treat analysis (76%), inadequate sequence generation (83%), lack of evidence of concealed allocation (90%) and inadequate blinding (60%). Twenty-three studies assessed compliance (21%). Fifty-one (47%) studies reported all collected outcomes. Sixteen trials (15%) were sponsored by industry. All comparisons that had only a single study were graded as low-quality evidence.

Episodic migraines

The primary outcome was headaches per month. Outcomes from placebo-controlled trials for all beta-blockers and time-points are provided in Tables 2–3. Outcomes at 8 weeks was the most commonly reported time point. Among patients with episodic migraines (Table 2), the average number of headaches at baseline was 4.9 headaches/month (95% CI: 4.4–5.4). The best studied beta-blocker was propranolol, which was more effective than placebo at 8 and 12 weeks (8 weeks: -1.5 ha/month, 95% CI: -2.3 to -0.65); 12 weeks: -1.2 ha/month, 95% CI: -1.8 to -0.60, Fig 2). Propranolol outcomes at 8 and 12 weeks were both graded as high-quality evidence. TSA analysis of propranolol vs. placebo for headache frequency demonstrated that it is unlikely that these results are due to a Type 1 error (Fig 3). Other beta-blockers that were more effective than placebo at 8 weeks (Fig 4) included bisoprolol (-0.70 ha/month, 95% CI: -1.4 to -0.05, low quality), metoprolol (-0.86 ha/month, 95% CI: -1.4 to -0.34, moderate quality) and timolol (-0.77 ha/month, 95% CI: -1.4 to -0.12, moderate quality). The remaining beta-blockers, in single trials did not significantly reduce headache frequency (Fig 3). There was a similar pattern at twelve weeks.

[Figure omitted. See PDF.]

Fig 2. Headaches per month, Propranolol v. Placebo.

https://doi.org/10.1371/journal.pone.0212785.g002

[Figure omitted. See PDF.]

Fig 3. Trial Sequential Analysis (Propranolol v. Placebo).

https://doi.org/10.1371/journal.pone.0212785.g003

[Figure omitted. See PDF.]

Fig 4. Headaches per month, other Beta Blockers v Placebo.

https://doi.org/10.1371/journal.pone.0212785.g004

[Figure omitted. See PDF.]

Table 2. Placebo controlled primary outcome (headache frequency per month).

https://doi.org/10.1371/journal.pone.0212785.t002

[Figure omitted. See PDF.]

Table 3. Secondary outcomes of placebo controlled trials.

https://doi.org/10.1371/journal.pone.0212785.t003

Among secondary outcomes, the majority of trials studied subjects with episodic migraine headaches (Table 3). Propranolol was the most commonly studied beta-blocker. Propranolol was more likely to reduce headaches by 50% than placebo at 12 weeks (RR: 1.4, 95% CI: 1.1–1.8, NNT: 4.5, 95% CI: 2.8–12.9). Other effective beta-blockers included atenolol (RR: 1.8, 95% CI: 1.0–3.2, NNT: 6.3, 95% CI: 3.2–332.4), metoprolol (RR: 1.9, 95% CI: 1.3–2.8, NNT: 4.7, 95% CI:3.0–10.4) and timolol (RR: 1.8, 95% CI: 1.4–2.3, NNT: 4.2, 95% CI: 2.7–8.8,). At 8 weeks, metoprolol reduced analgesic medication use (-4.0 doses/month, 95% CI: -7.5 to -0.48) as did propranolol at 12 weeks (-2.1 doses/month, 95% CI: -3.2 to -0.95). The headache index was modestly reduced by a number of different beta-blockers including atenolol (SMD: -0.62, 95% CI: -1.2 to -0.004), metoprolol (SMD: -0.42, 95% CI: -0.77 to -0.07), propranolol (SMD: -0.48, 95% CI: -0.75 to -0.22) and timolol (SMD: -0.53, 95% CI: -0.84 to -0.21). At 8 weeks, headache severity was modestly reduced by both metoprolol (SMD: -0.53, 95% CI: -0.71 to -0.14) and propranolol (SMD: -0.51, 95% CI: -0.76 to -0.26). Headache duration was reduced by metoprolol (-2.0 hours, 95% CI: -3.7 to -0.26) and propranolol (-6.1 hours, 95% CI: -16.2 to -0.39).

Network meta-analysis.

For the primary outcome, headache frequency, the network meta-analysis found no difference at 8 weeks (p = 0.27) in effectiveness in comparisons between propranolol (n = 9) compared to bisoprolol (n = 2), metoprolol (n = 3) and nadolol (n = 3). Similarly, at 12 weeks, there was no difference (p = 0.84) n effectiveness in comparisons between propranolol (n = 9) compared to bisoprolol (n = 2), nadolol (n = 3) and timolol (n = 2). The 8- and 12-week analysis confirmed this lack of difference between all beta-blockers (Fig 5), including those with single trials (Fig 6)

[Figure omitted. See PDF.]

Fig 5. Network meta-analysis map.

https://doi.org/10.1371/journal.pone.0212785.g005

[Figure omitted. See PDF.]

Fig 6. Results of network meta-analysis comparisons.

https://doi.org/10.1371/journal.pone.0212785.g006

Comparative effectiveness trials.

There were 83 randomized trials that included at least one comparison to a non-placebo treatment. Propranolol was the most commonly compared beta-blocker (n = 72, 87%). Propranolol was compared to pharmacologic interventions in 50 trials. Eleven comparisons that were from single trials (5-hydroxytryptophan, aspirin, atenolol, candesartan, clonidine, cyclandelate, mefenamic acid, naproxen, nifedipine, nimodipine, nortriptyline, pindolol, riboflavin). Comparisons with more than one study included: amitriptyline (n = 2), femoxetine (n = 2), flunarizine (n = 11), metoprolol (n = 4), nadolol (n = 3), nimodipine (n = 2), timolol (n = 2) tofenamic acid (n = 2), topiramate (n = 3) and valproate (n = 3). Several combinations were tested including propranolol + amitriptyline vs. amitriptyline (n = 1), and propranolol + flunarizine was compared to flunarizine. Propranolol combined with topiramate was compared with topiramate alone. Nonpharmacologic interventions were compared to propranolol in three trials (acupuncture, behavioral management, biofeedback). Metoprolol was assessed in 14 trials, 8 were comparisons with pharmacologic interventions (aspirin, bisoprolol, clomipramine, clonidine, flunarizine, nebivolol, pizotifen) and one with nonpharmacologic (acupuncture). Metoprolol was compared to a combination of metoprolol and fluoxetine in 2 trials and the combination of metoprolol and flunarizine was compared to flunarizine alone in 2 trials.

The primary outcome comparison (headache frequency) is provided in Table 4, and secondary outcomes are in Table 5. The majority of comparisons were single trials, making definitive conclusions difficult. Metoprolol, but not propranolol, was more effective than aspirin. Metoprolol was more effective than clomipramine, though comparable to acupuncture, bisoprolol, clonidine, flunarizine, nebivolol and pizotifen. Adding fluoxetine to metoprolol or flunarizine to either propranolol or metoprolol did not improve headache frequency. All comparisons were graded as low-quality. Propranolol was more effective than femoxetine, mefenamic acid, naproxen, nifedipine and very low-dose (40mg) nortriptyline, but comparable to 5-hydroxytryptophan, acupuncture, atenolol, behavioral management, biofeedback, candesartan, clonidine, cyclandelate, flunarizine, metoprolol, nadolol, naproxen, nimodipine, riboflavin, timolol, tolfenamic acid, topiramate and valproic acid. All comparisons were single trials and were rated as low-quality evidence with the exception of the comparisons to flunarizine and metoprolol at 8 weeks that were graded as moderate or high-quality. The network meta-analysis confirmed these findings, but suggested that metoprolol was also superior to naproxen (SMD: -1.2, 95% CI: -1.6 to -0.78).

[Figure omitted. See PDF.]

Table 4. Primary outcome (headache frequency) of comparative effectiveness trials.

https://doi.org/10.1371/journal.pone.0212785.t004

[Figure omitted. See PDF.]

Table 5. Secondary outcomes of comparative effectiveness trials.

https://doi.org/10.1371/journal.pone.0212785.t005

Chronic migraine

There were four trials that evaluated beta-blockers for chronic migraine headaches, none were placebo controlled. (Table 6). Propranolol was compared to flunarizine [151], nortriptyline [76], valproic acid [105] and to the combination of propranolol and flunarizine [151]. In addition, a combination of propranolol and topiramate was compared to topiramate alone [129]. Propranolol was no better than valproic acid or flunarizine and the combinations (propranolol + topiramate and propranolol + flunarizine) was no better than topiramate and flunarizine alone (Table 6).

[Figure omitted. See PDF.]

Table 6. Non-episodic trials.

https://doi.org/10.1371/journal.pone.0212785.t006

Tension-type headache

There was only one trial evaluating tension-type headache, comparing the combination of pindolol and amitriptyline to placebo and to amitriptyline alone [57]. The combination of pindolol and amitriptyline was more effective than placebo at reducing headache frequency at 4 and 8 weeks (Table 6) and in reducing headaches by at least 50% (RR: 3.8, 95% CI: 1.5–9.3), but equally effective with amitriptyline.

Adverse events

Participants on beta-blockers were more likely to experience side effects than those on placebo (RR: 1.2, 95% CI: 1.0–1.4), though they were not more likely to withdraw (RR: 0.99, 95% CI: 0.83 to 1.2). Specific side effects more common with beta-blockers included dizziness (RR: 1.5, 95% CI: 1.0–2.3) and fatigue (RR: 1.5, 95% CI: 1.2–2.0). Depression, gastrointestinal problems, paresthesia’s and weight gain were not significantly different than placebo.

Propranolol was the only beta-blocker with sufficient numbers of studies to perform sensitivity analysis. There was no evidence of publication bias for propranolol’s reduction of headache frequency at 8 weeks (Egger’s p = 0.77) or at 12 weeks (p = 0.62). There was no evidence of an effect of quality (p = 0.97), age (p = 0.71), percent women (p = 0.28), percentage of dropouts (p = 0.55), dose (p = 0.61), intention to treat analysis (p = 0.35), concealed allocation (p = 0.38) or appropriateness of blinding (p = 0.98).

Discussion

This review included one hundred and eight randomized controlled trials. Nearly all evaluated the efficacy of beta-blockers for episodic migraine headaches. Compared to placebo, propranolol was effective in reducing episodic migraine frequency. The effect began as early as four weeks. Migraine headache sufferers experienced an average reduction of 1.3 headaches/month; this translates to a reduction from 4.8 to 3.5 headaches a month. Subjects given propranolol were more likely to report at least 50% reduction in headaches and to reduce their consumption of analgesic medications. In addition to reducing the number of headaches, the residual headaches were less severe and shorter in duration compared to those receiving placebo. Outcomes from the propranolol comparisons to placebo were rated as high-quality evidence. In three trials, metoprolol also reduced headache frequency, though the reduction was less than 1 headache a month. Conclusions regarding the efficacy of other beta-blockers is less certain, as most were studied in just one trial each. Atenolol, bisoprolol and timolol had weak evidence of benefit. Acebutolol, alprenolol and nadolol appeared to be ineffective in migraine prophylaxis. This is unlikely to be due to properties of the beta-blockers. Propranolol is nonselective as is alprenolol and nadolol. Metoprolol, also effective is a ß-1 selective drug as is atenolol, bisoprolol and acebutolol. Given that acebutolol, alprenolol and nadolol were only studied in one trial each, it is possible that this may be either random variation in outcomes or a problem with the trials (such as dose or duration). The network analysis suggests that the benefit of beta-blocker may be a class effect.

The literature comparing beta-blockers to other modalities consisted mostly of single-trials with the exception of the comparison of propranolol to metoprolol (moderate quality, no difference) and to flunarizine (high quality, no difference). Flunarizine, not available in the United States, is well-established as effective in treating migraine headache. Universally, beta-blockers were associated with bradycardia and with lower average pulse rates than placebo trials. This is not surprising given their impact on chronotropy. Other side effects more common among participants taking beta-blockers included dizziness and fatigue, though subjects on beta-blockers were not more likely to withdraw from the studies.

While these conclusions are similar to previous reviews, this analysis is a unique contribution in many ways, first it included many more trials than previously reported, including Chinese trials that had previously not been included. Secondly, all beta-blockers were carefully parsed by type of headache (tension v. migraine, episodic v. chronic). Third, this study examined outcomes at the specific times reported, it is common for meta-analyses to pool trials at the last time point, regardless of whether there were significant differences in that time-point. Fourth, trial sequential analysis that demonstrated the adequacy of the current database for propranolol, suggesting that there is low likelihood of type 1 error in the conclusions. Fifth, the network meta-analysis didn’t show clear benefit of one beta-blocker over another, suggesting a class effect, though other beta-blockers have weaker evidence for benefit.

An important question, unanswered in this review, is how effective beta-blockers are compared to other commonly used prophylactic regimens. Propranolol, metoprolol and flunarizine appear to have similar efficacy. The other comparisons were all single-trial comparisons, making definitive conclusions impossible. In a previous review, tricyclic antidepressants resulted in a reduction in headache frequency for patients experiencing chronic migraines of 1.3 SMD, compared to placebo, a large effect [17]. In this study, there was only had one trial on chronic migraines, and the calculated SMD was 0.58, about half of the effect previously reported for TCAs. In a network meta-analysis of chronic migraines, tricyclic antidepressants were more effective than propranolol [17] but propranolol was similar in efficacy to antiepileptics and flunarizine, similar to findings in this study, though it is important to note that the majority of trials for beta-blockers are for episodic rather than chronic migraines. Definitive answer to this comparative effectiveness question requires additional studies that directly compare the different prophylactic modalities.

This review has several important limitations. First, while the quality of evidence for the comparison between propranolol and placebo was high, in general, the remaining comparisons were of low quality, consisting mostly of underpowered single randomized trials. While all the included trials were randomized, there were significant methodologic problems; combining poorly designed studies can lead to questionable results. It is important to note that most of the comparisons were graded as being of low-quality evidence because of the paucity of studies and concern about study problems. Secondly, studies were inconsistent in reporting outcomes, so even when there were more than one trial available, specific outcomes may only be provided by a single study. Moreover, there were significant problems with selective reporting of outcomes and many studies did not collect information on headache frequency, the measure preferred by the International Headache Society. Third, the number of studies available precluded sensitivity analyses, such as assessing for publication bias or exploring sources of heterogeneity. Fourth, beta-blockers have been studied almost exclusively in the management of episodic migraine headaches. Their benefit for chronic episodic or tension-type headaches is uncertain. Fifth, because of the paucity of trials for most beta-blockers the network analysis was underpowered to show differences between beta-blockers, Sixth, the average age of participants was 38, and mostly female. While this reflects the demographics of headache, it limits applicability to older adults.

Conclusions

Propranolol is effective in reducing the burden of patients with episodic migraine headaches, reducing headaches from 5 to 3 headaches a month. This means that migraine sufferers given propranolol will have substantial residual headache burden. Propranolol reduces headaches by more than 50% as well as reducing the number of analgesic medication doses required. It also reduces the severity or duration of the headaches experienced. Propranolol and metoprolol exert similar effects and propranolol is as effective as flunarizine. The data for other beta-blockers and other comparisons are less clear.

Supporting information

[Figure omitted. See PDF.]

S1 Table. Prisma checklist.

https://doi.org/10.1371/journal.pone.0212785.s001

(DOC)

S2 Table. Search strategy.

https://doi.org/10.1371/journal.pone.0212785.s002

(DOCX)

S3 Table. Quality ratings of included trials.

https://doi.org/10.1371/journal.pone.0212785.s003

(DOCX)

Acknowledgments

The views reflected in this manuscript are those of the authors and should not be construed, in any way, to be those of the Department of Veterans Affairs.

Citation: Jackson JL, Kuriyama A, Kuwatsuka Y, Nickoloff S, Storch D, Jackson W, et al. (2019) Beta-blockers for the prevention of headache in adults, a systematic review and meta-analysis. PLoS ONE 14(3): e0212785. https://doi.org/10.1371/journal.pone.0212785

References

1. Rasmussen BK. Epidemiology of headache. Cephalalgia 2001; 21(7):774–777. pmid:11595011

2. Wang SJ. Epidemiology of migraine and other types of headache in Asia. Current Neurology & Neuroscience Reports 2003; 3(2):104–108.

3. Radtke A, Neuhauser H. Prevalence and burden of headache and migraine in Germany. Headache 2009; 49(1):79–89. pmid:19125877

4. Karli N, Zarifoglu M, Ertafs M, Saip S, Ozturk V, Bicakci S et al. Economic impact of primary headaches in Turkey: a university hospital based study: part II. J Headache Pain 2006; 7(2):75–82. pmid:16538424

5. Falavigna A, Teles AR, Velho MC, Vedana VM, Silva RC, Mazzocchin T et al. Prevalence and impact of headache in undergraduate students in Southern Brazil. Arq Neuropsiquiatr 2010; 68(6):873–877. pmid:21243244

6. Lipton RB, Bigal ME, Kolodner K, Stewart WF, Liberman JN, Steiner TJ. The family impact of migraine: population-based studies in the USA and UK. Cephalalgia 2003; 23(6):429–440. pmid:12807522

7. Lipton RB, Liberman JN, Kolodner KB, Bigal ME, Dowson A, Stewart WF. Migraine headache disability and health-related quality-of-life: a population-based case-control study from England. Cephalalgia 2003; 23(6):441–450. pmid:12807523

8. Adams AM, Serrano D, Buse DC, Reed ML, Marske V, Fanning KM et al. The impact of chronic migraine: The Chronic Migraine Epidemiology and Outcomes (CaMEO) Study methods and baseline results. Cephalalgia 2015; 35(7):563–578. pmid:25304766

9. Buse DC, Manack AN, Fanning KM, Serrano D, Reed ML, Turkel CC et al. Chronic migraine prevalence, disability, and sociodemographic factors: results from the American Migraine Prevalence and Prevention Study. Headache 2012; 52(10):1456–1470. pmid:22830411

10. Blumenfeld AM, Varon SF, Wilcox TK, Buse DC, Kawata AK, Manack A et al. Disability, HRQoL and resource use among chronic and episodic migraineurs: results from the International Burden of Migraine Study (IBMS). Cephalalgia 2011; 31(3):301–315. pmid:20813784

11. Leonardi M, Raggi A, Bussone G, D'Amico D. Health-related quality of life, disability and severity of disease in patients with migraine attending to a specialty headache center. Headache 2010; 50(10):1576–1586. pmid:21029083

12. Raggi A, Leonardi M, Bussone G, D'Amico D. 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 2010.

13. Tepper SJ. A pivotal moment in 50 years of headache history: the first American Migraine Study. Headache 2008; 48(5):730–731. pmid:18471125

14. Freitag FG. The cycle of migraine: patients' quality of life during and between migraine attacks. Clin Ther 2007; 29(5):939–949. pmid:17697913

15. Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML. Burden of migraine in the United States: disability and economic costs. Archives of Internal Medicine 1999; 159(8):813–818. pmid:10219926

16. Goldberg LD. The cost of migraine and its treatment. Am J Manag Care 2005; 11(2 Suppl):S62–S67.

17. Jackson JL, Cogbill E, Santana-Davila R, Eldredge C, Collier W, Gradall A et al. A Comparative Effectiveness Meta-Analysis of Drugs for the Prophylaxis of Migraine Headache. Plos One 2015; 10(7):e0130733. pmid:26172390

18. Ferrante T, Manzoni GC, Russo M, Camarda C, Taga A, Veronesi L et al. Prevalence of tension-type headache in adult general population: the PACE study and review of the literature. Neurological Sciences 2013; 34 Suppl 1:S137–S138.

19. Lyngberg AC, Rasmussen BK, Jorgensen T, Jensen R. Has the prevalence of migraine and tension-type headache changed over a 12-year period? European Journal of Epidemiology 2005; 20(3):243–249. pmid:15921042

20. Rasmussen BK, Jensen R, Schroll M, Olesen J. Epidemiology of headache in a general population—A prevalence study. Journal of Clinical Epidemiology 1991; 44(11):1147–1157. pmid:1941010

21. Schwartz BS, Stewart WF, Simon D, Lipton RB. Epidemiology of tension-type headache. JAMA 1998; 279(5):381–383. pmid:9459472

22. Stovner LJ, Hagen K, Jensen J, Katsarava Z, Lipton RB, Scher AI et al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia 2007; 27(3):193–210. pmid:17381554

23. Abu Bakar N, Tanprawate S, Lambru G, Torkamani M, Jahanshahi M, Matharu M. Quality of life in primary headache disorders: A review. Cephalalgia 2016; 36(1):67–91. pmid:25888584

24. Latinovic R, Gulliford M, Ridsdale L. Headache and migraine in primary care: consultation, prescription, and referral rates in a large population. J Neurol Neurosurg Psychiatry 2006; 77(3):385–387. pmid:16484650

25. Linde M, Gustavsson A, Stovner LJ, Steiner TJ, Barr AJ., Katsarava Z et al. The cost of headache disorders in Europe: the Eurolight project. European Journal of Neurology 2012; 19(5):703–711. pmid:22136117

26. Chronicle E, Mulleners W. Anticonvulsant drugs for migraine prophylaxis. Cochrane Library 2004;(3).

27. Linde K, Rossnagel K. Propranolol for migraine prophylaxis. Cochrane Database Syst Rev 2004;(2):CD003225. pmid:15106196

28. Jackson JL, Kuriyama A, Hayashino Y. Botulinum toxin A for prophylactic treatment of migraine and tension headaches in adults: a meta-analysis. JAMA 2012; 307(16):1736–1745. pmid:22535858

29. Pringsheim T, Davenport WJ, Becker WJ. Prophylaxis of migraine headache. CMAJ 2010; 182(7):E269–E276. pmid:20159899

30. Lance JW, Anthony M. Clinical trial of a new serotonin antagonist, BC105, in the prevention of migraine. Med J Aust 1968; 1(2):54–55. pmid:4867512

31. Moja PL, Cusi C, Sterzi RR, Canepari C. Selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type headaches. Cochrane Database Syst Rev 2005;(3):CD002919. pmid:16034880

32. Jackson JL, Shimeall W, Sessums L, Dezee KJ, Becher D, Diemer M et al. Tricyclic antidepressants and headaches: systematic review and meta-analysis. BMJ 2010; 341:c5222. pmid:20961988

33. Rapaport AM. Recurrent migraine: cost-effective care. Neurology 1994; 44(5 Suppl 3):S25–S28.

34. Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 2012; 78(17):1337–1345. pmid:22529202

35. Ferrari A, Pasciullo G, Savino G, Cicero AF, Ottani A, Bertolini A et al. Headache treatment before and after the consultation of a specialized centre: a pharmacoepidemiology study. Cephalalgia 2004; 24(5):356–362. pmid:15096224

36. Takaki H, Onzuka D, Hagihara A. Migraine-preventive prescription patters by specialty in ambulatory care settings in the United States. Prev Med 2017; 9:62–67.

37. Hepp Z, Dodick D. Persistence and switching patterns of oral migraine prophylactic medications among patients with chronic migraine: a retrospective claims analysis. Cephalagia 2017; 37(5):470–485.

38. Mafi JN, Edwards ST, Pedersen NP, Davis RB, McCarthy EP, Landon BE. Trends in the ambulatory management of headache: analysis of NAMCS and NHAMCS data 1999–2010. J Gen Intern Med 2015; 30(5):548–555. pmid:25567755

39. Holroyd KA, Penzien DB, Cordingley GE. Propranolol in the management of recurrent migraine: a meta-analytic review. Headache 1991; 31(5):333–340. pmid:1830566

40. Linde K, Rossnagel K. Propranolol for migraine prophylaxis. Cochrane Database Syst Rev 2004;(2):CD003225. pmid:15106196

41. Shamliyan TA, Choi JY, Ramakrishnan R, Miller JB, Wang SY, Taylor FR et al. Preventive pharmacologic treatments for episodic migraine in adults. J Gen Intern Med 2013; 28(9):1225–1237. pmid:23592242

42. Moher D, Liverati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLOS Medicine 2009; 6(7):e1000097. pmid:19621072

43. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018; 38(1):1–211. pmid:29368949

44. Bendtsen L, Bigal ME, Cerbo R, et al. Guidelines for controlled trials of drugs in tension-type headache: Second edition. Cephalalgia 2010; 30(1):1–16. pmid:19614696

45. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2. www.cochrane-handbook.org. 2011. Ref Type: Generic

46. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17(1):1–12. pmid:8721797

47. Kazis LE, Anderson JJ, Meenan RF. Effect sizes for interpreting changes in health status. Medical Care 1989; 27 Suppl 3:S178–S189.

48. Follmann D, Elliott P, Suh I, Cutler J. Variance imputation for overviews of clinical trials with continuous response. Journal of Clinical Epidemiology 1992; 45(7):769–773. pmid:1619456

49. Galbraith RF. A note on graphical presentation of estimated odds ratios from several clinical trials. Statistics in Medicine 1988; 7(8):889–894. pmid:3413368

50. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327(7414):557–560. pmid:12958120

51. DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials 1986; 7(3):177–188. pmid:3802833

52. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Comparison of two methods to detect publication bias in meta-analysis. JAMA 2006; 295(6):676–680. pmid:16467236

53. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315(7109):629–634. pmid:9310563

54. Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol 2008; 61(1):64–75. pmid:18083463

55. Knapp G, Hartung J. Improved tests for a random effects meta-regression with a single covariate. Stat Med 2003; 22(17):2693–2710. pmid:12939780

56. White I. Multivariate random-effects meta-analysis. Stata Journal 2009; 9:40–56.

57. Agius AM, Jones NS, Muscat R. A Randomized Controlled Trial comparing the efficacy of low-dose amitriptyline, amitriptyline with pindolol and surrogate placebo in the treatment of chronic tension-type facial pain. 2013; 51(2):143–153.

58. Ahuja GK, Verma AK. Propranolol in prophylaxis of migraine. Indian J Med Res 1985; 82:263–265. pmid:3908306

59. al-Qassab HK, Findley LJ. Comparison of propranolol LA 80 mg and propranolol LA 160 mg in migraine prophylaxis: a placebo controlled study. Cephalalgia 1993; 13(2):128–131. pmid:8495455

60. Albers GW, Simon LT, Hamik A, Peroutka SJ. Nifedipine versus propranolol for the initial prophylaxis of migraine. Headache 1989; 29(4):215–218. pmid:2654067

61. Andersson PG, Petersen EN. Propranolol and femoxetine, a HT-uptake inhibitor, in migraine prophylaxis. A double-blind crossover study. Acta Neurol Scand 1981; 64(4):280–288. pmid:7032183

62. Andersson PG, Dahl S, Hansen JH, Hansen PE, Hedman C, Kristensen TN et al. Prophylactic treatment of classical and non-classical migraine with metoprolol—a comparison with placebo. Cephalalgia 1983; 3(4):207–212. pmid:6640652

63. Ashtari F, Shaygannejad V, Akbari M. A double-blind, randomized trial of low-dose topiramate vs propranolol in migraine prophylaxis. 2008; 118(5):301–305.

64. Baldrati A, Cortelli P, Procaccianti G, Gamberini G, D'Alessandro R, Baruzzi A et al. Propranolol and acetylsalicylic acid in migraine prophylaxis. Double-blind crossover study. Acta Neurol Scand 1983; 67(3):181–186. pmid:6868956

65. Behan PO, Reid M. Propranolol in the treatment of migraine. Practitioner 1980; 224(1340):201–203. pmid:6988825

66. Bonuso S, Di SE, Marano E, de AS, Amato D, Scellini T et al. Long-term outcome of migraine therapy: predictive value of the frontotemporal nitroglycerin test. Neurology 1998; 51(5):1475–1478. pmid:9818888

67. Bordini CA, Arruda MA, Ciciarelli MC, Speciali JG. Propranolol vs flunarizine vs flunarizine plus propranolol in migraine without aura prophylaxis. A double-blind trial. Arq Neuropsiquiatr 1997; 55(3B):536–541. pmid:9629401

68. Borgesen SE, Nielsen JL, Moller CE. Prophylactic treatment of migraine with propranolol. A clinical trial. Acta Neurol Scand 1974; 50(5):651–656. pmid:4611129

69. Briggs RS, Millac PA. Timolol in migraine prophylaxis. Headache 1979; 19:379–381. pmid:511540

70. Carroll JD, Reidy M, Savundra PA, Cleave N, McAinsh J. Long-acting propranolol in the prophylaxis of migraine: a comparative study of two doses. Cephalalgia 1990; 10(2):101–105. pmid:2193712

71. Dahlof C. No clearcut longterm prophylactic effect of one month of treatment with propranolol in migraineurs. Cephalalgia 1987; 7:459–460.

72. Diener HC, Foh M, Iaccarino C, Wessely P, Isler H, Strenge H et al. Cyclandelate in the prophylaxis of migraine: a randomized, parallel, double-blind study in comparison with placebo and propranolol. The Study group. Cephalalgia 1996; 16(6):441–447. pmid:8902255

73. Diener HC, Hartung E, Chrubasik J, Evers S, Schoenen J, Eikermann A et al. A comparative study of oral acetylsalicyclic acid and metoprolol for the prophylactic treatment of migraine. A randomized, controlled, double-blind, parallel group phase III study. Cephalalgia 2001; 21(2):120–128. pmid:11422094

74. Diener HC, Matias-Guiu J, Hartung E, Pfaffenrath V, Ludin HP, Nappi G et al. Efficacy and tolerability in migraine prophylaxis of flunarizine in reduced doses: a comparison with propranolol 160 mg daily. Cephalalgia 2002; 22(3):209–221. pmid:12047461

75. Diener HC, Tfelt-Hansen P, Dahlof C, Lainez MJ, Sandrini G, Wang SJ et al. Topiramate in migraine prophylaxis—results from a placebo-controlled trial with propranolol as an active control. J Neurol 2004; 251(8):943–950. pmid:15316798

76. Domingues RB, Pirajá Da Silva AL, Domingues SA, Aquino CCH, Kuster GW. A double-blind randomized controlled trial of low doses of propranolol, nortriptyline, and the combination of propranolol and nortriptyline for the preventive treatment of migraine. 2009; 67(4):973–977.

77. Ekbom K, Lundberg PO. Clinical trial of LB-46 (d, 1-4-(2-hydroxy-3-isopropylaminopropoxy)indol. An adrenergic beta-receptor blocking agent in migraine prophylaxis. Headache 1972; 12(1):15–17. pmid:4402287

78. Ekbom K. Alprenolol for migraine prophylaxis. Headache 1975; 15(2):129–132. pmid:1097368

79. Ekbom K, Zetterman M. Oxprenolol in the treatment of migraine. Acta Neurol Scand 1977; 56(2):181–184. pmid:331835

80. Formisano R, Falaschi P, Cerbo R, Proietti A, Catarci T, D'Urso R et al. Nimodipine in migraine: clinical efficacy and endocrinological effects. Eur J Clin Pharmacol 1991; 41(1):69–71. pmid:1782981

81. Forssman B, Henriksson KG, Johannsson V. Propranolol for migraine prophylaxis. Headache 1976; 16:238–245. pmid:977330

82. Forssman B, Lindblad CJ, Zbornikova V. Atenolol for migraine prophylaxis. Headache 1983; 23(4):188–190. pmid:6350226

83. Freitag FG, Diamond S. Nadolol and placebo comparison study in the prophylactic treatment of migraine. J Am Osteopath Assoc 1984; 84(4):343–347. pmid:6150909

84. Gawel MJ, Kreeft J, Nelson RF, Simard D, Arnott WS. Comparison of the efficacy and safety of flunarizine to propranolol in the prophylaxis of migraine. Can J Neurol Sci 1992; 19(3):340–345. pmid:1393843

85. Gerber WD, Diener HC, Scholz E, Niederberger U. Responders and non-responders to metoprolol, propranolol and nifedipine treatment in migraine prophylaxis: a dose-range study based on time-series analysis. Cephalalgia 1991; 11(1):37–45. pmid:2036669

86. Gerber WD, Schellenberg R, Thom M, Haufe C, Bolsche F, Wedekind W et al. Cyclandelate versus propranolol in the prophylaxis of migraine—a double-blind placebo-controlled study. Funct Neurol 1995; 10(1):27–35. pmid:7649498

87. Ghobadi SH, Jivad N. The prophylactic activity of propranol and nimodipineon migraine headache. 2013; 8(2):144–146.

88. Grotemeyer KH, Husstedt IW, Schlake HP. [Betablocker vs placebo in vasomotor headache. A double-blind crossover study]. Dtsch Med Wochenschr 1987; 112(45):1740–1743. pmid:2890509

89. Grotemeyer KH, Schlake HP, Husstedt IW. [Prevention of migraine with metoprolol and flunarizine. A double-blind crossover study]. Nervenarzt 1988; 59(9):549–552. pmid:3054595

90. Grotemeyer KH, Scharafinski HW, Schlake HP, Husstedt IW. Acetylsalicylic acid vs. metoprolol in migraine prophylaxis—a double-blind cross-over study. Headache 1990; 30(10):639–641. pmid:2272812

91. Havanka-Kanniainen H, Hokkanen E, Myllyla VV. Long acting propranolol in the prophylaxis of migraine. Comparison of the daily doses of 80 mg and 160 mg. Headache 1988; 28(9):607–611. pmid:3248938

92. Hedman C, Winther K, Knudsen JB. The difference between non-selective and beta 1-selective beta-blockers in their effect on platelet function in migraine patients. Acta Neurol Scand 1986; 74(6):475–478. pmid:3030039

93. Hesse J, Mogelvang B, Simonsen H. Acupuncture versus metoprolol in migraine prophylaxis: a randomized trial of trigger point inactivation. J Intern Med 1994; 235(5):451–456. pmid:8182401

94. Holdorff B, Sinn M, Roth G. Propranolol for prophylaxis of migraine. Medizinische Klinik 1977; 72(25):1115–1118. pmid:329085

95. Holroyd KA, Cottrell CK, O'Donnell FJ, Cordingley GE, Drew JB, Carlson BW et al. Effect of preventive (Î2 blocker) treatment, behavioural migraine management, or their combination on outcomes of optimised acute treatment in frequent migraine: Randomised controlled trial. 2010; 341(7776):769. pmid:20880898

96. Johannsson V, Nilsson LR, Widelius T, Javerfalk T, Hellman P, Akesson JA et al. Atenolol in migraine prophylaxis a double-blind cross-over multicentre study. Headache 1987; 27(7):372–374. pmid:3308768

97. Johnson RH, Hornabrook RW, Lambie DG. Comparison of mefenamic acid and propranolol with placebo in migraine prophylaxis. Acta Neurol Scand 1986; 73(5):490–492. pmid:3524092

98. Kangasniemi P, Hedman C. Metoprolol and propranolol in the prophylactic treatment of classical and common migraine. A double-blind study. Cephalalgia 1984; 4(2):91–96. pmid:6428749

99. Kangasniemi P, Andersen AR, Andersson PG, Gilhus NE, Hedman C, Hultgren M et al. Classic migraine: effective prophylaxis with metoprolol. Cephalalgia 1987; 7(4):231–238. pmid:3322569

100. Kangasniemi PJ, Nyrke T, Lang AH, Petersen E. Femoxetine—a new 5-HT uptake inhibitor—and propranolol in the prophylactic treatment of migraine. Acta neurologica Scandinavica 1983; 68:262–267. pmid:6606930

101. Kaniecki RG. A comparison of divalproex with propranolol and placebo for the prophylaxis of migraine without aura. Arch Neurol 1997; 54(9):1141–1145. pmid:9311358

102. Kass B, Nestvold K. Propranolol (Inderal) and clonidine (Catapressan) in the prophylactic treatment of migraine. A comparative trial. Acta Neurol Scand 1980; 61(6):351–356. pmid:6998250

103. Kaushik R, Kaushik RM, Mahajan SK, Rajesh V. Biofeedback assisted diaphragmatic breathing and systematic relaxation versus propranolol in long term prophylaxis of migraine. Complement Ther Med 2005; 13(3):165–174. pmid:16150370

104. Kjaersgard Rasmussen MJ, Holt LB, Borg L, Soelberg SP, Hansen PE. Tolfenamic acid versus propranolol in the prophylactic treatment of migraine. Acta Neurol Scand 1994; 89(6):446–450. pmid:7976233

105. Klapper JA. An open label cross-over comparison of divalproex sodium and propranolol HCl in the prevention of migraine headaches. HEADACHE Q 1994; 5:50–53.

106. Kozubski W, Prusinski A. [Sodium valproate versus propranolol in the prophylactic treatment of migraine]. Neurol Neurochir Pol 1995; 29(6):937–947. pmid:8714731

107. Kuritzky A, Hering R. Prophylactic treatment of migraine with long acting propranolol—a comparison with placebo. Cephalalgia 1987; 7:457–458.

108. Langohr HD, Gerber WD, Koletzki E, Mayer K, Schroth G. Clomipramine and metoprolol in migraine prophylaxis—a double-blind crossover study. Headache 1985; 25(2):107–113. pmid:3886599

109. Louis P, Schoenen J, Hedman C. Metoprolol v. clonidine in the prophylactic treatment of migraine. Cephalalgia 1985; 5(3):159–165. pmid:3899370

110. Lucking CH, Oestreich W, Schmidt R, Soyka D. Flunarizine vs. propranolol in the prophylaxis of migraine: two double-blind comparative studies in more than 400 patients. Cephalalgia 1988; 8 Suppl 8:21–26.

111. Ludin HP. Flunarizine and propranolol in the treatment of migraine. Headache 1989; 29(4):219–224. pmid:2654068

112. Maissen CP, Ludin HP. [Comparison of the effect of 5-hydroxytryptophan and propranolol in the interval treatment of migraine]. Schweiz Med Wochenschr 1991; 121(43):1585–1590. pmid:1947955

113. Malvea BP, Gwon N, Graham JR. Propranolol prophylaxis of migraine. Headache 1973; 12(4):163–167. pmid:4566216

114. Mathew NT. Prophylaxis of migraine and mixed headache. A randomized controlled study. Headache 1981; 21(3):105–109. pmid:7021472

115. Mikkelsen B, Pedersen KK, Christiansen LV. Prophylactic treatment of migraine with tolfenamic acid, propranolol and placebo. Acta Neurol Scand 1986; 73(4):423–427. pmid:3727918

116. Nadelmann JW, Phil M, Stevens J, Saper JR. Propranolol in the prophylaxis of migraine. Headache 1986; 26(4):175–182. pmid:3519529

117. Nambiar NJ, Aiyappa C, Srinivasa R. Oral riboflavin versus oral propranolol in migraine prophylaxis: An open label randomized controlled trial. 2011; 16(3):223–229.

118. Nanda RN, Johnson RH, Gray J, Keogh HJ, Melville ID. A double blind trial of acebutolol for migraine prophylaxis. Headache 1978; 18(1):20–22. pmid:348644

119. Olerud B, Gustavsson CL, Furberg B. Nadolol and propranolol in migraine management. Headache 1986; 26(10):490–493. pmid:3546194

120. Olsson JE, Behring HC, Forssman B, Hedman C, Hedman G, Johansson F et al. Metoprolol and propranolol in migraine prophylaxis: a double-blind multicentre study. Acta Neurol Scand 1984; 70(3):160–168. pmid:6391066

121. Palferman TG, Gibberd FB, Simmonds JP. Prophylactic propranolol in the treatment of headache. Br J Clin Pract 1983; 37(1):28–29. pmid:6340710

122. Pita E, Higueras A, Bolanos J, Perez N, Mundo A. Propranolol and migraine. A clinical trial. Arch Farmacol Toxicol 1977; 3(3):273–278. pmid:350168

123. Pradalier A, Serratrice G, Collard M, Hirsch E, Feve J, Masson M et al. Long-acting propranolol in migraine prophylaxis: results of a double-blind, placebo-controlled study. Cephalalgia 1989; 9(4):247–253. pmid:2692838

124. Ryan RE Sr., Ryan RE Jr., Sudilovsky A. Nadolol and placebo comparison study in the prophylactic treatment of migraine. Panminerva Med 1982; 24(2):89–94. pmid:6128710

125. Ryan RE Sr. Comparative study of nadolol and propranolol in prophylactic treatment of migraine. Am Heart J 1984; 108(4 Pt 2):1156–1159.

126. Sargent J, Solbach P, Damasio H, Baumel B, Corbett J, Eisner L et al. A comparison of naproxen sodium to propranolol hydrochloride and a placebo control for the prophylaxis of migraine headache. Headache 1985; 25(6):320–324. pmid:3902723

127. Schellenberg R, Lichtenthal A, Wohling H, Graf C, Brixius K. Nebivolol and metoprolol for treating migraine: an advance on beta-blocker treatment? Headache 2008; 48(1):118–125. pmid:18184294

128. Shimell CJ, Fritz VU, Levien SL. A comparative trial of flunarizine and propranolol in the prevention of migraine. S Afr Med J 1990; 77(2):75–77. pmid:2404346

129. Silberstein SD, Dodick DW, Lindblad AS, Holroyd K, Harrington M, Mathew NTet al. Randomized, placebo-controlled trial of propranolol added to topiramate in chronic migraine. Neurology 2012; 78(13):976–984. pmid:22377815

130. Siniatchkin M, Andrasik F, Kropp P, Niederberger U, Strenge H, Averkina N et al. Central mechanisms of controlled-release metoprolol in migraine: a double-blind, placebo-controlled study. Cephalalgia 2007; 27(9):1024–1032. pmid:17680819

131. Sorensen PS, Larsen BH, Rasmussen MJ, Kinge E, Iversen H, Alslev T et al. Flunarizine versus metoprolol in migraine prophylaxis: a double-blind, randomized parallel group study of efficacy and tolerability. Headache 1991; 31(10):650–657. pmid:1769820

132. Soyka D, Oestreich W. Flunarizine versus propranolol in interval treatment of migraine. Nervenheilkunde 1990; 9:45–51.

133. Standnes B. The prophylactic effect of timolol versus propranolol and placebo in common migraine: beta-blockers in migraine. Cephalalgia 1982; 2(3):165–170. pmid:6758949

134. Steiner TJ, Joseph R, Hedman C, Rose FC. Metoprolol in the prophylaxis of migraine: parallel-groups comparison with placebo and dose-ranging follow-up. Headache 1988; 28(1):15–23. pmid:3277926

135. Stellar S, Ahrens SP, Meibohm AR, Reines SA. Migraine prevention with timolol. A double-blind crossover study. JAMA 1984; 252(18):2576–2580. pmid:6387197

136. Stensrud P, Sjaastad O. Short-term clinical trial of phopranolol in racemic form (Inderal), D-propranolol and placebo in migraine. Acta Neurol Scand 1976; 53(3):229–232. pmid:773081

137. Stensrud P, Sjaastad O. Comparative trial of Tenormin (atenolol) and Inderal (propranolol) in migraine. Headache 1980; 20(4):204–207. pmid:6993420

138. Stovner LJ, Linde M, Gravdahl GB, Tronvik E, Aamodt AH, Sand T et al. A comparative study of candesartan versus propranolol for migraine prophylaxis: A randomised, triple-blind, placebo-controlled, double cross-over study. Cephalalgia 2013; 34(7):523–532. pmid:24335848

139. Streng A, Linde K, Hoppe A, Pfaffenrath V, Hammes M, Wagenpfeil S et al. Effectiveness and tolerability of acupuncture compared with metoprolol in migraine prophylaxis. Headache 2006; 46(10):1492–1502. pmid:17115982

140. Sudilovsky A, Elkind AH, Ryan RE Sr., Saper JR, Stern MA, Meyer JH. Comparative efficacy of nadolol and propranolol in the management of migraine. Headache 1987; 27(8):421–426. pmid:3312113

141. Tfelt-Hansen P, Standnes B, Kangasneimi P, Hakkarainen H, Olesen J. Timolol vs propranolol vs placebo in common migraine prophylaxis: a double-blind multicenter trial. Acta Neurol Scand 1984; 69(1):1–8. pmid:6367336

142. van de Ven LL, Franke CL, Koehler PJ. Prophylactic treatment of migraine with bisoprolol: a placebo-controlled study. Cephalalgia 1997; 17(5):596–599. pmid:9251876

143. Vilming S, Standnes B, Hedman C. Metoprolol and pizotifen in the prophylactic treatment of classical and common migraine. A double-blind investigation. Cephalalgia 1985; 5(1):17–23. pmid:3986895

144. Weber RB, Reinmuth OM. The treatment of migraine with propranolol. Neurology 1971; 21:404–405.

145. Wideroe TE, Vigander T. Propranolol in the treatment of migraine. Br Med J 1974; 2(5921):699–701. pmid:4604977

146. Worz R, Reinhardt-Benmalek B, Foh M, Grotemeyer KH, Scharafinski HW. [Prevention of migraine using bisoprolol. Results of a double-blind study versus metoprolol]. Fortschr Med 1992; 110(14):268–272. pmid:1351025

147. Nair KG. A pilot study of the value of propranolol in migraine. J Postgrad Med 1975; 21(3):111–113. pmid:1107526

148. Chen J. Clinical study of topiramate in preventing migraine attacks. Sichuan Medical Journal 2009; 30(1):119.

149. Ziegler DK, Hurwitz A, Preskorn S, Hassanein R, Seim J. Propranolol and amitriptyline in prophylaxis of migraine. Pharmacokinetic and therapeutic effects. Arch Neurol 1993; 50(8):825–830. pmid:8352668

150. Gong X, Zhang J. Therapeutic effect of metoprolol tartrate combined with flunarizine on migraine in the treatment of migraine. Journ of Integrative Medicine, Cardiovascular and Cerebrovascular Diseases 2016; 25(14):24–2957.

151. Ke D. Sibiling combined with propranolol to treat migraine. Modern Practical Medicine 2003; 15(12):760.

152. Li P. Double-blind therapeutic effect of â-blockers on menopausal migraine. Chinese Journal of Practical Nervous Diseases 2006; 9(5):120–121.

153. Li S. Therapeutic effect of sodium valproate on prevention of migraine recurrence. Sichuan Medical Journal 2004; 25(4):416.

154. Ma W. Therapeutic effect of metoprolol tartrate combined with flunarizine on migraine in the treatment of migraine. Modern Practical Medicine 2011; 23(11):1275–1276.

155. Wen JB. Clinical effect analysis of sibelium prophylactic treatment of migraine. Contemporary Medicine 2016; 22(6):141.

156. Yang Y, Wang G. Observation on the efficacy of propranolol in preventing menopausal migraine. Chinese Journal of Misdiagnosis 2006; 6(24):4760–4761.

157. Yang Y. The effect of metoprolol combined with fluoxetine on preventing migraine and its effect on serotonin. Chinese Journal of Modern Drug Application 2016; 10(6):109–110.

158. Yuan Q, Lu X. Preliminary randomized controlled trial of topiramate and propranolol to prevent migraine attacks. Huaxi Pharmaceutical Journal 2005; 20(2):182–183.

159. Zhou J, Zhu Y, Zheng W, Chen Y, Lin L, Tian X. The efficacy of metoprolol combined with fluoxetine in preventing migraine. Journal of Clinical and Experimental Medicine 2015; 14(10):836–839.

160. Zhu J, Wei Q, Yan T. Therapeutic effect of sibelium on migraine. Journal of Medical Forum 2005; 26(1):51–52.

161. Li Z, Li X, Xiong X. A clinical study of Sibelium combining Topiramate in prophylactic treatment of migraine. Chinese Journal of Primary Medicine and Pharmacy 2002; 19(5):419–420.

162. Sjaastad O, Stensrud P. Clinical trial of a beta-receptor blocking agent (LB 46) in migraine prophylaxis. Acta Neurol Scand 1972; 48(1):124–128. pmid:4401692

163. Dongxiang H. Clinical trial of propranolol and amitriptyline in the treatment of migraine. Yunnan Medicine 2010; 31(5):523–525.

164. Li Z, Li X, Xiong X. A clinical study of sibelium combining topiramate in prophylactic treatment of migraine. Chinese JMAP 2002; 19(5):419–421.